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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).
2020: Aldoss I, Douer D. How I treat the toxicities of pegasparaginase in adults with acute lymphoblastic leukemia. Blood. 2020 Mar 26;135(13):987-995. link to original articlePubMed
2019: Ravandi F. How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2019 Jan 10;133(2):130-136. link to PMC article
2015: Curran E, Stock W. How I treat acute lymphoblastic leukemia in older adolescents and young adults. Blood. 2015 Jun 11;125(24):3702-10. Epub 2015 Mar 24. link to PMC articlePubMed
Note: dosing details are as provided in the protocol for GIMEMA LAL2116.
Chemotherapy
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
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 articlePubMed NCT00391989
GIMEMA LAL 0904: Chiaretti S, Vitale A, Vignetti M, Piciocchi A, Fazi P, Elia L, Falini B, Ronco F, Ferrara F, De Fabritiis P, Luppi M, La Nasa G, Tedeschi A, Califano C, Fanin R, Dore F, Mandelli F, Meloni G, Foà R. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study. Haematologica. 2016 Dec;101(12):1544-1552. link to original articlelink to PMC articlePubMed
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 articlecontains verified protocolPubMed NCT02744768
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
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 articlecontains verified protocolPubMed NCT00391989
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 articlecontains verified protocolPubMed NCT02744768
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.
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.
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 articlecontains verified protocolPubMed
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 articlePubMed
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 articlelink to PMC articlePubMed
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 articlecontains verified protocollink to PMC articlePubMed
CCCG-ALL-2015: Shen S, Chen X, Cai J, Yu J, Gao J, Hu S, Zhai X, Liang C, Ju X, Jiang H, Jin R, Wu X, Wang N, Tian X, Pan K, Jiang H, Sun L, Fang Y, Li CK, Hu Q, Yang M, Zhu Y, Zhang H, Li C, Pei D, Jeha S, Yang JJ, Cheng C, Tang J, Zhu X, Pui CH. Effect of Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA Oncol. 2020 Jan 16;6(3):358–66. Epub ahead of print. link to original articlelink to PMC articlePubMed ChiCTR-IPR-14005706
CCCG-ALL-2015: Shen S, Chen X, Cai J, Yu J, Gao J, Hu S, Zhai X, Liang C, Ju X, Jiang H, Jin R, Wu X, Wang N, Tian X, Pan K, Jiang H, Sun L, Fang Y, Li CK, Hu Q, Yang M, Zhu Y, Zhang H, Li C, Pei D, Jeha S, Yang JJ, Cheng C, Tang J, Zhu X, Pui CH. Effect of Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA Oncol. 2020 Jan 16;6(3):358–66. Epub ahead of print. link to original articlelink to PMC articlePubMed ChiCTR-IPR-14005706
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 articlecontains verified protocolPubMed
Note #1: 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. Note #2: Sasaki et al. 2016 is a post-hoc analysis, not a randomized trial.
Part A (cycles 1, 3, 5, 7)
Chemotherapy
Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m2)
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 have 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)
Chemotherapy
Methotrexate (MTX) 1000 mg/m2 IV continuous infusion over 24 hours, started on day 1
Folinic acid (Leucovorin) 50 mg IV once on day 3; 12 hours after Methotrexate (MTX) is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
Leucovorin rescue with Folinic acid (Leucovorin) 50 mg IV every 6 hours 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
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
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 (Ara-C) 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
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
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 articlecontains 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. 2004link to PMC articlePubMed
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 articlelink to PMC articlePubMed
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. link to original articlelink to PMC articlePubMed
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 articlelink to PMC articlePubMed NCT00792948
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)
Chemotherapy
Methotrexate (MTX) 1000 mg/m2 IV continuous infusion over 24 hours, started on day 1
Folinic acid (Leucovorin) 50 mg IV once on day 3; 12 hours after Methotrexate (MTX) is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
Leucovorin rescue with Folinic acid (Leucovorin) 50 mg IV every 6 hours 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
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
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 (Ara-C) 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
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
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 articlecontains verified protocolPubMed
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 articlelink to PMC articlePubMed
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 articlePubMed NCT00327678
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)
Chemotherapy
Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m2)
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)
Chemotherapy
Methotrexate (MTX) 1000 mg/m2 IV continuous infusion over 24 hours, started on day 1
Folinic acid (Leucovorin) 50 mg IV once on day 3; 12 hours after Methotrexate (MTX) is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
Leucovorin rescue with Folinic acid (Leucovorin) 50 mg IV every 6 hours 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
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
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 articlecontains partial protocol detailslink to PMC articlePubMed NCT01424982
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. link to original articlelink to PMC articlePubMed
GIMEMA LAL 0904: Chiaretti S, Vitale A, Vignetti M, Piciocchi A, Fazi P, Elia L, Falini B, Ronco F, Ferrara F, De Fabritiis P, Luppi M, La Nasa G, Tedeschi A, Califano C, Fanin R, Dore F, Mandelli F, Meloni G, Foà R. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study. Haematologica. 2016 Dec;101(12):1544-1552. link to original articlecontains verified protocollink to PMC articlePubMed
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 articlePubMed NCT00327678
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.
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 articlecontains protocolPubMed
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 articlePubMed
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 articlePubMed
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 articlecontains verified protocolPubMed
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 articlePubMed
Blinatumomab (Blincyto) 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg/m2)
42-day cycle for at least 2 and up to 5 cycles
References
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 articlecontains verified protocolPubMed NCT02744768
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 articlecontains verified protocolPubMed
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 articlePubMed
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 articlelink to PMC articlePubMed
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 articlecontains verified protocollink to PMC articlePubMed
ALL-SCT-BFM-2003: Peters C, Schrappe M, von Stackelberg A, Schrauder A, Bader P, Ebell W, Lang P, Sykora KW, Schrum J, Kremens B, Ehlert K, Albert MH, Meisel R, Matthes-Martin S, Gungor T, Holter W, Strahm B, Gruhn B, Schulz A, Woessmann W, Poetschger U, Zimmermann M, Klingebiel T. Stem-cell transplantation in children with acute lymphoblastic leukemia: a prospective international multicenter trial comparing sibling donors with matched unrelated donors-the ALL-SCT-BFM-2003 trial. J Clin Oncol. 2015 Apr 10;33(11):1265-74. Epub 2015 Mar 9. link to original articlePubMed
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
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 articlePubMed
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 articlePubMed
GIMEMA LAL 0904: Chiaretti S, Vitale A, Vignetti M, Piciocchi A, Fazi P, Elia L, Falini B, Ronco F, Ferrara F, De Fabritiis P, Luppi M, La Nasa G, Tedeschi A, Califano C, Fanin R, Dore F, Mandelli F, Meloni G, Foà R. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study. Haematologica. 2016 Dec;101(12):1544-1552. link to original articlecontains verified protocollink to PMC articlePubMed
COG AALL0031: Schultz KR, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, Wang C, Davies SM, Gaynon PS, Trigg M, Rutledge R, Burden L, Jorstad D, Carroll A, Heerema NA, Winick N, Borowitz MJ, Hunger SP, Carroll WL, Camitta B. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a Children's Oncology Group study. J Clin Oncol. 2009 Nov 1;27(31):5175-81. Epub 2009 Oct 5. link to original articlelink to PMC articlePubMed
Update: Schultz KR, Carroll A, Heerema NA, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, Zheng HW, Davies SM, Gaynon PS, Trigg M, Rutledge R, Jorstad D, Winick N, Borowitz MJ, Hunger SP, Carroll WL, Camitta B; Children’s Oncology Group. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children's Oncology Group study AALL0031. Leukemia. 2014 Jul;28(7):1467-71. Epub 2014 Jan 20. link to original articlelink to PMC articlePubMed
Note: this regimen did not meet the primary efficacy endpoint in the ITT population, but there was a possible signal in the as-treated population. See paper for details beyond "IB". To be completed (?)
EsPhALL: Biondi A, Schrappe M, De Lorenzo P, Castor A, Lucchini G, Gandemer V, Pieters R, Stary J, Escherich G, Campbell M, Li CK, Vora A, Aricò M, Röttgers S, Saha V, Valsecchi MG. Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol. 2012 Sep;13(9):936-45. Epub 2012 Aug 14. link to original articlelink to PMC articlePubMed NCT00287105
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)
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 articlecontains verified protocolPubMed
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
Patients who achieve CR: allogeneic hematopoietic stem cell transplant, or autologous HSCT if no donor available. Details not provided.
References
GIMEMA LAL 0904: Chiaretti S, Vitale A, Vignetti M, Piciocchi A, Fazi P, Elia L, Falini B, Ronco F, Ferrara F, De Fabritiis P, Luppi M, La Nasa G, Tedeschi A, Califano C, Fanin R, Dore F, Mandelli F, Meloni G, Foà R. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study. Haematologica. 2016 Dec;101(12):1544-1552. link to original articlecontains verified protocollink to PMC articlePubMed
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 articlecontains 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. 2004link to PMC articlePubMed NCT00390793
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 articlelink to PMC articlePubMed
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 articlelink to PMC articlePubMed NCT00792948
This is only offered to patients who achieved a CR. 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.
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 articlecontains 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. 2004link to PMC articlePubMed NCT00390793
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 articlelink to PMC articlePubMed
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 articlelink to PMC articlePubMed NCT00792948
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
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 articlecontains verified protocolPubMed
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 articlelink to PMC articlePubMed
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 articlePubMed NCT00327678
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 articlecontains verified protocolPubMed
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)
Cycle 2 onwards: 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)
6-week cycle for 2 to 5 cycles
References
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 articlecontains verified protocolPubMed
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.
Continued indefinitely
References
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 articlecontains verified protocollink to PMC articlePubMed
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 articlecontains verified protocollink to PMC articlePubMed
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 articlecontains verified protocollink to PMC articlePubMed
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 PMC articlePubMed
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 articlelink to PMC articlePubMed
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 articlecontains verified protocolPubMed
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 articlelink to PMC articlePubMed
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 articlecontains verified protocolPubMed
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 articlelink to PMC articlePubMed
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 articlecontains protocolPubMed
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 articlePubMed
Ponatinib (Iclusig) 45 mg PO once per day; may be taken either with or without food
Continued indefinitely
References
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 articlelink to PMC articlePubMed
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