B-cell acute lymphoblastic leukemia

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Note: biomarker-specific regimens have been moved to dedicated pages:

50 regimens on this page
64 variants on this page


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

Guidelines

ESMO

NCCN

Prephase

Prednisone monotherapy

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Regimen #1, flat dose

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

Note: this regimen was meant for patients up to 60 years old. The original Huguet et al. 2009 article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. See paper for details on CNS prophylaxis and treatment.

Chemotherapy

CNS treatment

Subsequent treatment

Regimen #2, increasing doses

Study Evidence
Chiaretti et al. 2016 (GIMEMA LAL 0904) Phase II

Note: the manuscript does not give details on how quickly the dose is ramped up. Patients in this study had Ph+ ALL.

Chemotherapy

Subsequent treatment

References

  1. 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. Chiaretti S, Vitale A, Vignetti M, Piciocchi A, Fazi P, Elia L, Falini B, Ronco F, Ferrara F, De Fabritiis P, Luppi M, La Nasa G, Tedeschi A, Califano C, Fanin R, Dore F, Mandelli F, Meloni G, Foà R. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study. Haematologica. 2016 Dec;101(12):1544-1552. link to original article link to PMC article contains verified protocol PubMed

Vincristine & Prednisone

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VP: Vincristine & Prednisone

Regimen

Study Evidence
Sallan et al. 1978 Non-randomized

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

Chemotherapy

One course

References

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

Upfront induction therapy

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

Treatment followed by L-asparaginase & methotrexate early intensification.

References

  1. Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article contains verified protocol PubMed
    1. Update: Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. link to original article PubMed
    2. Update: Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. link to original article link to PMC article PubMed
    3. Update: Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. link to original article contains verified protocol link to PMC article PubMed

Cyclophosphamide, Daunorubicin, Vincristine, Prednisone

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Regimen

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

Chemotherapy

One course, followed by consolidation (see paper for details)

References

  1. Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. link to original article contains verified protocol PubMed

Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone

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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 #1

Study Evidence Comparator Efficacy
Huguet et al. 2009 (GRAALL-2003) Phase II
Maury et al. 2016 (GRAALL-R 2005) Phase III Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab Seems to have inferior EFS

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

Preceding treatment

Chemotherapy

  • Cyclophosphamide (Cytoxan) as follows:
    • 750 mg/m2 IV over 3 hours once per day on days 1 & 15 in "good early responders" (GRAALL-2003) and all patients (GRAALL 2005)
    • GRAALL-2003: 750 mg/m2 IV once on day 1, then 500 mg/m2 IV q12h on days 15 & 16 in "poor early responders"
  • Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1 to 3, then 30 mg/m2 IV once per day on days 15 & 16
  • Asparaginase (Elspar) 6000 units/m2/day IV over 60 minutes once per day on days 8, 10, 12, 20, 22, 24, 26, 28
  • Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22
  • Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 14

CNS prophylaxis

Supportive medications

  • Lenograstim (Granocyte) as follows:
    • GRAALL-2003: 150 mcg/m2 SC once per day from day 17 until myeloid recovery
    • GRAALL 2005: 263 mcg SC once per day from day 18 until first day with ANC greater than 1000/uL

Patients with resistant disease received cytarabine & idarubicin salvage prior to further consolidation. All others proceeded to pediatric-like GRAALL consolidation.

Regimen #2, "HyperC"

Study Evidence Comparator Efficacy
Maury et al. 2016 (GRAALL-R 2005) Phase III Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab Seems to have inferior EFS

This is the "HyperC" arm of GRAALL 2005.

Preceding treatment

Chemotherapy

CNS prophylaxis

Supportive medications

Patients with resistant disease received cytarabine & idarubicin salvage prior to further consolidation. All others proceeded to pediatric-like GRAALL consolidation.

Regimen #3

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

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

Chemotherapy ("Induction phase I")

One course

Treatment followed by induction phase II or salvage, see paper for details.

Regimen #4, "Larson regimen"

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

Chemotherapy ("Course I")

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

To be followed by Larson regimen (CALGB 8811) early intensification ("Course II").

References

  1. Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains verified protocol PubMed
  2. Annino L, Vegna ML, Camera A, Specchia G, Visani G, Fioritoni G, Ferrara F, Peta A, Ciolli S, Deplano W, Fabbiano F, Sica S, Di Raimondo F, Cascavilla N, Tabilio A, Leoni P, Invernizzi R, Baccarani M, Rotoli B, Amadori S, Mandelli F; GIMEMA Group. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002 Feb 1;99(3):863-71. link to original article contains verified protocol PubMed
  3. 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. Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; for GRAALL. Rituximab in B-Lineage Adult Acute Lymphoblastic Leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed

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

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Regimen #1

Study Evidence Comparator Efficacy
Maury et al. 2016 (GRAALL-R 2005) Phase III Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone Seems to have superior EFS

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

Preceding treatment

Chemotherapy

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

Patients with resistant disease received cytarabine, idarubicin, rituximab salvage prior to further consolidation. All others proceeded to pediatric-like GRAALL consolidation with rituximab.

Regimen #2, "HyperC"

Study Evidence Comparator Efficacy
Maury et al. 2016 (GRAALL-R 2005) Phase III Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone Seems to have superior EFS

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

Preceding treatment

Chemotherapy

CNS prophylaxis

Supportive medications

Patients with resistant disease received cytarabine, idarubicin, rituximab salvage prior to further consolidation. All others proceeded to pediatric-like GRAALL consolidation with rituximab.

References

  1. Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; for GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed

Cyclophosphamide, Doxorubicin, L-Asparaginase, Vincristine, Prednisolone

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Regimen

Study Evidence
Takeuchi et al. 2002 (JALSG-ALL93) Non-randomized

Unlikely to be completed, here for historic context only.

Chemotherapy

References

  1. Takeuchi J, Kyo T, Naito K, Sao H, Takahashi M, Miyawaki S, Kuriyama K, Ohtake S, Yagasaki F, Murakami H, Asou N, Ino T, Okamoto T, Usui N, Nishimura M, Shinagawa K, Fukushima T, Taguchi H, Morii T, Mizuta S, Akiyama H, Nakamura Y, Ohshima T, Ohno R. Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: the JALSG-ALL93 study. Leukemia. 2002 Jul;16(7):1259-66. link to original article PubMed

Cyclophosphamide, Idarubicin, Vincristine, Prednisone

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Regimen

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

Chemotherapy

One course, followed by consolidation (see paper for details)

References

  1. Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. link to original article contains verified protocol PubMed

Daunorubicin, L-Asparaginase, Vincristine, Prednisone

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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 #1

Study Evidence
Hoelzer et al. 1984 Non-randomized

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

Chemotherapy

4-week course

See paper for details of treatment beyond induction.

Regimen #2

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

To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 91%. There are many local variants of this protocol, which begins with "Phase I":

Chemotherapy

CNS prophylaxis

4-week course

Treatment followed by cyclophosphamide, cytarabine, mercaptopurine induction ("Phase 2").

Regimen #3

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

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

Chemotherapy ("Induction phase I")

One course

Treatment followed by induction phase II or salvage, see paper for details.

Regimen #4, "Linker regimen"

Study Evidence
Linker et al. 1987 Phase II

Chemotherapy, part 1

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

To be followed by Linker regimen consolidation therapy.

Regimen #5

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

Chemotherapy

One course

See paper for details of treatment beyond induction.

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. 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. Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W, Niemeyer C, Henze G, Feldges A, Zintl F, Kornhuber B, Ritter J, Welte K, Gadner H, Riehm H. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood. 2000 Jun 1;95(11):3310-22. link to original article PubMed
  5. Annino L, Vegna ML, Camera A, Specchia G, Visani G, Fioritoni G, Ferrara F, Peta A, Ciolli S, Deplano W, Fabbiano F, Sica S, Di Raimondo F, Cascavilla N, Tabilio A, Leoni P, Invernizzi R, Baccarani M, Rotoli B, Amadori S, Mandelli F; GIMEMA Group. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002 Feb 1;99(3):863-71. link to original article contains verified protocol PubMed
  6. Kamps WA, Bökkerink JP, Hakvoort-Cammel FG, Veerman AJ, Weening RS, van Wering ER, van Weerden JF, Hermans J, Slater R, van den Berg E, Kroes WG, van der Does-van den Berg A. BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991-1996). Leukemia. 2002 Jun;16(6):1099-111. link to original article PubMed
  7. 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
  8. Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008 Mar 1;111(5):2563-72. Epub 2007 Dec 21. link to original article link to PMC article PubMed
  9. Seibel NL, Steinherz PG, Sather HN, Nachman JB, Delaat C, Ettinger LJ, Freyer DR, Mattano LA Jr, Hastings CA, Rubin CM, Bertolone K, Franklin JL, Heerema NA, Mitchell TL, Pyesmany AF, La MK, Edens C, Gaynon PS. Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2008 Mar 1;111(5):2548-55. link to original article link to PMC article PubMed
  10. Möricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dördelmann M, Löning L, Beier R, Ludwig WD, Ratei R, Harbott J, Boos J, Mann G, Niggli F, Feldges A, Henze G, Welte K, Beck JD, Klingebiel T, Niemeyer C, Zintl F, Bode U, Urban C, Wehinger H, Niethammer D, Riehm H, Schrappe M; German-Austrian-Swiss ALL-BFM Study Group. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood. 2008 May 1;111(9):4477-89. doi: 10.1182/blood-2007-09-112920. Epub 2008 Feb 19. Erratum in: Blood. 2009 Apr 30;113(18):4478. Dosage error in article text. link to original article PubMed

Daunorubicin, Pegaspargase, Vincristine, Dexamethasone

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Regimen

Study Evidence
See note (AALL1131) Non-randomized portion of RCT

Note: this regimen is available as a protocol but no manuscript has been published yet, to our knowledge. Per the protocol, it is intended only for patients less than 10 years old.

Chemotherapy

CNS prophylaxis

  • Cytarabine (Cytosar) as follows:
    • Ages 1 to 1.99: 30 mg IT once on day 1
    • Ages 2 to 2.99: 50 mg IT once on day 1
    • Age 3 and older: 70 mg IT once on day 1
  • Methotrexate (MTX) as follows:
    • Ages 1 to 1.99: 8 mg IT once per day on days 8 & 29
    • Ages 2 to 2.99: 10 mg IT once per day on days 8 & 29
    • Ages 3 to 8.99: 12 mg IT once per day on days 8 & 29
    • Age 9 and older: 15 mg IT once per day on days 8 & 29

4-week course

See protocol for details of treatment beyond induction.

References

  1. TBD, see note

Daunorubicin, Pegaspargase, Vincristine, Prednisone

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Regimen, "ABFM"

Study Evidence
Rytting et al. 2014 Non-randomized

ABFM: Augmented Berlin-Frankfurt-Münster regimen
Note: this regimen is available as a protocol (AALL1131) and is briefly described in Rytting et al. 2014. However, Rytting et al. 2014 states that the protocol has been previously published in Seibel et al. 2008, which uses asparaginase, not pegaspargase. Details below are from the AALL1131 protocol.

Chemotherapy

CNS prophylaxis

  • Cytarabine (Cytosar) as follows:
    • Ages 1 to 1.99: 30 mg IT once on day 1
    • Ages 2 to 2.99: 50 mg IT once on day 1
    • Age 3 and older: 70 mg IT once on day 1
  • Methotrexate (MTX) as follows:
    • Ages 1 to 1.99: 8 mg IT once per day on days 8 & 29
    • Ages 2 to 2.99: 10 mg IT once per day on days 8 & 29
    • Ages 3 to 8.99: 12 mg IT once per day on days 8 & 29
    • Age 9 and older: 15 mg IT once per day on days 8 & 29

4-week course

See protocol for details of treatment beyond induction.

References

  1. Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008 Mar 1;111(5):2563-72. Epub 2007 Dec 21. link to original article link to PMC article PubMed
  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

Hyper-CVAD/MA

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

Regimen

Study Evidence
Thomas et al. 1999 Phase II

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

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, then 800 mg/m2 IV over 22 hours on day 1
  • Cytarabine (Cytosar) as follows:
    • For patients younger than 60 years old: 3000 mg/m2 IV over 2 hours Q12H on days 2 & 3 (4 total doses)
    • For patients at least 60 years old: 1000 mg/m2 IV over 2 hours Q12H on days 2 & 3 (4 total doses)
  • Methylprednisolone (Solumedrol) 50 mg IV Q12H on days 1 to 3 This is only mentioned in the Kantarjian et al. 2010 publication, and it isn't clear if it's meant to be a supportive or antineoplastic medication.

Supportive medications

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%

For known CNS disease

  • Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT alternating with Cytarabine (Cytosar) 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
  • Then Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT given weeks 1 & 3 and Cytarabine (Cytosar) 100 mg IT, given weeks 2 & 4
  • Once those 4 weeks are complete, then intrathecal treatment is given similar to the prophylactic schedule, with each drug given once during every remaining cycle of induction therapy:

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

References

  1. 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. 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

L-Asparaginase, Vincristine, Dexamethasone

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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 Comparator Efficacy
Bostrom et al. 2003 (CCG-1922) Phase III L-asparaginase, Vincristine, Prednisone Superior EFS
Mitchell et al. 2005 (UK MRC ALL97) Phase III L-asparaginase, Vincristine, Prednisolone Superior EFS

Unlikely to be completed, here for historic context only.

Chemotherapy

References

  1. Bostrom BC, Sensel MR, Sather HN, Gaynon PS, La MK, Johnston K, Erdmann GR, Gold S, Heerema NA, Hutchinson RJ, Provisor AJ, Trigg ME; Children's Cancer Group. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood. 2003 May 15;101(10):3809-17. Epub 2003 Jan 16. link to original article PubMed
  2. Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A, Eden TO; Medical Research Council Childhood Leukaemia Working Party. Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol. 2005 Jun;129(6):734-45. link to original article PubMed

L-Asparaginase, Vincristine, Prednisolone

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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 Comparator Efficacy
Mitchell et al. 2005 (UK MRC ALL97) Phase III L-asparaginase, Vincristine, Dexamethasone Inferior EFS

Unlikely to be completed, here for historic context only.

Chemotherapy

References

  1. Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A, Eden TO; Medical Research Council Childhood Leukaemia Working Party. Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol. 2005 Jun;129(6):734-45. link to original article PubMed

L-Asparaginase, Vincristine, Prednisone

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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 Comparator Efficacy
Gottlieb et al. 1984 (CALGB) Randomized Daunorubicin, L-Asparaginase, Vincristine, Prednisone Inferior CR rate
van der Does-van den Berg et al. 1989 (DCLSG ALL V) Phase III Daunorubicin, L-Asparaginase, Vincristine, Prednisone Seems not superior
Bostrom et al. 2003 (CCG-1922) Phase III L-asparaginase, Vincristine, Dexamethasone Inferior EFS

Unlikely to be completed, here for historic context only.

Chemotherapy

References

  1. Gottlieb AJ, Weinberg V, Ellison RR, Henderson ES, Terebelo H, Rafla S, Cuttner J, Silver RT, Carey RW, Levy RN, et al. Efficacy of daunorubicin in the therapy of adult acute lymphocytic leukemia: a prospective randomized trial by cancer and leukemia group B. Blood. 1984 Jul;64(1):267-74. link to original article PubMed
  2. van der Does-van den Berg A, van Wering ER, Suciu S, Solbu G, van 't Veer MB, Rammeloo JA, de Koning J, van Zanen GE. Effectiveness of rubidomycin in induction therapy with vincristine, prednisone, and L-asparaginase for standard risk childhood acute lymphocytic leukemia: results of a Dutch phase III study (ALL V). A report on behalf of the Dutch Childhood Leukemia Study Group (DCLSG). Am J Pediatr Hematol Oncol. 1989 Summer;11(2):125-33. PubMed
  3. Bostrom BC, Sensel MR, Sather HN, Gaynon PS, La MK, Johnston K, Erdmann GR, Gold S, Heerema NA, Hutchinson RJ, Provisor AJ, Trigg ME; Children's Cancer Group. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood. 2003 May 15;101(10):3809-17. Epub 2003 Jan 16. link to original article PubMed

Mini-Hyper-CVD/MA & Inotuzumab ozogamicin

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Mini-Hyper-CVD/MA: Mini (lower intensity) Hyperfractionated Cyclophosphamide, Vincristine, Dexamethasone alternating with Methotrexate and Ara-C (Cytarabine)

Regimen

Study Evidence
O'Brien et al. 2013 Non-randomized, <20 pts

Unlikely to be completed unless published in manuscript form.

References

  1. Abstract: Susan O'Brien, Deborah A. Thomas, Elias Jabbour, Stefan Faderl, Farhad Ravandi, Gautam Borthakur, Sergernne York, Rebecca Garris, Jorge E. Cortes, Hagop M. Kantarjian. Inotuzumab Ozogamicin In Combination With Low-Intensity Chemotherapy (Mini-hyper-CVD) As Frontline Therapy For Older Patients (≥60 years) With Acute Lymphoblastic Leukemia (ALL). Blood Nov 2013,122(21)1432 link to original abstract

R-Hyper-CVAD/R-MA

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

Regimen

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

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

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

Supportive medications

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

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

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 (Cytosar) reduced to 1000 mg/m2 for patients greater than or equal to 60 years old, creatinine greater than or equal to 1.5 mg/dL or 0 hour MTX level greater than or equal to 20,000 nmol/L
  • Vincristine (Oncovin) reduced to 1 mg for bilirubin greater than 2 mg/dL or NCI common toxicity criteria Grade 2+ peripheral neuropathy, omitted for bilirubin greater than 3 mg/dL or for ileus
  • Doxorubicin (Adriamycin) reduced by 50% for bilirubin 2 to 3 mg/dL, by 75% for bilirubin 3 to 5 mg/dL (eliminated for bilirubin greater than 5 mg/dL or for gastric/small-bowel involvement with Course 1 to reduce duration of myelosuppression given risk of perforation)
  • Methotrexate (MTX) reduced by 50% for CrCl 10 to 50 mL/min/1.73m2 (eliminated for CrCl less than 10 mL/min/1.73m2), by 25% to 75% for delayed excretion and/or nephrotoxicity with prior course (dependent on severity) or by 50% for pleural effusions/ascites with drainage of fluid as feasible.

References

  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 M. D. Anderson Cancer Center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas. Clin Lymphoma Myeloma. 2007 Dec;8 Suppl 2:S57-62. PubMed
  2. Thomas DA, O'Brien S, Faderl S, Garcia-Manero G, Ferrajoli A, Wierda W, Ravandi F, Verstovsek S, Jorgensen JL, Bueso-Ramos C, Andreeff M, Pierce S, Garris R, Keating MJ, Cortes J, Kantarjian HM. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol. 2010 Aug 20;28(24):3880-9. Epub 2010 Jul 26. link to original article link to PMC article PubMed

Early intensification therapy

Larson regimen (CALGB 8811)

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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
Larson et al. 1995 (CALGB 8811) Phase II

Preceding treatment

Chemotherapy ("Course II")

28-day cycle for 2 cycles

Treatment followed by mercaptopurine, methotrexate, WB-XRT interim maintenance ("Course III").

References

  1. Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains verified protocol PubMed

L-Asparaginase & Methotrexate

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Note: Asparaginase (Elspar) was discontinued by the manufacturer in December 2012, and is now essentially out of stock. Alternatives include Pegaspargase (Oncaspar) or Asparaginase Erwinia chrysanthemi (Erwinaze).

Regimen

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

Preceding treatment

Chemotherapy

Supportive medications

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

Patients who were younger than 50 years of age and had an HLA-matched sibling donor, as well as Ph+ patients with any donor, proceeded to etoposide & TBI, then allo HSCT. All others were randomized to etoposide & TBI, then auto HSCT versus International ALL Trial consolidation.

References

  1. 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.

Allogeneic hematopoietic stem cell transplant

To be completed

References

  1. Thiebaut A, Vernant JP, Degos L, Huguet FR, Reiffers J, Sebban C, Lepage E, Thomas X, Fière D. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation. A follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am. 2000 Dec;14(6):1353-66. PubMed
  2. Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. link to original article PubMed

International ALL Trial (MRC UKALL XII/ECOG E2993)

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Regimen

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

Preceding treatment

Chemotherapy, Cycle 1

Chemotherapy, Cycle 2

To start 4 weeks after Cycle 1

Chemotherapy, Cycle 3

To start 4 weeks after Cycle 2

Chemotherapy, Cycle 4

To start 8 weeks after Cycle 3

CNS Prophylaxis

  • Cytarabine (Cytosar) 50 mg IT once per week for 4 weeks, then once per quarter for 4 doses (8 doses, total)
  • Cranial irradiation to 2400 cGy

Treatment followed by POMP maintenance.

References

  1. 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, WB-XRT

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Regimen

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

Preceding treatment

Chemoradiotherapy ("Course III")

12-week course

Treatment followed by Larson regimen (CALGB 8811) late intensification ("Course IV").

References

  1. Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains verified protocol PubMed

Linker regimen (consolidation)

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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
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

Treatment followed by mercaptopurine & methotrexate maintenance.

References

  1. Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. link to original article contains verified protocol PubMed content property of HemOnc.org
    1. Update: Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. link to original article contains verified protocol PubMed

Pediatric-like GRAALL consolidation

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Regimen

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

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

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

Supportive medications

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

Supportive medications

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

Supportive medications

Patients with CR after cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction received cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone late intensification between cycles 6 and 7. Patients with CR after cytarabine & idarubicin salvage received cytarabine & idarubicin late intensification between cycles 6 and 7. All patients proceeded to POMP maintenance after completion of consolidation.

References

  1. Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains verified protocol PubMed

Late intensification

Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone

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Regimen

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

Note: the original article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here.

Preceding treatment

Chemotherapy

Supportive medications

Patients then proceeded back to pediatric-like GRAALL consolidation.

References

  1. 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

Patients then proceeded back to pediatric-like GRAALL consolidation.

References

  1. 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

Larson regimen (CALGB 8811)

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Regimen

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

Preceding treatment

Chemotherapy ("Course IV")

8-week course

To be followed by POMP maintenance ("Course V").

References

  1. Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains verified protocol PubMed

Maintenance after upfront therapy

Mercaptopurine & Methotrexate

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Regimen

Study Evidence
Linker et al. 1987 Phase II

Preceding treatment

Chemotherapy

30-month course

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

Regimen #1

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

Preceding treatment

Chemotherapy

24-month course

Regimen #2

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

Preceding treatment

Chemotherapy

Continue for a total of 2.5 years from the start of phase III

Regimen #3

Study Evidence
Kantarjian et al. 2004 Phase II

Note: Kantarjian et al. 2004 said how many days each drug is given per month, but did not specifically say, for example, that certain drugs are taken on days 1 to 5 of the cycle.

Preceding treatment

Chemotherapy

Supportive medications

1-month cycles for 2 years

Regimen #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. Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains verified protocol PubMed
  2. 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. 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. Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains verified protocol PubMed

Relapsed or refractory

Augmented Hyper-CVAD & Asparaginase

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Regimen

Study Evidence
Faderl et al. 2011 Phase II

To be completed

References

  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 #1

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

This is the FDA-approved dose & schedule. The most common comparator in TOWER was FLAG +/- anthracycline.

Chemotherapy

  • Blinatumomab (Blincyto) given as follows:
    • Cycle 1: 9 mcg/day IV continuous infusion on days 1 to 7, then 28 mcg/day on days 8 to 28
    • Cycles 2 to 5: 28 mcg/day IV continuous infusion on days 1 to 28

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

Patients in TOWER could proceed to blinatumomab maintenance.

Regimen #2

Study Evidence
von Stackelberg et al. 2016 Phase I/II

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

Chemotherapy

  • Blinatumomab (Blincyto) given as follows:
    • Cycle 1: 5 mcg/day IV continuous infusion on days 1 to 7, then 15 mcg/day on days 8 to 28
    • Cycles 2 to 5: 28 mcg/day IV continuous infusion on days 1 to 28

42-day cycle for up to 5 cycles

Regimen #3

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

Chemotherapy

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

References

  1. Topp MS, Kufer P, Gökbuget N, Goebeler M, Klinger M, Neumann S, Horst HA, Raff T, Viardot A, Schmid M, Stelljes M, Schaich M, Degenhard E, Köhne-Volland R, Brüggemann M, Ottmann O, Pfeifer H, Burmeister T, Nagorsen D, Schmidt M, Lutterbuese R, Reinhardt C, Baeuerle PA, Kneba M, Einsele H, Riethmüller G, Hoelzer D, Zugmaier G, Bargou RC. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011 Jun 20;29(18):2493-8. Epub 2011 May 16. link to original article contains verified protocol PubMed
    1. Update: Topp MS, Gökbuget N, Zugmaier G, Degenhard E, Goebeler ME, Klinger M, Neumann SA, Horst HA, Raff T, Viardot A, Stelljes M, Schaich M, Köhne-Volland R, Brüggemann M, Ottmann OG, Burmeister T, Baeuerle PA, Nagorsen D, Schmidt M, Einsele H, Riethmüller G, Kneba M, Hoelzer D, Kufer P, Bargou RC. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012 Dec 20;120(26):5185-7. link to original article PubMed
  2. Topp MS, Gökbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, Viardot A, Marks R, Diedrich H, Faul C, Reichle A, Horst HA, Brüggemann M, Wessiepe D, Holland C, Alekar S, Mergen N, Einsele H, Hoelzer D, Bargou RC. Phase II Trial of the Anti-CD19 Bispecific T Cell-Engager Blinatumomab Shows Hematologic and Molecular Remissions in Patients With Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia. J Clin Oncol. 2014 Dec 20;32(36):4134-40. Epub 2014 Nov 10. link to original article PubMed
    1. Update: Zugmaier G, Gökbuget N, Klinger M, Viardot A, Stelljes M, Neumann S, Horst HA, Marks R, Faul C, Diedrich H, Reichle A, Brüggemann M, Holland C, Schmidt M, Einsele H, Bargou RC, Topp MS. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood. 2015 Dec 10;126(24):2578-84. Epub 2015 Oct 19. link to original article link to PMC article PubMed
  3. Topp MS, Gökbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, Dombret H, Fielding AK, Heffner L, Larson RA, Neumann S, Foà R, Litzow M, Ribera JM, Rambaldi A, Schiller G, Brüggemann M, Horst HA, Holland C, Jia C, Maniar T, Huber B, Nagorsen D, Forman SJ, Kantarjian HM. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015 Jan;16(1):57-66. Epub 2014 Dec 16. Erratum in: Lancet Oncol. 2015 Apr;16(4):e158. link to original article PubMed
  4. von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, Bader P, O'Brien MM, Brethon B, Bhojwani D, Schlegel PG, Borkhardt A, Rheingold SR, Cooper TM, Zwaan CM, Barnette P, Messina C, Michel G, DuBois SG, Hu K, Zhu M, Whitlock JA, Gore L. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. J Clin Oncol. 2016 Dec 20;34(36):4381-4389. link to original article contains verified protocol PubMed
  5. Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Brüggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017 Mar 2;376(9):836-847. link to original article contains verified protocol PubMed

CCE

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CCE: Clofarabine, Cyclophosphamide, Etoposide

Regimen

Study Evidence
Locatelli et al. 2009 Non-randomized

Patients in this study were pediatric: ≤ 15 years old at diagnosis and ≤ 21 years old at time of treatment. No patients had CNS disease at time of treatment, and no patients received CNS prophylaxis.

Chemotherapy

Supportive medications

  • Prophylactic steroids used for patients with greater than 30 x 109 blasts/L in the peripheral blood prior to treatment

5-day course

2 out of 25 patients received a second course of CCE as consolidation therapy. Responding patients were given allogeneic HSCT if a suitable donor was immediately available or were given consolidation courses of chemotherapy including multiple agents active against ALL cells, chosen according to the treating physician's preference."

References

  1. Locatelli F, Testi AM, Bernardo ME, Rizzari C, Bertaina A, Merli P, Pession A, Giraldi E, Parasole R, Barberi W, Zecca M. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol. 2009 Nov;147(3):371-8. Epub 2009 Aug 29. link to original article contains verified protocol PubMed

Clofarabine monotherapy

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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
  2. Retrospective: Barba P, Sampol A, Calbacho M, Gonzalez J, Serrano J, Martínez-Sánchez P, Fernández P, García-Boyero R, Bueno J, Ribera JM. Clofarabine-based chemotherapy for relapsed/refractory adult acute lymphoblastic leukemia and lymphoblastic lymphoma. The Spanish experience. Am J Hematol. 2012 Jun;87(6):631-4. Epub 2012 Mar 19. link to original article PubMed

Cytarabine monotherapy

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Regimen

Study Evidence Comparator Efficacy
Kantarjian et al. 2016 Phase III Inotuzumab ozogamicin Seems to have inferior OS

Chemotherapy

  • Cytarabine (Cytosar) as follows:
    • For patients younger than 55 years old: 3000 mg/m2 IV Q12H
    • For patients at least 55 years old: 1500 mg/m2 IV Q12H

One course of up to 12 doses

References

  1. Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. link to original article PubMed

Cytarabine & Idarubicin

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Regimen

Study Evidence
Huguet et al. 2009 (GRAALL-2003) Phase II
Maury et al. 2016 (GRAALL-R 2005) Non-randomized portion of RCT

Note: the original GRAALL-2003 article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. This regimen is for patients not achieving CR1 with induction.

Preceding treatment

Chemotherapy

Supportive medications

  • Lenograstim (Granocyte) as follows:
    • GRAALL-2003: 150 mcg/m2 SC once per day from day 9 until myeloid recovery
    • GRAALL 2005: 263 mcg IV or SC once per day from day 9 until first day with ANC greater than 1000/uL

One course

Patients achieving CR1 after salvage induction proceeded to pediatric-like GRAALL consolidation.

References

  1. 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. Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; for GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed

Cytarabine, Idarubicin, Rituximab

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Regimen

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

This regimen is for patients not achieving CR1 with induction.

Preceding treatment

Chemotherapy

Supportive medications

One course

Patients achieving CR1 after salvage induction proceeded to pediatric-like GRAALL consolidation with rituximab.

References

  1. Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; for GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains verified protocol in supplement PubMed

Cytarabine & Mitoxantrone

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Regimen

Study Evidence Comparator Efficacy
Kantarjian et al. 2016 Phase III Inotuzumab ozogamicin Seems to have inferior OS

This regimen as reported resembles 7+3m; it is not clear whether the cytarabine is given as bolus or continuous infusion from the manuscript.

Chemotherapy

  • Cytarabine (Cytosar) 200 mg/m2/day IV on days 1 to 7
  • Mitoxantrone (Novantrone) 12 mg/m2 IV once per day on days 1 to 3
    • Dose reduction to 8 mg/m2 allowed on the basis of age, coexisting conditions, and previous anthracycline use

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

References

  1. Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. link to original article contains protocol PubMed

FLAG

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FLAG: FLudarabine, Ara-C (Cytarabine), G-CSF

Regimen

Study Evidence Comparator Efficacy
Kantarjian et al. 2016 Phase III Inotuzumab ozogamicin Seems to have inferior OS

Chemotherapy

  • Fludarabine (Fludara) 30 mg/m2 IV over 30 minutes once per day on days 2 to 6
  • Cytarabine (Cytosar) 2000 mg/m2 IV once per day on days 1 to 6
  • G-CSF 5 mcg/kg or at the institutional standard dose once per day (interval not specified)

28-day cycle for up to 4 cycles

References

  1. Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. link to original article PubMed

Hyper-CVAD/MA & Everolimus

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

Regimen

Study Evidence
Daver et al. 2015 Phase I/II

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

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

  • Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 3 hours Q12H on days 1 to 3 (6 total doses)
  • Vincristine (Oncovin) as follows:
    • Less than 18 years old: 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 4 & 11 (+/- 2 days)
    • Adults: 2 mg IV once per day on days 4 & 11 (+/- 2 days)
  • Doxorubicin (Adriamycin) 50 mg/m2 IV over 24 hours on day 4
  • Dexamethasone (Decadron) as follows:
    • Less than 18 years old: 20 mg/m2 (maximum dose of 40 mg) PO/IV once per day on days 1 to 4, 11 to 14 (+/- 2 days)
    • Adults: 40 mg PO/IV once per day on days 1 to 4, 11 to 14 (+/- 2 days)
  • Everolimus (Afinitor) 5 mg PO once per day

Supportive medications

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

  • Methotrexate (MTX) 200 mg/m2 IV over 2 hours, then 800 mg/m2 IV over 22 hours on day 1
  • Cytarabine (Cytosar) as follows:
    • For patients younger than 60 years old: 3000 mg/m2 IV over 2 hours Q12H on days 2 & 3 (4 total doses)
    • For patients at least 60 years old or with creatinine at least 1.5 x the upper limit of normal: 1000 mg/m2 IV over 2 hours Q12H on days 2 & 3 (4 total doses)
  • Methylprednisolone (Solumedrol) as follows:
    • Less than 18 years old: 25 mg/m2 (maximum dose of 50 mg) IV over 2 hours Q12H on days 1 to 3 (6 total doses)
    • Adults: 50 mg IV over 2 hours Q12H on days 1 to 3 (6 total doses)
      • It isn't clear if this is meant to be a supportive or antineoplastic medication.
  • Everolimus (Afinitor) 5 mg PO once per day

Supportive medications

  • Not defined

References

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

Inotuzumab ozogamicin monotherapy

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Regimen

Study Evidence Comparator Efficacy
Kantarjian et al. 2016 Phase III Cytarabine
Cytarabine & Mitoxantrone
FLAG 		Seems to have superior OS

Chemotherapy

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

28-day cycle (cycle 1 is 21 days) for up to 6 cycles

References

  1. Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, York S, Ravandi F, Kwari M, Faderl S, Rios MB, Cortes J, Fayad L, Tarnai R, Wang SA, Champlin R, Advani A, O'Brien S. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012 Apr;13(4):403-11. Epub 2012 Feb 21. link to original article PubMed
  2. Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. link to original article contains verified protocol PubMed

Mitoxantrone, Pegaspargase, Vincristine, Dexamethasone

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Regimen

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

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

Chemotherapy

CNS prophylaxis

  • Methotrexate (MTX) as follows:
    • Age less than 2: 8 mg IT once per day on days 1 & 8
    • Age 2: 10 mg IT once per day on days 1 & 8
    • Age older than 2: 12 mg IT once per day on days 1 & 8

4-week course

See paper for details of treatment beyond induction.

References

  1. Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, Green N, Révész T, Darbyshire P, Love S, Saha V. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010 Dec 11;376(9757):2009-17. Epub 2010 Dec 3. link to original article contains verified protocol link to PMC article PubMed

Tisagenlecleucel monotherapy

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Regimen

Study Evidence Efficacy
O'Brien et al. 2012 (RALLY) Phase II ORR: 81%

Preceding treatment

Immunotherapy

  • Tisagenlecleucel (Kymriah) as follows:
    • Up to 50 kg: 2.0 to 5.0 x 106 CTL019 transduced viable T-cells per kg body weight
    • Greater than 50 kg: 1.0 to 2.5 x 108 CTL019 transduced viable T-cells

One course

References

  1. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018 Feb 1;378(5):439-448. link to original article link to supplementary protocol contains verified protocol in supplement PubMed

Vincristine liposomal monotherapy

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Regimen

Study Evidence Efficacy
O'Brien et al. 2012 (RALLY) Phase II ORR: 35%

Chemotherapy

28-day cycles

References

  1. O'Brien S, Schiller G, Lister J, Damon L, Goldberg S, Aulitzky W, Ben-Yehuda D, Stock W, Coutre S, Douer D, Heffner LT, Larson M, Seiter K, Smith S, Assouline S, Kuriakose P, Maness L, Nagler A, Rowe J, Schaich M, Shpilberg O, Yee K, Schmieder G, Silverman JA, Thomas D, Deitcher SR, Kantarjian H. High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. J Clin Oncol. 2013 Feb 20;31(6):676-83. Epub 2012 Nov 19. link to original article contains verified protocol link to PMC article PubMed

Maintenance after subsequent lines of therapy

Blinatumomab monotherapy

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Regimen

Study Evidence Comparator Efficacy
Kantarjian et al. 2017 (TOWER) Phase III Standard maintenance chemotherapy Superior OS

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

Preceding treatment

Chemotherapy

12-week cycle for up to 12 months

References

  1. Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Brüggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017 Mar 2;376(9):836-847. link to original article contains verified protocol PubMed

Pediatric ALL

Pediatric ALL regimens tend to be very complex. This list on ped-onc.org appears to be fairly comprehensive and includes regimen details for some of the common regimens e.g. COG-AALL0232. For now we will try to include a list of references here and potentially build these regimens here, over time.

References

  1. Domenech C, Suciu S, De Moerloose B, Mazingue F, Plat G, Ferster A, Uyttebroeck A, Sirvent N, Lutz P, Yakouben K, Munzer M, Röhrlich P, Plantaz D, Millot F, Philippet P, Dastugue N, Girard S, Cavé H, Benoit Y, Bertrandfor Y; Children's Leukemia Group (CLG) of European Organisation for Research and Treatment of Cancer (EORTC). Dexamethasone (6 mg/m2/day) and prednisolone (60 mg/m2/day) were equally effective as induction therapy for childhood acute lymphoblastic leukemia in the EORTC CLG 58951 randomized trial. Haematologica. 2014 Jul;99(7):1220-7. Epub 2014 Apr 11. link to PMC article PubMed

Investigational agents

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

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