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: certain regimens have been moved to dedicated pages:

48 regimens on this page
62 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"

  • 2020: Aldoss I, Douer D. How I treat the toxicities of pegasparaginase in adults with acute lymphoblastic leukemia. Blood. 2020 Mar 26;135(13):987-995. link to original article PubMed
  • 2020: Aldoss I, Forman SJ. How I treat adults with advanced acute lymphoblastic leukemia eligible for CD19-targeted immunotherapy. Blood. 2020 Mar 12;135(11):804-813. link to original article PubMed
  • 2015: Curran E, Stock W. How I treat acute lymphoblastic leukemia in older adolescents and young adults. Blood. 2015 Jun 11;125(24):3702-10. Epub 2015 Mar 24. link to PMC article PubMed
  • 2015: Frey NV, Luger SM. How I treat adults with relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia. Blood. 2015 Jul 30;126(5):589-96. Epub 2015 May 12. link to original article PubMed

NCCN

Prephase

Prednisone monotherapy

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Regimen

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

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 prophylaxis

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

Vincristine & Prednisone

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VP: Vincristine & Prednisone

Regimen

Study Years of enrollment Evidence
McCredie et al. 1983 (SWOG-7416 1975-1977 Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

5-day course

References

  1. SWOG-7416: McCredie KB, Gehan EA, Freireich EJ, Hewlett JS, Coltman CA Jr, Hussein KK, Balcerzak SP, Chen TT. Management of adult acute leukemia: a Southwest Oncology Group study. Cancer. 1983 Sep 15;52(6):958-66. link to original article contains verified protocol PubMed

Upfront induction therapy

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 Years of enrollment Evidence Comparator Comparative Efficacy
Thomas et al. 2004 (LALA-94) 1994-2002 Phase III (C) Cyclophosphamide, Idarubicin, Vincristine, Prednisone Seems to have inferior DFS

Chemotherapy

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 Years of enrollment Evidence Comparator Comparative Efficacy
Labar et al. 2010 (EORTC ALL-4) 1995-2003 Phase III (C) Cyclophosphamide, Daunorubicin, Vincristine, Dexamethasone Did not meet primary endpoint of EFS72

Chemotherapy

CNS prophylaxis

28-day course

Subsequent treatment

  • HAM consolidation

References

  1. EORTC ALL-4: Labar B, Suciu S, Willemze R, Muus P, Marie JP, Fillet G, Berneman Z, Jaksic B, Feremans W, Bron D, Sinnige H, Mistrik M, Vreugdenhil G, De Bock R, Nemet D, Gilotay C, Amadori S, de Witte T; EORTC Leukemia Group. Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group. Haematologica. 2010 Sep;95(9):1489-95. Epub 2010 Apr 7. link to original article link to PMC article contains verified protocol PubMed

Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone

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Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Huguet et al. 2009 (GRAALL-2003) 2003-2005 Phase II
Maury et al. 2016 (GRAALL-2005/R) 2006-2014 Phase III (C) Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab Seems to have inferior EFS
Huguet et al. 2018 (GRAALL-2005) 2006-2014 Phase III (C) Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone; hyperfractionated cyclophosphamide Did not meet primary endpoint of EFS

Note: this "pediatric-like" regimen was meant for patients up to 60 years old. The original Huguet et al. 2009 article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. See paper for details on CNS treatment. This is the "standard-dose cyclophosphamide" arm of GRAALL-2005.

Preceding treatment

Chemotherapy

  • Cyclophosphamide (Cytoxan) as follows:
    • 750 mg/m2 IV over 3 hours once per day on days 1 & 15 in "good early responders" (GRAALL-2003) and all patients (GRAALL-2005)
    • GRAALL-2003: 750 mg/m2 IV once on day 1, then 500 mg/m2 IV every 12 hours on days 15 & 16 in "poor early responders"
  • Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1 to 3, then 30 mg/m2 IV once per day on days 15 & 16
  • Asparaginase (Elspar) 6000 units/m2 IV over 60 minutes once per day on days 8, 10, 12, 20, 22, 24, 26, 28
  • Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22
  • Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 14

CNS prophylaxis

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

Regimen variant #2, "HyperC"

Study Years of enrollment Evidence Comparator Comparative Efficacy
Maury et al. 2016 (GRAALL-2005/R) 2006-2014 Phase III (C) Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab Seems to have inferior EFS
Huguet et al. 2018 (GRAALL-2005) 2006-2014 Phase III (E-esc) Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone; standard-dose cyclophosphamide Did not meet primary endpoint of EFS

This is the "HyperC" arm of GRAALL-2005. Given the negative report in 2018, this experimental arm should be considered as historic reference.

Preceding treatment

Chemotherapy

CNS prophylaxis

Supportive medications

28-day course

Subsequent treatment

Regimen variant #3

Study Years of enrollment Evidence Comparator Comparative Efficacy
Annino et al. 2002 (GIMEMA ALL 0288) 1988-1996 Phase III (E-esc) DOLP Did not meet primary endpoint of CR rate

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

Chemotherapy, "Induction phase I"

31-day course

Subsequent treatment

  • Induction phase II or salvage, see paper for details

Regimen variant #4, "Larson regimen"

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

Chemotherapy, "Course I"

  • Cyclophosphamide (Cytoxan) as follows:
    • For patients younger than 60 years old: 1200 mg/m2 IV once on day 1
    • For patients at least 60 years old: 800 mg/m2 IV once on day 1
  • Daunorubicin (Cerubidine) as follows:
    • For patients younger than 60 years old: 45 mg/m2 IV once per day on days 1 to 3
    • For patients at least 60 years old: 30 mg/m2 IV once per day on days 1 to 3
  • Asparaginase (Elspar) 6000 units/m2 SC once per day on days 5, 8, 11, 15, 18, 22
  • Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22
  • Prednisone (Sterapred) as follows:
    • For patients younger than 60 years old: 60 mg/m2 PO once per day on days 1 to 21
    • For patients at least 60 years old: 60 mg/m2 PO once per day on days 1 to 7

28-day course

Subsequent treatment

References

  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. 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; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed NCT00327678
  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. Intensified therapy of acute lymphoblastic leukemia in adults: report of the randomized GRAALL-2005 clinical trial. J Clin Oncol. 2018 Aug 20;36(24):2514-2523. Epub 2018 Jun 4. link to original article PubMed NCT00327678

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

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Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Maury et al. 2016 (GRAALL-2005/R) 2006-2014 Phase III (E-esc) Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone Seems to have superior EFS

Note: this regimen was meant for CD20+ patients less than 60 years old. This is the "standard" arm of GRAALL-2005/R.

Preceding treatment

Chemotherapy

Targeted therapy

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; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed NCT00327678

Cyclophosphamide, Idarubicin, Vincristine, Prednisone

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Thomas et al. 2004 (LALA-94) 1994-2002 Phase III (E-switch-ic) Cyclophosphamide, Daunorubicin, Vincristine, Prednisone Seems to have superior DFS

Chemotherapy

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; SAKK. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. link to original article contains verified protocol PubMed
    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

Regimen variant #1, 25/5000/1.5/60

Study Evidence
Hoelzer et al. 1984 Non-randomized

Of historic interest. This is "Phase 1" of induction.

Chemotherapy

4-week course

Subsequent treatment

  • See paper for details of treatment beyond induction

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

Study Years of enrollment Evidence Comparator Comparative Efficacy
Annino et al. 2002 (GIMEMA ALL 0288) 1988-1996 Phase III (C) Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone Did not meet primary endpoint of CR rate

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

Chemotherapy

31-day course

Subsequent treatment

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

Regimen variant #3, 45/500/2/40

Study Years of enrollment Evidence Comparator Comparative Efficacy
Gottlieb et al. 1984 (CALGB 7612) 1976-1980 Randomized (E-esc) L-asparaginase, Vincristine, Prednisone Superior CR rate

Chemotherapy

31-day course

Subsequent treatment

  • See paper for details of treatment beyond induction

Protocol variant #4, 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

Regimen variant #5, 60/10,000/1.4/60, daily dauno

Study Evidence
Pullarkat et al. 2008 (SWOG S9400) Phase II

Note: this was the dosing used after the protocol amendment of September 1, 1999.

Chemotherapy

  • Daunorubicin (Cerubidine) 60 mg/m2 IV once per day on days 1 to 3
    • Persistent leukemia on day 21: 60 mg/m2 IV once per day on days 22 & 23
  • Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
    • Persistent leukemia on day 21: 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 29 & 36
  • Asparaginase (Elspar) 10,000 units IM or IV once per day on days 15 to 24
  • Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 28
    • No leukemia on day 21: taper to off by day 42
    • Persistent leukemia on day 21: 60 mg/m2/day PO on days 29 to 42

6-week course

Subsequent treatment

  • See paper for details

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

Daunorubicin, Pegaspargase, Vincristine, Prednisone

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Regimen variant #1, "ABFM"

Study Evidence
Rytting et al. 2014 Non-randomized
Stock et al. 2019 (CALGB 10403) Non-randomized

ABFM: Augmented Berlin-Frankfurt-Münster regimen

Chemotherapy

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

Regimen variant #2, higher-dose dauno

Study Evidence
Pullarkat et al. 2008 (SWOG S9400) Non-randomized

Note: Table 1 lists vincristine as being given PO, which is surely an error. Likewise, prednisone is listed as IV. Pegaspargase was only given until the protocol amendment of September 1, 1999.

Chemotherapy

  • Daunorubicin (Cerubidine) as follows:
    • Part 1 (all patients): 60 mg/m2 IV once per day on days 1 to 3
    • Part 2 (persistent leukemia on d21): 60 mg/m2 IV once per day on days 22 & 23
  • Pegaspargase (Oncaspar) as follows:
    • Part 1 (all patients): 2000 units/m2 IV once on day 15
    • Part 2 (persistent leukemia on d21): 2000 units/m2 IV once on day 38
  • Vincristine (Oncovin) as follows:
    • Part 1 (all patients): 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
    • Part 2 (persistent leukemia on d21): 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 29 & 36
  • Prednisone (Sterapred) as follows:
    • Part 1 (all patients): 60 mg/m2/day PO on days 1 to 28
    • Part 2 (CR on d21): tapered from day 29 to 42
    • Part 2 (persistent leukemia on d21): 60 mg/m2/day PO on days 29 to 42

42-day course

Subsequent treatment

  • See protocol for details of treatment beyond induction

References

  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

Hyper-CVAD/MA

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Hyper-CVAD/MA: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone alternating with Methotrexate, Ara-C (Cytarabine)

Protocol

Study Evidence
Koller et al. 1997 Non-randomized
Thomas et al. 1999 Phase II
Kantarjian et al. 2000 Phase II
Thomas et al. 2004 Non-randomized

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

  • Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m2)
  • Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
  • Doxorubicin (Adriamycin) as follows:
    • Normal EF: 50 mg/m2 IV continuous infusion over 24 hours, started on day 4
    • EF less than 50%: 25 mg/m2/day IV continuous infusion over 48 hours, started on day 4 (total dose per cycle: 50 mg/m2)
  • Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4, 11 to 14

Supportive medications

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

Protocol

Study Evidence
Kantarjian et al. 2018 (MDACC 2010-0991) Phase II

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

Chemotherapy

Antibody-drug conjugate therapy

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

Chemotherapy

Antibody-drug conjugate therapy

28-day cycle for 8 cycles

Subsequent treatment

References

  1. MDACC 2010-0991: Kantarjian H, Ravandi F, Short NJ, Huang X, Jain N, Sasaki K, Daver N, Pemmaraju N, Khoury JD, Jorgensen J, Alvarado Y, Konopleva M, Garcia-Manero G, Kadia T, Yilmaz M, Bortakhur G, Burger J, Kornblau S, Wierda W, DiNardo C, Ferrajoli A, Jacob J, Garris R, O'Brien S, Jabbour E. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2018 Feb;19(2):240-248. Epub 2018 Jan 16. link to original article PubMed

R-Hyper-CVAD/R-MA

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R-Hyper-CVAD/R-MA: Rituximab, Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone alternating with Rituximab, Methotrexate, Ara-C (Cytarabine)

Protocol

Study Evidence
Thomas et al. 2006 Pilot, <20 patients reported
Thomas et al. 2010 (MDACC ID02-230) Non-randomized

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

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

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • Cycles 1 & 3: 375 mg/m2 IV over 2 to 6 hours once per day on days 1 & 11
    • Cycles 5 & 7: no rituximab

Chemotherapy

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

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

Targeted therapy

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

Chemotherapy

  • Methotrexate (MTX) 1000 mg/m2 IV continuous infusion over 24 hours, started on day 1
  • Cytarabine (Ara-C) 3000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m2)

Supportive medications

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. MDACC ID02-230: Thomas DA, O'Brien S, Faderl S, Garcia-Manero G, Ferrajoli A, Wierda W, Ravandi F, Verstovsek S, Jorgensen JL, Bueso-Ramos C, Andreeff M, Pierce S, Garris R, Keating MJ, Cortes J, Kantarjian HM. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol. 2010 Aug 20;28(24):3880-9. Epub 2010 Jul 26. link to original article link to PMC article PubMed NCT00671658

Extended induction therapy

Note: these regimens are used when a pre-specified endpoint during remission induction was not achieved.

Daunorubicin, Pegaspargase, Vincristine, Prednisone

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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

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
Stock et al. 2019 (CALGB 10403) Non-randomized

Preceding treatment

Chemotherapy

50-day course

Subsequent treatment

  • 6-MP, Capizzi MTX, Pegaspargase interim maintenance

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

Blinatumomab monotherapy

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Regimen

Study Years of enrollment Evidence Efficacy
Gökbuget et al. 2018 (BLAST) 2010-2014 Phase II (RT) CR after 1 cycle: 78%

Note: these patients had MRD after induction; also note that this is BSA-based dosing.

Preceding treatment

  • "A minimum of 3 blocks of intensive chemotherapy"

Immunotherapy

  • Blinatumomab (Blincyto) 15 mcg/m2/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 420 mcg/m2)

42-day cycle for up to 4 cycles

Subsequent treatment

  • Patients who had an allogeneic donor could proceed to allogeneic hematopoietic stem cell transplant any time after cycle 1

References

  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 Years of enrollment Evidence Comparator Comparative Efficacy Non-relapse mortality
Thomas et al. 1979 1976-1977 Non-randomized
Sebban et al. 1994 (LALA 87) 1986-1991 Phase III (E-esc) Chemotherapy or Auto HSCT Did not meet primary endpoint of OS60
Thomas et al. 2004 (LALA-94) 1994-2002 Non-randomized portion of RCT


Details in the manuscripts are limited.

Chemotherapy

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 original 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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Regimen

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. 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

International ALL Trial

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Protocol

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) 1993-2003 Phase III (C) Etoposide & TBI, then auto HSCT Seems to have superior OS

Preceding treatment

Chemotherapy, Cycle 1

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 Years of enrollment Evidence Comparator Comparative Efficacy
Sakura et al. 2017 (JALSG ALL202-O) 2002-2011 Phase III (E-esc) MTX (intermediate dose), 6-MP, VCR Seems to have superior DFS

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Given as cycles 2 and 5 of consolidation for patients younger than 50.

Chemotherapy

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 UMIN C000000063

Linker regimen (consolidation)

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Protocol

Study Evidence
Linker et al. 1987 Phase II

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

Preceding treatment

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

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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Protocol

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

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

Preceding treatment

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, 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

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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Regimen variant #1, 2 years

Study Evidence
Stock et al. 2019 (CALGB 10403) Non-randomized

Note: also known as maintenance "Course V". This duration was intended for female patients.

Preceding treatment

Chemotherapy

  • Mercaptopurine (6-MP) 75 mg/m2 PO once per day
  • Methotrexate (MTX) as follows:
    • Cycles 1 to 4: 20 mg/m2 PO once per day on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
    • Cycles 5 to 8: 20 mg/m2 PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
  • Vincristine (Oncovin) 1.5 mg (maximum dose of 2 mg) IV once per day on days 1, 29, 57
  • Dexamethasone (Decadron) 3 mg/m2 PO or IV twice per day on days 1 to 5, 29 to 33, 57 to 61

CNS prophylaxis

  • Methotrexate (MTX) as follows:
    • Cycles 1 to 4: 15 mg IT once per day on days 1 & 29
    • Cycles 5 to 8: 15 mg IT once on day 1

12-week cycle for 8 cycles (2 years)

Regimen variant #2, 3 years

Study Evidence
Stock et al. 2019 (CALGB 10403) Non-randomized

Note: also known as maintenance "Course V". This duration was intended for male patients.

Preceding treatment

Chemotherapy

  • Mercaptopurine (6-MP) 75 mg/m2 PO once per day
  • Methotrexate (MTX) as follows:
    • Cycles 1 to 4: 20 mg/m2 PO once per day on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
    • Cycles 5 to 12: 20 mg/m2 PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
  • Vincristine (Oncovin) 1.5 mg (maximum dose of 2 mg) IV once per day on days 1, 29, 57
  • Dexamethasone (Decadron) 3 mg/m2 PO or IV twice per day on days 1 to 5, 29 to 33, 57 to 61

CNS prophylaxis

  • Methotrexate (MTX) as follows:
    • Cycles 1 to 4: 15 mg IT once per day on days 1 & 29
    • Cycles 5 to 12: 15 mg IT once on day 1

12-week cycle for 12 cycles (3 years)

References

  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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Regimen

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

POMP

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

Regimen variant #1

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

Preceding treatment

Chemotherapy

1-month cycle for 24 cycles (2 years)

Regimen variant #2

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993) 1993-2003 Phase III (C) Etoposide & TBI, then auto HSCT Seems to have superior OS

Preceding treatment

Chemotherapy

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

Regimen variant #3

Study Evidence
Kantarjian et al. 2000 Phase II

Note: this is the IV POMP used from 1995 onwards. Exact timing of drugs is not given, for example, that certain drugs are taken on days 1 to 5 of the cycle.

Preceding treatment

Chemotherapy

Supportive medications

1-month cycle for 24 cycles (2 years)

Regimen variant #4

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

Preceding treatment

Chemotherapy, "Course V"

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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Regimen variant #1

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Topp et al. 2014 (MT103-211) 2012-2013 Phase II (RT)
Kantarjian et al. 2017 (TOWER) 2014-2015 Phase III (E-RT-switch-ooc) Standard re-induction chemotherapy Superior OS

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

Immunotherapy

  • Blinatumomab (Blincyto) as follows:
    • Cycle 1: 9 mcg/day IV continuous infusion over 7 days, started on day 1, then 28 mcg/day IV continuous infusion over 21 days, started on day 8 (total dose: 651 mcg)
    • Cycles 2 to 5: 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)

42-day cycle for up to 5 cycles (2 cycles for induction and 3 additional cycles for consolidation)

Subsequent treatment

Regimen variant #2

Study Evidence
Topp et al. 2011 (MT103-202) Phase II
Topp et al. 2014 (MT103-206) Phase II

Immunotherapy

  • Blinatumomab (Blincyto) 15 mcg/m2/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 420 mcg/m2)

42-day course

Subsequent treatment

  • Patients who had an allogeneic donor could receive an allogeneic hematopoietic stem cell transplant any time after cycle 1. Patients who had response could receive up to an additional 3 cycles of consolidation therapy--same as above.

References

  1. MT103-202: Topp MS, Kufer P, Gökbuget N, Goebeler M, Klinger M, Neumann S, Horst HA, Raff T, Viardot A, Schmid M, Stelljes M, Schaich M, Degenhard E, Köhne-Volland R, Brüggemann M, Ottmann O, Pfeifer H, Burmeister T, Nagorsen D, Schmidt M, Lutterbuese R, Reinhardt C, Baeuerle PA, Kneba M, Einsele H, Riethmüller G, Hoelzer D, Zugmaier G, Bargou RC. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011 Jun 20;29(18):2493-8. Epub 2011 May 16. link to original article contains verified protocol PubMed NCT00560794
    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. MT103-206: Topp MS, Gökbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, Viardot A, Marks R, Diedrich H, Faul C, Reichle A, Horst HA, Brüggemann M, Wessiepe D, Holland C, Alekar S, Mergen N, Einsele H, Hoelzer D, Bargou RC. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014 Dec 20;32(36):4134-40. Epub 2014 Nov 10. link to original article PubMed NCT01209286
    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. MT103-211: Topp MS, Gökbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, Dombret H, Fielding AK, Heffner L, Larson RA, Neumann S, Foà R, Litzow M, Ribera JM, Rambaldi A, Schiller G, Brüggemann M, Horst HA, Holland C, Jia C, Maniar T, Huber B, Nagorsen D, Forman SJ, Kantarjian HM. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015 Jan;16(1):57-66. Epub 2014 Dec 16. Erratum in: Lancet Oncol. 2015 Apr;16(4):e158. link to original article PubMed NCT01466179
  4. 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 link to PMC article PubMed NCT02013167
    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

Clofarabine monotherapy

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Regimen

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

Chemotherapy

3- 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

Cytarabine monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kantarjian et al. 2016 (INO-VATE ALL) 2012-2014 Phase III (C) Inotuzumab ozogamicin Seems to have inferior OS

Chemotherapy

  • Cytarabine (Ara-C) as follows:
    • For patients younger than 55: 3000 mg/m2 IV every 12 hours on days 1 to 6 (total dose: 36,000 mg/m2)
    • For patients at least 55: 1500 mg/m2 IV every 12 hours on days 1 to 6 (total dose: 18,000 mg/m2)

6-day course

References

  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 link to PMC article 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; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed NCT00327678

Cytarabine, Idarubicin, Rituximab

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Regimen

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

This regimen is for patients not achieving CR1 with induction.

Preceding treatment

Chemotherapy

Targeted therapy

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; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed NCT00327678

Cytarabine & Mitoxantrone (MC)

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MC: Mitoxantrone & Cytarabine

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kantarjian et al. 2016 (INO-VATE ALL) 2012-2014 Phase III (C) Inotuzumab ozogamicin Seems to have inferior OS

Chemotherapy

  • Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose per cycle: 1400 mg/m2)
  • Mitoxantrone (Novantrone) 12 mg/m2 IV over 20 minutes once per day on days 1 to 3
    • Dose reduction to 8 mg/m2 allowed on the basis of age, coexisting conditions, and previous anthracycline use

15- to 20-day cycle for up to 4 cycles

References

  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 link to PMC article 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 Years of enrollment Evidence Comparator Comparative Efficacy
Kantarjian et al. 2016 (INO-VATE ALL) 2012-2014 Phase III (C) Inotuzumab ozogamicin Seems to have inferior OS

Chemotherapy

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 link to PMC article 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

Protocol

Study Evidence
Daver et al. 2015 (MDACC 2009-0100) Phase I/II

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

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

Chemotherapy

  • Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 3 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m2)
  • Vincristine (Oncovin) as follows:
    • Younger than 18: 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 4 & 11 (+/- 2 days)
    • 18 and older: 2 mg IV once per day on days 4 & 11 (+/- 2 days)
  • Doxorubicin (Adriamycin) 50 mg/m2 IV continuous infusion over 24 hours, started on day 4
  • Dexamethasone (Decadron) as follows:
    • Younger than 18: 20 mg/m2 (maximum dose of 40 mg) IV or PO once per day on days 1 to 4, 11 to 14 (+/- 2 days)
    • 18 and older: 40 mg IV or PO once per day on days 1 to 4, 11 to 14 (+/- 2 days)

Targeted therapy

Supportive medications

  • Mesna (Mesnex) 600 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 1800 mg/m2)
  • Pegfilgrastim (Neulasta) 6 mg SC once, approximately 24 hours after completion of chemotherapy

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

Chemotherapy

  • Methotrexate (MTX) 200 mg/m2 IV over 2 hours once on day 1, then 800 mg/m2 IV over 22 hours (total dose per cycle: 1000 mg/m2)
  • Cytarabine (Ara-C) as follows:
    • Younger than 60: 3000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m2)
    • 60 and older, or with creatinine at least 1.5 x the upper limit of normal: 1000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m2)
  • Methylprednisolone (Solumedrol) as follows:
    • Younger than 18: 25 mg/m2 (maximum dose of 50 mg) IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 150 mg/m2)
    • 18 and older: 50 mg IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 300 mg/m2)
      • It isn't clear if this is meant to be a supportive or antineoplastic medication.

Targeted therapy

Supportive medications

  • Not defined

References

  1. MDACC 2009-0100: Daver N, Boumber Y, Kantarjian H, Ravandi F, Cortes J, Rytting ME, Kawedia JD, Basnett J, Culotta KS, Zeng Z, Lu H, Richie MA, Garris R, Xiao L, Liu W, Baggerly KA, Jabbour E, O'Brien S, Burger J, Bendall LJ, Thomas D, Konopleva M. A Phase I/II study of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia. Clin Cancer Res. 2015 Jun 15;21(12):2704-14. Epub 2015 Feb 27. link to original article link to PMC article contains partial protocol in supplement PubMed

Inotuzumab ozogamicin monotherapy

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Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Kantarjian et al. 2012 (MDACC 2009-0872) 2010-2011 Phase II
Kantarjian et al. 2016 (INO-VATE ALL) 2012-2014 Phase III (E-RT-switch-ooc) Investigator's choice of:
1. Cytarabine
2. MC
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.

Antibody-drug conjugate therapy

  • Inotuzumab ozogamicin (Besponsa) 0.8 mg/m2 IV once on day 1, then 0.5 mg/m2 IV once per day on days 8 & 15
    • For patients achieving CR or CRi, day 1 dose was reduced to 0.5 mg/m2

21-day cycle for 1 cycle, then 28-day cycle for up to 5 cycles

References

  1. MDACC 2009-0872: Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, York S, Ravandi F, Kwari M, Faderl S, Rios MB, Cortes J, Fayad L, Tarnai R, Wang SA, Champlin R, Advani A, O'Brien S. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012 Apr;13(4):403-11. Epub 2012 Feb 21. link to original article contains protocol PubMed NCT01134575
  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 link to PMC article 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

Tisagenlecleucel monotherapy

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Regimen

Study Years of enrollment Evidence Efficacy
Maude et al. 2014 (UPCC04409) 2012-2014 Phase I/IIa
Maude et al. 2018 (ELIANA) 2015-2017 Phase II (RT) ORR: 81%

Note: dosing instructions are based on ELIANA.

Preceding treatment

  • 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. UPCC04409: Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507-17. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. link to original article link to PMC article PubMed NCT01029366
  2. 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 link to PMC article PubMed NCT02435849

Vincristine liposomal monotherapy

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Regimen

Study Years of enrollment Evidence Efficacy
O'Brien et al. 2012 (RALLY) 2007-NR Phase II (RT) ORR: 35%

Chemotherapy

28-day cycles

References

  1. RALLY: 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 NCT00495079

Consolidation after salvage therapy

Blinatumomab monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Brown et al. 2021 (COG AALL1331) 2014-2019 Phase III (E-switch-ooc) Standard salvage consolidation chemotherapy Might have superior DFS

Note: insufficient dosing information was present in the abstract.

Immunotherapy

Subsequent treatment

  • Allogeneic hematopoietic stem cell transplant

References

  1. COG AALL1331: Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Pulsipher MA, Hunger SP, Loh ML. Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):833-842. link to original article PubMed NCT02101853

Cyclophosphamide & TBI, then allo HSCT

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Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rudolph et al. 1973 1968-1969 Non-randomized, <20 pts in subgroup
Kersey et al. 1987 1982-1985 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. Kersey JH, Weisdorf D, Nesbit ME, LeBien TW, Woods WG, McGlave PB, Kim T, Vallera DA, Goldman AI, Bostrom B, Hurd D, Ramsay NKC. Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia. N Engl J Med. 1987 Aug 20;317(8):461-7. link to original article PubMed

Maintenance after subsequent lines of therapy

Blinatumomab monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kantarjian et al. 2017 (TOWER) 2014-2015 Phase III (E-RT-switch-ooc) Standard maintenance chemotherapy Superior OS

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

Preceding treatment

Immunotherapy

  • Blinatumomab (Blincyto) 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)

12-week cycle for up to 5 cycles (1 year)

References

  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 link to PMC article PubMed NCT02013167
    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

Investigational agents

These are drugs under study with at least some promising results for this disease.

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