Chronic myelogenous leukemia

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Section editor
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Sanjay R. Mohan, MD, MSCI
Nashville, TN
30 regimens on this page
42 variants on this page

Contents


Guidelines

ELN

ESMO

NCCN

Chronic phase, first-line therapy

Bosutinib monotherapy

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Variant #1, 400 mg/d

FDA-recommended dose
Study Evidence Comparator Efficacy
Cortes et al. 2017 (BFORE) Phase III (E) Imatinib Seems to have superior MMR rate at 12 months

Chemotherapy

Continued indefinitely

Variant #2, 500 mg/d

Study Evidence Comparator Efficacy
Cortes et al. 2012 (BELA) Phase III (E) Imatinib Superior MMR rate at 12 months

Suboptimal response defined as no complete hematologic response (CHR) by week 8 or complete cytogenetic response (CCyR) by week 12.

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

Continued indefinitely

References

  1. BELA: Cortes JE, Kim DW, Kantarjian HM, Brümmendorf TH, Dyagil I, Griskevicius L, Malhotra H, Powell C, Gogat K, Countouriotis AM, Gambacorti-Passerini C. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012 Oct 1;30(28):3486-92. Epub 2012 Sep 4. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Gambacorti-Passerini C, Cortes JE, Lipton JH, Dmoszynska A, Wong RS, Rossiev V, Pavlov D, Gogat Marchant K, Duvillié L, Khattry N, Kantarjian HM, Brümmendorf TH. Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia. Am J Hematol. 2014 Oct;89(10):947-53. Epub 2014 Jul 21. link to original article link to PMC article PubMed
    2. Update: Brümmendorf TH, Cortes JE, de Souza CA, Guilhot F, Duvillié L, Pavlov D, Gogat K, Countouriotis AM, Gambacorti-Passerini C. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br J Haematol. 2015 Jan;168(1):69-81. Epub 2014 Sep 8. link to original article link to PMC article PubMed
  2. BFORE: Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim DW, Dyagil I, Glushko N, Milojkovic D, le Coutre P, Garcia-Gutierrez V, Reilly L, Jeynes-Ellis A, Leip E, Bardy-Bouxin N, Hochhaus A, Brümmendorf TH. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE Trial. J Clin Oncol. 2018 Jan 20;36(3):231-237. Epub 2017 Nov 1. link to original article contains protocol PubMed

Cytarabine & Interferon alfa-2b

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Regimen

Study Evidence Comparator Efficacy
Guilhot et al. 1997 Phase III (E) Interferon alfa-2b Seems to have superior OS
O'Brien et al. 2003 (IRIS) Phase III (C) Imatinib Inferior FFP

Note: IRIS does not specify the type of interferon alfa so this is extrapolated from Guilhot et al. 1997. Many patients on this arm of IRIS crossed over to imatinib; this experience is summarized in Guilhot et al. 2009.

Chemoimmunotherapy

Continued indefinitely

References

  1. Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau JL, Maloisel F, Bouabdallah R, Guyotat D, Cheron N, Nicolini F, Abgrall JF, Tanzer J, Navarro M, Bordessoule D, Morice P, Ifrah N, Rochant H, Vilque JP, Delain M, Bauters F, Guilhot J; French Chronic Myeloid Leukemia Study Group. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med. 1997 Jul 24;337(4):223-9. link to original article contains verified protocol PubMed
  2. IRIS: O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ; IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003 Mar 13;348(11):994-1004. link to original article contains verified protocol PubMed
    1. Update: Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA; IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006 Dec 7;355(23):2408-17. link to original article PubMed
    2. Subgroup analysis: Guilhot F, Druker B, Larson RA, Gathmann I, So C, Waltzman R, O'Brien SG. High rates of durable response are achieved with imatinib after treatment with interferon alpha plus cytarabine: results from the International Randomized Study of Interferon and STI571 (IRIS) trial. Haematologica. 2009 Dec;94(12):1669-75. Epub 2009 Jul 31. link to original article link to PMC article PubMed
    3. Update: Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, Baccarani M, Deininger MW, Cervantes F, Fujihara S, Ortmann CE, Menssen HD, Kantarjian H, O'Brien SG, Druker BJ; IRIS Investigators. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017 Mar 9;376(10):917-927. link to original article PubMed

Dasatinib monotherapy

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Regimen

FDA-recommended dose
Study Evidence Comparator Efficacy
Cortes et al. 2009 Phase II
Kantarjian et al. 2010 (DASISION) Phase III (E) Imatinib Superior MMR rate
Radich et al. 2012 (SWOG S0325 Phase 2) Phase III (E) Imatinib Seems not superior

Chemotherapy

Continued indefinitely

References

  1. Cortes JE, Jones D, O'Brien S, Jabbour E, Ravandi F, Koller C, Borthakur G, Walker B, Zhao W, Shan J, Kantarjian H. Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol. 2010 Jan 20;28(3):398-404. Epub 2009 Dec 14. link to original article link to PMC article PubMed
  2. DASISION: Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, Moiraghi B, Shen Z, Mayer J, Pasquini R, Nakamae H, Huguet F, Boqué C, Chuah C, Bleickardt E, Bradley-Garelik MB, Zhu C, Szatrowski T, Shapiro D, Baccarani M. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2260-70. Epub 2010 Jun 5. link to original article contains protocol PubMed
    1. Update: Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Undurraga MS, Wang J, Kassack Ipiña JJ, Kim DW, Ogura M, Pavlovsky C, Junghanss C, Milone JH, Nicolini FE, Robak T, Van Droogenbroeck J, Vellenga E, Bradley-Garelik MB, Zhu C, Hochhaus A. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012 Feb 2;119(5):1123-9. Epub 2011 Dec 9. link to original article link to PMC article PubMed
    2. Update: Jabbour E, Kantarjian HM, Saglio G, Steegmann JL, Shah NP, Boqué C, Chuah C, Pavlovsky C, Mayer J, Cortes J, Baccarani M, Kim DW, Bradley-Garelik MB, Mohamed H, Wildgust M, Hochhaus A. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2014 Jan 23;123(4):494-500. Epub 2013 Dec 5. link to original article link to PMC article PubMed
    3. Subgroup analysis: Fujisawa S, Nakamae H, Ogura M, Ishizawa K, Taniwaki M, Utsunomiya A, Matsue K, Takamatsu Y, Usuki K, Tanimoto M, Ishida Y, Akiyama H, Onishi S. Efficacy and safety of dasatinib versus imatinib in Japanese patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP): Subset analysis of the DASISION trial with 2-year follow-up. Int J Hematol. 2014 Feb;99(2):141-53. Epub 2013 Dec 20. link to original article PubMed
    4. Update: Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C, Shah NP, Chuah C, Casanova L, Bradley-Garelik B, Manos G, Hochhaus A. Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncol. 2016 Jul 10;34(20):2333-40. Epub 2016 May 23. link to original article link to PMC article PubMed
  3. SWOG S0325 Phase 2: Radich JP, Kopecky KJ, Appelbaum FR, Kamel-Reid S, Stock W, Malnassy G, Paietta E, Wadleigh M, Larson RA, Emanuel P, Tallman M, Lipton J, Turner AR, Deininger M, Druker BJ. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood. 2012 Nov 8;120(19):3898-905. Epub 2012 Aug 22. link to original article link to PMC article PubMed

Hydroxyurea & Interferon alfa

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Regimen

Study Evidence Comparator Efficacy
Hehlmann et al. 2003 (CML-Study II) Phase III (E) Hydroxyurea Superior OS
Hehlmann et al. 2007 (CML-Study III) Phase III (E) Allogeneic HSCT Seems to have superior OS
Gratwohl et al. 2015 (CML-Study IIIA) Phase III (C) Allogeneic HSCT Seems not superior

Of historic interest, and one of the few regimens compared in large RCTs against allogeneic HSCT.

Chemoimmunotherapy

References

  1. CML-Study II: Hehlmann R, Berger U, Pfirrmann M, high-rise A, Metzgeroth G, Maywald O, Hasford J, Reiter A, Hossfeld DK, Kolb HJ, Löffler H, Pralle H, Queisser W, Griesshammer M, Nerl C, Kuse R, Tobler A, Eimermacher H, Tichelli A, Aul C, Wilhelm M, Fischer JT, Perker M, Scheid C, Schenk M, Weiss J, Meier CR, Kremers S, Labedzki L, Schmeiser T, Lohrmann HP, Heimpel H; German CML Study Group. Randomized comparison of interferon alpha and hydroxyurea with hydroxyurea monotherapy in chronic myeloid leukemia (CML-study II): prolongation of survival by the combination of interferon alpha and hydroxyurea. Leukemia. 2003 Aug;17(8):1529-37. link to original article PubMed
  2. CML-Study III: Hehlmann R, Berger U, Pfirrmann M, Heimpel H, Hochhaus A, Hasford J, Kolb HJ, Lahaye T, Maywald O, Reiter A, Hossfeld DK, Huber C, Löffler H, Pralle H, Queisser W, Tobler A, Nerl C, Solenthaler M, Goebeler ME, Griesshammer M, Fischer T, Kremers S, Eimermacher H, Pfreundschuh M, Hirschmann WD, Lechner K, Wassmann B, Falge C, Kirchner HH, Gratwohl A. Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood. 2007 Jun 1;109(11):4686-92. Epub 2007 Feb 22. link to original article PubMed
  3. CML-Study IIIA: Gratwohl A, Pfirrmann M, Zander A, Kröger N, Beelen D, Novotny J, Nerl C, Scheid C, Spiekermann K, Mayer J, Sayer HG, Falge C, Bunjes D, Döhner H, Ganser A, Schmidt-Wolf I, Schwerdtfeger R, Baurmann H, Kuse R, Schmitz N, Wehmeier A, Fischer JT, Ho AD, Wilhelm M, Goebeler ME, Lindemann HW, Bormann M, Hertenstein B, Schlimok G, Baerlocher GM, Aul C, Pfreundschuh M, Fabian M, Staib P, Edinger M, Schatz M, Fauser A, Arnold R, Kindler T, Wulf G, Rosselet A, Hellmann A, Schäfer E, Prümmer O, Schenk M, Hasford J, Heimpel H, Hossfeld DK, Kolb HJ, Büsche G, Haferlach C, Schnittger S, Müller MC, Reiter A, Berger U, Saußele S, Hochhaus A, Hehlmann R; SAKK; German CML Study Group. Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment. Leukemia. 2016 Mar;30(3):562-9. Epub 2015 Oct 14. link to original article PubMed

Imatinib monotherapy

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Regimen

FDA-recommended dose
Study Evidence Comparator Efficacy
O'Brien et al. 2003 (IRIS) Phase III (E) Cytarabine & Interferon alfa Superior FFP
Kantarjian et al. 2006 Retrospective
Baccarani et al. 2009 (GIMEMA CML/022) Phase III (C) High-dose imatinib Seems not superior
Kantarjian et al. 2010 (DASISION) Phase III (C) Dasatinib Inferior MMR rate
Saglio et al. 2010 (ENESTnd) Phase III (C) 1. Nilotinib 300 mg BID Seems to have inferior TTP
2. Nilotinib 400 mg BID Inferior TTP
Preudhomme et al. 2010 (SPIRIT) Phase III (C) 1. Imatinib 600 mg daily Not reported
2. Imatinib & Interferon alfa Inferior MMR rate at 12 months
3. Imatinib & LoDAC Not reported
Hehlmann et al. 2011 (CML-Study IV) Phase III (C) 1. High-dose imatinib Inferior MMR rate at 12 months
2. Imatinib & Interferon alfa Not reported
Cortes et al. 2012 (BELA) Phase III (C) Bosutinib Inferior MMR rate at 12 months
Radich et al. 2012 (SWOG S0325 Phase 2) Phase III (C) Dasatinib Seems not superior
Deininger et al. 2013 (SWOG S0325 Phase 1) Randomized Phase II (C) High-dose imatinib Seems to have inferior MMR rate at 12 months
Hughes et al. 2014 (ENESTcmr) Non-randomized portion of RCT
Yeung et al. 2014 (TIDEL-II) Non-randomized
Wang et al. 2015 (ENESTchina) Phase III (C) Nilotinib Inferior MMR rate at 12 months
Lipton et al. 2016 (EPIC) Phase III (C) Ponatinib Might have inferior MMR rate at 12 months
Cortes et al. 2017 (BFORE) Phase III (C) Bosutinib Seems to have inferior MMR rate at 12 months
Kwak et al. 2017 (RERISE) Phase III (C) 1. Radotinib 300 mg BID Inferior MMR rate at 12 months
2. Radotinib 400 mg BID Seems to have inferior MMR rate at 12 months

Note: EPIC was terminated early, "following concerns about vascular adverse events observed in patients given ponatinib in other trials."

Chemotherapy

Continued indefinitely

Subsequent treatment

  • ENESTcmr, patients with detectable BCR-ABL1 after at least 2 years of therapy: continued imatinib versus nilotinib
  • TIDEL-II: Patients failing to meet molecular targets were either dose-increased to imatinib 800 mg per day and then switched to nilotinib 3 months later if they were still failing to meet targets, or switched to nilotinib directly. This was not a randomization.

References

  1. IRIS: O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ; IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003 Mar 13;348(11):994-1004. link to original article contains verified protocol PubMed
    1. Update: Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA; IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006 Dec 7;355(23):2408-17. link to original article PubMed
    2. Subgroup analysis: Guilhot F, Druker B, Larson RA, Gathmann I, So C, Waltzman R, O'Brien SG. High rates of durable response are achieved with imatinib after treatment with interferon alpha plus cytarabine: results from the International Randomized Study of Interferon and STI571 (IRIS) trial. Haematologica. 2009 Dec;94(12):1669-75. Epub 2009 Jul 31. link to original article link to PMC article PubMed
    3. Update: Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, Baccarani M, Deininger MW, Cervantes F, Fujihara S, Ortmann CE, Menssen HD, Kantarjian H, O'Brien SG, Druker BJ; IRIS Investigators. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017 Mar 9;376(10):917-927. link to original article PubMed
  2. Retrospective: Kantarjian HM, Talpaz M, O'Brien S, Jones D, Giles F, Garcia-Manero G, Faderl S, Ravandi F, Rios MB, Shan J, Cortes J. Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. Blood. 2006 Sep 15;108(6):1835-40. Epub 2006 May 18. link to original article PubMed content property of HemOnc.org
  3. GIMEMA CML/022: Baccarani M, Rosti G, Castagnetti F, Haznedaroglu I, Porkka K, Abruzzese E, Alimena G, Ehrencrona H, Hjorth-Hansen H, Kairisto V, Levato L, Martinelli G, Nagler A, Lanng Nielsen J, Ozbek U, Palandri F, Palmieri F, Pane F, Rege-Cambrin G, Russo D, Specchia G, Testoni N, Weiss-Bjerrum O, Saglio G, Simonsson B. Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study. Blood. 2009 May 7;113(19):4497-504. Epub 2009 Mar 4. link to original article contains verified protocol PubMed
    1. Update: Castagnetti F, Gugliotta G, Breccia M, Stagno F, Iurlo A, Albano F, Abruzzese E, Martino B, Levato L, Intermesoli T, Pregno P, Rossi G, Gherlinzoni F, Leoni P, Cavazzini F, Venturi C, Soverini S, Testoni N, Alimena G, Cavo M, Martinelli G, Pane F, Saglio G, Rosti G, Baccarani M; GIMEMA CML Working Party. Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib. Leukemia. 2015 Sep;29(9):1823-31. Epub 2015 Jun 19. link to original article PubMed
  4. DASISION: Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, Moiraghi B, Shen Z, Mayer J, Pasquini R, Nakamae H, Huguet F, Boqué C, Chuah C, Bleickardt E, Bradley-Garelik MB, Zhu C, Szatrowski T, Shapiro D, Baccarani M. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2260-70. Epub 2010 Jun 5. link to original article contains protocol PubMed
    1. Update: Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Undurraga MS, Wang J, Kassack Ipiña JJ, Kim DW, Ogura M, Pavlovsky C, Junghanss C, Milone JH, Nicolini FE, Robak T, Van Droogenbroeck J, Vellenga E, Bradley-Garelik MB, Zhu C, Hochhaus A. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012 Feb 2;119(5):1123-9. Epub 2011 Dec 9. link to original article link to PMC article PubMed
    2. Update: Jabbour E, Kantarjian HM, Saglio G, Steegmann JL, Shah NP, Boqué C, Chuah C, Pavlovsky C, Mayer J, Cortes J, Baccarani M, Kim DW, Bradley-Garelik MB, Mohamed H, Wildgust M, Hochhaus A. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2014 Jan 23;123(4):494-500. Epub 2013 Dec 5. link to original article link to PMC article PubMed
    3. Subgroup analysis: Fujisawa S, Nakamae H, Ogura M, Ishizawa K, Taniwaki M, Utsunomiya A, Matsue K, Takamatsu Y, Usuki K, Tanimoto M, Ishida Y, Akiyama H, Onishi S. Efficacy and safety of dasatinib versus imatinib in Japanese patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP): Subset analysis of the DASISION trial with 2-year follow-up. Int J Hematol. 2014 Feb;99(2):141-53. Epub 2013 Dec 20. link to original article PubMed
    4. Update: Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C, Shah NP, Chuah C, Casanova L, Bradley-Garelik B, Manos G, Hochhaus A. Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncol. 2016 Jul 10;34(20):2333-40. Epub 2016 May 23. link to original article link to PMC article PubMed
  5. ENESTnd: Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM; ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2251-9. Epub 2010 Jun 5. link to original article contains protocol PubMed
    1. Update: Kantarjian HM, Hochhaus A, Saglio G, De Souza C, Flinn IW, Stenke L, Goh YT, Rosti G, Nakamae H, Gallagher NJ, Hoenekopp A, Blakesley RE, Larson RA, Hughes TP. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011 Sep;12(9):841-51. Epub 2011 Aug 17. Erratum in: Lancet Oncol. 2011 Oct;12(11):989. link to original article contains verified protocol PubMed
    2. Update: Larson RA, Hochhaus A, Hughes TP, Clark RE, Etienne G, Kim DW, Flinn IW, Kurokawa M, Moiraghi B, Yu R, Blakesley RE, Gallagher NJ, Saglio G, Kantarjian HM. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012 Oct;26(10):2197-203. Epub 2012 May 18. link to original article PubMed
    3. Update: Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, le Coutre PD, Etienne G, Dorlhiac-Llacer PE, Clark RE, Flinn IW, Nakamae H, Donohue B, Deng W, Dalal D, Menssen HD, Kantarjian HM. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016 May;30(5):1044-54. Epub 2016 Feb 3. link to original article link to PMC article PubMed
  6. SPIRIT: Preudhomme C, Guilhot J, Nicolini FE, Guerci-Bresler A, Rigal-Huguet F, Maloisel F, Coiteux V, Gardembas M, Berthou C, Vekhoff A, Rea D, Jourdan E, Allard C, Delmer A, Rousselot P, Legros L, Berger M, Corm S, Etienne G, Roche-Lestienne C, Eclache V, Mahon FX, Guilhot F; SPIRIT Investigators; France Intergroupe des Leucémies Myéloïdes Chroniques (Fi-LMC). Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med. 2010 Dec 23;363(26):2511-21. link to original article contains verified protocol PubMed
  7. CML-Study IV: Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Müller MC, Pletsch N, Proetel U, Haferlach C, Schlegelberger B, Balleisen L, Hänel M, Pfirrmann M, Krause SW, Nerl C, Pralle H, Gratwohl A, Hossfeld DK, Hasford J, Hochhaus A, Saussele S. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-a in newly diagnosed chronic myeloid leukemia. J Clin Oncol. 2011 Apr 20;29(12):1634-42. Epub 2011 Mar 21. link to original article contains verified protocol PubMed
    1. Update: Hehlmann R, Müller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A, Proetel U, Pletsch N, Pfirrmann M, Haferlach C, Schnittger S, Einsele H, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Ehninger G, Heim D, Heimpel H, Nerl C, Krause SW, Hossfeld DK, Kolb HJ, Hasford J, Saußele S, Hochhaus A. Deep Molecular Response Is Reached by the Majority of Patients Treated With Imatinib, Predicts Survival, and Is Achieved More Quickly by Optimized High-Dose Imatinib: Results From the Randomized CML-Study IV. J Clin Oncol. 2014 Feb 10;32(5):415-23. Epub 2013 Dec 2. link to original article contains verified protocol PubMed
    2. Update: Kalmanti L, Saussele S, Lauseker M, Müller MC, Dietz CT, Heinrich L, Hanfstein B, Proetel U, Fabarius A, Krause SW, Rinaldetti S, Dengler J, Falge C, Oppliger-Leibundgut E, Burchert A, Neubauer A, Kanz L, Stegelmann F, Pfreundschuh M, Spiekermann K, Scheid C, Pfirrmann M, Hochhaus A, Hasford J, Hehlmann R. Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV. Leukemia. 2015 May;29(5):1123-32. Epub 2015 Feb 13. link to original article PubMed
    3. Update: Hehlmann R, Lauseker M, Saußele S, Pfirrmann M, Krause S, Kolb HJ, Neubauer A, Hossfeld DK, Nerl C, Gratwohl A, Baerlocher GM, Heim D, Brümmendorf TH, Fabarius A, Haferlach C, Schlegelberger B, Müller MC, Jeromin S, Proetel U, Kohlbrenner K, Voskanyan A, Rinaldetti S, Seifarth W, Spieß B, Balleisen L, Goebeler MC, Hänel M, Ho A, Dengler J, Falge C, Kanz L, Kremers S, Burchert A, Kneba M, Stegelmann F, Köhne CA, Lindemann HW, Waller CF, Pfreundschuh M, Spiekermann K, Berdel WE, Müller L, Edinger M, Mayer J, Beelen DW, Bentz M, Link H, Hertenstein B, Fuchs R, Wernli M, Schlegel F, Schlag R, de Wit M, Trümper L, Hebart H, Hahn M, Thomalla J, Scheid C, Schafhausen P, Verbeek W, Eckart MJ, Gassmann W, Pezzutto A, Schenk M, Brossart P, Geer T, Bildat S, Schäfer E, Hochhaus A, Hasford J. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017 Nov;31(11):2398-2406. Epub 2017 Aug 14. link to original article PubMed
  8. BELA: Cortes JE, Kim DW, Kantarjian HM, Brümmendorf TH, Dyagil I, Griskevicius L, Malhotra H, Powell C, Gogat K, Countouriotis AM, Gambacorti-Passerini C. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012 Oct 1;30(28):3486-92. Epub 2012 Sep 4. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Gambacorti-Passerini C, Cortes JE, Lipton JH, Dmoszynska A, Wong RS, Rossiev V, Pavlov D, Gogat Marchant K, Duvillié L, Khattry N, Kantarjian HM, Brümmendorf TH. Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia. Am J Hematol. 2014 Oct;89(10):947-53. Epub 2014 Jul 21. link to original article link to PMC article PubMed
    2. Update: Brümmendorf TH, Cortes JE, de Souza CA, Guilhot F, Duvillié L, Pavlov D, Gogat K, Countouriotis AM, Gambacorti-Passerini C. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br J Haematol. 2015 Jan;168(1):69-81. Epub 2014 Sep 8. link to original article link to PMC article PubMed
  9. SWOG S0325 Phase 2: Radich JP, Kopecky KJ, Appelbaum FR, Kamel-Reid S, Stock W, Malnassy G, Paietta E, Wadleigh M, Larson RA, Emanuel P, Tallman M, Lipton J, Turner AR, Deininger M, Druker BJ. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood. 2012 Nov 8;120(19):3898-905. Epub 2012 Aug 22. link to original article link to PMC article PubMed
  10. SWOG S0325 Phase 1: Deininger MW, Kopecky KJ, Radich JP, Kamel-Reid S, Stock W, Paietta E, Emanuel PD, Tallman M, Wadleigh M, Larson RA, Lipton JH, Slovak ML, Appelbaum FR, Druker BJ. Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized phase II trial in newly diagnosed chronic phase chronic myeloid leukaemia. Br J Haematol. 2014 Jan;164(2):223-32. Epub 2013 Nov 4. link to original article contains verified protocol link to PMC article PubMed
  11. ENESTcmr: Hughes TP, Lipton JH, Spector N, Cervantes F, Pasquini R, Clementino NC, Dorlhiac Llacer PE, Schwarer AP, Mahon FX, Rea D, Branford S, Purkayastha D, Collins L, Szczudlo T, Leber B. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood. 2014 Jul 31;124(5):729-36. Epub 2014 Jun 19. link to original article contains verified protocol PubMed
    1. Update: Hughes TP, Leber B, Cervantes F, Spector N, Pasquini R, Clementino NCD, Schwarer AP, Dorlhiac-Llacer PE, Mahon FX, Rea D, Guerci-Bresler A, Kamel-Reid S, Bendit I, Acharya S, Glynos T, Dalal D, Branford S, Lipton JH. Sustained deep molecular responses in patients switched to nilotinib due to persistent BCR-ABL1 on imatinib: final ENESTcmr randomized trial results. Leukemia. 2017 Nov;31(11):2529-2531. Epub 2017 Aug 3. link to original article link to PMC article PubMed
  12. TIDEL-II: Yeung DT, Osborn MP, White DL, Branford S, Braley J, Herschtal A, Kornhauser M, Issa S, Hiwase DK, Hertzberg M, Schwarer AP, Filshie R, Arthur CK, Kwan YL, Trotman J, Forsyth CJ, Taper J, Ross DM, Beresford J, Tam C, Mills AK, Grigg AP, Hughes TP; Australasian Leukaemia and Lymphoma Group. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood. 2015 Feb 5;125(6):915-23. Epub 2014 Dec 17. link to original article contains verified protocol link to PMC article PubMed
  13. ENESTchina: Wang J, Shen ZX, Saglio G, Jin J, Huang H, Hu Y, Du X, Li J, Meng F, Zhu H, Hu J, Wang J, Hou M, Hertle S, Menssen HD, Ortmann CE, Tribouley C, Yuan Y, Baccarani M, Huang X. Phase 3 study of nilotinib vs imatinib in Chinese patients with newly diagnosed chronic myeloid leukemia in chronic phase: ENESTchina. Blood. 2015 Apr 30;125(18):2771-8. Epub 2015 Mar 12. link to original article contains verified protocol link to PMC article PubMed
  14. EPIC: Lipton JH, Chuah C, Guerci-Bresler A, Rosti G, Simpson D, Assouline S, Etienne G, Nicolini FE, le Coutre P, Clark RE, Stenke L, Andorsky D, Oehler V, Lustgarten S, Rivera VM, Clackson T, Haluska FG, Baccarani M, Cortes JE, Guilhot F, Hochhaus A, Hughes T, Kantarjian HM, Shah NP, Talpaz M, Deininger MW; EPIC investigators. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2016 May;17(5):612-21. Epub 2016 Apr 12. link to original article contains protocol PubMed
  15. BFORE: Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim DW, Dyagil I, Glushko N, Milojkovic D, le Coutre P, Garcia-Gutierrez V, Reilly L, Jeynes-Ellis A, Leip E, Bardy-Bouxin N, Hochhaus A, Brümmendorf TH. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE Trial. J Clin Oncol. 2018 Jan 20;36(3):231-237. Epub 2017 Nov 1. link to original article contains protocol PubMed
  16. RERISE: Kwak JY, Kim SH, Oh SJ, Zang DY, Kim H, Kim JA, Do YR, Kim HJ, Park JS, Choi CW, Lee WS, Mun YC, Kong JH, Chung JS, Shin HJ, Kim DY, Park J, Jung CW, Bunworasate U, Comia NS, Jootar S, Reksodiputro AH, Caguioa PB, Lee SE, Kim DW. Phase III clinical trial (RERISE study) results of efficacy and safety of radotinib compared with imatinib in newly diagnosed chronic phase chronic myeloid leukemia. Clin Cancer Res. 2017 Dec 1;23(23):7180-7188. Epub 2017 Sep 22. link to original article contains protocol PubMed

Imatinib monotherapy, high dose

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Regimen

Study Evidence Comparator Efficacy
Castagnetti et al. 2009 (GIMEMA CML/021) Phase II
Baccarani et al. 2009 (GIMEMA CML/022) Phase III (E) Standard-dose imatinib Seems not superior
Cortes et al. 2010 Phase III (E) Standard-dose imatinib Seems not superior
Hehlmann et al. 2011 (CML-Study IV) Phase III (E) 1. Standard-dose imatinib Superior MMR rate at 12 months
2. Imatinib & Interferon alfa Superior MMR rate at 12 months
Thielen et al. 2013 Phase III (C) Cytarabine & HD-Imatinib Seems not superior
Deininger et al. 2013 (SWOG S0325 Phase 1) Randomized Phase II (E) Standard-dose imatinib Seems to have superior MMR rate at 12 months

Note: GIMEMA CML/021 used a lead-in dose of 400 mg PO once per day for 2 weeks, followed by escalation to 400 mg PO BID.

Chemotherapy

  • Imatinib (Gleevec) 800 mg PO once per day (CML-Study IV) or 400 mg PO BID (S0325, GIMEMA studies)

Continued indefinitely

References

  1. GIMEMA CML/021: Castagnetti F, Palandri F, Amabile M, Testoni N, Luatti S, Soverini S, Iacobucci I, Breccia M, Rege Cambrin G, Stagno F, Specchia G, Galieni P, Iuliano F, Pane F, Saglio G, Alimena G, Martinelli G, Baccarani M, Rosti G; GIMEMA CML Working Party. Results of high-dose imatinib mesylate in intermediate Sokal risk chronic myeloid leukemia patients in early chronic phase: a phase 2 trial of the GIMEMA CML Working Party. Blood. 2009 Apr 9;113(15):3428-34. Epub 2009 Feb 11. link to original article contains verified protocol PubMed
    1. Update: Castagnetti F, Gugliotta G, Breccia M, Stagno F, Iurlo A, Albano F, Abruzzese E, Martino B, Levato L, Intermesoli T, Pregno P, Rossi G, Gherlinzoni F, Leoni P, Cavazzini F, Venturi C, Soverini S, Testoni N, Alimena G, Cavo M, Martinelli G, Pane F, Saglio G, Rosti G, Baccarani M; GIMEMA CML Working Party. Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib. Leukemia. 2015 Sep;29(9):1823-31. Epub 2015 Jun 19. link to original article PubMed
  2. GIMEMA CML/022: Baccarani M, Rosti G, Castagnetti F, Haznedaroglu I, Porkka K, Abruzzese E, Alimena G, Ehrencrona H, Hjorth-Hansen H, Kairisto V, Levato L, Martinelli G, Nagler A, Lanng Nielsen J, Ozbek U, Palandri F, Palmieri F, Pane F, Rege-Cambrin G, Russo D, Specchia G, Testoni N, Weiss-Bjerrum O, Saglio G, Simonsson B. Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study. Blood. 2009 May 7;113(19):4497-504. Epub 2009 Mar 4. link to original article contains verified protocol PubMed
    1. Update: Castagnetti F, Gugliotta G, Breccia M, Stagno F, Iurlo A, Albano F, Abruzzese E, Martino B, Levato L, Intermesoli T, Pregno P, Rossi G, Gherlinzoni F, Leoni P, Cavazzini F, Venturi C, Soverini S, Testoni N, Alimena G, Cavo M, Martinelli G, Pane F, Saglio G, Rosti G, Baccarani M; GIMEMA CML Working Party. Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib. Leukemia. 2015 Sep;29(9):1823-31. Epub 2015 Jun 19. link to original article PubMed
  3. Cortes JE, Baccarani M, Guilhot F, Druker BJ, Branford S, Kim DW, Pane F, Pasquini R, Goldberg SL, Kalaycio M, Moiraghi B, Rowe JM, Tothova E, De Souza C, Rudoltz M, Yu R, Krahnke T, Kantarjian HM, Radich JP, Hughes TP. Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol. 2010 Jan 20;28(3):424-30. Epub 2009 Dec 14. Erratum in: J Clin Oncol. 2010 May 1;28(13):2314. link to original article link to PMC article contains protocol PubMed
  4. CML-Study IV: Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Müller MC, Pletsch N, Proetel U, Haferlach C, Schlegelberger B, Balleisen L, Hänel M, Pfirrmann M, Krause SW, Nerl C, Pralle H, Gratwohl A, Hossfeld DK, Hasford J, Hochhaus A, Saussele S. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-a in newly diagnosed chronic myeloid leukemia. J Clin Oncol. 2011 Apr 20;29(12):1634-42. Epub 2011 Mar 21. link to original article contains verified protocol PubMed
    1. Update: Hehlmann R, Müller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A, Proetel U, Pletsch N, Pfirrmann M, Haferlach C, Schnittger S, Einsele H, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Ehninger G, Heim D, Heimpel H, Nerl C, Krause SW, Hossfeld DK, Kolb HJ, Hasford J, Saußele S, Hochhaus A. Deep Molecular Response Is Reached by the Majority of Patients Treated With Imatinib, Predicts Survival, and Is Achieved More Quickly by Optimized High-Dose Imatinib: Results From the Randomized CML-Study IV. J Clin Oncol. 2014 Feb 10;32(5):415-23. Epub 2013 Dec 2. link to original article contains verified protocol PubMed
    2. Update: Kalmanti L, Saussele S, Lauseker M, Müller MC, Dietz CT, Heinrich L, Hanfstein B, Proetel U, Fabarius A, Krause SW, Rinaldetti S, Dengler J, Falge C, Oppliger-Leibundgut E, Burchert A, Neubauer A, Kanz L, Stegelmann F, Pfreundschuh M, Spiekermann K, Scheid C, Pfirrmann M, Hochhaus A, Hasford J, Hehlmann R. Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV. Leukemia. 2015 May;29(5):1123-32. Epub 2015 Feb 13. link to original article PubMed
    3. Update: Hehlmann R, Lauseker M, Saußele S, Pfirrmann M, Krause S, Kolb HJ, Neubauer A, Hossfeld DK, Nerl C, Gratwohl A, Baerlocher GM, Heim D, Brümmendorf TH, Fabarius A, Haferlach C, Schlegelberger B, Müller MC, Jeromin S, Proetel U, Kohlbrenner K, Voskanyan A, Rinaldetti S, Seifarth W, Spieß B, Balleisen L, Goebeler MC, Hänel M, Ho A, Dengler J, Falge C, Kanz L, Kremers S, Burchert A, Kneba M, Stegelmann F, Köhne CA, Lindemann HW, Waller CF, Pfreundschuh M, Spiekermann K, Berdel WE, Müller L, Edinger M, Mayer J, Beelen DW, Bentz M, Link H, Hertenstein B, Fuchs R, Wernli M, Schlegel F, Schlag R, de Wit M, Trümper L, Hebart H, Hahn M, Thomalla J, Scheid C, Schafhausen P, Verbeek W, Eckart MJ, Gassmann W, Pezzutto A, Schenk M, Brossart P, Geer T, Bildat S, Schäfer E, Hochhaus A, Hasford J. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017 Nov;31(11):2398-2406. Epub 2017 Aug 14. link to original article PubMed
  5. Thielen N, van der Holt B, Verhoef GE, Ammerlaan RA, Sonneveld P, Janssen JJ, Deenik W, Falkenburg JH, Kersten MJ, Sinnige HA, Schipperus M, Schattenberg A, van Marwijk Kooy R, Smit WM, Chu IW, Valk PJ, Ossenkoppele GJ, Cornelissen JJ. High-dose imatinib versus high-dose imatinib in combination with intermediate-dose cytarabine in patients with first chronic phase myeloid leukemia: a randomized phase III trial of the Dutch-Belgian HOVON study group. Ann Hematol. 2013 Aug;92(8):1049-56. Epub 2013 Apr 10. link to original article PubMed
  6. SWOG S0325: Deininger MW, Kopecky KJ, Radich JP, Kamel-Reid S, Stock W, Paietta E, Emanuel PD, Tallman M, Wadleigh M, Larson RA, Lipton JH, Slovak ML, Appelbaum FR, Druker BJ. Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized phase II trial in newly diagnosed chronic phase chronic myeloid leukaemia. Br J Haematol. 2014 Jan;164(2):223-32. Epub 2013 Nov 4. link to original article contains verified protocol link to PMC article PubMed

Imatinib monotherapy, intermittent therapy

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Regimen

Study Evidence
Russo et al. 2013 Phase II

Eligible patients had been taking imatinib for at least two years and were in a complete cytogenetic response

Chemotherapy

  • Imatinib (Gleevec) any "standard dose" PO once per day as follows:
    • Weeks 1 to 4: 1 week on, 1 week off
    • Weeks 5 to 12: 2 weeks on, 2 weeks off
    • Week 13 onwards: 1 month on, 1 month off

Treatment continues indefinitely or until loss of complete cytogenetic response is observed. Patients who lost major molecular response could go back to once per day therapy after the first year.

References

  1. Russo D, Martinelli G, Malagola M, Skert C, Soverini S, Iacobucci I, De Vivo A, Testoni N, Castagnetti F, Gugliotta G, Turri D, Bergamaschi M, Pregno P, Pungolino E, Stagno F, Breccia M, Martino B, Intermesoli T, Fava C, Abruzzese E, Tiribelli M, Bigazzi C, Cesana BM, Rosti G, Baccarani M. Effects and outcome of a policy of intermittent imatinib treatment in elderly patients with chronic myeloid leukemia. Blood. 2013 Jun 27;121(26):5138-44. Epub 2013 May 15. link to original article contains verified protocol PubMed

Imatinib monotherapy, planned discontinuation

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Variant #1, ; Mahon et al. 2013 (STIM2)

Study Evidence
Mahon et al. 2010 (STIM1) Phase II
Mahon et al. 2013 (STIM2) Phase II

Chemotherapy

Treatment is discontinued if "sustained DMR defined as remission lasting more than 2 consecutive years and confirmed on five datapoints of BCR–ABL analyses by quantitative RT-PCR during these 2 years" occurs.

Variant #2

Study Evidence
Ross et al. 2013 (TWISTER) Phase II

Chemotherapy

Treatment is discontinued after a minimum of 3 years of imatinib and 2 years of sustained undetectable minimal residual disease by conventional PCR.

References

  1. Mahon FX, Réa D, Guilhot J, Guilhot F, Huguet F, Nicolini F, Legros L, Charbonnier A, Guerci A, Varet B, Etienne G, Reiffers J, Rousselot P; Intergroupe Français des Leucémies Myéloïdes Chroniques. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010 Nov;11(11):1029-35. Epub 2010 Oct 19. link to original article PubMed
    1. Update: Etienne G, Guilhot J, Rea D, Rigal-Huguet F, Nicolini F, Charbonnier A, Guerci-Bresler A, Legros L, Varet B, Gardembas M, Dubruille V, Tulliez M, Noel MP, Ianotto JC, Villemagne B, Carré M, Guilhot F, Rousselot P, Mahon FX. Long-Term Follow-Up of the French Stop Imatinib (STIM1) Study in Patients With Chronic Myeloid Leukemia. J Clin Oncol. 2017 Jan 20;35(3):298-305. link to original article PubMed
  2. Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT, Dang P, Goyne JM, Slader C, Filshie RJ, Mills AK, Melo JV, White DL, Grigg AP, Hughes TP. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013 Jul 25;122(4):515-22. Epub 2013 May 23. link to original article PubMed
  3. Abstract: Francois-Xavier Mahon, MD, PhD, Franck E. Nicolini, Marie-Pierre Noël, Martine Escoffre, Aude Charbonnier, Delphine Rea, Viviane Dubruille, Bruno R. Varet, Laurence Legros, Agnès Guerci, Gabriel Etienne, Francois Guilhot, Stéphanie Dulucq, Philippe Rousselot, Joelle Guilhot. Preliminary Report Of The STIM2 Study: A Multicenter Stop Imatinib Trial For Chronic Phase Chronic Myeloid Leukemia De Novo Patients On Imatinib. Blood Nov 2013,122(21)654 link to original abstract

Imatinib & LoDAC

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Imatinib & LoDAC: Imatinib & Low Dose Ara-C

Regimen

Study Evidence Comparator Efficacy
Preudhomme et al. 2010 (SPIRIT) Phase III (E) 1. Imatinib 400 mg daily Not reported
2. Imatinib 600 mg daily Not reported
3. Imatinib & Interferon alfa Not reported

Chemotherapy

28-day cycles for at least 12 months or until progression

References

  1. SPIRIT: Preudhomme C, Guilhot J, Nicolini FE, Guerci-Bresler A, Rigal-Huguet F, Maloisel F, Coiteux V, Gardembas M, Berthou C, Vekhoff A, Rea D, Jourdan E, Allard C, Delmer A, Rousselot P, Legros L, Berger M, Corm S, Etienne G, Roche-Lestienne C, Eclache V, Mahon FX, Guilhot F; SPIRIT Investigators; France Intergroupe des Leucémies Myéloïdes Chroniques (Fi-LMC). Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med. 2010 Dec 23;363(26):2511-21. link to original article contains partial verified protocol PubMed

Imatinib & Interferon alfa-2a

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Variant #1, peginterferon

Study Evidence Comparator Efficacy
Preudhomme et al. 2010 (SPIRIT) Phase III (E) 1. Imatinib 400 mg daily Superior MMR rate at 12 months
2. Imatinib 600 mg daily Not reported
3. Imatinib & LoDAC Not reported

Preudhomme et al. amended their protocol to reduce the dose of peginterferon; Johnson-Ansah et al. demonstrated (post-hoc) that the reduced dose was still efficacious.

Chemoimmunotherapy

Continued indefinitely

Variant #2

Study Evidence Comparator Efficacy
Hehlmann et al. 2011 (CML-Study IV) Phase III (E) 1. Imatinib Not reported
2. Imatinib, high dose Inferior MMR rate at 12 months

Chemoimmunotherapy

Continued indefinitely

References

  1. SPIRIT: Preudhomme C, Guilhot J, Nicolini FE, Guerci-Bresler A, Rigal-Huguet F, Maloisel F, Coiteux V, Gardembas M, Berthou C, Vekhoff A, Rea D, Jourdan E, Allard C, Delmer A, Rousselot P, Legros L, Berger M, Corm S, Etienne G, Roche-Lestienne C, Eclache V, Mahon FX, Guilhot F; SPIRIT Investigators; France Intergroupe des Leucémies Myéloïdes Chroniques (Fi-LMC). Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med. 2010 Dec 23;363(26):2511-21. link to original article contains verified protocol PubMed
    1. Post-hoc analysis: Johnson-Ansah H, Guilhot J, Rousselot P, Rea D, Legros L, Rigal-Huguet F, Nicolini FE, Mahon FX, Preudhomme C, Guilhot F. Tolerability and efficacy of pegylated interferon-a-2a in combination with imatinib for patients with chronic-phase chronic myeloid leukemia. Cancer. 2013 Dec 15;119(24):4284-9. Epub 2013 Sep 16. link to original article PubMed
  2. CML-Study IV: Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Müller MC, Pletsch N, Proetel U, Haferlach C, Schlegelberger B, Balleisen L, Hänel M, Pfirrmann M, Krause SW, Nerl C, Pralle H, Gratwohl A, Hossfeld DK, Hasford J, Hochhaus A, Saussele S. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-a in newly diagnosed chronic myeloid leukemia. J Clin Oncol. 2011 Apr 20;29(12):1634-42. Epub 2011 Mar 21. link to original article contains verified protocol PubMed
    1. Update: Hehlmann R, Müller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A, Proetel U, Pletsch N, Pfirrmann M, Haferlach C, Schnittger S, Einsele H, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Ehninger G, Heim D, Heimpel H, Nerl C, Krause SW, Hossfeld DK, Kolb HJ, Hasford J, Saußele S, Hochhaus A. Deep Molecular Response Is Reached by the Majority of Patients Treated With Imatinib, Predicts Survival, and Is Achieved More Quickly by Optimized High-Dose Imatinib: Results From the Randomized CML-Study IV. J Clin Oncol. 2014 Feb 10;32(5):415-23. Epub 2013 Dec 2. link to original article contains verified protocol PubMed
    2. Update: Kalmanti L, Saussele S, Lauseker M, Müller MC, Dietz CT, Heinrich L, Hanfstein B, Proetel U, Fabarius A, Krause SW, Rinaldetti S, Dengler J, Falge C, Oppliger-Leibundgut E, Burchert A, Neubauer A, Kanz L, Stegelmann F, Pfreundschuh M, Spiekermann K, Scheid C, Pfirrmann M, Hochhaus A, Hasford J, Hehlmann R. Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV. Leukemia. 2015 May;29(5):1123-32. Epub 2015 Feb 13. link to original article PubMed
    3. Update: Hehlmann R, Lauseker M, Saußele S, Pfirrmann M, Krause S, Kolb HJ, Neubauer A, Hossfeld DK, Nerl C, Gratwohl A, Baerlocher GM, Heim D, Brümmendorf TH, Fabarius A, Haferlach C, Schlegelberger B, Müller MC, Jeromin S, Proetel U, Kohlbrenner K, Voskanyan A, Rinaldetti S, Seifarth W, Spieß B, Balleisen L, Goebeler MC, Hänel M, Ho A, Dengler J, Falge C, Kanz L, Kremers S, Burchert A, Kneba M, Stegelmann F, Köhne CA, Lindemann HW, Waller CF, Pfreundschuh M, Spiekermann K, Berdel WE, Müller L, Edinger M, Mayer J, Beelen DW, Bentz M, Link H, Hertenstein B, Fuchs R, Wernli M, Schlegel F, Schlag R, de Wit M, Trümper L, Hebart H, Hahn M, Thomalla J, Scheid C, Schafhausen P, Verbeek W, Eckart MJ, Gassmann W, Pezzutto A, Schenk M, Brossart P, Geer T, Bildat S, Schäfer E, Hochhaus A, Hasford J. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017 Nov;31(11):2398-2406. Epub 2017 Aug 14. link to original article PubMed

Interferon alfa monotherapy

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Regimen

Study Evidence Comparator Efficacy
Talpaz et al. 1986 Non-randomized
Tura et al. 1994 Phase III (E) 1. Busulfan
2. Hydroxyurea
Superior OS
Allan et al. 1995 Phase III (E) 1. Busulfan
2. Hydroxyurea
Superior OS
Guilhot et al. 1997 Phase III (C) LoDAC & Interferon alfa Seems to have inferior OS

Of historical interest; many of the older trials do not specify the exact type of interferon alfa.

Immunotherapy

Continued indefinitely

References

  1. Talpaz M, Kantarjian HM, McCredie K, Trujillo JM, Keating MJ, Gutterman JU. Hematologic remission and cytogenetic improvement induced by recombinant human interferon alpha A in chronic myelogenous leukemia. N Engl J Med. 1986 Apr 24;314(17):1065-9. link to original article PubMed
  2. Tura S, Baccarani M, Zuffa E, Russo D, Fanin R, Zaccaria A, Fiacchini M; Italian Cooperative Study Group on Chronic Myeloid Leukemia. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med. 1994 Mar 24;330(12):820-5. link to original article PubMed
  3. Allan NC, Richards SM, Shepherd PC; The UK Medical Research Council's Working Parties for Therapeutic Trials in Adult Leukaemia. UK Medical Research Council randomised, multicentre trial of interferon-alpha n1 for chronic myeloid leukaemia: improved survival irrespective of cytogenetic response. Lancet. 1995 Jun 3;345(8962):1392-7. link to original article PubMed
  4. Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau JL, Maloisel F, Bouabdallah R, Guyotat D, Cheron N, Nicolini F, Abgrall JF, Tanzer J, Navarro M, Bordessoule D, Morice P, Ifrah N, Rochant H, Vilque JP, Delain M, Bauters F, Guilhot J; French Chronic Myeloid Leukemia Study Group. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med. 1997 Jul 24;337(4):223-9. link to original article contains verified protocol PubMed

Nilotinib monotherapy

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Variant #1, 300 mg BID

FDA-recommended dose
Study Evidence Comparator Efficacy
Saglio et al. 2010 (ENESTnd) Phase III (E) 1. Imatinib Seems to have superior TTP
2. Nilotinib 400 mg BID Not reported
Wang et al. 2015 (ENESTchina) Phase III (E) Imatinib Superior MMR rate at 12 months

The ENESTnd study was not powered to detect differences between the two doses of nilotinib.

Chemotherapy

Continued indefinitely

Variant #2, 400 mg BID

Study Evidence Comparator Efficacy
Rosti et al. 2009 Phase II
Saglio et al. 2010 (ENESTnd) Phase III (E) 1. Imatinib Superior TTP
2. Nilotinib 300 mg BID Not reported

The ENESTnd study was not powered to detect differences between the two doses of nilotinib.

Chemotherapy

Continued indefinitely

References

  1. Rosti G, Palandri F, Castagnetti F, Breccia M, Levato L, Gugliotta G, Capucci A, Cedrone M, Fava C, Intermesoli T, Cambrin GR, Stagno F, Tiribelli M, Amabile M, Luatti S, Poerio A, Soverini S, Testoni N, Martinelli G, Alimena G, Pane F, Saglio G, Baccarani M; GIMEMA CML Working Party. Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Blood. 2009 Dec 3;114(24):4933-8. Epub 2009 Oct 12. link to original article contains verified protocol PubMed
    1. Update: Gugliotta G, Castagnetti F, Breccia M, Levato L, D'Adda M, Stagno F, Tiribelli M, Salvucci M, Fava C, Martino B, Cedrone M, Bocchia M, Trabacchi E, Cavazzini F, Usala E, Rossi AR, Bochicchio MT, Soverini S, Alimena G, Cavo M, Pane F, Martinelli G, Saglio G, Baccarani M, Rosti G; GIMEMA CML Working Party. Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia. Haematologica. 2015 Sep;100(9):1146-50. Epub 2015 Jun 25. link to original article link to PMC article PubMed
  2. ENESTnd: Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM; ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2251-9. Epub 2010 Jun 5. link to original article contains protocol PubMed
    1. Update: Kantarjian HM, Hochhaus A, Saglio G, De Souza C, Flinn IW, Stenke L, Goh YT, Rosti G, Nakamae H, Gallagher NJ, Hoenekopp A, Blakesley RE, Larson RA, Hughes TP. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011 Sep;12(9):841-51. Epub 2011 Aug 17. Erratum in: Lancet Oncol. 2011 Oct;12(11):989. link to original article contains verified protocol PubMed
    2. Update: Larson RA, Hochhaus A, Hughes TP, Clark RE, Etienne G, Kim DW, Flinn IW, Kurokawa M, Moiraghi B, Yu R, Blakesley RE, Gallagher NJ, Saglio G, Kantarjian HM. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012 Oct;26(10):2197-203. Epub 2012 May 18. link to original article PubMed
    3. Update: Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, le Coutre PD, Etienne G, Dorlhiac-Llacer PE, Clark RE, Flinn IW, Nakamae H, Donohue B, Deng W, Dalal D, Menssen HD, Kantarjian HM. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016 May;30(5):1044-54. Epub 2016 Feb 3. link to original article link to PMC article PubMed
  3. ENESTchina: Wang J, Shen ZX, Saglio G, Jin J, Huang H, Hu Y, Du X, Li J, Meng F, Zhu H, Hu J, Wang J, Hou M, Hertle S, Menssen HD, Ortmann CE, Tribouley C, Yuan Y, Baccarani M, Huang X. Phase 3 study of nilotinib vs imatinib in Chinese patients with newly diagnosed chronic myeloid leukemia in chronic phase: ENESTchina. Blood. 2015 Apr 30;125(18):2771-8. Epub 2015 Mar 12. link to original article contains verified protocol link to PMC article PubMed

Radotinib monotherapy

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Variant #1, 300 mg BID

Study Evidence Comparator Efficacy
Kwak et al. 2017 (RERISE) Phase III (E) 1. Imatinib Superior MMR rate at 12 months
2. Radotinib 400 mg BID Not reported

Chemotherapy

Continued indefinitely

Variant #2, 400 mg BID

Study Evidence Comparator Efficacy
Kim et al. 2014 Phase II
Kwak et al. 2017 (RERISE) Phase III (E) 1. Imatinib Seems to have superior MMR rate at 12 months
2. Radotinib 300 mg BID Not reported

Chemotherapy

Continued indefinitely

References

  1. Kim SH, Menon H, Jootar S, Saikia T, Kwak JY, Sohn SK, Park JS, Jeong SH, Kim HJ, Kim YK, Oh SJ, Kim H, Zang DY, Chung JS, Shin HJ, Do YR, Kim JA, Kim DY, Choi CW, Park S, Park HL, Lee GY, Cho DJ, Shin JS, Kim DW. Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Haematologica. 2014 Jul;99(7):1191-6. Epub 2014 Apr 4. link to original article link to PMC article contains verified protocol PubMed
  2. Kwak JY, Kim SH, Oh SJ, Zang DY, Kim H, Kim JA, Do YR, Kim HJ, Park JS, Choi CW, Lee WS, Mun YC, Kong JH, Chung JS, Shin HJ, Kim DY, Park J, Jung CW, Bunworasate U, Comia NS, Jootar S, Reksodiputro AH, Caguioa PB, Lee SE, Kim DW. Phase III clinical trial (RERISE study) results of efficacy and safety of radotinib compared with imatinib in newly diagnosed chronic phase chronic myeloid leukemia. Clin Cancer Res. 2017 Dec 1;23(23):7180-7188. Epub 2017 Sep 22. link to original article contains protocol PubMed

Chronic phase, relapsed or refractory

Bosutinib monotherapy

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Regimen

FDA-recommended dose
Study Evidence
Cortes et al. 2011 (B1871006) Phase I/II

Note: the dosing described is that reported for the phase 2 portion of the phase 1/2 study. Suboptimal response defined as no complete hematologic response (CHR) by week 8 or complete cytogenetic response (CCyR) by week 12.

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

Continued indefinitely

References

  1. B1871006: 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

BuCyTBI, then allo HSCT

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BuCyTBI: Busulfan, Cyclophosphamide, Total Body Irradiation

Regimen

Study Evidence
Fefer et al. 1979 Pilot, <20 pts

Chemoradiotherapy

References

  1. Fefer A, Cheever MA, Thomas ED, Boyd C, Ramberg R, Glucksberg H, Buckner CD, Storb R. Disappearance of Ph1-positive cells in four patients with chronic granulocytic leukemia after chemotherapy, irradiation and marrow transplantation from an identical twin. N Engl J Med. 1979 Feb 15;300(7):333-7. link to original article PubMed

Busulfan monotherapy

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Regimen

Study Evidence
Schilling & Meyer 1956 Non-randomized, <20 pts
Unugur et al. 1957 Non-randomized

Of historic interest.

Chemotherapy

References

  1. Schilling RF, Meyer OO. Treatment of chronic granulocytic leukemia with 1, 4-dimethanesulfonyloxybutane (Myleran). N Engl J Med. 1956 May 24;254(21):986-9. link to original article PubMed
  2. Unugur A, Schulman E, Dameshek W. Treatment of chronic granulocytic leukemia with Myleran. N Engl J Med. 1957 Apr 18;256(16):727-34. link to original article PubMed

Cyclophosphamide & TBI, then allo HSCT

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Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study Evidence
Fefer et al. 1982 Non-randomized, <20 pts
Goldman et al. 1986 Non-randomized
Hansen et al. 1998 Non-randomized

Details in the manuscripts are limited.

Chemoradiotherapy

Stem cells transfused on day 0

References

  1. Fefer A, Cheever MA, Greenberg PD, Appelbaum FR, Boyd CN, Buckner CD, Kaplan HG, Ramberg R, Sanders JE, Storb R, Thomas ED. Treatment of chronic granulocytic leukemia with chemoradiotherapy and transplantation of marrow from identical twins. N Engl J Med. 1982 Jan 14;306(2):63-8. link to original article PubMed
  2. Goldman JM, Apperley JF, Jones L, Marcus R, Goolden AW, Batchelor R, Hale G, Waldmann H, Reid CD, Hows J, Gordon-Smith E, Catovsky D, Galton DAG. Bone marrow transplantation for patients with chronic myeloid leukemia. N Engl J Med. 1986 Jan 23;314(4):202-7. PubMed
  3. Hansen JA, Gooley TA, Martin PJ, Appelbaum F, Chauncey TR, Clift RA, Petersdorf EW, Radich J, Sanders JE, Storb RF, Sullivan KM, Anasetti C. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med. 1998 Apr 2;338(14):962-8. link to original article PubMed

Dasatinib monotherapy

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Variant #1, 70 mg BID

Study Evidence Comparator Efficacy
Talpaz et al. 2006 (BMS-CA180002) Phase 1, >20 pts in this dosing cohort
Hochhaus et al. 2006 Phase II
Kantarjian et al. 2007 Randomized Phase II (E) High-dose imatinib Superior PFS
Shah et al. 2008 (CA180-034) Phase III (C) 1. Dasatinib 100 mg daily Seems not superior
2. Dasatinib 140 mg daily Seems not superior
3. Dasatinib 50 mg BID Seems not superior

Note: this is the most common dosing used in BMS-CA180002, but was not specifically recommended as the dose for subsequent trials.

Chemotherapy

  • Dasatinib (Sprycel) 70 mg PO BID
    • Reduction to 40 mg PO BID or escalation to 90 mg PO BID allowed under certain circumstances; see original papers for details.

Variant #2, 100 mg/d

FDA-recommended dose
Study Evidence Comparator Efficacy
Shah et al. 2008 (CA180-034) Phase III (E) 1. Dasatinib 140 mg daily Seems not superior
2. Dasatinib 50 mg BID Seems not superior
3. Dasatinib 70 mg BID Seems not superior

Note: dose escalation is not described in the FDA-recommended dosing.

Chemotherapy

  • Dasatinib (Sprycel) 100 mg PO once per day
    • Dose may be escalated to 140 mg PO once per day or 70 mg PO BID depending on response, see paper.

References

  1. Phase 1: Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O'Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006 Jun 15;354(24):2531-41. link to original article PubMed
  2. Post-hoc analysis: Quintas-Cardama A, Kantarjian H, Jones D, Nicaise C, O'Brien S, Giles F, Talpaz M, Cortes J. Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure. Blood. 2007 Jan 15;109(2):497-9. Epub 2006 Sep 21. link to original article PubMed
  3. Hochhaus A, Kantarjian HM, Baccarani M, Lipton JH, Apperley JF, Druker BJ, Facon T, Goldberg SL, Cervantes F, Niederwieser D, Silver RT, Stone RM, Hughes TP, Muller MC, Ezzeddine R, Countouriotis AM, Shah NP. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007 Mar 15;109(6):2303-9. Epub 2006 Nov 30. Erratum in: Blood. 2007 Sep 1;110(5):1438. link to original article contains verified protocol PubMed
    1. Update: Hochhaus A, Baccarani M, Deininger M, Apperley JF, Lipton JH, Goldberg SL, Corm S, Shah NP, Cervantes F, Silver RT, Niederwieser D, Stone RM, Dombret H, Larson RA, Roy L, Hughes T, Müller MC, Ezzeddine R, Countouriotis AM, Kantarjian HM. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008 Jun;22(6):1200-6. Epub 2008 Apr 10. link to original article contains verified protocol PubMed
  4. Kantarjian H, Pasquini R, Hamerschlak N, Rousselot P, Holowiecki J, Jootar S, Robak T, Khoroshko N, Masszi T, Skotnicki A, Hellmann A, Zaritsky A, Golenkov A, Radich J, Hughes T, Countouriotis A, Shah N. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007 Jun 15;109(12):5143-50. Epub 2007 Feb 22. link to original article contains verified protocol PubMed
  5. CA180-034: Shah NP, Kantarjian HM, Kim DW, Réa D, Dorlhiac-Llacer PE, Milone JH, Vela-Ojeda J, Silver RT, Khoury HJ, Charbonnier A, Khoroshko N, Paquette RL, Deininger M, Collins RH, Otero I, Hughes T, Bleickardt E, Strauss L, Francis S, Hochhaus A. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol. 2008 Jul 1;26(19):3204-12. Epub 2008 Jun 9. link to original article contains verified protocol PubMed
    1. Update: Shah NP, Kim DW, Kantarjian H, Rousselot P, Llacer PE, Enrico A, Vela-Ojeda J, Silver RT, Khoury HJ, Müller MC, Lambert A, Matloub Y, Hochhaus A. Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica. 2010 Feb;95(2):232-40. link to original article link to PMC article PubMed
    2. Update: Shah NP, Guilhot F, Cortes JE, Schiffer CA, le Coutre P, Brümmendorf TH, Kantarjian HM, Hochhaus A, Rousselot P, Mohamed H, Healey D, Cunningham M, Saglio G. Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood. 2014 Apr 10;123(15):2317-24. Epub 2014 Feb 25. link to original article link to PMC article PubMed
    3. Update: Shah NP, Rousselot P, Schiffer C, Rea D, Cortes JE, Milone J, Mohamed H, Healey D, Kantarjian H, Hochhaus A, Saglio G. Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA180-034. Am J Hematol. 2016 Sep;91(9):869-74. Epub 2016 Jun 20. link to PMC article PubMed

Imatinib monotherapy

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Variant #1, 400 mg/d

Study Evidence Comparator Efficacy
Druker et al. 2001 Phase 1
Kantarjian et al. 2002 (International STI571 CML Study Group) Phase II
Petzer et al. 2010 (ISTAHIT) Phase III (C) High-dose, then standard-dose imatinib Inferior MMR rate at 6 months
Hughes et al. 2014 (ENESTcmr) Phase III (C) Nilotinib Inferior MMR rate at 24 months

Note: patients in ENESTcmr in this arm were already taking this dose of imatinib prior to randomization.

Preceding treatment

  • ENESTcmr: Imatinib for at least 2 years, with detectable BCR-ABL1

Chemotherapy

Continued indefinitely

Variant #2, 600 mg/d

Study Evidence Comparator Efficacy
Hughes et al. 2014 (ENESTcmr) Phase III (C) Nilotinib Inferior MMR rate at 24 months
Cortes et al. 2016 (LASOR) Phase III (E) Nilotinib Seems not superior

Note: patients in ENESTcmr in this arm were already taking this dose of imatinib prior to randomization.

Preceding treatment

Chemotherapy

Continued indefinitely

Variant #3, 800 mg/d

Study Evidence Comparator Efficacy
Kantarjian et al. 2007 Randomized Phase II (E) Dasatinib Inferior PFS
Yeung et al. 2014 (TIDEL-II) Non-randomized

Preceding treatment

Chemotherapy

Continued indefinitely

Subsequent treatment

  • TIDEL-II: Patients were switched to nilotinib 3 months later if they were still failing to meet targets (see paper for details)

Variant #4, high-dose, then standard-dose

Study Evidence Comparator Efficacy
Petzer et al. 2010 (ISTAHIT) Phase III (E) Standard-dose imatinib Superior MMR rate at 6 months

Chemotherapy

Continued indefinitely

References

  1. Phase I: Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001 Apr 5;344(14):1031-7. link to original article PubMed
  2. International STI571 CML Study Group: Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta D, Capdeville R, Zoellner U, Talpaz M, Druker B, Goldman J, O'Brien SG, Russell N, Fischer T, Ottmann O, Cony-Makhoul P, Facon T, Stone R, Miller C, Tallman M, Brown R, Schuster M, Loughran T, Gratwohl A, Mandelli F, Saglio G, Lazzarino M, Russo D, Baccarani M, Morra E; International STI571 CML Study Group. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002 Feb 28;346(9):645-52. link to original article PubMed
    1. Update: Hochhaus A, Druker B, Sawyers C, Guilhot F, Schiffer CA, Cortes J, Niederwieser DW, Gambacorti-Passerini C, Stone RM, Goldman J, Fischer T, O'Brien SG, Reiffers JJ, Mone M, Krahnke T, Talpaz M, Kantarjian HM. Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment. Blood. 2008 Feb 1;111(3):1039-43. Epub 2007 Oct 11. link to original article contains protocol PubMed
  3. Kantarjian H, Pasquini R, Hamerschlak N, Rousselot P, Holowiecki J, Jootar S, Robak T, Khoroshko N, Masszi T, Skotnicki A, Hellmann A, Zaritsky A, Golenkov A, Radich J, Hughes T, Countouriotis A, Shah N. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007 Jun 15;109(12):5143-50. Epub 2007 Feb 22. link to original article contains verified protocol PubMed
  4. Case series: Palandri F, Iacobucci I, Martinelli G, Amabile M, Poerio A, Testoni N, Soverini S, Castagnetti F, De Vivo A, Breccia M, Specchia G, Abruzzese E, Martino B, Cilloni D, Saglio G, Pane F, Liberati AM, Rosti G, Baccarani M; GIMEMA Working Party on CML. Long-term outcome of complete cytogenetic responders after imatinib 400 mg in late chronic phase, philadelphia-positive chronic myeloid leukemia: the GIMEMA Working Party on CML. J Clin Oncol. 2008 Jan 1;26(1):106-11. link to original article PubMed
  5. ISTAHIT: Petzer AL, Wolf D, Fong D, Lion T, Dyagil I, Masliak Z, Bogdanovic A, Griskevicius L, Lejniece S, Goranov S, Gercheva L, Stojanovic A, Peytchev D, Tzvetkov N, Griniute R, Oucheva R, Ulmer H, Kwakkelstein M, Rancati F, Gastl G. High-dose imatinib improves cytogenetic and molecular remissions in patients with pretreated Philadelphia-positive, BCR-ABL-positive chronic phase chronic myeloid leukemia: first results from the randomized CELSG phase III CML 11 "ISTAHIT" study. Haematologica. 2010 Jun;95(6):908-13. Epub 2010 Feb 9. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Petzer AL, Fong D, Lion T, Dyagil I, Masliak Z, Bogdanovic A, Griskevicius L, Lejniece S, Goranov S, Gercheva L, Stojanovic A, Peytchev D, Tzvetkov N, Griniute R, Stanchev A, Grubinger T, Kwakkelstein M, Schuld P, Gastl G, Wolf D. High-dose imatinib induction followed by standard-dose maintenance in pre-treated chronic phase chronic myeloid leukemia patients--final analysis of a randomized, multicenter, phase III trial. Haematologica. 2012 Oct;97(10):1562-9. Epub 2012 Apr 17. link to original article contains verified protocol link to PMC article PubMed
  6. ENESTcmr: Hughes TP, Lipton JH, Spector N, Cervantes F, Pasquini R, Clementino NC, Dorlhiac Llacer PE, Schwarer AP, Mahon FX, Rea D, Branford S, Purkayastha D, Collins L, Szczudlo T, Leber B. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood. 2014 Jul 31;124(5):729-36. Epub 2014 Jun 19. link to original article contains verified protocol PubMed
    1. Update: Hughes TP, Leber B, Cervantes F, Spector N, Pasquini R, Clementino NCD, Schwarer AP, Dorlhiac-Llacer PE, Mahon FX, Rea D, Guerci-Bresler A, Kamel-Reid S, Bendit I, Acharya S, Glynos T, Dalal D, Branford S, Lipton JH. Sustained deep molecular responses in patients switched to nilotinib due to persistent BCR-ABL1 on imatinib: final ENESTcmr randomized trial results. Leukemia. 2017 Nov;31(11):2529-2531. Epub 2017 Aug 3. link to original article link to PMC article PubMed
  7. TIDEL-II: Yeung DT, Osborn MP, White DL, Branford S, Braley J, Herschtal A, Kornhauser M, Issa S, Hiwase DK, Hertzberg M, Schwarer AP, Filshie R, Arthur CK, Kwan YL, Trotman J, Forsyth CJ, Taper J, Ross DM, Beresford J, Tam C, Mills AK, Grigg AP, Hughes TP; Australasian Leukaemia and Lymphoma Group. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood. 2015 Feb 5;125(6):915-23. Epub 2014 Dec 17. link to original article contains verified protocol link to PMC article PubMed
  8. LASOR: Cortes JE, De Souza CA, Ayala M, Lopez JL, Bullorsky E, Shah S, Huang X, Babu KG, Abdulkadyrov K, de Oliveira JS, Shen ZX, Sacha T, Bendit I, Liang Z, Owugah T, Szczudlo T, Khanna S, Fellague-Chebra R, le Coutre PD. Switching to nilotinib versus imatinib dose escalation in patients with chronic myeloid leukaemia in chronic phase with suboptimal response to imatinib (LASOR): a randomised, open-label trial. Lancet Haematol. 2016 Dec;3(12):e581-e591. link to original article contains protocol PubMed

Interferon alfa-2b & DLI

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DLI: Donor Lymphocyte Infusion

Regimen

Study Evidence
Porter et al. 1994 Non-randomized, <20 pts

Of historic interest; patients had relapsed after allogeneic HSCT

Immunotherapy

References

  1. Porter DL, Roth MS, McGarigle C, Ferrara JL, Antin JH. Induction of graft-versus-host disease as immunotherapy for relapsed chronic myeloid leukemia. N Engl J Med. 1994 Jan 13;330(2):100-6. link to original article PubMed

Nilotinib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Kantarjian et al. 2006 (A2101) Phase I/II
Hughes et al. 2014a (ENESTnd extension) Non-randomized portion of RCT
Hughes et al. 2014b (ENESTcmr) Phase III (E) Imatinib Superior MMR rate at 24 months
Yeung et al. 2014 (TIDEL-II) Non-randomized
Cortes et al. 2016 (LASOR) Phase III (E) Imatinib 600 mg daily Seems not superior

Preceding treatment

Chemotherapy

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
    1. Update: Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, Ossenkoppele GJ, Nicolini FE, O'Brien SG, Litzow M, Bhatia R, Cervantes F, Haque A, Shou Y, Resta DJ, Weitzman A, Hochhaus A, le Coutre P. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007 Nov 15;110(10):3540-6. Epub 2007 Aug 22. link to original article contains verified protocol PubMed
    2. Update: Kantarjian HM, Giles FJ, Bhalla KN, Pinilla-Ibarz J, Larson RA, Gattermann N, Ottmann OG, Hochhaus A, Radich JP, Saglio G, Hughes TP, Martinelli G, Kim DW, Shou Y, Gallagher NJ, Blakesley R, Baccarani M, Cortes J, le Coutre PD. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011 Jan 27;117(4):1141-5. Epub 2010 Nov 22. link to original article link to PMC article PubMed
    3. Update: Giles FJ, le Coutre PD, Pinilla-Ibarz J, Larson RA, Gattermann N, Ottmann OG, Hochhaus A, Radich JP, Saglio G, Hughes TP, Martinelli G, Kim DW, Novick S, Gillis K, Fan X, Cortes J, Baccarani M, Kantarjian HM. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia. 2013 Jan;27(1):107-12. Epub 2012 Jul 5. link to original article PubMed
  2. ENESTnd extension: Hughes TP, Hochhaus A, Kantarjian HM, Cervantes F, Guilhot F, Niederwieser D, le Coutre PD, Rosti G, Ossenkoppele G, Lobo C, Shibayama H, Fan X, Menssen HD, Kemp C, Larson RA, Saglio G. Safety and efficacy of switching to nilotinib 400 mg twice daily for patients with chronic myeloid leukemia in chronic phase with suboptimal response or failure on front-line imatinib or nilotinib 300 mg twice daily. Haematologica. 2014 Jul;99(7):1204-11. Epub 2014 Feb 14. link to original article link to PMC article PubMed
  3. ENESTcmr: Hughes TP, Lipton JH, Spector N, Cervantes F, Pasquini R, Clementino NC, Dorlhiac Llacer PE, Schwarer AP, Mahon FX, Rea D, Branford S, Purkayastha D, Collins L, Szczudlo T, Leber B. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood. 2014 Jul 31;124(5):729-36. Epub 2014 Jun 19. link to original article contains verified protocol PubMed
    1. Update: Hughes TP, Leber B, Cervantes F, Spector N, Pasquini R, Clementino NCD, Schwarer AP, Dorlhiac-Llacer PE, Mahon FX, Rea D, Guerci-Bresler A, Kamel-Reid S, Bendit I, Acharya S, Glynos T, Dalal D, Branford S, Lipton JH. Sustained deep molecular responses in patients switched to nilotinib due to persistent BCR-ABL1 on imatinib: final ENESTcmr randomized trial results. Leukemia. 2017 Nov;31(11):2529-2531. Epub 2017 Aug 3. link to original article link to PMC article PubMed
  4. TIDEL-II: Yeung DT, Osborn MP, White DL, Branford S, Braley J, Herschtal A, Kornhauser M, Issa S, Hiwase DK, Hertzberg M, Schwarer AP, Filshie R, Arthur CK, Kwan YL, Trotman J, Forsyth CJ, Taper J, Ross DM, Beresford J, Tam C, Mills AK, Grigg AP, Hughes TP; Australasian Leukaemia and Lymphoma Group. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood. 2015 Feb 5;125(6):915-23. Epub 2014 Dec 17. link to original article contains verified protocol link to PMC article PubMed
  5. LASOR: Cortes JE, De Souza CA, Ayala M, Lopez JL, Bullorsky E, Shah S, Huang X, Babu KG, Abdulkadyrov K, de Oliveira JS, Shen ZX, Sacha T, Bendit I, Liang Z, Owugah T, Szczudlo T, Khanna S, Fellague-Chebra R, le Coutre PD. Switching to nilotinib versus imatinib dose escalation in patients with chronic myeloid leukaemia in chronic phase with suboptimal response to imatinib (LASOR): a randomised, open-label trial. Lancet Haematol. 2016 Dec;3(12):e581-e591. link to original article contains protocol PubMed

Omacetaxine monotherapy

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Regimen

Study Evidence
Cortes et al. 2012 (Omacetaxine 202 Study Group) Phase II
Cortes et al. 2013 (Omacetaxine 203 Study Group) Phase II

Chemotherapy, induction phase

28-day cycles, given until hematologic response is achieved, followed by:

Chemotherapy, maintenance phase

Supportive medications

  • Granulocyte colony stimulating factor (G-CSF) only allowed if febrile neutropenia occurred.
  • Erythropoietin/Epoetin alfa (Procrit), Darbepoetin alfa (Aranesp), or blood transfusions were allowed at any time for management of any grade of anemia.

28-day cycles

References

  1. Cortes J, Lipton JH, Rea D, Digumarti R, Chuah C, Nanda N, Benichou AC, Craig AR, Michallet M, Nicolini FE, Kantarjian H; on behalf of the Omacetaxine 202 Study Group. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood. 2012 Sep 27;120(13):2573-2580. Epub 2012 Aug 15. link to original article contains verified protocol link to PMC article PubMed
    1. Pooled subgroup analysis: Nicolini FE, Khoury HJ, Akard L, Rea D, Kantarjian H, Baccarani M, Leonoudakis J, Craig A, Benichou AC, Cortes J. Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors. Haematologica. 2013 Jul;98(7):e78-9. Epub 2013 Jun 10. link to original article link to PMC article PubMed
    2. Pooled update: Cortes JE, Kantarjian HM, Rea D, Wetzler M, Lipton JH, Akard L, Khoury HJ, Michallet M, Guerci-Bresler A, Chuah C, Hellmann A, Digumarti R, Parikh PM, Legros L, Warzocha K, Baccarani M, Li E, Munteanu M, Nicolini FE. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic-or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up. Cancer. 2015 May 15;121(10):1637-44. Epub 2015 Jan 13. link to original article PubMed
  2. Cortes J, Digumarti R, Parikh PM, Wetzler M, Lipton JH, Hochhaus A, Craig AR, Benichou AC, Nicolini FE, Kantarjian HM; Omacetaxine 203 Study Group. Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol. 2013 May;88(5):350-4. Epub 2013 Mar 7. link to original article PubMed
    1. Pooled subgroup analysis: Nicolini FE, Khoury HJ, Akard L, Rea D, Kantarjian H, Baccarani M, Leonoudakis J, Craig A, Benichou AC, Cortes J. Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors. Haematologica. 2013 Jul;98(7):e78-9. Epub 2013 Jun 10. link to original article link to PMC article PubMed
    2. Pooled update: Cortes JE, Kantarjian HM, Rea D, Wetzler M, Lipton JH, Akard L, Khoury HJ, Michallet M, Guerci-Bresler A, Chuah C, Hellmann A, Digumarti R, Parikh PM, Legros L, Warzocha K, Baccarani M, Li E, Munteanu M, Nicolini FE. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic-or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up. Cancer. 2015 May 15;121(10):1637-44. Epub 2015 Jan 13. link to original article PubMed

Ponatinib monotherapy

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Regimen

Study Evidence
Cortes et al. 2012 (AP24534-07-101) Phase 1, >20 pts
Cortes et al. 2013 (PACE) Phase II

Chemotherapy

Continued indefinitely

References

  1. Phase 1: Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, O'Hare T, Hu S, Narasimhan NI, Rivera VM, Clackson T, Turner CD, Haluska FG, Druker BJ, Deininger MW, Talpaz M. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012 Nov 29;367(22):2075-88. link to original article contains verified protocol link to PMC article PubMed
  2. 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: Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Lustgarten S, Rivera VM, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes TP, Shah NP, Kantarjian HM. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018 Jul 26;132(4):393-404. Epub 2018 Mar 22. link to original article link to PMC article PubMed

Accelerated phase, first-line therapy

Imatinib monotherapy

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Regimen

FDA-recommended dose
Study Evidence
Rea et al. 2012 Retrospective

Details of the regimen were not discernible from the manuscript. This is the FDA-recommended dose.

Chemotherapy

Continued indefinitely

References

  1. Retrospective: Rea D, Etienne G, Nicolini F, Cony-Makhoul P, Johnson-Ansah H, Legros L, Huguet F, Tulliez M, Gardembas M, Bouabdallah K, Rousselot P, Cayuela JM, Guilhot F, Mahon FX. First-line imatinib mesylate in patients with newly diagnosed accelerated phase-chronic myeloid leukemia. Leukemia. 2012 Oct;26(10):2254-9. Epub 2012 Mar 30. link to original article PubMed

Accelerated phase, previously treated

Dasatinib monotherapy

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Variant #1, 70 mg BID

Study Evidence Comparator Efficacy
Guilhot et al. 2007 Phase II
Kantarjian et al. 2009 (CA180-035) Phase III (C) Dasatinib 140 mg daily Seems not superior

Chemotherapy

Variant #2, 140 mg/d

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

Chemotherapy

References

  1. Guilhot F, Apperley J, Kim DW, Bullorsky EO, Baccarani M, Roboz GJ, Amadori S, de Souza CA, Lipton JH, Hochhaus A, Heim D, Larson RA, Branford S, Muller MC, Agarwal P, Gollerkeri A, Talpaz M. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood. 2007 May 15;109(10):4143-50. Epub 2007 Jan 30. link to original article 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

Nilotinib monotherapy

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Regimen

Study Evidence
Giles et al. 2010 Phase II
Nicolini et al. 2011 (ENACT) Phase IIIb

Chemotherapy

References

  1. Giles FJ, Abruzzese E, Rosti G, Kim DW, Bhatia R, Bosly A, Goldberg S, Kam GL, Jagasia M, Mendrek W, Fischer T, Facon T, Dünzinger U, Marin D, Mueller MC, Shou Y, Gallagher NJ, Larson RA, Mahon FX, Baccarani M, Cortes J, Kantarjian HM. Nilotinib is active in chronic and accelerated phase chronic myeloid leukemia following failure of imatinib and dasatinib therapy. Leukemia. 2010 Jul;24(7):1299-301. Epub 2010 Jun 3. link to PMC article PubMed
    1. Update: le Coutre PD, Giles FJ, Hochhaus A, Apperley JF, Ossenkoppele GJ, Blakesley R, Shou Y, Gallagher NJ, Baccarani M, Cortes J, Kantarjian HM. Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results. Leukemia. 2012 Jun;26(6):1189-94. Epub 2011 Nov 11. link to original article PubMed
  2. Nicolini FE, Masszi T, Shen Z, Gallagher NJ, Jootar S, Powell BL, Dorlhiac-Llacer PE, Zheng M, Szczudlo T, Turkina A. Expanding Nilotinib Access in Clinical Trials (ENACT), an open-label multicenter study of oral nilotinib in adult patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase or blast crisis. Leuk Lymphoma. 2012 May;53(5):907-14. Epub 2011 Dec 5. link to original article PubMed

Omacetaxine monotherapy

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Regimen

Study Evidence
Cortes et al. 2012 (Omacetaxine 202 Study Group) Phase II
Cortes et al. 2013 (Omacetaxine 203 Study Group) Phase II

Chemotherapy, induction phase

28-day cycles, given until hematologic response is achieved, followed by:

Chemotherapy, maintenance phase

Supportive medications

  • Granulocyte colony stimulating factor (G-CSF) only allowed if febrile neutropenia occurred.
  • Erythropoietin/Epoetin alfa (Procrit), Darbepoetin alfa (Aranesp), or blood transfusions were allowed at any time for management of any grade of anemia.

28-day cycles

References

  1. Cortes J, Lipton JH, Rea D, Digumarti R, Chuah C, Nanda N, Benichou AC, Craig AR, Michallet M, Nicolini FE, Kantarjian H; on behalf of the Omacetaxine 202 Study Group. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood. 2012 Sep 27;120(13):2573-2580. Epub 2012 Aug 15. link to original article contains verified protocol link to PMC article PubMed
    1. Pooled subgroup analysis: Nicolini FE, Khoury HJ, Akard L, Rea D, Kantarjian H, Baccarani M, Leonoudakis J, Craig A, Benichou AC, Cortes J. Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors. Haematologica. 2013 Jul;98(7):e78-9. Epub 2013 Jun 10. link to original article link to PMC article PubMed
    2. Pooled update: Cortes JE, Kantarjian HM, Rea D, Wetzler M, Lipton JH, Akard L, Khoury HJ, Michallet M, Guerci-Bresler A, Chuah C, Hellmann A, Digumarti R, Parikh PM, Legros L, Warzocha K, Baccarani M, Li E, Munteanu M, Nicolini FE. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic-or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up. Cancer. 2015 May 15;121(10):1637-44. Epub 2015 Jan 13. link to original article PubMed
  2. Cortes J, Digumarti R, Parikh PM, Wetzler M, Lipton JH, Hochhaus A, Craig AR, Benichou AC, Nicolini FE, Kantarjian HM; Omacetaxine 203 Study Group. Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol. 2013 May;88(5):350-4. Epub 2013 Mar 7. link to original article PubMed
    1. Pooled subgroup analysis: Nicolini FE, Khoury HJ, Akard L, Rea D, Kantarjian H, Baccarani M, Leonoudakis J, Craig A, Benichou AC, Cortes J. Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors. Haematologica. 2013 Jul;98(7):e78-9. Epub 2013 Jun 10. link to original article link to PMC article PubMed
    2. Pooled update: Cortes JE, Kantarjian HM, Rea D, Wetzler M, Lipton JH, Akard L, Khoury HJ, Michallet M, Guerci-Bresler A, Chuah C, Hellmann A, Digumarti R, Parikh PM, Legros L, Warzocha K, Baccarani M, Li E, Munteanu M, Nicolini FE. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic-or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up. Cancer. 2015 May 15;121(10):1637-44. Epub 2015 Jan 13. link to original article PubMed

Ponatinib monotherapy

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Regimen

Study Evidence
Cortes et al. 2012 (AP24534-07-101) Phase 1, >20 pts
Cortes et al. 2013 (PACE) Phase II

Chemotherapy

Continued indefinitely

References

  1. Phase 1: Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, O'Hare T, Hu S, Narasimhan NI, Rivera VM, Clackson T, Turner CD, Haluska FG, Druker BJ, Deininger MW, Talpaz M. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012 Nov 29;367(22):2075-88. link to original article contains verified protocol link to PMC article PubMed
  2. 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: Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Lustgarten S, Rivera VM, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes TP, Shah NP, Kantarjian HM. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018 Jul 26;132(4):393-404. Epub 2018 Mar 22. link to original article link to PMC article PubMed

Blast crisis

Bosutinib monotherapy

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Regimen

FDA-recommended dose
Study Evidence
Cortes et al. 2011 (B1871006) Phase I/II

Note: the dosing described is that reported for the phase 2 portion of the phase 1/2 study. Suboptimal response defined as no complete hematologic response (CHR) by week 8 or complete cytogenetic response (CCyR) by week 12.

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

Continued indefinitely

References

  1. B1871006: 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 BID

Study Evidence Comparator Efficacy
Cortes et al. 2006 (START-B/START-L) Phase II
Saglio et al. 2010 (CA180-035) Phase III (C) Dasatinib 140 mg daily Seems not superior

Chemotherapy

Dasatinib (Sprycel) 70 mg PO BID

Variant #2, 140 mg/d

FDA-recommended dose
Study Evidence Comparator Efficacy
Saglio et al. 2010 (CA180-035) Phase III (E) Dasatinib 70 mg BID Seems not superior

Chemotherapy

Dasatinib (Sprycel) 140 mg PO once per day

References

  1. START-B/START-L: Cortes J, Rousselot P, Kim DW, Ritchie E, Hamerschlak N, Coutre S, Hochhaus A, Guilhot F, Saglio G, Apperley J, Ottmann O, Shah N, Erben P, Branford S, Agarwal P, Gollerkeri A, Baccarani M. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. 2007 Apr 15;109(8):3207-13. Epub 2006 Dec 21. link to original article PubMed
  2. CA180-035: 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
Druker et al. 2001 Phase I
Sawyers et al. 2002 Phase II

Note: these studies used doses ranging from 300 to 1000 mg PO once per day. This is the FDA-recommended dose.

Chemotherapy

Continued indefinitely

References

  1. Phase I: Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001 Apr 5;344(14):1038-42. link to original article PubMed
  2. Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG, Schiffer CA, Talpaz M, Guilhot F, Deininger MW, Fischer T, O'Brien SG, Stone RM, Gambacorti-Passerini CB, Russell NH, Reiffers JJ, Shea TC, Chapuis B, Coutre S, Tura S, Morra E, Larson RA, Saven A, Peschel C, Gratwohl A, Mandelli F, Ben-Am M, Gathmann I, Capdeville R, Paquette RL, Druker BJ. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 2002 May 15;99(10):3530-9. link to original article PubMed

Vincristine & Prednisone

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Regimen

Study Evidence
Marks et al. 1978 Non-randomized

Of historic interest.

Chemotherapy

References

  1. Marks SM, Baltimore D, McCaffrey R. Terminal transferase as a predictor of initial responsiveness to vincristine and prednisone in blastic chronic myelogenous leukemia: a co-operative study. N Engl J Med. 1978 Apr 13;298(15):812-4. link to original article PubMed

Response Criteria

  • Tam CS, Kantarjian H, Garcia-Manero G, Borthakur G, O'Brien S, Ravandi F, Shan J, Cortes J. Failure to achieve a major cytogenetic response by 12 months defines inadequate response in patients receiving nilotinib or dasatinib as second or subsequent line therapy for chronic myeloid leukemia. Blood. 2008 Aug 1;112(3):516-8. Epub 2008 May 20. link to original article link to PMC article PubMed
  • CML response criteria (BloodRef.com) based on 2013 European LeukemiaNet Recommendations for Management of Chronic Myeloid Leukemia

Risk Scores