B-cell acute lymphoblastic leukemia
Section editor | |
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Martin W. Schoen, MD, MPH Saint Louis University St. Louis, MO ![]() |
Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. If you still can't find it, please let us know so we can add it!
Note: biomarker- and site-specific regimens have been moved to dedicated pages:
57 regimens on this page
82 variants on this page
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Contents
- 1 Guidelines
- 2 Prephase
- 3 Upfront induction therapy
- 3.1 Calaspargase, Daunorubicin, Vincristine, Prednisone
- 3.2 Cyclophosphamide, Cytarabine, Mercaptopurine
- 3.3 Cyclophosphamide, Daunorubicin, Vincristine, Prednisone
- 3.4 Cyclophosphamide, Daunorubicin, Vincristine, Prednisolone
- 3.5 Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone
- 3.6 Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab
- 3.7 Cyclophosphamide, Idarubicin, Vincristine, Prednisone
- 3.8 DOLP
- 3.8.1 Regimen variant #1, 25/5000/1.5/60
- 3.8.2 Regimen variant #2, 25/6000/1.5/60
- 3.8.3 Regimen variant #3, 30/5000/1.5/60 ("Phase A" of ALL-BFM 95)
- 3.8.4 Regimen variant #4, 30/10,000/1.5/60 ("Protocol I")
- 3.8.5 Regimen variant #5, 40/6000/2/60-40 ("Phase I" of GIMEMA ALL 0288)
- 3.8.6 Regimen variant #6, 40/10,000/1.5/60 ("Induction Protocol I" of ALL-BFM 86)
- 3.8.7 Regimen variant #7, 45/500/2/40
- 3.8.8 Protocol variant #8, 50/6000/2/60 ("Linker regimen")
- 3.8.9 Regimen variant #9, 60/10,000/1.4/60, daily dauno
- 3.8.10 Regimen variant #10, 60/10,000/1.4/60, weekly dauno ("Phase I" of E2993 regimen)
- 3.8.11 References
- 3.9 DOLP (Prednisolone)
- 3.10 Daunorubicin, Pegaspargase, Vincristine, Dexamethasone
- 3.11 Daunorubicin, Pegaspargase, Vincristine, Prednisone
- 3.12 Doxorubicin, 6-MP, Pegaspargase, Vincristine, Prednisolone
- 3.13 Hyper-CVAD/MA
- 3.14 Mini-Hyper-CVD/MA & Inotuzumab ozogamicin
- 3.15 Pegaspargase, Vincristine, Prednisone
- 3.16 R-Hyper-CVAD/R-MA
- 4 Extended induction therapy
- 5 Early intensification therapy
- 6 Consolidation after upfront therapy (including post-remission therapy)
- 6.1 AALL0232 consolidation
- 6.2 Augmented BFM consolidation
- 6.3 Blinatumomab monotherapy
- 6.4 Cyclophosphamide & TBI, then allo HSCT
- 6.5 Etoposide & TBI, then allo HSCT
- 6.6 International ALL Trial
- 6.7 Mercaptopurine, Methotrexate, Vincristine
- 6.8 Linker regimen (consolidation)
- 6.9 Pediatric-like GRAALL consolidation
- 6.9.1 Protocol
- 6.9.1.1 Preceding treatment
- 6.9.1.2 Chemotherapy, Consolidation A (Cycles 1, 4, 7)
- 6.9.1.3 Supportive medications
- 6.9.1.4 Chemotherapy, Consolidation B (Cycles 2, 5, 8)
- 6.9.1.5 Supportive medications
- 6.9.1.6 Chemotherapy, Consolidation C (Cycles 3, 6, 9)
- 6.9.1.7 Supportive medications
- 6.9.1.8 Subsequent treatment
- 6.9.2 References
- 6.9.1 Protocol
- 7 Interim maintenance
- 8 Late intensification
- 9 Maintenance after upfront therapy
- 10 Relapsed or refractory
- 10.1 Augmented Hyper-CVAD & Asparaginase
- 10.2 Blinatumomab monotherapy
- 10.3 CCE
- 10.4 Clofarabine monotherapy
- 10.5 Cytarabine monotherapy
- 10.6 Cytarabine & Idarubicin
- 10.7 Cytarabine, Idarubicin, Rituximab
- 10.8 Cytarabine & Mitoxantrone
- 10.9 FLAG
- 10.10 Hyper-CVAD/MA & Everolimus
- 10.11 Inotuzumab ozogamicin monotherapy
- 10.12 Mitoxantrone, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone
- 10.13 Mitoxantrone, Pegaspargase, Vincristine, Dexamethasone
- 10.14 Tisagenlecleucel monotherapy
- 10.15 Vincristine liposomal monotherapy
- 11 Consolidation after salvage therapy
- 12 Maintenance after subsequent lines of therapy
- 13 Pediatric ALL
- 14 Investigational agents
Please note, mature B-cell ALL (L3) is now classified as Burkitt lymphoma/leukemia. Regimens for this variant are available here
Guidelines
ESMO
- 2016: Hoelzer et al. Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
EWALL/EBMT
"How I Treat"
- 2020: Hunger & Raetz. How I treat relapsed acute lymphoblastic leukemia in the pediatric population
- 2020: Aldoss I, Douer D. How I treat the toxicities of pegasparaginase in adults with acute lymphoblastic leukemia. Blood. 2020 Mar 26;135(13):987-995. link to original article PubMed
- 2020: Aldoss I, Forman SJ. How I treat adults with advanced acute lymphoblastic leukemia eligible for CD19-targeted immunotherapy. Blood. 2020 Mar 12;135(11):804-813. link to original article PubMed
- 2015: Curran E, Stock W. How I treat acute lymphoblastic leukemia in older adolescents and young adults. Blood. 2015 Jun 11;125(24):3702-10. Epub 2015 Mar 24. link to PMC article PubMed
- 2015: Frey NV, Luger SM. How I treat adults with relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia. Blood. 2015 Jul 30;126(5):589-96. Epub 2015 May 12. link to original article PubMed
NCCN
- NCCN Guidelines - Acute Lymphoblastic Leukemia
- NCCN Guidelines - Pediatric Acute Lymphoblastic Leukemia
Prephase
Prednisone monotherapy
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Regimen variant #1, flat dose
Study | Evidence |
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Huguet et al. 2009 (GRAALL-2003) | Phase II |
Möricke et al. 2016 (AIEOP-BFM ALL 2000) | Non-randomized portion of RCT |
Note: in GRAALL-2003, this regimen was meant for patients up to 60 years old. The original Huguet et al. 2009 article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. See paper for details on CNS prophylaxis and treatment.
Chemotherapy
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 7
CNS prophylaxis
- Methotrexate (MTX) 15 mg IT once on day 1
7-day course
Subsequent treatment
- GRAALL-2003: Cyclophosphamide, Daunorubicin, L-asparaginase, Vincristine, Prednisone induction
- AIEOP-BFM ALL 2000: Daunorubicin, L-Asparaginase, Vincristine, Prednisone versus Daunorubicin, L-Asparaginase, Vincristine, Dexamethasone induction
Regimen variant #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 PO, increasing to 60 mg/m2/day PO by day 7
7-day course
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
- AIEOP-BFM ALL 2000: Möricke A, Zimmermann M, Valsecchi MG, Stanulla M, Biondi A, Mann G, Locatelli F, Cazzaniga G, Niggli F, Aricò M, Bartram CR, Attarbaschi A, Silvestri D, Beier R, Basso G, Ratei R, Kulozik AE, Lo Nigro L, Kremens B, Greiner J, Parasole R, Harbott J, Caruso R, von Stackelberg A, Barisone E, Rössig C, Conter V, Schrappe M. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016 Apr 28;127(17):2101-12. Epub 2016 Feb 17. link to original article contains verified protocol in supplement PubMed
Vincristine & Prednisone
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VP: Vincristine & Prednisone
Regimen variant #1
Study | Evidence |
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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
21-day course
Regimen variant #2
Study | Years of enrollment | Evidence |
---|---|---|
McCredie et al. 1983 (SWOG-7416 | 1975-1977 | Non-randomized portion of RCT |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Chemotherapy
- Vincristine (Oncovin) 2 mg IV once on day 1
- Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
5-day 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
- SWOG-7416: McCredie KB, Gehan EA, Freireich EJ, Hewlett JS, Coltman CA Jr, Hussein KK, Balcerzak SP, Chen TT. Management of adult acute leukemia: a Southwest Oncology Group study. Cancer. 1983 Sep 15;52(6):958-66. link to original article contains verified protocol PubMed
Upfront induction therapy
Calaspargase, Daunorubicin, Vincristine, Prednisone
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Angiolillo et al. 2014 (COG AALL07P4) | 2008-2010 | Randomized (E-RT-switch-ic) | Daunorubicin, Pegaspargase, Vincristine, Prednisone | Longer half-life |
Chemotherapy
- Calaspargase (Asparlas) 2500 units/m2 IV once on day 4
- Daunorubicin (Cerubidine) 25 mg/m2 IV once per day on days 1, 8, 15, 22
- 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 twice per day on days 1 to 28
5-week course
Subsequent treatment
- See protocol for details of treatment beyond induction
References
- COG AALL07P4: Angiolillo AL, Schore RJ, Devidas M, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Keilani T, Lane AR, Loh ML, Reaman GH, Adamson PC, Wood B, Wood C, Zheng HW, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children's Oncology Group Study AALL07P4. J Clin Oncol. 2014 Dec 1;32(34):3874-82. Epub 2014 Oct 27. link to original article link to PMC article contains verified protocol PubMed
Cyclophosphamide, Cytarabine, Mercaptopurine
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Regimen
Study | Evidence |
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Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) | Non-randomized portion of RCT |
Preceding treatment
- Ph-: "Phase 1" induction: DOLP
- Ph+: "Phase 1" induction: Daunorubicin, L-asparaginase, Vincristine, Prednisone, Imatinib
Chemotherapy
- Cyclophosphamide (Cytoxan) 650 mg/m2 IV once per day on days 1, 15, 29
- Cytarabine (Ara-C) 75 mg/m2 IV once per day on days 1 to 4, 8 to 11, 15 to 18, 22 to 25
- Mercaptopurine (6-MP) 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
29-day course
Subsequent treatment
- L-asparaginase & Methotrexate early intensification
References
- MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. 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 | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Thomas et al. 2004 (LALA-94) | 1994-2002 | Phase III (C) | 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
28-day course
Subsequent treatment
- Consolidation (see paper for details)
References
- LALA-94: Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. link to original article contains verified protocol PubMed
- Update: Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. link to original article PubMed
Cyclophosphamide, Daunorubicin, Vincristine, Prednisolone
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
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Labar et al. 2010 (EORTC ALL-4) | 1995-2003 | Phase III (C) | Cyclophosphamide, Daunorubicin, Vincristine, Dexamethasone | Did not meet primary endpoint of EFS72 |
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, 23
- Prednisolone (Millipred) 60 mg/m2/day IV or PO on days 1 to 8, 15 to 22
CNS prophylaxis
- Methotrexate (MTX) 15 mg IT once per day on days 1, 8, 15, 22, 28
28-day course
Subsequent treatment
- HAM consolidation
References
- EORTC ALL-4: Labar B, Suciu S, Willemze R, Muus P, Marie JP, Fillet G, Berneman Z, Jaksic B, Feremans W, Bron D, Sinnige H, Mistrik M, Vreugdenhil G, De Bock R, Nemet D, Gilotay C, Amadori S, de Witte T; EORTC Leukemia Group. Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group. Haematologica. 2010 Sep;95(9):1489-95. Epub 2010 Apr 7. link to original article link to PMC article contains verified protocol PubMed
Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone
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Regimen variant #1
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Huguet et al. 2009 (GRAALL-2003) | 2003-2005 | Phase II | ||
Maury et al. 2016 (GRAALL-2005/R) | 2006-2014 | Phase III (C) | Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab | Seems to have inferior EFS |
Huguet et al. 2018 (GRAALL-2005) | 2006-2014 | Phase III (C) | Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone; hyperfractionated cyclophosphamide | Did not meet primary endpoint of EFS |
Note: this "pediatric-like" regimen was meant for patients up to 60 years old. The original Huguet et al. 2009 article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. See paper for details on CNS treatment. This is the "standard-dose cyclophosphamide" arm of GRAALL-2005.
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 every 12 hours 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 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 (Ara-C) 40 mg IT once per day on days 1 & 8
- Methylprednisolone (Solumedrol) 40 mg IT once per day on days 1 & 8
Supportive 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
Subsequent treatment
- Patients with resistant disease: Cytarabine & idarubicin salvage prior to further consolidation
- All others: Pediatric-like GRAALL consolidation
Regimen variant #2, "HyperC"
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Maury et al. 2016 (GRAALL-2005/R) | 2006-2014 | Phase III (C) | Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab | Seems to have inferior EFS |
Huguet et al. 2018 (GRAALL-2005) | 2006-2014 | Phase III (E-esc) | Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone; standard-dose cyclophosphamide | Did not meet primary endpoint of EFS |
This is the "HyperC" arm of GRAALL-2005. Given the negative report in 2018, this experimental arm should be considered as historic reference.
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 3 hours once on day 1, then 300 mg/m2 IV over 3 hours every 12 hours on days 15 to 17 (total dose: 2550 mg/m2)
- 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 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 (Ara-C) 40 mg IT once per day on days 1 & 8
- Methylprednisolone (Solumedrol) 40 mg IT once per day on days 1 & 8
Supportive medications
- Lenograstim (Granocyte) 263 mcg SC once per day from day 18 until first day with ANC greater than 1000/uL
28-day course
Subsequent treatment
- Patients with resistant disease: Cytarabine & idarubicin salvage prior to further consolidation
- Responders: Pediatric-like GRAALL consolidation
Regimen variant #3
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Annino et al. 2002 (GIMEMA ALL 0288) | 1988-1996 | Phase III (E-esc) | DOLP | Did not meet primary endpoint of CR rate |
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 PO on days 1 to 14, then 40 mg/m2/day PO on days 15 to 31
31-day course
Subsequent treatment
- Induction phase II or salvage, see paper for details
Regimen variant #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
28-day 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, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains verified protocol PubMed
- GIMEMA ALL 0288: Annino L, Vegna ML, Camera A, Specchia G, Visani G, Fioritoni G, Ferrara F, Peta A, Ciolli S, Deplano W, Fabbiano F, Sica S, Di Raimondo F, Cascavilla N, Tabilio A, Leoni P, Invernizzi R, Baccarani M, Rotoli B, Amadori S, Mandelli F; GIMEMA. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002 Feb 1;99(3):863-71. link to original article contains verified protocol 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
- GRAALL-2005/R: Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed NCT00327678
- GRAALL-2005: Huguet F, Chevret S, Leguay T, Thomas X, Boissel N, Escoffre-Barbe M, Chevallier P, Hunault M, Vey N, Bonmati C, Lepretre S, Marolleau JP, Pabst T, Rousselot P, Buzyn A, Cahn JY, Lhéritier V, Béné MC, Asnafi V, Delabesse E, Macintyre E, Chalandon Y, Ifrah N, Dombret H; Group of Research on Adult ALL. Intensified therapy of acute lymphoblastic leukemia in adults: report of the randomized GRAALL-2005 clinical trial. J Clin Oncol. 2018 Aug 20;36(24):2514-2523. Epub 2018 Jun 4. link to original article PubMed NCT00327678
Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab
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Regimen variant #1
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Maury et al. 2016 (GRAALL-2005/R) | 2006-2014 | Phase III (E-esc) | 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-2005/R.
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 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
Targeted therapy
- 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 (Ara-C) 40 mg IT once per day on days 1 & 8
- Methylprednisolone (Solumedrol) 40 mg IT once per day on days 1 & 8
Supportive 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
Subsequent treatment
- Patients with resistant disease: Cytarabine, idarubicin, rituximab salvage prior to further consolidation
- All others: Pediatric-like GRAALL consolidation with rituximab
References
- GRAALL-2005/R: Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed NCT00327678
Cyclophosphamide, Idarubicin, Vincristine, Prednisone
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Thomas et al. 2004 (LALA-94) | 1994-2002 | Phase III (E-switch-ic) | 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
28-day course
Subsequent treatment
- Consolidation (see paper for details)
References
- LALA-94: Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D; SAKK. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. link to original article contains verified protocol PubMed
- Update: Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. link to original article PubMed
DOLP
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DOLP: Daunorubicin, Oncovin (Vincristine), L-Asparaginase, Prednisone
DVPA: Daunorubicin, Vincristine, Prednisone, Asparaginase
Regimen variant #1, 25/5000/1.5/60
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
- Vincristine (Oncovin) 1.5 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
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 28
4-week course
Subsequent treatment
- See paper for details of treatment beyond induction
Regimen variant #2, 25/6000/1.5/60
Study | Evidence |
---|---|
Seibel et al. 2008 (COG CCG-1961) | Non-randomized portion of RCT |
Note: exact days were not specified for the L-asparaginase; suggested days are similar to those used in subsequent parts of the protocol.
Chemotherapy
- Daunorubicin (Cerubidine) 25 mg/m2 IV once per day on days 1, 8, 15, 22
- Vincristine (Oncovin) 1.5 mg/m2 IV once per day on days 1, 8, 15, 22
- Asparaginase (Elspar) 6000 units/m2 IM once per day on days 3, 5, 7, 10, 12, 14, 17, 19, 21
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 28
CNS therapy
- Cytarabine (Ara-C) IT once on day 0 (dose not specified)
- Methotrexate (MTX) IT once per day on days 7 & 28 (dose not specified)
4-week course
Subsequent treatment
- Standard versus increased intensity post-remission therapy (see paper for details)
Regimen variant #3, 30/5000/1.5/60 ("Phase A" of ALL-BFM 95)
Study | Evidence |
---|---|
Möricke et al. 2008 (ALL-BFM 95) | Non-randomized |
Note: see paper for details on dose adjustments based on risk.
Chemotherapy
- Daunorubicin (Cerubidine) 30 mg/m2 IV over 60 minutes once per day on days 8, 15, 22, 29
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
- Asparaginase (Elspar) 5000 units IV over 60 minutes once per day on days 12, 15, 18, 21, 24, 27, 30, 33
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 28
CNS therapy
- Methotrexate (MTX) 12 mg IT once per day on days 1, 12, 33
5-week course
Subsequent treatment
- See paper for details
Regimen variant #4, 30/10,000/1.5/60 ("Protocol I")
Study | Evidence |
---|---|
Schrappe et al. 2000 (ALL-BFM 90) | Non-randomized |
Kamps et al. 2002 (DCLSG ALL-8) | Non-randomized |
Note: see papers for details on dose adjustments based on risk.
Chemotherapy
- Daunorubicin (Cerubidine) 30 mg/m2 IV over 60 minutes once per day on days 8, 15, 22, 29
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
- Asparaginase (Elspar) 10,000 units IV over 60 minutes once per day on days 12, 15, 18, 21, 24, 27, 30, 33
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 28
CNS therapy
- Methotrexate (MTX) 12 mg IT once per day on days 1, 15, 29
5-week course
Subsequent treatment
- See papers for details
Regimen variant #5, 40/6000/2/60-40 ("Phase I" of GIMEMA ALL 0288)
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Annino et al. 2002 (GIMEMA ALL 0288) | 1988-1996 | Phase III (C) | Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone | Did not meet primary endpoint of CR rate |
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
- Daunorubicin (Cerubidine) 40 mg/m2 IV once per day on days 1, 8, 15, 22
- Vincristine (Oncovin) 2 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
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 14, then 40 mg/m2/day PO on days 15 to 31
31-day course
Subsequent treatment
- Induction phase II or salvage (see paper for details)
Regimen variant #6, 40/10,000/1.5/60 ("Induction Protocol I" of ALL-BFM 86)
Study | Evidence |
---|---|
Reiter et al. 1994 (ALL-BFM 86) | Non-randomized portion of RCT |
Kamps et al. 1999 (DCLSG ALL-7) | Non-randomized portion of RCT |
Chemotherapy
- Daunorubicin (Cerubidine) 40 mg/m2 IV once per day on days 8, 15, 22, 29
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
- L-Asparaginase 10,000 units/m2 IV once per day on days 19, 22, 25, 28, 31, 34, 37, 40
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 28
6-week course
Subsequent treatment
- Induction phase II (see papers for details)
Regimen variant #7, 45/500/2/40
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gottlieb et al. 1984 (CALGB 7612) | 1976-1980 | Randomized (E-esc) | L-asparaginase, Vincristine, Prednisone | Superior CR rate |
Chemotherapy
- Daunorubicin (Cerubidine) 45 mg/m2 IV once per day on days 1 to 3
- Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15
- Asparaginase (Elspar) 500 units/kg IV once per day on days 22 to 31
- Prednisone (Sterapred) 40 mg/m2/day PO on days 1 to 22, then tapered to off by day 29
31-day course
Subsequent treatment
- See paper for details of treatment beyond induction
Protocol variant #8, 50/6000/2/60 ("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
- Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22
- Asparaginase (Elspar) 6000 units/m2 IM once per day on days 17 to 28
- 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
- Vincristine (Oncovin) 2 mg IV once per day on days 29 & 36
- Asparaginase (Elspar) 6000 units/m2 IM once per day on days 29 to 35
- 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 variant #9, 60/10,000/1.4/60, daily dauno
Study | Evidence |
---|---|
Pullarkat et al. 2008 (SWOG S9400) | Phase II |
Note: this was the dosing used after the protocol amendment of September 1, 1999.
Chemotherapy
- Daunorubicin (Cerubidine) 60 mg/m2 IV once per day on days 1 to 3
- Persistent leukemia on day 21: 60 mg/m2 IV once per day on days 22 & 23
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
- Persistent leukemia on day 21: 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 29 & 36
- Asparaginase (Elspar) 10,000 units IM or IV once per day on days 15 to 24
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 28
- No leukemia on day 21: taper to off by day 42
- Persistent leukemia on day 21: 60 mg/m2/day PO on days 29 to 42
6-week course
Subsequent treatment
- See paper for details
Regimen variant #10, 60/10,000/1.4/60, weekly dauno ("Phase I" of E2993 regimen)
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%.
Chemotherapy
- Daunorubicin (Cerubidine) 60 mg/m2 IV once per day on days 1, 8, 15, 22
- Vincristine (Oncovin) 1.4 mg/m2 IV once per day on days 1, 8, 15, 22
- Asparaginase (Elspar) 10,000 units IM or IV once per day on days 17 to 28
- Prednisone (Sterapred) 60 mg/m2/day 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")
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
- CALGB 7612: Gottlieb AJ, Weinberg V, Ellison RR, Henderson ES, Terebelo H, Rafla S, Cuttner J, Silver RT, Carey RW, Levy RN, Hutchinson JL, Raich P, Cooper MR, Wiernik P, Anderson JR, Holland JF. Efficacy of daunorubicin in the therapy of adult acute lymphocytic leukemia: a prospective randomized trial by Cancer and Leukemia Group B. Blood. 1984 Jul;64(1):267-74. 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
- ALL-BFM 86: Reiter A, Schrappe M, Ludwig WD, Hiddemann W, Sauter S, Henze G, Zimmermann M, Lampert F, Havers W, Niethammer D, Odenwald E, Ritter J, Mann G, Welte K, Gadner H, Riehm H. Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: results and conclusions of the multicenter trial ALL-BFM 86. Blood. 1994 Nov 1;84(9):3122-33. link to original article contains verified protocol PubMed
- DCLSG ALL-7: Kamps WA, Bökkerink JP, Hählen K, Hermans J, Riehm H, Gadner H, Schrappe M, Slater R, van den Berg-de Ruiter E, Smets LA, de Vaan GA, Weening RS, van Weerden JF, van Wering ER, den der Does-van den Berg A. Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM-86 without cranial radiotherapy: results of Dutch Childhood Leukemia Study Group protocol ALL-7 (1988-1991). Blood. 1999 Aug 15;94(4):1226-36. link to original article PubMed
- ALL-BFM 90: 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; German-Austrian-Swiss ALL-BFM Study Group. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. Blood. 2000 Jun 1;95(11):3310-22. link to original article contains verified protocol PubMed
- Subgroup analysis: Schrauder A, Reiter A, Gadner H, Niethammer D, Klingebiel T, Kremens B, Peters C, Ebell W, Zimmermann M, Niggli F, Ludwig WD, Riehm H, Welte K, Schrappe M. Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol. 2006 Dec 20;24(36):5742-9. 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. 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 refers to ALL-BFM 90 protocol 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 S9400: Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008 Mar 1;111(5):2563-72. Epub 2007 Dec 21. link to original article link to PMC article contains verified protocol PubMed
- COG CCG-1961: 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 contains verified protocol 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. Epub 2008 Feb 19. Erratum in: Blood. 2009 Apr 30;113(18):4478. Dosage error in article text. link to original article contains verified protocol PubMed
- Subgroup analysis: Schrauder A, Reiter A, Gadner H, Niethammer D, Klingebiel T, Kremens B, Peters C, Ebell W, Zimmermann M, Niggli F, Ludwig WD, Riehm H, Welte K, Schrappe M. Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol. 2006 Dec 20;24(36):5742-9. link to original article PubMed
DOLP (Prednisolone)
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DOLP: Daunorubicin, Oncovin (Vincristine), L-Asparaginase, Prednisolone
Regimen variant #1, 30/10,000/1.5/60
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
de Moerloose et al. 2010 (EORTC CLG 58951) | 1999-2002 | Phase III (C) | Daunorubicin, L-Asparaginase, Vincristine, Dexamethasone | Did not meet primary endpoint of EFS |
Note: see paper for details on CNS therapy and dose adjustments based on risk; these instructions include a 7-day pre-phase and are for AR1 patients.
Chemotherapy
- Daunorubicin (Cerubidine) 30 mg/m2 IV once per day on days 8, 15, 22, 29
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
- Asparaginase (Elspar) 10,000 units (route not specified) once per day on days 12, 15, 18, 22, 25, 29, 32, 35
- Prednisolone (Millipred) 60 mg/m2/day PO on days 1 to 28, then tapered over 9 days
5-week course
Subsequent treatment
- See paper for details
Regimen variant #2, 45/6000/1.5/40
Study | Evidence |
---|---|
Chessells et al. 1992 (UK MRC ALLX) | Non-randomized portion of RCT |
Note: exact days for L-asparaginase were not specified in the protocol.
Chemotherapy
- Daunorubicin (Cerubidine) 45 mg/m2 IV once per day on days 1 & 2
- Vincristine (Oncovin) 1.5 mg/m2 IV once per day on days 1, 8, 15, 22, 29
- Asparaginase (Elspar) 6000 units/m2 SC once per day on days 3, 5, 7, 10, 12, 14, 17, 19, 21
- Prednisolone (Millipred) 40 mg/m2/day PO on days 1 to 28
29-day course
Subsequent treatment
- Intensification (randomized) or Cy/TBI with allo HSCT, depending on donor availability
References
- UK MRC ALLX: Chessells JM, Bailey C, Wheeler K, Richards SM. Bone marrow transplantation for high-risk childhood lymphoblastic leukaemia in first remission: experience in MRC UKALL X. Lancet. 1992 Sep 5;340(8819):565-8. link to original article contains verified protocol PubMed
- Update: Chessells JM, Bailey C, Richards SM; Medical Research Council Working Party on Childhood Leukaemia. Intensification of treatment and survival in all children with lymphoblastic leukaemia: results of UK Medical Research Council trial UKALL X. Lancet. 1995 Jan 21;345(8943):143-8. link to original article PubMed
- EORTC CLG 58951: De Moerloose B, Suciu S, Bertrand Y, Mazingue F, Robert A, Uyttebroeck A, Yakouben K, Ferster A, Margueritte G, Lutz P, Munzer M, Sirvent N, Norton L, Boutard P, Plantaz D, Millot F, Philippet P, Baila L, Benoit Y, Otten J; Children's Leukemia Group of the European Organisation for Research and Treatment of Cancer. Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951. Blood. 2010 Jul 8;116(1):36-44. Epub 2010 Apr 20. link to original article link to PMC article contains verified protocol PubMed NCT00003728
- Update: 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, Bertrand Y; Children's Leukemia Group (CLG) of European Organisation for Research and Treatment of Cancer. 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 original article link to PMC article PubMed
- Update: Mondelaers V, Suciu S, De Moerloose B, Ferster A, Mazingue F, Plat G, Yakouben K, Uyttebroeck A, Lutz P, Costa V, Sirvent N, Plouvier E, Munzer M, Poirée M, Minckes O, Millot F, Plantaz D, Maes P, Hoyoux C, Cavé H, Rohrlich P, Bertrand Y, Benoit Y; Children–s Leukemia Group (CLG) of the European Organisation for Research and Treatment of Cancer. Prolonged versus standard native E coli asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951. Haematologica. 2017 Oct;102(10):1727-1738. Epub 2017 Jul 27. link to original article link to PMC article PubMed
Daunorubicin, Pegaspargase, Vincristine, Dexamethasone
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Regimen
Study | Evidence |
---|---|
Burke et al. 2019 (COG AALL1131) | Non-randomized portion of RCT |
Note: the referenced publication does not specifically focus on induction; the full regimen is available as a protocol. Per the protocol, it is intended only for patients less than 10 years old.
Chemotherapy
- Daunorubicin (Cerubidine) 25 mg/m2 IV 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 IV or PO twice per day on days 1 to 14
CNS prophylaxis
- Cytarabine (Ara-C) 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
Subsequent treatment
- See protocol for details of treatment beyond induction
References
- COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article PubMed
Daunorubicin, Pegaspargase, Vincristine, Prednisone
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Regimen variant #1, "ABFM"
Study | Evidence |
---|---|
Rytting et al. 2014 | Non-randomized |
Stock et al. 2019 (CALGB 10403) | Non-randomized |
ABFM: Augmented Berlin-Frankfurt-Münster regimen
Chemotherapy
- Daunorubicin (Cerubidine) 25 mg/m2 IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
- Pegaspargase (Oncaspar) 2500 units/m2 IM or 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 IV or PO twice per day on days 1 to 28
CNS prophylaxis
- Cytarabine (Ara-C) 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
Subsequent treatment
- Rytting et al. 2014: See protocol for details of treatment beyond induction
- CALGB 10403, CR: AALL0232 consolidation
- CALGB 10403, not CR: ABFM extended induction
Regimen variant #2, higher-dose dauno
Study | Evidence |
---|---|
Pullarkat et al. 2008 (SWOG S9400) | Non-randomized |
Note: Table 1 lists vincristine as being given PO, which is surely an error. Likewise, prednisone is listed as IV. Pegaspargase was only given until the protocol amendment of September 1, 1999.
Chemotherapy
- Daunorubicin (Cerubidine) as follows:
- Part 1 (all patients): 60 mg/m2 IV once per day on days 1 to 3
- Part 2 (persistent leukemia on d21): 60 mg/m2 IV once per day on days 22 & 23
- Pegaspargase (Oncaspar) as follows:
- Part 1 (all patients): 2000 units/m2 IV once on day 15
- Part 2 (persistent leukemia on d21): 2000 units/m2 IV once on day 38
- Vincristine (Oncovin) as follows:
- Part 1 (all patients): 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
- Part 2 (persistent leukemia on d21): 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 29 & 36
- Prednisone (Sterapred) as follows:
- Part 1 (all patients): 60 mg/m2/day PO on days 1 to 28
- Part 2 (CR on d21): tapered from day 29 to 42
- Part 2 (persistent leukemia on d21): 60 mg/m2/day PO on days 29 to 42
42-day course
Subsequent treatment
- See protocol for details of treatment beyond induction
References
- SWOG S9400: Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008 Mar 1;111(5):2563-72. Epub 2007 Dec 21. link to original article link to PMC article contains verified protocol 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
- CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article contains verified protocol PubMed
Doxorubicin, 6-MP, Pegaspargase, Vincristine, Prednisolone
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Regimen
Study | Evidence |
---|---|
Albertsen et al. 2019 (NOPHO ALL2008) | Non-randomized portion of RCT |
See protocol for initiation dependencies of 6-MP and pegaspargase.
Chemotherapy
- Doxorubicin (Adriamycin) 40 mg/m2 IV over 4 hours once per day on days 1 & 22
- Mercaptopurine (6-MP) 25 mg/m2 PO once per day on days 30 to 35
- Pegaspargase (Oncaspar) 1000 units/m2 IM once on day 30
- Vincristine (Oncovin) as follows:
- Younger than 18: 2 mg/m2 (maximum dose of 2.5 mg) IV once per day on days 1, 8, 15, 22, 29
- 18 or older: 2 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22, 29
- Prednisolone (Millipred) 20 mg/m2 PO three times per day on days 1 to 29, then 10 mg/m2 PO three times per day on days 30 to 32, then 5 mg/m2 PO three times per day on days 33 to 35, then 2.5 mg/m2 PO three times per day on days 36 to 38
CNS prophylaxis
- Methotrexate (MTX) as follows:
- Ages 1 to 1.9: 8 mg IT once per day on days 1, 8, 15, 29
- Ages 2 to 2.9: 10 mg IT once per day on days 1, 8, 15, 29
- Age 3 and older: 12 mg IT once per day on days 1, 8, 15, 29
5-week course
Subsequent treatment
- See protocol for details of treatment beyond induction
References
- NOPHO ALL2008: Albertsen BK, Grell K, Abrahamsson J, Lund B, Vettenranta K, Jónsson ÓG, Frandsen TL, Wolthers BO, Heyman M, Schmiegelow K. Intermittent versus continuous PEG-asparaginase to reduce asparaginase-associated toxicities: a NOPHO ALL2008 randomized study. J Clin Oncol. 2019 Jul 1;37(19):1638-1646. Epub 2019 Apr 12. link to original article contains verified protocol in supplement PubMed
Hyper-CVAD/MA
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Hyper-CVAD/MA: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone alternating with Methotrexate, Ara-C (Cytarabine)
Protocol
Study | Evidence |
---|---|
Koller et al. 1997 | Non-randomized |
Thomas et al. 1999 | Phase II |
Kantarjian et al. 2000 | Phase II |
Thomas et al. 2004 | Non-randomized |
Chemotherapy, Part A (cycles 1, 3, 5, 7)
- Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m2)
- Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
- Doxorubicin (Adriamycin) as follows:
- Normal EF: 50 mg/m2 IV continuous infusion over 24 hours, started on day 4
- EF less than 50%: 25 mg/m2/day IV continuous infusion over 48 hours, started on day 4 (total dose per cycle: 50 mg/m2)
- Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4, 11 to 14
Supportive medications
- Mesna (Mesnex) 600 mg/m2/day IV continuous infusion over 72 hours, started on day 1, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
- ONE of the following antibiotics:
- Ciprofloxacin (Cipro) 500 mg PO twice per day
- Levofloxacin (Levaquin) 500 mg PO once per day
- Trimethoprim-Sulfamethoxazole (Bactrim DS) (160/800 mg) PO twice per day
- Fluconazole (Diflucan) 200 mg PO once per day
- ONE of the following antivirals:
- Acyclovir (Zovirax) 200 mg PO twice per day
- Valacyclovir (Valtrex) 500 mg PO once per day
- Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
Next cycle to start as soon as ANC is greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 109/L
Chemotherapy, Part B (cycles 2, 4, 6, 8)
- Methotrexate (MTX) 200 mg/m2 IV over 2 hours once on day 1, then 800 mg/m2 IV over 22 hours (total dose per cycle: 1000 mg/m2)
- Cytarabine (Ara-C) as follows:
- Patients younger than 60: 3000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m2)
- Patients 60 or older: 1000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m2)
- Methylprednisolone (Solumedrol) 50 mg IV every 12 hours 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 on day 3, 12 hours after Methotrexate (MTX) is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
- ONE of the following antibiotics:
- Ciprofloxacin (Cipro) 500 mg PO twice per day
- Levofloxacin (Levaquin) 500 mg PO once per day
- Trimethoprim-Sulfamethoxazole (Bactrim DS) (160/800 mg) PO twice per day
- Fluconazole (Diflucan) 200 mg PO once per day
- ONE of the following antivirals:
- Acyclovir (Zovirax) 200 mg PO twice per day
- Valacyclovir (Valtrex) 500 mg PO once per day
- Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
Next cycle to start as soon as ANC is greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 109/L
CNS prophylaxis
- Methotrexate (MTX) as follows:
- LP: 12 mg IT once on day 2
- Ommaya reservoir: 6 mg IT once on day 2
- Cytarabine (Ara-C) 100 mg IT on either day 7 or 8
Given each cycle for a total of 6 or 8 intrathecal treatments (i.e. 3 each of methotrexate and cytarabine or 4 each of methotrexate and cytarabine), depending on risk for CNS relapse based serum lactate dehydrogenase (LDH) greater than 1400 IU/L and/or proliferative index percentage of S + G2M greater than or equal to 14%
CNS treatment
- Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT alternating with Cytarabine (Ara-C) 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
- Then Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT given weeks 1 & 3 and Cytarabine (Ara-C) 100 mg IT, given weeks 2 & 4
- Once those 4 weeks are complete, then intrathecal treatment is given similar to the prophylactic schedule, with each drug given once during every remaining cycle of induction therapy:
- Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT once on day 2
- Cytarabine (Ara-C) 100 mg IT once on day 7 OR 8
Subsequent treatment
- Certain patient populations (see e.g. Kantarjian et al. 2004) proceed to receive POMP maintenance
References
- Review: Cortes J, O'Brien SM, Pierce S, Keating MJ, Freireich EJ, Kantarjian HM. The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia. Blood. 1995 Sep 15;86(6):2091-7. 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. link to original article 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
Mini-Hyper-CVD/MA & Inotuzumab ozogamicin
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Mini-Hyper-CVD/MA & Inotuzumab ozogamicin: Mini (lower intensity) Hyperfractionated Cyclophosphamide, Vincristine, Dexamethasone alternating with Methotrexate and Ara-C (Cytarabine) & Inotuzumab ozogamicin
Protocol
Study | Evidence |
---|---|
Kantarjian et al. 2018 (MDACC 2010-0991) | Phase II |
Part A (cycles 1, 3, 5, 7)
Chemotherapy
- Cyclophosphamide (Cytoxan) 150 mg/m2 IV every 12 hours on days 1 to 3 (total dose per cycle: 900 mg/m2)
- Vincristine (Oncovin) 2 mg IV once per day on days 1 & 8
- Dexamethasone (Decadron) 20 mg IV or PO once per day on days 1 to 4, 11 to 14
Targeted therapy
- Inotuzumab ozogamicin (Besponsa) as follows:
- Cycles 1 & 3: 1.3 to 1.8 mg/m2 IV once on day 3
- Cycles 5 & 7: 1 to 1.3 mg/m2 IV once on day 3
Part B (cycles 2, 4, 6, 8)
Chemotherapy
- Methotrexate (MTX) 250 mg/m2 IV once on day 1
- Cytarabine (Ara-C) 500 mg/m2 IV every 12 hours on days 2 & 3 (total dose per cycle: 2000 mg/m2)
Targeted therapy
- Inotuzumab ozogamicin (Besponsa) as follows:
- Cycles 2 & 4: 1.3 to 1.8 mg/m2 IV once on day 3
- Cycles 6 & 8: 1 to 1.3 mg/m2 IV once on day 3
28-day cycle for 8 cycles
Subsequent treatment
- Dose-reduced POMP x 3 y
References
- MDACC 2010-0991: Kantarjian H, Ravandi F, Short NJ, Huang X, Jain N, Sasaki K, Daver N, Pemmaraju N, Khoury JD, Jorgensen J, Alvarado Y, Konopleva M, Garcia-Manero G, Kadia T, Yilmaz M, Bortakhur G, Burger J, Kornblau S, Wierda W, DiNardo C, Ferrajoli A, Jacob J, Garris R, O'Brien S, Jabbour E. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2018 Feb;19(2):240-248. Epub 2018 Jan 16. link to original article PubMed
Pegaspargase, Vincristine, Prednisone
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Avramis et al. 2002 (CCG 1962) | 1997-1998 | Randomized (E-RT-switch-ic) | L-Asparaginase, Vincristine, Prednisone | Did not meet secondary endpoint of EFS |
Note: the primary endpoint of this study was incidence of high-titer ASNase antibodies in the first dose intensification, which is neither an efficacy nor a toxicity endpoint.
Chemotherapy
Subsequent treatment
- See protocol for details of treatment beyond induction
References
- CCG 1962: Avramis VI, Sencer S, Periclou AP, Sather H, Bostrom BC, Cohen LJ, Ettinger AG, Ettinger LJ, Franklin J, Gaynon PS, Hilden JM, Lange B, Majlessipour F, Mathew P, Needle M, Neglia J, Reaman G, Holcenberg JS, Stork L. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood. 2002 Mar 15;99(6):1986-94. Erratum in: Blood 2002 Sep 1;100(5):1531. link to original article PubMed
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)
Protocol
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.
Part A (cycles 1, 3, 5, 7)
Targeted therapy
- 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
Chemotherapy
- Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m2)
- Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
- Doxorubicin (Adriamycin) 50 mg/m2 IV continuous infusion over 24 hours, started on day 4
- Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4, 11 to 14
Supportive medications
- Mesna (Mesnex) 600 mg/m2/day IV continuous infusion over 72 hours, started on day 1, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan) (total dose per cycle: 1800 mg/m2)
- 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
Part B (cycles 2, 4, 6, 8)
Targeted therapy
- 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
Chemotherapy
- Methotrexate (MTX) 1000 mg/m2 IV continuous infusion over 24 hours, started on day 1
- Cytarabine (Ara-C) 3000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m2)
Supportive medications
- Folinic acid (Leucovorin) 50 mg IV once on day 3, 12 hours after Methotrexate (MTX) is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
- Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting on day 4, 24 hours after completion of chemotherapy, given until WBC greater than 3 x 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 (Ara-C) 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 (Ara-C) 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 MD Anderson Cancer Center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas. Clin Lymphoma Myeloma. 2007 Dec;8 Suppl 2:S57-62. 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
Extended induction therapy
Note: these regimens are used when a pre-specified endpoint during remission induction was not achieved.
Daunorubicin, Pegaspargase, Vincristine, Prednisone
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Regimen, "ABFM"
Study | Evidence |
---|---|
Stock et al. 2019 (CALGB 10403) | Non-randomized |
ABFM: Augmented Berlin-Frankfurt-Münster regimen
Preceding treatment
- ABFM induction, with inadequate response
Chemotherapy
- Daunorubicin (Cerubidine) 25 mg/m2 IV once on day 1
- Pegaspargase (Oncaspar) 2500 units/m2 IM or IV once on day 4
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1 & 8
- Prednisone (Sterapred) 30 mg/m2 IV or PO twice per day on days 1 to 14
2-week course
Subsequent treatment
References
- CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article contains verified protocol PubMed
Early intensification therapy
CALGB 8811 early intensification
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Regimen
Study | Evidence |
---|---|
Larson et al. 1995 (CALGB 8811) | Phase II |
Preceding treatment
Chemotherapy, "Course II"
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
- Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 14
- Cytarabine (Ara-C) 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
CNS prophylaxis
- Methotrexate (MTX) 15 mg IT once on day 1
28-day cycle for 2 cycles
Subsequent treatment
- Mercaptopurine, Methotrexate, WB-XRT interim maintenance ("Course III")
References
- CALGB 8811: Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. 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) 3000 mg/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)
Subsequent treatment
- Patients who were younger than 50 years of age and had an HLA-matched sibling donor, as well as Ph+ patients with any donor: Etoposide & TBI, then allo HSCT
- All others: Etoposide & TBI, then auto HSCT versus International ALL Trial consolidation
References
- MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. 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
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Mahoney et al. 1998 (POG 9005) | 1991-1993 | Phase III (E-switch-ic) | LDMTX/IVMP | Seems to have superior CCR |
Lauer et al. 2001 (POG 9006) | 1991-1994 | Phase III (C) | Intensive chemotherapy | Might have inferior EFS |
Preceding treatment
- POG 9006: DOLP induction
Chemotherapy
Subsequent treatment
- POG 9006: 6-MP & MTX maintenance
References
- POG 9005: Mahoney DH Jr, Shuster J, Nitschke R, Lauer SJ, Winick N, Steuber CP, Camitta B. Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-risk B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group phase III trial. J Clin Oncol. 1998 Jan;16(1):246-54. link to original article PubMed
- POG 9006: Lauer SJ, Shuster JJ, Mahoney DH Jr, Winick N, Toledano S, Munoz L, Kiefer G, Pullen JD, Steuber CP, Camitta BM. A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial. Leukemia. 2001 Jul;15(7):1038-45. link to original 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.
AALL0232 consolidation
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Regimen
Study | Evidence |
---|---|
Larsen et al. 2016 (COG AALL0232) | Non-randomized portion of RCT |
Stock et al. 2019 (CALGB 10403) | Non-randomized |
Preceding treatment
- CALGB 10403: ABFM induction
Chemotherapy
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once per day on days 1 & 29
- Cytarabine (Ara-C) 75 mg/m2 IV or SC once per day on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
- Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 14, 29 to 42
- Pegaspargase (Oncaspar) 2500 units/m2 IM or IV once per day on days 15 & 43
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
50-day course
Subsequent treatment
- AALL2023: 6-MP, Capizzi MTX, Pegaspargase, Vincristine interim maintenance versus 6-MP, HD-MTX, Vincristine interim maintenance
- CALGB 10403: 6-MP, Capizzi MTX, Pegaspargase interim maintenance
References
- COG AALL0232: Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, Mattano LA Jr, Cole C, Eicher A, Haugan M, Sorenson M, Heerema NA, Carroll AA, Gastier-Foster JM, Borowitz MJ, Wood BL, Willman CL, Winick NJ, Hunger SP, Carroll WL. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from Children's Oncology Group study AALL0232. J Clin Oncol. 2016 Jul 10;34(20):2380-8. Epub 2016 Apr 25. link to original article link to PMC article contains verified protocol PubMed
- CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article contains verified protocol PubMed
Augmented BFM consolidation
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Nachman et al. 1998 | 1991-1995 | Phase III (E-esc) | Standard BFM consolidation | Seems to have superior OS |
Unlikely to be completed, but of historic interest.
Chemotherapy
- Cyclophosphamide (Cytoxan)
- Cytarabine (Ara-C)
- Asparaginase (Elspar)
- Mercaptopurine (6-MP)
- Vincristine (Oncovin)
References
- Nachman JB, Sather HN, Sensel MG, Trigg ME, Cherlow JM, Lukens JN, Wolff L, Uckun FM, Gaynon PS. Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med. 1998 Jun 4;338(23):1663-71. link to original article PubMed
Blinatumomab monotherapy
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Regimen
Study | Years of enrollment | Evidence | Efficacy |
---|---|---|---|
Gökbuget et al. 2018 (BLAST) | 2010-2014 | Phase II (RT) | CR after 1 cycle: 78% |
Note: these patients had MRD after induction; also note that this is BSA-based dosing.
Preceding treatment
- "A minimum of 3 blocks of intensive chemotherapy"
Immunotherapy
- Blinatumomab (Blincyto) 15 mcg/m2/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 420 mcg/m2)
42-day cycle for up to 4 cycles
Subsequent treatment
- Patients who had an allogeneic donor could proceed to allogeneic hematopoietic stem cell transplant any time after cycle 1
References
- BLAST: Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, Diedrich H, Topp MS, Brüggemann M, Horst HA, Havelange V, Stieglmaier J, Wessels H, Haddad V, Benjamin JE, Zugmaier G, Nagorsen D, Bargou RC. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018 Apr 5;131(14):1522-1531. Epub 2018 Jan 22. link to original article contains verified protocol PubMed
Cyclophosphamide & TBI, then allo HSCT
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Cy/TBI: Cyclophosphamide & Total Body Irradiation
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Non-relapse mortality |
---|---|---|---|---|---|
Thomas et al. 1979 | 1976-1977 | Non-randomized | |||
Sebban et al. 1994 (LALA 87) | 1986-1991 | Phase III (E-esc) | Chemotherapy or Auto HSCT | Did not meet primary endpoint of OS60 | |
Thomas et al. 2004 (LALA-94) | 1994-2002 | Non-randomized portion of RCT |
Details in the manuscripts are limited.
Chemotherapy
- Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on two consecutive days
Radiotherapy
- Total body irradiation, 10 to 12 Gy total
Immunotherapy
Stem cells transfused on day 0
References
- Thomas ED, Sanders JE, Flournoy N, Johnson FL, Buckner CD, Clift RA, Fefer A, Goodell BW, Storb R, Weiden PL. Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood. 1979 Aug;54(2):468-76. link to original article contains protocol PubMed
- LALA 87: Sebban C, Lepage E, Vernant JP, Gluckman E, Attal M, Reiffers J, Sutton L, Racadot E, Michallet M, Maraninchi D, Dreyfus F, Fiere D; French Group of Therapy of Adult Acute Lymphoblastic Leukemia. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. J Clin Oncol. 1994 Dec;12(12):2580-7. link to original article PubMed
- Update: Thiebaut A, Vernant JP, Degos L, Huguet FR, Reiffers J, Sebban C, Lepage E, Thomas X, Fière D. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation: a follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am. 2000 Dec;14(6):1353-66. link to original article PubMed
- LALA-94: Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. link to original article contains verified protocol PubMed
- Update: Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. link to original article PubMed
Etoposide & TBI, then allo HSCT
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Regimen variant #1
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Balduzzi et al. 2005 | 1995-2000 | Quasi-randomized | Chemotherapy | Seems to have superior DFS |
Peters et al. 2015 (ALL-SCT-BFM 2003) | 2003-2011 | Non-randomized |
Chemotherapy
- Etoposide (Vepesid) 60 mg/kg (maximum dose of 3600 mg) IV once on day -3
Radiotherapy
- Total body irradiation (TBI) 200 cGy twice per day in 6 fractions on days -6 to -4 with lung shielding at 10 Gy (total dose: 1200 cGy)
Immunotherapy
Stem cells transfused on day 0
Regimen variant #2
Study | Evidence |
---|---|
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) | Non-randomized portion of RCT |
Chemotherapy
- Etoposide (Vepesid) 60 mg/kg IV once on day -3
Radiotherapy
- Total body irradiation (TBI) 220 cGy twice per day in 6 fractions on days -6 to -4 (total dose: 1320 cGy)
Immunotherapy
Stem cells transfused on day 0
References
- Balduzzi A, Valsecchi MG, Uderzo C, De Lorenzo P, Klingebiel T, Peters C, Stary J, Felice MS, Magyarosy E, Conter V, Reiter A, Messina C, Gadner H, Schrappe M. Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet. 2005 Aug 20-26;366(9486):635-42. link to original article contains verified protocol 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
- ALL-SCT-BFM-2003: Peters C, Schrappe M, von Stackelberg A, Schrauder A, Bader P, Ebell W, Lang P, Sykora KW, Schrum J, Kremens B, Ehlert K, Albert MH, Meisel R, Matthes-Martin S, Gungor T, Holter W, Strahm B, Gruhn B, Schulz A, Woessmann W, Poetschger U, Zimmermann M, Klingebiel T. Stem-cell transplantation in children with acute lymphoblastic leukemia: a prospective international multicenter trial comparing sibling donors with matched unrelated donors-the ALL-SCT-BFM-2003 trial. J Clin Oncol. 2015 Apr 10;33(11):1265-74. Epub 2015 Mar 9. link to original article PubMed
International ALL Trial
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Protocol
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) | 1993-2003 | Phase III (C) | Etoposide & TBI, then auto HSCT | Seems to have superior OS |
Preceding treatment
Chemotherapy, Cycle 1
- Cytarabine (Ara-C) 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
4-week course, followed by:
Chemotherapy, Cycle 2
- Cytarabine (Ara-C) 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
4-week course, followed by:
Chemotherapy, Cycle 3
- 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 (Ara-C) 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
8-week course, followed by:
Chemotherapy, Cycle 4
- Cytarabine (Ara-C) 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 (Ara-C) 50 mg IT once per week for 4 weeks, then once per quarter for 4 doses
- Whole-brain irradiation to 2400 cGy
Subsequent treatment
- POMP maintenance
References
- MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. 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 | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sakura et al. 2017 (JALSG ALL202-O) | 2002-2011 | Phase III (E-esc) | 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 (6-MP) 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 every 6 hours 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 UMIN C000000063
Linker regimen (consolidation)
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Protocol
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) 12,000 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 (Ara-C) 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) 12,000 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 on days 3 to 5, starting after Methotrexate (MTX) is complete (at 42 hours)
Subsequent treatment
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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Protocol
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 (Ara-C) 2000 mg/m2 IV every 12 hours on days 1 & 2
- Dexamethasone (Decadron) 10 mg (route not specified) every 12 hours 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 (duration not specified), started 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 (6-MP) 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
Subsequent treatment
- Patients with CR after induction: Cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone late intensification between cycles 6 and 7
- Patients with CR after salvage: Cytarabine & idarubicin late intensification between cycles 6 and 7
- All patients: 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
Interim maintenance
Mercaptopurine, Methotrexate, Vincristine
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Larsen et al. 2016 (COG AALL0232) | 2004-2011 | Phase III (E-switch-ic) | Mercaptopurine, Capizzi MTX, Pegaspargase, Vincristine | Superior EFS |
Chemotherapy
- Mercaptopurine (6-MP) 25 mg/m2 PO once per day on days 1 to 56
- Methotrexate (MTX) 5000 mg/m2 IV once per day on days 1, 15, 29, 43
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
Intrathecal component
- Methotrexate (MTX) once per day on days 1 & 29
References
- COG AALL0232: Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, Mattano LA Jr, Cole C, Eicher A, Haugan M, Sorenson M, Heerema NA, Carroll AA, Gastier-Foster JM, Borowitz MJ, Wood BL, Willman CL, Winick NJ, Hunger SP, Carroll WL. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from Children's Oncology Group study AALL0232. J Clin Oncol. 2016 Jul 10;34(20):2380-8. Epub 2016 Apr 25. link to original article link to PMC 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
Chemotherapy, ("Course III")
- Mercaptopurine (6-MP) 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
Radiotherapy
- Cranial radiation, 24 Gy total given in 10 fractions from days 1 to 12
CNS prophylaxis
- Methotrexate (MTX) 15 mg IT once per day on days 1, 8, 15, 22, 29
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, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains verified protocol PubMed
Methotrexate & Pegaspargase
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Regimen
Study | Evidence |
---|---|
Stock et al. 2019 (CALGB 10403) | Non-randomized |
Note: the instructions for dose escalation of MTX in the manuscript are confusing; the authors have been contacted for clarification.
Preceding treatment
Chemotherapy
- Methotrexate (MTX) 100 mg/m2 IV once on day 1, then 150 mg/m2 IV once on day 11, then 200 mg/m2 IV once on day 21, then 250 mg/m2 IV once on day 31, then 300 mg/m2 IV once on day 41
- Pegaspargase (Oncaspar) 2500 units IM or IV once per day on days 2 & 22
CNS prophylaxis
- Methotrexate (MTX) 15 mg IT once per day on days 1 & 31
42-day course
Subsequent treatment
References
- CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article contains verified protocol PubMed
Methotrexate & Vincristine
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Matloub et al. 2011 (COG CCG-1991) | 2000-2005 | Phase III (E-de-esc) | Mercaptopurine, MTX, Vincristine, Dexamethasone | Superior EFS |
Chemotherapy
References
- COG CCG-1991: Matloub Y, Bostrom BC, Hunger SP, Stork LC, Angiolillo A, Sather H, La M, Gastier-Foster JM, Heerema NA, Sailer S, Buckley PJ, Thomson B, Cole C, Nachman JB, Reaman G, Winick N, Carroll WL, Devidas M, Gaynon PS. Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2011 Jul 14;118(2):243-51. Epub 2011 May 11. link to original article link to PMC article PubMed
Late intensification
Cyclophosphamide, Cytarabine, Pegaspargase, Thioguanine, Vincristine, Dexamethasone
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Regimen
Study | Evidence |
---|---|
Stock et al. 2019 (CALGB 10403) | Non-randomized |
Note: also known as delayed intensification "Course IV".
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 29
- Cytarabine (Ara-C) 75 mg/m2 IV or SC once per day on days 29 to 32, 36 to 39
- Pegaspargase (Oncaspar) 2500 units/m2 IM or IV once per day on days 4 +/-1 day & 43
- Thioguanine (Tabloid) 60 mg/m2 PO once per day on days 29 to 42
- Vincristine (Oncovin) 1.5 mg (maximum dose of 2 mg) IV once per day on days 1, 8, 43, 50
- Dexamethasone (Decadron) 5 mg/m2 PO or IV twice per day on days 1 to 7, 15 to 21
CNS prophylaxis
- Methotrexate (MTX) 15 mg IT once per day on days 1, 29, 36
50-day course
Subsequent treatment
References
- CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article contains verified protocol PubMed
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 every 12 hours on day 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 PO 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
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
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 (Ara-C) 2000 mg/m2 IV every 12 hours 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
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
CALGB 8811 late intensification
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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 (Ara-C) 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
- CALGB 8811: Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains verified protocol PubMed
Maintenance after upfront therapy
Mercaptopurine, Methotrexate, Vincristine, Dexamethasone
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Regimen variant #1, 2 years
Study | Evidence |
---|---|
Stock et al. 2019 (CALGB 10403) | Non-randomized |
Note: also known as maintenance "Course V". This duration was intended for female patients.
Preceding treatment
Chemotherapy
- Mercaptopurine (6-MP) 75 mg/m2 PO once per day
- Methotrexate (MTX) as follows:
- Cycles 1 to 4: 20 mg/m2 PO once per day on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
- Cycles 5 to 8: 20 mg/m2 PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
- Vincristine (Oncovin) 1.5 mg (maximum dose of 2 mg) IV once per day on days 1, 29, 57
- Dexamethasone (Decadron) 3 mg/m2 PO or IV twice per day on days 1 to 5, 29 to 33, 57 to 61
CNS prophylaxis
- Methotrexate (MTX) as follows:
- Cycles 1 to 4: 15 mg IT once per day on days 1 & 29
- Cycles 5 to 8: 15 mg IT once on day 1
12-week cycle for 8 cycles (2 years)
Regimen variant #2, 3 years
Study | Evidence |
---|---|
Stock et al. 2019 (CALGB 10403) | Non-randomized |
Note: also known as maintenance "Course V". This duration was intended for male patients.
Preceding treatment
Chemotherapy
- Mercaptopurine (6-MP) 75 mg/m2 PO once per day
- Methotrexate (MTX) as follows:
- Cycles 1 to 4: 20 mg/m2 PO once per day on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
- Cycles 5 to 12: 20 mg/m2 PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
- Vincristine (Oncovin) 1.5 mg (maximum dose of 2 mg) IV once per day on days 1, 29, 57
- Dexamethasone (Decadron) 3 mg/m2 PO or IV twice per day on days 1 to 5, 29 to 33, 57 to 61
CNS prophylaxis
- Methotrexate (MTX) as follows:
- Cycles 1 to 4: 15 mg IT once per day on days 1 & 29
- Cycles 5 to 12: 15 mg IT once on day 1
12-week cycle for 12 cycles (3 years)
References
- CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article contains verified protocol PubMed
Mercaptopurine & Methotrexate
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Regimen variant #1, 50/20
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Millot et al. 2001 (EORTC 58881) | 1990-1996 | Phase III (C) | 6-MP & MTX; IV 6-MP & PO MTX | Superior DFS (*) |
Conter et al. 2007 (I-BFM-SG IR ALL) | 1995-2000 | Phase III (C) | D-OMP | Did not meet primary endpoint of DFS |
Note: reported efficacy for EORTC 58881 is based on the 2005 update.
Preceding treatment
- I-BFM-SG IR ALL: BFM re-induction
Chemotherapy
- Mercaptopurine (6-MP) 50 mg/m2 PO once per day
- Methotrexate (MTX) 20 mg/m2 PO once on day 1
7-day cycle for 74 cycles or a total of 2 years from start of treatment
Regimen variant #2, 75/20
Study | Evidence |
---|---|
Linker et al. 1987 | Phase II |
Preceding treatment
Chemotherapy
- Mercaptopurine (6-MP) 75 mg/m2 PO once per day
- Methotrexate (MTX) 20 mg/m2 PO once on day 1
7-day cycle for 130 cycles (30 months)
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
- EORTC 58881: Millot F, Suciu S, Philippe N, Benoit Y, Mazingue F, Uyttebroeck A, Lutz P, Mechinaud F, Robert A, Boutard P, Marguerite G, Ferster A, Plouvier E, Rialland X, Behard C, Plantaz D, Dresse MF, Philippet P, Norton L, Thyss A, Dastugue N, Waterkeyn C, Vilmer E, Otten J; Children's Leukemia Cooperative Group of the European Organiztaion for Research and Treatment of Cancer. Value of high-dose cytarabine during interval therapy of a Berlin-Frankfurt-Munster-based protocol in increased-risk children with acute lymphoblastic leukemia and lymphoblastic lymphoma: results of the European Organisation for Research and Treatment of Cancer 58881 randomized phase III trial. J Clin Oncol. 2001 Apr 1;19(7):1935-42. link to original article PubMed
- Update: Duval M, Suciu S, Ferster A, Rialland X, Nelken B, Lutz P, Benoit Y, Robert A, Manel AM, Vilmer E, Otten J, Philippe N. Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children's Leukemia Group phase 3 trial. Blood. 2002 Apr 15;99(8):2734-9. link to original article PubMed
- Update: van der Werff Ten Bosch J, Suciu S, Thyss A, Bertrand Y, Norton L, Mazingue F, Uyttebroeck A, Lutz P, Robert A, Boutard P, Ferster A, Plouvier E, Maes P, Munzer M, Plantaz D, Dresse MF, Philippet P, Sirvent N, Waterkeyn C, Vilmer E, Philippe N, Otten J. Value of intravenous 6-mercaptopurine during continuation treatment in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma: final results of a randomized phase III trial (58881) of the EORTC CLG. Leukemia. 2005 May;19(5):721-6. link to original article PubMed
- I-BFM-SG IR ALL: Conter V, Valsecchi MG, Silvestri D, Campbell M, Dibar E, Magyarosy E, Gadner H, Stary J, Benoit Y, Zimmermann M, Reiter A, Riehm H, Masera G, Schrappe M. Pulses of vincristine and dexamethasone in addition to intensive chemotherapy for children with intermediate-risk acute lymphoblastic leukaemia: a multicentre randomised trial. Lancet. 2007 Jan 13;369(9556):123-31. link to original article contains verified protocol PubMed NCT00411541
POMP
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POMP: Purinethol (Mercaptopurine), Oncovin (Vincristine), Methotrexate, Prednisone
Regimen variant #1
Study | Evidence |
---|---|
Huguet et al. 2009 (GRAALL-2003) | Phase II |
Preceding treatment
Chemotherapy
- Mercaptopurine (6-MP) 60 mg/m2 PO once per day
- Vincristine (Oncovin) as follows:
- Months 1 to 12: 2 mg IV once on day 1
- Methotrexate (MTX) 25 mg/m2 PO once per day on days 1, 8, 15, 22
- Prednisone (Sterapred) as follows:
- Months 1 to 12: 40 mg/m2/day PO on days 1 to 7
1-month cycle for 24 cycles (2 years)
Regimen variant #2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) | 1993-2003 | Phase III (C) | Etoposide & TBI, then auto HSCT | Seems to have superior OS |
Preceding treatment
Chemotherapy
- Mercaptopurine (6-MP) 75 mg/m2 PO once per day
- Vincristine (Oncovin) 1.4 mg/m2 IV once on day 1
- Methotrexate (MTX) 20 mg/m2 IV or PO once per week
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 5
3-month cycle for 10 cycles (2.5 years from the start of phase III)
Regimen variant #3
Study | Evidence |
---|---|
Kantarjian et al. 2000 | Phase II |
Note: this is the IV POMP used from 1995 onwards. Exact timing of drugs is not given, for example, that certain drugs are taken on days 1 to 5 of the cycle.
Preceding treatment
- Hyper-CVAD/MA x 8
Chemotherapy
- Mercaptopurine (6-MP) 1000 mg/m2 IV over 60 minutes once per day on days 1 to 5
- Vincristine (Oncovin) 2 mg IV once on day 1
- Methotrexate (MTX) 10 mg/m2 IV over 60 minutes once per day on days 1 to 5
- Prednisone (Sterapred) 200 mg PO once per day on days 1 to 5
Supportive medications
- Trimethoprim/Sulfamethoxazole (dose not specified) PO twice per day on Saturday and Sunday for the first 6 months
- ONE of the following antivirals, for the first 6 months:
- Acyclovir (Zovirax) 200 mg PO once per day or 3 times per week
- Valacyclovir (Valtrex) 500 mg PO once per day or 3 times per week
1-month cycle for 24 cycles (2 years)
Regimen variant #4
Study | Evidence |
---|---|
Larson et al. 1995 (CALGB 8811) | Phase II |
Preceding treatment
Chemotherapy, "Course V"
- Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 28
- Vincristine (Oncovin) 2 mg IV once on day 1
- Methotrexate (MTX) 20 mg/m2 PO once per day on days 1, 8, 15, 22
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 5
28-day cycles, continue until 24 months from diagnosis
References
- CALGB 8811: Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. 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
- 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
- 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
Chemotherapy
- Cyclophosphamide (Cytoxan)
- Vincristine (Oncovin)
- Doxorubicin (Adriamycin)
- Dexamethasone (Decadron)
- Pegaspargase (Oncaspar)
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 variant #1
FDA-recommended dose |
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Topp et al. 2014 (MT103-211) | 2012-2013 | Phase II (RT) | ||
Kantarjian et al. 2017 (TOWER) | 2014-2015 | Phase III (E-RT-switch-ooc) | Standard re-induction chemotherapy | Superior OS |
The most common comparator in TOWER was FLAG +/- anthracycline.
Immunotherapy
- Blinatumomab (Blincyto) as follows:
- Cycle 1: 9 mcg/day IV continuous infusion over 7 days, started on day 1, then 28 mcg/day IV continuous infusion over 21 days, started on day 8 (total dose: 651 mcg)
- Cycles 2 to 5: 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)
42-day cycle for up to 5 cycles (2 cycles for induction and 3 additional cycles for consolidation)
Subsequent treatment
- TOWER: Optional blinatumomab maintenance
Regimen variant #2
Study | Years of enrollment | Evidence |
---|---|---|
von Stackelberg et al. 2016 (MT103-205) | 2012-2014 | Phase I/II (RT) |
Note: this is the MTD of a phase I/II trial enrolling children under the age of 18.
Immunotherapy
- Blinatumomab (Blincyto) as follows:
- Cycle 1: 5 mcg/day IV continuous infusion over 7 days, started on day 1, then 15 mcg/day IV continuous infusion over 21 days, started on day 8 (total dose: 350 mcg)
- Cycles 2 to 5: 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)
42-day cycle for up to 5 cycles
Regimen variant #3
Study | Evidence |
---|---|
Topp et al. 2011 (MT103-202) | Phase II |
Topp et al. 2014 (MT103-206) | Phase II |
Immunotherapy
- Blinatumomab (Blincyto) 15 mcg/m2/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 420 mcg/m2)
42-day course
Subsequent treatment
- Patients who had an allogeneic donor could receive an allogeneic hematopoietic stem cell transplant any time after cycle 1. Patients who had response could receive up to an additional 3 cycles of consolidation therapy--same as above.
References
- MT103-202: Topp MS, Kufer P, Gökbuget N, Goebeler M, Klinger M, Neumann S, Horst HA, Raff T, Viardot A, Schmid M, Stelljes M, Schaich M, Degenhard E, Köhne-Volland R, Brüggemann M, Ottmann O, Pfeifer H, Burmeister T, Nagorsen D, Schmidt M, Lutterbuese R, Reinhardt C, Baeuerle PA, Kneba M, Einsele H, Riethmüller G, Hoelzer D, Zugmaier G, Bargou RC. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011 Jun 20;29(18):2493-8. Epub 2011 May 16. 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
- MT103-206: Topp MS, Gökbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, Viardot A, Marks R, Diedrich H, Faul C, Reichle A, Horst HA, Brüggemann M, Wessiepe D, Holland C, Alekar S, Mergen N, Einsele H, Hoelzer D, Bargou RC. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014 Dec 20;32(36):4134-40. Epub 2014 Nov 10. 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
- MT103-211: Topp MS, Gökbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, Dombret H, Fielding AK, Heffner L, Larson RA, Neumann S, Foà R, Litzow M, Ribera JM, Rambaldi A, Schiller G, Brüggemann M, Horst HA, Holland C, Jia C, Maniar T, Huber B, Nagorsen D, Forman SJ, Kantarjian HM. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015 Jan;16(1):57-66. Epub 2014 Dec 16. Erratum in: Lancet Oncol. 2015 Apr;16(4):e158. link to original article PubMed
- MT103-205: 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
- TOWER: Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Brüggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017 Mar 2;376(9):836-847. link to original article contains verified protocol PubMed
- HRQoL analysis: Topp MS, Zimmerman Z, Cannell P, Dombret H, Maertens J, Stein A, Franklin J, Tran Q, Cong Z, Schuh AC. Health-related quality of life in adults with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab. Blood. 2018 Jun 28;131(26):2906-2914. Epub 2018 May 8. link to original article 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 variant #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 variant #2, 52 mg/m2
Study | Years of enrollment | Evidence |
---|---|---|
Jeha et al. 2003 | 2000-2002 | Phase 1, <20 pts (RT) |
Jeha et al. 2006 | 2002-2004 | Phase II (RT) |
Note: this dose was the MTD in Jeha et al. 2003.
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
- Phase 1: Jeha S, Gandhi V, Chan KW, McDonald L, Ramirez I, Madden R, Rytting M, Brandt M, Keating M, Plunkett W, Kantarjian H. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood. 2004 Feb 1;103(3):784-9. Epub 2003 Oct 9. link to original article 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 | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kantarjian et al. 2016 (INO-VATE ALL) | 2012-2014 | Phase III (C) | Inotuzumab ozogamicin | Seems to have inferior OS |
Chemotherapy
- Cytarabine (Ara-C) as follows:
- For patients younger than 55: 3000 mg/m2 IV every 12 hours on days 1 to 6 (total dose: 36,000 mg/m2)
- For patients at least 55: 1500 mg/m2 IV every 12 hours on days 1 to 6 (total dose: 18,000 mg/m2)
6-day course
References
- INO-VATE ALL: Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. link to original article contains protocol link to PMC article PubMed
- Update: Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. 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-2005/R) | 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 (Ara-C) 2000 mg/m2 IV over 3 hours every 12 hours on days 1 to 4 (total dose: 16,000 mg/m2)
- 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
Subsequent treatment
- Patients achieving CR1 after salvage: 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-2005/R: Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed NCT00327678
Cytarabine, Idarubicin, Rituximab
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Regimen
Study | Evidence |
---|---|
Maury et al. 2016 (GRAALL-2005/R) | Non-randomized portion of RCT |
This regimen is for patients not achieving CR1 with induction.
Preceding treatment
Chemotherapy
- Cytarabine (Ara-C) 2000 mg/m2 IV over 3 hours every 12 hours on days 1 to 4 (total dose: 16,000 mg/m2)
- Idarubicin (Idamycin) 12 mg/m2 IV over 60 minutes once per day on days 1 to 3
Targeted therapy
- 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, starting on day 9, continuing until first day with ANC greater than 1000/uL
One course
Subsequent treatment
- Patients achieving CR1 after salvage: Pediatric-like GRAALL consolidation with rituximab
References
- GRAALL-2005/R: Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed NCT00327678
Cytarabine & Mitoxantrone
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kantarjian et al. 2016 (INO-VATE ALL) | 2012-2014 | Phase III (C) | Inotuzumab ozogamicin | Seems to have inferior OS |
Chemotherapy
- Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose per cycle: 1400 mg/m2)
- Mitoxantrone (Novantrone) 12 mg/m2 IV over 20 minutes 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
- INO-VATE ALL: Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. link to original article link to original protocol contains verified protocol in supplement link to PMC article PubMed
- Update: Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. link to original article PubMed
FLAG
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FLAG: FLudarabine, Ara-C (Cytarabine), G-CSF
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kantarjian et al. 2016 (INO-VATE ALL) | 2012-2014 | Phase III (C) | 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 (Ara-C) 2000 mg/m2 IV once per day on days 1 to 6
Growth factor therapy
- 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
- INO-VATE ALL: Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. link to original article contains protocol link to PMC article PubMed
- Update: Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. 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
Protocol
Study | Evidence |
---|---|
Daver et al. 2015 (MDACC 2009-0100) | 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.
Part A (cycles 1, 3, 5, 7)
Chemotherapy
- Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 3 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m2)
- Vincristine (Oncovin) as follows:
- Younger than 18: 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 4 & 11 (+/- 2 days)
- 18 and older: 2 mg IV once per day on days 4 & 11 (+/- 2 days)
- Doxorubicin (Adriamycin) 50 mg/m2 IV continuous infusion over 24 hours, started on day 4
- Dexamethasone (Decadron) as follows:
- Younger than 18: 20 mg/m2 (maximum dose of 40 mg) IV or PO once per day on days 1 to 4, 11 to 14 (+/- 2 days)
- 18 and older: 40 mg IV or PO once per day on days 1 to 4, 11 to 14 (+/- 2 days)
Targeted therapy
- Everolimus (Afinitor) 5 mg PO once per day
Supportive medications
- Mesna (Mesnex) 600 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 1800 mg/m2)
- Pegfilgrastim (Neulasta) 6 mg SC once, approximately 24 hours after completion of chemotherapy
Part B (cycles 2, 4, 6, 8)
Chemotherapy
- Methotrexate (MTX) 200 mg/m2 IV over 2 hours once on day 1, then 800 mg/m2 IV over 22 hours (total dose per cycle: 1000 mg/m2)
- Cytarabine (Ara-C) as follows:
- Younger than 60: 3000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m2)
- 60 and older, or with creatinine at least 1.5 x the upper limit of normal: 1000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m2)
- Methylprednisolone (Solumedrol) as follows:
- Younger than 18: 25 mg/m2 (maximum dose of 50 mg) IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 150 mg/m2)
- 18 and older: 50 mg IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 300 mg/m2)
- It isn't clear if this is meant to be a supportive or antineoplastic medication.
Targeted therapy
- Everolimus (Afinitor) 5 mg PO once per day
Supportive medications
- Not defined
References
- MDACC 2009-0100: Daver N, Boumber Y, Kantarjian H, Ravandi F, Cortes J, Rytting ME, Kawedia JD, Basnett J, Culotta KS, Zeng Z, Lu H, Richie MA, Garris R, Xiao L, Liu W, Baggerly KA, Jabbour E, O'Brien S, Burger J, Bendall LJ, Thomas D, Konopleva M. A Phase I/II study of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia. Clin Cancer Res. 2015 Jun 15;21(12):2704-14. Epub 2015 Feb 27. link to original article link to PMC article contains partial protocol in supplement PubMed
Inotuzumab ozogamicin monotherapy
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Regimen
FDA-recommended dose |
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kantarjian et al. 2012 (MDACC 2009-0872) | 2010-2011 | Phase II | ||
Kantarjian et al. 2016 (INO-VATE ALL) | 2012-2014 | Phase III (E-RT-switch-ooc) | Investigator's choice of: 1. Cytarabine 2. Cytarabine & Mitoxantrone 3. FLAG |
Seems to have superior OS |
Note: the protocol in the text of Kantarjian et al. 2016 is confusing, as it does not specify BSA-based dosing; the original protocol is clear on this, as is the FDA package insert.
Targeted therapy
- Inotuzumab ozogamicin (Besponsa) 0.8 mg/m2 IV once on day 1, then 0.5 mg/m2 IV once per day on days 8 & 15
- For patients achieving CR or CRi, day 1 dose was reduced to 0.5 mg/m2
21-day cycle for 1 cycle, then 28-day cycle for up to 5 cycles
References
- MDACC 2009-0872: Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, York S, Ravandi F, Kwari M, Faderl S, Rios MB, Cortes J, Fayad L, Tarnai R, Wang SA, Champlin R, Advani A, O'Brien S. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012 Apr;13(4):403-11. Epub 2012 Feb 21. link to original article contains protocol PubMed NCT01134575
- INO-VATE ALL: Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. link to original article link to original protocol contains verified protocol in supplement link to PMC article PubMed
- Update: Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. link to original article PubMed
Mitoxantrone, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Parker et al. 2010 (CCLG ALL R3) | 2003-2007 | Phase III (E-switch-ic) | Idarubicin, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone | Superior OS |
Note: per the protocol, this regimen is intended only for patients 18 and younger. This regimen is for patients allergic to pegaspargase.
Chemotherapy
- Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 1 & 8
- 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
Subsequent treatment
- See paper for details of treatment beyond induction
References
- CCLG ALL R3: 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 ISCRTN45724312
Mitoxantrone, Pegaspargase, Vincristine, Dexamethasone
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Parker et al. 2010 (CCLG ALL R3) | 2003-2007 | Phase III (E-switch-ic) | 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
- 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
Subsequent treatment
- See paper for details of treatment beyond induction
References
- CCLG ALL R3: 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 ISCRTN45724312
Tisagenlecleucel monotherapy
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Regimen
Study | Years of enrollment | Evidence | Efficacy |
---|---|---|---|
Grupp et al. 2013 (Pedi CART19) | 2011-NR | Pilot | |
Maude et al. 2014 (UPCC04409) | 2012-2014 | Phase I/IIa | |
Maude et al. 2018 (ELIANA) | 2015-2017 | Phase II (RT) | ORR: 81% |
Note: dosing instructions are based on ELIANA.
Preceding treatment
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 IV once on day 0
- Greater than 50 kg: 1.0 to 2.5 x 108 CTL019 transduced viable T-cells IV once on day 0
One course
References
- Pedi CART19: Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013 Apr 18;368(16):1509-1518. Epub 2013 Mar 25. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. link to original article link to PMC article PubMed NCT01626495
- UPCC04409: Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507-17. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. link to original article link to PMC article PubMed NCT01029366
- ELIANA: Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018 Feb 1;378(5):439-448. link to original article link to supplementary protocol contains verified protocol in supplement PubMed
Vincristine liposomal monotherapy
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Regimen
Study | Years of enrollment | Evidence | Efficacy |
---|---|---|---|
O'Brien et al. 2012 (RALLY) | NR | Phase II (RT) | ORR: 35% |
Chemotherapy
- Vincristine liposomal (Marqibo) 2.25 mg/m2 IV over 60 minutes once per day 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
Consolidation after salvage therapy
Cyclophosphamide & TBI, then allo HSCT
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Cy/TBI: Cyclophosphamide & Total Body Irradiation
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Rudolph et al. 1973 | 1968-1969 | Non-randomized, <20 pts in subgroup | ||
Johnson et al. 1981 | 1976-1980 | Non-randomized | ||
Kersey et al. 1987 | 1982-1985 | Quasi-randomized | Auto HSCT | Superior RFS |
Details in the manuscripts are limited.
Chemotherapy
- Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on two consecutive days
Radiotherapy
- Total body irradiation, 10 to 12 Gy total
Immunotherapy
Stem cells transfused on day 0
References
- Rudolph RH, Fefer A, Thomas ED, Buckner CD, Clift RA, Storb R. Isogeneic marrow grafts for hematologic malignancy in man. Arch Intern Med. 1973 Aug;132(2):279-85. link to original article PubMed
- Update: Fefer A, Einstein AB, Thomas ED, Buckner CD, Clift RA, Glucksberg H, Neiman PE, Storb R. Bone-marrow transplantation for hematologic neoplasia in 16 patients with identical twins. N Engl J Med. 1974 Jun 20;290(25):1389-93. link to original article PubMed
- Johnson FL, Thomas ED, Clark BS, Chard RL, Hartmann JR, Storb R. A comparison of marrow transplantation with chemotherapy for children with acute lymphoblastic leukemia in second or subsequent remission. N Engl J Med. 1981 Oct 8;305(15):846-51. link to original article PubMed
- Kersey JH, Weisdorf D, Nesbit ME, LeBien TW, Woods WG, McGlave PB, Kim T, Vallera DA, Goldman AI, Bostrom B, Hurd D, Ramsay NKC. Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia. N Engl J Med. 1987 Aug 20;317(8):461-7. link to original article PubMed
Maintenance after subsequent lines of therapy
Blinatumomab monotherapy
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kantarjian et al. 2017 (TOWER) | 2014-2015 | Phase III (E-RT-switch-ooc) | Standard maintenance chemotherapy | Superior OS |
The most common comparator was not specified but is presumably POMP.
Preceding treatment
Immunotherapy
- Blinatumomab (Blincyto) 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)
12-week cycle for up to 5 cycles (1 year)
References
- TOWER: Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Brüggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017 Mar 2;376(9):836-847. link to original article contains verified protocol PubMed
- HRQoL analysis: Topp MS, Zimmerman Z, Cannell P, Dombret H, Maertens J, Stein A, Franklin J, Tran Q, Cong Z, Schuh AC. Health-related quality of life in adults with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab. Blood. 2018 Jun 28;131(26):2906-2914. Epub 2018 May 8. link to original article 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.
Investigational agents
These are drugs under study with at least some promising results for this disease.