B-cell acute lymphoblastic leukemia, Ph-positive

Section editor
	Ashwin Kishtagari, MD Vanderbilt University Nashville, TN, USA LinkedIn

Note: these are regimens specific to Ph+ B-cell ALL; please see the main B-cell ALL page for other regimens, including portions of a course of therapy that are not biomarker-specific (such as pre-phase prednisone and post-induction transplant).
Note: certain regimens have been moved to dedicated pages:

• Pediatric B-cell ALL, Ph-positive

27 regimens on this page 29 variants on this page

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ESMO

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

NCCN

• NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Acute Lymphoblastic Leukemia.

Pre-phase

Prednisone monotherapy

Regimen

Study	Dates of enrollment	Evidence
Foà et al. 2011 (GIMEMA LAL1205)	NR	Phase 2
Chiaretti et al. 2016 (GIMEMA LAL 0904)	2004-10 to 2010-04	Phase 2
Foà et al. 2020 (GIMEMA LAL2116)	2017-05-09 to 2019-01-09	Phase 2

Note: dosing details are as provided in the protocol for GIMEMA LAL2116.

Glucocorticoid therapy

• Prednisone (Sterapred) 20 mg/m²/day PO on day -6, then 30 mg/m²/day PO on day -5, then 40 mg/m²/day PO on day -4, then 50 mg/m²/day PO on day -3, then 60 mg/m²/day PO on days -2 to 0

7-day course

Subsequent treatment

• GIMEMA LAL1205 & GIMEMA LAL2116: Dasatinib & Prednisone induction
• GIMEMA LAL 0904: Imatinib & Prednisone induction

References

1. GIMEMA LAL1205: Foà R, Vitale A, Vignetti M, Meloni G, Guarini A, De Propris MS, Elia L, Paoloni F, Fazi P, Cimino G, Nobile F, Ferrara F, Castagnola C, Sica S, Leoni P, Zuffa E, Fozza C, Luppi M, Candoni A, Iacobucci I, Soverini S, Mandelli F, Martinelli G, Baccarani M; GIMEMA Acute Leukemia Working Party. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011 Dec 15;118(25):6521-8. Epub 2011 Sep 19. link to original article PubMed NCT00391989
2. GIMEMA LAL 0904: Chiaretti S, Vitale A, Vignetti M, Piciocchi A, Fazi P, Elia L, Falini B, Ronco F, Ferrara F, De Fabritiis P, Luppi M, La Nasa G, Tedeschi A, Califano C, Fanin R, Dore F, Mandelli F, Meloni G, Foà R. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study. Haematologica. 2016 Dec;101(12):1544-1552. Epub 2016 Aug 11. link to original article link to PMC article PubMed NCT00458848
3. GIMEMA LAL2116: Foà R, Bassan R, Vitale A, Elia L, Piciocchi A, Puzzolo MC, Canichella M, Viero P, Ferrara F, Lunghi M, Fabbiano F, Bonifacio M, Fracchiolla N, Di Bartolomeo P, Mancino A, De Propris MS, Vignetti M, Guarini A, Rambaldi A, Chiaretti S; GIMEMA Investigators. Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults. N Engl J Med. 2020 Oct 22;383(17):1613-1623. link to original article contains dosing details in manuscript PubMed NCT02744768

Upfront induction therapy

Dasatinib & Prednisone

Regimen variant #1, dasatinib 70 mg twice per day

Study	Dates of enrollment	Evidence
Foà et al. 2011 (GIMEMA LAL1205)	NR	Phase 2

Preceding treatment

• Pre-phase prednisone

Targeted therapy

• Dasatinib (Sprycel) 70 mg PO twice per day on days 1 to 84

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m²/day (maximum dose of 120 mg) PO on days 1 to 24, then tapered and stopped at day 32

CNS therapy, prophylaxis

• Methotrexate (MTX) (dose not specified) IT once per day on days 22 & 43

12-week course

Subsequent treatment

• Post-induction treatment is not specified

Regimen variant #2, dasatinib 140 mg once per day

Study	Dates of enrollment	Evidence
Foà et al. 2020 (GIMEMA LAL2116)	2017-05-09 to 2019-01-09	Phase 2

Preceding treatment

• Pre-phase prednisone

Targeted therapy

• Dasatinib (Sprycel) 140 mg PO once per day on days 1 to 84

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 24, then 40 mg/m²/day PO on days 25 & 26, then 20 mg/m²/day PO on days 27 & 28, then 10 mg/m²/day PO on days 29 & 30, then 5 mg/m²/day PO on day 31

12-week course

Subsequent treatment

• Dasatinib & Blinatumomab consolidation

References

1. GIMEMA LAL1205: Foà R, Vitale A, Vignetti M, Meloni G, Guarini A, De Propris MS, Elia L, Paoloni F, Fazi P, Cimino G, Nobile F, Ferrara F, Castagnola C, Sica S, Leoni P, Zuffa E, Fozza C, Luppi M, Candoni A, Iacobucci I, Soverini S, Mandelli F, Martinelli G, Baccarani M; GIMEMA Acute Leukemia Working Party. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011 Dec 15;118(25):6521-8. Epub 2011 Sep 19. link to original article contains dosing details in manuscript PubMed NCT00391989
2. GIMEMA LAL2116: Foà R, Bassan R, Vitale A, Elia L, Piciocchi A, Puzzolo MC, Canichella M, Viero P, Ferrara F, Lunghi M, Fabbiano F, Bonifacio M, Fracchiolla N, Di Bartolomeo P, Mancino A, De Propris MS, Vignetti M, Guarini A, Rambaldi A, Chiaretti S; GIMEMA Investigators. Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults. N Engl J Med. 2020 Oct 22;383(17):1613-1623. link to original article contains dosing details in manuscript PubMed NCT02744768
3. ECOG EA9181: NCT04530565

Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Imatinib

Regimen

Study	Dates of enrollment	Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	1993-2003	Non-randomized part of phase 3 RCT

Note: 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 IM or IV once per day on days 17 to 28
• Vincristine (Oncovin) 1.4 mg/m² IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 28

Targeted therapy

• 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 therapy, prophylaxis

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

4-week course

Subsequent treatment

• Cyclophosphamide, cytarabine, mercaptopurine induction ("Phase 2")

References

1. MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article contains dosing details in manuscript PubMed NCT00002514
   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 dosing details in manuscript link to PMC article PubMed
2. GIMEMA ALL2820: NCT04722848

Daunorubicin, Vincristine, Prednisolone, Nilotinib

Regimen

Study	Dates of enrollment	Evidence
Kim et al. 2015 (AMC-UUCM-2008-0310)	2009-2012	Phase 2

Chemotherapy

• Daunorubicin (Cerubidine) 90 mg/m²/day IV continuous infusion over 72 hours, started on day 1 (total dose: 270 mg/m²)
• Vincristine (Oncovin) 2 mg IV once per day on days 1 & 8

Glucocorticoid therapy

• Prednisolone (Millipred) 60 mg/m² PO once per day on days 1 to 14
  • Alternate: 48 mg/m² IV once per day on days 1 to 14

Targeted therapy

• Nilotinib (Tasigna) 400 mg PO twice per day, starting on day 8

CNS therapy, prophylaxis

• Methotrexate (MTX) 15 mg IT, mixed with hydrocortisone
• Hydrocortisone (Cortef) 50 mg IT, mixed with methotrexate
• Up to 10 doses given during or after induction

14-day course, with ongoing nilotinib

Subsequent treatment

• Nilotinib-based consolidation or allogeneic HSCT. Transplant regimen left to the discretion of the investigator

References

1. AMC-UUCM-2008-0310: 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 dosing details in manuscript PubMed NCT00844298

Hyper-CVAD/MA & Dasatinib

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ravandi et al. 2010 (MDACC 2006-0478)	2006-2009	Phase 2
Sasaki et al. 2016	NR	Propensity score analysis	Hyper-CVAD/MA & Ponatinib	Seems to have inferior OS
Ravandi et al. 2016 (SWOG S0805)	2009-2013	Phase 2

Note: the dosing of dasatinib changed three times for this protocol. The initial protocol was 50 mg PO twice per day, 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 references. Sasaki et al. 2016 is a post-hoc analysis, not a randomized trial.

Chemotherapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Cyclophosphamide (Cytoxan) 300 mg/m² IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m²)
• Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
• Doxorubicin (Adriamycin) by the following imaging-based criteria:
  • Normal LVEF: 50 mg/m² IV continuous infusion over 24 hours, started on day 4
  • LVEF less than 50%: 25 mg/m²/day IV continuous infusion over 48 hours, started on day 4 (total dose per cycle: 50 mg/m²)

Glucocorticoid therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4, 11 to 14

Supportive therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Mesna (Mesnex) 600 mg/m²/day IV continuous infusion over 72 hours, started on day 1, given 1 hour prior to cyclophosphamide and completed 12 hours after the last dose of cyclophosphamide
• ONE of the following antibiotics:
  • Ciprofloxacin (Cipro) 500 mg PO twice per day
  • Levofloxacin (Levaquin) 500 mg PO once per day
  • Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day
• Fluconazole (Diflucan) 200 mg PO once per day
• ONE of the following antivirals:
  • Acyclovir (Zovirax) 200 mg PO twice per day
  • Valacyclovir (Valtrex) 500 mg PO once per day
• Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/μL
• 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
  • Sodium bicarbonate (no dosage or frequency listed) PO on days 1 to 3

Chemotherapy, MA portion (cycles 2, 4, 6, 8; "Part B")

• Methotrexate (MTX) 1000 mg/m² IV continuous infusion over 24 hours, started on day 1
• Cytarabine (Ara-C) by the following age-based criteria:
  • Younger than 60 years old: 3000 mg/m² IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m²)
  • 60 years old or older: 1000 mg/m² IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m²)

Supportive therapy, MA portion (cycles 2, 4, 6, 8; "Part B")

• Leucovorin (Folinic acid) 50 mg IV once on day 3; 12 hours after methotrexate is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
  • Leucovorin rescue with Leucovorin (Folinic acid) 50 mg IV every 6 hours if serum methotrexate levels were greater than 20,000 nmol/L at 0 hours after completion of methotrexate; 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 twice per day
  • Levofloxacin (Levaquin) 500 mg PO once per day
  • Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day
• Fluconazole (Diflucan) 200 mg PO once per day
• ONE of the following antivirals:
  • Acyclovir (Zovirax) 200 mg PO twice per day
  • Valacyclovir (Valtrex) 500 mg PO once per day
• 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/μL
• Acetazolamide (Diamox) (no dosage/schedule listed) used if urine pH less than 7 to promote excretion

Targeted therapy, both portions

• Dasatinib (Sprycel) as follows:
  • Cycle 1: 100 mg PO once per day on days 1 to 14
  • Cycles 2 to 8: 70 mg PO once per day

CNS prophylaxis, both portions

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

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%

CNS treatment, both portions

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

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

Subsequent treatment

• SWOG S0805, patients achieving a CR who had an available matched sibling or 10/10 matched unrelated donor: Etoposide & TBI, then allogeneic HSCT
• SWOG S0805, patients not achieving a CR or who did not have an available matched sibling or 10/10 matched unrelated donor: Dasatinib, vincristine, and prednisone maintenance

References

1. MDACC 2006-0478: 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 dosing details in manuscript--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 NCT00390793
   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. Retrospective: 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. Epub 2016 Aug 1. link to original article link to PMC article PubMed
3. SWOG S0805: Ravandi F, Othus M, O’Brien SM, Forman SJ, Ha CS, Wong JY, Tallman MS, Paietta E, Racevskis J, Uy GL, Horowitz M, Takebe N, Little R, Borate U, Kebriaei P, Kingsbury L, Kantarjian HM, Radich JP, Erba HP, Appelbaum FR. US intergroup study of chemotherapy plus dasatinib and allogeneic stem cell transplant in Philadelphia chromosome positive ALL. Blood Adv. 2016;1(3):250-259. link to original article link to PMC article PubMed NCT00792948

Hyper-CVAD/MA & Imatinib

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Thomas et al. 2003	2001-2003	Phase 2
Chalandon et al. 2015 (GRAAPH-2005)	2006-2011	Phase 3 (C)	Imatinib, Vincristine, Dexamethasone	Did not meet primary endpoint of MMR rate after cycle 2

Chemotherapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Cyclophosphamide (Cytoxan) 300 mg/m² IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m²)
• Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
• Doxorubicin (Adriamycin) by the following imaging-based criteria:
  • Normal LVEF: 50 mg/m² IV continuous infusion over 24 hours, started on day 4
  • LVEF less than 50%: 25 mg/m²/day IV continuous infusion over 48 hours, started on day 4 (total dose per cycle: 50 mg/m²)

Glucocorticoid therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4, 11 to 14

Targeted therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Imatinib (Gleevec) 400 mg PO once per day on days 1 to 14

Supportive therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Mesna (Mesnex) 600 mg/m²/day IV continuous infusion over 72 hours, started on day 1, given 1 hour prior to cyclophosphamide and completed 12 hours after the last dose of cyclophosphamide
• ONE of the following antibiotics:
  • Ciprofloxacin (Cipro) 500 mg PO twice per day
  • Levofloxacin (Levaquin) 500 mg PO once per day
  • Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day
• Fluconazole (Diflucan) 200 mg PO once per day
• ONE of the following antivirals:
  • Acyclovir (Zovirax) 200 mg PO twice per day
  • Valacyclovir (Valtrex) 500 mg PO once per day
• Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/μL
• 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
  • Sodium bicarbonate (no dosage or frequency listed) PO on days 1 to 3

Chemotherapy, MA portion (cycles 2, 4, 6, 8; "Part B")

• Methotrexate (MTX) 1000 mg/m² IV continuous infusion over 24 hours, started on day 1
• Cytarabine (Ara-C) by the following age-based criteria:
  • Younger than 60 years old: 3000 mg/m² IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m²)
  • 60 years old or older: 1000 mg/m² IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m²)

Targeted therapy, MA portion (cycles 2, 4, 6, 8; "Part B")

• Imatinib (Gleevec) 400 mg PO once per day on days 1 to 14

Supportive therapy, MA portion (cycles 2, 4, 6, 8; "Part B")

• Leucovorin (Folinic acid) 50 mg IV once on day 3; 12 hours after methotrexate is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
  • Leucovorin rescue with Leucovorin (Folinic acid) 50 mg IV every 6 hours if serum methotrexate levels were greater than 20,000 nmol/L at 0 hours after completion of methotrexate; 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 twice per day
  • Levofloxacin (Levaquin) 500 mg PO once per day
  • Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day
• Fluconazole (Diflucan) 200 mg PO once per day
• ONE of the following antivirals:
  • Acyclovir (Zovirax) 200 mg PO twice per day
  • Valacyclovir (Valtrex) 500 mg PO once per day
• 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/μL
• Acetazolamide (Diamox) (no dosage/schedule listed) used if urine pH less than 7 to promote excretion

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

CNS prophylaxis, both portions

• Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
• Cytarabine (Ara-C) 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%

CNS treatment for known CNS disease, both portions

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

Subsequent treatment

• Imatinib, Vincristine, Prednisone maintenance

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 dosing details in manuscript 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
2. GRAAPH-2005: Chalandon Y, Thomas X, Hayette S, Cayuela JM, Abbal C, Huguet F, Raffoux E, Leguay T, Rousselot P, Lepretre S, Escoffre-Barbe M, Maury S, Berthon C, Tavernier E, Lambert JF, Lafage-Pochitaloff M, Lhéritier V, Chevret S, Ifrah N, Dombret H; Group for Research on Adult Acute Lymphoblastic Leukemia. Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015 Jun 11;125(24):3711-9. Epub 2015 Apr 15. Erratum in: Blood. 2015 Sep 3;126(10):1261. link to original article PubMed NCT00327678

Hyper-CVAD/MA & Ponatinib

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Jabbour et al. 2015 (MDACC 2011-0030)	2011-2013	Phase 2
Sasaki et al. 2016	NR	Propensity score analysis	Hyper-CVAD/MA & 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.

Chemotherapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Cyclophosphamide (Cytoxan) 300 mg/m² IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m²)
• Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
• Doxorubicin (Adriamycin) by the following imaging-based criteria:
  • Normal LVEF: 50 mg/m² IV continuous infusion over 24 hours, started on day 4
  • LVEF less than 50%: 25 mg/m²/day IV continuous infusion over 48 hours, started on day 4 (total dose per cycle: 50 mg/m²)

Glucocorticoid therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4, 11 to 14

Targeted therapy, Hyper-CVAD portion ("Part A")

• 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 therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Mesna (Mesnex) 600 mg/m²/day IV continuous infusion over 72 hours, started on day 1, given 1 hour prior to cyclophosphamide and completed 12 hours after the last dose of cyclophosphamide
• ONE of the following antibiotics:
  • Ciprofloxacin (Cipro) 500 mg PO twice per day
  • Levofloxacin (Levaquin) 500 mg PO once per day
  • Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day
• Fluconazole (Diflucan) 200 mg PO once per day
• ONE of the following antivirals:
  • Acyclovir (Zovirax) 200 mg PO twice per day
  • Valacyclovir (Valtrex) 500 mg PO once per day
• Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/μL
• 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
  • Sodium bicarbonate (no dosage or frequency listed) PO on days 1 to 3

Chemotherapy, MA portion (cycles 2, 4, 6, 8; "Part B")

• Methotrexate (MTX) 1000 mg/m² IV continuous infusion over 24 hours, started on day 1
• Cytarabine (Ara-C) by the following age-based criteria:
  • Younger than 60 years old: 3000 mg/m² IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m²)
  • 60 years old or older: 1000 mg/m² IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m²)

Targeted therapy, MA portion (cycles 2, 4, 6, 8; "Part B")

• Ponatinib (Iclusig) 45 mg PO once per day

Supportive therapy, MA portion (cycles 2, 4, 6, 8; "Part B")

• Leucovorin (Folinic acid) 50 mg IV once on day 3; 12 hours after methotrexate is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
  • Leucovorin rescue with Leucovorin (Folinic acid) 50 mg IV every 6 hours if serum methotrexate levels were greater than 20,000 nmol/L at 0 hours after completion of methotrexate; 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 twice per day
  • Levofloxacin (Levaquin) 500 mg PO once per day
  • Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day
• Fluconazole (Diflucan) 200 mg PO once per day
• ONE of the following antivirals:
  • Acyclovir (Zovirax) 200 mg PO twice per day
  • Valacyclovir (Valtrex) 500 mg PO once per day
• 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/μL
• Acetazolamide (Diamox) (no dosage/schedule listed) used if urine pH less than 7 to promote excretion

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

References

1. MDACC 2011-0030: 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 NCT01424982
   1. Retrospective: 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. Epub 2016 Aug 1. link to original article link to PMC article PubMed

Imatinib & Prednisone

Regimen

Study	Dates of enrollment	Evidence
Chiaretti et al. 2016 (GIMEMA LAL 0904)	2004-10 to 2010-04	Phase 2

Preceding treatment

• Pre-phase prednisone

Targeted therapy

• Imatinib (Gleevec) 600 mg PO once per day on days 1 to 50

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 24, then tapered and stopped at day 32

CNS therapy, prophylaxis

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

50-day course

Subsequent treatment

• HAM & imatinib consolidation

References

1. GIMEMA LAL 0904: Chiaretti S, Vitale A, Vignetti M, Piciocchi A, Fazi P, Elia L, Falini B, Ronco F, Ferrara F, De Fabritiis P, Luppi M, La Nasa G, Tedeschi A, Califano C, Fanin R, Dore F, Mandelli F, Meloni G, Foà R. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study. Haematologica. 2016 Dec;101(12):1544-1552. Epub 2016 Aug 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00458848

Imatinib, Vincristine, Dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Chalandon et al. 2015 (GRAAPH-2005)	2006-2011	Phase 3 (E-de-esc)	Hyper-CVAD/MA & Imatinib	Did not meet primary endpoint of MMR rate after cycle 2

Preceding treatment

• Pre-phase prednisone

Targeted therapy

• Imatinib (Gleevec) 400 mg PO twice per day on days 1 to 28

Chemotherapy

• Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg/day PO on days 1, 2, 8, 9, 15, 16, 22, 23

Supportive therapy

• Filgrastim (Neupogen) 5 mcg/kg IV or SC once per day from day 15 until ANC recovery

28-day course

Subsequent treatment

• HAM & imatinib consolidation

References

1. GRAAPH-2005: Chalandon Y, Thomas X, Hayette S, Cayuela JM, Abbal C, Huguet F, Raffoux E, Leguay T, Rousselot P, Lepretre S, Escoffre-Barbe M, Maury S, Berthon C, Tavernier E, Lambert JF, Lafage-Pochitaloff M, Lhéritier V, Chevret S, Ifrah N, Dombret H; Group for Research on Adult Acute Lymphoblastic Leukemia. Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015 Jun 11;125(24):3711-9. Epub 2015 Apr 15. Erratum in: Blood. 2015 Sep 3;126(10):1261. link to original article PubMed NCT00327678

Ponatinib & Blinatumomab

Regimen

Study	Dates of enrollment	Evidence
Jabbour et al. 2022 (MDACC 2016-0792)	2018-2022	Phase 2

Targeted therapy

• Ponatinib (Iclusig) 30 mg PO once per day on days 1 to 42

Immunotherapy

• Blinatumomab (Blincyto) as follows:
  • Cycles 1 up to 5: 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)

42-day cycles

References

1. MDACC 2016-0792: Jabbour E, Short NJ, Jain N, Huang X, Montalban-Bravo G, Banerjee P, Rezvani K, Jiang X, Kim KH, Kanagal-Shamanna R, Khoury JD, Patel K, Kadia TM, Daver N, Chien K, Alvarado Y, Garcia-Manero G, Issa GC, Haddad FG, Kwari M, Thankachan J, Delumpa R, Macaron W, Garris R, Konopleva M, Ravandi F, Kantarjian H. Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukaemia: a US, single-centre, single-arm, phase 2 trial. Lancet Haematol. 2023 Jan;10(1):e24-e34. Epub 2022 Nov 16. link to original article contains dosing details in abstract PubMed NCT03263572

Ponatinib, Vincristine, Dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Jabbour et al. 2024 (PhALLCON)	2018-2022	Phase 3 (E-RT-switch-ic)	Imatinib, Vincristine, Dexamethasone	Superior MRD-negative CR rate after cycle 3 (primary endpoint) MRD-negative CR rate after cycle 3: 34.4% vs 16.7%

Targeted therapy

• Ponatinib (Iclusig) 30 mg PO once per day on days 1 to 28

Chemotherapy

• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once per day on days 1 & 14

Glucocorticoid therapy

• Dexamethasone (Decadron) by the following age-based criteria:
  • Younger than 60 years old: 40 mg PO once per day on days 1 to 4, 11 to 14
  • 60 years old and older: 20 mg PO once per day on days 1 to 4, 11 to 14

28-day cycle for 3 cycles

Subsequent treatment

• MTX/Ara-C & Ponatinib consolidation

References

1. PhALLCON: Jabbour E, Kantarjian HM, Aldoss I, Montesinos P, Leonard JT, Gómez-Almaguer D, Baer MR, Gambacorti-Passerini C, McCloskey J, Minami Y, Papayannidis C, Rocha V, Rousselot P, Vachhani P, Wang ES, Wang B, Hennessy M, Vorog A, Patel N, Yeh T, Ribera JM. Ponatinib vs Imatinib in Frontline Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2024 May 9:e244783. Epub ahead of print. link to original article contains dosing details in supplement link to PMC article PubMed NCT03589326

Consolidation after upfront therapy (including post-remission therapy)

Note that many of these regimens are complex and as such will be referred to by their study name, not by the individual drug names. This is also a phase of treatment often referred to as post-remission or postinduction therapy.

Cyclophosphamide & TBI, then allo HSCT

Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Thomas et al. 1979	1976-1977	Non-randomized
Sebban et al. 1994 (LALA 87)	1986-1991	Phase 3 (E-esc)	Chemotherapy or Auto HSCT	Seems to have superior OS1
Thomas et al. 2004 (LALA-94)	1994-2002	Non-randomized part of RCT

¹While LALA 87 was a negative trial, the subgroup of high-risk ALL, including Ph+ ALL, appeared to have a superior outcome in the allo HSCT arm.

Details in most of the manuscripts are limited.

Chemotherapy

• Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on days -3 & -2

Radiotherapy

• Total body irradiation by the following study-specific criteria:
  • Zhang et al. 2023: 450 cGy once per day on days -5 & -4 (900 cGy total)
  • Other studies: 10 to 1200 cGy total

Immunotherapy

• Allogeneic stem cells transfused on day 0

One course

References

1. Thomas ED, Sanders JE, Flournoy N, Johnson FL, Buckner CD, Clift RA, Fefer A, Goodell BW, Storb R, Weiden PL. Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood. 1979 Aug;54(2):468-76. link to original article contains dosing details in abstract PubMed
2. LALA 87: Sebban C, Lepage E, Vernant JP, Gluckman E, Attal M, Reiffers J, Sutton L, Racadot E, Michallet M, Maraninchi D, Dreyfus F, Fiere D; French Group of Therapy of Adult Acute Lymphoblastic Leukemia. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. J Clin Oncol. 1994 Dec;12(12):2580-7. link to original article PubMed
   1. Update: Thiebaut A, Vernant JP, Degos L, Huguet FR, Reiffers J, Sebban C, Lepage E, Thomas X, Fière D. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation: a follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am. 2000 Dec;14(6):1353-66. link to original article PubMed
3. LALA-94: Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. link to original article contains dosing details in manuscript PubMed NCT00002700
   1. Update: Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group; Swiss Group for Clinical Cancer Research. 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

Dasatinib & Blinatumomab

Regimen

Study	Dates of enrollment	Evidence
Foà et al. 2020 (GIMEMA LAL2116)	2017-05-09 to 2019-01-09	Phase 2

Preceding treatment

• Dasatinib & Prednisone induction

Targeted therapy

• Dasatinib (Sprycel) 140 mg PO once per day

Immunotherapy

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

42-day cycle for at least 2 and up to 5 cycles

References

1. GIMEMA LAL2116: Foà R, Bassan R, Vitale A, Elia L, Piciocchi A, Puzzolo MC, Canichella M, Viero P, Ferrara F, Lunghi M, Fabbiano F, Bonifacio M, Fracchiolla N, Di Bartolomeo P, Mancino A, De Propris MS, Vignetti M, Guarini A, Rambaldi A, Chiaretti S; GIMEMA Investigators. Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults. N Engl J Med. 2020 Oct 22;383(17):1613-1623. link to original article contains dosing details in manuscript PubMed NCT02744768

Etoposide & TBI, then allo HSCT

Regimen

Study	Dates of enrollment	Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	1993-2003	Non-randomized part of phase 3 RCT

Chemotherapy

• Etoposide (Vepesid) 60 mg/kg IV once on day -3

Radiotherapy

• Total body irradiation (TBI) 220 cGy twice per day in 6 fractions on days -6 to -4 (total dose: 1320 cGy)

Immunotherapy

• Allogeneic stem cells transfused on day 0

One course

References

1. MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article contains dosing details in manuscript PubMed NCT00002514
   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 dosing details in manuscript link to PMC article PubMed

HAM & Imatinib

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

Regimen

Study	Dates of enrollment	Evidence
de Labarthe et al. 2006 (GRAAPH-2003)	2004-01 to 2005-10	Phase 2
Chiaretti et al. 2016 (GIMEMA LAL 0904)	2004-10 to 2010-04	Phase 2

Preceding treatment

• Imatinib & Prednisone induction

Chemotherapy

• Cytarabine (Ara-C) 3000 mg/m² IV every 12 hours on days 1 to 4 (total dose: 24,000 mg/m²)
• Mitoxantrone (Novantrone) 10 mg/m² IV once per day on days 1 to 3

Targeted therapy

• Imatinib (Gleevec) 600 mg PO once per day

CNS therapy, prophylaxis

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

4-day course; total duration of imatinib is not specified

Subsequent treatment

• GIMEMA LAL 0904, patients who did not achieve CR with induction: Cytarabine, idarubicin, imatinib late intensification
• GIMEMA LAL 0904, patients who achieve CR after consolidation: allogeneic hematopoietic stem cell transplant, or autologous HSCT if no donor available (details not provided)

References

1. GRAAPH-2003: de Labarthe A, Rousselot P, Huguet-Rigal F, Delabesse E, Witz F, Maury S, Réa D, Cayuela JM, Vekemans MC, Reman O, Buzyn A, Pigneux A, Escoffre M, Chalandon Y, MacIntyre E, Lhéritier V, Vernant JP, Thomas X, Ifrah N, Dombret H; Group for Research on Adult Acute Lymphoblastic Leukemia. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood. 2007 Feb 15;109(4):1408-13. Epub 2006 Oct 24. link to original article PubMed
   1. Update: Tanguy-Schmidt A, Rousselot P, Chalandon Y, Cayuela JM, Hayette S, Vekemans MC, Escoffre M, Huguet F, Réa D, Delannoy A, Cahn JY, Vernant JP, Ifrah N, Dombret H, Thomas X. Long-term follow-up of the imatinib GRAAPH-2003 study in newly diagnosed patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: a GRAALL study. Biol Blood Marrow Transplant. 2013 Jan;19(1):150-5. Epub 2012 Sep 6. link to original article PubMed
2. GIMEMA LAL 0904: Chiaretti S, Vitale A, Vignetti M, Piciocchi A, Fazi P, Elia L, Falini B, Ronco F, Ferrara F, De Fabritiis P, Luppi M, La Nasa G, Tedeschi A, Califano C, Fanin R, Dore F, Mandelli F, Meloni G, Foà R. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study. Haematologica. 2016 Dec;101(12):1544-1552. Epub 2016 Aug 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00458848

Nilotinib-based consolidation

Regimen

Study	Dates of enrollment	Evidence
Kim et al. 2015 (AMC-UUCM-2008-0310)	2009-2012	Phase 2

Preceding treatment

• Daunorubicin, Vincristine, Prednisolone, Nilotinib induction

Chemotherapy, A portion (cycle 1)

• Daunorubicin (Cerubidine) 45 mg/m²/day IV continuous infusion over 48 hours, started on day 1 (total dose: 90 mg/m²)
• Vincristine (Oncovin) 2 mg IV once per day on days 1 & 8

Glucocorticoid therapy, A portion (cycle 1)

• Prednisolone (Millipred) 60 mg/m² PO once per day on days 1 to 14

Targeted therapy, consolidation A (cycle 1)

• Nilotinib (Tasigna) 400 mg PO twice per day

Chemotherapy, B portion (cycles 2 & 4)

• Cytarabine (Ara-C) 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

Targeted therapy, B portion (cycles 2 & 4)

• Nilotinib (Tasigna) 400 mg PO twice per day

Chemotherapy, C portion (cycles 3 & 5)

• Methotrexate (MTX) 220 mg/m² IV bolus once per day on days 1 & 15, then 60 mg/m²/hr IV continuous infusion over 36 hours (total dose per cycle: 2380 mg/m²)

Targeted therapy, C portion (cycles 3 & 5)

• Nilotinib (Tasigna) 400 mg PO twice per day

Supportive therapy, C portion (cycles 3 & 5)

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

5 cycles; duration of each cycle of consolidation is not specified but is presumably based on toxicities and count recovery

Subsequent treatment

• Nilotinib maintenance

References

1. AMC-UUCM-2008-0310: 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 dosing details in manuscript PubMed NCT00844298

Late intensification

Cytarabine, Idarubicin, Imatinib

Regimen

Study	Dates of enrollment	Evidence
Chiaretti et al. 2016 (GIMEMA LAL 0904)	2004-10 to 2010-04	Phase 2

This is for patients who did not achieve CHR with induction.

Preceding treatment

• HAM & Imatinib consolidation

Chemotherapy

• Cytarabine (Ara-C) 3000 mg/m² IV once per day on days 1 to 5
• Idarubicin (Idamycin) 40 mg/m² IV once on day 3

Targeted therapy

• Imatinib (Gleevec) 600 mg PO once per day

CNS therapy, prophylaxis

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

5-day course; total duration of imatinib is not specified

Subsequent treatment

• GIMEMA LAL 0904, CR: allogeneic HSCT or autologous HSCT if no donor available. Details not provided.

References

1. GIMEMA LAL 0904: Chiaretti S, Vitale A, Vignetti M, Piciocchi A, Fazi P, Elia L, Falini B, Ronco F, Ferrara F, De Fabritiis P, Luppi M, La Nasa G, Tedeschi A, Califano C, Fanin R, Dore F, Mandelli F, Meloni G, Foà R. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study. Haematologica. 2016 Dec;101(12):1544-1552. Epub 2016 Aug 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00458848

Maintenance after upfront therapy

Dasatinib monotherapy

Regimen

Study	Evidence
Ravandi et al. 2010 (MDACC 2006-0478)	Phase 2
Ravandi et al. 2016 (SWOG S0805)	Phase 2

Preceding treatment

• Dasatinib, Vincristine, Prednisone maintenance x 2y

Targeted therapy

• Dasatinib (Sprycel) 100 mg PO once per day

Continued indefinitely

References

1. MDACC 2006-0478: 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 dosing details in manuscript--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 NCT00390793
   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. SWOG S0805: Ravandi F, Othus M, O’Brien SM, Forman SJ, Ha CS, Wong JY, Tallman MS, Paietta E, Racevskis J, Uy GL, Horowitz M, Takebe N, Little R, Borate U, Kebriaei P, Kingsbury L, Kantarjian HM, Radich JP, Erba HP, Appelbaum FR. US intergroup study of chemotherapy plus dasatinib and allogeneic stem cell transplant in Philadelphia chromosome positive ALL. Blood Adv. 2016;1(3):250-259. link to original article link to PMC article PubMed NCT00792948

Dasatinib, Vincristine, Prednisone

Regimen

Study	Evidence
Ravandi et al. 2010 (MDACC 2006-0478)	Phase 2
Ravandi et al. 2016 (SWOG S0805)	Phase 2

Note: 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.

Preceding treatment

• Hyper-CVAD/MA & Dasatinib induction x 8, with CR

Targeted therapy

• Dasatinib (Sprycel) 100 mg PO once per day

Chemotherapy

• Vincristine (Oncovin) 2 mg IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 200 mg PO once per day on days 1 to 5

28-day cycle for 26 cycles (2 years)

Subsequent treatment

• Dasatinib maintenance

References

1. MDACC 2006-0478: 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 dosing details in manuscript--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 NCT00390793
   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. SWOG S0805: Ravandi F, Othus M, O’Brien SM, Forman SJ, Ha CS, Wong JY, Tallman MS, Paietta E, Racevskis J, Uy GL, Horowitz M, Takebe N, Little R, Borate U, Kebriaei P, Kingsbury L, Kantarjian HM, Radich JP, Erba HP, Appelbaum FR. US intergroup study of chemotherapy plus dasatinib and allogeneic stem cell transplant in Philadelphia chromosome positive ALL. Blood Adv. 2016;1(3):250-259. link to original article link to PMC article PubMed NCT00792948

Imatinib, Vincristine, Prednisone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Thomas et al. 2003	2001-2003	Phase 2
Chalandon et al. 2015 (GRAAPH-2005)	2006-2011	Phase 3 (C)	Imatinib, Vincristine, Dexamethasone	Did not meet primary endpoint of MMR rate after cycle 2

Preceding treatment

• Hyper-CVAD/MA & Imatinib induction x 8

Targeted therapy

• Imatinib (Gleevec) 600 mg PO once per day on days 1 to 28

Chemotherapy

• Vincristine (Oncovin) 2 mg IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 200 mg PO once per day on days 1 to 5

28-day cycle for 5 cycles, then Hyper-CVAD & Imatinib Part A x 1 cycle, then 28-day cycle for 6 cycles, then Hyper-CVAD & Imatinib Part A x 1 cycle

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 dosing details in manuscript 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
2. GRAAPH-2005: Chalandon Y, Thomas X, Hayette S, Cayuela JM, Abbal C, Huguet F, Raffoux E, Leguay T, Rousselot P, Lepretre S, Escoffre-Barbe M, Maury S, Berthon C, Tavernier E, Lambert JF, Lafage-Pochitaloff M, Lhéritier V, Chevret S, Ifrah N, Dombret H; Group for Research on Adult Acute Lymphoblastic Leukemia. Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015 Jun 11;125(24):3711-9. Epub 2015 Apr 15. Erratum in: Blood. 2015 Sep 3;126(10):1261. link to original article PubMed NCT00327678

Nilotinib monotherapy

Regimen

Study	Dates of enrollment	Evidence
Kim et al. 2015 (AMC-UUCM-2008-0310)	2009-2012	Phase 2

Preceding treatment

• Nilotinib-based consolidation

Targeted therapy

• Nilotinib (Tasigna) 400 mg PO twice per day on days 1 to 28

28-day cycle for 26 cycles (2 years)

References

1. AMC-UUCM-2008-0310: 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 dosing details in manuscript PubMed NCT00844298

Relapsed or refractory

Blinatumomab monotherapy

Regimen

Study	Dates of enrollment	Evidence
Martinelli et al. 2017 (ALCANTARA)	2014-2015	Phase 2 (RT)

Immunotherapy

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

42-day cycle for 2 to 5 cycles

References

1. ALCANTARA: Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Topp MS, Fielding AK, Rambaldi A, Ritchie EK, Papayannidis C, Sterling LR, Benjamin J, Stein A. Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study. J Clin Oncol. 2017 Jun 1;35(16):1795-1802. Epub 2017 Mar 29. Erratum in: J Clin Oncol. 2017 Aug 10;35(23):2722. J Clin Oncol. 2017 Aug 20;35(24):2856. link to original article contains dosing details in manuscript PubMed NCT02000427
   1. Update: Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Rambaldi A, Ritchie EK, Papayannidis C, Tuglus CA, Morris JD, Stein A. Long-term follow-up of blinatumomab in patients with relapsed/refractory Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukaemia: Final analysis of ALCANTARA study. Eur J Cancer. 2021 Mar;146:107-114. Epub 2021 Feb 13. link to original article PubMed

Bosutinib monotherapy

Regimen

Study	Evidence
Kantarjian et al. 2011 (Study 200)	Phase 1/2

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

Targeted therapy

• Bosutinib (Bosulif) 500 mg PO once per day, taken with food

Continued indefinitely

Dose and schedule modifications

• 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.

References

1. Study 200: Cortes JE, Kantarjian HM, Brümmendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A, Besson N, Abbas R, Wang J, Leip E, Gambacorti-Passerini C. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011 Oct 27;118(17):4567-76. Epub 2011 Aug 24. Erratum in: Blood. 2013 Oct 3;122(14):2524. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00261846
   1. Update: Khoury HJ, Cortes JE, Kantarjian HM, Gambacorti-Passerini C, Baccarani M, Kim DW, Zaritskey A, Countouriotis A, Besson N, Leip E, Kelly V, Brümmendorf TH. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012 Apr 12;119(15):3403-12. Epub 2012 Feb 27. link to original article contains dosing details in manuscript link to PMC article PubMed
   2. Update: 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 dosing details in manuscript link to PMC article PubMed
   3. Update: Gambacorti-Passerini C, Brümmendorf TH, Kim DW, Turkina AG, Masszi T, Assouline S, Durrant S, Kantarjian HM, Khoury HJ, Zaritskey A, Shen ZX, Jin J, Vellenga E, Pasquini R, Mathews V, Cervantes F, Besson N, Turnbull K, Leip E, Kelly V, Cortes JE. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up. Am J Hematol. 2014 Jul;89(7):732-42. Epub 2014 Apr 28. link to original article link to PMC article PubMed
   4. Update: Gambacorti-Passerini C, Kantarjian HM, Kim DW, Khoury HJ, Turkina AG, Brümmendorf TH, Matczak E, Bardy-Bouxin N, Shapiro M, Turnbull K, Leip E, Cortes JE. Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors. Am J Hematol. 2015 Sep;90(9):755-68. Epub 2015 Jun 1. link to original article link to PMC article PubMed

Dasatinib monotherapy

Regimen variant #1, 70 mg twice per day

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ottmann et al. 2007 (START-L)	2005	Phase 2 (RT)
Kantarjian et al. 2009 (CA180-035)	2005-07 to 2006-03	Phase 3 (C)	Dasatinib; 140 mg once per day	Inconclusive whether non-inferior MHR1

¹Reported efficacy for CA180-035 is based on the 2010 subgroup analysis.

Targeted therapy

• Dasatinib (Sprycel) 70 mg PO twice per day on days 1 to 28

28-day cycles

Regimen variant #2, 140 mg/day

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kantarjian et al. 2009 (CA180-035)	2005-07 to 2006-03	Phase 3 (E-switch-ic)	Dasatinib; 70 mg twice per day	Inconclusive whether non-inferior MHR1 (primary endpoint)

¹Reported efficacy for CA180-035 is based on the 2010 subgroup analysis.

Targeted therapy

• Dasatinib (Sprycel) 140 mg PO once per day on days 1 to 28

28-day cycles

References

1. START-L: 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 dosing details in manuscript PubMed NCT00101595
2. CA180-035: Kantarjian H, Cortes J, Kim DW, Dorlhiac-Llacer P, Pasquini R, DiPersio J, Müller MC, Radich JP, Khoury HJ, Khoroshko N, Bradley-Garelik MB, Zhu C, Tallman MS. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood. 2009 Jun 18;113(25):6322-9. Epub 2009 Apr 15. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00123487
   1. Subgroup analysis: 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 dosing details in manuscript PubMed
   2. Subgroup analysis: Saglio G, Hochhaus A, Goh YT, Masszi T, Pasquini R, Maloisel F, Erben P, Cortes J, Paquette R, Bradley-Garelik MB, Zhu C, Dombret H. Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer. 2010 Aug 15;116(16):3852-61. link to original article link to PMC article PubMed

Imatinib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence
Ottmann et al. 2002	1999-2000	Phase 2 (RT)

Targeted therapy

• Imatinib (Gleevec) 600 mg PO once per day

Continued indefinitely

References

1. Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT, Tura S, Fischer T, Deininger MW, Schiffer CA, Baccarani M, Gratwohl A, Hochhaus A, Hoelzer D, Fernandes-Reese S, Gathmann I, Capdeville R, O'Brien SG. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood. 2002 Sep 15;100(6):1965-71. link to original article contains dosing details in abstract PubMed

Nilotinib monotherapy

Regimen

Study	Dates of enrollment	Evidence
Kantarjian et al. 2006 (A2101)	2004-2005	Phase 1/2

Targeted therapy

• Nilotinib (Tasigna) 300 to 400 mg PO twice per day

Continued indefinitely

References

1. A2101: 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 NCT00109707

Ponatinib monotherapy

Regimen

Study	Dates of enrollment	Evidence
Cortes et al. 2013 (PACE)	2010-2011	Phase 2 (RT)

Targeted therapy

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

Continued indefinitely

References

1. PACE: 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 contains dosing details in manuscript PubMed NCT01207440
   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