B-cell acute lymphoblastic leukemia, Ph-positive

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Martin W. Schoen, MD, MPH
Saint Louis University
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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).

25 regimens on this page
27 variants on this page

Contents


Guidelines

ESMO

"How I treat"

  • 2015: Curran E, Stock W. How I treat acute lymphoblastic leukemia in older adolescents and young adults. Blood. 2015 Jun 11;125(24):3702-10. Epub 2015 Mar 24. link to PMC article PubMed

NCCN

Upfront induction therapy

Dasatinib & Prednisone

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Regimen

Study Evidence
Foà et al. 2011 (GIMEMA LAL1205) Phase II

Preceding treatment

Chemotherapy

CNS prophylaxis

12-week course

Subsequent treatment

  • Post-induction treatment is not specified

References

  1. 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 verified protocol PubMed

Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Imatinib

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Regimen

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

To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 91%. 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
  • Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 28
  • Imatinib (Gleevec) 400 mg PO once per day, increased to 600 mg PO once per day "wherever possible"
    • Note: Two variants have been tested: from 2003 to 2005, imatinib was added after induction; from 2005 onward, imatinib was added during induction. Various durations are proposed, see Fielding et al. 2013 for more details.

CNS prophylaxis

4-week course

Subsequent treatment

References

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

Daunorubicin, Vincristine, Prednisolone, Nilotinib

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Regimen

Study Evidence
Kim et al. 2015 (AMC-UUCM-2008-0310) Phase II

Chemotherapy

CNS Prophylaxis

14-day course, with ongoing nilotinib

Subsequent treatment

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 verified protocol PubMed

Hyper-CVAD & Dasatinib

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

Regimen

Study Evidence Comparator Comparative Efficacy
Ravandi et al. 2010 Phase II
Sasaki et al. 2016 Propensity score analysis Hyper-CVAD & Ponatinib Seems to have inferior OS
Ravandi et al. 2016 (SWOG S0805) Phase II

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.

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

  • Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m2)
  • Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
  • Doxorubicin (Adriamycin) as follows:
    • Normal EF: 50 mg/m2 IV continuous infusion over 24 hours, started on day 4
    • EF less than 50%: 25 mg/m2/day IV continuous infusion over 48 hours, started on day 4 (total dose per cycle: 50 mg/m2)
  • Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4, 11 to 14
  • Dasatinib (Sprycel) as follows:
    • Cycle 1: 100 mg PO once per day on days 1 to 14
    • Cycles 3, 5, 7: 70 mg PO once per day

Supportive medications

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

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

  • Methotrexate (MTX) 1000 mg/m2 IV continuous infusion over 24 hours, started on day 1
  • Cytarabine (Ara-C) as follows:
    • Younger than 60: 3000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m2)
    • 60 and older: 1000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m2)
  • Dasatinib (Sprycel) 70 mg PO once per day

Supportive medications

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

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
  • 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:
  • Therapeutic external radiation is given to patients with CNS disease at presentation

Subsequent treatment

References

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

Hyper-CVAD & Imatinib

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

Regimen

Study Evidence Comparator Comparative Efficacy
Thomas et al. 2003 Phase II
Chalandon et al. 2015 (GRAAPH-2005) Phase III (C) Imatinib, Vincristine, Dexamethasone Seems not superior

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

Supportive medications

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

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

  • Methotrexate (MTX) 1000 mg/m2 IV continuous infusion over 24 hours, started on day 1
  • Cytarabine (Ara-C) as follows:
    • Younger than 60: 3000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m2)
    • 60 and older: 1000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m2)
  • Imatinib (Gleevec) 400 mg PO once per day on days 1 to 14

Supportive medications

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

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
  • 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:
  • Therapeutic external radiation is given to patients with CNS disease at presentation

Subsequent treatment

References

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

Hyper-CVAD & Ponatinib

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

Regimen

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

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

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

  • Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m2)
  • Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
  • Doxorubicin (Adriamycin) as follows:
    • Normal EF: 50 mg/m2 IV continuous infusion over 24 hours, started on day 4
    • EF less than 50%: 25 mg/m2/day IV continuous infusion over 48 hours, started on day 4 (total dose per cycle: 50 mg/m2)
  • Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4, 11 to 14
  • Ponatinib (Iclusig) as follows:
    • Cycle 1: 45 mg PO once per day on days 1 to 14
    • Cycles 3, 5, 7: 45 mg PO once per day

Supportive medications

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

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

  • Methotrexate (MTX) 1000 mg/m2 IV continuous infusion over 24 hours, started on day 1
  • Cytarabine (Ara-C) as follows:
    • Younger than 60: 3000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m2)
    • 60 and older: 1000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m2)
  • Ponatinib (Iclusig) 45 mg PO once per day

Supportive medications

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

References

  1. Jabbour E, Kantarjian H, Ravandi F, Thomas D, Huang X, Faderl S, Pemmaraju N, Daver N, Garcia-Manero G, Sasaki K, Cortes J, Garris R, Yin CC, Khoury JD, Jorgensen J, Estrov Z, Bohannan Z, Konopleva M, Kadia T, Jain N, DiNardo C, Wierda W, Jeanis V, O'Brien S. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study. Lancet Oncol. 2015 Nov;16(15):1547-55. Epub 2015 Sep 30. link to original article contains partial protocol details link to PMC article PubMed
    1. 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 article link to PMC article PubMed

Imatinib & Prednisone

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Regimen

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

Preceding treatment

Chemotherapy

CNS prophylaxis

50-day course

Subsequent treatment

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. link to original article contains verified protocol link to PMC article PubMed

Imatinib, Vincristine, Dexamethasone

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Regimen

Study Evidence Comparator Comparative Efficacy
Chalandon et al. 2015 (GRAAPH-2005) Phase III (E) Hyper-CVAD & Imatinib Seems not superior

Preceding treatment

Chemotherapy

Supportive medications

28-day course

Subsequent treatment

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 (GRAALL). 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

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

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Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study Evidence Comparator Comparative Efficacy
Thomas et al. 1979 Non-randomized
Sebban et al. 1994 (LALA 87) Phase III (E) Chemotherapy or Auto HSCT Seems to have superior OS (*)
Thomas et al. 2004 (LALA-94) Non-randomized portion of RCT

Note: while 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 the manuscripts are limited.

Chemotherapy

Radiotherapy


Immunotherapy

Stem cells transfused on day 0

References

  1. Thomas ED, Sanders JE, Flournoy N, Johnson FL, Buckner CD, Clift RA, Fefer A, Goodell BW, Storb R, Weiden PL. Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood. 1979 Aug;54(2):468-76. link to original article contains protocol PubMed
  2. LALA 87: Sebban C, Lepage E, Vernant JP, Gluckman E, Attal M, Reiffers J, Sutton L, Racadot E, Michallet M, Maraninchi D, Dreyfus F, Fiere D; French Group of Therapy of Adult Acute Lymphoblastic Leukemia. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. J Clin Oncol. 1994 Dec;12(12):2580-7. link to original article PubMed
    1. Update: Thiebaut A, Vernant JP, Degos L, Huguet FR, Reiffers J, Sebban C, Lepage E, Thomas X, Fière D. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation: a follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am. 2000 Dec;14(6):1353-66. link to SD article PubMed
  3. LALA-94: Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. link to original article contains verified protocol PubMed
    1. Update: Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. link to original article PubMed

Etoposide & TBI, then allo HSCT

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Variant #1

Study Evidence
Peters et al. 2015 (ALL-SCT-BFM 2003) Non-randomized

Chemotherapy

Radiotherapy


Immunotherapy

Stem cells transfused on day 0

Variant #2

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

Chemotherapy

Radiotherapy


Immunotherapy

Stem cells transfused on day 0

References

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

HAM & Imatinib

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

Regimen

Study Evidence
de Labarthe et al. 2006 (GRAAPH-2003) Phase II
Chiaretti et al. 2016 (GIMEMA LAL 0904) Phase II

Preceding treatment

Chemotherapy

CNS 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 (GRAALL). 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. link to original article contains verified protocol link to PMC article PubMed

Etoposide, Ifosfamide, Imatinib

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Regimen

Study Evidence
Schultz et al. 2009 (COG AALL0031) Non-randomized (RT)

Chemotherapy

References

  1. 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 article link to PMC article PubMed
    1. 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 article link to PMC article PubMed

Imatinib-based consolidation

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Regimen

Study Evidence Comparator Comparative Efficacy
Biondi et al. 2012 (EsPhALL) Phase III (E) No imatinib in consolidation Seems not superior

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 (?)

Preceding treatment

  • Berlin–Frankfurt–Munster high-risk backbone

Chemotherapy, "IB"

CNS prophylaxis

References

  1. 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 article link to PMC article PubMed

Nilotinib-based consolidation

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Regimen

Study Evidence
Kim et al. 2015 (AMC-UUCM-2008-0310) Phase II

Preceding treatment

Chemotherapy, Consolidation A (Cycle 1)

Chemotherapy, Consolidation B (Cycles 2 & 4)

Chemotherapy, Consolidation C (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)
  • Nilotinib (Tasigna) 400 mg PO twice per day

Supportive medications

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

Duration of each cycle of consolidation is not specified but is presumably based on toxicities and count recovery

Subsequent treatment

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 verified protocol PubMed

Late intensification

Cytarabine, Idarubicin, Imatinib

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Regimen

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

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

Preceding treatment

Chemotherapy

CNS 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

  • Patients who achieve CR: allogeneic hematopoietic stem cell transplant, 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. link to original article contains verified protocol link to PMC article PubMed

Maintenance after upfront therapy

Dasatinib monotherapy

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Regimen

Study Evidence
Ravandi et al. 2010 Phase II
Ravandi et al. 2016 (SWOG S0805) Phase II

Preceding treatment

Chemotherapy

Continued indefinitely

References

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

Dasatinib, Vincristine, Prednisone

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Regimen

Study Evidence
Ravandi et al. 2010 Phase II
Ravandi et al. 2016 (SWOG S0805) Phase II

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.

Preceding treatment

Chemotherapy

28-day cycle for 26 cycles (2 years)

Subsequent treatment

References

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

Imatinib, Vincristine, Prednisone

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Regimen

Study Evidence Comparator Comparative Efficacy
Thomas et al. 2003 Phase II
Chalandon et al. 2015 (GRAAPH-2005) Phase III (C) Imatinib, Vincristine, Dexamethasone Seems not superior

Preceding treatment

Chemotherapy

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 verified protocol PubMed
    1. Update: Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O' Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the frontline treatment of adult patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61. Epub 2015 Feb 14. link to original article link to PMC article PubMed
  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 (GRAALL). 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

Nilotinib monotherapy

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Regimen

Study Evidence
Kim et al. 2015 (AMC-UUCM-2008-0310) Phase II

Preceding treatment

Chemotherapy

2-year course

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 verified protocol PubMed

Relapsed or refractory

Blinatumomab monotherapy

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Regimen

Study Evidence
Martinelli et al. 2017 (ALCANTARA) Phase II (RT)

Chemotherapy

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 PubMed

Bosutinib monotherapy

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Regimen

Study Evidence
Kantarjian et al. 2011 (Study 200) Phase I/II

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

Chemotherapy

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

Continued indefinitely

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 verified protocol link to PMC article PubMed
    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 verified protocol 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 verified protocol 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 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

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Variant #1, 70 mg twice per day

Study Evidence Comparator Comparative Efficacy
Ottmann et al. 2007 (START-L) Phase II
Kantarjian et al. 2009 (CA180-035) Phase III (C) Dasatinib 140 mg once per day Seems not superior (*)

Note: reported efficacy for CA180-035 is based on the 2010 subgroup analysis.

Chemotherapy

Continued indefinitely

Variant #2, 140 mg/day

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Kantarjian et al. 2009 (CA180-035) Phase III (E) Dasatinib 70 mg twice per day Seems not superior (*)

Note: reported efficacy for CA180-035 is based on the 2010 subgroup analysis.

Chemotherapy

Continued indefinitely

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 verified protocol PubMed
  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 PubMed
    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 verified protocol 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

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Regimen

FDA-recommended dose
Study Evidence
Ottmann et al. 2002 Phase II (RT)

Chemotherapy

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 protocol PubMed

Nilotinib monotherapy

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Regimen

Study Evidence
Kantarjian et al. 2006 (A2101) Phase II

Chemotherapy

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

Ponatinib monotherapy

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Regimen

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

Chemotherapy

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 PubMed
    1. Update: Abstract: Dong-Wook Kim, Javier Pinilla-Ibarz, Philipp D le Coutre, Ronald Paquette, Charles Chuah, Franck E. Nicolini, Jane F Apperley, H. Jean Khoury, Moshe Talpaz, John F. DiPersio, Daniel J DeAngelo, Elisabetta Abruzzese, Delphine Rea, Michele Baccarani, Martin C. Müller, Carlo Gambacorti-Passerini, Stephanie Lustgarten, Victor M. Rivera, Tim Clackson, Christopher D Turner, Frank G Haluska, François Guilhot, Michael W. Deininger, Andreas Hochhaus, Timothy P. Hughes, John M Goldman, Neil P. Shah, Hagop M. Kantarjian. Ponatinib In Patients (pts) With Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Resistant Or Intolerant To Dasatinib Or Nilotinib, Or With The T315I BCR-ABL Mutation: 2-Year Follow-Up Of The PACE Trial. Blood Nov 2013,122(21)650 link to original abstract