Difference between revisions of "B-cell acute lymphoblastic leukemia"
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− | |[http://www.bloodjournal.org/content/64/1/267.long Gottlieb et al. 1984 | + | |[http://www.bloodjournal.org/content/64/1/267.long Gottlieb et al. 1984] |
|style="background-color:#1a9851"|Randomized | |style="background-color:#1a9851"|Randomized | ||
|[[#L-Asparaginase.2C_Vincristine.2C_Prednisone|L-asparaginase, Vincristine, Prednisone]] | |[[#L-Asparaginase.2C_Vincristine.2C_Prednisone|L-asparaginase, Vincristine, Prednisone]] | ||
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## '''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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1835410 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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1835410 PubMed] | ||
# Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W, Niemeyer C, Henze G, Feldges A, Zintl F, Kornhuber B, Ritter J, Welte K, Gadner H, Riehm H. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood. 2000 Jun 1;95(11):3310-22. [http://www.bloodjournal.org/content/95/11/3310.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10828010 PubMed] | # Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W, Niemeyer C, Henze G, Feldges A, Zintl F, Kornhuber B, Ritter J, Welte K, Gadner H, Riehm H. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood. 2000 Jun 1;95(11):3310-22. [http://www.bloodjournal.org/content/95/11/3310.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10828010 PubMed] | ||
− | # 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 Group. 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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11806988 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 Group. 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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11806988 PubMed] |
− | # Kamps WA, Bökkerink JP, Hakvoort-Cammel FG, Veerman AJ, Weening RS, van Wering ER, van Weerden JF, Hermans J, Slater R, van den Berg E, Kroes WG, van der Does-van den Berg A. BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991-1996). Leukemia. 2002 Jun;16(6):1099-111. [https://www.nature.com/leu/journal/v16/n6/full/2402489a.html link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12040440 PubMed] | + | # '''DCLSG ALL-8:''' Kamps WA, Bökkerink JP, Hakvoort-Cammel FG, Veerman AJ, Weening RS, van Wering ER, van Weerden JF, Hermans J, Slater R, van den Berg E, Kroes WG, van der Does-van den Berg A. BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991-1996). Leukemia. 2002 Jun;16(6):1099-111. [https://www.nature.com/leu/journal/v16/n6/full/2402489a.html link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12040440 PubMed] |
− | # 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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16105981 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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16105981 PubMed] |
## '''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://www.ncbi.nlm.nih.gov/pubmed/18048644 PubMed] | ## '''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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/19244158 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://www.ncbi.nlm.nih.gov/pubmed/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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24277073 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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24277073 PubMed] | ||
− | # 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] [https://www.ncbi.nlm.nih.gov/pubmed/18156492 PubMed] | + | # '''SWOG 9400:''' 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] [https://www.ncbi.nlm.nih.gov/pubmed/18156492 PubMed] |
# Seibel NL, Steinherz PG, Sather HN, Nachman JB, Delaat C, Ettinger LJ, Freyer DR, Mattano LA Jr, Hastings CA, Rubin CM, Bertolone K, Franklin JL, Heerema NA, Mitchell TL, Pyesmany AF, La MK, Edens C, Gaynon PS. Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2008 Mar 1;111(5):2548-55. [http://www.bloodjournal.org/content/111/5/2548.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254538/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18039957 PubMed] | # Seibel NL, Steinherz PG, Sather HN, Nachman JB, Delaat C, Ettinger LJ, Freyer DR, Mattano LA Jr, Hastings CA, Rubin CM, Bertolone K, Franklin JL, Heerema NA, Mitchell TL, Pyesmany AF, La MK, Edens C, Gaynon PS. Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2008 Mar 1;111(5):2548-55. [http://www.bloodjournal.org/content/111/5/2548.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254538/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18039957 PubMed] | ||
− | # Möricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dördelmann M, Löning L, Beier R, Ludwig WD, Ratei R, Harbott J, Boos J, Mann G, Niggli F, Feldges A, Henze G, Welte K, Beck JD, Klingebiel T, Niemeyer C, Zintl F, Bode U, Urban C, Wehinger H, Niethammer D, Riehm H, Schrappe M; German-Austrian-Swiss ALL-BFM Study Group. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood. 2008 May 1;111(9):4477-89. doi: 10.1182/blood-2007-09-112920. Epub 2008 Feb 19. Erratum in: Blood. 2009 Apr 30;113(18):4478. Dosage error in article text. [http://www.bloodjournal.org/content/111/9/4477.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18285545 PubMed] | + | # '''ALL-BFM 95:''' Möricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dördelmann M, Löning L, Beier R, Ludwig WD, Ratei R, Harbott J, Boos J, Mann G, Niggli F, Feldges A, Henze G, Welte K, Beck JD, Klingebiel T, Niemeyer C, Zintl F, Bode U, Urban C, Wehinger H, Niethammer D, Riehm H, Schrappe M; German-Austrian-Swiss ALL-BFM Study Group. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood. 2008 May 1;111(9):4477-89. doi: 10.1182/blood-2007-09-112920. Epub 2008 Feb 19. Erratum in: Blood. 2009 Apr 30;113(18):4478. Dosage error in article text. [http://www.bloodjournal.org/content/111/9/4477.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18285545 PubMed] |
==Daunorubicin, Pegaspargase, Vincristine, Dexamethasone {{#subobject:088146|Regimen=1}}== | ==Daunorubicin, Pegaspargase, Vincristine, Dexamethasone {{#subobject:088146|Regimen=1}}== |
Revision as of 19:03, 20 March 2018
Note: biomarker-specific regimens have been moved to dedicated pages:
50 regimens on this page
64 variants on this page
|
Please note, mature B-cell ALL (L3) is now classified as Burkitt lymphoma/leukemia. Regimens for this variant are available here
Guidelines
ESMO
- 2016: Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PubMed
NCCN
Prephase
Prednisone monotherapy
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Regimen #1, flat dose
Study | Evidence |
---|---|
Huguet et al. 2009 (GRAALL-2003) | Phase II |
Note: 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.
Chemotherapy
- Prednisone (Sterapred) 60 mg/m2/day on days -7 to -1
CNS treatment
- Methotrexate (MTX) 15 mg IT once at some point between days -7 and -4
Subsequent treatment
Regimen #2, increasing doses
Study | Evidence |
---|---|
Chiaretti et al. 2016 (GIMEMA LAL 0904) | Phase II |
Note: the manuscript does not give details on how quickly the dose is ramped up. Patients in this study had Ph+ ALL.
Chemotherapy
- Prednisone (Sterapred) 10 mg/m2/day, increasing to 60 mg/m2/day by day 7
Subsequent treatment
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. link to original article contains verified protocol PubMed
- GIMEMA LAL 0904: Chiaretti S, Vitale A, Vignetti M, Piciocchi A, Fazi P, Elia L, Falini B, Ronco F, Ferrara F, De Fabritiis P, Luppi M, La Nasa G, Tedeschi A, Califano C, Fanin R, Dore F, Mandelli F, Meloni G, Foà R. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study. Haematologica. 2016 Dec;101(12):1544-1552. link to original article link to PMC article contains verified protocol PubMed
Vincristine & Prednisone
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VP: Vincristine & Prednisone
Regimen
Study | Evidence |
---|---|
Sallan et al. 1978 | Non-randomized |
Note: this regimen is of historic interest as an induction regimen; it is still occasionally used as pre-phase in patients too ill to get cytotoxic chemotherapy at time of diagnosis.
Chemotherapy
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15
- Prednisone (Sterapred) 40 mg/m2/day PO on days 1 to 21
One course
References
- Sallan SE, Cammita BM, Cassady JR, Nathan DG, Frei E 3rd. Intermittent combination chemotherapy with adriamycin for childhood acute lymphoblastic leukemia: clinical results. Blood. 1978 Mar;51(3):425-33. link to original article contains verified protocol PubMed
Upfront induction therapy
Cyclophosphamide, Cytarabine, Mercaptopurine
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Regimen
Study | Evidence |
---|---|
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) | Non-randomized portion of RCT |
Preceding treatment
- "Phase 1" induction: Daunorubicin, L-asparaginase, Vincristine, Prednisone
Chemotherapy
- Cyclophosphamide (Cytoxan) 650 mg/m2 IV once per day on days 1, 15, 29
- Cytarabine (Cytosar) 75 mg/m2 IV once per day on days 1 to 4, 8 to 11, 15 to 18, 22 to 25
- Mercaptopurine (Purinethol) 6 mg/m2 PO once per day on days 1 to 28
CNS prophylaxis
- Methotrexate (MTX) 12 mg IT once per day on days 1, 8, 15, 22
One course
Subsequent treatment
- L-asparaginase & Methotrexate early intensification
References
- 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. link to original article contains verified protocol PubMed
- 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. link to original article 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. link to original article link to PMC article 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. link to original article contains verified protocol link to PMC article PubMed
Cyclophosphamide, Daunorubicin, Vincristine, Prednisone
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Thomas et al. 2004 (LALA-94) | Phase III | Cyclophosphamide, Idarubicin, Vincristine, Prednisone | Seems to have inferior DFS |
Chemotherapy
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once per day on days 1 & 8
- Daunorubicin (Cerubidine) 30 mg/m2 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
- Prednisone (Sterapred) 60 mg/m2/day IV or PO on days 1 to 7, 15 to 21
One course, followed by consolidation (see paper for details)
References
- 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. link to original article contains verified protocol PubMed
Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone
back to top |
Regimen #1
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Huguet et al. 2009 (GRAALL-2003) | Phase II | ||
Maury et al. 2016 (GRAALL-R 2005) | Phase III | Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab | Seems to have inferior 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" arm of GRAALL 2005.
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) as follows:
- 750 mg/m2 IV over 3 hours once per day on days 1 & 15 in "good early responders" (GRAALL-2003) and all patients (GRAALL 2005)
- GRAALL-2003: 750 mg/m2 IV once on day 1, then 500 mg/m2 IV q12h on days 15 & 16 in "poor early responders"
- Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1 to 3, then 30 mg/m2 IV once per day on days 15 & 16
- Asparaginase (Elspar) 6000 units/m2/day 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
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 14
CNS prophylaxis
- Methotrexate (MTX) 15 mg IT once per day on days 1 & 8
- Cytarabine (Cytosar) 40 mg IT once per day on days 1 & 8
- Methylprednisolone (Solumedrol) 40 mg IT once per day on days 1 & 8
Supportive medications
- Lenograstim (Granocyte) as follows:
- GRAALL-2003: 150 mcg/m2 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
Patients with resistant disease received cytarabine & idarubicin salvage prior to further consolidation. All others proceeded to pediatric-like GRAALL consolidation.
Regimen #2, "HyperC"
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Maury et al. 2016 (GRAALL-R 2005) | Phase III | Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab | Seems to have inferior EFS |
This is the "HyperC" arm of GRAALL 2005.
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) as follows:
- 750 mg/m2 IV over 3 hours once on day 1
- 300 mg/m2 IV over 3 hours q12h on days 15 to 17 (6 doses)
- Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1 to 3, then 30 mg/m2 IV once per day on days 15 & 16
- Asparaginase (Elspar) 6000 units/m2/day 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
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 14
CNS prophylaxis
- Methotrexate (MTX) 15 mg IT once per day on days 1 & 8
- Cytarabine (Cytosar) 40 mg IT once per day on days 1 & 8
- Methylprednisolone (Solumedrol) 40 mg IT once per day on days 1 & 8
Supportive medications
- Lenograstim (Granocyte) 263 mcg SC once per day from day 18 until first day with ANC greater than 1000/uL
Patients with resistant disease received cytarabine & idarubicin salvage prior to further consolidation. All others proceeded to pediatric-like GRAALL consolidation.
Regimen #3
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Annino et al. 2002 (GIMEMA ALL 0288) | Phase III | Daunorubicin, L-Asparaginase, Vincristine, Prednisone | Seems not superior |
Note: vincristine is clearly shown as 2 mg/m2 in Table 1, but this is an unusual dose; consider discussing with the authors if you are going to utilize this regimen.
Chemotherapy ("Induction phase I")
- Cyclophosphamide (Cytoxan) 800 mg/m2 IV once per day on days 1 & 2
- Daunorubicin (Cerubidine) 40 mg/m2 IV once per day on days 1, 8, 15, 22
- L-Asparaginase 6000 units/m2 SC once per day on days 22 to 31
- Vincristine (Oncovin) 2 mg/m2 IV once per day on days 1, 8, 15, 22
- Prednisone (Sterapred) 60 mg/m2/day on days 1 to 14, then 40 mg/m2/day on days 15 to 31
One course
Treatment followed by induction phase II or salvage, see paper for details.
Regimen #4, "Larson regimen"
Study | Evidence |
---|---|
Larson et al. 1995 (CALGB 8811) | Phase II |
Chemotherapy ("Course I")
- Cyclophosphamide (Cytoxan) as follows:
- For patients younger than 60 years old: 1200 mg/m2 IV once on day 1
- For patients at least 60 years old: 800 mg/m2 IV once on day 1
- Daunorubicin (Cerubidine) as follows:
- For patients younger than 60 years old: 45 mg/m2 IV once per day on days 1 to 3
- For patients at least 60 years old: 30 mg/m2 IV once per day on days 1 to 3
- Asparaginase (Elspar) 6000 units/m2 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
- Prednisone (Sterapred) as follows:
- For patients younger than 60 years old: 60 mg/m2 PO once per day on days 1 to 21
- For patients at least 60 years old: 60 mg/m2 PO once per day on days 1 to 7
One course
Subsequent treatment
References
- Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. 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. link to original article contains verified protocol PubMed
- 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 Group. 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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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; for GRAALL. Rituximab in B-Lineage Adult Acute Lymphoblastic Leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed
Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab
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Regimen #1
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Maury et al. 2016 (GRAALL-R 2005) | Phase III | Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone | 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-R 2005.
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 3 hours once per day on days 1 & 15
- Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1 to 3, then 30 mg/m2 IV once per day on days 15 & 16
- Asparaginase (Elspar) 6000 units/m2/day 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
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 14
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1 & 7
CNS prophylaxis
- Methotrexate (MTX) 15 mg IT once per day on days 1 & 8
- Cytarabine (Cytosar) 40 mg IT once per day on days 1 & 8
- Methylprednisolone (Solumedrol) 40 mg IT once per day on days 1 & 8
Supportive medications
- Lenograstim (Granocyte) as follows:
- GRAALL-2003: 150 mcg/m2 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
Patients with resistant disease received cytarabine, idarubicin, rituximab salvage prior to further consolidation. All others proceeded to pediatric-like GRAALL consolidation with rituximab.
Regimen #2, "HyperC"
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Maury et al. 2016 (GRAALL-R 2005) | Phase III | Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone | Seems to have superior EFS |
Note: this regimen was meant for CD20+ patients less than 60 years old. This is the "HyperC" arm of GRAALL-R 2005.
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) as follows:
- 750 mg/m2 IV over 3 hours once on day 1
- 300 mg/m2 IV over 3 hours q12h on days 15 to 17 (6 doses)
- Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1 to 3, then 30 mg/m2 IV once per day on days 15 & 16
- Asparaginase (Elspar) 6000 units/m2/day 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
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 14
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1 & 7
CNS prophylaxis
- Methotrexate (MTX) 15 mg IT once per day on days 1 & 8
- Cytarabine (Cytosar) 40 mg IT once per day on days 1 & 8
- Methylprednisolone (Solumedrol) 40 mg IT once per day on days 1 & 8
Supportive medications
- Lenograstim (Granocyte) 263 mcg SC once per day from day 18 until first day with ANC greater than 1000/uL
Patients with resistant disease received cytarabine, idarubicin, rituximab salvage prior to further consolidation. All others proceeded to pediatric-like GRAALL consolidation with rituximab.
References
- 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; for GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed
Cyclophosphamide, Doxorubicin, L-Asparaginase, Vincristine, Prednisolone
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Regimen
Study | Evidence |
---|---|
Takeuchi et al. 2002 (JALSG-ALL93) | Non-randomized |
Unlikely to be completed, here for historic context only.
Chemotherapy
- Cyclophosphamide (Cytoxan)
- Doxorubicin (Adriamycin)
- L-Asparaginase
- Vincristine (Oncovin)
- Prednisolone (Millipred)
References
- Takeuchi J, Kyo T, Naito K, Sao H, Takahashi M, Miyawaki S, Kuriyama K, Ohtake S, Yagasaki F, Murakami H, Asou N, Ino T, Okamoto T, Usui N, Nishimura M, Shinagawa K, Fukushima T, Taguchi H, Morii T, Mizuta S, Akiyama H, Nakamura Y, Ohshima T, Ohno R. Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: the JALSG-ALL93 study. Leukemia. 2002 Jul;16(7):1259-66. link to original article PubMed
Cyclophosphamide, Idarubicin, Vincristine, Prednisone
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Thomas et al. 2004 (LALA-94) | Phase III | Cyclophosphamide, Daunorubicin, Vincristine, Prednisone | Seems to have superior DFS |
Chemotherapy
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once per day on days 1 & 8
- Idarubicin (Idamycin) 9 mg/m2 IV once per day on days 1, 2, 3, 8
- Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22
- Prednisone (Sterapred) 60 mg/m2/day IV or PO on days 1 to 7, 15 to 21
One course, followed by consolidation (see paper for details)
References
- 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. link to original article contains verified protocol PubMed
Daunorubicin, L-Asparaginase, Vincristine, Prednisone
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Regimen #1
Study | Evidence |
---|---|
Hoelzer et al. 1984 | Non-randomized |
Of historic interest. This is "Phase 1" of induction.
Chemotherapy
- Daunorubicin (Cerubidine) 25 mg/m2 IV once per day on days 1, 8, 15, 22
- Asparaginase (Elspar) 5000 units IV once per day on days 1 to 14
- Vincristine (Oncovin) 1.5 mg/m2 IV once per day on days 1, 8, 15, 22
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 28
4-week course
See paper for details of treatment beyond induction.
Regimen #2
Study | Evidence |
---|---|
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) | Non-randomized portion of RCT |
To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 91%. There are many local variants of this protocol, which begins with "Phase I":
Chemotherapy
- Daunorubicin (Cerubidine) 60 mg/m2 IV once per day on days 1, 8, 15, 22
- Asparaginase (Elspar) 10,000 units IV or IM once per day on days 17 to 28
- Vincristine (Oncovin) 1.4 mg/m2 IV once per day on days 1, 8, 15, 22
- Prednisone (Sterapred) 60 mg/m2 PO in divided doses on days 1 to 28
CNS prophylaxis
- Methotrexate (MTX) 12.5 mg IT once on day 15
4-week course
Subsequent treatment
- Cyclophosphamide, Cytarabine, Mercaptopurine induction ("Phase 2")
Regimen #3
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Annino et al. 2002 (GIMEMA ALL 0288) | Phase III | Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone | Seems not superior |
Note: vincristine is clearly shown as 2 mg/m2 in Table 1, but this is an unusual dose; consider discussing with the authors if you are going to utilize this regimen.
Chemotherapy ("Induction phase I")
- Daunorubicin (Cerubidine) 40 mg/m2 IV once per day on days 1, 8, 15, 22
- L-Asparaginase 6000 units/m2 SC once per day on days 22 to 31
- Vincristine (Oncovin) 2 mg/m2 IV once per day on days 1, 8, 15, 22
- Prednisone (Sterapred) 60 mg/m2/day on days 1 to 14, then 40 mg/m2/day on days 15 to 31
One course
Treatment followed by induction phase II or salvage, see paper for details.
Regimen #4, "Linker regimen"
Study | Evidence |
---|---|
Linker et al. 1987 | Phase II |
Chemotherapy, part 1
- Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1 to 3
- Asparaginase (Elspar) 6000 units/m2 IM once per day on days 17 to 28
- Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 28
If bone marrow on day 14 has residual leukemia:
Chemotherapy, part 2
- Daunorubicin (Cerubidine) 50 mg/m2 IV once on day 15
If bone marrow on day 28 has residual leukemia:
Chemotherapy, part 3
- Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 29 & 30
- Asparaginase (Elspar) 6000 units/m2 IM once per day on days 29 to 35
- Vincristine (Oncovin) 2 mg IV once per day on days 29 & 36
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 29 to 42
CNS 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 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
Subsequent treatment
Regimen #5
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Gottlieb et al. 1984 | Randomized | L-asparaginase, Vincristine, Prednisone | Superior CR rate |
Chemotherapy
- Daunorubicin (Cerubidine) 45 mg/m2 IV once per day on days 1 to 3
- Asparaginase (Elspar) 500 units/kg IV once per day on days 22 to 31
- Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15
- Prednisone (Sterapred) 40 mg/m2/day PO on days 1 to 22, then tapered to off by day 29
One course
See paper for details of treatment beyond induction.
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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol 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. link to original article contains verified protocol 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. link to original article contains verified protocol PubMed
- Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W, Niemeyer C, Henze G, Feldges A, Zintl F, Kornhuber B, Ritter J, Welte K, Gadner H, Riehm H. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood. 2000 Jun 1;95(11):3310-22. link to original article 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 Group. 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. link to original article contains verified protocol PubMed
- DCLSG ALL-8: Kamps WA, Bökkerink JP, Hakvoort-Cammel FG, Veerman AJ, Weening RS, van Wering ER, van Weerden JF, Hermans J, Slater R, van den Berg E, Kroes WG, van der Does-van den Berg A. BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991-1996). Leukemia. 2002 Jun;16(6):1099-111. link to original article 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. link to original article contains verified protocol PubMed
- 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. link to original article 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. link to original article link to PMC article 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. link to original article contains verified protocol link to PMC article PubMed
- SWOG 9400: 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. link to original article link to PMC article PubMed
- Seibel NL, Steinherz PG, Sather HN, Nachman JB, Delaat C, Ettinger LJ, Freyer DR, Mattano LA Jr, Hastings CA, Rubin CM, Bertolone K, Franklin JL, Heerema NA, Mitchell TL, Pyesmany AF, La MK, Edens C, Gaynon PS. Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2008 Mar 1;111(5):2548-55. link to original article link to PMC article PubMed
- ALL-BFM 95: Möricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dördelmann M, Löning L, Beier R, Ludwig WD, Ratei R, Harbott J, Boos J, Mann G, Niggli F, Feldges A, Henze G, Welte K, Beck JD, Klingebiel T, Niemeyer C, Zintl F, Bode U, Urban C, Wehinger H, Niethammer D, Riehm H, Schrappe M; German-Austrian-Swiss ALL-BFM Study Group. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood. 2008 May 1;111(9):4477-89. doi: 10.1182/blood-2007-09-112920. Epub 2008 Feb 19. Erratum in: Blood. 2009 Apr 30;113(18):4478. Dosage error in article text. link to original article PubMed
Daunorubicin, Pegaspargase, Vincristine, Dexamethasone
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Regimen
Study | Evidence |
---|---|
See note (AALL1131) | Non-randomized portion of RCT |
Note: this regimen is available as a protocol but no manuscript has been published yet, to our knowledge. Per the protocol, it is intended only for patients less than 10 years old.
Chemotherapy
- Daunorubicin (Cerubidine) 25 mg/m2 IV push over 1 to 15 minutes once per day on days 1, 8, 15, 22
- Pegaspargase (Oncaspar) 2500 units/m2 IV over 1 to 2 hours once on day 4
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
- Dexamethasone (Decadron) 5 mg/m2 PO/IV BID on days 1 to 14
CNS prophylaxis
- Cytarabine (Cytosar) as follows:
- 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) as follows:
- 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
See protocol for details of treatment beyond induction.
References
- TBD, see note
Daunorubicin, Pegaspargase, Vincristine, Prednisone
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Regimen, "ABFM"
Study | Evidence |
---|---|
Rytting et al. 2014 | Non-randomized |
ABFM: Augmented Berlin-Frankfurt-Münster regimen
Note: this regimen is available as a protocol (AALL1131) and is briefly described in Rytting et al. 2014. However, Rytting et al. 2014 states that the protocol has been previously published in Seibel et al. 2008, which uses asparaginase, not pegaspargase. Details below are from the AALL1131 protocol.
Chemotherapy
- Daunorubicin (Cerubidine) 25 mg/m2 IV push over 1 to 15 minutes once per day on days 1, 8, 15, 22
- Pegaspargase (Oncaspar) 2500 units/m2 IV over 1 to 2 hours once on day 4
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
- Prednisone (Sterapred) 30 mg/m2 PO/IV BID on days 1 to 28
CNS prophylaxis
- Cytarabine (Cytosar) as follows:
- 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) as follows:
- 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
See protocol for details of treatment beyond induction.
References
- 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. link to original article link to PMC article PubMed
- 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. link to original article contains verified protocol link to PMC article 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. link to original article PubMed
Hyper-CVAD/MA
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Hyper-CVAD/MA: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone alternating with Methotrexate, Ara-C (Cytarabine)
Regimen
Study | Evidence |
---|---|
Thomas et al. 1999 | Phase II |
Chemotherapy, Part A (cycles 1, 3, 5, 7):
- Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours Q12H on days 1 to 3 (6 total doses)
- Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
- Doxorubicin (Adriamycin) 50 mg/m2 IV over 24 hours (over 48 hours in patients with ejection fractions (EF) less than 50%) on day 4
- Dexamethasone (Decadron) 40 mg PO/IV once per day on days 1 to 4, 11 to 14
Supportive medications
- Mesna (Mesnex) 600 mg/m2/day IV continuous infusion on days 1 to 3, 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 BID
- Levofloxacin (Levaquin) 500 mg PO once per day
- Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID
- Fluconazole (Diflucan) 200 mg PO once per day
- ONE of the following antivirals:
- Acyclovir (Zovirax) 200 mg PO BID
- 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 109/L
Chemotherapy, Part B (cycles 2, 4, 6, 8):
- Methotrexate (MTX) 200 mg/m2 IV over 2 hours, then 800 mg/m2 IV over 22 hours on day 1
- Cytarabine (Cytosar) as follows:
- For patients younger than 60 years old: 3000 mg/m2 IV over 2 hours Q12H on days 2 & 3 (4 total doses)
- For patients at least 60 years old: 1000 mg/m2 IV over 2 hours Q12H on days 2 & 3 (4 total doses)
- Methylprednisolone (Solumedrol) 50 mg IV Q12H on days 1 to 3 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.
Supportive medications
- Folinic acid (Leucovorin) 50 mg IV once 12 hours after Methotrexate (MTX) is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level less than 100 nmol/L
- ONE of the following antibiotics:
- Ciprofloxacin (Cipro) 500 mg PO BID
- Levofloxacin (Levaquin) 500 mg PO once per day
- Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID
- Fluconazole (Diflucan) 200 mg PO once per day
- ONE of the following antivirals:
- Acyclovir (Zovirax) 200 mg PO BID
- 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 109/L
CNS prophylaxis
- Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
- Cytarabine (Cytosar) 100 mg IT on 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%
For known CNS disease
- Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT alternating with Cytarabine (Cytosar) 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 (Cytosar) 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 (Cytosar) 100 mg IT once on day 7 OR 8
Certain patient populations (see e.g. Kantarjian et al. 2004) proceed to receive POMP maintenance therapy.
References
- 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. link to original article 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. 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. link to original article contains verified protocol 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. link to original article contains verified protocol 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. link to original article contains verified protocol 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. link to original article contains verified protocol PubMed
L-Asparaginase, Vincristine, Dexamethasone
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Bostrom et al. 2003 (CCG-1922) | Phase III | L-asparaginase, Vincristine, Prednisone | Superior EFS |
Mitchell et al. 2005 (UK MRC ALL97) | Phase III | L-asparaginase, Vincristine, Prednisolone | Superior EFS |
Unlikely to be completed, here for historic context only.
Chemotherapy
References
- Bostrom BC, Sensel MR, Sather HN, Gaynon PS, La MK, Johnston K, Erdmann GR, Gold S, Heerema NA, Hutchinson RJ, Provisor AJ, Trigg ME; Children's Cancer Group. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood. 2003 May 15;101(10):3809-17. Epub 2003 Jan 16. link to original article PubMed
- Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A, Eden TO; Medical Research Council Childhood Leukaemia Working Party. Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol. 2005 Jun;129(6):734-45. link to original article PubMed
L-Asparaginase, Vincristine, Prednisolone
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Mitchell et al. 2005 (UK MRC ALL97) | Phase III | L-asparaginase, Vincristine, Dexamethasone | Inferior EFS |
Unlikely to be completed, here for historic context only.
Chemotherapy
References
- Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A, Eden TO; Medical Research Council Childhood Leukaemia Working Party. Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol. 2005 Jun;129(6):734-45. link to original article PubMed
L-Asparaginase, Vincristine, Prednisone
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Gottlieb et al. 1984 (CALGB) | Randomized | Daunorubicin, L-Asparaginase, Vincristine, Prednisone | Inferior CR rate |
van der Does-van den Berg et al. 1989 (DCLSG ALL V) | Phase III | Daunorubicin, L-Asparaginase, Vincristine, Prednisone | Seems not superior |
Bostrom et al. 2003 (CCG-1922) | Phase III | L-asparaginase, Vincristine, Dexamethasone | Inferior EFS |
Unlikely to be completed, here for historic context only.
Chemotherapy
References
- Gottlieb AJ, Weinberg V, Ellison RR, Henderson ES, Terebelo H, Rafla S, Cuttner J, Silver RT, Carey RW, Levy RN, et al. 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. link to original article PubMed
- van der Does-van den Berg A, van Wering ER, Suciu S, Solbu G, van 't Veer MB, Rammeloo JA, de Koning J, van Zanen GE. Effectiveness of rubidomycin in induction therapy with vincristine, prednisone, and L-asparaginase for standard risk childhood acute lymphocytic leukemia: results of a Dutch phase III study (ALL V). A report on behalf of the Dutch Childhood Leukemia Study Group (DCLSG). Am J Pediatr Hematol Oncol. 1989 Summer;11(2):125-33. PubMed
- Bostrom BC, Sensel MR, Sather HN, Gaynon PS, La MK, Johnston K, Erdmann GR, Gold S, Heerema NA, Hutchinson RJ, Provisor AJ, Trigg ME; Children's Cancer Group. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood. 2003 May 15;101(10):3809-17. Epub 2003 Jan 16. link to original article PubMed
Mini-Hyper-CVD/MA & Inotuzumab ozogamicin
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Mini-Hyper-CVD/MA: Mini (lower intensity) Hyperfractionated Cyclophosphamide, Vincristine, Dexamethasone alternating with Methotrexate and Ara-C (Cytarabine)
Regimen
Study | Evidence |
---|---|
O'Brien et al. 2013 | Non-randomized, <20 pts |
Unlikely to be completed unless published in manuscript form.
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 link to original abstract
R-Hyper-CVAD/R-MA
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R-Hyper-CVAD/R-MA: Rituximab, Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone alternating with Rituximab, Methotrexate, Ara-C (Cytarabine)
Regimen
Study | Evidence |
---|---|
Thomas et al. 2006 | Pilot, <20 patients reported |
Thomas et al. 2010 | Non-randomized |
See papers for details of treatment beyond induction/consolidation, which differ substantially between "standard" and "modified" protocols.
Chemotherapy, Part A (cycles 1, 3, 5, 7)
- Rituximab (Rituxan) as follows:
- Cycles 1 & 3: 375 mg/m2 IV over 2 to 6 hours once per day on days 1 & 11
- Cycles 5 & 7: no rituximab
- Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours Q12H on days 1 to 3 (6 total doses)
- Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
- Doxorubicin (Adriamycin) 50 mg/m2 IV continuous infusion over 24 hours on day 4
- Dexamethasone (Decadron) 40 mg PO/IV once per day on days 1 to 4, 11 to 14
Supportive medications
- Mesna (Mesnex) 600 mg/m2/day IV continuous infusion on days 1 to 3, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
- Filgrastim (Neupogen) 10 mcg/kg SC once per day starting 24 hours after completion of chemotherapy, given until WBC greater than 3 x 109/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 109/L and platelet count greater than 50 x 109/L
Chemotherapy, Part B (cycles 2, 4, 6, 8)
- Rituximab (Rituxan) as follows:
- Cycles 2 & 4: 375 mg/m2 IV over 2 to 6 hours once per day on days 2 & 8
- Cycles 6 & 8: no rituximab
- Methotrexate (MTX) 1000 mg/m2 IV over 24 hours on day 1
- Cytarabine (Cytosar) 3000 mg/m2 IV over 2 hours Q12H on days 2 & 3 (4 total doses)
Supportive medications
- Folinic acid (Leucovorin) 50 mg IV once 12 hours after Methotrexate (MTX) is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level less than 100 nmol/L
- Filgrastim (Neupogen) 10 mcg/kg SC once per day starting 24 hours after completion of chemotherapy, given until WBC greater than 3 x 109/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 109/L and platelet count greater than 50 x 109/L
CNS prophylaxis
- Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
- Cytarabine (Cytosar) 100 mg IT 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 (Cytosar) reduced to 1000 mg/m2 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/1.73m2 (eliminated for CrCl less than 10 mL/min/1.73m2), 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.
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. link to original article contains verified protocol PubMed
- Update: Fayad L, Thomas D, Romaguera J. Update of the M. D. 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. PubMed
- 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. link to original article link to PMC article PubMed
Early intensification therapy
CALGB 8811
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Regimen
Study | Evidence |
---|---|
Larson et al. 1995 (CALGB 8811) | Phase II |
Preceding treatment
Chemotherapy ("Course II")
- Methotrexate (MTX) 15 mg IT once on day 1
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
- Mercaptopurine (Purinethol) 60 mg/m2 PO once per day on days 1 to 14
- Cytarabine (Cytosar) 75 mg/m2 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/m2 SC once per day on days 15, 18, 22, 25
28-day cycle for 2 cycles
Subsequent treatment
- Mercaptopurine, Methotrexate, WB-XRT interim maintenance ("Course III")
References
- Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. 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. link to original article contains verified protocol PubMed
L-Asparaginase & Methotrexate
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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).
Regimen
Study | Evidence |
---|---|
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) | Non-randomized portion of RCT |
Preceding treatment
Chemotherapy
- Methotrexate (MTX) 3 g/m2 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 medications
- Folinic acid (Leucovorin) at "standard" doses
3 cycles (length of cycle not specified in original reference)
Patients who were younger than 50 years of age and had an HLA-matched sibling donor, as well as Ph+ patients with any donor, proceeded to etoposide & TBI, then allo HSCT. All others were randomized to etoposide & TBI, then auto HSCT versus International ALL Trial consolidation.
References
- 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. link to original article contains verified protocol PubMed
- 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. link to original article 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. link to original article link to PMC article 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. link to original article contains verified protocol link to PMC article 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.
Allogeneic hematopoietic stem cell transplant
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To be completed
References
- LALA 87: 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. PubMed
- 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. link to original article PubMed
International ALL Trial
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) | Phase III | Etoposide & TBI, then auto HSCT | Seems to have superior OS |
Preceding treatment
Chemotherapy, Cycle 1
- Cytarabine (Cytosar) 75 mg/m2 IV once per day on days 1 to 5
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
- Vincristine (Oncovin) 1.4 mg/m2 IV once per day on days 1, 8, 15, 22
- Dexamethasone (Decadron) 10 mg/m2 PO once per day on days 1 to 28
Chemotherapy, Cycle 2
To start 4 weeks after Cycle 1
- Cytarabine (Cytosar) 75 mg/m2 IV once per day on days 1 to 5
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
Chemotherapy, Cycle 3
To start 4 weeks after Cycle 2
- Daunorubicin (Cerubidine) 25 mg/m2 IV once per day on days 1, 8, 15, 22
- Cyclophosphamide (Cytoxan) 650 mg/m2 IV once on day 29
- Cytarabine (Cytosar) 75 mg/m2 IV once per day on days 31 to 34, 38 to 41
- Thioguanine (Tabloid) 60 mg/m2 PO once per day on days 29 to 42
Chemotherapy, Cycle 4
To start 8 weeks after Cycle 3
- Cytarabine (Cytosar) 75 mg/m2 IV once per day on days 1 to 5
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
CNS Prophylaxis
- Cytarabine (Cytosar) 50 mg IT once per week for 4 weeks, then once per quarter for 4 doses (8 doses, total)
- Cranial irradiation to 2400 cGy
Subsequent treatment
- POMP maintenance
References
- 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. link to original article contains verified protocol PubMed
- 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. link to original article 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. link to original article link to PMC article 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. link to original article contains verified protocol link to PMC article PubMed
Mercaptopurine, Methotrexate, Vincristine
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Sakura et al. 2017 (JALSG ALL202-O) | Phase III | MTX (intermediate dose), 6-MP, VCR | 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.
Chemotherapy
- Mercaptopurine (Purinethol) 25 mg/m2 PO once per day on days 1 to 21
- Methotrexate (MTX) 3000 mg/m2 IV once per day on days 1 & 15
- Vincristine (Oncovin) 1.3 mg/m2 (maximum dose of 2 mg) IV once per day on days 1 & 15
Intrathecal component
- 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 medications
- Folinic acid (Leucovorin) 50 mg IV once, then 15 mg IV once q6h for a total of 8 doses, beginning 36 h after the start of Methotrexate (MTX) infusion
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.link to original article contains verified protocol PubMed
Mercaptopurine, Methotrexate, WB-XRT
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Regimen
Study | Evidence |
---|---|
Larson et al. 1995 (CALGB 8811) | Phase II |
Preceding treatment
Chemoradiotherapy ("Course III")
- Methotrexate (MTX) 15 mg IT once per day on days 1, 8, 15, 22, 29
- Mercaptopurine (Purinethol) 60 mg/m2 PO once per day on days 1 to 70
- Methotrexate (MTX) 20 mg/m2 PO once per day on days 36, 43, 50, 57, 64
- Cranial radiation, 24 Gy total given in 10 fractions from days 1 to 12
12-week course
Subsequent treatment
References
- CALGB 8811: Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. 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. link to original article contains verified protocol PubMed
Linker regimen (consolidation)
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Regimen
Study | Evidence |
---|---|
Linker et al. 1987 | Phase II |
Each cycle is approximately one month, based on recovery of ANC to greater than 1000/uL and platelet count to greater than 100 x 109/L.
Preceding treatment
Chemotherapy, Treatment A (cycles 1, 3, 5, 7)
- Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1 & 2
- Vincristine (Oncovin) 2 mg IV once per day on days 1 & 8
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 14
- Asparaginase (Elspar) 12000 units/m2 IM once per day on days 2, 4, 7, 9, 11, 14
Approximately one-month cycle
Chemotherapy, Treatment B (cycles 2, 4, 6, 8)
- Teniposide (Vumon) 165 mg/m2 IV once per day on days 1, 4, 8, 11
- Cytarabine (Cytosar) 300 mg/m2 IV once per day on days 1, 4, 8, 11
Approximately one-month cycle
Chemotherapy, Treatment C (cycle 9)
- Methotrexate (MTX) 690 mg/m2 IV over 42 hours on day 1
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 14
- Asparaginase (Elspar) 12000 units/m2 IM once per day on days 2, 4, 7, 9, 11, 14
Approximately one-month cycle
Supportive medications
- Folinic acid (Leucovorin) 15 mg/m2 IV every 6 hours x 12 doses, starting after Methotrexate (MTX) is complete (at 42 hours)
Subsequent treatment
- Mercaptopurine & Methotrexate maintenance
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. link to original article contains verified protocol PubMed content property of 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. link to original article contains verified protocol PubMed
Pediatric-like GRAALL consolidation
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Regimen
Study | Evidence |
---|---|
Huguet et al. 2009 (GRAALL-2003) | Phase II |
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. ====Preceding treatment====
- Cyclophosphamide, Daunorubicin, L-asparaginase, Vincristine, Prednisone induction or Cytarabine & Idarubicin salvage
Chemotherapy, Consolidation A (Cycles 1, 4, 7)
- Cytarabine (Cytosar) 2000 mg/m2 IV q12h on days 1 & 2
- Dexamethasone (Decadron) 10 mg (route not specified) q12h on days 1 & 2
- Asparaginase (Elspar) 10,000 units/m2 (route not specified) once on day 3
Supportive medications
- Lenograstim (Granocyte) 150 mcg/m2 SC once per day on days 7 to 13
Chemotherapy, Consolidation B (Cycles 2, 5, 8)
- Methotrexate (MTX) 3000 mg/m2 IV continuous infusion on day 15
- Vincristine (Oncovin) 2 mg IV once on day 15
- Asparaginase (Elspar) 10,000 units/m2 (route not specified) once on day 16
- Mercaptopurine (Purinethol) 60 mg/m2 PO once per day on days 15 to 21
Supportive medications
- Lenograstim (Granocyte) 150 mcg/m2 SC once per day on days 22 to 27
Chemotherapy, Consolidation C (Cycles 3, 6, 9)
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 29 & 30
- Etoposide (Vepesid) 75 mg/m2 IV once per day on days 29 & 30
- Methotrexate (MTX) 25 mg/m2 (route not specified) once on day 29
Supportive medications
- Lenograstim (Granocyte) 150 mcg/m2 SC once per day from day 31 until myeloid recovery
Patients with CR after cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction received cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone late intensification between cycles 6 and 7. Patients with CR after cytarabine & idarubicin salvage received cytarabine & idarubicin late intensification between cycles 6 and 7. All patients proceeded to POMP maintenance after completion of consolidation.
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. link to original article contains verified protocol PubMed
Late intensification
Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone
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Regimen
Study | Evidence |
---|---|
Huguet et al. 2009 (GRAALL-2003) | Phase II |
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.
Preceding treatment
- Pediatric-like GRAALL consolidation cycle 6, if patients achieved CR1 after cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction
Chemotherapy
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV q12h on days 15
- Daunorubicin (Cerubidine) 30 mg/m2 IV once per day on days 1 to 3
- Asparaginase (Elspar) 6000 units/m2/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
- Prednisone (Sterapred) 60 mg/m2/day on days 1 to 14
Supportive medications
- Lenograstim (Granocyte) 150 mcg/m2 SC once per day if ANC less than 500/uL until myeloid recovery
Patients then proceeded back to pediatric-like GRAALL consolidation.
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. link to original article contains verified protocol PubMed
Cytarabine & Idarubicin
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Regimen
Study | Evidence |
---|---|
Huguet et al. 2009 (GRAALL-2003) | Phase II |
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.
Preceding treatment
- Pediatric-like GRAALL consolidation cycle 6, if patients achieved CR1 after cytarabine & idarubicin salvage
Chemotherapy
- Cytarabine (Cytosar) 2000 mg/m2 IV q12h on days 1 to 4
- Idarubicin (Idamycin) 9 mg/m2 IV once per day on days 1 to 3
Supportive medications
- Lenograstim (Granocyte) 150 mcg/m2 SC once per day from day 9 until myeloid recovery
Patients then proceeded back to pediatric-like GRAALL consolidation.
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. link to original article contains verified protocol PubMed
CALGB 8811
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Regimen
Study | Evidence |
---|---|
Larson et al. 1995 (CALGB 8811) | Phase II |
Preceding treatment
Chemotherapy ("Course IV")
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 1, 8, 15
- Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15
- Dexamethasone (Decadron) 10 mg/m2 PO once per day on days 1 to 14
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 29
- Thioguanine (Tabloid) 60 mg/m2 PO once per day on days 29 to 42
- Cytarabine (Cytosar) 75 mg/m2 SC once per day on days 29 to 32, 36 to 39
8-week course
Subsequent treatment
- POMP maintenance ("Course V")
References
- Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. 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. link to original article contains verified protocol PubMed
Maintenance after upfront therapy
Mercaptopurine & Methotrexate
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Regimen
Study | Evidence |
---|---|
Linker et al. 1987 | Phase II |
Preceding treatment
Chemotherapy
- Mercaptopurine (Purinethol) 75 mg/m2 PO once per day
- Methotrexate (MTX) 20 mg/m2 PO once per week
30-month course
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. link to original article contains verified protocol 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. link to original article contains verified protocol PubMed
POMP
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POMP: Prednisone, Oncovin (Vincristine), Methotrexate, Purinethol (Mercaptopurine)
Regimen #1
Study | Evidence |
---|---|
Huguet et al. 2009 (GRAALL-2003) | Phase II |
Preceding treatment
Chemotherapy
- Prednisone (Sterapred) 40 mg/m2/day PO on days 1 to 7 of each month x 12 months
- Vincristine (Oncovin) 2 mg IV once on day 1 of each month x 12 months
- Methotrexate (MTX) 25 mg/m2 PO once per week x 24 months
- Mercaptopurine (Purinethol) 60 mg/m2 PO once per day x 24 months
24-month course
Regimen #2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) | Phase III | Etoposide & TBI, then auto HSCT | Seems to have superior OS |
Preceding treatment
Chemotherapy
- Prednisone (Sterapred) 60 mg/m2 PO once per day for 5 days every 3 months
- Vincristine (Oncovin) 1.4 mg/m2 IV once every 3 months
- Methotrexate (MTX) 20 mg/m2 PO or IV once per week
- Mercaptopurine (Purinethol) 75 mg/m2 PO once per day
Continue for a total of 2.5 years from the start of phase III
Regimen #3
Study | Evidence |
---|---|
Kantarjian et al. 2004 | Phase II |
Note: Kantarjian et al. 2004 said how many days each drug is given per month, but did not specifically say, for example, that certain drugs are taken on days 1 to 5 of the cycle.
Preceding treatment
- Hyper-CVAD/MA x 8
Chemotherapy
- Prednisone (Sterapred) 200 mg PO once per day for 5 days, given with Vincristine (Oncovin)
- Vincristine (Oncovin) 2 mg IV once per month
- Methotrexate (MTX) 10 mg/m2 IV over 60 minutes once per day for 5 days
- Mercaptopurine (Purinethol) 1000 mg/m2 IV over 60 minutes once per day for 5 days
Supportive medications
- Trimethoprim/Sulfamethoxazole (dosage not listed) PO BID on Saturday and Sunday for the first 6 months
- ONE of the following antivirals:
- Acyclovir (Zovirax) 200 mg PO once per day or 3 times per week for the first 6 months
- Valacyclovir (Valtrex) 500 mg PO once per day or 3 times per week for the first 6 months
1-month cycles for 2 years
Regimen #4
Study | Evidence |
---|---|
Larson et al. 1995 (CALGB 8811) | Phase II |
Preceding treatment
Chemotherapy ("Course V")
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 5
- Vincristine (Oncovin) 2 mg IV once on day 1
- Methotrexate (MTX) 20 mg/m2 PO once per day on days 1, 8, 15, 22
- Mercaptopurine (Purinethol) 60 mg/m2 PO once per day on days 1 to 28
28-day cycles, continue until 24 months from diagnosis
References
- Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. 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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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. link to original article 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. link to original article link to PMC article 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. link to original article contains verified protocol link to PMC article 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. link to original article contains verified protocol PubMed
Relapsed or refractory
Augmented Hyper-CVAD & Asparaginase
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Regimen
Study | Evidence |
---|---|
Faderl et al. 2011 | Phase II |
To be completed
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. link to original article PubMed
Blinatumomab monotherapy
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Regimen #1
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Topp et al. 2014 (MT103-211) | Phase II | ||
Kantarjian et al. 2017 (TOWER) | Phase III | Standard re-induction chemotherapy | Superior OS |
This is the FDA-approved dose & schedule. The most common comparator in TOWER was FLAG +/- anthracycline.
Chemotherapy
- Blinatumomab (Blincyto) given as follows:
- Cycle 1: 9 mcg/day IV continuous infusion on days 1 to 7, then 28 mcg/day on days 8 to 28
- Cycles 2 to 5: 28 mcg/day IV continuous infusion on days 1 to 28
42-day cycle for up to 5 cycles (2 cycles for induction and 3 additional cycles for consolidation)
Patients in TOWER could proceed to blinatumomab maintenance.
Regimen #2
Study | Evidence |
---|---|
von Stackelberg et al. 2016 | Phase I/II |
Note: this is the MTD of a phase I/II trial enrolling children under the age of 18.
Chemotherapy
- Blinatumomab (Blincyto) given as follows:
- Cycle 1: 5 mcg/day IV continuous infusion on days 1 to 7, then 15 mcg/day on days 8 to 28
- Cycles 2 to 5: 28 mcg/day IV continuous infusion on days 1 to 28
42-day cycle for up to 5 cycles
Regimen #3
Study | Evidence |
---|---|
Topp et al. 2011 | Phase II |
Topp et al. 2014 (MT103-206) | Phase II |
Chemotherapy
- Blinatumomab (Blincyto) 15 mcg/m2/day IV continuous infusion for days 1 to 28
42-day cycle; 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.
References
- 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. link to original article contains verified protocol PubMed
- 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. link to original article 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. link to original article link to PMC article PubMed
- 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. link to original article PubMed
- 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. link to original article link to PMC article PubMed
- 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. link to original article PubMed
- von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, Bader P, O'Brien MM, Brethon B, Bhojwani D, Schlegel PG, Borkhardt A, Rheingold SR, Cooper TM, Zwaan CM, Barnette P, Messina C, Michel G, DuBois SG, Hu K, Zhu M, Whitlock JA, Gore L. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. J Clin Oncol. 2016 Dec 20;34(36):4381-4389. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
CCE
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CCE: Clofarabine, Cyclophosphamide, Etoposide
Regimen
Study | Evidence |
---|---|
Locatelli et al. 2009 | Non-randomized |
Patients in this study were pediatric: ≤ 15 years old at diagnosis and ≤ 21 years old at time of treatment. No patients had CNS disease at time of treatment, and no patients received CNS prophylaxis.
Chemotherapy
- Clofarabine (Clolar) 40 mg/m2 IV over 2 hours once per day on days 1 to 5, given first
- Cyclophosphamide (Cytoxan) 400 mg/m2 IV over 60 minutes once per day on days 1 to 5
- Etoposide (Vepesid) 150 mg/m2 IV over 2 hours once per day on days 1 to 5
Supportive medications
- Prophylactic steroids used for patients with greater than 30 x 109 blasts/L in the peripheral blood prior to treatment
5-day course
2 out of 25 patients received a second course of CCE as consolidation therapy. Responding patients were given allogeneic HSCT if a suitable donor was immediately available or were given consolidation courses of chemotherapy including multiple agents active against ALL cells, chosen according to the treating physician's preference."
References
- Locatelli F, Testi AM, Bernardo ME, Rizzari C, Bertaina A, Merli P, Pession A, Giraldi E, Parasole R, Barberi W, Zecca M. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol. 2009 Nov;147(3):371-8. Epub 2009 Aug 29. link to original article contains verified protocol PubMed
Clofarabine monotherapy
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Regimen #1, 40 mg/m2
Study | Evidence |
---|---|
Kantarjian et al. 2003 | Phase II, <20 patients in this arm |
Chemotherapy
- Clofarabine (Clolar) 40 mg/m2 IV over 60 minutes once per day on days 1 to 5
3- to 6-week cycles, depending on response count recovery
Regimen #2, 52 mg/m2
Study | Evidence |
---|---|
Jeha et al. 2006 | Phase II |
Chemotherapy
- Clofarabine (Clolar) 52 mg/m2 IV over 2 hours once per day on days 1 to 5
2- to 6-week cycles, depending on response count recovery
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. link to original article contains verified protocol PubMed
- Jeha S, Gaynon PS, Razzouk BI, Franklin J, Kadota R, Shen V, Luchtman-Jones L, Rytting M, Bomgaars LR, Rheingold S, Ritchey K, Albano E, Arceci RJ, Goldman S, Griffin T, Altman A, Gordon B, Steinherz L, Weitman S, Steinherz P. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. 2006 Apr 20;24(12):1917-23. link to original article contains protocol PubMed
Cytarabine monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kantarjian et al. 2016 | Phase III | Inotuzumab ozogamicin | Seems to have inferior OS |
Chemotherapy
- Cytarabine (Cytosar) as follows:
- For patients younger than 55 years old: 3000 mg/m2 IV Q12H
- For patients at least 55 years old: 1500 mg/m2 IV Q12H
One course of up to 12 doses
References
- 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. link to original article PubMed
Cytarabine & Idarubicin
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Regimen
Study | Evidence |
---|---|
Huguet et al. 2009 (GRAALL-2003) | Phase II |
Maury et al. 2016 (GRAALL-R 2005) | Non-randomized portion of 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.
Preceding treatment
Chemotherapy
- Cytarabine (Cytosar) 2000 mg/m2 IV over 3 hours q12h on days 1 to 4 (8 doses)
- Idarubicin (Idamycin) 12 mg/m2 IV over 60 minutes once per day on days 1 to 3
Supportive medications
- Lenograstim (Granocyte) as follows:
- GRAALL-2003: 150 mcg/m2 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
Patients achieving CR1 after salvage induction proceeded to pediatric-like GRAALL consolidation.
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. link to original article contains verified protocol PubMed
- GRAALL-R 2005: 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; for GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed
Cytarabine, Idarubicin, Rituximab
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Regimen
Study | Evidence |
---|---|
Maury et al. 2016 (GRAALL-R 2005) | Non-randomized portion of RCT |
This regimen is for patients not achieving CR1 with induction.
Preceding treatment
Chemotherapy
- Cytarabine (Cytosar) 2000 mg/m2 IV over 3 hours q12h on days 1 to 4 (8 doses)
- Idarubicin (Idamycin) 12 mg/m2 IV over 60 minutes once per day on days 1 to 3
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1 & 7
Supportive medications
- Lenograstim (Granocyte) 263 mcg IV or SC once per day from day 9 until first day with ANC greater than 1000/uL
One course
Patients achieving CR1 after salvage induction proceeded to pediatric-like GRAALL consolidation with rituximab.
References
- 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; for GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed
Cytarabine & Mitoxantrone
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kantarjian et al. 2016 | Phase III | Inotuzumab ozogamicin | Seems to have inferior OS |
This regimen as reported resembles 7+3m; it is not clear whether the cytarabine is given as bolus or continuous infusion from the manuscript.
Chemotherapy
- Cytarabine (Cytosar) 200 mg/m2/day IV on days 1 to 7
- Mitoxantrone (Novantrone) 12 mg/m2 IV once per day on days 1 to 3
- Dose reduction to 8 mg/m2 allowed on the basis of age, coexisting conditions, and previous anthracycline use
15-to-20-day cycle for up to 4 cycles
References
- 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. link to original article contains protocol PubMed
FLAG
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FLAG: FLudarabine, Ara-C (Cytarabine), G-CSF
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kantarjian et al. 2016 | Phase III | Inotuzumab ozogamicin | Seems to have inferior OS |
Chemotherapy
- Fludarabine (Fludara) 30 mg/m2 IV over 30 minutes once per day on days 2 to 6
- Cytarabine (Cytosar) 2000 mg/m2 IV once per day on days 1 to 6
- 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
References
- 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. link to original article PubMed
Hyper-CVAD/MA & Everolimus
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Hyper-CVAD/MA & Everolimus: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone alternating with Methotrexate, Ara-C (Cytarabine), with Everolimus
Regimen
Study | Evidence |
---|---|
Daver et al. 2015 | Phase I/II |
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.
Chemotherapy, Part A (cycles 1, 3, 5, 7):
- Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 3 hours Q12H on days 1 to 3 (6 total doses)
- Vincristine (Oncovin) as follows:
- Less than 18 years old: 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 4 & 11 (+/- 2 days)
- Adults: 2 mg IV once per day on days 4 & 11 (+/- 2 days)
- Doxorubicin (Adriamycin) 50 mg/m2 IV over 24 hours on day 4
- Dexamethasone (Decadron) as follows:
- Less than 18 years old: 20 mg/m2 (maximum dose of 40 mg) PO/IV once per day on days 1 to 4, 11 to 14 (+/- 2 days)
- Adults: 40 mg PO/IV once per day on days 1 to 4, 11 to 14 (+/- 2 days)
- Everolimus (Afinitor) 5 mg PO once per day
Supportive medications
- Mesna (Mesnex) 600 mg/m2/day IV continuous infusion on days 1 to 3
- Pegfilgrastim (Neulasta) 6 mg SC once approximately 24 hours after completion of chemotherapy
Chemotherapy, Part B (cycles 2, 4, 6, 8):
- Methotrexate (MTX) 200 mg/m2 IV over 2 hours, then 800 mg/m2 IV over 22 hours on day 1
- Cytarabine (Cytosar) as follows:
- For patients younger than 60 years old: 3000 mg/m2 IV over 2 hours Q12H on days 2 & 3 (4 total doses)
- For patients at least 60 years old or with creatinine at least 1.5 x the upper limit of normal: 1000 mg/m2 IV over 2 hours Q12H on days 2 & 3 (4 total doses)
- Methylprednisolone (Solumedrol) as follows:
- Less than 18 years old: 25 mg/m2 (maximum dose of 50 mg) IV over 2 hours Q12H on days 1 to 3 (6 total doses)
- Adults: 50 mg IV over 2 hours Q12H on days 1 to 3 (6 total doses)
- It isn't clear if this is meant to be a supportive or antineoplastic medication.
- Everolimus (Afinitor) 5 mg PO once per day
Supportive medications
- Not defined
References
- 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. link to original article link to PMC article contains partial protocol in supplement PubMed
Inotuzumab ozogamicin monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kantarjian et al. 2016 | Phase III | Cytarabine Cytarabine & Mitoxantrone FLAG |
Seems to have superior OS |
Chemotherapy
- Inotuzumab ozogamicin (Besponsa) 0.8 mg IV once on day 1, then 0.5 mg IV once per day on days 8 & 15
- For patients achieving CR or CRi, day 1 dose was reduced to 0.5 mg
28-day cycle (cycle 1 is 21 days) for up to 6 cycles
References
- 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. link to original article PubMed
- 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. link to original article contains verified protocol PubMed
Mitoxantrone, Pegaspargase, Vincristine, Dexamethasone
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Parker et al. 2010 (UK ALL R3) | Phase III | Idarubicin, Pegaspargase, Vincristine, Dexamethasone | Superior OS |
Note: per the protocol, this regimen is intended only for patients 18 and younger.
Chemotherapy
- Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 1 & 8
- Pegaspargase (Oncaspar) 1000 units/m2 IM once per day on days 3 & 18
- Allergic patients: Asparaginase Erwinia chrysanthemi (Erwinaze) 20,000 units IM once per day on days 3, 5, 7, 9, 11, 13, 18, 20, 22, 24, 26, 28
- Vincristine (Oncovin) 1.5 mg/m2 IV once per day on days 3, 10, 17, 24
- Dexamethasone (Decadron) 20 mg/m2 PO once per day on days 1 to 5, 15 to 19
CNS prophylaxis
- Methotrexate (MTX) as follows:
- Age less than 2: 8 mg IT once per day on days 1 & 8
- Age 2: 10 mg IT once per day on days 1 & 8
- Age older than 2: 12 mg IT once per day on days 1 & 8
4-week course
See paper for details of treatment beyond induction.
References
- Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, Green N, Révész T, Darbyshire P, Love S, Saha V. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010 Dec 11;376(9757):2009-17. Epub 2010 Dec 3. link to original article contains verified protocol link to PMC article PubMed
Tisagenlecleucel monotherapy
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Regimen
Study | Evidence | Efficacy |
---|---|---|
Maude et al. 2018 | Phase II | ORR: 81% |
Preceding treatment
- Lymphodepleting therapy with Cyclophosphamide & Fludarabine or Cytarabine & Etoposide
Immunotherapy
- Tisagenlecleucel (Kymriah) as follows:
- Up to 50 kg: 2.0 to 5.0 x 106 CTL019 transduced viable T-cells per kg body weight
- Greater than 50 kg: 1.0 to 2.5 x 108 CTL019 transduced viable T-cells
One course
References
- 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. link to original article link to supplementary protocol contains verified protocol in supplement PubMed
Vincristine liposomal monotherapy
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Regimen
Study | Evidence | Efficacy |
---|---|---|
O'Brien et al. 2012 (RALLY) | Phase II | ORR: 35% |
Chemotherapy
- Vincristine liposomal (Marqibo) 2.25 mg/m2 IV over 60 minutes on days 1, 8, 15, 22
28-day cycles
References
- O'Brien S, Schiller G, Lister J, Damon L, Goldberg S, Aulitzky W, Ben-Yehuda D, Stock W, Coutre S, Douer D, Heffner LT, Larson M, Seiter K, Smith S, Assouline S, Kuriakose P, Maness L, Nagler A, Rowe J, Schaich M, Shpilberg O, Yee K, Schmieder G, Silverman JA, Thomas D, Deitcher SR, Kantarjian H. High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. J Clin Oncol. 2013 Feb 20;31(6):676-83. Epub 2012 Nov 19. link to original article contains verified protocol link to PMC article PubMed
Maintenance after subsequent lines of therapy
Blinatumomab monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Kantarjian et al. 2017 (TOWER) | Phase III | Standard maintenance chemotherapy | Superior OS |
The most common comparator in TOWER was not specified but is presumably POMP.
Preceding treatment
Chemotherapy
- Blinatumomab (Blincyto) 28 mcg/day IV continuous infusion on days 1 to 28
12-week cycle for up to 12 months
References
- 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. link to original article contains verified protocol PubMed
Pediatric ALL
Pediatric ALL regimens tend to be very complex. This list on ped-onc.org appears to be fairly comprehensive and includes regimen details for some of the common regimens e.g. COG-AALL0232. For now we will try to include a list of references here and potentially build these regimens here, over time.
References
- Domenech C, Suciu S, De Moerloose B, Mazingue F, Plat G, Ferster A, Uyttebroeck A, Sirvent N, Lutz P, Yakouben K, Munzer M, Röhrlich P, Plantaz D, Millot F, Philippet P, Dastugue N, Girard S, Cavé H, Benoit Y, Bertrandfor Y; Children's Leukemia Group (CLG) of European Organisation for Research and Treatment of Cancer (EORTC). Dexamethasone (6 mg/m2/day) and prednisolone (60 mg/m2/day) were equally effective as induction therapy for childhood acute lymphoblastic leukemia in the EORTC CLG 58951 randomized trial. Haematologica. 2014 Jul;99(7):1220-7. Epub 2014 Apr 11. link to PMC article PubMed
Investigational agents
These are drugs under study with at least some promising results for this disease.