Difference between revisions of "Staging page"

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[[#top|Back to Top]]
 
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{{#lst:Section editor transclusions|leuk}}
 
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''Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the [[B-cell acute lymphoblastic leukemia_-_historical|historical regimens page]]. If you still can't find it, please let us know so we can add it!''
 
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<big>'''Note: certain regimens have been moved to dedicated pages:
 
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*'''[[B-cell acute lymphoblastic leukemia,_Ph-positive|B-cell ALL, Ph-positive]]
 
−
*'''[[CNS leukemia]]
 
−
*'''[[T-cell acute lymphoblastic leukemia]]
 
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*'''[[B-cell acute lymphoblastic leukemia, pediatric|Pediatric B-cell ALL]]
 
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*'''[[B-cell acute lymphoblastic leukemia,_Ph-positive,_pediatric|Pediatric B-cell ALL, Ph-positive]]
 
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</big>
 
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{| class="wikitable" style="float:right; margin-right: 5px;"
 
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|-
 
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|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
 
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<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 
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|}
 
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{{TOC limit|limit=3}}
 
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''Please note, mature B-cell ALL (L3) is now classified as Burkitt lymphoma/leukemia. Regimens for this variant are available [http://hemonc.org/wiki/Aggressive_Non-Hodgkin_lymphoma#BL_or_Burkitt-like_lymphoma.2C_untreated here]''
 
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=Guidelines=
 
−
==[http://www.esmo.org/ ESMO]==
 
−
*'''2016:''' Hoelzer et al. [https://www.esmo.org/Guidelines/Haematological-Malignancies/Acute-Lymphoblastic-Leukaemia Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
 
−
==EWALL/EBMT==
 
−
*'''2019:''' Giebel et al. [https://www.nature.com/articles/s41409-018-0373-4 Hematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission: a position statement of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)]
 
−
=="How I Treat"==
 
−
*'''2020:''' Aldoss I, Douer D. How I treat the toxicities of pegasparaginase in adults with acute lymphoblastic leukemia. Blood. 2020 Mar 26;135(13):987-995. [https://doi.org/10.1182/blood.2019002477 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31977001 PubMed]
 
−
*'''2020:''' Aldoss I, Forman SJ. How I treat adults with advanced acute lymphoblastic leukemia eligible for CD19-targeted immunotherapy. Blood. 2020 Mar 12;135(11):804-813. [https://doi.org/10.1182/blood.2019002132 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31899793 PubMed]
 
−
*'''2015:''' Curran E, Stock W. How I treat acute lymphoblastic leukemia in older adolescents and young adults. Blood. 2015 Jun 11;125(24):3702-10. Epub 2015 Mar 24. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463735/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25805810 PubMed]
 
−
*'''2015:''' Frey NV, Luger SM. How I treat adults with relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia. Blood. 2015 Jul 30;126(5):589-96. Epub 2015 May 12. [http://www.bloodjournal.org/content/126/5/589.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25966988 PubMed]
 
−
==[https://www.nccn.org/ NCCN]==
 
−
*[https://www.nccn.org/professionals/physician_gls/pdf/all.pdf NCCN Guidelines - Acute Lymphoblastic Leukemia]
 
−
=Prephase=
 
−
==Prednisone monotherapy {{#subobject:8ca13b|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:2fd1d7|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
 
−
|2003-2005
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
''Note: in GRAALL-2003, this regimen was meant for patients up to 60 years old. The original Huguet et al. 2009 article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. See paper for details on CNS prophylaxis and treatment.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 7
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] 15 mg IT once on day 1
 
−
'''7-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-asparaginase, Vincristine, Prednisone]] induction
 
−
</div></div>
 
−
===References===
 
−
# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
 
−
==Vincristine & Prednisone {{#subobject:663781|Regimen=1}}==
 
−
VP: '''<u>V</u>'''incristine & '''<u>P</u>'''rednisone
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:78gjc7|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1002/1097-0142(19830915)52:6%3C958::aid-cncr2820520604%3E3.0.co;2-z McCredie et al. 1983 (SWOG-7416]
 
−
|1975-1977
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once on day 1
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 100 mg PO once per day on days 1 to 5
 
−
'''5-day course'''
 
−
</div></div>
 
−
===References===
 
−
# '''SWOG-7416:''' McCredie KB, Gehan EA, Freireich EJ, Hewlett JS, Coltman CA Jr, Hussein KK, Balcerzak SP, Chen TT. Management of adult acute leukemia: a Southwest Oncology Group study. Cancer. 1983 Sep 15;52(6):958-66. [https://doi.org/10.1002/1097-0142(19830915)52:6%3C958::aid-cncr2820520604%3E3.0.co;2-z link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/6883280 PubMed]
 
−
=Upfront induction therapy=
 
−
==Cyclophosphamide, Cytarabine, Mercaptopurine {{#subobject:317919|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:d69105|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*MRC UKALL XII/ECOG E2993, Ph-: "Phase 1" induction: [[#DOLP|DOLP]]
 
−
*MRC UKALL XII/ECOG E2993, Ph+: "Phase 1" induction: [[B-cell_acute_lymphoblastic_leukemia,_Ph-positive#Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone.2C_Imatinib|Daunorubicin, L-asparaginase, Vincristine, Prednisone, Imatinib]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once per day on days 1, 15, 29
 
−
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 4, 8 to 11, 15 to 18, 22 to 25
 
−
*[[Mercaptopurine (6-MP)]] 6 mg/m<sup>2</sup> PO once per day on days 1 to 28
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] 12 mg IT once per day on days 1, 8, 15, 22
 
−
'''29-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#L-Asparaginase_.26_Methotrexate|L-asparaginase & Methotrexate]] early intensification
 
−
</div></div>
 
−
===References===
 
−
# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
 
−
## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]
 
−
## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
 
−
## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
 
−
==Cyclophosphamide, Daunorubicin, Vincristine, Prednisone {{#subobject:29d427|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:7ff1ac|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2004.10.050 Thomas et al. 2004 (LALA-94)]
 
−
|1994-2002
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Cyclophosphamide.2C_Idarubicin.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Idarubicin, Vincristine, Prednisone]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior DFS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 3, 15, 16
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day IV or PO on days 1 to 7, 15 to 21
 
−
'''28-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Consolidation (see paper for details)
 
−
</div></div>
 
−
===References===
 
−
# '''LALA-94:''' Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. [https://doi.org/10.1200/jco.2004.10.050 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15353542 PubMed] NCT00002700
 
−
## '''Update:''' Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. [https://doi.org/10.1038/sj.leu.2404420 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17039234 PubMed]
 
−
==Cyclophosphamide, Daunorubicin, Vincristine, Prednisolone {{#subobject:30z427|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:adf38f|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930949/ Labar et al. 2010 (EORTC ALL-4)]
 
−
|1995-2003
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Cyclophosphamide.2C_Daunorubicin.2C_Vincristine.2C_Dexamethasone_99|Cyclophosphamide, Daunorubicin, Vincristine, Dexamethasone]]
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS72
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 3, 15, 16
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 23
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisolone (Millipred)]] 60 mg/m<sup>2</sup>/day IV or PO on days 1 to 8, 15 to 22
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1, 8, 15, 22, 28
 
−
'''28-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#HAM_88|HAM]] consolidation
 
−
</div></div>
 
−
===References===
 
−
# '''EORTC ALL-4:''' Labar B, Suciu S, Willemze R, Muus P, Marie JP, Fillet G, Berneman Z, Jaksic B, Feremans W, Bron D, Sinnige H, Mistrik M, Vreugdenhil G, De Bock R, Nemet D, Gilotay C, Amadori S, de Witte T; [[Study_Groups#EORTC|EORTC]] Leukemia Group. Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group. Haematologica. 2010 Sep;95(9):1489-95. Epub 2010 Apr 7. [http://www.haematologica.org/content/95/9/1489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930949/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20378563 PubMed]
 
−
==Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone {{#subobject:0cee78|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1 {{#subobject:2aaaf3|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
 
−
|2003-2005
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[https://doi.org/10.1056/NEJMoa1605085 Maury et al. 2016 (GRAALL-2005/R)]
 
−
|2006-2014
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone.2C_Rituximab|Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior EFS
 
−
|-
 
−
|[https://doi.org/10.1200/JCO.2017.76.8192 Huguet et al. 2018 (GRAALL-2005)]
 
−
|2006-2014
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone]]; hyperfractionated cyclophosphamide
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 
−
|-
 
−
|}
 
−
''Note: this "pediatric-like" regimen was meant for patients up to 60 years old. The original Huguet et al. 2009 article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. See paper for details on CNS treatment. This is the "standard-dose cyclophosphamide" arm of GRAALL-2005.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Prednisone_monotherapy|Prednisone prephase]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] by the following criteria:
 
−
**"Good early responders" (GRAALL-2003) and all patients (GRAALL-2005): 750 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 & 15
 
−
**"Poor early responders" (GRAALL-2003): 750 mg/m<sup>2</sup> IV once on day 1, then 500 mg/m<sup>2</sup> IV every 12 hours on days 15 & 16
 
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3, then 30 mg/m<sup>2</sup> IV once per day on days 15 & 16
 
−
*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> IV over 60 minutes once per day on days 8, 10, 12, 20, 22, 24, 26, 28
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 14
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1 & 8
 
−
*[[Cytarabine (Ara-C)]] 40 mg IT once per day on days 1 & 8
 
−
*[[Methylprednisolone (Solumedrol)]] 40 mg IT once per day on days 1 & 8
 
−
====Supportive therapy====
 
−
*[[Lenograstim (Granocyte)]] by the following study-specific criteria:
 
−
**GRAALL-2003: 150 mcg/m<sup>2</sup> SC once per day from day 17 until myeloid recovery
 
−
**GRAALL-2005: 263 mcg SC once per day from day 18 until first day with ANC greater than 1000/uL
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Patients with resistant disease: [[#Cytarabine_.26_Idarubicin_2|Cytarabine & idarubicin]] salvage prior to further consolidation
 
−
*All others: [[#Pediatric-like_GRAALL_consolidation|Pediatric-like GRAALL]] consolidation
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, "HyperC" {{#subobject:7096ea|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1056/NEJMoa1605085 Maury et al. 2016 (GRAALL-2005/R)]
 
−
|2006-2014
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone.2C_Rituximab|Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior EFS
 
−
|-
 
−
|[https://doi.org/10.1200/JCO.2017.76.8192 Huguet et al. 2018 (GRAALL-2005)]
 
−
|2006-2014
 
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
 
−
|[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone]]; standard-dose cyclophosphamide
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 
−
|-
 
−
|}
 
−
''This is the "HyperC" arm of GRAALL-2005. Given the negative report in 2018, this experimental arm should be considered as historic reference.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Prednisone_monotherapy|Prednisone prephase]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV over 3 hours once on day 1, then 300 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 15 to 17 (total dose: 2550 mg/m<sup>2</sup>)
 
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3, then 30 mg/m<sup>2</sup> IV once per day on days 15 & 16
 
−
*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> IV over 60 minutes once per day on days 8, 10, 12, 20, 22, 24, 26, 28
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 14
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1 & 8
 
−
*[[Cytarabine (Ara-C)]] 40 mg IT once per day on days 1 & 8
 
−
*[[Methylprednisolone (Solumedrol)]] 40 mg IT once per day on days 1 & 8
 
−
====Supportive therapy====
 
−
*[[Lenograstim (Granocyte)]] 263 mcg SC once per day from day 18 until first day with ANC greater than 1000/uL
 
−
'''28-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Patients with resistant disease: [[#Cytarabine_.26_Idarubicin_2|Cytarabine & idarubicin]] salvage prior to further consolidation
 
−
*Responders: [[#Pediatric-like_GRAALL_consolidation|Pediatric-like GRAALL]] consolidation
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #3 {{#subobject:1bf42b|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/99/3/863.long Annino et al. 2002 (GIMEMA ALL 0288)]
 
−
|1988-1996
 
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
 
−
|[[#DOLP|DOLP]]
 
−
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR rate
 
−
|-
 
−
|}
 
−
''Note: vincristine is clearly shown as 2 mg/m<sup>2</sup> in Table 1, but this is an unusual dose; consider discussing with the authors if you are going to utilize this regimen.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy, "Induction phase I"====
 
−
*[[Cyclophosphamide (Cytoxan)]] 800 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
*[[Daunorubicin (Cerubidine)]] 40 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Asparaginase (Elspar)|L-Asparaginase]] 6000 units/m<sup>2</sup> SC once per day on days 22 to 31
 
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 14, then 40 mg/m<sup>2</sup>/day PO on days 15 to 31
 
−
'''31-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Induction phase II or salvage, see paper for details
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #4, "Larson regimen" {{#subobject:e460e0|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy, "Course I"====
 
−
*[[Cyclophosphamide (Cytoxan)]] by the following age-based criteria:
 
−
**Younger than 60: 1200 mg/m<sup>2</sup> IV once on day 1
 
−
**60 or older: 800 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Daunorubicin (Cerubidine)]] by the following age-based criteria:
 
−
**Younger than 60: 45 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
**60 or older: 30 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> SC once per day on days 5, 8, 11, 15, 18, 22
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] by the following age-based criteria:
 
−
**Younger than 60: 60 mg/m<sup>2</sup> PO once per day on days 1 to 21
 
−
**60 or older: 60 mg/m<sup>2</sup> PO once per day on days 1 to 7
 
−
'''28-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#CALGB_8811_early_intensification|Larson regimen (CALGB 8811)]] early intensification ("Course II")
 
−
</div></div>
 
−
===References===
 
−
# '''CALGB 8811:''' Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://www.bloodjournal.org/content/85/8/2025.full.pdf+html link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/7718875 PubMed]
 
−
# '''GIMEMA ALL 0288:''' Annino L, Vegna ML, Camera A, Specchia G, Visani G, Fioritoni G, Ferrara F, Peta A, Ciolli S, Deplano W, Fabbiano F, Sica S, Di Raimondo F, Cascavilla N, Tabilio A, Leoni P, Invernizzi R, Baccarani M, Rotoli B, Amadori S, Mandelli F; GIMEMA. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002 Feb 1;99(3):863-71. [http://www.bloodjournal.org/content/99/3/863.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11806988 PubMed]
 
−
# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
 
−
<!-- # '''Abstract:''' Maury et al. Addition of Rituximab Improves the Outcome of Adult Patients with CD20-Positive, Ph-Negative, B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Results of the Randomized Graall-R 2005 Study. ASH 2015 Annual Meeting Abstract 1.[https://ash.confex.com/ash/2015/webprogram/Paper82882.html link to abstract] -->
 
−
# '''GRAALL-2005/R:''' Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. [https://doi.org/10.1056/NEJMoa1605085 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1605085/suppl_file/nejmoa1605085_protocol.pdf link to supplement] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/27626518 PubMed] NCT00327678
 
−
# '''GRAALL-2005:''' Huguet F, Chevret S, Leguay T, Thomas X, Boissel N, Escoffre-Barbe M, Chevallier P, Hunault M, Vey N, Bonmati C, Lepretre S, Marolleau JP, Pabst T, Rousselot P, Buzyn A, Cahn JY, Lhéritier V, Béné MC, Asnafi V, Delabesse E, Macintyre E, Chalandon Y, Ifrah N, Dombret H; Group of Research on Adult ALL. Intensified therapy of acute lymphoblastic leukemia in adults: report of the randomized GRAALL-2005 clinical trial. J Clin Oncol. 2018 Aug 20;36(24):2514-2523. Epub 2018 Jun 4. [https://doi.org/10.1200/JCO.2017.76.8192 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29863974 PubMed] NCT00327678
 
−
==Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab {{#subobject:18fec2|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1 {{#subobject:aa59d3|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1056/NEJMoa1605085 Maury et al. 2016 (GRAALL-2005/R)]
 
−
|2006-2014
 
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
 
−
|[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone]]
 
−
|style="background-color:#91cf60"|Seems to have superior EFS
 
−
|-
 
−
|}
 
−
''Note: this regimen was meant for CD20+ patients less than 60 years old. This is the "standard" arm of '''GRAALL-2005/R'''.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Prednisone_monotherapy|Prednisone prephase]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 & 15
 
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3, then 30 mg/m<sup>2</sup> IV once per day on days 15 & 16
 
−
*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> IV over 60 minutes once per day on days 8, 10, 12, 20, 22, 24, 26, 28
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 14
 
−
====Targeted therapy====
 
−
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1 & 7
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1 & 8
 
−
*[[Cytarabine (Ara-C)]] 40 mg IT once per day on days 1 & 8
 
−
*[[Methylprednisolone (Solumedrol)]] 40 mg IT once per day on days 1 & 8
 
−
====Supportive therapy====
 
−
*[[Lenograstim (Granocyte)]] by the following study-specific criteria:
 
−
**GRAALL-2003: 150 mcg/m<sup>2</sup> SC once per day from day 17 until myeloid recovery
 
−
**GRAALL-2005: 263 mcg SC once per day from day 18 until first day with ANC greater than 1000/uL
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Patients with resistant disease: [[#Cytarabine.2C_Idarubicin.2C_Rituximab|Cytarabine, idarubicin, rituximab]] salvage prior to further consolidation
 
−
*All others: Pediatric-like GRAALL consolidation with rituximab
 
−
</div></div>
 
−
===References===
 
−
<!-- # '''Abstract:''' Maury et al. Addition of Rituximab Improves the Outcome of Adult Patients with CD20-Positive, Ph-Negative, B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Results of the Randomized Graall-R 2005 Study. ASH 2015 Annual Meeting Abstract 1.[https://ash.confex.com/ash/2015/webprogram/Paper82882.html link to abstract] -->
 
−
# '''GRAALL-2005/R:''' Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. [https://doi.org/10.1056/NEJMoa1605085 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1605085/suppl_file/nejmoa1605085_protocol.pdf link to supplement] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/27626518 PubMed] NCT00327678
 
−
==Cyclophosphamide, Idarubicin, Vincristine, Prednisone {{#subobject:4c1f91|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:435069|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2004.10.050 Thomas et al. 2004 (LALA-94)]
 
−
|1994-2002
 
−
|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
 
−
|[[#Cyclophosphamide.2C_Daunorubicin.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, Vincristine, Prednisone]]
 
−
|style="background-color:#91cf60"|Seems to have superior DFS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
*[[Idarubicin (Idamycin)]] 9 mg/m<sup>2</sup> IV once per day on days 1, 2, 3, 8
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day IV or PO on days 1 to 7, 15 to 21
 
−
'''28-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Consolidation (see paper for details)
 
−
</div></div>
 
−
===References===
 
−
# '''LALA-94:''' Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D; SAKK. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. [https://doi.org/10.1200/jco.2004.10.050 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15353542 PubMed] NCT00002700
 
−
## '''Update:''' Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. [https://doi.org/10.1038/sj.leu.2404420 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17039234 PubMed]
 
−
==DOLP {{#subobject:3c9897|Regimen=1}}==
 
−
DOLP: '''<u>D</u>'''aunorubicin, '''<u>O</u>'''ncovin (Vincristine), '''<u>L</u>'''-Asparaginase, '''<u>P</u>'''rednisone
 
−
<br>DVPA: '''<u>D</u>'''aunorubicin, '''<u>V</u>'''incristine, '''<u>P</u>'''rednisone, '''<u>A</u>'''sparaginase
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, 25/5000/1.5/60 {{#subobject:7b55e1|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/64/1/38.long Hoelzer et al. 1984]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|}
 
−
''Of historic interest. This is "Phase 1" of induction.''
 
−
====Chemotherapy====
 
−
*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Asparaginase (Elspar)]] 5000 units IV once per day on days 1 to 14
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 28
 
−
'''4-week course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*See paper for details of treatment beyond induction
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, 40/6000/2/60-40 ("Phase I" of GIMEMA ALL 0288) {{#subobject:6da40d|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/99/3/863.long Annino et al. 2002 (GIMEMA ALL 0288)]
 
−
|1988-1996
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone]]
 
−
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR rate
 
−
|-
 
−
|}
 
−
''Note: vincristine is clearly shown as 2 mg/m<sup>2</sup> in Table 1, but this is an unusual dose; consider discussing with the authors if you are going to utilize this regimen.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Daunorubicin (Cerubidine)]] 40 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Asparaginase (Elspar)|L-Asparaginase]] 6000 units/m<sup>2</sup> SC once per day on days 22 to 31
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 14, then 40 mg/m<sup>2</sup>/day PO on days 15 to 31
 
−
'''31-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Induction phase II or salvage (see paper for details)
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #3, 45/500/2/40 {{#subobject:1e5376|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/64/1/267.long Gottlieb et al. 1984 (CALGB 7612)]
 
−
|1976-1980
 
−
|style="background-color:#1a9851"|Randomized (E-RT-esc)
 
−
|[[B-cell acute lymphoblastic leukemia_-_historical#L-Asparaginase.2C_Vincristine.2C_Prednisone|L-asparaginase, Vincristine, Prednisone]]
 
−
|style="background-color:#1a9850"|Superior CR rate
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Daunorubicin (Cerubidine)]] 45 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15
 
−
*[[Asparaginase (Elspar)]] 500 units/kg IV once per day on days 22 to 31
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day PO on days 1 to 22, then tapered to off by day 29
 
−
'''31-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*See paper for details of treatment beyond induction
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #4, 50/6000/2/60 ("Linker regimen") {{#subobject:9ce40a|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1182/blood.V69.4.1242.1242 Linker et al. 1987]
 
−
|1980-1986
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Daunorubicin (Cerubidine)]] by the following criteria:
 
−
**All patients: 50 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
**Bone marrow on day 14 has residual leukemia: 50 mg/m<sup>2</sup> IV once on day 15
 
−
**Bone marrow on day 28 has residual leukemia: 50 mg/m<sup>2</sup> IV once per day on days 29 & 30
 
−
*[[Vincristine (Oncovin)]] by the following criteria:
 
−
**All patients: 2 mg IV once per day on days 1, 8, 15, 22
 
−
**Bone marrow on day 28 has residual leukemia: 2 mg IV once per day on days 29 & 36
 
−
*[[Asparaginase (Elspar)]] by the following criteria:
 
−
**All patients: 6000 units/m<sup>2</sup> IM once per day on days 17 to 28
 
−
**Bone marrow on day 28 has residual leukemia: 6000 units/m<sup>2</sup> IM once per day on days 29 to 35
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] by the following criteria:
 
−
**All patients: 60 mg/m<sup>2</sup> PO once per day on days 1 to 28
 
−
**Bone marrow on day 28 has residual leukemia: 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
 
−
====CNS therapy, prophylaxis====
 
−
*This is for patients without CNS involvement at diagnosis, and is started within 1 week of achieving complete remission:
 
−
*Cranial radiation, 18 Gy total given in 10 fractions over 12 to 14 days
 
−
*[[Methotrexate (MTX)]] 12 mg IT once per week x 6 doses concurrent with radiation
 
−
====CNS therapy, treatment====
 
−
*This is for patients with CNS involvement at diagnosis:
 
−
*Cranial radiation, 28 Gy total given
 
−
*[[Methotrexate (MTX)]] 12 mg IT once per week x 10 doses that starts while they are receiving induction therapy, then given once per month during the first year of therapy
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#Linker_regimen_.28consolidation.29|Linker regimen consolidation therapy]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #5, 60/10,000/1.4/60, daily dauno {{#subobject:8ad81b|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254550/ Pullarkat et al. 2008 (SWOG S9400)]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
''Note: this was the dosing used after the protocol amendment of September 1, 1999.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Daunorubicin (Cerubidine)]] by the following response-based criteria:
 
−
**All patients: 60 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
**Persistent leukemia on day 21: 60 mg/m<sup>2</sup> IV once per day on days 22 & 23
 
−
*[[Vincristine (Oncovin)]] by the following response-based criteria:
 
−
**All patients: 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
 
−
**Persistent leukemia on day 21: 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 29 & 36
 
−
*[[Asparaginase (Elspar)]] 10,000 units IM or IV once per day on days 15 to 24
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] by the following response-based criteria:
 
−
**All patients: 60 mg/m<sup>2</sup>/day PO on days 1 to 28
 
−
**No leukemia on day 21: taper to off by day 42
 
−
**Persistent leukemia on day 21: 60 mg/m<sup>2</sup>/day PO on days 29 to 42
 
−
'''6-week course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*See paper for details
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #6, 60/10,000/1.4/60, weekly dauno ("Phase I" of E2993 regimen) {{#subobject:6d5745|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
''To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 91%.''
 
−
====Chemotherapy====
 
−
*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Asparaginase (Elspar)]] 10,000 units IM or IV once per day on days 17 to 28
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO in divided doses on days 1 to 28
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] 12.5 mg IT once on day 15
 
−
'''4-week course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine|Cyclophosphamide, Cytarabine, Mercaptopurine]] induction ("Phase 2")
 
−
</div></div>
 
−
===References===
 
−
# Hoelzer D, Thiel E, Löffler H, Bodenstein H, Plaumann L, Büchner T, Urbanitz D, Koch P, Heimpel H, Engelhardt R, Muller U, Wendt FC, Sodomann H, Ruhl H, Herrmann F, Kaboth W, Dietzfelbinger H, Pralle H, Lunscken Ch, Hellriegel KP, Spors S, Nowrousian RM, Fischer J, Fulle H, Mitrou PS, Pfreundschuh M, Gorg Ch, Emmerich B, Queisser W, Meyer P, Labedzki L, Essers U, Konig H, Mainzer K, Herrmann R, Messerer D, Zwingers T. Intensified therapy in acute lymphoblastic and acute undifferentiated leukemia in adults. Blood. 1984 Jul;64(1):38-47. [http://www.bloodjournal.org/content/64/1/38.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/6375764 PubMed]
 
−
# '''CALGB 7612:''' Gottlieb AJ, Weinberg V, Ellison RR, Henderson ES, Terebelo H, Rafla S, Cuttner J, Silver RT, Carey RW, Levy RN, Hutchinson JL, Raich P, Cooper MR, Wiernik P, Anderson JR, Holland JF. Efficacy of daunorubicin in the therapy of adult acute lymphocytic leukemia: a prospective randomized trial by Cancer and Leukemia Group B. Blood. 1984 Jul;64(1):267-74. [http://www.bloodjournal.org/content/64/1/267.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/6375760 PubMed]
 
−
# Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. [https://doi.org/10.1182/blood.V69.4.1242.1242 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3470055 PubMed]
 
−
## '''Update:''' Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. [http://www.bloodjournal.org/content/78/11/2814.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1835410 PubMed]
 
−
# '''GIMEMA ALL 0288:''' Annino L, Vegna ML, Camera A, Specchia G, Visani G, Fioritoni G, Ferrara F, Peta A, Ciolli S, Deplano W, Fabbiano F, Sica S, Di Raimondo F, Cascavilla N, Tabilio A, Leoni P, Invernizzi R, Baccarani M, Rotoli B, Amadori S, Mandelli F; GIMEMA. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002 Feb 1;99(3):863-71. [http://www.bloodjournal.org/content/99/3/863.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11806988 PubMed]
 
−
# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
 
−
## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]
 
−
## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
 
−
## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
 
−
# '''SWOG S9400:''' Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008 Mar 1;111(5):2563-72. Epub 2007 Dec 21. [http://www.bloodjournal.org/content/111/5/2563.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254550/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18156492 PubMed] NCT00002665
 
−
==Daunorubicin, Pegaspargase, Vincristine, Dexamethasone {{#subobject:1526yg|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:cf4hg1|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8969057/ Marks et al. 2022 (UKALL14)]
 
−
|2012-2017
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#Daunorubicin.2C_Pegaspargase.2C_Vincristine.2C_Dexamethasone.2C_Rituximab_99|Daunorubicin, Pegaspargase, Vincristine, Dexamethasone, Rituximab]]
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 
−
|-
 
−
|}
 
−
''Note: the manuscript contains an error in the timing of daunorubicin and vincristine; the correct schedule is available in the supplement. The authors have been notified of the error, and the correct schedule is used below.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Dexamethasone_monotherapy_88|Pre-phase dexamethasone]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
 
−
*[[Pegaspargase (Oncaspar)]] by the following age-based criteria:
 
−
**Age 40 years and younger: 1000 units/m<sup>2</sup> IV once per day on days 4 & 18
 
−
**Age 41 years or older: 1000 units/m<sup>2</sup> IV once on day 18
 
−
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
 
−
====Glucocorticoid therapy====
 
−
*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup>/day PO on days 1 to 4, 8 to 11, 15 to 18
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] 12.5 mg IT once on day 14
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*See paper for protocol details
 
−
</div></div>
 
−
===References===
 
−
#'''UKALL14:''' Marks DI, Kirkwood AA, Rowntree CJ, Aguiar M, Bailey KE, Beaton B, Cahalin P, Castleton AZ, Clifton-Hadley L, Copland M, Goldstone AH, Kelly R, Lawrie E, Lee S, McMillan AK, McMullin MF, Menne TF, Mitchell RJ, Moorman AV, Patel B, Patrick P, Smith P, Taussig D, Yallop D, Alapi KZ, Fielding AK. Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial. Lancet Haematol. 2022 Apr;9(4):e262-e275. [https://doi.org/10.1016/s2352-3026(22)00038-2 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8969057/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35358441/ PubMed] NCT01085617
 
−
==Daunorubicin, Pegaspargase, Vincristine, Prednisone {{#subobject:1524a2|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, "ABFM" {{#subobject:cf403e|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239168/ Rytting et al. 2014]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ Stock et al. 2019 (CALGB 10403)]
 
−
| style="background-color:#91cf61" |Non-randomized
 
−
|-
 
−
|}
 
−
ABFM: '''<u>A</u>'''ugmented '''<u>B</u>'''erlin-'''<u>F</u>'''rankfurt-'''<u>M</u>'''ünster regimen<br>
 
−
====Chemotherapy====
 
−
*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
 
−
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IM or IV over 1 to 2 hours once on day 4
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 28
 
−
====CNS therapy, prophylaxis====
 
−
*[[Cytarabine (Ara-C)]] by the following age-based criteria:
 
−
**Ages 1 to 1.99: 30 mg IT once on day 1
 
−
**Ages 2 to 2.99: 50 mg IT once on day 1
 
−
**Age 3 and older: 70 mg IT once on day 1
 
−
*[[Methotrexate (MTX)]] by the following age-based criteria:
 
−
**Ages 1 to 1.99: 8 mg IT once per day on days 8 & 29
 
−
**Ages 2 to 2.99: 10 mg IT once per day on days 8 & 29
 
−
**Ages 3 to 8.99: 12 mg IT once per day on days 8 & 29
 
−
**Age 9 and older: 15 mg IT once per day on days 8 & 29
 
−
'''4-week course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Rytting et al. 2014: See protocol for details of treatment beyond induction
 
−
*CALGB 10403, CR: [[#AALL0232_consolidation|AALL0232]] consolidation
 
−
*CALGB 10403, not CR: [[#Daunorubicin.2C_Pegaspargase.2C_Vincristine.2C_Prednisone|ABFM extended]] induction
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, higher-dose dauno {{#subobject:e88a83|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254550/ Pullarkat et al. 2008 (SWOG S9400)]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|}
 
−
''Note: Table 1 lists vincristine as being given PO, which is surely an error. Likewise, prednisone is listed as IV. Pegaspargase was only given until the protocol amendment of September 1, 1999.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Daunorubicin (Cerubidine)]] by the following response-based criteria:
 
−
**Part 1 (all patients): 60 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
**Part 2 (persistent leukemia on d21): 60 mg/m<sup>2</sup> IV once per day on days 22 & 23
 
−
*[[Pegaspargase (Oncaspar)]] by the following response-based criteria:
 
−
**Part 1 (all patients): 2000 units/m<sup>2</sup> IV once on day 15
 
−
**Part 2 (persistent leukemia on d21): 2000 units/m<sup>2</sup> IV once on day 38
 
−
*[[Vincristine (Oncovin)]] by the following response-based criteria:
 
−
**Part 1 (all patients): 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
 
−
**Part 2 (persistent leukemia on d21): 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 29 & 36
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] by the following response-based criteria:
 
−
**Part 1 (all patients): 60 mg/m<sup>2</sup>/day PO on days 1 to 28
 
−
**Part 2 (CR on d21): tapered from day 29 to 42
 
−
**Part 2 (persistent leukemia on d21): 60 mg/m<sup>2</sup>/day PO on days 29 to 42
 
−
'''42-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*See protocol for details of treatment beyond induction
 
−
</div></div>
 
−
===References===
 
−
# '''SWOG S9400:''' Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008 Mar 1;111(5):2563-72. Epub 2007 Dec 21. [http://www.bloodjournal.org/content/111/5/2563.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254550/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18156492 PubMed] NCT00002665
 
−
# Rytting ME, Thomas DA, O'Brien SM, Ravandi-Kashani F, Jabbour EJ, Franklin AR, Kadia TM, Pemmaraju N, Daver NG, Ferrajoli A, Garcia-Manero G, Konopleva MY, Cortes JE, Borthakur G, Garris R, Cardenas-Turanzas M, Schroeder K, Jorgensen JL, Kornblau SM, Kantarjian HM. Augmented Berlin-Frankfurt-Münster therapy in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL). Cancer. 2014 Dec 1;120(23):3660-8. Epub 2014 Jul 17. [https://doi.org/10.1002/cncr.28930 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239168/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25042398 PubMed]
 
−
## '''Update:''' Rytting ME, Jabbour EJ, Jorgensen JL, Ravandi F, Franklin AR, Kadia TM, Pemmaraju N, Daver NG, Ferrajoli A, Garcia-Manero G, Konopleva MY, Borthakur G, Garris R, Wang S, Pierce S, Schroeder K, Kornblau SM, Thomas DA, Cortes JE, O'Brien SM, Kantarjian HM. Final results of a single institution experience with a pediatric-based regimen, the augmented Berlin-Frankfurt-Münster (ABFM), in adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL), and comparison to the hyper-CVAD regimen. Am J Hematol. 2016 Aug;91(8):819-23. Epub 2016 May 14. [https://doi.org/10.1002/ajh.24419 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5558853/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27178680 PubMed]
 
−
# '''CALGB 10403:''' Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. [http://www.bloodjournal.org/content/133/14/1548.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30658992 PubMed] NCT00558519
 
−
==Hyper-CVAD/MA {{#subobject:8e1d75|Regimen=1}}==
 
−
Hyper-CVAD/MA: '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone alternating with '''<u>M</u>'''ethotrexate, '''<u>A</u>'''ra-C (Cytarabine)
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Protocol {{#subobject:70e9ec|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.nature.com/articles/2400861 Koller et al. 1997]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|[https://doi.org/10.1200/jco.1999.17.8.2461 Thomas et al. 1999]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2000.18.3.547 Kantarjian et al. 2000]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|[http://www.bloodjournal.org/content/104/6/1624.long Thomas et al. 2004]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy, Part A (cycles 1, 3, 5, 7)====
 
−
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m<sup>2</sup>)
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 4 & 11
 
−
*[[Doxorubicin (Adriamycin)]] by the following criteria:
 
−
**Normal EF: 50 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 4
 
−
**EF less than 50%: 25 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 4 (total dose per cycle: 50 mg/m<sup>2</sup>)
 
−
====Glucocorticoid therapy====
 
−
*[[Dexamethasone (Decadron)]] 40 mg IV or PO once per day on days 1 to 4, 11 to 14
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] 600 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1, starting 1 hour before [[Cyclophosphamide (Cytoxan)]] and completed 12 hours after the last dose of [[Cyclophosphamide (Cytoxan)]]
 
−
*ONE of the following antibiotics:
 
−
**[[Ciprofloxacin (Cipro)]] 500 mg PO twice per day
 
−
**[[Levofloxacin (Levaquin)]] 500 mg PO once per day
 
−
**[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO twice per day
 
−
*[[Fluconazole (Diflucan)]] 200 mg PO once per day
 
−
*ONE of the following antivirals:
 
−
**[[Acyclovir (Zovirax)]] 200 mg PO twice per day
 
−
**[[Valacyclovir (Valtrex)]] 500 mg PO once per day
 
−
*[[Filgrastim (Neupogen)]] 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
 
−
'''Next cycle to start as soon as ANC is greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10<sup>9</sup>/L'''
 
−
====Chemotherapy, Part B (cycles 2, 4, 6, 8)====
 
−
*[[Methotrexate (MTX)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, then 800 mg/m<sup>2</sup> IV over 22 hours (total dose per cycle: 1000 mg/m<sup>2</sup>)
 
−
*[[Cytarabine (Ara-C)]] by the following age-based criteria:
 
−
**Younger than 60: 3000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m<sup>2</sup>)
 
−
**60 or older: 1000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m<sup>2</sup>)
 
−
====Glucocorticoid therapy====
 
−
*[[Methylprednisolone (Solumedrol)]] 50 mg IV every 12 hours on days 1 to 3 (see note)
 
−
**''Note: This is only mentioned in the Kantarjian et al. 2010 publication, and it isn't clear if it's meant to be a supportive or antineoplastic medication.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Supportive therapy====
 
−
*[[Folinic acid (Leucovorin)]] 50 mg IV once on day 3, 12 hours after [[Methotrexate (MTX)]] is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
 
−
*ONE of the following antibiotics:
 
−
**[[Ciprofloxacin (Cipro)]] 500 mg PO twice per day
 
−
**[[Levofloxacin (Levaquin)]] 500 mg PO once per day
 
−
**[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO twice per day
 
−
*[[Fluconazole (Diflucan)]] 200 mg PO once per day
 
−
*ONE of the following antivirals:
 
−
**[[Acyclovir (Zovirax)]] 200 mg PO twice per day
 
−
**[[Valacyclovir (Valtrex)]] 500 mg PO once per day
 
−
*[[Filgrastim (Neupogen)]] 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
 
−
'''Next cycle to start as soon as ANC is greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10<sup>9</sup>/L'''
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] by the following criteria:
 
−
**LP: 12 mg IT once on day 2
 
−
**Ommaya reservoir: 6 mg IT once on day 2
 
−
*[[Cytarabine (Ara-C)]] 100 mg IT once on either day 7 or 8
 
−
'''Given each cycle for a total of 6 or 8 intrathecal treatments (i.e. 3 each of methotrexate and cytarabine or 4 each of methotrexate and cytarabine), depending on risk for CNS relapse based serum lactate dehydrogenase (LDH) greater than 1400 IU/L and/or proliferative index percentage of S + G2M greater than or equal to 14%'''
 
−
====CNS therapy, treatment====
 
−
*[[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT alternating with [[Cytarabine (Ara-C)]] 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
 
−
*Then [[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT given weeks 1 & 3 and [[Cytarabine (Ara-C)]] 100 mg IT, given weeks 2 & 4
 
−
*Once those 4 weeks are complete, then intrathecal treatment is given similar to the prophylactic schedule, with each drug given once during every remaining cycle of induction therapy:
 
−
**[[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT once on day 2
 
−
**[[Cytarabine (Ara-C)]] 100 mg IT once on either day 7 or 8
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Certain patient populations (see e.g. Kantarjian et al. 2004) proceed to receive [[#POMP|POMP]] maintenance
 
−
</div></div>
 
−
===References===
 
−
# '''Review:''' Cortes J, O'Brien SM, Pierce S, Keating MJ, Freireich EJ, Kantarjian HM. The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia. Blood. 1995 Sep 15;86(6):2091-7. [http://www.bloodjournal.org/content/86/6/2091.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/7662956 PubMed]
 
−
# Koller CA, Kantarjian HM, Thomas D, O'Brien S, Rios MB, Kornblau S, Murphy S, Keating M. The hyper-CVAD regimen improves outcome in relapsed acute lymphoblastic leukemia. Leukemia. 1997 Dec;11(12):2039-44. [https://www.nature.com/articles/2400861 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9447817 PubMed]
 
−
# Thomas DA, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, Cabanillas FF, Murphy S, Keating MJ, Kantarjian H. Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol. 1999 Aug;17(8):2461-70. [https://doi.org/10.1200/jco.1999.17.8.2461 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10561310 PubMed]
 
−
# Kantarjian HM, O'Brien S, Smith TL, Cortes J, Giles FJ, Beran M, Pierce S, Huh Y, Andreeff M, Koller C, Ha CS, Keating MJ, Murphy S, Freireich EJ. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000 Feb;18(3):547-61. [https://doi.org/10.1200/jco.2000.18.3.547 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10653870 PubMed]
 
−
## '''Update:''' Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S, Bueso-Ramos CE, Pierce S, Shan J, Koller C, Beran M, Keating M, Freireich EJ. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004 Dec 15;101(12):2788-801. [https://doi.org/10.1002/cncr.20668 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15481055 PubMed]
 
−
# Thomas DA, O'Brien S, Cortes J, Giles FJ, Faderl S, Verstovsek S, Ferrajoli A, Koller C, Beran M, Pierce S, Ha CS, Cabanillas F, Keating MJ, Kantarjian H. Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood. 2004 Sep 15;104(6):1624-30. Epub 2004 Jun 3. [http://www.bloodjournal.org/content/104/6/1624.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15178574 PubMed]
 
−
==Mini-Hyper-CVD/MA & Inotuzumab ozogamicin {{#subobject:c0320b|Regimen=1}}==
 
−
Mini-Hyper-CVD/MA & Inotuzumab ozogamicin: '''<u>Mini</u>''' (lower intensity) '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>D</u>'''examethasone alternating with '''<u>M</u>'''ethotrexate and '''<u>A</u>'''ra-C (Cytarabine) & Inotuzumab ozogamicin
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Protocol {{#subobject:c32f4a|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1016/S1470-2045(18)30011-1 Kantarjian et al. 2018 (MDACC 2010-0991)]
 
−
|2011-2017
 
−
| style="background-color:#91cf61" |Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
========
 
−
====Chemotherapy, Part A====
 
−
*[[Cyclophosphamide (Cytoxan)]] as follows:
 
−
**Cycles 1, 3, 5, 7: 150 mg/m<sup>2</sup> IV every 12 hours on days 1 to 3 (total dose per cycle: 900 mg/m<sup>2</sup>)
 
−
*[[Vincristine (Oncovin)]] as follows:
 
−
**Cycles 1, 3, 5, 7: 2 mg IV once per day on days 1 & 8
 
−
====Glucocorticoid therapy, Part A====
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1, 3, 5, 7: 20 mg IV or PO once per day on days 1 to 4, 11 to 14
 
−
====Antibody-drug conjugate therapy, Part A====
 
−
*[[Inotuzumab ozogamicin (Besponsa)]] as follows:
 
−
**Cycles 1 & 3: 1.3 to 1.8 mg/m<sup>2</sup> IV once on day 3
 
−
**Cycles 5 & 7: 1 to 1.3 mg/m<sup>2</sup> IV once on day 3
 
−
========
 
−
====Chemotherapy, Part B====
 
−
*[[Methotrexate (MTX)]] as follows:
 
−
**Cycles 2, 4, 6, 8: 250 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Cytarabine (Ara-C)]] as follows:
 
−
**Cycles 2, 4, 6, 8: 500 mg/m<sup>2</sup> IV every 12 hours on days 2 & 3 (total dose per cycle: 2000 mg/m<sup>2</sup>)
 
−
====Antibody-drug conjugate therapy, Part B====
 
−
*[[Inotuzumab ozogamicin (Besponsa)]] as follows:
 
−
**Cycles 2 & 4: 1.3 to 1.8 mg/m<sup>2</sup> IV once on day 3
 
−
**Cycles 6 & 8: 1 to 1.3 mg/m<sup>2</sup> IV once on day 3
 
−
'''28-day cycle for 8 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#POMP|Dose-reduced POMP]] x 3 y
 
−
</div></div>
 
−
===References===
 
−
<!-- # '''Abstract:''' Susan O'Brien, Deborah A. Thomas, Elias Jabbour, Stefan Faderl, Farhad Ravandi, Gautam Borthakur, Sergernne York, Rebecca Garris, Jorge E. Cortes, Hagop M. Kantarjian. Inotuzumab Ozogamicin In Combination With Low-Intensity Chemotherapy (Mini-hyper-CVD) As Frontline Therapy For Older Patients (≥60 years) With Acute Lymphoblastic Leukemia (ALL). Blood Nov 2013,122(21)1432 [http://www.bloodjournal.org/content/122/21/1432 link to original abstract] -->
 
−
# '''MDACC 2010-0991:''' Kantarjian H, Ravandi F, Short NJ, Huang X, Jain N, Sasaki K, Daver N, Pemmaraju N, Khoury JD, Jorgensen J, Alvarado Y, Konopleva M, Garcia-Manero G, Kadia T, Yilmaz M, Bortakhur G, Burger J, Kornblau S, Wierda W, DiNardo C, Ferrajoli A, Jacob J, Garris R, O'Brien S, Jabbour E. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2018 Feb;19(2):240-248. Epub 2018 Jan 16. [https://doi.org/10.1016/S1470-2045(18)30011-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29352703 PubMed] NCT01371630
 
−
==R-Hyper-CVAD/R-MA {{#subobject:7daccd|Regimen=1}}==
 
−
R-Hyper-CVAD/R-MA: '''<u>R</u>'''ituximab, '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone alternating with '''<u>R</u>'''ituximab, '''<u>M</u>'''ethotrexate, '''<u>A</u>'''ra-C (Cytarabine)
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Protocol {{#subobject:9af66b|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1002/cncr.21776 Thomas et al. 2006]
 
−
|style="background-color:#ffffbe"|Pilot, <20 patients reported
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940403/ Thomas et al. 2010 (MDACC ID02-230)]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|}
 
−
''See papers for details of treatment beyond induction/consolidation, which differ substantially between "standard" and "modified" protocols.''
 
−
====Targeted therapy, Part A (cycles 1, 3, 5, 7)====
 
−
*[[Rituximab (Rituxan)]] as follows:
 
−
**Cycles 1 & 3: 375 mg/m<sup>2</sup> IV over 2 to 6 hours once per day on days 1 & 11
 
−
====Chemotherapy, Part A (cycles 1, 3, 5, 7)====
 
−
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m<sup>2</sup>)
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 4 & 11
 
−
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 4
 
−
====Glucocorticoid therapy, Part A (cycles 1, 3, 5, 7)====
 
−
*[[Dexamethasone (Decadron)]] 40 mg IV or PO once per day on days 1 to 4, 11 to 14
 
−
====Supportive therapy, Part A (cycles 1, 3, 5, 7)====
 
−
*[[Mesna (Mesnex)]] 600 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1, starting 1 hour before [[Cyclophosphamide (Cytoxan)]] and completed 12 hours after the last dose of [[Cyclophosphamide (Cytoxan)]] (total dose per cycle: 1800 mg/m<sup>2</sup>)
 
−
*[[Filgrastim (Neupogen)]] 10 mcg/kg SC once per day, starting 24 hours after completion of chemotherapy, given until WBC greater than 3 x 10<sup>9</sup>/L or bone pain present
 
−
*ONE of the following antibiotics:
 
−
**[[:Category:Fluoroquinolone|Fluoroquinolone]]
 
−
**[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg dose/route not specified
 
−
*[[Fluconazole (Diflucan)]] dose/route not specified
 
−
*ONE of the following antivirals:
 
−
**[[Acyclovir (Zovirax)]] dose/route not specified
 
−
**[[Valacyclovir (Valtrex)]] dose/route not specified
 
−
'''Next cycle to start no sooner than 14 days or as soon as "unmaintained" WBC count is greater than 3 x 10<sup>9</sup>/L and platelet count greater than 50 x 10<sup>9</sup>/L'''
 
−
====Targeted therapy, Part B (cycles 2, 4, 6, 8)====
 
−
*[[Rituximab (Rituxan)]] as follows:
 
−
**Cycles 2 & 4: 375 mg/m<sup>2</sup> IV over 2 to 6 hours once per day on days 2 & 8
 
−
====Chemotherapy, Part B (cycles 2, 4, 6, 8)====
 
−
*[[Methotrexate (MTX)]] 1000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
 
−
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m<sup>2</sup>)
 
−
====Supportive therapy, Part B (cycles 2, 4, 6, 8)====
 
−
*[[Folinic acid (Leucovorin)]] 50 mg IV once on day 3, 12 hours after [[Methotrexate (MTX)]] is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
 
−
*[[Filgrastim (Neupogen)]] 10 mcg/kg SC once per day, starting on day 4, 24 hours after completion of chemotherapy, given until WBC greater than 3 x 10<sup>9</sup>/L or bone pain present
 
−
*ONE of the following antibiotics:
 
−
**Fluoroquinolone
 
−
**[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg dose/route not specified
 
−
*[[Fluconazole (Diflucan)]] dose/route not specified
 
−
*ONE of the following antivirals:
 
−
**[[Acyclovir (Zovirax)]] dose/route not specified
 
−
**[[Valacyclovir (Valtrex)]] dose/route not specified
 
−
'''Next cycle to start no sooner than 14 days or as soon as "unmaintained" WBC count is greater than 3 x 10<sup>9</sup>/L and platelet count greater than 50 x 10<sup>9</sup>/L'''
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT once on day 2
 
−
*[[Cytarabine (Ara-C)]] 100 mg IT once on day 7
 
−
'''Given each cycle for a total of 16 intrathecal treatments.'''
 
−
''If CNS disease present, therapy augmented to twice per week alternating (MTX, ara-C) treatments until CSF cell count normalizes and cytology is negative, then continues for 4 more alternating once per week treatments; prophylaxis course then resumes.''
 
−
'''8 alternating cycles'''
 
−
====Dose modifications====
 
−
*[[Cytarabine (Ara-C)]] reduced to 1000 mg/m<sup>2</sup> for patients greater than or equal to 60 years old, creatinine greater than or equal to 1.5 mg/dL or 0 hour MTX level greater than or equal to 20,000 nmol/L
 
−
*[[Vincristine (Oncovin)]] reduced to 1 mg for bilirubin greater than 2 mg/dL or NCI common toxicity criteria Grade 2+ peripheral neuropathy, omitted for bilirubin greater than 3 mg/dL or for ileus
 
−
*[[Doxorubicin (Adriamycin)]] reduced by 50% for bilirubin 2 to 3 mg/dL, by 75% for bilirubin 3 to 5 mg/dL (eliminated for bilirubin greater than 5 mg/dL or for gastric/small-bowel involvement with Course 1 to reduce duration of myelosuppression given risk of perforation)
 
−
*[[Methotrexate (MTX)]] reduced by 50% for CrCl 10 to 50 mL/min/1.73m<sup>2</sup> (eliminated for CrCl less than 10 mL/min/1.73m<sup>2</sup>), by 25% to 75% for delayed excretion and/or nephrotoxicity with prior course (dependent on severity) or by 50% for pleural effusions/ascites with drainage of fluid as feasible.
 
−
</div></div>
 
−
===References===
 
−
# Thomas DA, Faderl S, O'Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, Giles FJ, Verstovsek S, Wierda WG, Pierce SA, Shan J, Brandt M, Hagemeister FB, Keating MJ, Cabanillas F, Kantarjian H. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006 Apr 1;106(7):1569-80. [https://doi.org/10.1002/cncr.21776 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16502413 PubMed]
 
−
## '''Update:''' Fayad L, Thomas D, Romaguera J. Update of the MD Anderson Cancer Center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas. Clin Lymphoma Myeloma. 2007 Dec;8 Suppl 2:S57-62. [https://doi.org/10.3816/clm.2007.s.034 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18284717 PubMed]
 
−
# '''MDACC ID02-230:''' Thomas DA, O'Brien S, Faderl S, Garcia-Manero G, Ferrajoli A, Wierda W, Ravandi F, Verstovsek S, Jorgensen JL, Bueso-Ramos C, Andreeff M, Pierce S, Garris R, Keating MJ, Cortes J, Kantarjian HM. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol. 2010 Aug 20;28(24):3880-9. Epub 2010 Jul 26. [https://doi.org/10.1200/jco.2009.26.9456 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940403/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20660823 PubMed] NCT00671658
 
−
=Extended induction therapy=
 
−
''Note: these regimens are used when a pre-specified endpoint during remission induction was not achieved.''
 
−
==Daunorubicin, Pegaspargase, Vincristine, Prednisone {{#subobject:1734a2|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen, "ABFM" {{#subobject:cbc322e|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ Stock et al. 2019 (CALGB 10403)]
 
−
| style="background-color:#91cf61" |Non-randomized
 
−
|-
 
−
|}
 
−
ABFM: '''<u>A</u>'''ugmented '''<u>B</u>'''erlin-'''<u>F</u>'''rankfurt-'''<u>M</u>'''ünster regimen<br>
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Daunorubicin.2C_Pegaspargase.2C_Vincristine.2C_Prednisone|ABFM]] induction, with inadequate response
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IM or IV once on day 4
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 14
 
−
'''2-week course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#AALL0232_consolidation|AALL0232]] consolidation
 
−
</div></div>
 
−
===References===
 
−
# '''CALGB 10403:''' Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. [http://www.bloodjournal.org/content/133/14/1548.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30658992 PubMed] NCT00558519
 
−
=Early intensification therapy=
 
−
==CALGB 8811 early intensification {{#subobject:225653|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:b3e19a|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-asparaginase, Vincristine, Prednisone induction ("Course I")]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy, "Course II"====
 
−
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14
 
−
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC once per day on days 1 to 4, 8 to 11
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 15 & 22
 
−
*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> SC once per day on days 15, 18, 22, 25
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] 15 mg IT once on day 1
 
−
'''28-day cycle for 2 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#Mercaptopurine.2C_Methotrexate.2C_WB-XRT|Mercaptopurine, Methotrexate, WB-XRT]] interim maintenance ("Course III")
 
−
</div></div>
 
−
===References===
 
−
# '''CALGB 8811:''' Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://www.bloodjournal.org/content/85/8/2025.full.pdf+html link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/7718875 PubMed]
 
−
==L-Asparaginase & Methotrexate {{#subobject:0c63ca|Regimen=1}}==
 
−
'''Note: [[Asparaginase (Elspar)]] was discontinued by the manufacturer in December 2012, and is now essentially out of stock. Alternatives include [[Pegaspargase (Oncaspar)]] or [[Asparaginase Erwinia chrysanthemi (Erwinaze)]].'''
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:51817e|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine|Cyclophosphamide, Cytarabine, Mercaptopurine induction ("Phase 2")]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Methotrexate (MTX)]] 3000 mg/m<sup>2</sup> IV once per day on days 1, 8, 22
 
−
*[[Asparaginase (Elspar)]] 10,000 units (route not specified) once per day on days 2, 9, 23
 
−
====Supportive therapy====
 
−
*[[Folinic acid (Leucovorin)]] at "standard" doses
 
−
'''3 cycles (length of cycle not specified in original reference)'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Patients who were younger than 50 years of age and had an HLA-matched sibling donor, as well as Ph+ patients with any donor: [[Transplant_conditioning_regimens#Etoposide_.26_TBI_2|Etoposide & TBI, then allo HSCT]]
 
−
*All others: [[Transplant_conditioning_regimens#Etoposide_.26_TBI|Etoposide & TBI, then auto HSCT]] versus [[#International_ALL_Trial|International ALL Trial]] consolidation
 
−
</div></div>
 
−
===References===
 
−
# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
 
−
## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]
 
−
## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
 
−
## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
 
−
=Consolidation after upfront therapy (including post-remission therapy)=
 
−
''Note that many of these regimens are complex and as such will be referred to by their study name, not by the individual drug names. This is also a phase of treatment often referred to as post-remission or postinduction therapy.''
 
−
==AALL0232 consolidation {{#subobject:065gg9|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:342b6d|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 50%"|Study
 
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ Stock et al. 2019 (CALGB 10403)]
 
−
| style="background-color:#91cf61" |Non-randomized
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Daunorubicin.2C_Pegaspargase.2C_Vincristine.2C_Prednisone|ABFM]] induction
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 29
 
−
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV or SC once per day on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
 
−
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14, 29 to 42
 
−
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IM or IV once per day on days 15 & 43
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
 
−
'''50-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*6-MP, Capizzi MTX, Pegaspargase interim maintenance
 
−
</div></div>
 
−
===References===
 
−
# '''CALGB 10403:''' Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. [http://www.bloodjournal.org/content/133/14/1548.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30658992 PubMed] NCT00558519
 
−
==Blinatumomab monotherapy {{#subobject:065ff9|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:687b6d|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|Years of enrollment
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6027091/ Gökbuget et al. 2018 (BLAST)]
 
−
|2010-2014
 
−
|style="background-color:#91cf61"|Phase 2 (RT)
 
−
| style="background-color:#e0ecf4" |CR after 1 cycle: 78%
 
−
|-
 
−
|}
 
−
''Note: these patients had MRD after induction; also note that this is BSA-based dosing.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*"A minimum of 3 blocks of intensive [[Regimen_classes#Chemotherapy|chemotherapy]]"
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Immunotherapy====
 
−
*[[Blinatumomab (Blincyto)]] 15 mcg/m<sup>2</sup>/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 420 mcg/m<sup>2</sup>)
 
−
'''42-day cycle for up to 4 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Patients who had an allogeneic donor could proceed to allogeneic hematopoietic stem cell transplant any time after cycle 1
 
−
</div></div>
 
−
===References===
 
−
# '''BLAST:''' Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, Diedrich H, Topp MS, Brüggemann M, Horst HA, Havelange V, Stieglmaier J, Wessels H, Haddad V, Benjamin JE, Zugmaier G, Nagorsen D, Bargou RC. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018 Apr 5;131(14):1522-1531. Epub 2018 Jan 22. [https://doi.org/10.1182/blood-2017-08-798322 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6027091/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29358182 PubMed] NCT01207388
 
−
## '''Update:''' Gökbuget N, Zugmaier G, Dombret H, Stein A, Bonifacio M, Graux C, Faul C, Brüggemann M, Taylor K, Mergen N, Reichle A, Horst HA, Havelange V, Topp MS, Bargou RC. Curative outcomes following blinatumomab in adults with minimal residual disease B-cell precursor acute lymphoblastic leukemia. Leuk Lymphoma. 2020 Nov;61(11):2665-2673. Epub 2020 Jul 3. [https://doi.org/10.1080/10428194.2020.1780583 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32619115/ PubMed]
 
−
==Cyclophosphamide & TBI, then allo HSCT {{#subobject:a9f7e8|Regimen=1}}==
 
−
Cy/TBI: '''<u>Cy</u>'''clophosphamide & '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:6ca28d|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 17%"|Study
 
−
!style="width: 15%"|Years of enrollment
 
−
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 17%"|Comparator
 
−
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Non-relapse mortality]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/54/2/468.long Thomas et al. 1979]
 
−
|1976-1977
 
−
| style="background-color:#91cf61" |Non-randomized
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
|-
 
−
|[https://doi.org/10.1200/JCO.1994.12.12.2580 Sebban et al. 1994 (LALA 87)]
 
−
|1986-1991
 
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
 
−
|Chemotherapy or Auto HSCT
 
−
|style="background-color:#ffffbf"|Did not meet primary endpoint of OS60
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2004.10.050 Thomas et al. 2004 (LALA-94)]
 
−
|1994-2002
 
−
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
|-
 
−
|}
 
−
{{#lst:Allogeneic HSCT|6ca28d}}
 
−
====Immunotherapy====
 
−
*[[Allogeneic stem cells]]
 
−
'''Stem cells transfused on day 0'''
 
−
</div></div>
 
−
===References===
 
−
# Thomas ED, Sanders JE, Flournoy N, Johnson FL, Buckner CD, Clift RA, Fefer A, Goodell BW, Storb R, Weiden PL. Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood. 1979 Aug;54(2):468-76. [http://www.bloodjournal.org/content/54/2/468.long link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/378292 PubMed]
 
−
# '''LALA 87:''' Sebban C, Lepage E, Vernant JP, Gluckman E, Attal M, Reiffers J, Sutton L, Racadot E, Michallet M, Maraninchi D, Dreyfus F, Fiere D; French Group of Therapy of Adult Acute Lymphoblastic Leukemia. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. J Clin Oncol. 1994 Dec;12(12):2580-7. [https://doi.org/10.1200/JCO.1994.12.12.2580 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7989932 PubMed]
 
−
## '''Update:''' Thiebaut A, Vernant JP, Degos L, Huguet FR, Reiffers J, Sebban C, Lepage E, Thomas X, Fière D. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation: a follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am. 2000 Dec;14(6):1353-66. [https://doi.org/10.1016/s0889-8588(05)70190-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11147227 PubMed]
 
−
# '''LALA-94:''' Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. [https://doi.org/10.1200/jco.2004.10.050 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15353542 PubMed] NCT00002700
 
−
## '''Update:''' Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. [https://doi.org/10.1038/sj.leu.2404420 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17039234 PubMed]
 
−
==Etoposide & TBI, then allo HSCT {{#subobject:b389e1|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:e4216b|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
 
−
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
{{#lst:Allogeneic HSCT|e4216b}}
 
−
====Immunotherapy====
 
−
*[[Allogeneic stem cells]]
 
−
'''Stem cells transfused on day 0'''
 
−
</div></div>
 
−
===References===
 
−
# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
 
−
## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]
 
−
## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
 
−
## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
 
−
==International ALL Trial {{#subobject:a1cf91|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Protocol {{#subobject:1d1710|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
 
−
|1993-2003
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[Transplant_conditioning_regimens#Etoposide_.26_TBI|Etoposide & TBI, then auto HSCT]]
 
−
|style="background-color:#91cf60"|Seems to have superior OS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#L-Asparaginase_.26_Methotrexate|L-asparaginase & Methotrexate intensification]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy, Cycle 1====
 
−
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
====Glucocorticoid therapy====
 
−
*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 28
 
−
'''4-week course, followed by:'''
 
−
====Chemotherapy, Cycle 2====
 
−
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
'''4-week course, followed by:'''
 
−
====Chemotherapy, Cycle 3====
 
−
*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once on day 29
 
−
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV once per day on days 31 to 34, 38 to 41
 
−
*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
 
−
'''8-week course, followed by:'''
 
−
====Chemotherapy, Cycle 4====
 
−
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
====CNS therapy, prophylaxis====
 
−
*[[Cytarabine (Ara-C)]] 50 mg IT once per week for 4 weeks, then once per quarter for 4 doses
 
−
*[[External_beam_radiotherapy|Whole-brain irradiation]] to 2400 cGy
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#POMP|POMP]] maintenance
 
−
</div></div>
 
−
===References===
 
−
# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
 
−
## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]
 
−
## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
 
−
## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
 
−
==Mercaptopurine, Methotrexate, Vincristine {{#subobject:72025a|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:b9e09c|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.nature.com/articles/leu2017283 Sakura et al. 2017 (JALSG ALL202-O)]
 
−
|2002-2011
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[#Mercaptopurine.2C_Methotrexate.2C_Vincristine_88|MTX, 6-MP, Vincristine]]; intermediate-dose MTX
 
−
| style="background-color:#91cf60" |Seems to have superior DFS
 
−
|-
 
−
|}
 
−
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Given as cycles 2 and 5 of consolidation for patients younger than 50.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup> PO once per day on days 1 to 21
 
−
*[[Methotrexate (MTX)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 15
 
−
*[[Vincristine (Oncovin)]] 1.3 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 15
 
−
====CNS therapy====
 
−
*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1 & 15
 
−
*[[Dexamethasone (Decadron)]] 4 mg IT once per day on days 1 & 15
 
−
====Supportive therapy====
 
−
*[[Folinic acid (Leucovorin)]] 50 mg IV once, then 15 mg IV every 6 hours for a total of 8 doses, beginning 36 h after the '''start''' of [[Methotrexate (MTX)]] infusion
 
−
</div></div>
 
−
===References===
 
−
# '''JALSG ALL202-O:''' Sakura T, Hayakawa F, Sugiura I, Murayama T, Imai K, Usui N, Fujisawa S, Yamauchi T, Yujiri T, Kakihana K, Ito Y, Kanamori H, Ueda Y, Miyata Y, Kurokawa M, Asou N, Ohnishi K, Ohtake S, Kobayashi Y, Matsuo K, Kiyoi H, Miyazaki Y, Naoe T. High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG. Leukemia. 2018 Mar;32(3):626-632. Epub 2017 Sep 15.[https://www.nature.com/articles/leu2017283 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28914260 PubMed] UMIN C000000063
 
−
==Linker regimen (consolidation) {{#subobject:3a5313|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Protocol {{#subobject:33e7c0|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1182/blood.V69.4.1242.1242 Linker et al. 1987]
 
−
|1980-1986
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
''Each cycle is approximately one month, based on recovery of ANC to greater than 1000/uL and platelet count to greater than 100 x 10<sup>9</sup>/L.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#DOLP|DOLP]] induction
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy, Treatment A (cycles 1, 3, 5, 7)====
 
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1 & 8
 
−
*[[Asparaginase (Elspar)]] 12,000 units/m<sup>2</sup> IM once per day on days 2, 4, 7, 9, 11, 14
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14
 
−
'''Approximately one-month cycle'''
 
−
====Chemotherapy, Treatment B (cycles 2, 4, 6, 8)====
 
−
*[[Teniposide (Vumon)]] 165 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
*[[Cytarabine (Ara-C)]] 300 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
'''Approximately one-month cycle'''
 
−
====Chemotherapy, Treatment C (cycle 9)====
 
−
*[[Methotrexate (MTX)]] 690 mg/m<sup>2</sup> IV continuous infusion over 42 hours, started on day 1
 
−
*[[Asparaginase (Elspar)]] 12,000 units/m<sup>2</sup> IM once per day on days 2, 4, 7, 9, 11, 14
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14
 
−
'''Approximately one-month cycle'''
 
−
====Supportive therapy====
 
−
*[[Folinic acid (Leucovorin)]] 15 mg/m<sup>2</sup> IV every 6 hours on days 3 to 5, starting after [[Methotrexate (MTX)]] is complete (at 42 hours)
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#Mercaptopurine_.26_Methotrexate_2|6-MP & MTX]] maintenance
 
−
</div></div>
 
−
===References===
 
−
# Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. [https://doi.org/10.1182/blood.V69.4.1242.1242 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3470055 PubMed] content property of [http://hemonc.org HemOnc.org]
 
−
## '''Update:''' Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. [http://www.bloodjournal.org/content/78/11/2814.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1835410 PubMed]
 
−
==Pediatric-like GRAALL consolidation {{#subobject:32d4f7|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Protocol {{#subobject:5fe62b|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
 
−
|2003-2005
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
''Note: the original article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. Also note that each consolidation "block" flows into the next A->B->C and days are scheduled thusly.
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-asparaginase, Vincristine, Prednisone]] induction or [[#Cytarabine_.26_Idarubicin_2|Cytarabine & Idarubicin]] salvage
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy, Consolidation A (Cycles 1, 4, 7)====
 
−
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV every 12 hours on days 1 & 2
 
−
*[[Asparaginase (Elspar)]] 10,000 units/m<sup>2</sup> (route not specified) once on day 3
 
−
====Glucocorticoid therapy====
 
−
*[[Dexamethasone (Decadron)]] 10 mg (route not specified) every 12 hours on days 1 & 2
 
−
====Supportive therapy====
 
−
*[[Lenograstim (Granocyte)]] 150 mcg/m<sup>2</sup> SC once per day on days 7 to 13
 
−
====Chemotherapy, Consolidation B (Cycles 2, 5, 8)====
 
−
*[[Methotrexate (MTX)]] 3000 mg/m<sup>2</sup> IV continuous infusion (duration not specified), started on day 15
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once on day 15
 
−
*[[Asparaginase (Elspar)]] 10,000 units/m<sup>2</sup> (route not specified) once on day 16
 
−
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 15 to 21
 
−
====Supportive therapy====
 
−
*[[Lenograstim (Granocyte)]] 150 mcg/m<sup>2</sup> SC once per day on days 22 to 27
 
−
====Chemotherapy, Consolidation C (Cycles 3, 6, 9)====
 
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once per day on days 29 & 30
 
−
*[[Etoposide (Vepesid)]] 75 mg/m<sup>2</sup> IV once per day on days 29 & 30
 
−
*[[Methotrexate (MTX)]] 25 mg/m<sup>2</sup> (route not specified) once on day 29
 
−
====Supportive therapy====
 
−
*[[Lenograstim (Granocyte)]] 150 mcg/m<sup>2</sup> SC once per day from day 31 until myeloid recovery
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Patients with CR after induction: [[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone_2|Cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone late intensification]] between cycles 6 and 7
 
−
*Patients with CR after salvage: [[#Cytarabine_.26_Idarubicin|Cytarabine & idarubicin late intensification]] between cycles 6 and 7
 
−
*All patients: [[#POMP|POMP]] maintenance after completion of consolidation
 
−
</div></div>
 
−
===References===
 
−
# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
 
−
=Interim maintenance=
 
−
==Mercaptopurine, Methotrexate, WB-XRT {{#subobject:64a822|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:4011bd|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#CALGB_8811_early_intensification|Larson regimen (CALGB 8811) early intensification ("Course II")]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy, ("Course III")====
 
−
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 70
 
−
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per day on days 36, 43, 50, 57, 64
 
−
====Radiotherapy====
 
−
*[[External_beam_radiotherapy|Cranial radiation]], 24 Gy total given in 10 fractions from days 1 to 12
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1, 8, 15, 22, 29
 
−
'''12-week course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#CALGB_8811_late_intensification|Larson regimen (CALGB 8811) late intensification ("Course IV")]]
 
−
</div></div>
 
−
===References===
 
−
# '''CALGB 8811:''' Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://www.bloodjournal.org/content/85/8/2025.full.pdf+html link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/7718875 PubMed]
 
−
==Methotrexate & Pegaspargase {{#subobject:0c25ba|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:5acj9e|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ Stock et al. 2019 (CALGB 10403)]
 
−
| style="background-color:#91cf61" |Non-randomized
 
−
|-
 
−
|}
 
−
''Note: the instructions for dose escalation of MTX in the manuscript are confusing; the authors have been contacted for clarification.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#AALL0232_consolidation|AALL0232 consolidation ("Course II")]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV once on day 1, then 150 mg/m<sup>2</sup> IV once on day 11, then 200 mg/m<sup>2</sup> IV once on day 21, then 250 mg/m<sup>2</sup> IV once on day 31, then 300 mg/m<sup>2</sup> IV once on day 41
 
−
*[[Pegaspargase (Oncaspar)]] 2500 units IM or IV once per day on days 2 & 22
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1 & 31
 
−
'''42-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#Cyclophosphamide.2C_Cytarabine.2C_Pegaspargase.2C_Thioguanine.2C_Vincristine.2C_Dexamethasone|Delayed intensification ("Course IV")]]
 
−
</div></div>
 
−
===References===
 
−
# '''CALGB 10403:''' Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. [http://www.bloodjournal.org/content/133/14/1548.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30658992 PubMed] NCT00558519
 
−
=Late intensification=
 
−
==Cyclophosphamide, Cytarabine, Pegaspargase, Thioguanine, Vincristine, Dexamethasone {{#subobject:5176nxe|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:2acb245|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ Stock et al. 2019 (CALGB 10403)]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|}
 
−
''Note: also known as delayed intensification "Course IV".''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Methotrexate_.26_Pegaspargase|MTX & Pegaspargase interim]] maintenance
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once on day 29
 
−
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV or SC once per day on days 29 to 32, 36 to 39
 
−
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IM or IV once per day on days 4 +/-1 day & 43
 
−
*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 43, 50
 
−
====Glucocorticoid therapy====
 
−
*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> PO or IV twice per day on days 1 to 7, 15 to 21
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1, 29, 36
 
−
'''50-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#Mercaptopurine.2C_Methotrexate.2C_Vincristine.2C_Dexamethasone|Mercaptopurine, Methotrexate, Vincristine, Dexamethasone]] maintenance
 
−
</div></div>
 
−
===References===
 
−
# '''CALGB 10403:''' Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. [http://www.bloodjournal.org/content/133/14/1548.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30658992 PubMed] NCT00558519
 
−
==Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone {{#subobject:51eb0e|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:2b7045|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
 
−
|2003-2005
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
''Note: the original article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Pediatric-like_GRAALL_consolidation|Pediatric-like GRAALL]] consolidation cycle 6, if patients achieved CR1 after cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV every 12 hours on day 15
 
−
*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup>/day (route not specified) on days 8, 10, 12, 18, 20, 22
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 14
 
−
====Supportive therapy====
 
−
*[[Lenograstim (Granocyte)]] 150 mcg/m<sup>2</sup> SC once per day if ANC less than 500/uL until myeloid recovery
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#Pediatric-like_GRAALL_consolidation|Pediatric-like GRAALL]] consolidation
 
−
</div></div>
 
−
===References===
 
−
# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
 
−
==Cytarabine & Idarubicin {{#subobject:284aff|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:3d4896|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
 
−
|2003-2005
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
''Note: the original article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here.
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Pediatric-like_GRAALL_consolidation|Pediatric-like GRAALL]] consolidation cycle 6, if patients achieved CR1 after cytarabine & idarubicin salvage
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV every 12 hours on days 1 to 4
 
−
*[[Idarubicin (Idamycin)]] 9 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
====Supportive therapy====
 
−
*[[Lenograstim (Granocyte)]] 150 mcg/m<sup>2</sup> SC once per day from day 9 until myeloid recovery
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#Pediatric-like_GRAALL_consolidation|Pediatric-like GRAALL]] consolidation
 
−
</div></div>
 
−
===References===
 
−
# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
 
−
==CALGB 8811 late intensification {{#subobject:712de6|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:2ea5b7|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Mercaptopurine.2C_Methotrexate.2C_WB-XRT|Mercaptopurine, Methotrexate, WB-XRT interim maintenance ("Course III")]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy, "Course IV"====
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15
 
−
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once on day 29
 
−
*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
 
−
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC once per day on days 29 to 32, 36 to 39
 
−
====Glucocorticoid therapy====
 
−
*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 14
 
−
'''8-week course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#POMP|POMP]] maintenance ("Course V")
 
−
</div></div>
 
−
===References===
 
−
# '''CALGB 8811:''' Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://www.bloodjournal.org/content/85/8/2025.full.pdf+html link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/7718875 PubMed]
 
−
=Maintenance after upfront therapy=
 
−
==Mercaptopurine, Methotrexate, Vincristine, Dexamethasone {{#subobject:51acxe|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, 2 years {{#subobject:253v245|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ Stock et al. 2019 (CALGB 10403)]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|}
 
−
''Note: also known as maintenance "Course V". This duration was intended for female patients.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Cyclophosphamide.2C_Cytarabine.2C_Pegaspargase.2C_Thioguanine.2C_Vincristine.2C_Dexamethasone|Delayed intensification "Course IV"]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day
 
−
*[[Methotrexate (MTX)]] as follows:
 
−
**Cycles 1 to 4: 20 mg/m<sup>2</sup> PO once per day on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
 
−
**Cycles 5 to 8: 20 mg/m<sup>2</sup> PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
 
−
*[[Vincristine (Oncovin)]] 1.5 mg (maximum dose of 2 mg) IV once per day on days 1, 29, 57
 
−
====Glucocorticoid therapy====
 
−
*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> PO or IV twice per day on days 1 to 5, 29 to 33, 57 to 61
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] as follows:
 
−
**Cycles 1 to 4: 15 mg IT once per day on days 1 & 29
 
−
**Cycles 5 to 8: 15 mg IT once on day 1
 
−
'''12-week cycle for 8 cycles (2 years)'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, 3 years {{#subobject:25acb1|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ Stock et al. 2019 (CALGB 10403)]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|}
 
−
''Note: also known as maintenance "Course V". This duration was intended for male patients.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Cyclophosphamide.2C_Cytarabine.2C_Pegaspargase.2C_Thioguanine.2C_Vincristine.2C_Dexamethasone|Delayed intensification "Course IV"]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day
 
−
*[[Methotrexate (MTX)]] as follows:
 
−
**Cycles 1 to 4: 20 mg/m<sup>2</sup> PO once per day on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
 
−
**Cycles 5 to 12: 20 mg/m<sup>2</sup> PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
 
−
*[[Vincristine (Oncovin)]] 1.5 mg (maximum dose of 2 mg) IV once per day on days 1, 29, 57
 
−
====Glucocorticoid therapy====
 
−
*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> PO or IV twice per day on days 1 to 5, 29 to 33, 57 to 61
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] as follows:
 
−
**Cycles 1 to 4: 15 mg IT once per day on days 1 & 29
 
−
**Cycles 5 to 12: 15 mg IT once on day 1
 
−
'''12-week cycle for 12 cycles (3 years)'''
 
−
</div></div>
 
−
===References===
 
−
# '''CALGB 10403:''' Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. [http://www.bloodjournal.org/content/133/14/1548.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30658992 PubMed] NCT00558519
 
−
==Mercaptopurine & Methotrexate {{#subobject:6366a6|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:1fc958|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1182/blood.V69.4.1242.1242 Linker et al. 1987]
 
−
|1980-1986
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Linker_regimen_.28consolidation.29|Linker regimen]] consolidation
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day
 
−
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on day 1
 
−
'''7-day cycle for 130 cycles (30 months)'''
 
−
</div></div>
 
−
===References===
 
−
# Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. [https://doi.org/10.1182/blood.V69.4.1242.1242 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3470055 PubMed]
 
−
## '''Update:''' Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. [http://www.bloodjournal.org/content/78/11/2814.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1835410 PubMed]
 
−
==POMP {{#subobject:31219|Regimen=1}}==
 
−
POMP: '''<u>P</u>'''urinethol (Mercaptopurine), '''<u>O</u>'''ncovin (Vincristine), '''<u>M</u>'''ethotrexate, '''<u>P</u>'''rednisone
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1 {{#subobject:93b1b3|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
 
−
|2003-2005
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Pediatric-like_GRAALL_consolidation|Pediatric-like GRAALL]] consolidation
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day
 
−
*[[Vincristine (Oncovin)]] as follows:
 
−
**Months 1 to 12: 2 mg IV once on day 1
 
−
*[[Methotrexate (MTX)]] 25 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] as follows:
 
−
**Months 1 to 12: 40 mg/m<sup>2</sup>/day PO on days 1 to 7
 
−
'''1-month cycle for 24 cycles (2 years)'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2 {{#subobject:7e9f28|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
 
−
|1993-2003
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[Transplant_conditioning_regimens#Etoposide_.26_TBI|Etoposide & TBI, then auto HSCT]]
 
−
|style="background-color:#91cf60"|Seems to have superior OS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#International_ALL_Trial|International ALL Trial]] consolidation
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day
 
−
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> IV or PO once per week
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
−
'''3-month cycle for 10 cycles (2.5 years from the start of phase III)'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #3 {{#subobject:9374ec|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2000.18.3.547 Kantarjian et al. 2000]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
''Note: this is the IV POMP used from 1995 onwards. Exact timing of drugs is not given, for example, that certain drugs are taken on days 1 to 5 of the cycle.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Hyper-CVAD.2FMA|Hyper-CVAD/MA]] x 8
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Mercaptopurine (6-MP)]] 1000 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once on day 1
 
−
*[[Methotrexate (MTX)]] 10 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 200 mg PO once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim/Sulfamethoxazole]] (dose not specified) PO twice per day on Saturday and Sunday for the first 6 months
 
−
*ONE of the following antivirals, for the first 6 months:
 
−
**[[Acyclovir (Zovirax)]] 200 mg PO once per day or 3 times per week
 
−
**[[Valacyclovir (Valtrex)]] 500 mg PO once per day or 3 times per week
 
−
'''1-month cycle for 24 cycles (2 years)'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #4 {{#subobject:91c8d4|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#CALGB_8811_late_intensification|Larson regimen (CALGB 8811) late intensification ("Course IV")]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy, "Course V"====
 
−
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 28
 
−
*[[Vincristine (Oncovin)]] 2 mg IV once on day 1
 
−
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
−
'''28-day cycles, continue until 24 months from diagnosis'''
 
−
</div></div>
 
−
===References===
 
−
# '''CALGB 8811:''' Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://www.bloodjournal.org/content/85/8/2025.full.pdf+html link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/7718875 PubMed]
 
−
# Kantarjian HM, O'Brien S, Smith TL, Cortes J, Giles FJ, Beran M, Pierce S, Huh Y, Andreeff M, Koller C, Ha CS, Keating MJ, Murphy S, Freireich EJ. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000 Feb;18(3):547-61. [https://doi.org/10.1200/jco.2000.18.3.547 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10653870 PubMed]
 
−
## '''Update:''' Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S, Bueso-Ramos CE, Pierce S, Shan J, Koller C, Beran M, Keating M, Freireich EJ. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004 Dec 15;101(12):2788-801. [https://doi.org/10.1002/cncr.20668 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15481055 PubMed]
 
−
# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
 
−
## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]
 
−
## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
 
−
## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
 
−
# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
 
−
=Relapsed or refractory=
 
−
==Augmented Hyper-CVAD & Asparaginase {{#subobject:aab460|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:d89fd9|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(11)70128-8 Faderl et al. 2011]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
To be completed
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]]
 
−
*[[Vincristine (Oncovin)]]
 
−
*[[Doxorubicin (Adriamycin)]]
 
−
*[[Pegaspargase (Oncaspar)]]
 
−
====Glucocorticoid therapy====
 
−
*[[Dexamethasone (Decadron)]]
 
−
</div></div>
 
−
===References===
 
−
# Faderl S, Thomas DA, O'Brien S, Ravandi F, Garcia-Manero G, Borthakur G, Ferrajoli A, Verstovsek S, Ayoubi M, Rytting M, Feliu J, Kantarjian HM. Augmented hyper-CVAD based on dose-intensified vincristine, dexamethasone, and asparaginase in adult acute lymphoblastic leukemia salvage therapy. Clin Lymphoma Myeloma Leuk. 2011 Feb;11(1):54-9. [http://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(11)70128-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21454191 PubMed]
 
−
==Blinatumomab monotherapy {{#subobject:e7b2c6|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1 {{#subobject:2db105|Variant=1}}===
 
−
{| class="wikitable" style="color:white; background-color:#404040"
 
−
|<small>'''FDA-recommended dose'''</small>
 
−
|-
 
−
|}
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1016/S1470-2045(14)71170-2 Topp et al. 2014 (MT103-211)]
 
−
|2012-2013
 
−
|style="background-color:#91cf61"|Phase 2 (RT)
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5881572/ Kantarjian et al. 2017 (TOWER)]
 
−
|2014-2015
 
−
|style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc)
 
−
|Standard re-induction chemotherapy
 
−
|style="background-color:#1a9850"|Superior OS
 
−
|-
 
−
|}
 
−
''The most common comparator in TOWER was FLAG +/- anthracycline.''
 
−
====Immunotherapy====
 
−
*[[Blinatumomab (Blincyto)]] as follows:
 
−
**Cycle 1: 9 mcg/day IV continuous infusion over 7 days, started on day 1, then 28 mcg/day IV continuous infusion over 21 days, started on day 8 (total dose: 651 mcg)
 
−
**Cycles 2 to 5: 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)
 
−
'''42-day cycle for up to 5 cycles''' (2 cycles for induction and 3 additional cycles for consolidation)
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*TOWER: Optional [[#Blinatumomab_monotherapy_3|blinatumomab]] maintenance
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2 {{#subobject:aadee8|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2010.32.7270 Topp et al. 2011 (MT103-202)]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|[https://doi.org/10.1200/JCO.2014.56.3247 Topp et al. 2014 (MT103-206)]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Immunotherapy====
 
−
*[[Blinatumomab (Blincyto)]] 15 mcg/m<sup>2</sup>/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 420 mcg/m<sup>2</sup>)
 
−
'''42-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Patients who had an allogeneic donor could receive an allogeneic hematopoietic stem cell transplant any time after cycle 1. Patients who had response could receive up to an additional 3 cycles of consolidation therapy--same as above.
 
−
</div></div>
 
−
===References===
 
−
<!-- # '''Abstract:''' Max S. Topp, Nicola Goekbuget, Anthony Selwyn Stein, Ralf C. Bargou, Hervé Dombret, Adele K. Fielding, Josep M. Ribera, Robin Foà, Gerhard Zugmaier, Chris Holland, Tapan Maniar, Birgit Huber, Dirk Nagorsen, Hagop M. Kantarjian. Confirmatory open-label, single-arm, multicenter phase 2 study of the BiTE antibody blinatumomab in patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL). J Clin Oncol 32:5s, 2014 (suppl; abstr 7005^). [http://meetinglibrary.asco.org/content/129500-144 link to abstract] -->
 
−
# '''MT103-202:''' Topp MS, Kufer P, Gökbuget N, Goebeler M, Klinger M, Neumann S, Horst HA, Raff T, Viardot A, Schmid M, Stelljes M, Schaich M, Degenhard E, Köhne-Volland R, Brüggemann M, Ottmann O, Pfeifer H, Burmeister T, Nagorsen D, Schmidt M, Lutterbuese R, Reinhardt C, Baeuerle PA, Kneba M, Einsele H, Riethmüller G, Hoelzer D, Zugmaier G, Bargou RC. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011 Jun 20;29(18):2493-8. Epub 2011 May 16. [https://doi.org/10.1200/jco.2010.32.7270 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21576633 PubMed] NCT00560794
 
−
## '''Update:''' Topp MS, Gökbuget N, Zugmaier G, Degenhard E, Goebeler ME, Klinger M, Neumann SA, Horst HA, Raff T, Viardot A, Stelljes M, Schaich M, Köhne-Volland R, Brüggemann M, Ottmann OG, Burmeister T, Baeuerle PA, Nagorsen D, Schmidt M, Einsele H, Riethmüller G, Kneba M, Hoelzer D, Kufer P, Bargou RC. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012 Dec 20;120(26):5185-7. [http://www.bloodjournal.org/content/120/26/5185.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/23024237 PubMed]
 
−
## '''Update:''' Gökbuget N, Zugmaier G, Klinger M, Kufer P, Stelljes M, Viardot A, Horst HA, Neumann S, Brüggemann M, Ottmann OG, Burmeister T, Wessiepe D, Topp MS, Bargou R. Long-term relapse-free survival in a phase 2 study of blinatumomab for the treatment of patients with minimal residual disease in B-lineage acute lymphoblastic leukemia. Haematologica. 2017 Apr;102(4):e132-e135. Epub 2017 Jan 12. [http://www.haematologica.org/content/102/4/e132.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395124/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28082340 PubMed]
 
−
# '''MT103-206:''' Topp MS, Gökbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, Viardot A, Marks R, Diedrich H, Faul C, Reichle A, Horst HA, Brüggemann M, Wessiepe D, Holland C, Alekar S, Mergen N, Einsele H, Hoelzer D, Bargou RC. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014 Dec 20;32(36):4134-40. Epub 2014 Nov 10. [https://doi.org/10.1200/JCO.2014.56.3247 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25385737 PubMed] NCT01209286
 
−
## '''Update:''' Zugmaier G, Gökbuget N, Klinger M, Viardot A, Stelljes M, Neumann S, Horst HA, Marks R, Faul C, Diedrich H, Reichle A, Brüggemann M, Holland C, Schmidt M, Einsele H, Bargou RC, Topp MS. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood. 2015 Dec 10;126(24):2578-84. Epub 2015 Oct 19. [http://www.bloodjournal.org/content/126/24/2578.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671107/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26480933 PubMed]
 
−
# '''MT103-211:''' Topp MS, Gökbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, Dombret H, Fielding AK, Heffner L, Larson RA, Neumann S, Foà R, Litzow M, Ribera JM, Rambaldi A, Schiller G, Brüggemann M, Horst HA, Holland C, Jia C, Maniar T, Huber B, Nagorsen D, Forman SJ, Kantarjian HM. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015 Jan;16(1):57-66. Epub 2014 Dec 16. Erratum in: Lancet Oncol. 2015 Apr;16(4):e158. [https://doi.org/10.1016/S1470-2045(14)71170-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25524800 PubMed] NCT01466179
 
−
# '''TOWER:''' Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Brüggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017 Mar 2;376(9):836-847. [https://doi.org/10.1056/NEJMoa1609783 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5881572/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28249141 PubMed] NCT02013167
 
−
## '''HRQoL analysis:''' Topp MS, Zimmerman Z, Cannell P, Dombret H, Maertens J, Stein A, Franklin J, Tran Q, Cong Z, Schuh AC. Health-related quality of life in adults with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab. Blood. 2018 Jun 28;131(26):2906-2914. Epub 2018 May 8. [https://doi.org/10.1182/blood-2017-09-804658 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6024638/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29739753 PubMed]
 
−
==Brexucabtagene autoleucel monotherapy {{#subobject:4z3u14|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:6np0a6|Variant=1}}===
 
−
{| class="wikitable" style="color:white; background-color:#404040"
 
−
|<small>'''FDA-recommended dose'''</small>
 
−
|-
 
−
|}
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1016/s0140-6736(21)01222-8 Shah et al. 2021 (ZUMA-3)]
 
−
|2018-2019
 
−
| style="background-color:#91cf61" |Phase 2 (RT)
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[Autologous_HSCT#FC|FC conditioning]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Immunotherapy====
 
−
*[[Brexucabtagene autoleucel (Tecartus)]] 1 x 10<sup>6</sup> CAR T cells/kg IV once on day 0
 
−
</div></div>
 
−
===References===
 
−
#'''ZUMA-3:''' Shah BD, Ghobadi A, Oluwole OO, Logan AC, Boissel N, Cassaday RD, Leguay T, Bishop MR, Topp MS, Tzachanis D, O'Dwyer KM, Arellano ML, Lin Y, Baer MR, Schiller GJ, Park JH, Subklewe M, Abedi M, Minnema MC, Wierda WG, DeAngelo DJ, Stiff P, Jeyakumar D, Feng C, Dong J, Shen T, Milletti F, Rossi JM, Vezan R, Masouleh BK, Houot R. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021 Aug 7;398(10299):491-502. Epub 2021 Jun 4. [https://doi.org/10.1016/s0140-6736(21)01222-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34097852/ PubMed] NCT02614066
 
−
==Clofarabine monotherapy {{#subobject:6befdc|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:9e7379|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/102/7/2379.long Kantarjian et al. 2003]
 
−
|style="background-color:#ffffbe"|Phase 2, <20 patients in this arm
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Clofarabine (Clolar)]] 40 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
 
−
'''3- to 6-week cycles, depending on response count recovery'''
 
−
</div></div>
 
−
===References===
 
−
# Kantarjian H, Gandhi V, Cortes J, Verstovsek S, Du M, Garcia-Manero G, Giles F, Faderl S, O'Brien S, Jeha S, Davis J, Shaked Z, Craig A, Keating M, Plunkett W, Freireich EJ. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003 Oct 1;102(7):2379-86. Epub 2003 Jun 5. [http://www.bloodjournal.org/content/102/7/2379.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12791647 PubMed]
 
−
==Cytarabine monotherapy {{#subobject:4dcf05|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:045c1c|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594743/ Kantarjian et al. 2016 (INO-VATE ALL)]
 
−
|2012-2014
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Inotuzumab_ozogamicin_monotherapy|Inotuzumab ozogamicin]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior OS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cytarabine (Ara-C)]] by the following criteria:
 
−
**Younger than 55: 3000 mg/m<sup>2</sup> IV every 12 hours on days 1 to 6 (total dose: 36,000 mg/m<sup>2</sup>)
 
−
**55 or older: 1500 mg/m<sup>2</sup> IV every 12 hours on days 1 to 6 (total dose: 18,000 mg/m<sup>2</sup>)
 
−
'''6-day course'''
 
−
</div></div>
 
−
===References===
 
−
<!-- no pre-pub disclosed -->
 
−
# '''INO-VATE ALL:''' Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. [https://doi.org/10.1056/NEJMoa1509277 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594743/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27292104 PubMed] NCT01564784
 
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## '''Update:''' Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. [https://doi.org/10.1002/cncr.32116 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6618133/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30920645 PubMed]
 
−
==Cytarabine & Idarubicin {{#subobject:d6d882|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:9cfc92|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
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!style="width: 33%"|Study
 
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!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
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|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
 
−
|2003-2005
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|[https://doi.org/10.1056/NEJMoa1605085 Maury et al. 2016 (GRAALL-2005/R)]
 
−
|2006-2014
 
−
|style="background-color:#91cf61"|Non-randomized portion of phase 3 RCT
 
−
|-
 
−
|}
 
−
''Note: the original '''GRAALL-2003''' article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. This regimen is for patients not achieving CR1 with induction.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-aspariginase, Vincristine, Prednisone]] induction
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1 to 4 (total dose: 16,000 mg/m<sup>2</sup>)
 
−
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3
 
−
====Supportive therapy====
 
−
*[[Lenograstim (Granocyte)]] by the following study-specific criteria:
 
−
**GRAALL-2003: 150 mcg/m<sup>2</sup> SC once per day from day 9 until myeloid recovery
 
−
**GRAALL-2005: 263 mcg IV or SC once per day from day 9 until first day with ANC greater than 1000/uL
 
−
'''One course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Patients achieving CR1 after salvage: [[#Pediatric-like_GRAALL_consolidation|Pediatric-like GRAALL]] consolidation
 
−
</div></div>
 
−
===References===
 
−
# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
 
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# '''GRAALL-2005/R:''' Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. [https://doi.org/10.1056/NEJMoa1605085 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1605085/suppl_file/nejmoa1605085_protocol.pdf link to supplement] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/27626518 PubMed] NCT00327678
 
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==Cytarabine, Idarubicin, Rituximab {{#subobject:7ae2cb|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:748401|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1056/NEJMoa1605085 Maury et al. 2016 (GRAALL-2005/R)]
 
−
|2006-2014
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
''This regimen is for patients not achieving CR1 with induction.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone.2C_Rituximab|Cyclophosphamide, Daunorubicin, L-aspariginase, Vincristine, Prednisone, Rituximab]] induction
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1 to 4 (total dose: 16,000 mg/m<sup>2</sup>)
 
−
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3
 
−
====Targeted therapy====
 
−
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1 & 7
 
−
====Supportive therapy====
 
−
*[[Lenograstim (Granocyte)]] 263 mcg IV or SC once per day, starting on day 9, continuing until first day with ANC greater than 1000/uL
 
−
'''One course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Patients achieving CR1 after salvage: Pediatric-like GRAALL consolidation with rituximab
 
−
</div></div>
 
−
===References===
 
−
# '''GRAALL-2005/R:''' Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. [https://doi.org/10.1056/NEJMoa1605085 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1605085/suppl_file/nejmoa1605085_protocol.pdf link to supplement] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/27626518 PubMed] NCT00327678
 
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==Cytarabine & Mitoxantrone (MC) {{#subobject:6237f0|Regimen=1}}==
 
−
MC: '''<u>M</u>'''itoxantrone & '''<u>C</u>'''ytarabine
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
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===Regimen {{#subobject:395e92|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
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!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594743/ Kantarjian et al. 2016 (INO-VATE ALL)]
 
−
|2012-2014
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Inotuzumab_ozogamicin_monotherapy|Inotuzumab ozogamicin]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior OS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose per cycle: 1400 mg/m<sup>2</sup>)
 
−
*[[Mitoxantrone (Novantrone)]] 12 mg/m<sup>2</sup> IV over 20 minutes once per day on days 1 to 3
 
−
'''15- to 20-day cycle for up to 4 cycles'''
 
−
====Dose modifications====
 
−
*[[Mitoxantrone (Novantrone)]] dose reduction to 8 mg/m<sup>2</sup> allowed on the basis of age, coexisting conditions, and previous anthracycline use
 
−
</div></div>
 
−
===References===
 
−
# '''INO-VATE ALL:''' Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. [https://doi.org/10.1056/NEJMoa1509277 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1509277/suppl_file/nejmoa1509277_protocol.pdf link to original protocol] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594743/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27292104 PubMed] NCT01564784
 
−
## '''Update:''' Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. [https://doi.org/10.1002/cncr.32116 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6618133/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30920645 PubMed]
 
−
==FLAG {{#subobject:600e85|Regimen=1}}==
 
−
FLAG: '''<u>FL</u>'''udarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:e2c900|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594743/ Kantarjian et al. 2016 (INO-VATE ALL)]
 
−
|2012-2014
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Inotuzumab_ozogamicin_monotherapy|Inotuzumab ozogamicin]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior OS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 2 to 6
 
−
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 6
 
−
====Growth factor therapy====
 
−
*[[:Category:Granulocyte_colony-stimulating_factors|G-CSF]] 5 mcg/kg or at the institutional standard dose once per day (interval not specified)
 
−
'''28-day cycle for up to 4 cycles'''
 
−
</div></div>
 
−
===References===
 
−
# '''INO-VATE ALL:''' Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. [https://doi.org/10.1056/NEJMoa1509277 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594743/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27292104 PubMed] NCT01564784
 
−
## '''Update:''' Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. [https://doi.org/10.1002/cncr.32116 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6618133/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30920645 PubMed]
 
−
==Hyper-CVAD/MA & Everolimus {{#subobject:71a41c|Regimen=1}}==
 
−
Hyper-CVAD/MA & Everolimus: '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone alternating with '''<u>M</u>'''ethotrexate, '''<u>A</u>'''ra-C (Cytarabine), with Everolimus
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Protocol {{#subobject:2efb7e|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470787/ Daver et al. 2015 (MDACC 2009-0100)]
 
−
|2010-2014
 
−
|style="background-color:#91cf61"|Phase 1/2
 
−
|-
 
−
|}
 
−
''Note: there are some difference between this protocol and other published Hyper-CVAD protocols, including flexibility in the timing of vincristine and dexamethasone. Some details were missing, in particular the supportive medications for the B cycles. The everolimus dose is the MTD.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy, all cycles====
 
−
*[[Everolimus (Afinitor)]] 5 mg PO once per day
 
−
====Chemotherapy, Part A (cycles 1, 3, 5, 7)====
 
−
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m<sup>2</sup>)
 
−
*[[Vincristine (Oncovin)]] by the following age-based criteria:
 
−
**Younger than 18: 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 4 & 11 (+/- 2 days)
 
−
**18 and older: 2 mg IV once per day on days 4 & 11 (+/- 2 days)
 
−
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 4
 
−
====Glucocorticoid therapy, Part A (cycles 1, 3, 5, 7)====
 
−
*[[Dexamethasone (Decadron)]] by the following age-based criteria:
 
−
**Younger than 18: 20 mg/m<sup>2</sup> (maximum dose of 40 mg) IV or PO once per day on days 1 to 4, 11 to 14 (+/- 2 days)
 
−
**18 and older: 40 mg IV or PO once per day on days 1 to 4, 11 to 14 (+/- 2 days)
 
−
====Supportive therapy, Part A (cycles 1, 3, 5, 7)====
 
−
*[[Mesna (Mesnex)]] 600 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 1800 mg/m<sup>2</sup>)
 
−
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once, approximately 24 hours after completion of chemotherapy
 
−
====Chemotherapy, Part A (cycles 1, 3, 5, 7)====
 
−
*[[Methotrexate (MTX)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, then 800 mg/m<sup>2</sup> IV over 22 hours (total dose per cycle: 1000 mg/m<sup>2</sup>)
 
−
*[[Cytarabine (Ara-C)]] by the following age-based criteria:
 
−
**Younger than 60: 3000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m<sup>2</sup>)
 
−
**60 and older, or with creatinine at least 1.5 x the upper limit of normal: 1000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m<sup>2</sup>)
 
−
====Glucocorticoid therapy, Part A (cycles 1, 3, 5, 7)====
 
−
*[[Methylprednisolone (Solumedrol)]] by the following age-based criteria:
 
−
**Younger than 18: 25 mg/m<sup>2</sup> (maximum dose of 50 mg) IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 150 mg/m<sup>2</sup>)
 
−
**18 and older: 50 mg IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 300 mg/m<sup>2</sup>)
 
−
***''It isn't clear if this is meant to be a supportive or antineoplastic medication.''
 
−
</div></div>
 
−
===References===
 
−
# '''MDACC 2009-0100:''' Daver N, Boumber Y, Kantarjian H, Ravandi F, Cortes J, Rytting ME, Kawedia JD, Basnett J, Culotta KS, Zeng Z, Lu H, Richie MA, Garris R, Xiao L, Liu W, Baggerly KA, Jabbour E, O'Brien S, Burger J, Bendall LJ, Thomas D, Konopleva M. A Phase I/II study of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia. Clin Cancer Res. 2015 Jun 15;21(12):2704-14. Epub 2015 Feb 27. [http://clincancerres.aacrjournals.org/content/21/12/2704.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470787/ link to PMC article] '''contains partial protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/25724525 PubMed] NCT00968253
 
−
==Inotuzumab ozogamicin monotherapy {{#subobject:d90806|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:8be9f9|Variant=1}}===
 
−
{| class="wikitable" style="color:white; background-color:#404040"
 
−
|<small>'''FDA-recommended dose'''</small>
 
−
|-
 
−
|}
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1016/S1470-2045(11)70386-2 Kantarjian et al. 2012 (MDACC 2009-0872)]
 
−
|2010-2011
 
−
| style="background-color:#91cf61" |Phase 2
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594743/ Kantarjian et al. 2016 (INO-VATE ALL)]
 
−
|2012-2014
 
−
|style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc)
 
−
|Investigator's choice of:<br> 1. [[#Cytarabine_monotherapy|Cytarabine]]<br> 2. [[#Cytarabine_.26_Mitoxantrone_.28MC.29|MC]]<br> 3. [[#FLAG|FLAG]]
 
−
|style="background-color:#91cf60"|Seems to have superior OS
 
−
|-
 
−
|}
 
−
''Note: the protocol in the text of Kantarjian et al. 2016 is confusing, as it does not specify BSA-based dosing; the original protocol is clear on this, as is the FDA package insert.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Antibody-drug conjugate therapy====
 
−
*[[Inotuzumab ozogamicin (Besponsa)]] as follows:
 
−
**Cycle 1: 0.8 mg/m<sup>2</sup> IV once on day 1, then 0.5 mg/m<sup>2</sup> IV once per day on days 8 & 15
 
−
**Cycles 2 to 6, patients achieving CR or CRi: 0.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 
−
**Cycles 2 to 6, less than CR: 0.8 mg/m<sup>2</sup> IV once on day 1, then 0.5 mg/m<sup>2</sup> IV once per day on days 8 & 15
 
−
'''21-day cycle for 1 cycle, then 28-day cycle for up to 5 cycles'''
 
−
</div></div>
 
−
===References===
 
−
# '''MDACC 2009-0872:''' Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, York S, Ravandi F, Kwari M, Faderl S, Rios MB, Cortes J, Fayad L, Tarnai R, Wang SA, Champlin R, Advani A, O'Brien S. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012 Apr;13(4):403-11. Epub 2012 Feb 21. [https://doi.org/10.1016/S1470-2045(11)70386-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22357140 PubMed] NCT01134575
 
−
# '''INO-VATE ALL:''' Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. [https://doi.org/10.1056/NEJMoa1509277 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1509277/suppl_file/nejmoa1509277_protocol.pdf link to original protocol] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594743/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27292104 PubMed] NCT01564784
 
−
## '''Update:''' Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. [https://doi.org/10.1002/cncr.32116 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6618133/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30920645 PubMed]
 
−
==Tisagenlecleucel monotherapy {{#subobject:d68f14|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:60fc19|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|Years of enrollment
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267531/ Maude et al. 2014 (UPCC04409)]
 
−
|2012-2014
 
−
|style="background-color:#91cf61"|Phase 1/2a
 
−
|
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5996391/ Maude et al. 2018 (ELIANA)]
 
−
|2015-2017
 
−
|style="background-color:#91cf61"|Phase 2 (RT)
 
−
|ORR: 81%
 
−
|-
 
−
|}
 
−
''Note: dosing instructions are based on ELIANA.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*Lymphodepleting therapy with [[Autologous_HSCT#FC|FC]] or [[Autologous_HSCT#CYVE|CYVE]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Immunotherapy====
 
−
*[[Tisagenlecleucel (Kymriah)]] by the following criteria:
 
−
**Up to 50 kg: 2 to 5 x 10<sup>6</sup> CTL019 transduced viable T-cells per kg body weight IV once on day 0
 
−
**Greater than 50 kg: 1.0 to 2.5 x 10<sup>8</sup> CTL019 transduced viable T-cells IV once on day 0
 
−
'''One course'''
 
−
</div></div>
 
−
===References===
 
−
# '''UPCC04409:''' Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507-17. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. [https://doi.org/10.1056/NEJMoa1407222 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267531/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25317870 PubMed] NCT01029366
 
−
# '''ELIANA:''' Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018 Feb 1;378(5):439-448. [https://doi.org/10.1056/NEJMoa1709866 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1709866/suppl_file/nejmoa1709866_protocol.pdf link to supplementary protocol] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5996391/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29385370 PubMed] NCT02435849
 
−
=Consolidation after salvage therapy=
 
−
==Blinatumomab monotherapy {{#subobject:e7bh86|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:2db2g7|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7926290/ Brown et al. 2021 (COG AALL1331)]
 
−
|2014-2019
 
−
|style="background-color:#1a9851"|Phase 3 (E-switch-ooc)
 
−
|Standard salvage consolidation chemotherapy
 
−
| style="background-color:#d9ef8b" |Might have superior DFS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Immunotherapy====
 
−
*[[Blinatumomab (Blincyto)]] 15 mcg/m<sup>2</sup>/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 420 mcg/m<sup>2</sup>)
 
−
'''35-day cycle for 2 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Allogeneic hematopoietic stem cell transplant
 
−
</div></div>
 
−
===References===
 
−
# '''COG AALL1331:''' Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Pulsipher MA, Hunger SP, Loh ML. Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):833-842. [https://doi.org/10.1001/jama.2021.0669 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7926290/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33651090/ PubMed] NCT02101853
 
−
==Cyclophosphamide & TBI, then allo HSCT {{#subobject:a9e6e8|Regimen=1}}==
 
−
Cy/TBI: '''<u>Cy</u>'''clophosphamide & '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:1ba28d|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/581686 Rudolph et al. 1973]
 
−
|1968-1970
 
−
| style="background-color:#ffffbe" |Non-randomized, <20 pts in subgroup
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
|-
 
−
|[https://doi.org/10.1056/NEJM198708203170801 Kersey et al. 1987]
 
−
|1982-1985
 
−
|style="background-color:#1a9851"|Quasi-randomized
 
−
|Auto HSCT
 
−
| style="background-color:#1a9850" |Superior RFS
 
−
|-
 
−
|}
 
−
{{#lst:Allogeneic HSCT|6ca28d}}
 
−
====Immunotherapy====
 
−
*[[Allogeneic stem cells]]
 
−
'''Stem cells transfused on day 0'''
 
−
</div></div>
 
−
===References===
 
−
# Rudolph RH, Fefer A, Thomas ED, Buckner CD, Clift RA, Storb R. Isogeneic marrow grafts for hematologic malignancy in man. Arch Intern Med. 1973 Aug;132(2):279-85. [https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/581686 link to original article] [https://pubmed.ncbi.nlm.nih.gov/4268940 PubMed]
 
−
## '''Update:''' Fefer A, Einstein AB, Thomas ED, Buckner CD, Clift RA, Glucksberg H, Neiman PE, Storb R. Bone-marrow transplantation for hematologic neoplasia in 16 patients with identical twins. N Engl J Med. 1974 Jun 20;290(25):1389-93. [https://doi.org/10.1056/NEJM197406202902501 link to original article] [https://pubmed.ncbi.nlm.nih.gov/4597885 PubMed]
 
−
# Kersey JH, Weisdorf D, Nesbit ME, LeBien TW, Woods WG, McGlave PB, Kim T, Vallera DA, Goldman AI, Bostrom B, Hurd D, Ramsay NKC. Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia. N Engl J Med. 1987 Aug 20;317(8):461-7. [https://doi.org/10.1056/NEJM198708203170801 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3302708 PubMed]
 
−
=Maintenance after subsequent lines of therapy=
 
−
==Blinatumomab monotherapy {{#subobject:94aea7|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:1e4bff|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5881572/ Kantarjian et al. 2017 (TOWER)]
 
−
|2014-2015
 
−
|style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc)
 
−
|Standard maintenance chemotherapy
 
−
|style="background-color:#1a9850"|Superior OS
 
−
|-
 
−
|}
 
−
''The most common comparator was not specified but is presumably POMP.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Blinatumomab_monotherapy_2|Blinatumomab induction and]] consolidation
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Immunotherapy====
 
−
*[[Blinatumomab (Blincyto)]] 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)
 
−
'''12-week cycle for up to 5 cycles (1 year)'''
 
−
</div></div>
 
−
===References===
 
−
# '''TOWER:''' Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Brüggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017 Mar 2;376(9):836-847. [https://doi.org/10.1056/NEJMoa1609783 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5881572/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28249141 PubMed] NCT02013167
 
−
## '''HRQoL analysis:''' Topp MS, Zimmerman Z, Cannell P, Dombret H, Maertens J, Stein A, Franklin J, Tran Q, Cong Z, Schuh AC. Health-related quality of life in adults with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab. Blood. 2018 Jun 28;131(26):2906-2914. Epub 2018 May 8. [https://doi.org/10.1182/blood-2017-09-804658 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6024638/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29739753 PubMed]
 
−
=Investigational agents=
 
−
''These are drugs under study with at least some promising results for this disease.''
 
−
*[[Epratuzumab (humanised anti-CD22 antibody)]]
 
−
[[Category:B-cell acute lymphoblastic leukemia regimens]]
 
−
[[Category:Disease-specific pages]]
 
−
[[Category:Acute lymphoblastic leukemias]]
 

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