B-cell acute lymphoblastic leukemia

 Share 

Use of this site is subject to you reading and agreeing with the terms set forth in the disclaimer.

Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are invited to contribute to the site.

53 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

• Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. (2016) PubMed

NCCN

• NCCN Guidelines - Acute Lymphoblastic Leukemia

Prephase

Prednisone (Sterapred)

back to top

Regimen

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

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

Chemotherapy

• Prednisone (Sterapred) 60 mg/m²/day on days -7 to -1

CNS treatment

• Methotrexate (MTX) 15 mg IT once at some point between days -7 and -4

Patients then proceeded to cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction.

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 early 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 PubMed

Induction therapy, Ph-negative

Cyclophosphamide, Cytarabine, Mercaptopurine

back to top

Regimen

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

Treatment preceded by "Phase 1" induction: daunorubicin, L-asparaginase, vincristine, prednisone.

Chemotherapy

• Cyclophosphamide (Cytoxan) 650 mg/m² IV once per day on days 1, 15, 29
• Cytarabine (Cytosar) 75 mg/m² IV once per day on days 1 to 4, 8 to 11, 15 to 18, 22 to 25
• Mercaptopurine (Purinethol) 6 mg/m² PO once per day on days 1 to 28

CNS prophylaxis

• Methotrexate (MTX) 12 mg IT once per day on days 1, 8, 15, 22

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

back to top

Regimen

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once per day on days 1 & 8
• Daunorubicin (Cerubidine) 30 mg/m² IV once per day on days 1 to 3, 15, 16
• Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22
• Prednisone (Sterapred) 60 mg/m²/day IV or PO on days 1 to 7, 15 to 21

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

References

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

back to top

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 prophylaxis and treatment. Treatment preceded by prednisone prephase.

Chemotherapy

• Cyclophosphamide (Cytoxan) as follows:
  • 750 mg/m² IV once per day on days 1 & 15 in "good early responders"
  • 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 (route not specified) 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 on days 1 to 14

Supportive medications

• Lenograstim (Granocyte) 150 mcg/m² SC once per day from day 17 until myeloid recovery

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

Regimen #2

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

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

Chemotherapy ("Induction phase I")

• Cyclophosphamide (Cytoxan) 800 mg/m² IV once per day on days 1 & 2
• Daunorubicin (Cerubidine) 40 mg/m² IV once per day on days 1, 8, 15, 22
• L-Asparaginase 6000 units/m² SC once per day on days 22 to 31
• Vincristine (Oncovin) 2 mg/m² IV once per day on days 1, 8, 15, 22
• Prednisone (Sterapred) 60 mg/m²/day on days 1 to 14, then 40 mg/m²/day on days 15 to 31

One course

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

Regimen #3, "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 early 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 PubMed

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

back to top

Regimen

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. Details were scant in the abstract but a total of 16 to 18 Rituximab (Rituxan) 375 mg/m² infusions were given during the course of therapy. This will be fleshed out when the manuscript is published.

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 PubMed

Cyclophosphamide, Doxorubicin, L-Asparaginase, Vincristine, Prednisolone

back to top

Regimen

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

Unlikely to be completed, here for historic context only.

Chemotherapy

• Cyclophosphamide (Cytoxan)
• Doxorubicin (Adriamycin)
• L-Asparaginase
• Vincristine (Oncovin)
• Prednisolone (Millipred)

References

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

back to top

Regimen

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once per day on days 1 & 8
• Idarubicin (Idamycin) 9 mg/m² IV once per day on days 1, 2, 3, 8
• Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22
• Prednisone (Sterapred) 60 mg/m²/day IV or PO on days 1 to 7, 15 to 21

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

References

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

back to top

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

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

Chemotherapy

• Daunorubicin (Cerubidine) 60 mg/m² IV once per day on days 1, 8, 15, 22
• Asparaginase (Elspar) 10,000 units IV or IM once per day on days 17 to 28
• Vincristine (Oncovin) 1.4 mg/m² IV once per day on days 1, 8, 15, 22
• Prednisone (Sterapred) 60 mg/m² PO in divided doses on days 1 to 28

Ph+ patients

• Imatinib (Gleevec) 400 mg PO once per day, increased to 600 mg PO once per day "wherever possible"
  • Note: Two variants have been tested: from 2003 to 2005, imatinib was added after induction; from 2005 onward, imatinib was added during induction. Various durations are proposed, see Fielding et al. 2013 for more details.

CNS prophylaxis

• Methotrexate (MTX) 12.5 mg IT once on day 15

4-week course

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

Regimen #2

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

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

Chemotherapy ("Induction phase I")

• Daunorubicin (Cerubidine) 40 mg/m² IV once per day on days 1, 8, 15, 22
• L-Asparaginase 6000 units/m² SC once per day on days 22 to 31
• Vincristine (Oncovin) 2 mg/m² IV once per day on days 1, 8, 15, 22
• Prednisone (Sterapred) 60 mg/m²/day on days 1 to 14, then 40 mg/m²/day on days 15 to 31

One course

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

Regimen #3, "Linker regimen"

Study	Evidence
Linker et al. 1987	Phase II

Chemotherapy, part 1

• Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 1 to 3
• Asparaginase (Elspar) 6000 units/m² IM once per day on days 17 to 28
• Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 28

If bone marrow on day 14 has residual leukemia:

Chemotherapy, part 2

• Daunorubicin (Cerubidine) 50 mg/m² IV once on day 15

If bone marrow on day 28 has residual leukemia:

Chemotherapy, part 3

• Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 29 & 30
• Asparaginase (Elspar) 6000 units/m² IM once per day on days 29 to 35
• Vincristine (Oncovin) 2 mg IV once per day on days 29 & 36
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 29 to 42

CNS prophylaxis

• This is for patients without CNS involvement at diagnosis, and is started within 1 week of achieving complete remission:
• Cranial radiation, 18 Gy total given in 10 fractions over 12 to 14 days
• Methotrexate (MTX) 12 mg IT once per week x 6 doses concurrent with radiation

CNS treatment

• This is for patients with CNS involvement at diagnosis:
• Cranial radiation, 28 Gy total given
• Methotrexate (MTX) 12 mg IT once per week x 10 doses that starts while they are receiving induction therapy, then given once per month during the first year of therapy

To be followed by Linker regimen consolidation therapy.

References

1. Hoelzer D, Thiel E, Löffler H, Bodenstein H, Plaumann L, Büchner T, Urbanitz D, Koch P, Heimpel H, Engelhardt R, et al. Intensified therapy in acute lymphoblastic and acute undifferentiated leukemia in adults. Blood. 1984 Jul;64(1):38-47. link to original article PubMed
2. 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
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

back to top

Regimen

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

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

Chemotherapy

• Daunorubicin (Cerubidine) 25 mg/m² IV push over 1 to 15 minutes once per day on days 1, 8, 15, 22
• Pegaspargase (Oncaspar) 2500 units/m² IV over 1 to 2 hours once on day 4
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
• Dexamethasone (Decadron) 5 mg/m² PO/IV BID on days 1 to 14

CNS prophylaxis

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

4-week course

See protocol for details of treatment beyond induction.

References

1. TBD, see note

Daunorubicin, Pegaspargase, Vincristine, Prednisone

back to top

Regimen, "ABFM"

Study	Evidence
Rytting et al. 2014	Non-randomized

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

Chemotherapy

• Daunorubicin (Cerubidine) 25 mg/m² IV push over 1 to 15 minutes once per day on days 1, 8, 15, 22
• Pegaspargase (Oncaspar) 2500 units/m² IV over 1 to 2 hours once on day 4
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
• Prednisone (Sterapred) 30 mg/m² PO/IV BID on days 1 to 28

CNS prophylaxis

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

4-week course

See protocol for details of treatment beyond induction.

References

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

back to top

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

Regimen

Study	Evidence
Thomas et al. 1999	Phase II

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

• Cyclophosphamide (Cytoxan) 300 mg/m² IV over 2 hours Q12H on days 1 to 3 (6 total doses)
• Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
• Doxorubicin (Adriamycin) 50 mg/m² IV over 24 hours (over 48 hours in patients with ejection fractions (EF) less than 50%) on day 4
• Dexamethasone (Decadron) 40 mg PO/IV once per day on days 1 to 4, 11 to 14

Supportive medications

• Mesna (Mesnex) 600 mg/m²/day IV continuous infusion on days 1 to 3, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
• ONE of the following antibiotics:
  • Ciprofloxacin (Cipro) 500 mg PO BID
  • Levofloxacin (Levaquin) 500 mg PO once per day
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID
• Fluconazole (Diflucan) 200 mg PO once per day
• ONE of the following antivirals:
  • Acyclovir (Zovirax) 200 mg PO BID
  • Valacyclovir (Valtrex) 500 mg PO once per day
• Filgrastim (Neupogen) 10 mcg/kg SC once per day starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL

Next cycle to start as soon as ANC is greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10⁹/L

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

• Methotrexate (MTX) 200 mg/m² IV over 2 hours, then 800 mg/m² IV over 22 hours on day 1
• Cytarabine (Cytosar) as follows:
  • For patients younger than 60 years old: 3000 mg/m² IV over 2 hours Q12H on days 2 & 3 (4 total doses)
  • For patients at least 60 years old: 1000 mg/m² IV over 2 hours Q12H on days 2 & 3 (4 total doses)
• Methylprednisolone (Solumedrol) 50 mg IV Q12H on days 1 to 3 This is only mentioned in the Kantarjian et al. 2010 publication, and it isn't clear if it's meant to be a supportive or antineoplastic medication.

Supportive medications

• Folinic acid (Leucovorin) 50 mg IV once 12 hours after Methotrexate (MTX) is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level less than 100 nmol/L
• ONE of the following antibiotics:
  • Ciprofloxacin (Cipro) 500 mg PO BID
  • Levofloxacin (Levaquin) 500 mg PO once per day
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID
• Fluconazole (Diflucan) 200 mg PO once per day
• ONE of the following antivirals:
  • Acyclovir (Zovirax) 200 mg PO BID
  • Valacyclovir (Valtrex) 500 mg PO once per day
• Filgrastim (Neupogen) 10 mcg/kg SC once per day starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL

Next cycle to start as soon as ANC is greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10⁹/L

CNS prophylaxis

• Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
• Cytarabine (Cytosar) 100 mg IT on day 7 OR 8

Given each cycle for a total of 6 or 8 intrathecal treatments (i.e. 3 each of methotrexate and cytarabine or 4 each of methotrexate and cytarabine), depending on risk for CNS relapse based serum lactate dehydrogenase (LDH) greater than 1400 IU/L and/or proliferative index percentage of S + G2M greater than or equal to 14%

For known CNS disease

• Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT alternating with Cytarabine (Cytosar) 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
• Then Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT given weeks 1 & 3 and Cytarabine (Cytosar) 100 mg IT, given weeks 2 & 4
• Once those 4 weeks are complete, then intrathecal treatment is given similar to the prophylactic schedule, with each drug given once during every remaining cycle of induction therapy:
  • Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT once on day 2
  • Cytarabine (Cytosar) 100 mg IT once on day 7 OR 8

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

References

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. 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
3. 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
4. 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

back to top

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

Unlikely to be completed, here for historic context only.

Chemotherapy

• Asparaginase (Elspar)
• Vincristine (Oncovin)
• Dexamethasone (Decadron)

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

back to top

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

Unlikely to be completed, here for historic context only.

Chemotherapy

• Asparaginase (Elspar)
• Vincristine (Oncovin)
• Prednisolone (Millipred)

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

back to top

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

Unlikely to be completed, here for historic context only.

Chemotherapy

• Asparaginase (Elspar)
• Vincristine (Oncovin)
• Prednisone (Sterapred)

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

back to top

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

back to top

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

Regimen #1, modified hyper-CVAD

Study	Evidence
Thomas et al. 2010	Non-randomized

To be completed

Regimen #2

Study	Evidence
Thomas et al. 2006	Pilot, <20 patients reported

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

• Rituximab (Rituxan) as follows:
  • Cycles 1 & 3: 375 mg/m² IV over 2 to 6 hours once per day on days 1 & 11
  • Cycles 5 & 7: no rituximab
• Cyclophosphamide (Cytoxan) 300 mg/m² IV over 2 hours Q12H on days 1 to 3 (6 total doses)
• Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
• Doxorubicin (Adriamycin) 50 mg/m² IV continuous infusion over 24 hours on day 4
• Dexamethasone (Decadron) 40 mg PO/IV once per day on days 1 to 4, 11 to 14

Supportive medications

• Mesna (Mesnex) 600 mg/m²/day IV continuous infusion on days 1 to 3, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
• Filgrastim (Neupogen) 10 mcg/kg SC once per day starting 24 hours after completion of chemotherapy, given until WBC greater than 3 x 10⁹/L or bone pain present
• ONE of the following antibiotics:
  • Fluoroquinolone
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) dose/route not specified
• Fluconazole (Diflucan) dose/route not specified
• ONE of the following antivirals:
  • Acyclovir (Zovirax) dose/route not specified
  • Valacyclovir (Valtrex) dose/route not specified

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

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

• Rituximab (Rituxan) as follows:
  • Cycles 2 & 4: 375 mg/m² IV over 2 to 6 hours once per day on days 2 & 8
  • Cycles 6 & 8: no rituximab
• Methotrexate (MTX) 1000 mg/m² IV over 24 hours on day 1
• Cytarabine (Cytosar) 3000 mg/m² IV over 2 hours Q12H on days 2 & 3 (4 total doses)

Supportive medications

• Folinic acid (Leucovorin) 50 mg IV once 12 hours after Methotrexate (MTX) is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level less than 100 nmol/L
• Filgrastim (Neupogen) 10 mcg/kg SC once per day starting 24 hours after completion of chemotherapy, given until WBC greater than 3 x 10⁹/L or bone pain present
• ONE of the following antibiotics:
  • Fluoroquinolone
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) dose/route not specified
• Fluconazole (Diflucan) dose/route not specified
• ONE of the following antivirals:
  • Acyclovir (Zovirax) dose/route not specified
  • Valacyclovir (Valtrex) dose/route not specified

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

CNS prophylaxis

• Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
• Cytarabine (Cytosar) 100 mg IT on day 7

Given each cycle for a total of 16 intrathecal treatments. If CNS disease present, therapy augmented to twice per week alternating (MTX, ara-C) treatments until CSF cell count normalizes and cytology is negative, then continues for 4 more alternating once per week treatments; prophylaxis course then resumes.

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

Induction therapy, Ph-positive

Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Imatinib

back to top

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
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." Note that, for simplicity, the flow from this phase to others does not include the imatinib; please check the original reference for further details on imatinib dosing.

Chemotherapy

• Daunorubicin (Cerubidine) 65 mg/m² IV once per day on days 1, 8, 15, 22
• Asparaginase (Elspar) 10,000 units IV or IM once per day on days 17 to 28
• Vincristine (Oncovin) 1.4 mg/m² IV once per day on days 1, 8, 15, 22
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 28
• Imatinib (Gleevec) 400 mg PO once per day, increased to 600 mg PO once per day "wherever possible"
  • Note: Two variants have been tested: from 2003 to 2005, imatinib was added after induction; from 2005 onward, imatinib was added during induction. Various durations are proposed, see Fielding et al. 2013 for more details.

CNS prophylaxis

• Methotrexate (MTX) 12 mg IT once on day 15

4-week course

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

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

Daunorubicin, Vincristine, Prednisolone, Nilotinib

back to top

Regimen

Study	Evidence
Kim et al. 2015	Phase II

Chemotherapy

• Daunorubicin (Cerubidine) 90 mg/m²/day IV continuous infusion on days 1 to 3 (total dose: 270 mg/m²)
• Vincristine (Oncovin) 2 mg IV once per day on days 1 & 8
• Prednisolone (Millipred) 60 mg/m² PO or 48 mg/m² IV once per day on days 1 to 14
• Nilotinib (Tasigna) 400 mg PO BID starting on day 8

CNS Prophylaxis

• Methotrexate (MTX) 15 mg mixed with Hydrocortisone (Cortef) 50 mg IT

Up to 10 doses given during or after induction

Treatment followed by nilotinib-based consolidation or allogeneic hematopoetic cell transplant. Transplant regimen left to the discretion of the investigator.

References

1. Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. link to original article contains verified protocol PubMed

Hyper-CVAD & Dasatinib

back to top

Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Ravandi et al. 2010	Phase II
Sasaki et al. 2016	Propensity score analysis	Hyper-CVAD & Ponatinib	Seems to have inferior OS

Note #1: the dosing of dasatinib has changed three times for this protocol. The initial protocol was 50 mg PO BID, which was then changed to 100 mg PO once per day after these were shown to be equivalent in a separate trial. Starting with patient #43, the protocol was further amended to 100 mg of dasatinib once per day in the first 14 days of the first cycle only, followed by 70 mg once per day continuously from the second cycle through completion of induction. These details are described in the update referenced below.
Note #2: Sasaki et al. 2016 is a post-hoc analysis, not a randomized trial.

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

• Cyclophosphamide (Cytoxan) 300 mg/m² IV over 2 hours Q12H on days 1 to 3 (6 total doses)
• Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
• Doxorubicin (Adriamycin) 50 mg/m² IV continuous infusion over 24 hours on day 4
  • Infusion given over 48 hours in patients with ejection fractions (EF) less than 50%
• Dexamethasone (Decadron) 40 mg PO or IV once per day on days 1 to 4, 11 to 14
• Dasatinib (Sprycel) as follows:
  • Cycle 1: 100 mg PO once per day on days 1 to 14
  • Cycles 3, 5, 7: 70 mg PO once per day

Supportive medications

• Mesna (Mesnex) 600 mg/m²/day IV continuous infusion on days 1 to 3, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
• ONE of the following antibiotics:
  • Ciprofloxacin (Cipro) 500 mg PO BID
  • Levofloxacin (Levaquin) 500 mg PO once per day
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID
• Fluconazole (Diflucan) 200 mg PO once per day
• ONE of the following antivirals:
  • Acyclovir (Zovirax) 200 mg PO BID
  • Valacyclovir (Valtrex) 500 mg PO once per day
• Filgrastim (Neupogen) 10 mcg/kg SC once per day starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
• Cycle 1 also involved:
  • Hydration options included D5 water or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 50 to 100 mL/H
  • Allopurinol (Zyloprim) to decrease likelihood of tumor lysis syndrome; Rasburicase (Elitek) could be used instead for patients with high white blood cell counts at initial presentation
  • Oral sodium bicarbonate (no dosage or frequency listed) on days 1 to 3

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used ANC greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10⁹/L

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

• Methotrexate (MTX) 1000 mg/m² IV continuous infusion over 24 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)
• Dasatinib (Sprycel) 70 mg PO once per day

Supportive medications

• Folinic acid (Leucovorin) 50 mg IV once 12 hours after Methotrexate (MTX) is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level less than 100 nmol/L
  • Leucovorin rescue with Folinic acid (Leucovorin) 50 mg IV Q6H if serum methotrexate levels were greater than 20,000 nmol/L at 0 hours after completion of Methotrexate (MTX); greater than 1000 nmol/L at 24 hours; greater than 100 nmol/L at 48 hours
• ONE of the following antibiotics:
  • Ciprofloxacin (Cipro) 500 mg PO BID
  • Levofloxacin (Levaquin) 500 mg PO once per day
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID
• Fluconazole (Diflucan) 200 mg PO once per day
• ONE of the following antivirals:
  • Acyclovir (Zovirax) 200 mg PO BID
  • Valacyclovir (Valtrex) 500 mg PO once per day
• D5W or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 100 to 125 mL/H
• Filgrastim (Neupogen) 10 mcg/kg SC once per day starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
• Acetazolamide (Diamox) (no dosage/schedule listed) used if urine pH less than 7 to promote excretion

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used ANC greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10⁹/L

CNS prophylaxis

• Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT once on day 2
• Cytarabine (Cytosar) 100 mg IT once on day 7

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 of at least 14%

For known CNS disease

• Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT alternating with Cytarabine (Cytosar) 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
• Then Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT given weeks 1 & 3 and Cytarabine (Cytosar) 100 mg IT, given weeks 2 & 4
• Once those 4 weeks are complete, then intrathecal treatment is given similar to the prophylactic schedule, with each drug given once during every remaining cycle of induction therapy:
  • Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT once on day 2
  • Cytarabine (Cytosar) 100 mg IT once on day 7
• Therapeutic external radiation is given to patients with CNS disease at presentation

Patients achieving a CR proceeded to maintenance dasatinib, vincristine, and prednisone.

References

1. Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. link to original article contains verified protocol--parts of the protocol were not explicitly listed in this reference, which instead referred to Thomas et al. 2004 and Kantarjian et al. 2004 link to PMC article PubMed
   1. Update: Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. link to original article link to PMC article PubMed
   2. Post-hoc analysis: Sasaki K, Jabbour EJ, Ravandi F, Short NJ, Thomas DA, Garcia-Manero G, Daver NG, Kadia TM, Konopleva MY, Jain N, Issa GC, Jeanis V, Moore HG, Garris RS, Pemmaraju N, Cortes JE, O'Brien SM, Kantarjian HM. Hyper-CVAD plus ponatinib versus hyper-CVAD plus dasatinib as frontline therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: A propensity score analysis. Cancer. 2016 Dec 1;122(23):3650-3656. link to original article link to PMC article PubMed
2. Ravandi, F., Othus, M., O'Brien, S. M., Forman, S. J., Ha, C. S., Wong, J. Y., Tallman, M. S., Paietta, E., Racevskis, J., Uy, G. L., Horowitz, M., Takebe, N., Little, R., Borate, U., Kebriaei, P., Kingsbury, L., Kantarjian, H. M., Radich, J. P., Erba, H. P., & Appelbaum, F. R. (2016). US intergroup study of chemotherapy plus dasatinib and allogeneic stem cell transplant in Philadelphia chromosome positive ALL. Blood Advances, 1(3), 250-259. link to original article

Hyper-CVAD & Imatinib

back to top

Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study	Evidence
Thomas et al. 2003	Phase II

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

• Cyclophosphamide (Cytoxan) 300 mg/m² IV over 2 hours Q12H on days 1 to 3 (6 total doses)
• Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
• Doxorubicin (Adriamycin) 50 mg/m² IV over 24 hours (over 48 hours in patients with ejection fractions (EF) less than 50%) on day 4
• Dexamethasone (Decadron) 40 mg PO/IV once per day on days 1 to 4, 11 to 14
• Imatinib (Gleevec) 400 mg PO once per day on days 1 to 14

Supportive medications

• Mesna (Mesnex) 600 mg/m²/day IV continuous infusion on days 1 to 3, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
• ONE of the following antibiotics:
  • Ciprofloxacin (Cipro) 500 mg PO BID
  • Levofloxacin (Levaquin) 500 mg PO once per day
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID
• Fluconazole (Diflucan) 200 mg PO once per day
• ONE of the following antivirals:
  • Acyclovir (Zovirax) 200 mg PO BID
  • Valacyclovir (Valtrex) 500 mg PO once per day
• Filgrastim (Neupogen) 10 mcg/kg SC once per day starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
• Cycle 1 also involved:
  • Hydration options included D5 water or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 50 to 100 mL/H
  • Allopurinol (Zyloprim) to decrease likelihood of tumor lysis syndrome; Rasburicase (Elitek) could be used instead for patients with high white blood cell counts at initial presentation
  • Oral sodium bicarbonate (no dosage or frequency listed) on days 1 to 3

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used ANC greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10⁹/L

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

• Methotrexate (MTX) 1000 mg/m² IV over 24 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)
• Imatinib (Gleevec) 400 mg PO once per day on days 1 to 14

Supportive medications

• Folinic acid (Leucovorin) 50 mg IV once 12 hours after Methotrexate (MTX) is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level less than 100 nmol/L
  • Leucovorin rescue with Folinic acid (Leucovorin) 50 mg IV Q6H if serum methotrexate levels were greater than 20,000 nmol/L at 0 hours after completion of Methotrexate (MTX); greater than 1000 nmol/L at 24 hours; greater than 100 nmol/L at 48 hours
• ONE of the following antibiotics:
  • Ciprofloxacin (Cipro) 500 mg PO BID
  • Levofloxacin (Levaquin) 500 mg PO once per day
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID
• Fluconazole (Diflucan) 200 mg PO once per day
• ONE of the following antivirals:
  • Acyclovir (Zovirax) 200 mg PO BID
  • Valacyclovir (Valtrex) 500 mg PO once per day
• D5W or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 100 to 125 mL/H
• Filgrastim (Neupogen) 10 mcg/kg SC once per day starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
• Acetazolamide (Diamox) (no dosage/schedule listed) used if urine pH less than 7 to promote excretion

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used ANC greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10⁹/L

CNS prophylaxis

• Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
• Cytarabine (Cytosar) 100 mg IT on day 7 OR 8

Given each cycle for a total of 6 or 8 intrathecal treatments (i.e. 3 each of methotrexate and cytarabine or 4 each of methotrexate and cytarabine), depending on risk for CNS relapse based serum lactate dehydrogenase (LDH) greater than 1400 IU/L and/or proliferative index percentage of S + G2M of at least 14%

For known CNS disease

• Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT alternating with Cytarabine (Cytosar) 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
• Then Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT given weeks 1 & 3 and Cytarabine (Cytosar) 100 mg IT, given weeks 2 & 4
• Once those 4 weeks are complete, then intrathecal treatment is given similar to the prophylactic schedule, with each drug given once during every remaining cycle of induction therapy:
  • Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
  • Cytarabine (Cytosar) 100 mg IT on day 7 OR 8
• Therapeutic external radiation is given to patients with CNS disease at presentation

Maintenance therapy after completing 8 cycles of the intensive Part A and Part B chemotherapy

• Imatinib (Gleevec) 600 mg PO once per day on days 1 to 28
• Vincristine (Oncovin) 2 mg IV once on day 1
• Prednisone (Sterapred) 200 mg PO once per day on days 1 to 5

28-day cycle for 5 cycles; then, in month 6, Hyper-CVAD Part A x 1 cycle as described above; then resume maintenance therapy, 28-day cycle for 6 cycles; then, in month 13, Hyper-CVAD Part A x 1 cycle as described above

References

1. Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407. Epub 2003 Oct 9. link to original article contains verified protocol PubMed
   1. Update: Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O' Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the frontline treatment of adult patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61. Epub 2015 Feb 14. link to original article link to PMC article PubMed

Hyper-CVAD & Ponatinib

back to top

Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study	Evidence	Comparator	Efficacy
Jabbour et al. 2015	Phase II
Sasaki et al. 2016	Propensity score analysis	Hyper-CVAD & Dasatinib	Seems to have superior OS

Note: Sasaki et al. 2016 is a post-hoc analysis, not a randomized trial. Jabbour et al. 2015 refers to Thomas et al. 2004 (Hyper-CVAD & Imatinib) for regimen details; these are replicated here.

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

• Cyclophosphamide (Cytoxan) 300 mg/m² IV over 2 hours Q12H on days 1 to 3 (6 total doses)
• Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
• Doxorubicin (Adriamycin) 50 mg/m² IV over 24 hours (over 48 hours in patients with ejection fractions (EF) less than 50%) on day 4
• Dexamethasone (Decadron) 40 mg PO/IV once per day on days 1 to 4, 11 to 14
• Ponatinib (Iclusig) as follows:
  • Cycle 1: 45 mg PO once per day on days 1 to 14
  • Cycles 3, 5, 7: 45 mg PO once per day

Supportive medications

• Mesna (Mesnex) 600 mg/m²/day IV continuous infusion on days 1 to 3, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
• ONE of the following antibiotics:
  • Ciprofloxacin (Cipro) 500 mg PO BID
  • Levofloxacin (Levaquin) 500 mg PO once per day
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID
• Fluconazole (Diflucan) 200 mg PO once per day
• ONE of the following antivirals:
  • Acyclovir (Zovirax) 200 mg PO BID
  • Valacyclovir (Valtrex) 500 mg PO once per day
• Filgrastim (Neupogen) 10 mcg/kg SC once per day starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
• Cycle 1 also involved:
  • Hydration options included D5 water or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 50 to 100 mL/H
  • Allopurinol (Zyloprim) to decrease likelihood of tumor lysis syndrome; Rasburicase (Elitek) could be used instead for patients with high white blood cell counts at initial presentation
  • Oral sodium bicarbonate (no dosage or frequency listed) on days 1 to 3

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used ANC greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10⁹/L

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

• Methotrexate (MTX) 1000 mg/m² IV over 24 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)
• Ponatinib (Iclusig) 45 mg PO once per day

Supportive medications

• Folinic acid (Leucovorin) 50 mg IV once 12 hours after Methotrexate (MTX) is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level less than 100 nmol/L
  • Leucovorin rescue with Folinic acid (Leucovorin) 50 mg IV Q6H if serum methotrexate levels were greater than 20,000 nmol/L at 0 hours after completion of Methotrexate (MTX); greater than 1000 nmol/L at 24 hours; greater than 100 nmol/L at 48 hours
• ONE of the following antibiotics:
  • Ciprofloxacin (Cipro) 500 mg PO BID
  • Levofloxacin (Levaquin) 500 mg PO once per day
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID
• Fluconazole (Diflucan) 200 mg PO once per day
• ONE of the following antivirals:
  • Acyclovir (Zovirax) 200 mg PO BID
  • Valacyclovir (Valtrex) 500 mg PO once per day
• D5W or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 100 to 125 mL/H
• Filgrastim (Neupogen) 10 mcg/kg SC once per day starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
• Acetazolamide (Diamox) (no dosage/schedule listed) used if urine pH less than 7 to promote excretion

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used ANC greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10⁹/L

References

1. Jabbour E, Kantarjian H, Ravandi F, Thomas D, Huang X, Faderl S, Pemmaraju N, Daver N, Garcia-Manero G, Sasaki K, Cortes J, Garris R, Yin CC, Khoury JD, Jorgensen J, Estrov Z, Bohannan Z, Konopleva M, Kadia T, Jain N, DiNardo C, Wierda W, Jeanis V, O'Brien S. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study. Lancet Oncol. 2015 Nov;16(15):1547-55. Epub 2015 Sep 30. link to original article contains partial protocol details link to PMC article PubMed
   1. Post-hoc analysis: Sasaki K, Jabbour EJ, Ravandi F, Short NJ, Thomas DA, Garcia-Manero G, Daver NG, Kadia TM, Konopleva MY, Jain N, Issa GC, Jeanis V, Moore HG, Garris RS, Pemmaraju N, Cortes JE, O'Brien SM, Kantarjian HM. Hyper-CVAD plus ponatinib versus hyper-CVAD plus dasatinib as frontline therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: A propensity score analysis. Cancer. 2016 Dec 1;122(23):3650-3656. link to original article link to PMC article PubMed

Imatinib & Prednisone

back to top

Regimen

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

Treatment preceded by pre-phase prednisone.

Chemotherapy

• Imatinib (Gleevec) 600 mg PO once per day for 50 days
• Prednisone (Sterapred) 60 mg/m²/day until day 24, then tapered and stopped at day 32

CNS prophylaxis

• Methotrexate (MTX) 15 mg IT once per day on days 21 & 35

One course

Treatment followed by HAM & imatinib consolidation.

References

1. 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 contains verified protocol link to PMC article PubMed

Early intensification therapy

Larson regimen (CALGB 8811)

back to top

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

Treatment preceded by cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction ("Course I").

Chemotherapy ("Course II")

• Methotrexate (MTX) 15 mg IT once on day 1
• Cyclophosphamide (Cytoxan) 1000 mg/m² IV once on day 1
• Mercaptopurine (Purinethol) 60 mg/m² PO once per day on days 1 to 14
• Cytarabine (Cytosar) 75 mg/m² SC once per day on days 1 to 4, 8 to 11
• Vincristine (Oncovin) 2 mg IV once per day on days 15 & 22
• Asparaginase (Elspar) 6000 units/m² SC once per day on days 15, 18, 22, 25

28-day cycle for 2 cycles

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

back to top

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

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

Chemotherapy

• Methotrexate (MTX) 3 g/m² IV once per day on days 1, 8, 22
• Asparaginase (Elspar) 10,000 units (route not specified) once per day on days 2, 9, 23

Supportive medications

• Folinic acid (Leucovorin) at "standard" doses

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

Patients who were younger than 50 years of age and had an HLA-matched sibling donor, as well as Ph+ patients with any donor, proceeded to etoposide & TBI -> alloHCT. All others were randomized to etoposide & TBI -> autoHCT 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 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 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

HAM & Imatinib

back to top

HAM: High-dose Ara-C (Cytarabine) & Mitoxantrone

Regimen

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

Treatment preceded by imatinib & prednisone induction.

Chemotherapy

• Cytarabine (Cytosar) 3000 mg/m² IV q12h on days 1 to 4 (8 doses)
• Mitoxantrone (Novantrone) 10 mg/m² IV once per day on days 1 to 3
• Imatinib (Gleevec) 600 mg PO once per day

CNS prophylaxis

• Methotrexate (MTX) 15 mg IT repeated for a total of 14 doses (including all phases of treatment)

One course; total duration of imatinib is not specified

Patients who did not achieve CR with induction proceeded to cytarabine, idarubicin, imatinib late intensification. Patients who achieve CR after consolidation proceed to allogeneic transplant, or autologous transplant if no donor available. Details not provided.

References

1. 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 contains verified protocol link to PMC article PubMed

International ALL Trial (MRC UKALL XII/ECOG E2993)

back to top

Regimen

Study	Evidence	Comparator	Efficacy
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	Phase III	Etoposide & TBI -> autoHCT	Seems to have superior OS

Treatment preceded by L-asparaginase & methotrexate intensification.

Cycle 1

• Cytarabine (Cytosar) 75 mg/m² IV once per day on days 1 to 5
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 5
• Vincristine (Oncovin) 1.4 mg/m² IV once per day on days 1, 8, 15, 22
• Dexamethasone (Decadron) 10 mg/m² PO once per day on days 1 to 28

Cycle 2

To start 4 weeks after Cycle 1

• Cytarabine (Cytosar) 75 mg/m² IV once per day on days 1 to 5
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 5

Cycle 3

To start 4 weeks after Cycle 2

• Daunorubicin (Cerubidine) 25 mg/m² IV once per day on days 1, 8, 15, 22
• Cyclophosphamide (Cytoxan) 650 mg/m² IV once on day 29
• Cytarabine (Cytosar) 75 mg/m² IV once per day on days 31 to 34, 38 to 41
• Thioguanine (Tabloid) 60 mg/m² PO once per day on days 29 to 42

Cycle 4

To start 8 weeks after Cycle 3

• Cytarabine (Cytosar) 75 mg/m² IV once per day on days 1 to 5
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 5

CNS Prophylaxis

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

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

back to top

Regimen

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

Treatment preceded by Larson regimen (CALGB 8811) early intensification ("Course II").

Chemoradiotherapy ("Course III")

• Methotrexate (MTX) 15 mg IT once per day on days 1, 8, 15, 22, 29
• Mercaptopurine (Purinethol) 60 mg/m² PO once per day on days 1 to 70
• Methotrexate (MTX) 20 mg/m² PO once per day on days 36, 43, 50, 57, 64
• Cranial radiation, 24 Gy total given in 10 fractions from days 1 to 12

12-week course

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)

back to top

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

Treatment preceded by daunorubicin, L-asparaginase, vincristine, prednisone induction. 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.

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

• Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 1 & 2
• Vincristine (Oncovin) 2 mg IV once per day on days 1 & 8
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 14
• Asparaginase (Elspar) 12000 units/m² IM once per day on days 2, 4, 7, 9, 11, 14

Approximately one-month cycle

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

• Teniposide (Vumon) 165 mg/m² IV once per day on days 1, 4, 8, 11
• Cytarabine (Cytosar) 300 mg/m² IV once per day on days 1, 4, 8, 11

Approximately one-month cycle

Treatment C (cycle 9)

• Methotrexate (MTX) 690 mg/m² IV over 42 hours on day 1
• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 14
• Asparaginase (Elspar) 12000 units/m² IM once per day on days 2, 4, 7, 9, 11, 14

Approximately one-month cycle

Supportive medications

• Folinic acid (Leucovorin) 15 mg/m² IV every 6 hours x 12 doses, starting after Methotrexate (MTX) is complete (at 42 hours)

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

Nilotinib-based consolidation

back to top

Regimen

Study	Evidence
Kim et al. 2015	Phase II

Treatment preceded by daunorubicin, vincristine, prednisolone, nilotinib induction. Duration of each cycle of consolidation is not specified but is presumably based on toxicities and count recovery. Nilotinib is taken continuously during consolidation.

Consolidation A (Cycle 1)

• Daunorubicin (Cerubidine) 45 mg/m²/day IV continuous infusion on days 1 & 2 (total dose 90 mg/m²)
• Vincristine (Oncovin) 2 mg IV once per day on days 1 & 8
• Prednisolone (Millipred) 60 mg/m² PO once per day on days 1 to 14
• Nilotinib (Tasigna) 400 mg PO BID

Consolidation B (Cycles 2 & 4)

• Cytarabine (Cytosar) 2000 mg/m² IV over 2 hours once per day on days 1 to 4
• Etoposide (Vepesid) 150 mg/m² IV over 3 hours once per day on days 1 to 4
• Nilotinib (Tasigna) 400 mg PO BID

Consolidation C (Cycles 3 & 5)

• Methotrexate (MTX) 220 mg/m² IV bolus, then 60 mg/m²/hr IV continuous infusion for 36 hours twice per cycle (days 1 & 2, 15 & 16)
• Nilotinib (Tasigna) 400 mg PO BID

Supportive medications

• Folinic acid (Leucovorin) 50 mg/m² IV every 6 hours x 3 doses, then PO (dose not specified) until serum methotrexate level less than 0.05

Treatment followed by nilotinib maintenance.

References

1. Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. link to original article contains verified protocol PubMed

Pediatric-like GRAALL consolidation

back to top

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. Treatment preceded by cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction or cytarabine & idarubicin salvage.

Consolidation A (Cycles 1, 4, 7)

• Cytarabine (Cytosar) 2000 mg/m² IV q12h on days 1 & 2
• Dexamethasone (Decadron) 10 mg (route not specified) q12h on days 1 & 2
• Asparaginase (Elspar) 10,000 units/m² (route not specified) once on day 3

Supportive medications

• Lenograstim (Granocyte) 150 mcg/m² SC once per day on days 7 to 13

Consolidation B (Cycles 2, 5, 8)

• Methotrexate (MTX) 3000 mg/m² IV continuous infusion on day 15
• Vincristine (Oncovin) 2 mg IV once on day 15
• Asparaginase (Elspar) 10,000 units/m² (route not specified) once on day 16
• Mercaptopurine (Purinethol) 60 mg/m² PO once per day on days 15 to 21

Supportive medications

• Lenograstim (Granocyte) 150 mcg/m² SC once per day on days 22 to 27

Consolidation C (Cycles 3, 6, 9)

• Cyclophosphamide (Cytoxan) 500 mg/m² IV once per day on days 29 & 30
• Etoposide (Vepesid) 75 mg/m² IV once per day on days 29 & 30
• Methotrexate (MTX) 25 mg/m² (route not specified) once on day 29

Supportive medications

• Lenograstim (Granocyte) 150 mcg/m² SC once per day from day 31 until myeloid recovery

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

References

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 early article contains verified protocol PubMed

Late intensification

Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone

back to top

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. Treatment preceded by pediatric-like GRAALL consolidation cycle 6, and is for patients achieving CR after cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction.

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg/m² IV q12h on days 15
• Daunorubicin (Cerubidine) 30 mg/m² IV once per day on days 1 to 3
• Asparaginase (Elspar) 6000 units/m²/day (route not specified) on days 8, 10, 12, 18, 20, 22
• Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15
• Prednisone (Sterapred) 60 mg/m²/day on days 1 to 14

Supportive medications

• Lenograstim (Granocyte) 150 mcg/m² SC once per day if ANC less than 500/uL until myeloid recovery

Patients then proceeded back to pediatric-like GRAALL consolidation.

References

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 early article contains verified protocol PubMed

Cytarabine & Idarubicin

back to top

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. Treatment preceded by pediatric-like GRAALL consolidation cycle 6, and is for patients achieving CR after cytarabine & idarubicin salvage.

Chemotherapy

• Cytarabine (Cytosar) 2000 mg/m² IV q12h on days 1 to 4
• Idarubicin (Idamycin) 9 mg/m² IV once per day on days 1 to 3

Supportive medications

• Lenograstim (Granocyte) 150 mcg/m² SC once per day from day 9 until myeloid recovery

Patients then proceeded back to pediatric-like GRAALL consolidation.

References

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 early article contains verified protocol PubMed

Cytarabine, Idarubicin, Imatinib

back to top

Regimen

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

Treatment preceded by HAM & imatinib consolidation and is for patients who did not achieve CHR with induction.

Chemotherapy

• Cytarabine (Cytosar) 3000 mg/m² IV once per day on days 1 to 5
• Idarubicin (Idamycin) 40 mg/m² IV once on day 3
• Imatinib (Gleevec) 600 mg PO once per day

CNS prophylaxis

• Methotrexate (MTX) 15 mg IT repeated for a total of 14 doses (including all phases of treatment)

One course; total duration of imatinib is not specified

Patients who achieve CR proceed to allogeneic transplant, or autologous transplant if no donor available. Details not provided.

References

1. 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 contains verified protocol link to PMC article PubMed

Larson regimen (CALGB 8811)

back to top

Regimen

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

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

Chemotherapy ("Course IV")

• Doxorubicin (Adriamycin) 30 mg/m² IV once per day on days 1, 8, 15
• Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15
• Dexamethasone (Decadron) 10 mg/m² PO once per day on days 1 to 14
• Cyclophosphamide (Cytoxan) 1000 mg/m² IV once on day 29
• Thioguanine (Tabloid) 60 mg/m² PO once per day on days 29 to 42
• Cytarabine (Cytosar) 75 mg/m² SC once per day on days 29 to 32, 36 to 39

8-week course

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 therapy

Dasatinib, Vincristine, Prednisone

back to top

Regimen

Study	Evidence
Ravandi et al. 2010	Phase II

Treatment preceded by HyperCVAD & Dasatinib x 8, and only offered to patients who achieved a CR.

Chemotherapy

• Dasatinib (Sprycel) 100 mg PO once per day on days 1 to 28
• Vincristine (Oncovin) 2 mg IV once on day 1
• Prednisone (Sterapred) 200 mg PO once per day on days 1 to 5

28-day cycles for 2 years

Maintenance therapy could be interrupted by provider's choice--typically only given to people with at least minimal residual disease (MRD) or more--in month 6 and 13 to give Hyper-CVAD Part A x 1 cycle. Then, after 2 years of maintenance therapy, patients proceed to dasatinib monotherapy:

• Dasatinib (Sprycel) 100 mg PO once per day, continued indefinitely

References

1. Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. link to original article contains verified protocol--parts of the protocol were not explicitly listed in this reference, which instead referred to Thomas et al. 2004 and Kantarjian et al. 2004 link to PMC article PubMed
   1. Update: Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. link to original article link to PMC article PubMed

Mercaptopurine & Methotrexate

back to top

Regimen

Study	Evidence
Linker et al. 1987	Phase II

Treatment preceded by Linker regimen consolidation therapy.

Chemotherapy

• Mercaptopurine (Purinethol) 75 mg/m² PO once per day
• Methotrexate (MTX) 20 mg/m² PO once per week

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

Nilotinib (Tasigna)

back to top

Regimen

Study	Evidence
Kim et al. 2015	Phase II

Treatment preceded by nilotinib-based consolidation.

Chemotherapy

• Nilotinib (Tasigna) 400 mg PO BID

2-year course

References

1. Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. link to original article contains verified protocol PubMed

POMP

back to top

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

Regimen #1

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

Treatment preceded by pediatric-like GRAALL consolidation.

Chemotherapy

• Prednisone (Sterapred) 40 mg/m²/day PO on days 1 to 7 of each month x 12 months
• Vincristine (Oncovin) 2 mg IV once on day 1 of each month x 12 months
• Methotrexate (MTX) 25 mg/m² PO once per week x 24 months
• Mercaptopurine (Purinethol) 60 mg/m² PO once per day x 24 months

24-month course

Regimen #2

Study	Evidence	Comparator	Efficacy
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	Phase III	Etoposide & TBI -> autoHCT	Seems to have superior OS

Treatment preceded by International ALL Trial consolidation.

Chemotherapy

• Prednisone (Sterapred) 60 mg/m² PO once per day for 5 days every 3 months
• Vincristine (Oncovin) 1.4 mg/m² IV once every 3 months
• Methotrexate (MTX) 20 mg/m² PO or IV once per week
• Mercaptopurine (Purinethol) 75 mg/m² PO once per day

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

Regimen #3

Study	Evidence
Kantarjian et al. 2004	Phase II

Treatment preceded by Hyper-CVAD (induction). 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.

Chemotherapy

• Prednisone (Sterapred) 200 mg PO once per day for 5 days, given with Vincristine (Oncovin)
• Vincristine (Oncovin) 2 mg IV once per month
• Methotrexate (MTX) 10 mg/m² IV over 1 hour once per day for 5 days
• Mercaptopurine (Purinethol) 1000 mg/m² IV over 1 hour once per day for 5 days

Supportive medications

• Trimethoprim/Sulfamethoxazole (dosage not listed) PO BID on Saturday and Sunday for the first 6 months
• ONE of the following antivirals:
  • Acyclovir (Zovirax) 200 mg PO once per day or 3 times per week for the first 6 months
  • Valacyclovir (Valtrex) 500 mg PO once per day or 3 times per week for the first 6 months

1-month cycles for 2 years

Regimen #4

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

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

Chemotherapy ("Course V")

• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 5
• Vincristine (Oncovin) 2 mg IV once on day 1
• Methotrexate (MTX) 20 mg/m² PO once per day on days 1, 8, 15, 22
• Mercaptopurine (Purinethol) 60 mg/m² PO once per day on days 1 to 28

28-day cycles, continue until 24 months from diagnosis

References

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 early article contains verified protocol PubMed

Relapsed/refractory, Ph-negative

Augmented Hyper-CVAD & Asparaginase

back to top

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

back to top

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

6-week 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

6-week cycle for up to 5 cycles

Regimen #3

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

Chemotherapy

• Blinatumomab (Blincyto) 15 mcg/m²/day IV continuous infusion for days 1 to 28

6-week 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

back to top

CCE: Clofarabine, Cyclophosphamide, Etoposide

Regimen

Study	Evidence
Locatelli et al. 2009	Non-randomized

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

Chemotherapy

• Clofarabine (Clolar) 40 mg/m² IV over 2 hours once per day on days 1 to 5, given first
• Cyclophosphamide (Cytoxan) 400 mg/m² IV over 1 hour once per day on days 1 to 5
• Etoposide (Vepesid) 150 mg/m² IV over 2 hours once per day on days 1 to 5

Supportive medications

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

5-day course

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

References

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

back to top

Regimen

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

Chemotherapy

• Clofarabine (Clolar) 40 mg/m² IV over 60 minutes once per day on days 1 to 5

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

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

back to top

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

back to top

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. Treatment preceded by cyclophosphamide, daunorubicin, L-aspariginase, vincristine, prednisone induction.

Chemotherapy

• Cytarabine (Cytosar) 2000 mg/m² IV q12h on days 1 to 4
• Idarubicin (Idamycin) 12 mg/m² IV once per day on days 1 to 3

Supportive medications

• Lenograstim (Granocyte) 150 mcg/m² SC once per day from day 9 until myeloid recovery

Patients achieving CR after salvage 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 early article contains verified protocol PubMed

Cytarabine & Mitoxantrone

back to top

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

back to top

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 & Everolimus

back to top

Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study	Evidence
Daver et al. 2015	Phase II

To be completed

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 PubMed

Inotuzumab ozogamicin monotherapy

back to top

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

Vincristine liposomal (Marqibo)

back to top

Regimen

Study	Evidence
O'Brien et al. 2012 (RALLY)	Phase II

Chemotherapy

• Vincristine liposomal (Marqibo) 2.25 mg/m² IV over 1 hour on days 1, 8, 15, 22

28-day cycles, continued until "response achievement, leukemia progression, toxicity, or decision to pursue other therapy"

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

Relapsed/refractory, Ph-positive

Bosutinib (Bosulif)

back to top

Regimen

Study	Evidence
Kantarjian et al. 2013	Phase I/II

Note: the dosing described is that reported for the phase 2 portion of the phase 1/2 study.

Chemotherapy

• Bosutinib (Bosulif) 500 mg PO once per day, take with food
  • If no grade 3 or higher drug-related toxicity occurs, dose can be escalated to 600 mg PO once per day if response is suboptimal. Suboptimal response defined as no complete hematologic response (CHR) by week 8 or complete cytogenetic response (CCyR) by week 12.

Given until progression of disease or unacceptable toxicity

References

1. Kantarjian HM, Cortes JE, Kim DW, Khoury HJ, Brümmendorf TH, Porkka K, Martinelli G, Durrant S, Leip E, Kelly V, Turnbull K, Besson N, Gambacorti-Passerini C. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood. 2014 Feb 27;123(9):1309-18. Epub 2013 Dec 17. link to original article contains verified protocol link to PMC article PubMed

Dasatinib (Sprycel)

back to top

Regimen #1

Study	Evidence	Comparator	Efficacy
Ottmann et al. 2007 (START-L)	Phase II
Lilly et al. 2010	Phase III	Dasatinib 140 mg once per day	Seems not superior

Chemotherapy

• Dasatinib (Sprycel) 70 mg PO twice per day

Given until progression of disease or unacceptable toxicity

Regimen #2

Study	Evidence	Comparator	Efficacy
Lilly et al. 2010	Phase III	Dasatinib 70 mg BID	Seems not superior

Chemotherapy

• Dasatinib (Sprycel) 140 mg PO once per day

Given until progression of disease or unacceptable toxicity

References

1. Ottmann O, Dombret H, Martinelli G, Simonsson B, Guilhot F, Larson RA, Rege-Cambrin G, Radich J, Hochhaus A, Apanovitch AM, Gollerkeri A, Coutre S. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood. 2007 Oct 1;110(7):2309-15. Epub 2007 May 11. link to original article contains verified protocol PubMed
2. Lilly MB, Ottmann OG, Shah NP, Larson RA, Reiffers JJ, Ehninger G, Müller MC, Charbonnier A, Bullorsky E, Dombret H, Brigid Bradley-Garelik M, Zhu C, Martinelli G. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: Results from a phase 3 study. Am J Hematol. 2010 Mar;85(3):164-70. link to original article contains verified protocol PubMed

Nilotinib (Tasigna)

back to top

Regimen

Study	Evidence
Kantarjian et al. 2006	Phase II

Chemotherapy

• Nilotinib (Tasigna) 300 to 400 mg PO BID

References

1. Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006 Jun 15;354(24):2542-51. link to original article PubMed

Ponatinib (Iclusig)

back to top

Regimen

Study	Evidence
Cortes et al. 2013 (PACE)	Phase II

Chemotherapy

• Ponatinib (Iclusig) 45 mg PO once per day; may be taken either with or without food

Given until progression of disease or unacceptable toxicity

References

1. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, Dipersio J, Deangelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H; the PACE Investigators. A Phase 2 Trial of Ponatinib in Philadelphia Chromosome-Positive Leukemias. N Engl J Med. 2013 Nov 7;369(19):1783-96. Epub 2013 Nov 1. link to original article link to PMC article PubMed
   1. Update: Abstract: Dong-Wook Kim, Javier Pinilla-Ibarz, Philipp D le Coutre, Ronald Paquette, Charles Chuah, Franck E. Nicolini, Jane F Apperley, H. Jean Khoury, Moshe Talpaz, John F. DiPersio, Daniel J DeAngelo, Elisabetta Abruzzese, Delphine Rea, Michele Baccarani, Martin C. Müller, Carlo Gambacorti-Passerini, Stephanie Lustgarten, Victor M. Rivera, Tim Clackson, Christopher D Turner, Frank G Haluska, François Guilhot, Michael W. Deininger, Andreas Hochhaus, Timothy P. Hughes, John M Goldman, Neil P. Shah, Hagop M. Kantarjian. Ponatinib In Patients (pts) With Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Resistant Or Intolerant To Dasatinib Or Nilotinib, Or With The T315I BCR-ABL Mutation: 2-Year Follow-Up Of The PACE Trial. Blood Nov 2013,122(21)650 link to original abstract

Maintenance

Blinatumomab monotherapy

back to top

Regimen

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

Treatment preceded by blinatumomab induction and consolidation. The most common comparator in TOWER was not specified but is presumably POMP.

Chemotherapy

• Blinatumomab (Blincyto) 28 mcg/day IV continuous infusion on days 1 to 28

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.

• Epratuzumab (humanised anti-CD22 antibody)