Chronic myeloid leukemia

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Note: certain regimens have been moved to dedicated pages:
*Pediatric CML
Last updated on 2024-12-02:35 regimens on this page
49 variants on this page
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==BSH==
*2020: Smith et al. A British Society for Haematology Guideline on the diagnosis and management of chronic myeloid leukaemia EuroPMC
==ELN==
*2013: Baccarani et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia link to PMC article EuroPMC
==ESMO==
*2017: Hochhaus et al. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2009: Baccarani & Dreyling. Chronic myelogenous leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2007: Simonsson. Chronic myelogenous leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2005: Simonsson et al. ESMO Minimum Clinical Recommendations for the diagnosis, treatment and follow-up of chronic myelogenous leukemia (CML) EuroPMC
==NCCN==
*NCCN Guidelines - Chronic Myeloid Leukemia
**2024: Shah et al. Chronic Myeloid Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology EuroPMC
**2020: Deininger et al. Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. EuroPMC
**2015: Zelenetz et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2015. link to PMC article EuroPMC
**2014: O'Brien et al. Chronic Myelogenous Leukemia, Version 1.2015 EuroPMC
**2013: O'Brien et al. Chronic Myelogenous Leukemia, Version 1.2014. link to PMC article EuroPMC
**2012: O'Brien et al. Chronic myelogenous leukemia. EuroPMC
**2009: O'Brien et al. NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia. EuroPMC
**2007: O'Brien et al. Chronic myelogenous leukemia. EuroPMC
**2003: O'Brien et al. Chronic myelogenous leukemia clinical practice guidelines in oncology. EuroPMC
=Chronic phase, first-line therapy=
==Asciminib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Hochhaus et al. 2024 (ASC4FIRST)	2021-11-05 to 2022-12-20	Phase 3 (E-RT-switch-ic)	Investigator's choice of:1a. Bosutinib1b. Dasatinib1c. Imatinib1d. Nilotinib	Higher MMR48w (primary endpoint)MMR48w: 67.7% vs 49%
====Targeted therapy====
*Asciminib (Scemblix) 80 mg PO once per day
Continued indefinitely
===References===
#ASC4FIRST: Hochhaus A, Wang J, Kim DW, Kim DDH, Mayer J, Goh YT, le Coutre P, Takahashi N, Kim I, Etienne G, Andorsky D, Issa GC, Larson RA, Bombaci F, Kapoor S, McCulloch T, Malek K, Yau L, Ifrah S, Hoch M, Cortes JE, Hughes TP; ASC4FIRST Investigators. Asciminib in Newly Diagnosed Chronic Myeloid Leukemia. N Engl J Med. 2024 Sep 12;391(10):885-898. Epub 2024 May 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04971226
==Bosutinib monotherapy==
===Regimen variant #1, 400 mg/day===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Cortes et al. 2017 (BFORE) 	2014-07 to 2015-08 	Phase 3 (E-RT-switch-ic)	Imatinib 	Seems to have higher MMR12 (primary endpoint)
Hochhaus et al. 2024 (ASC4FIRST)	2021-11-05 to 2022-12-20	Phase 3 (C) 	Asciminib 	Lower MMR48w
====Targeted therapy====
*Bosutinib (Bosulif) 400 mg PO once per day
Continued indefinitely
===Regimen variant #2, 500 mg/day===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Cortes et al. 2012 (BELA)	2008-02 to 2009-07 	Phase 3 (E-switch-ic)	Imatinib 	Did not meet primary endpoint of CCyR12
Note: Suboptimal response is defined as no complete hematologic response (CHR) by week 8 or complete cytogenetic response (CCyR) by week 12.
====Targeted therapy====
*Bosutinib (Bosulif) 500 mg PO once per day, taken with food
Continued indefinitely
====Dose and schedule modifications====
*If no grade 3 or higher drug-related toxicity occurs, Bosutinib (Bosulif) can be escalated to 600 mg PO once per day if response is suboptimal
===References===
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00574873
## 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 EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02130557
##PRO analysis: Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim DW, Milojkovic D, le Coutre P, Garcia-Gutierrez V, Crescenzo R, Mamolo C, Reisman A, Hochhaus A, Brümmendorf TH; BFORE Study Investigators. Patient-reported outcomes in the phase 3 BFORE trial of bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia. J Cancer Res Clin Oncol. 2019 Jun;145(6):1589-1599. Epub 2019 Apr 15. link to original article EuroPMC
##Update: Brümmendorf TH, Cortes JE, Milojkovic D, Gambacorti-Passerini C, Clark RE, le Coutre P, Garcia-Gutierrez V, Chuah C, Kota V, Lipton JH, Rousselot P, Mauro MJ, Hochhaus A, Hurtado Monroy R, Leip E, Purcell S, Yver A, Viqueira A, Deininger MW; BFORE study investigators. Bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia: final results from the BFORE trial. Leukemia. 2022 Jul;36(7):1825-1833. Epub 2022 May 28. link to original article link to PMC article EuroPMC
#ASC4FIRST: Hochhaus A, Wang J, Kim DW, Kim DDH, Mayer J, Goh YT, le Coutre P, Takahashi N, Kim I, Etienne G, Andorsky D, Issa GC, Larson RA, Bombaci F, Kapoor S, McCulloch T, Malek K, Yau L, Ifrah S, Hoch M, Cortes JE, Hughes TP; ASC4FIRST Investigators. Asciminib in Newly Diagnosed Chronic Myeloid Leukemia. N Engl J Med. 2024 Sep 12;391(10):885-898. Epub 2024 May 31. link to original article EuroPMC dosing details on CT.gov have been reviewed by our editors NCT04971226
==Cytarabine & Interferon alfa-2b==
===Regimen variant #1, uncapped===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Guilhot et al. 1997 	1991-1996 	Phase 3 (E-esc) 	Interferon alfa-2b 	Seems to have longer OS
Baccarani et al. 2002	1994-1997 	Phase 3 (E-esc) 	Interferon alfa-2b 	Higher MCgR24
Kühr et al. 2003 	1994-1999 	Phase 3 (E-switch-ic)	Hydrea & IFN alfa-2b	Did not meet primary endpoint of OS
Deenik et al. 2006 	1998-2001 	Phase 3 (C) 	7+2i & IFN 	Seems to have longer OS (secondary endpoint)Did not meet primary endpoint of EFS
====Chemotherapy====
*Cytarabine (Ara-C) 20 mg/m2 SC once per day on days 1 to 10
====Immunotherapy====
*Interferon alfa-2b (Intron-A) 5,000,000 units/m2 SC once per day
1-month cycles
===Regimen variant #2, capped===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
O'Brien et al. 2003 (IRIS)	2000-06 to 2001-01 	Phase 3 (C)	Imatinib 	Lower 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.
====Chemotherapy====
*Cytarabine (Ara-C) 20 mg/m2 (maximum dose of 40 mg) SC once per day on days 1 to 10
====Immunotherapy====
*Interferon alfa-2b (Intron-A) 5,000,000 units/m2 SC once per day
**IRIS describes this as the "target dose" (method of dose escalation not specified)
1-month cycles
===References===
# Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau JL, Maloisel F, Bouabdallah R, Guyotat D, Cheron N, Nicolini F, Abgrall JF, Tanzer J; Intergroupe Français des Leucémies Myéloïdes Chroniques. 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# Baccarani M, Rosti G, de Vivo A, Bonifazi F, Russo D, Martinelli G, Testoni N, Amabile M, Fiacchini M, Montefusco E, Saglio G, Tura S; Italian Cooperative Study Group on Myeloid Leukemia. A randomized study of interferon-alpha versus interferon-alpha and low-dose arabinosyl cytosine in chronic myeloid leukemia. Blood. 2002 Mar 1;99(5):1527-35. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00006343
## 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 EuroPMC
## Update: Hochhaus A, O'Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, Goldman JM, Müller MC, Radich JP, Rudoltz M, Mone M, Gathmann I, Hughes TP, Larson RA; IRIS Investigators. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009 Jun;23(6):1054-61. Epub 2009 Mar 12. Erratum in: Leukemia. 2010 May;24(5):1102. link to original article EuroPMC
## 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 EuroPMC
## 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 link to PMC article EuroPMC
# Kühr T, Burgstaller S, Apfelbeck U, Linkesch W, Seewann H, Fridrik M, Michlmayr G, Krieger O, Lutz D, Lin W, Pont J, Köck L, Abbrederis K, Baldinger C, Buder R, Geissler D, Hausmaninger H, Lang A, Zabernigg A, Duba C, Hilbe W, Eisterer W, Fiegl M, Greil R, Gastl G, Thaler J; Austrian CML Study Group. A randomized study comparing interferon (IFN alpha) plus low-dose cytarabine and interferon plus hydroxyurea (HU) in early chronic-phase chronic myeloid leukemia (CML). Leuk Res. 2003 May;27(5):405-11. link to original article EuroPMC
# Deenik W, van der Holt B, Verhoef GE, Schattenberg AV, Verdonck LF, Daenen SM, Zachée P, Westveer PH, Smit WM, Wittebol S, Schouten HC, Löwenberg B, Ossenkoppele GJ, Cornelissen JJ. High-vs low-dose cytarabine combined with interferon alfa in patients with first chronic phase chronic myeloid leukemia: a prospective randomized phase III study. Ann Hematol. 2007 Feb;86(2):117-25. Epub 2006 Oct 10. link to original article link to PMC article EuroPMC
==Dasatinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Cortes et al. 2009 (MDACC 2005-0422) 	2005-2009 	Phase 2 	 	
Radich et al. 2012 (SWOG S0325 Phase 2)	2006-2009 	Phase 3 (E-switch-ic) 	Imatinib 	Did not meet primary endpoint of 4-log reduction of BCR-ABL levels at 12 months
Kantarjian et al. 2010 (DASISION) 	2007-09 to 2008-12 	Phase 3 (E-RT-switch-ic)	Imatinib 	Higher CCyR12 (primary endpoint)Superior MMR rate (secondary endpoint)
Matsumura et al. 2024 (JALSG CML212) 	2012-05 to 2016-01 	Phase 3 (C) 	Nilotinib 	Did not meet primary endpoint of MR4.5 by 18 monthsMR4.5 by 18 months: 30.8% vs 32.6%
Hochhaus et al. 2024 (ASC4FIRST) 	2021-11-05 to 2022-12-20	Phase 3 (C) 	Asciminib 	Lower MMR48w
====Targeted therapy====
*Dasatinib (Sprycel) 100 mg PO once per day
Continued indefinitely
===References===
# MDACC 2005-0422: 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 EuroPMC NCT00254423
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00481247
## 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00070499
#ASC4FIRST: Hochhaus A, Wang J, Kim DW, Kim DDH, Mayer J, Goh YT, le Coutre P, Takahashi N, Kim I, Etienne G, Andorsky D, Issa GC, Larson RA, Bombaci F, Kapoor S, McCulloch T, Malek K, Yau L, Ifrah S, Hoch M, Cortes JE, Hughes TP; ASC4FIRST Investigators. Asciminib in Newly Diagnosed Chronic Myeloid Leukemia. N Engl J Med. 2024 Sep 12;391(10):885-898. Epub 2024 May 31. link to original article EuroPMC dosing details on CT.gov have been reviewed by our editors NCT04971226
#JALSG CML212: Matsumura I, Ohtake S, Atsuta Y, Kurata M, Minami Y, Takahashi N, Nakaseko C, Iriyama N, Fujimaki K, Kakihana K, Ogasawara Y, Ono T, Okada M, Tauchi T, Miyamoto T, Ohnishi K, Sakaida E, Fujisawa S, Kobayashi Y, Asou N, Naoe T, Kiyoi H, Miyazaki Y. Nilotinib vs dasatinib in achieving MR4.5 for de novo chronic myeloid leukemia: the randomized JALSG CML212 study. Blood Adv. 2024 Oct 22;8(20):5237-5247. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000007909
==Imatinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
O'Brien et al. 2003 (IRIS) 	2000-06 to 2001-01 	Phase 3 (E-RT-switch-ooc) 	Cytarabine & Interferon alfa 	Higher FFP (primary endpoint)
Kantarjian et al. 2006 	2000-2004 	Retrospective 	 	
Hehlmann et al. 2011 (CML-Study IV) 	2002-2012 	Phase 3 (C) 	1. Imatinib; high-dose 	Lower MMR12
Hehlmann et al. 2011 (CML-Study IV) 	2002-2012 	Phase 3 (C) 	2. Imatinib & Interferon alfa 	Not reported
Preudhomme et al. 2010 (SPIRIT) 	2003-2007 	Phase 3 (C) 	1. Imatinib; 600 mg daily 	Not reported
Preudhomme et al. 2010 (SPIRIT) 	2003-2007 	Phase 3 (C) 	2. Imatinib & Peginterferon alfa-2a	Lower MMR12
Preudhomme et al. 2010 (SPIRIT) 	2003-2007 	Phase 3 (C) 	3. Imatinib & LoDAC 	Not reported
Baccarani et al. 2009 (GIMEMA CML/022) 	2004-2007 	Phase 3 (C) 	Imatinib; high-dose 	Did not meet primary endpoint of CCgR12
Deininger et al. 2013 (SWOG S0325 Phase 1)	2005-2007 	Randomized Phase 2 (C) 	Imatinib; high-dose 	Seems to have lower MMR12
Cortes et al. 2009 (TOPS) 	2005-06 to 2006-12 	Phase 3 (C) 	Imatinib; high-dose 	Did not meet primary endpoint of MMR12
Radich et al. 2012 (SWOG S0325 Phase 2) 	2006-2009 	Phase 3 (C) 	Dasatinib 	Did not meet primary endpoint of 4-log reduction of BCR-ABL levels at 12 months
Kantarjian et al. 2010 (DASISION) 	2007-09 to 2008-12 	Phase 3 (C) 	Dasatinib 	Lower MMR rate
Saglio et al. 2010 (ENESTnd) 	2007-09-06 to 2008-09-30	Phase 3 (C) 	1. Nilotinib; 300 mg twice per day 	Seems to have shorter TTP
Saglio et al. 2010 (ENESTnd) 	2007-09-06 to 2008-09-30	Phase 3 (C) 	2. Nilotinib; 400 mg twice per day 	Shorter TTP
Yeung et al. 2014 (TIDEL-II) 	2007-2011 	Non-randomized 	 	
Cortes et al. 2012 (BELA) 	2008-02 to 2009-07 	Phase 3 (C) 	Bosutinib 	Did not meet primary endpoint of CCyR12
Hughes et al. 2014 (ENESTcmr) 	2009-06-12 to 2010-06-30	Non-randomized part of phase 3 RCT	 	
Wang et al. 2015 (ENESTchina) 	2011-04-15 to 2011-07-28	Phase 3 (C) 	Nilotinib 	Lower MMR12
Lipton et al. 2016 (EPICCML) 	2012-08-14 to 2013-10-09	Phase 3 (C) 	Ponatinib 	Might have lower MMR12
Cortes et al. 2017 (BFORE) 	2014-07 to 2015-08 	Phase 3 (C) 	Bosutinib 	Seems to have lower MMR12
Kwak et al. 2017 (RERISE) 	2011-2014 	Phase 3 (C) 	1. Radotinib; 300 mg twice per day 	Lower MMR12
Kwak et al. 2017 (RERISE) 	2011-2014 	Phase 3 (C) 	2. Radotinib; 400 mg twice per day 	Seems to have lower MMR12
Zhang et al. 2020 (FESTnd) 	2014-2016 	Phase 3 (C) 	Flumatinib 	Seems to have lower MMR12
Hochhaus et al. 2024 (ASC4FIRST) 	2021-11-05 to 2022-12-20	Phase 3 (C) 	Asciminib 	Lower MMR48w
Note: EPIC was terminated early, "following concerns about vascular adverse events observed in patients given ponatinib in other trials;" it should not be confused with the trial by the same name in colorectal cancer.
====Targeted therapy====
*Imatinib (Gleevec) 400 mg PO once per day
Continued indefinitely
====Subsequent treatment====
*ENESTcmr, patients with detectable BCR-ABL1 after at least 2 years of therapy: imatinib continuation versus second-line nilotinib
*TIDEL-II: Patients failing to meet molecular targets were either dose-increased to second-line imatinib; 800 mg per day and then switched to nilotinib 3 months later if they were still failing to meet targets, or switched to second-line nilotinib directly. This was not a randomization.
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00006343
## 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 EuroPMC
## Update: Hochhaus A, O'Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, Goldman JM, Müller MC, Radich JP, Rudoltz M, Mone M, Gathmann I, Hughes TP, Larson RA; IRIS Investigators. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009 Jun;23(6):1054-61. Epub 2009 Mar 12. Erratum in: Leukemia. 2010 May;24(5):1102. link to original article EuroPMC
## 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 EuroPMC
## 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 link to PMC article EuroPMC
# 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 EuroPMC content property of HemOnc.org 
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00514488
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00481247
## 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00471497
## 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
## 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 EuroPMC
## Update: Kantarjian HM, Hughes TP, Larson RA, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Boquimpani C, Pasquini R, Clark RE, Dubruille V, Flinn IW, Kyrcz-Krzemien S, Medras E, Zanichelli M, Bendit I, Cacciatore S, Titorenko K, Aimone P, Saglio G, Hochhaus A. Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia. 2021 Feb;35(2):440-453. Epub 2021 Jan 7. link to original article link to PMC article EuroPMC
# TOPS: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00124748
# 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; Intergroupe Français des Leucémies Myéloïdes Chroniques. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med. 2010 Dec 23;363(26):2511-21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00219739
## 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 EuroPMC
## Update: Guilhot F, Rigal-Huguet F, Guilhot J, Guerci-Bresler AP, Maloisel F, Rea D, Coiteux V, Gardembas M, Berthou C, Vekhoff A, Jourdan E, Berger M, Fouillard L, Alexis M, Legros L, Rousselot P, Delmer A, Lenain P, Escoffre Barbe M, Gyan E, Bulabois CE, Dubruille V, Joly B, Pollet B, Cony-Makhoul P, Johnson-Ansah H, Mercier M, Caillot D, Charbonnier A, Kiladjian JJ, Chapiro J, Penot A, Dorvaux V, Vaida I, Santagostino A, Roy L, Zerazhi H, Deconinck E, Maisonneuve H, Plantier I, Lebon D, Arkam Y, Cambier N, Ghomari K, Miclea JM, Glaisner S, Cayuela JM, Chomel JC, Muller M, Lhermitte L, Delord M, Preudhomme C, Etienne G, Mahon FX, Nicolini FE; France Intergroupe des Leucémies Myéloïdes Chroniques. Long-term outcome of imatinib 400 mg compared to imatinib 600 mg or imatinib 400 mg daily in combination with cytarabine or pegylated interferon alpha 2a for chronic myeloid leukaemia: results from the French SPIRIT phase III randomised trial. Leukemia. 2021 Aug;35(8):2332-2345. Epub 2021 Jan 22. link to original article EuroPMC
# 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/day versus 400 mg/day versus 400 mg/day 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00055874
## 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
## 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 link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00574873
## 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 EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00070499
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00070499
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00760877
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC ANZCTR12607000325404
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01275196
# 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 dosing details in abstract have been reviewed by our editors EuroPMC NCT01650805
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02130557
##PRO analysis: Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim DW, Milojkovic D, le Coutre P, Garcia-Gutierrez V, Crescenzo R, Mamolo C, Reisman A, Hochhaus A, Brümmendorf TH; BFORE Study Investigators. Patient-reported outcomes in the phase 3 BFORE trial of bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia. J Cancer Res Clin Oncol. 2019 Jun;145(6):1589-1599. Epub 2019 Apr 15. link to original article EuroPMC
##Update: Brümmendorf TH, Cortes JE, Milojkovic D, Gambacorti-Passerini C, Clark RE, le Coutre P, Garcia-Gutierrez V, Chuah C, Kota V, Lipton JH, Rousselot P, Mauro MJ, Hochhaus A, Hurtado Monroy R, Leip E, Purcell S, Yver A, Viqueira A, Deininger MW; BFORE study investigators. Bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia: final results from the BFORE trial. Leukemia. 2022 Jul;36(7):1825-1833. Epub 2022 May 28. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01511289
## Update: Do YR, Kwak JY, Kim JA, Kim HJ, Chung JS, Shin HJ, Kim SH, Bunworasate U, Choi CW, Zang DY, Oh SJ, Jootar S, Reksodiputro AH, Lee WS, Mun YC, Kong JH, Caguioa PB, Kim H, Park J, Kim DW. Long-term data from a phase 3 study of radotinib versus imatinib in patients with newly diagnosed, chronic myeloid leukaemia in the chronic phase (RERISE). Br J Haematol. 2020 Apr;189(2):303-312. Epub 2020 Feb 3. link to original article link to PMC article EuroPMC
# FESTnd: Zhang L, Meng L, Liu B, Zhang Y, Zhu H, Cui J, Sun A, Hu Y, Jin J, Jiang H, Zhang X, Li Y, Liu L, Zhang W, Liu X, Gu J, Qiao J, Ouyang G, Liu X, Luo J, Jiang M, Xie X, Li J, Zhao C, Zhang M, Yang T, Wang J. Flumatinib versus Imatinib for Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia: A Phase III, Randomized, Open-label, Multi-center FESTnd Study. Clin Cancer Res. 2021 Jan 1;27(1):70-77. Epub 2020 Sep 14. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02204644
#Tian J, Song YP, Zhang GC, Wang SF, Chu XX, Chai Y, Wang CL, He AL, Zhang F, Shen XL, Zhang WH, Yang LH, Nie DN, Wang DM, Zhu HL, Gao D, Lou SF, Zhou ZP, Su GH, Li Y, Lin JY, Shi QZ, Ouyang GF, Jing HM, Chen SJ, Li J, Mi JQ. Oral arsenic plus imatinib versus imatinib solely for newly diagnosed chronic myeloid leukemia: a randomized phase 3 trial with 5-year outcomes. J Cancer Res Clin Oncol. 2024 Apr 11;150(4):189. link to original article link to PMC article EuroPMC CTR20170221
#ASC4FIRST: Hochhaus A, Wang J, Kim DW, Kim DDH, Mayer J, Goh YT, le Coutre P, Takahashi N, Kim I, Etienne G, Andorsky D, Issa GC, Larson RA, Bombaci F, Kapoor S, McCulloch T, Malek K, Yau L, Ifrah S, Hoch M, Cortes JE, Hughes TP; ASC4FIRST Investigators. Asciminib in Newly Diagnosed Chronic Myeloid Leukemia. N Engl J Med. 2024 Sep 12;391(10):885-898. Epub 2024 May 31. link to original article EuroPMC dosing details on CT.gov have been reviewed by our editors NCT04971226
==Imatinib monotherapy, high dose==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Hehlmann et al. 2011 (CML-Study IV) 	2002-2012 	Phase 3 (E-esc) 	1. Imatinib; standard-dose 	Higher MMR12 (primary endpoint)
Hehlmann et al. 2011 (CML-Study IV) 	2002-2012 	Phase 3 (E-esc) 	2. Imatinib & Interferon alfa	Higher MMR12 (primary endpoint)
Castagnetti et al. 2009 (GIMEMA CML/021) 	2004-2005 	Phase 2 	 	
Baccarani et al. 2009 (GIMEMA CML/022) 	2004-2007 	Phase 3 (E-esc) 	Imatinib; standard-dose 	Did not meet primary endpoint of CCgR12
Cortes et al. 2009 (TOPS) 	2005-06 to 2006-12 	Phase 3 (E-esc) 	Imatinib; standard-dose 	Did not meet primary endpoint of MMR12
Deininger et al. 2013 (SWOG S0325 Phase 1)	2005-2007 	Randomized Phase 2 (E-esc)	Imatinib; standard-dose 	Seems to have higher MMR12 (primary endpoint)
Thielen et al. 2013 (HOVON 78) 	2006 to not reported	Phase 3 (C) 	Cytarabine & HD-Imatinib 	Did not meet primary endpoint of MMR12MMR12: 56% vs 48%
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 twice per day.
====Targeted therapy====
*Imatinib (Gleevec) 800 mg PO once per day (CML-Study IV) or 400 mg PO twice per day (S0325, GIMEMA studies, TOPS)
Continued indefinitely
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00510926
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00514488
## 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 EuroPMC
# TOPS: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00124748
# 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/day versus 400 mg/day versus 400 mg/day 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00055874
## 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
## 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 link to PMC article EuroPMC
# HOVON 78: 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 EuroPMC NTR674
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00070499
==Imatinib monotherapy, intermittent therapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Russo et al. 2013 (INTERIM0407)	2008 to not reported	Phase 2
====Eligibility criteria====
*Imatinib for at least two years with a complete cytogenetic response
====Targeted therapy====
*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
Continued indefinitely or until loss of complete cytogenetic response is observed
====Subsequent treatment====
*INTERIM0407, patients who lost major molecular response after one year: second-line Imatinib; continuous
===References===
# INTERIM0407: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00858806
==Imatinib monotherapy, planned discontinuation==
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Mahon et al. 2010 (STIM1) 	2007-2009 	Phase 2
Awaiting publication (STIM2)	2011-2013 	Phase 2
Note: We could not locate a full manuscript describing the results of STIM2; an abstract is referenced below.
====Targeted therapy====
*Imatinib (Gleevec) (dose not specified) mg PO once per day
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.
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Ross et al. 2013 (TWISTER)	2006-2011 	Phase 2
====Targeted therapy====
*Imatinib (Gleevec) 150 to 800 mg PO once per day
Treatment is discontinued after a minimum of 3 years of imatinib and 2 years of sustained undetectable minimal residual disease by conventional PCR.
===References===
# STIM1: 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 dosing details not available in manuscript EuroPMC NCT00478985
## 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. Epub 2016 Oct 31. link to original article EuroPMC
# TWISTER: 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 dosing details in manuscript have been reviewed by our editors EuroPMC ACTRN12606000118505
# STIM2: 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 abstract NCT01343173
==Imatinib & LoDAC==
Imatinib & LoDAC: Imatinib & Low Dose Ara-C
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Preudhomme et al. 2010 (SPIRIT)	2003-2007 	Phase 3 (E-esc)	1. Imatinib; 400 mg once per day 	Not reported
Preudhomme et al. 2010 (SPIRIT)	2003-2007 	Phase 3 (E-esc)	2. Imatinib; 600 mg once per day 	Not reported
Preudhomme et al. 2010 (SPIRIT)	2003-2007 	Phase 3 (E-esc)	3. Imatinib & Peginterferon alfa-2a	Not reported
====Targeted therapy====
*Imatinib (Gleevec) 400 mg PO once per day
====Chemotherapy====
*Cytarabine (Ara-C) 20 mg/m2 SC once per day on days 15 to 28
28-day cycle for at least 13 cycles (1 year)
===References===
# 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; Intergroupe Français des Leucémies Myéloïdes Chroniques. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med. 2010 Dec 23;363(26):2511-21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00219739
## 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 EuroPMC
## Update: Guilhot F, Rigal-Huguet F, Guilhot J, Guerci-Bresler AP, Maloisel F, Rea D, Coiteux V, Gardembas M, Berthou C, Vekhoff A, Jourdan E, Berger M, Fouillard L, Alexis M, Legros L, Rousselot P, Delmer A, Lenain P, Escoffre Barbe M, Gyan E, Bulabois CE, Dubruille V, Joly B, Pollet B, Cony-Makhoul P, Johnson-Ansah H, Mercier M, Caillot D, Charbonnier A, Kiladjian JJ, Chapiro J, Penot A, Dorvaux V, Vaida I, Santagostino A, Roy L, Zerazhi H, Deconinck E, Maisonneuve H, Plantier I, Lebon D, Arkam Y, Cambier N, Ghomari K, Miclea JM, Glaisner S, Cayuela JM, Chomel JC, Muller M, Lhermitte L, Delord M, Preudhomme C, Etienne G, Mahon FX, Nicolini FE; France Intergroupe des Leucémies Myéloïdes Chroniques. Long-term outcome of imatinib 400 mg compared to imatinib 600 mg or imatinib 400 mg daily in combination with cytarabine or pegylated interferon alpha 2a for chronic myeloid leukaemia: results from the French SPIRIT phase III randomised trial. Leukemia. 2021 Aug;35(8):2332-2345. Epub 2021 Jan 22. link to original article EuroPMC
==Imatinib & Interferon alfa==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hehlmann et al. 2011 (CML-Study IV)	2002-2012 	Phase 3 (E-esc)	1. Imatinib 	Not reported
Hehlmann et al. 2011 (CML-Study IV)	2002-2012 	Phase 3 (E-esc)	2. Imatinib; high dose	Lower MMR12 (primary endpoint)
Note: the manuscript does not specify a type of interferon alfa. Interferon alfa dose was increased only if tolerated.
====Targeted therapy====
*Imatinib (Gleevec) 400 mg PO once per day on days 1 to 7
====Immunotherapy====
*Interferon alfa as follows:
**Cycles 1 to 6: 1,500,000 units SC once per day on days 1, 3, 5 (three times per week)
**Cycle 7 onwards: 3,000,000 units SC once per day on days 1, 3, 5 (three times per week)
7-day cycles
===References===
# 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/day versus 400 mg/day versus 400 mg/day 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 some dosing details in manuscript EuroPMC NCT00055874 
## 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
## 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 link to PMC article EuroPMC
==Imatinib & Peginterferon alfa-2a==
===Regimen variant #1, 45 mcg===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Preudhomme et al. 2010 (SPIRIT)	2003-2007 	Phase 3 (E-esc)	1. Imatinib; 400 mg once per day	Higher MMR12 (secondary endpoint)
Preudhomme et al. 2010 (SPIRIT)	2003-2007 	Phase 3 (E-esc)	2. Imatinib; 600 mg once per day	Not reported
Preudhomme et al. 2010 (SPIRIT)	2003-2007 	Phase 3 (E-esc)	3. Imatinib & LoDAC 	Not reported
Note: The SPIRIT protocol was amended to reduce the dose of peginterferon; Johnson-Ansah et al. demonstrated (post-hoc) that the reduced dose was still efficacious.
====Targeted therapy====
*Imatinib (Gleevec) 400 mg PO once per day on days 1 to 7
====Immunotherapy====
*Peginterferon alfa-2a (Pegasys) 45 mcg SC once on day 1
7-day cycles
===Regimen variant #2, 90 mcg===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Preudhomme et al. 2010 (SPIRIT)	2003-2007 	Phase 3 (E-esc)	1. Imatinib; 400 mg once per day	Higher MMR12 (secondary endpoint)
Preudhomme et al. 2010 (SPIRIT)	2003-2007 	Phase 3 (E-esc)	2. Imatinib; 600 mg once per day	Not reported
Preudhomme et al. 2010 (SPIRIT)	2003-2007 	Phase 3 (E-esc)	3. Imatinib & LoDAC 	Not reported
Note: The SPIRIT protocol was amended to reduce the dose of peginterferon; Johnson-Ansah et al. demonstrated (post-hoc) that the reduced dose was still efficacious.
====Targeted therapy====
*Imatinib (Gleevec) 400 mg PO once per day on days 1 to 7
====Immunotherapy====
*Peginterferon alfa-2a (Pegasys) 90 mcg SC once on day 1
7-day cycles
===References===
# 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; Intergroupe Français des Leucémies Myéloïdes Chroniques. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med. 2010 Dec 23;363(26):2511-21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00219739
## 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 EuroPMC
## Update: Guilhot F, Rigal-Huguet F, Guilhot J, Guerci-Bresler AP, Maloisel F, Rea D, Coiteux V, Gardembas M, Berthou C, Vekhoff A, Jourdan E, Berger M, Fouillard L, Alexis M, Legros L, Rousselot P, Delmer A, Lenain P, Escoffre Barbe M, Gyan E, Bulabois CE, Dubruille V, Joly B, Pollet B, Cony-Makhoul P, Johnson-Ansah H, Mercier M, Caillot D, Charbonnier A, Kiladjian JJ, Chapiro J, Penot A, Dorvaux V, Vaida I, Santagostino A, Roy L, Zerazhi H, Deconinck E, Maisonneuve H, Plantier I, Lebon D, Arkam Y, Cambier N, Ghomari K, Miclea JM, Glaisner S, Cayuela JM, Chomel JC, Muller M, Lhermitte L, Delord M, Preudhomme C, Etienne G, Mahon FX, Nicolini FE; France Intergroupe des Leucémies Myéloïdes Chroniques. Long-term outcome of imatinib 400 mg compared to imatinib 600 mg or imatinib 400 mg daily in combination with cytarabine or pegylated interferon alpha 2a for chronic myeloid leukaemia: results from the French SPIRIT phase III randomised trial. Leukemia. 2021 Aug;35(8):2332-2345. Epub 2021 Jan 22. link to original article EuroPMC
==Interferon alfa-2a monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Talpaz et al. 1986 (DM 82-49)	Not reported 	Non-randomized 	 	
Talpaz et al. 1987 (DM 84-38)	1981-1984 	Non-randomized (RT) 	 	
Tura et al. 1994 (MI400) 	1986-1988 	Phase 3 (E-RT-switch-ooc)	1a. Busulfan1b. Hydrea	Longer OS
====Immunotherapy====
*Interferon alfa-2a (Roferon-A) as follows:
**Weeks 1 & 2: 3,000,000 IU (route not specified) once per day
**Weeks 3 & 4: 6,000,000 IU (route not specified) once per day
**Weeks 5 to 35: 9,000,000 IU (route not specified) once per day
8-month course
====Subsequent treatment====
*Dose escalated according to karyotypic response (see paper for details)
===References===
# DM 82-49: 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 EuroPMC
## Pooled update: Kantarjian HM, Smith TL, O'Brien S, Beran M, Pierce S, Talpaz M. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. Ann Intern Med. 1995 Feb 15;122(4):254-61. link to original article EuroPMC
# DM 84-38: Talpaz M, Kantarjian HM, McCredie KB, Keating MJ, Trujillo J, Gutterman J. Clinical investigation of human alpha interferon in chronic myelogenous leukemia. Blood. 1987 May;69(5):1280-8. link to original article EuroPMC
## Pooled update: Kantarjian HM, Smith TL, O'Brien S, Beran M, Pierce S, Talpaz M. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. Ann Intern Med. 1995 Feb 15;122(4):254-61. link to original article EuroPMC
# MI400: 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Interferon alfa-2b monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Guilhot et al. 1997 	1991-1996 	Phase 3 (C)	LoDAC & Interferon alfa	Seems to have shorter OS
Kluin-Nelemans et al. 2004 (HOVON 20/MRC CML IV)	1993-2001 	Phase 3 (C)	IFN alfa-2b; low-dose 	Did not meet co-primary endpoints of OS/PFS/CHR rate/MCR rate
Michallet et al. 2004 	1998-1999 	Phase 3 (C)	Peg-IFN alfa-2b 	Inconclusive whether non-inferior MCR12
====Immunotherapy====
*Interferon alfa-2b (Intron-A) as follows:
**Cycle 1: 3,000,000 IU SC once per day on days 1 to 7
**Cycle 2: 5,000,000 IU SC once per day on days 1 to 7
**Cycle 3 onwards: 5,000,000 IU/m2 SC once per day on days 1 to 7
7-day cycles
===References===
# Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau JL, Maloisel F, Bouabdallah R, Guyotat D, Cheron N, Nicolini F, Abgrall JF, Tanzer J; Intergroupe Français des Leucémies Myéloïdes Chroniques. 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 EuroPMC
# Michallet M, Maloisel F, Delain M, Hellmann A, Rosas A, Silver RT, Tendler C; PEG-Intron CML Study Group. Pegylated recombinant interferon alpha-2b vs recombinant interferon alpha-2b for the initial treatment of chronic-phase chronic myelogenous leukemia: a phase III study. Leukemia. 2004 Feb;18(2):309-15. link to original article EuroPMC
# HOVON 20/MRC CML IV: Kluin-Nelemans HC, Buck G, le Cessie S, Richards S, Beverloo HB, Falkenburg JH, Littlewood T, Muus P, Bareford D, van der Lelie H, Green AR, Roozendaal KJ, Milne AE, Chapman CS, Shepherd P; MRC and HOVON groups. Randomized comparison of low-dose versus high-dose interferon-alfa in chronic myeloid leukemia: prospective collaboration of 3 joint trials by the MRC and HOVON groups. Blood. 2004 Jun 15;103(12):4408-15. Epub 2004 Mar 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002869
==Interferon alfa-n1 monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Allan et al. 1995	1986-1994 	Phase 3 (E-switch-ooc)	1a. Busulfan1b. Hydrea	Longer OS
====Immunotherapy====
*Interferon alfa-n1 (Wellferon) 3,000,000 units SC once per day on days 1 to 21
21-day cycles
====Dose and schedule modifications====
*Dose was modified for both efficacy and toxicity; see paper for details.
===References===
# Allan NC, Richards SM, Shepherd PC; 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# ECOG E7995: NCT00002868
==Nilotinib monotherapy==
===Regimen variant #1, 300 mg twice per day===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Saglio et al. 2010 (ENESTnd) 	2007-09-06 to 2008-09-30	Phase 3 (E-RT-switch-ic)	1. Imatinib 	Seems to have longer TTP (secondary endpoint)Superior MMR12 (primary endpoint)
Saglio et al. 2010 (ENESTnd) 	2007-09-06 to 2008-09-30	Phase 3 (E-RT-switch-ic)	2. Nilotinib; 400 mg twice per day	Not reported
Wang et al. 2015 (ENESTchina) 	2011-04-15 to 2011-07-28	Phase 3 (E-switch-ic) 	Imatinib 	Higher MMR12 (primary endpoint)
Hochhaus et al. 2024 (ASC4FIRST)	2021-11-05 to 2022-12-20	Phase 3 (C) 	Asciminib 	Lower MMR48w
Note: The ENESTnd study was not powered to detect differences between the two doses of nilotinib.
====Targeted therapy====
*Nilotinib (Tasigna) 300 mg PO twice per day on days 1 to 28
28-day cycles
===Regimen variant #2, 400 mg twice per day===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Rosti et al. 2009 (CML0307) 	2007-2008 	Phase 2 	 	
Saglio et al. 2010 (ENESTnd)	2007-09-06 to 2008-09-30	Phase 3 (E-RT-switch-ic)	1. Imatinib 	Longer TTP (secondary endpoint)Superior MMR12 (primary endpoint)
Saglio et al. 2010 (ENESTnd)	2007-09-06 to 2008-09-30	Phase 3 (E-RT-switch-ic)	2. Nilotinib; 300 mg twice per day	Not reported
Note: The ENESTnd study was not powered to detect differences between the two doses of nilotinib.
====Targeted therapy====
*Nilotinib (Tasigna) 400 mg PO on days 1 to 28
28-day cycles
===Regimen variant #3, planned discontinuation===
Study 	Dates of enrollment 	Evidence
Hochhaus et al. 2017 (ENESTfreedom)	2013-03-04 to 2013-11-22	Phase 2 (RT)
Note: See manuscript for exact details of the treatment timeline.
====Targeted therapy====
*Nilotinib (Tasigna) (dose not specified) PO
Continued for at least 3 years
===References===
# CML0307: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00481052
## 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, Russo Rossi A, 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00471497
## 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
## 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 EuroPMC
## Update: Kantarjian HM, Hughes TP, Larson RA, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Boquimpani C, Pasquini R, Clark RE, Dubruille V, Flinn IW, Kyrcz-Krzemien S, Medras E, Zanichelli M, Bendit I, Cacciatore S, Titorenko K, Aimone P, Saglio G, Hochhaus A. Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia. 2021 Feb;35(2):440-453. Epub 2021 Jan 7. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01275196
# ENESTfreedom: Hochhaus A, Masszi T, Giles FJ, Radich JP, Ross DM, Gómez Casares MT, Hellmann A, Stentoft J, Conneally E, García-Gutiérrez V, Gattermann N, Wiktor-Jedrzejczak W, le Coutre PD, Martino B, Saussele S, Menssen HD, Deng W, Krunic N, Bedoucha V, Saglio G. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia. 2017 Jul;31(7):1525-1531. Epub 2017 Feb 20. link to original article link to PMC article EuroPMC NCT01784068
## Update: Ross DM, Masszi T, Gómez Casares MT, Hellmann A, Stentoft J, Conneally E, Garcia-Gutierrez V, Gattermann N, le Coutre PD, Martino B, Saussele S, Giles FJ, Radich JP, Saglio G, Deng W, Krunic N, Bédoucha V, Gopalakrishna P, Hochhaus A. Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: 96-week update of the ENESTfreedom study. J Cancer Res Clin Oncol. 2018 May;144(5):945-954. Epub 2018 Feb 22. link to original article link to PMC article EuroPMC
## Update: Radich JP, Hochhaus A, Masszi T, Hellmann A, Stentoft J, Casares MTG, García-Gutiérrez JV, Conneally E, le Coutre PD, Gattermann N, Martino B, Saussele S, Giles FJ, Ross DM, Aimone P, Li S, Titorenko K, Saglio G. Treatment-free remission following frontline nilotinib in patients with chronic phase chronic myeloid leukemia: 5-year update of the ENESTfreedom trial. Leukemia. 2021 May;35(5):1344-1355. Epub 2021 Mar 11. link to original article link to PMC article EuroPMC
#ASC4FIRST: Hochhaus A, Wang J, Kim DW, Kim DDH, Mayer J, Goh YT, le Coutre P, Takahashi N, Kim I, Etienne G, Andorsky D, Issa GC, Larson RA, Bombaci F, Kapoor S, McCulloch T, Malek K, Yau L, Ifrah S, Hoch M, Cortes JE, Hughes TP; ASC4FIRST Investigators. Asciminib in Newly Diagnosed Chronic Myeloid Leukemia. N Engl J Med. 2024 Sep 12;391(10):885-898. Epub 2024 May 31. link to original article EuroPMC dosing details on CT.gov have been reviewed by our editors NCT04971226
==Radotinib monotherapy==
===Regimen variant #1, 300 mg twice per day===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kwak et al. 2017 (RERISE)	2011-2014 	Phase 3 (E-switch-ic)	1. Imatinib 	Higher MMR12 (primary endpoint)
Kwak et al. 2017 (RERISE)	2011-2014 	Phase 3 (E-switch-ic)	2. Radotinib; 400 mg twice per day	Not reported
====Targeted therapy====
*Radotinib (Supect) 300 mg PO twice per day
Continued indefinitely
===Regimen variant #2, 400 mg twice per day===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kim et al. 2014 (IY5511A1201)	2009-2011 	Phase 2 	 	
Kwak et al. 2017 (RERISE) 	2011-2014 	Phase 3 (E-switch-ic)	1. Imatinib 	Seems to have higher MMR12 (primary endpoint)
Kwak et al. 2017 (RERISE) 	2011-2014 	Phase 3 (E-switch-ic)	2. Radotinib; 300 mg twice per day	Not reported
====Targeted therapy====
*Radotinib (Supect) 400 mg PO twice per day
Continued indefinitely
===References===
# IY5511A1201: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01602952
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01511289
## Update: Do YR, Kwak JY, Kim JA, Kim HJ, Chung JS, Shin HJ, Kim SH, Bunworasate U, Choi CW, Zang DY, Oh SJ, Jootar S, Reksodiputro AH, Lee WS, Mun YC, Kong JH, Caguioa PB, Kim H, Park J, Kim DW. Long-term data from a phase 3 study of radotinib versus imatinib in patients with newly diagnosed, chronic myeloid leukaemia in the chronic phase (RERISE). Br J Haematol. 2020 Apr;189(2):303-312. Epub 2020 Feb 3. link to original article link to PMC article EuroPMC
=Chronic phase, relapsed or refractory=
==Asciminib monotherapy==
===Regimen variant #1, 40 mg twice per day===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Réa et al. 2021 (ASCEMBL)	2017-2019 	Phase 3 (E-RT-switch-ooc)	Bosutinib 	Seems to have higher MMR24w (primary endpoint)Superior MMR1 (secondary endpoint)MMR96w: 37.6% vs 15.8%
1Reported efficacy is based on the 2022 update.
====Targeted therapy====
*Asciminib (Scemblix) 40 mg PO twice per day
Continued indefinitely
===Regimen variant #2, 200 mg twice per day===
FDA-recommended dose
Study 	Dates of enrollment	Evidence
Hughes et al. 2019 (CABL001X2101)	2014-2017 	Phase 1, >20 pts in this dose cohort (RT)
Note: details are from the FDA approval announcement, which describes n=45 patients treated at this dose level. The published manuscript only describes n=16 patients who received this dose level.
====Biomarker eligibility criteria====
*Bcr-Abl T315I mutation
====Targeted therapy====
*Asciminib (Scemblix) 200 mg PO twice per day
Continued indefinitely
===References===
# CABL001X2101: Hughes TP, Mauro MJ, Cortes JE, Minami H, Rea D, DeAngelo DJ, Breccia M, Goh YT, Talpaz M, Hochhaus A, le Coutre P, Ottmann O, Heinrich MC, Steegmann JL, Deininger MWN, Janssen JJWM, Mahon FX, Minami Y, Yeung D, Ross DM, Tallman MS, Park JH, Druker BJ, Hynds D, Duan Y, Meille C, Hourcade-Potelleret F, Vanasse KG, Lang F, Kim DW. Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure. N Engl J Med. 2019 Dec 12;381(24):2315-2326. link to original article link to PMC article EuroPMC NCT02081378
#ASCEMBL: Réa D, Mauro MJ, Boquimpani C, Minami Y, Lomaia E, Voloshin S, Turkina A, Kim DW, Apperley JF, Abdo A, Fogliatto LM, Kim DDH, le Coutre P, Saussele S, Annunziata M, Hughes TP, Chaudhri N, Sasaki K, Chee L, García-Gutiérrez V, Cortes JE, Aimone P, Allepuz A, Quenet S, Bédoucha V, Hochhaus A. A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Blood. 2021 Nov 25;138(21):2031-2041. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03106779
##HRQoL analysis: Réa D, Boquimpani C, Mauro MJ, Minami Y, Allepuz A, Maheshwari VK, D'Alessio D, Wu Y, Lawrance R, Narbutas S, Sharf G, Hochhaus A. Health-related quality of life of patients with resistant/intolerant chronic phase chronic myeloid leukemia treated with asciminib or bosutinib in the phase 3 ASCEMBL trial. Leukemia. 2023 May;37(5):1060-1067. Epub 2023 Apr 14. link to original article link to PMC article EuroPMC
==Bosutinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Cortes et al. 2011 (Study 200)	2006-2008 	Phase 1/2 (RT)	 	
Réa et al. 2021 (ASCEMBL) 	2017-2019 	Phase 3 (C) 	Asciminib 	Lower MMR
1Reported efficacy is based on the 2022 update.
Note: Suboptimal response in Study 200 was defined as no complete hematologic response (CHR) by week 8 or complete cytogenetic response (CCyR) by week 12.
====Targeted therapy====
*Bosutinib (Bosulif) 500 mg PO once per day, taken with food
Continued indefinitely
====Dose and schedule modifications====
*Study 200: If no grade 3 or higher drug-related toxicity occurs, Bosutinib (Bosulif) can be escalated to 600 mg PO once per day if response is suboptimal
===References===
# Study 200: Cortes JE, Kantarjian HM, Brümmendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A, Besson N, Abbas R, Wang J, Leip E, Gambacorti-Passerini C. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011 Oct 27;118(17):4567-76. Epub 2011 Aug 24. Erratum in: Blood. 2013 Oct 3;122(14):2524. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00261846
## 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
## 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
## Update: Gambacorti-Passerini C, Brümmendorf TH, Kim DW, Turkina AG, Masszi T, Assouline S, Durrant S, Kantarjian HM, Khoury HJ, Zaritskey A, Shen ZX, Jin J, Vellenga E, Pasquini R, Mathews V, Cervantes F, Besson N, Turnbull K, Leip E, Kelly V, Cortes JE. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up. Am J Hematol. 2014 Jul;89(7):732-42. Epub 2014 Apr 28. link to original article link to PMC article EuroPMC
## 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 EuroPMC
#ASCEMBL: Réa D, Mauro MJ, Boquimpani C, Minami Y, Lomaia E, Voloshin S, Turkina A, Kim DW, Apperley JF, Abdo A, Fogliatto LM, Kim DDH, le Coutre P, Saussele S, Annunziata M, Hughes TP, Chaudhri N, Sasaki K, Chee L, García-Gutiérrez V, Cortes JE, Aimone P, Allepuz A, Quenet S, Bédoucha V, Hochhaus A. A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Blood. 2021 Nov 25;138(21):2031-2041. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03106779
##HRQoL analysis: Réa D, Boquimpani C, Mauro MJ, Minami Y, Allepuz A, Maheshwari VK, D'Alessio D, Wu Y, Lawrance R, Narbutas S, Sharf G, Hochhaus A. Health-related quality of life of patients with resistant/intolerant chronic phase chronic myeloid leukemia treated with asciminib or bosutinib in the phase 3 ASCEMBL trial. Leukemia. 2023 May;37(5):1060-1067. Epub 2023 Apr 14. link to original article link to PMC article EuroPMC
==BuCyTBI, then allo HSCT==
BuCyTBI: Busulfan, Cyclophosphamide, Total Body Irradiation
===Regimen===
Study 	Dates of enrollment	Evidence
Fefer et al. 1979	1968-1976 	Pilot, fewer than 20 pts
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Cyclophosphamide & TBI, then allo HSCT==
Cy/TBI: Cyclophosphamide & Total Body Irradiation
===Regimen===
Study 	Dates of enrollment 	Evidence
Fefer et al. 1982 	1971-1980 	Non-randomized, fewer than 20 pts
Speck et al. 1984 	1978-07-01 to 1982-06-03	Registry
Goldman et al. 1986	1981-1984 	Non-randomized
Hansen et al. 1998 	1985-1994 	Non-randomized
===References===
# 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 EuroPMC
# Speck B, Bortin MM, Champlin R, Goldman JM, Herzig RH, McGlave PB, Messner HA, Weiner RS, Rimm AA. Allogeneic bone-marrow transplantation for chronic myelogenous leukaemia. Lancet. 1984 Mar 24;1(8378):665-8. link to original article EuroPMC
# 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. link to original article EuroPMC
# 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 EuroPMC
==Dasatinib monotherapy==
===Regimen variant #1, 70 mg twice per day=== 
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Talpaz et al. 2006 (BMS-CA180002)	2003-2005 	Phase 1, >20 pts in this dosing cohort	 	
Hochhaus et al. 2006 (CA180-013) 	2005 	Phase 2 (RT) 	 	
Kantarjian et al. 2007CML 	2005-02 to 2005-11 	Randomized Phase 2 (E-switch-ic) 	Imatinib; high-dose 	Longer PFS (secondary endpoint)
Shah et al. 2008 (CA180-034) 	2005-07 to 2006-03 	Phase 3 (E-RT-esc) 	1. Dasatinib; 100 mg once per day	Non-inferior MCyR (primary endpoint)
Shah et al. 2008 (CA180-034) 	2005-07 to 2006-03 	Phase 3 (E-RT-esc) 	2. Dasatinib; 140 mg once per day	Non-inferior MCyR (primary endpoint)
Shah et al. 2008 (CA180-034) 	2005-07 to 2006-03 	Phase 3 (E-RT-esc) 	3. Dasatinib; 50 mg twice per day	Non-inferior MCyR (primary endpoint)
Note: this is the most common dosing used in BMS-CA180002, but was not specifically recommended as the dose for subsequent trials. The trial by Kantarjian et al. 2007 should not be confused for one with the same name in MDS/CMML.
====Prior treatment criteria====
*BMS-CA180002, CA180-013, CA180-034: Failure of imatinib
*Kantarjian et al. 2007CML: Failure of standard-dose imatinib
====Targeted therapy====
*Dasatinib (Sprycel) 70 mg PO twice per day on days 1 to 28
28-day cycles
====Dose and schedule modifications====
*Dasatinib (Sprycel) reduction to 40 mg PO twice per day or escalation to 90 mg PO twice per day allowed under certain circumstances; see original papers for details.
===Regimen variant #2, 100 mg/day===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Shah et al. 2008 (CA180-034)	2005-07 to 2006-03 	Phase 3 (E-RT-de-esc)	1. Dasatinib; 140 mg once per day	Non-inferior MCyR (primary endpoint)
Shah et al. 2008 (CA180-034)	2005-07 to 2006-03 	Phase 3 (E-RT-de-esc)	2. Dasatinib; 50 mg twice per day	Non-inferior MCyR (primary endpoint)
Shah et al. 2008 (CA180-034)	2005-07 to 2006-03 	Phase 3 (E-RT-de-esc)	3. Dasatinib; 70 mg twice per day	Non-inferior MCyR (primary endpoint)
Note: dose escalation is not described in the FDA-recommended dosing.
====Prior treatment criteria====
*CA180-034: Failure of imatinib
====Targeted therapy====
*Dasatinib (Sprycel) 100 mg PO once per day
Continued indefinitely
====Dose and schedule modifications====
*Dasatinib (Sprycel) may be escalated to 140 mg PO once per day or 70 mg PO twice per day depending on response, see paper.
===References===
# BMS-CA180002: 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 EuroPMC NCT00064233
# 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 EuroPMC
# CA180-013: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00101660
## 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00123474
## 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 EuroPMC 
## 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 EuroPMC
## 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 original article link to PMC article EuroPMC
==Imatinib monotherapy==
===Regimen variant #1, 400 mg/day===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Druker et al. 2001a 	1998-2000 	Phase 1 	 	
Kantarjian et al. 2002 (STIA 0110)	1999-2000 	Phase 2 (RT)	 	
Petzer et al. 2010 (ISTAHIT) 	2004-2006 	Phase 3 (C) 	imatinib; high-dose, then imatinib; standard-dose	Lower MMR6
Hughes et al. 2014 (ENESTcmr) 	2009-06-12 to 2010-06-30	Phase 3 (C) 	Nilotinib 	Lower MMR24
Note: patients in ENESTcmr in this arm were already taking this dose of imatinib prior to randomization.
====Prior treatment criteria====
*Druker et al. 2001a: Failure of interferon alfa
====Preceding treatment====
*ENESTcmr: First-line Imatinib for at least 2 years, with detectable BCR-ABL1
====Targeted therapy====
*Imatinib (Gleevec) 400 mg PO once per day
Continued indefinitely
===Regimen variant #2, 600 mg/day===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Hughes et al. 2014 (ENESTcmr)	2009-06-12 to 2010-06-30	Phase 3 (C) 	Nilotinib 	Lower MMR24
Cortes et al. 2016 (LASOR) 	2009-2012 	Phase 3 (E-switch-ic)	Nilotinib 	Did not meet primary endpoint of CCyR6
Note: patients in ENESTcmr in this arm were already taking this dose of imatinib prior to randomization.
====Preceding treatment====
*ENESTcmr: First-line Imatinib for at least 2 years, with detectable BCR-ABL1
*LASOR: First-line Imatinib; standard-dose, with suboptimal response
====Targeted therapy====
*Imatinib (Gleevec) 600 mg PO once per day
Continued indefinitely
===Regimen variant #3, 800 mg/day===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Kantarjian et al. 2007CML 	2005-02 to 2005-11 	Randomized Phase 2 (E-switch-ic)	Dasatinib 	Shorter PFS (secondary endpoint)
Yeung et al. 2014 (TIDEL-II)	2007-2011 	Non-randomized 	 	
Note: The trial by Kantarjian et al. 2007 should not be confused for one with the same name in MDS/CMML.
====Preceding treatment====
*TIDEL-II: First-line Imatinib; 600 mg once per day
====Targeted therapy====
*Imatinib (Gleevec) 400 mg PO twice per day
Continued indefinitely
====Subsequent treatment====
*TIDEL-II: Patients were switched to third-line nilotinib 3 months later if they were still failing to meet targets (see paper for details)
===Regimen variant #4, high-dose, then standard-dose===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Petzer et al. 2010 (ISTAHIT)	2004-2006 	Phase 3 (E-esc)	Imatinib; standard-dose	Higher MMR6 (secondary endpoint)Did not meet primary endpoint of MCyR121
1Reported efficacy for ISTAHIT is based on the 2012 update.
====Targeted therapy====
*Imatinib (Gleevec) 800 mg PO once per day for 6 months, then 400 mg PO once per day
Continued indefinitely
===References===
# 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 EuroPMC
# STIA 0110: 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 EuroPMC
## 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00327262
## 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00760877
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC ANZCTR12607000325404
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00802841
==Nilotinib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Kantarjian et al. 2006 (A2101) 	2004-2005 	Phase 1/2 (RT) 	 	
Hughes et al. 2014a (ENESTnd extension)	Not reported 	Non-randomized part of phase 3 RCT	 	
Yeung et al. 2014 (TIDEL-II) 	2007-2011 	Non-randomized 	 	
Hughes et al. 2014b (ENESTcmr) 	2009-06-12 to 2010-06-30	Phase 3 (E-switch-ic) 	Imatinib 	Higher MMR24 (secondary endpoint)Did not meet primary endpoint of rate of confirmed best cumulative undetectable BCR-ABL1 by 12 months
Cortes et al. 2016 (LASOR) 	2009-2012 	Phase 3 (E-switch-ic) 	Imatinib; 600 mg daily	Did not meet primary endpoint of CCyR6
Mahon et al. 2018 (ENESTop) 	2012 to not reported 	Phase 2 (RT) 	 	
====Prior treatment criteria====
*A2101: Failure of imatinib
====Preceding treatment====
*ENESTnd extension: First-line Imatinib; standard dose or Imatinib; high-dose or nilotinib; 300 mg twice per day, with suboptimal response/treatment failure
*ENESTcmr: First-line Imatinib for at least 2 years, with detectable BCR-ABL1
*TIDEL-II: First-line Imatinib, with failure to meet molecular targets
*LASOR: First-line imatinib; standard-dose, with suboptimal response
====Targeted therapy====
*Nilotinib (Tasigna) 400 mg PO twice per day on days 1 to 28
28-day cycles
===References===
# 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 EuroPMC NCT00109707
## 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC NCT00471497
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00760877
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC ANZCTR12607000325404
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00802841
# ENESTop: Mahon FX, Boquimpani C, Kim DW, Benyamini N, Clementino NCD, Shuvaev V, Ailawadhi S, Lipton JH, Turkina AG, De Paz R, Moiraghi B, Nicolini FE, Dengler J, Sacha T, Takahashi N, Fellague-Chebra R, Acharya S, Wong S, Jin Y, Hughes TP. Treatment-Free Remission After Second-Line Nilotinib Treatment in Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Single-Group, Phase 2, Open-Label Study. Ann Intern Med. 2018 Apr 3;168(7):461-470. Epub 2018 Feb 20. link to original article EuroPMC NCT01698905
==Olverembatinib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Jiang et al. 2022 (HQP1351CC201)	2019-04-26 to 2019-10-08	Phase 2 (RT)
====Targeted therapy====
*Olverembatinib (HQP-1351) 40 mg PO once per day on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27
28-day cycles
===References===
#HQP1351CC201: Jiang Q, Li Z, Qin Y, Li W, Xu N, Liu B, Zhang Y, Meng L, Zhu H, Du X, Chen S, Liang Y, Hu Y, Liu X, Song Y, Men L, Chen Z, Niu Q, Wang H, Lu M, Yang D, Zhai Y, Huang X. Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial. J Hematol Oncol. 2022 Aug 18;15(1):113. Erratum in: J Hematol Oncol. 2022 Oct 31;15(1):159. Erratum in: J Hematol Oncol. 2023 Feb 20;16(1):13. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03883087 
==Omacetaxine monotherapy==
Study 	Dates of enrollment	Evidence
Cortes et al. 2012 (CGX-635-CML-202)	2006-2010 	Phase 2 (RT)
Cortes et al. 2013 (CGX-635-CML-203)	2007-2009 	Phase 2 (RT)
===Induction===
====Chemotherapy====
*Omacetaxine (Synribo) 1.25 mg/m2 SC twice per day on days 1 to 14
====Supportive therapy====
*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 cycle for 6 cycles
===Maintenance===
====Chemotherapy====
*Omacetaxine (Synribo) 1.25 mg/m2 SC twice per day on days 1 to 7
28-day cycle for 26 or more cycles
===References===
# CGX-635-CML-202: Cortes J, Lipton JH, Rea D, Digumarti R, Chuah C, Nanda N, Benichou AC, Craig AR, Michallet M, Nicolini FE, Kantarjian H; 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00375219
## 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 EuroPMC
## 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 link to PMC article EuroPMC
# CGX-635-CML-203: 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 link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00462943
## 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 EuroPMC
## 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 link to PMC article EuroPMC
==Ponatinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Cortes et al. 2012 (AP24534-07-101)	2008-2010 	Phase 1, >20 pts
Cortes et al. 2013 (PACE) 	2010-2011 	Phase 2 (RT)
Cortes et al. 2021 (OPTIC) 	2015-2019 	Phase 2 (RT)
====Targeted therapy====
*Ponatinib (Iclusig) 45 mg PO once per day, taken either with or without food
Continued indefinitely
===References===
# AP24534-07-101: 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00660920
# 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; 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01207440
## 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 EuroPMC
#OPTIC: Cortes J, Apperley J, Lomaia E, Moiraghi B, Undurraga Sutton M, Pavlovsky C, Chuah C, Sacha T, Lipton JH, Schiffer CA, McCloskey J, Hochhaus A, Rousselot P, Rosti G, de Lavallade H, Turkina A, Rojas C, Arthur CK, Maness L, Talpaz M, Mauro M, Hall T, Lu V, Srivastava S, Deininger M. Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial. Blood. 2021 Nov 25;138(21):2042-2050. link to original article link to PMC article EuroPMC NCT02467270
=Accelerated phase, first-line therapy=
==Imatinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence
Talpaz et al. 2002 (STI571 0109)	1999-2000 	Phase 2 (RT)
Note: this trial also evaluated 400 mg/d but the response rates were higher for the 600 mg/d dosing.
====Targeted therapy====
*Imatinib (Gleevec) 600 mg PO once per day
Continued indefinitely
===References===
# STI571 0109: Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F, Schiffer CA, Fischer T, Deininger MW, Lennard AL, Hochhaus A, Ottmann OG, Gratwohl A, Baccarani M, Stone R, Tura S, Mahon FX, Fernandes-Reese S, Gathmann I, Capdeville R, Kantarjian HM, Sawyers CL. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood. 2002 Mar 15;99(6):1928-37. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
=Accelerated phase, previously treated=
==Dasatinib monotherapy==
===Regimen variant #1, 70 mg twice per day===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Guilhot et al. 2007 (START-A) 	2004-2005 	Phase 2 	 	
Kantarjian et al. 2009 (CA180-035)	2005-07 to 2006-03 	Phase 3 (C)	Dasatinib; 140 mg once per day	Not reported
Note: CA180-035 was not designed to report comparative efficacy across subgroups; to our knowledge, the overall assessment of the primary endpoint has never been published.
====Targeted therapy====
*Dasatinib (Sprycel) 70 mg PO twice per day on days 1 to 28
28-day cycles
===Regimen variant #2, 140 mg/day=== 
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kantarjian et al. 2009 (CA180-035)	2005-07 to 2006-03 	Phase 3 (E-RT-switch-ic)	Dasatinib; 70 mg twice per day	Not reported
Note: this study was not designed to report comparative efficacy across subgroups; to our knowledge, the overall assessment of the primary endpoint has never been published.
====Targeted therapy====
*Dasatinib (Sprycel) 140 mg PO once per day on days 1 to 28
28-day cycles
===References===
# START-A: 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00123487
## Subgroup analysis: Lilly MB, Ottmann OG, Shah NP, Larson RA, Reiffers JJ, Ehninger G, Müller MC, Charbonnier A, Bullorsky E, Dombret H, Brigid Bradley-Garelik M, Zhu C, Martinelli G. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: results from a phase 3 study. Am J Hematol. 2010 Mar;85(3):164-70. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Subgroup analysis: Saglio G, Hochhaus A, Goh YT, Masszi T, Pasquini R, Maloisel F, Erben P, Cortes J, Paquette R, Bradley-Garelik MB, Zhu C, Dombret H. Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer. 2010 Aug 15;116(16):3852-61. link to original article link to PMC article EuroPMC
==Nilotinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Giles et al. 2010 	Not reported 	Phase 2
Nicolini et al. 2011 (ENACT)	2006-01 to 2007-06 	Phase 3b
====Targeted therapy====
*Nilotinib (Tasigna) 400 mg PO twice per day on days 1 to 28
28-day cycles
===References===
# 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 original article link to PMC article EuroPMC
## 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 EuroPMC
# ENACT: 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 EuroPMC NCT01126892
==Olverembatinib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Jiang et al. 2022 (HQP1351CC202)	2019-04-26 to 2019-10-08	Phase 2 (RT)
====Targeted therapy====
*Olverembatinib (HQP-1351) 40 mg PO once per day on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27
28-day cycles
===References===
#HQP1351CC202: Jiang Q, Li Z, Qin Y, Li W, Xu N, Liu B, Zhang Y, Meng L, Zhu H, Du X, Chen S, Liang Y, Hu Y, Liu X, Song Y, Men L, Chen Z, Niu Q, Wang H, Lu M, Yang D, Zhai Y, Huang X. Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial. J Hematol Oncol. 2022 Aug 18;15(1):113. Erratum in: J Hematol Oncol. 2022 Oct 31;15(1):159. Erratum in: J Hematol Oncol. 2023 Feb 20;16(1):13. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03883100
==Omacetaxine monotherapy==
Study 	Dates of enrollment	Evidence
Cortes et al. 2012 (CGX-635-CML-202)	2006-2010 	Phase 2 (RT)
Cortes et al. 2013 (CGX-635-CML-203)	2007-2009 	Phase 2 (RT)
===Induction===
====Chemotherapy====
*Omacetaxine (Synribo) 1.25 mg/m2 SC twice per day on days 1 to 14
====Supportive therapy====
*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 cycle for 6 cycles
===Maintenance===
====Chemotherapy====
*Omacetaxine (Synribo) 1.25 mg/m2 SC twice per day on days 1 to 7
28-day cycle for 26 or more cycles
===References===
# CGX-635-CML-202: Cortes J, Lipton JH, Rea D, Digumarti R, Chuah C, Nanda N, Benichou AC, Craig AR, Michallet M, Nicolini FE, Kantarjian H; 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00375219
## 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 EuroPMC
## 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 link to PMC article EuroPMC
# CGX-635-CML-203: 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 link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00462943
## 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 EuroPMC
## 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 link to PMC article EuroPMC
==Ponatinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Cortes et al. 2012 (AP24534-07-101)	2008-2010 	Phase 1, >20 pts
Cortes et al. 2013 (PACE) 	2010-2011 	Phase 2 (RT)
====Targeted therapy====
*Ponatinib (Iclusig) 45 mg PO once per day, taken either with or without food
Continued indefinitely
===References===
# AP24534-07-101 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00660920
# 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; 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01207440
## 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 EuroPMC
=Blast crisis=
==Bosutinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence
Cortes et al. 2011 (Study 200)	2006-2008 	Phase 1/2
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.
====Targeted therapy====
*Bosutinib (Bosulif) 500 mg PO once per day, taken with food
Continued indefinitely
====Dose and schedule modifications====
*If no grade 3 or higher drug-related toxicity occurs, Bosutinib (Bosulif) can be escalated to 600 mg PO once per day if response is suboptimal
===References===
# Study 200: Cortes JE, Kantarjian HM, Brümmendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A, Besson N, Abbas R, Wang J, Leip E, Gambacorti-Passerini C. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011 Oct 27;118(17):4567-76. Epub 2011 Aug 24. Erratum in: Blood. 2013 Oct 3;122(14):2524. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00261846
## 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
## 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
## Update: Gambacorti-Passerini C, Brümmendorf TH, Kim DW, Turkina AG, Masszi T, Assouline S, Durrant S, Kantarjian HM, Khoury HJ, Zaritskey A, Shen ZX, Jin J, Vellenga E, Pasquini R, Mathews V, Cervantes F, Besson N, Turnbull K, Leip E, Kelly V, Cortes JE. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up. Am J Hematol. 2014 Jul;89(7):732-42. Epub 2014 Apr 28. link to original article link to PMC article EuroPMC
## 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 EuroPMC
==Dasatinib monotherapy==
===Regimen variant #1, 70 mg twice per day=== 
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cortes et al. 2006 (START-L-BC) 	2004-2005 	Phase 2 	 	
Cortes et al. 2006 (START-B) 	2004-2005 	Phase 2 	 	
Kantarjian et al. 2009 (CA180-035)	2005-07 to 2006-03 	Phase 3 (C)	Dasatinib; 140 mg once per day	Not reported
Note: This cohort of START-L is named START-L-BC here, to distinguish from the Ph+ ALL cohort, which was the basis of FDA approval for that condition. CA180-035 was not designed to report comparative efficacy across subgroups; to our knowledge, the overall assessment of the primary endpoint has never been published.
====Targeted therapy====
*Dasatinib (Sprycel) 70 mg PO twice per day on days 1 to 28
28-day cycles
===Regimen variant #2, 140 mg/day=== 
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kantarjian et al. 2009 (CA180-035)	2005-07 to 2006-03 	Phase 3 (E-RT-switch-ic)	Dasatinib; 70 mg twice per day	Not reported
Note: CA180-035 was not designed to report comparative efficacy across subgroups; to our knowledge, the overall assessment of the primary endpoint has never been published.
====Targeted therapy====
*Dasatinib (Sprycel) 140 mg PO once per day on days 1 to 28
28-day cycles
===References===
# START-L-BC: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00101595
# START-B: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00101816
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00123487
## Subgroup analysis: Lilly MB, Ottmann OG, Shah NP, Larson RA, Reiffers JJ, Ehninger G, Müller MC, Charbonnier A, Bullorsky E, Dombret H, Brigid Bradley-Garelik M, Zhu C, Martinelli G. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: results from a phase 3 study. Am J Hematol. 2010 Mar;85(3):164-70. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Subgroup analysis: Saglio G, Hochhaus A, Goh YT, Masszi T, Pasquini R, Maloisel F, Erben P, Cortes J, Paquette R, Bradley-Garelik MB, Zhu C, Dombret H. Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer. 2010 Aug 15;116(16):3852-61. link to original article link to PMC article EuroPMC
==Imatinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence
Druker et al. 2001b	1999-2000 	Phase 1
Sawyers et al. 2002	1999-2000 	Phase 2 (RT)
Note: these studies used doses ranging from 300 to 1000 mg PO once per day. This is the FDA-recommended dose.
====Targeted therapy====
*Imatinib (Gleevec) 600 mg PO once per day
Continued indefinitely
===References===
# Phase I: Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Fernandes Reese S, 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 EuroPMC
# 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 EuroPMC
=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 EuroPMC
Category:Chronic myeloid leukemia regimens
Category:Disease-specific pages
Category:Myeloproliferative neoplasms