B-cell acute lymphoblastic leukemia

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 Martin W. Schoen, MD, MPH
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Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the 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
81 variants on this page

Contents


Please note, mature B-cell ALL (L3) is now classified as Burkitt lymphoma/leukemia. Regimens for this variant are available here

Guidelines

ESMO

EWALL/EBMT

"How I treat"

  • 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

Prephase

Prednisone monotherapy

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Variant #1, flat dose

Study Evidence
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

CNS treatment

7-day course

Subsequent treatment

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

7-day course

Subsequent treatment

References

  1. 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
  2. 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
  3. 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

Study Evidence
Sallan et al. 1978 Non-randomized

Note: this regimen is of historic interest as an induction regimen; it is still occasionally used as pre-phase in patients too ill to get cytotoxic chemotherapy at time of diagnosis.

Chemotherapy

21-day course

References

  1. Sallan SE, Cammita BM, Cassady JR, Nathan DG, Frei E 3rd. Intermittent combination chemotherapy with adriamycin for childhood acute lymphoblastic leukemia: clinical results. Blood. 1978 Mar;51(3):425-33. link to original article contains verified protocol PubMed

Upfront induction therapy

Calaspargase, Daunorubicin, Vincristine, Prednisone

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Regimen

Study Evidence Comparator Comparative Efficacy
Angiolillo et al. 2014 (COG AALL07P4) Randomized (E-RT) Daunorubicin, Pegaspargase, Vincristine, Prednisone Longer half-life

Chemotherapy

5-week course

Subsequent treatment

  • See protocol for details of treatment beyond induction

References

  1. 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
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

CNS prophylaxis

29-day course

Subsequent treatment

References

  1. 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
    1. 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
    2. 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
    3. Update: Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. link to original article contains verified protocol link to PMC article PubMed

Cyclophosphamide, Daunorubicin, Vincristine, Prednisone

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Regimen

Study Evidence Comparator Comparative Efficacy
Thomas et al. 2004 (LALA-94) Phase III (C) Cyclophosphamide, Idarubicin, Vincristine, Prednisone Seems to have inferior DFS

Chemotherapy

28-day course

Subsequent treatment

  • Consolidation (see paper for details)

References

  1. 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
    1. 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 Evidence Comparator Comparative Efficacy
Labar et al. 2010 (ALL-4) Phase III (C) Cyclophosphamide, Daunorubicin, Vincristine, Dexamethasone Seems not superior

Chemotherapy

CNS prophylaxis

28-day course

Subsequent treatment

  • HAM consolidation

References

  1. 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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Variant #1

Study Evidence Comparator Comparative Efficacy
Huguet et al. 2009 (GRAALL-2003) Phase II
Maury et al. 2016 (GRAALL-2005/R) Phase III (C) Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab Seems to have inferior EFS
Huguet et al. 2018 (GRAALL-2005) Phase III (C) Hyperfractionated cyclophosphamide Seems not superior

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

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

Variant #2, "HyperC"

Study Evidence Comparator Comparative Efficacy
Maury et al. 2016 (GRAALL-2005/R) Phase III (C) Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab Seems to have inferior EFS
Huguet et al. 2018 (GRAALL-2005) Phase III (E) Standard-dose cyclophosphamide Seems not superior

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

CNS prophylaxis

Supportive medications

28-day course

Subsequent treatment

Variant #3

Study Evidence Comparator Comparative Efficacy
Annino et al. 2002 (GIMEMA ALL 0288) Phase III (E) DOLP Seems not superior

Note: vincristine is clearly shown as 2 mg/m2 in Table 1, but this is an unusual dose; consider discussing with the authors if you are going to utilize this regimen.

Chemotherapy, "Induction phase I"

31-day course

Subsequent treatment

  • Induction phase II or salvage, see paper for details

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

  1. 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
  2. GIMEMA ALL 0288: Annino L, Vegna ML, Camera A, Specchia G, Visani G, Fioritoni G, Ferrara F, Peta A, Ciolli S, Deplano W, Fabbiano F, Sica S, Di Raimondo F, Cascavilla N, Tabilio A, Leoni P, Invernizzi R, Baccarani M, Rotoli B, Amadori S, Mandelli F; GIMEMA Group. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002 Feb 1;99(3):863-71. link to original article contains verified protocol PubMed
  3. 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
  4. 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; for GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed
  5. 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 (GRAALL). 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

Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab

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Variant #1

Study Evidence Comparator Comparative Efficacy
Maury et al. 2016 (GRAALL-2005/R) Phase III (E) 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

CNS prophylaxis

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

References

  1. 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; for GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed

Cyclophosphamide, Idarubicin, Vincristine, Prednisone

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Regimen

Study Evidence Comparator Comparative Efficacy
Thomas et al. 2004 (LALA-94) Phase III (E) Cyclophosphamide, Daunorubicin, Vincristine, Prednisone Seems to have superior DFS

Chemotherapy

28-day course

Subsequent treatment

  • Consolidation (see paper for details)

References

  1. 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
    1. 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

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

4-week course

Subsequent treatment

  • See paper for details of treatment beyond induction

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

CNS therapy

4-week course

Subsequent treatment

  • Standard versus increased intensity post-remission therapy (see paper for details)

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

CNS therapy

5-week course

Subsequent treatment

  • See paper for details

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

CNS therapy

5-week course

Subsequent treatment

  • See papers for details

Variant #5, 40/6000/2/60-40 ("Phase I" of GIMEMA ALL 0288)

Study Evidence Comparator Comparative Efficacy
Annino et al. 2002 (GIMEMA ALL 0288) Phase III (C) Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone Seems not superior

Note: vincristine is clearly shown as 2 mg/m2 in Table 1, but this is an unusual dose; consider discussing with the authors if you are going to utilize this regimen.

Chemotherapy

31-day course

Subsequent treatment

  • Induction phase II or salvage (see paper for details)

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

6-week course

Subsequent treatment

  • Induction phase II (see papers for details)

Variant #7, 45/500/2/40

Study Evidence Comparator Comparative Efficacy
Gottlieb et al. 1984 (CALGB 7612) Randomized (E) L-asparaginase, Vincristine, Prednisone Superior CR rate

Chemotherapy

31-day course

Subsequent treatment

  • See paper for details of treatment beyond induction

Variant #8, 50/6000/2/60 ("Linker regimen")

Study Evidence
Linker et al. 1987 Phase II

Chemotherapy, part 1

If bone marrow on day 14 has residual leukemia:

Chemotherapy, part 2

If bone marrow on day 28 has residual leukemia:

Chemotherapy, part 3

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

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

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

CNS prophylaxis

4-week course

Subsequent treatment

References

  1. 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
  2. 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
  3. 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
    1. 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
  4. 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
  5. 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
  6. 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
    1. 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
  7. GIMEMA ALL 0288: Annino L, Vegna ML, Camera A, Specchia G, Visani G, Fioritoni G, Ferrara F, Peta A, Ciolli S, Deplano W, Fabbiano F, Sica S, Di Raimondo F, Cascavilla N, Tabilio A, Leoni P, Invernizzi R, Baccarani M, Rotoli B, Amadori S, Mandelli F; GIMEMA Group. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002 Feb 1;99(3):863-71. link to original article contains verified protocol PubMed
  8. 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
  9. 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
    1. 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
    2. 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
    3. 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
  10. 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
  11. 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
  12. 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
    1. 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

Variant #1, 30/10,000/1.5/60

Study Evidence Comparator Comparative Efficacy
de Moerloose et al. 2010 (EORTC CLG 58951) Phase III (C) Daunorubicin, L-Asparaginase, Vincristine, Prednisone Seems not superior

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

5-week course

Subsequent treatment

  • See paper for details

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

29-day course

Subsequent treatment

  • Intensification (randomized) or Cy/TBI with allo HSCT, depending on donor availability

References

  1. 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
    1. 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
  2. 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 (EORTC). 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
    1. 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 (EORTC). Dexamethasone (6 mg/m2/day) and prednisolone (60 mg/m2/day) were equally effective as induction therapy for childhood acute lymphoblastic leukemia in the EORTC CLG 58951 randomized trial. Haematologica. 2014 Jul;99(7):1220-7. Epub 2014 Apr 11. link to original article link to PMC article PubMed
    2. 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 Organization for Research and Treatment of Cancer (EORTC). 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

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

  1. 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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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

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

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

  1. 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
  2. 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
    1. 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
  3. 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

  1. 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)

Regimen

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

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

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

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:

Subsequent treatment

  • Certain patient populations (see e.g. Kantarjian et al. 2004) proceed to receive POMP maintenance

References

  1. 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
  2. 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
  3. 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
  4. 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
    1. 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
  5. 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

Regimen

Study Evidence
Kantarjian et al. 2018 Phase II

Chemotherapy, Part A (cycles 1, 3, 5, 7):

Chemotherapy, Part B (cycles 2, 4, 6, 8):

28-day cycle for 8 cycles

Subsequent treatment

References

  1. 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 Evidence Comparator Comparative Efficacy
Avramis et al. 2002 (CCG 1962) Randomized (E-RT) L-Asparaginase, Vincristine, Prednisone Seems not superior

Chemotherapy

Subsequent treatment

  • See protocol for details of treatment beyond induction

References

  1. 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)

Regimen

Study Evidence
Thomas et al. 2006 Pilot, <20 patients reported
Thomas et al. 2010 Non-randomized

See papers for details of treatment beyond induction/consolidation, which differ substantially between "standard" and "modified" protocols.

Chemotherapy, Part A (cycles 1, 3, 5, 7)

Supportive medications

Next cycle to start no sooner than 14 days or as soon as "unmaintained" WBC count is greater than 3 x 109/L and platelet count greater than 50 x 109/L

Chemotherapy, Part B (cycles 2, 4, 6, 8)

  • Rituximab (Rituxan) as follows:
    • Cycles 2 & 4: 375 mg/m2 IV over 2 to 6 hours once per day on days 2 & 8
    • Cycles 6 & 8: no rituximab
  • Methotrexate (MTX) 1000 mg/m2 IV 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

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

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

  1. 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
    1. 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
  2. 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

Chemotherapy

2-week course

Subsequent treatment

References

  1. 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"

CNS prophylaxis

28-day cycle for 2 cycles

Subsequent treatment

References

  1. 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

Supportive medications

3 cycles (length of cycle not specified in original reference)

Subsequent treatment

References

  1. 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
    1. 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
    2. 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
    3. 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 Evidence Comparator Comparative Efficacy
Mahoney et al. 1998 (POG 9005) Phase III (E) LDMTX/IVMP Seems to have superior CCR
Lauer et al. 2001 (POG 9006) Phase III (C) Intensive chemotherapy Might have inferior EFS

Preceding treatment

Chemotherapy

Subsequent treatment

References

  1. 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
  2. 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

Chemotherapy

50-day course

Subsequent treatment

References

  1. 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
  2. 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 Evidence Comparator Comparative Efficacy
Nachman et al. 1998 Phase III (E) Standard BFM consolidation Seems to have superior OS

Unlikely to be completed, but of historic interest.

Chemotherapy

References

  1. 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 Evidence Efficacy
Gökbuget et al. 2018 (BLAST) 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"

Chemotherapy

  • 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

  1. 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 Evidence Comparator Efficacy Non-relapse mortality
Thomas et al. 1979 Non-randomized
Sebban et al. 1994 (LALA 87) Phase III (E) Chemotherapy or Auto HSCT Seems not superior
Thomas et al. 2004 (LALA-94) Non-randomized portion of RCT

Details in the manuscripts are limited.

Chemotherapy

Radiotherapy


Immunotherapy

Stem cells transfused on day 0

References

  1. 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
  2. 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
    1. 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 SD article PubMed
  3. 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
    1. 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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Variant #1

Study Evidence Comparator Comparative Efficacy
Balduzzi et al. 2005 Quasi-randomized Chemotherapy Seems to have superior DFS
Peters et al. 2015 (ALL-SCT-BFM 2003) Non-randomized

Chemotherapy

Radiotherapy


Immunotherapy

Stem cells transfused on day 0

Variant #2

Study Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) Non-randomized portion of RCT

Chemotherapy

Radiotherapy


Immunotherapy

Stem cells transfused on day 0

References

  1. 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
  2. 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
    1. 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
    2. 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
    3. 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
  3. 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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Regimen

Study Evidence Comparator Comparative Efficacy
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) Phase III (C) Etoposide & TBI, then auto HSCT Seems to have superior OS

Preceding treatment

Chemotherapy, Cycle 1

4-week course, followed by:

Chemotherapy, Cycle 2

4-week course, followed by:

Chemotherapy, Cycle 3

8-week course, followed by:

Chemotherapy, Cycle 4

CNS Prophylaxis

Subsequent treatment

References

  1. 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
    1. 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
    2. 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
    3. Update: Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. link to original article contains verified protocol link to PMC article PubMed

Mercaptopurine, Methotrexate, Vincristine

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Regimen

Study Evidence Comparator Comparative Efficacy
Sakura et al. 2017 (JALSG ALL202-O) Phase III (E) 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

Intrathecal component

Supportive medications

References

  1. 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

Linker regimen (consolidation)

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Regimen

Study Evidence
Linker et al. 1987 Phase II

Each cycle is approximately one month, based on recovery of ANC to greater than 1000/uL and platelet count to greater than 100 x 109/L.

Preceding treatment

Chemotherapy, Treatment A (cycles 1, 3, 5, 7)

Approximately one-month cycle

Chemotherapy, Treatment B (cycles 2, 4, 6, 8)

Approximately one-month cycle

Chemotherapy, Treatment C (cycle 9)

Approximately one-month cycle

Supportive medications

Subsequent treatment

References

  1. 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
    1. Update: Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. link to original article contains verified protocol PubMed

Pediatric-like GRAALL consolidation

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Regimen

Study Evidence
Huguet et al. 2009 (GRAALL-2003) Phase II

Note: the original article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. Also note that each consolidation "block" flows into the next A->B->C and days are scheduled thusly.

Preceding treatment

Chemotherapy, Consolidation A (Cycles 1, 4, 7)

Supportive medications

Chemotherapy, Consolidation B (Cycles 2, 5, 8)

Supportive medications

Chemotherapy, Consolidation C (Cycles 3, 6, 9)

Supportive medications

Subsequent treatment

References

  1. 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 Evidence Comparator Comparative Efficacy
Larsen et al. 2016 (COG AALL0232) Phase III (E) Mercaptopurine, Capizzi MTX, Pegaspargase, Vincristine Superior EFS

Chemotherapy

Intrathecal component

References

  1. 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")

Radiotherapy

CNS prophylaxis

12-week course

Subsequent treatment

References

  1. 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

42-day course

Subsequent treatment

References

  1. 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 Evidence Comparator Comparative Efficacy
Matloub et al. 2011 (COG CCG-1991) Phase III (E) Mercaptopurine, MTX, Vincristine, Dexamethasone Superior EFS

Chemotherapy

References

  1. 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

CNS prophylaxis

50-day course

Subsequent treatment

References

  1. 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

Chemotherapy

Supportive medications

Subsequent treatment

References

  1. 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

Chemotherapy

Supportive medications

Subsequent treatment

References

  1. 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"

8-week course

Subsequent treatment

  • POMP maintenance ("Course V")

References

  1. 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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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)

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

  1. 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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Variant #1, 50/20

Study Evidence Comparator Comparative Efficacy
Millot et al. 2001 (EORTC 58881) Phase III (C) IV 6-MP & PO MTX Superior DFS (*)
Conter et al. 2007 (I-BFM-SG IR ALL) Phase III (C) D-OMP Seems not superior

Note: reported efficacy for EORTC 58881 is based on the 2005 update.

Preceding treatment

  • I-BFM-SG IR ALL: BFM re-induction

Chemotherapy

7-day cycle for 74 cycles or a total of 2 years from start of treatment

Variant #2, 75/20

Study Evidence
Linker et al. 1987 Phase II

Preceding treatment

Chemotherapy

7-day cycle for 130 cycles (30 months)

References

  1. 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
    1. 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
  2. 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 Organization 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
    1. 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
    2. 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
  3. 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

POMP

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POMP: Purinethol (Mercaptopurine), Oncovin (Vincristine), Methotrexate, Prednisone

Variant #1

Study Evidence
Huguet et al. 2009 (GRAALL-2003) Phase II

Preceding treatment

Chemotherapy

1-month cycle for 24 cycles (2 years)

Variant #2

Study Evidence Comparator Comparative Efficacy
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) Phase III (C) Etoposide & TBI, then auto HSCT Seems to have superior OS

Preceding treatment

Chemotherapy

3-month cycle for 10 cycles (2.5 years from the start of phase III)

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

Chemotherapy

Supportive medications

1-month cycle for 24 cycles (2 years)

Variant #4

Study Evidence
Larson et al. 1995 (CALGB 8811) Phase II

Preceding treatment

Chemotherapy, "Course V"

28-day cycles, continue until 24 months from diagnosis

References

  1. 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
  2. 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
    1. 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
  3. 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
    1. 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
    2. 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
    3. 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
  4. 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

References

  1. 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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Variant #1

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Topp et al. 2014 (MT103-211) Phase II (RT)
Kantarjian et al. 2017 (TOWER) Phase III (E-RT) Standard re-induction chemotherapy Superior OS

The most common comparator in TOWER was FLAG +/- anthracycline.

Chemotherapy

  • 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

Variant #2

Study Evidence
von Stackelberg et al. 2016 (MT103-205) Phase I/II (RT)

Note: this is the MTD of a phase I/II trial enrolling children under the age of 18.

Chemotherapy

  • 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

Variant #3

Study Evidence
Topp et al. 2011 Phase II
Topp et al. 2014 (MT103-206) Phase II

Chemotherapy

  • Blinatumomab (Blincyto) 15 mcg/m2/day IV continuous infusion 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

  1. 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
    1. 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
    2. 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
  2. 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
    1. 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
  3. 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
  4. 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
  5. 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
    1. 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

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

  1. 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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Variant #1, 40 mg/m2

Study Evidence
Kantarjian et al. 2003 Phase II, <20 patients in this arm

Chemotherapy

3- to 6-week cycles, depending on response count recovery

Variant #2, 52 mg/m2

Study Evidence
Jeha et al. 2003 Phase 1, <20 pts (RT)
Jeha et al. 2006 Phase II (RT)

Note: this dose was the MTD in Jeha et al. 2003.

Chemotherapy

2- to 6-week cycles, depending on response count recovery

References

  1. 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
  2. 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
  3. Jeha S, Gaynon PS, Razzouk BI, Franklin J, Kadota R, Shen V, Luchtman-Jones L, Rytting M, Bomgaars LR, Rheingold S, Ritchey K, Albano E, Arceci RJ, Goldman S, Griffin T, Altman A, Gordon B, Steinherz L, Weitman S, Steinherz P. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. 2006 Apr 20;24(12):1917-23. link to original article contains protocol PubMed

Cytarabine monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Kantarjian et al. 2016 (INO-VATE ALL) 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

  1. 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 PubMed
    1. 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

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

References

  1. 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
  2. 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; for GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed

Cytarabine, Idarubicin, Rituximab

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Regimen

Study Evidence
Maury et al. 2016 (GRAALL-2005/R) Non-randomized portion of RCT

This regimen is for patients not achieving CR1 with induction.

Preceding treatment

Chemotherapy

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

  1. 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; for GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed

Cytarabine & Mitoxantrone

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Regimen

Study Evidence Comparator Comparative Efficacy
Kantarjian et al. 2016 (INO-VATE ALL) 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

  1. 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 PubMed
    1. 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 Evidence Comparator Comparative Efficacy
Kantarjian et al. 2016 (INO-VATE ALL) Phase III (C) Inotuzumab ozogamicin Seems to have inferior OS

Chemotherapy

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

  1. 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 PubMed
    1. 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

Regimen

Study Evidence
Daver et al. 2015 Phase I/II

Note: there are some difference between this protocol and other published Hyper-CVAD protocols, including flexibility in the timing of vincristine and dexamethasone. Some details were missing, in particular the supportive medications for the B cycles. The everolimus dose is the MTD.

Chemotherapy, Part A (cycles 1, 3, 5, 7):

  • Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 3 hours 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)
  • 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

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:
    • 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.
  • Everolimus (Afinitor) 5 mg PO once per day

Supportive medications

  • Not defined

References

  1. 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 Evidence Comparator Comparative Efficacy
Kantarjian et al. 2012 Phase II
Kantarjian et al. 2016 (INO-VATE ALL) Phase III (E-RT) 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.

Chemotherapy

  • 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

  1. 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
  2. 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 PubMed
    1. 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 Evidence Comparator Comparative Efficacy
Parker et al. 2010 (CCLG ALL R3) Phase III (E) 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

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

  1. 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

Mitoxantrone, Pegaspargase, Vincristine, Dexamethasone

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Regimen

Study Evidence Comparator Comparative Efficacy
Parker et al. 2010 (CCLG ALL R3) Phase III (E) Idarubicin, Pegaspargase, Vincristine, Dexamethasone Superior OS

Note: per the protocol, this regimen is intended only for patients 18 and younger.

Chemotherapy

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

  1. 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

Tisagenlecleucel monotherapy

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Regimen

Study Evidence Efficacy
Grupp et al. 2013 Pilot
Maude et al. 2014 Phase I/IIa
Maude et al. 2018 (ELIANA) Phase II (RT) ORR: 81%

Note: dosing instructions are based on ELIANA.

Preceding treatment

  • Lymphodepleting therapy with FC or CYVE

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

  1. 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
  2. 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
  3. 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 Evidence Efficacy
O'Brien et al. 2012 (RALLY) Phase II (RT) ORR: 35%

Chemotherapy

28-day cycles

References

  1. 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 Evidence Comparator Comparative Efficacy
Rudolph et al. 1973 Non-randomized, <20 pts in subgroup
Johnson et al. 1981 Non-randomized
Kersey et al. 1987 Quasi-randomized Auto HSCT Superior RFS

Details in the manuscripts are limited.

Chemotherapy

Radiotherapy


Immunotherapy

Stem cells transfused on day 0

References

  1. 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
    1. 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
  2. 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
  3. 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 Evidence Comparator Comparative Efficacy
Kantarjian et al. 2017 (TOWER) Phase III (E-RT) Standard maintenance chemotherapy Superior OS

The most common comparator was not specified but is presumably POMP.

Preceding treatment

Chemotherapy

  • 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

  1. 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
    1. 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.

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