Staging page

Section editor
	Sanjay R. Mohan, MD, MSCI Vanderbilt University Nashville, TN

Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. If you still can't find it, please let us know so we can add it!
Note: certain regimens have been moved to dedicated pages:

• Pediatric CML

0 regimens on this page 0 variants on this page

Guidelines

BSH

• 2020: Smith et al. A British Society for Haematology Guideline on the diagnosis and management of chronic myeloid leukaemia

ELN

• 2013: Baccarani et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia link to PMC article PubMed

ESMO

• 2017: Hochhaus et al. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

"How I Treat"

• 2022: Berman How I treat chronic-phase chronic myelogenous leukemia

NCCN

• NCCN Guidelines - Chronic Myeloid Leukemia

Chronic phase, first-line therapy

Bosutinib monotherapy

Regimen variant #1, 400 mg/day

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cortes et al. 2017 (BFORE)	2014-2015	Phase 3 (E-RT-switch-ic)	Imatinib	Seems to have superior MMR rate at 12 months
Awaiting publication (CABL001J12301)	2021-2024	Phase 3 (C)	Asciminib	TBD

Targeted therapy

• Bosutinib (Bosulif) 400 mg PO once per day

Continued indefinitely

Regimen variant #2, 500 mg/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cortes et al. 2012 (BELA)	2008-2009	Phase 3 (E-switch-ic)	Imatinib	Superior MMR rate at 12 months

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

Targeted therapy

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

Continued indefinitely

Dose 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

1. BELA: Cortes JE, Kim DW, Kantarjian HM, Brümmendorf TH, Dyagil I, Griskevicius L, Malhotra H, Powell C, Gogat K, Countouriotis AM, Gambacorti-Passerini C. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012 Oct 1;30(28):3486-92. Epub 2012 Sep 4. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00574873
   1. Update: Gambacorti-Passerini C, Cortes JE, Lipton JH, Dmoszynska A, Wong RS, Rossiev V, Pavlov D, Gogat Marchant K, Duvillié L, Khattry N, Kantarjian HM, Brümmendorf TH. Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia. Am J Hematol. 2014 Oct;89(10):947-53. Epub 2014 Jul 21. link to original article link to PMC article PubMed
   2. Update: Brümmendorf TH, Cortes JE, de Souza CA, Guilhot F, Duvillié L, Pavlov D, Gogat K, Countouriotis AM, Gambacorti-Passerini C. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br J Haematol. 2015 Jan;168(1):69-81. Epub 2014 Sep 8. link to original article link to PMC article PubMed
2. BFORE: Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim DW, Dyagil I, Glushko N, Milojkovic D, le Coutre P, Garcia-Gutierrez V, Reilly L, Jeynes-Ellis A, Leip E, Bardy-Bouxin N, Hochhaus A, Brümmendorf TH. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE Trial. J Clin Oncol. 2018 Jan 20;36(3):231-237. Epub 2017 Nov 1. link to original article contains dosing details in abstract link to PMC article PubMed NCT02130557
   1. 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 PubMed
3. CABL001J12301: contains dosing details on CT.gov NCT04971226

Cytarabine & Interferon alfa-2b

Regimen variant #1, uncapped

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Guilhot et al. 1997	1991-1996	Phase 3 (E-esc)	Interferon alfa-2b	Seems to have superior OS
Baccarani et al. 2002	1994-1997	Phase 3 (E-esc)	Interferon alfa-2b	Superior MCgR at 24 mo
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 superior OS

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
O'Brien et al. 2003 (IRIS)	2000-2001	Phase 3 (C)	Imatinib	Inferior FFP

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

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

1. Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau JL, Maloisel F, Bouabdallah R, Guyotat D, Cheron N, Nicolini F, Abgrall JF, Tanzer J; 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 contains dosing details in manuscript PubMed
2. 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 PubMed
3. IRIS: O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ; IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003 Mar 13;348(11):994-1004. link to original article contains dosing details in manuscript PubMed NCT00006343
   1. Update: Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA; IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006 Dec 7;355(23):2408-17. link to original article PubMed
   2. 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 PubMed
   3. Subgroup analysis: Guilhot F, Druker B, Larson RA, Gathmann I, So C, Waltzman R, O'Brien SG. High rates of durable response are achieved with imatinib after treatment with interferon alpha plus cytarabine: results from the International Randomized Study of Interferon and STI571 (IRIS) trial. Haematologica. 2009 Dec;94(12):1669-75. Epub 2009 Jul 31. link to original article link to PMC article PubMed
   4. Update: Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, Baccarani M, Deininger MW, Cervantes F, Fujihara S, Ortmann CE, Menssen HD, Kantarjian H, O'Brien SG, Druker BJ; IRIS Investigators. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017 Mar 9;376(10):917-927. link to original article PubMed
4. 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 PubMed
5. 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 PubMed

Dasatinib monotherapy

Regimen

FDA-recommended dose

Study	Years 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)	2007-2008	Phase 3 (E-RT-switch-ic)	Imatinib	Superior MMR rate
Awaiting publication (CABL001J12301)	2021-2024	Phase 3 (C)	Asciminib	TBD

Targeted therapy

• Dasatinib (Sprycel) 100 mg PO once per day

Continued indefinitely

References

1. 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 PubMed NCT00254423
2. DASISION: Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, Moiraghi B, Shen Z, Mayer J, Pasquini R, Nakamae H, Huguet F, Boqué C, Chuah C, Bleickardt E, Bradley-Garelik MB, Zhu C, Szatrowski T, Shapiro D, Baccarani M. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2260-70. Epub 2010 Jun 5. link to original article contains dosing details in abstract PubMed NCT00481247
   1. Update: Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Undurraga MS, Wang J, Kassack Ipiña JJ, Kim DW, Ogura M, Pavlovsky C, Junghanss C, Milone JH, Nicolini FE, Robak T, Van Droogenbroeck J, Vellenga E, Bradley-Garelik MB, Zhu C, Hochhaus A. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012 Feb 2;119(5):1123-9. Epub 2011 Dec 9. link to original article link to PMC article PubMed
   2. Update: Jabbour E, Kantarjian HM, Saglio G, Steegmann JL, Shah NP, Boqué C, Chuah C, Pavlovsky C, Mayer J, Cortes J, Baccarani M, Kim DW, Bradley-Garelik MB, Mohamed H, Wildgust M, Hochhaus A. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2014 Jan 23;123(4):494-500. Epub 2013 Dec 5. link to original article link to PMC article PubMed
   3. Subgroup analysis: Fujisawa S, Nakamae H, Ogura M, Ishizawa K, Taniwaki M, Utsunomiya A, Matsue K, Takamatsu Y, Usuki K, Tanimoto M, Ishida Y, Akiyama H, Onishi S. Efficacy and safety of dasatinib versus imatinib in Japanese patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP): Subset analysis of the DASISION trial with 2-year follow-up. Int J Hematol. 2014 Feb;99(2):141-53. Epub 2013 Dec 20. link to original article PubMed
   4. Update: Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C, Shah NP, Chuah C, Casanova L, Bradley-Garelik B, Manos G, Hochhaus A. Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncol. 2016 Jul 10;34(20):2333-40. Epub 2016 May 23. link to original article link to PMC article PubMed
3. SWOG S0325 Phase 2: Radich JP, Kopecky KJ, Appelbaum FR, Kamel-Reid S, Stock W, Malnassy G, Paietta E, Wadleigh M, Larson RA, Emanuel P, Tallman M, Lipton J, Turner AR, Deininger M, Druker BJ. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood. 2012 Nov 8;120(19):3898-905. Epub 2012 Aug 22. link to original article link to PMC article PubMed NCT00070499
4. CABL001J12301: contains dosing details on CT.gov NCT04971226

Imatinib monotherapy

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
O'Brien et al. 2003 (IRIS)	2000-2001	Phase 3 (E-RT-switch-ooc)	Cytarabine & Interferon alfa	Superior FFP
Kantarjian et al. 2006	2000-2004	Retrospective
Hehlmann et al. 2011 (CML-Study IV)	2002-2012	Phase 3 (C)	1. Imatinib; high-dose	Inferior MMR rate at 12 months
			2. Imatinib & Interferon alfa	Not reported
Preudhomme et al. 2010 (SPIRIT)	2003-2007	Phase 3 (C)	1. Imatinib; 600 mg daily	Not reported
			2. Imatinib & Peginterferon alfa-2a	Inferior MMR rate at 12 months
			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 CCgR at 12 mo
Deininger et al. 2013 (SWOG S0325 Phase 1)	2005-2007	Randomized Phase 2 (C)	High-dose imatinib	Seems to have inferior MMR rate at 12 months
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)	2007-2008	Phase 3 (C)	Dasatinib	Inferior MMR rate
Saglio et al. 2010 (ENESTnd)	2007-2008	Phase 3 (C)	1. Nilotinib; 300 mg twice per day	Seems to have inferior TTP
			2. Nilotinib; 400 mg twice per day	Inferior TTP
Yeung et al. 2014 (TIDEL-II)	2007-2011	Non-randomized
Cortes et al. 2012 (BELA)	2008-2009	Phase 3 (C)	Bosutinib	Inferior MMR rate at 12 months
Hughes et al. 2014 (ENESTcmr)	2009-2010	Non-randomized portion of phase 3 RCT
Wang et al. 2015 (ENESTchina)	2011	Phase 3 (C)	Nilotinib	Inferior MMR rate at 12 months
Lipton et al. 2016 (EPICCML)	2012-2013	Phase 3 (C)	Ponatinib	Might have inferior MMR rate at 12 months
Cortes et al. 2017 (BFORE)	2014-2015	Phase 3 (C)	Bosutinib	Seems to have inferior MMR rate at 12 months
Kwak et al. 2017 (RERISE)	2011-2014	Phase 3 (C)	1. Radotinib 300 mg twice per day	Inferior MMR rate at 12 months
			2. Radotinib 400 mg twice per day	Seems to have inferior MMR rate at 12 months
Zhang et al. 2020 (FESTnd)	2014-2016	Phase 3 (C)	Flumatinib	Seems to have inferior MMR rate at 12 months
Awaiting publication (CABL001J12301)	2021-2024	Phase 3 (C)	Asciminib	TBD

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: continued imatinib versus nilotinib
• TIDEL-II: Patients failing to meet molecular targets were either dose-increased to imatinib 800 mg per day and then switched to nilotinib 3 months later if they were still failing to meet targets, or switched to nilotinib directly. This was not a randomization.

References

1. IRIS: O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ; IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003 Mar 13;348(11):994-1004. link to original article contains dosing details in manuscript PubMed NCT00006343
   1. Update: Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA; IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006 Dec 7;355(23):2408-17. link to original article PubMed
   2. 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 PubMed
   3. Subgroup analysis: Guilhot F, Druker B, Larson RA, Gathmann I, So C, Waltzman R, O'Brien SG. High rates of durable response are achieved with imatinib after treatment with interferon alpha plus cytarabine: results from the International Randomized Study of Interferon and STI571 (IRIS) trial. Haematologica. 2009 Dec;94(12):1669-75. Epub 2009 Jul 31. link to original article link to PMC article PubMed
   4. Update: Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, Baccarani M, Deininger MW, Cervantes F, Fujihara S, Ortmann CE, Menssen HD, Kantarjian H, O'Brien SG, Druker BJ; IRIS Investigators. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017 Mar 9;376(10):917-927. link to original article PubMed
2. Retrospective: Kantarjian HM, Talpaz M, O'Brien S, Jones D, Giles F, Garcia-Manero G, Faderl S, Ravandi F, Rios MB, Shan J, Cortes J. Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. Blood. 2006 Sep 15;108(6):1835-40. Epub 2006 May 18. link to original article PubMed content property of HemOnc.org
3. GIMEMA CML/022: Baccarani M, Rosti G, Castagnetti F, Haznedaroglu I, Porkka K, Abruzzese E, Alimena G, Ehrencrona H, Hjorth-Hansen H, Kairisto V, Levato L, Martinelli G, Nagler A, Lanng Nielsen J, Ozbek U, Palandri F, Palmieri F, Pane F, Rege-Cambrin G, Russo D, Specchia G, Testoni N, Weiss-Bjerrum O, Saglio G, Simonsson B. Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study. Blood. 2009 May 7;113(19):4497-504. Epub 2009 Mar 4. link to original article contains dosing details in manuscript PubMed NCT00514488
   1. Update: Castagnetti F, Gugliotta G, Breccia M, Stagno F, Iurlo A, Albano F, Abruzzese E, Martino B, Levato L, Intermesoli T, Pregno P, Rossi G, Gherlinzoni F, Leoni P, Cavazzini F, Venturi C, Soverini S, Testoni N, Alimena G, Cavo M, Martinelli G, Pane F, Saglio G, Rosti G, Baccarani M; GIMEMA CML Working Party. Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib. Leukemia. 2015 Sep;29(9):1823-31. Epub 2015 Jun 19. link to original article PubMed
4. DASISION: Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, Moiraghi B, Shen Z, Mayer J, Pasquini R, Nakamae H, Huguet F, Boqué C, Chuah C, Bleickardt E, Bradley-Garelik MB, Zhu C, Szatrowski T, Shapiro D, Baccarani M. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2260-70. Epub 2010 Jun 5. link to original article contains dosing details in abstract PubMed NCT00481247
   1. Update: Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Undurraga MS, Wang J, Kassack Ipiña JJ, Kim DW, Ogura M, Pavlovsky C, Junghanss C, Milone JH, Nicolini FE, Robak T, Van Droogenbroeck J, Vellenga E, Bradley-Garelik MB, Zhu C, Hochhaus A. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012 Feb 2;119(5):1123-9. Epub 2011 Dec 9. link to original article link to PMC article PubMed
   2. Update: Jabbour E, Kantarjian HM, Saglio G, Steegmann JL, Shah NP, Boqué C, Chuah C, Pavlovsky C, Mayer J, Cortes J, Baccarani M, Kim DW, Bradley-Garelik MB, Mohamed H, Wildgust M, Hochhaus A. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2014 Jan 23;123(4):494-500. Epub 2013 Dec 5. link to original article link to PMC article PubMed
   3. Subgroup analysis: Fujisawa S, Nakamae H, Ogura M, Ishizawa K, Taniwaki M, Utsunomiya A, Matsue K, Takamatsu Y, Usuki K, Tanimoto M, Ishida Y, Akiyama H, Onishi S. Efficacy and safety of dasatinib versus imatinib in Japanese patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP): Subset analysis of the DASISION trial with 2-year follow-up. Int J Hematol. 2014 Feb;99(2):141-53. Epub 2013 Dec 20. link to original article PubMed
   4. Update: Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C, Shah NP, Chuah C, Casanova L, Bradley-Garelik B, Manos G, Hochhaus A. Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncol. 2016 Jul 10;34(20):2333-40. Epub 2016 May 23. link to original article link to PMC article PubMed
5. ENESTnd: Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM; ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2251-9. Epub 2010 Jun 5. link to original article contains dosing details in abstract PubMed NCT00471497
   1. Update: Kantarjian HM, Hochhaus A, Saglio G, De Souza C, Flinn IW, Stenke L, Goh YT, Rosti G, Nakamae H, Gallagher NJ, Hoenekopp A, Blakesley RE, Larson RA, Hughes TP. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011 Sep;12(9):841-51. Epub 2011 Aug 17. Erratum in: Lancet Oncol. 2011 Oct;12(11):989. link to original article contains dosing details in manuscript PubMed
   2. Update: Larson RA, Hochhaus A, Hughes TP, Clark RE, Etienne G, Kim DW, Flinn IW, Kurokawa M, Moiraghi B, Yu R, Blakesley RE, Gallagher NJ, Saglio G, Kantarjian HM. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012 Oct;26(10):2197-203. Epub 2012 May 18. link to original article PubMed
   3. Update: Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, le Coutre PD, Etienne G, Dorlhiac-Llacer PE, Clark RE, Flinn IW, Nakamae H, Donohue B, Deng W, Dalal D, Menssen HD, Kantarjian HM. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016 May;30(5):1044-54. Epub 2016 Feb 3. link to original article link to PMC article PubMed
   4. 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 PubMed
6. 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 contains dosing details in abstract PubMed NCT00124748
7. 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 contains dosing details in manuscript PubMed NCT00219739
   1. Post-hoc analysis: Johnson-Ansah H, Guilhot J, Rousselot P, Rea D, Legros L, Rigal-Huguet F, Nicolini FE, Mahon FX, Preudhomme C, Guilhot F. Tolerability and efficacy of pegylated interferon-a-2a in combination with imatinib for patients with chronic-phase chronic myeloid leukemia. Cancer. 2013 Dec 15;119(24):4284-9. Epub 2013 Sep 16. link to original article PubMed
   2. 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 PubMed
8. 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 dosing details in manuscript PubMed NCT00055874
   1. Update: Hehlmann R, Müller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A, Proetel U, Pletsch N, Pfirrmann M, Haferlach C, Schnittger S, Einsele H, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Ehninger G, Heim D, Heimpel H, Nerl C, Krause SW, Hossfeld DK, Kolb HJ, Hasford J, Saußele S, Hochhaus A. Deep Molecular Response Is Reached by the Majority of Patients Treated With Imatinib, Predicts Survival, and Is Achieved More Quickly by Optimized High-Dose Imatinib: Results From the Randomized CML-Study IV. J Clin Oncol. 2014 Feb 10;32(5):415-23. Epub 2013 Dec 2. link to original article contains dosing details in manuscript PubMed
   2. Update: Kalmanti L, Saussele S, Lauseker M, Müller MC, Dietz CT, Heinrich L, Hanfstein B, Proetel U, Fabarius A, Krause SW, Rinaldetti S, Dengler J, Falge C, Oppliger-Leibundgut E, Burchert A, Neubauer A, Kanz L, Stegelmann F, Pfreundschuh M, Spiekermann K, Scheid C, Pfirrmann M, Hochhaus A, Hasford J, Hehlmann R. Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV. Leukemia. 2015 May;29(5):1123-32. Epub 2015 Feb 13. link to original article PubMed
   3. Update: Hehlmann R, Lauseker M, Saußele S, Pfirrmann M, Krause S, Kolb HJ, Neubauer A, Hossfeld DK, Nerl C, Gratwohl A, Baerlocher GM, Heim D, Brümmendorf TH, Fabarius A, Haferlach C, Schlegelberger B, Müller MC, Jeromin S, Proetel U, Kohlbrenner K, Voskanyan A, Rinaldetti S, Seifarth W, Spieß B, Balleisen L, Goebeler MC, Hänel M, Ho A, Dengler J, Falge C, Kanz L, Kremers S, Burchert A, Kneba M, Stegelmann F, Köhne CA, Lindemann HW, Waller CF, Pfreundschuh M, Spiekermann K, Berdel WE, Müller L, Edinger M, Mayer J, Beelen DW, Bentz M, Link H, Hertenstein B, Fuchs R, Wernli M, Schlegel F, Schlag R, de Wit M, Trümper L, Hebart H, Hahn M, Thomalla J, Scheid C, Schafhausen P, Verbeek W, Eckart MJ, Gassmann W, Pezzutto A, Schenk M, Brossart P, Geer T, Bildat S, Schäfer E, Hochhaus A, Hasford J. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017 Nov;31(11):2398-2406. Epub 2017 Aug 14. link to original article link to PMC article PubMed
9. BELA: Cortes JE, Kim DW, Kantarjian HM, Brümmendorf TH, Dyagil I, Griskevicius L, Malhotra H, Powell C, Gogat K, Countouriotis AM, Gambacorti-Passerini C. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012 Oct 1;30(28):3486-92. Epub 2012 Sep 4. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00574873
   1. Update: Gambacorti-Passerini C, Cortes JE, Lipton JH, Dmoszynska A, Wong RS, Rossiev V, Pavlov D, Gogat Marchant K, Duvillié L, Khattry N, Kantarjian HM, Brümmendorf TH. Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia. Am J Hematol. 2014 Oct;89(10):947-53. Epub 2014 Jul 21. link to original article link to PMC article PubMed
   2. Update: Brümmendorf TH, Cortes JE, de Souza CA, Guilhot F, Duvillié L, Pavlov D, Gogat K, Countouriotis AM, Gambacorti-Passerini C. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br J Haematol. 2015 Jan;168(1):69-81. Epub 2014 Sep 8. link to original article link to PMC article PubMed
10. SWOG S0325 Phase 2: Radich JP, Kopecky KJ, Appelbaum FR, Kamel-Reid S, Stock W, Malnassy G, Paietta E, Wadleigh M, Larson RA, Emanuel P, Tallman M, Lipton J, Turner AR, Deininger M, Druker BJ. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood. 2012 Nov 8;120(19):3898-905. Epub 2012 Aug 22. link to original article link to PMC article PubMed NCT00070499
11. SWOG S0325 Phase 1: Deininger MW, Kopecky KJ, Radich JP, Kamel-Reid S, Stock W, Paietta E, Emanuel PD, Tallman M, Wadleigh M, Larson RA, Lipton JH, Slovak ML, Appelbaum FR, Druker BJ. Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized phase II trial in newly diagnosed chronic phase chronic myeloid leukaemia. Br J Haematol. 2014 Jan;164(2):223-32. Epub 2013 Nov 4. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00070499
12. ENESTcmr: Hughes TP, Lipton JH, Spector N, Cervantes F, Pasquini R, Clementino NC, Dorlhiac Llacer PE, Schwarer AP, Mahon FX, Rea D, Branford S, Purkayastha D, Collins L, Szczudlo T, Leber B. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood. 2014 Jul 31;124(5):729-36. Epub 2014 Jun 19. link to original article contains dosing details in manuscript PubMed NCT00760877
    1. Update: Hughes TP, Leber B, Cervantes F, Spector N, Pasquini R, Clementino NCD, Schwarer AP, Dorlhiac-Llacer PE, Mahon FX, Rea D, Guerci-Bresler A, Kamel-Reid S, Bendit I, Acharya S, Glynos T, Dalal D, Branford S, Lipton JH. Sustained deep molecular responses in patients switched to nilotinib due to persistent BCR-ABL1 on imatinib: final ENESTcmr randomized trial results. Leukemia. 2017 Nov;31(11):2529-2531. Epub 2017 Aug 3. link to original article link to PMC article PubMed
13. TIDEL-II: Yeung DT, Osborn MP, White DL, Branford S, Braley J, Herschtal A, Kornhauser M, Issa S, Hiwase DK, Hertzberg M, Schwarer AP, Filshie R, Arthur CK, Kwan YL, Trotman J, Forsyth CJ, Taper J, Ross DM, Beresford J, Tam C, Mills AK, Grigg AP, Hughes TP; Australasian Leukaemia and Lymphoma Group. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood. 2015 Feb 5;125(6):915-23. Epub 2014 Dec 17. link to original article contains dosing details in manuscript link to PMC article PubMed ANZCTR12607000325404
14. ENESTchina: Wang J, Shen ZX, Saglio G, Jin J, Huang H, Hu Y, Du X, Li J, Meng F, Zhu H, Hu J, Wang J, Hou M, Hertle S, Menssen HD, Ortmann CE, Tribouley C, Yuan Y, Baccarani M, Huang X. Phase 3 study of nilotinib vs imatinib in Chinese patients with newly diagnosed chronic myeloid leukemia in chronic phase: ENESTchina. Blood. 2015 Apr 30;125(18):2771-8. Epub 2015 Mar 12. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01275196
15. EPIC: Lipton JH, Chuah C, Guerci-Bresler A, Rosti G, Simpson D, Assouline S, Etienne G, Nicolini FE, le Coutre P, Clark RE, Stenke L, Andorsky D, Oehler V, Lustgarten S, Rivera VM, Clackson T, Haluska FG, Baccarani M, Cortes JE, Guilhot F, Hochhaus A, Hughes T, Kantarjian HM, Shah NP, Talpaz M, Deininger MW; EPIC investigators. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2016 May;17(5):612-21. Epub 2016 Apr 12. link to original article contains dosing details in abstract PubMed NCT01650805
16. BFORE: Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim DW, Dyagil I, Glushko N, Milojkovic D, le Coutre P, Garcia-Gutierrez V, Reilly L, Jeynes-Ellis A, Leip E, Bardy-Bouxin N, Hochhaus A, Brümmendorf TH. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE Trial. J Clin Oncol. 2018 Jan 20;36(3):231-237. Epub 2017 Nov 1. link to original article contains dosing details in abstract link to PMC article PubMed NCT02130557
    1. 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 PubMed
17. RERISE: Kwak JY, Kim SH, Oh SJ, Zang DY, Kim H, Kim JA, Do YR, Kim HJ, Park JS, Choi CW, Lee WS, Mun YC, Kong JH, Chung JS, Shin HJ, Kim DY, Park J, Jung CW, Bunworasate U, Comia NS, Jootar S, Reksodiputro AH, Caguioa PB, Lee SE, Kim DW. Phase III clinical trial (RERISE study) results of efficacy and safety of radotinib compared with imatinib in newly diagnosed chronic phase chronic myeloid leukemia. Clin Cancer Res. 2017 Dec 1;23(23):7180-7188. Epub 2017 Sep 22. link to original article contains dosing details in abstract PubMed NCT01511289
    1. 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 PubMed
18. 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 contains dosing details in abstract PubMed NCT02204644
19. CABL001J12301: contains dosing details on CT.gov NCT04971226

Imatinib monotherapy, high dose

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hehlmann et al. 2011 (CML-Study IV)	2002-2012	Phase 3 (E-esc)	1. Imatinib; standard-dose	Superior MMR rate at 12 months
			2. Imatinib & Interferon alfa	Superior MMR rate at 12 months
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 CCgR at 12 mo
Cortes et al. 2009 (TOPS)	2005-2006	Phase 3 (E-esc)	Imatinib; standard-dose	Did not meet primary endpoint of MMR at 12 mo
Deininger et al. 2013 (SWOG S0325 Phase 1)	2005-2007	Randomized Phase 2 (E-esc)	Imatinib; standard-dose	Seems to have superior MMR rate at 12 months
Thielen et al. 2013 (HOVON 78)	2006-NR	Phase 3 (C)	Cytarabine & HD-Imatinib	Did not meet primary endpoint of MMR at 12 mo

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)

Continued indefinitely

References

1. GIMEMA CML/021: Castagnetti F, Palandri F, Amabile M, Testoni N, Luatti S, Soverini S, Iacobucci I, Breccia M, Rege Cambrin G, Stagno F, Specchia G, Galieni P, Iuliano F, Pane F, Saglio G, Alimena G, Martinelli G, Baccarani M, Rosti G; GIMEMA CML Working Party. Results of high-dose imatinib mesylate in intermediate Sokal risk chronic myeloid leukemia patients in early chronic phase: a phase 2 trial of the GIMEMA CML Working Party. Blood. 2009 Apr 9;113(15):3428-34. Epub 2009 Feb 11. link to original article contains dosing details in manuscript PubMed NCT00510926
   1. Update: Castagnetti F, Gugliotta G, Breccia M, Stagno F, Iurlo A, Albano F, Abruzzese E, Martino B, Levato L, Intermesoli T, Pregno P, Rossi G, Gherlinzoni F, Leoni P, Cavazzini F, Venturi C, Soverini S, Testoni N, Alimena G, Cavo M, Martinelli G, Pane F, Saglio G, Rosti G, Baccarani M; GIMEMA CML Working Party. Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib. Leukemia. 2015 Sep;29(9):1823-31. Epub 2015 Jun 19. link to original article PubMed
2. GIMEMA CML/022: Baccarani M, Rosti G, Castagnetti F, Haznedaroglu I, Porkka K, Abruzzese E, Alimena G, Ehrencrona H, Hjorth-Hansen H, Kairisto V, Levato L, Martinelli G, Nagler A, Lanng Nielsen J, Ozbek U, Palandri F, Palmieri F, Pane F, Rege-Cambrin G, Russo D, Specchia G, Testoni N, Weiss-Bjerrum O, Saglio G, Simonsson B. Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study. Blood. 2009 May 7;113(19):4497-504. Epub 2009 Mar 4. link to original article contains dosing details in manuscript PubMed NCT00514488
   1. Update: Castagnetti F, Gugliotta G, Breccia M, Stagno F, Iurlo A, Albano F, Abruzzese E, Martino B, Levato L, Intermesoli T, Pregno P, Rossi G, Gherlinzoni F, Leoni P, Cavazzini F, Venturi C, Soverini S, Testoni N, Alimena G, Cavo M, Martinelli G, Pane F, Saglio G, Rosti G, Baccarani M; GIMEMA CML Working Party. Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib. Leukemia. 2015 Sep;29(9):1823-31. Epub 2015 Jun 19. link to original article PubMed
3. 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 contains dosing details in abstract PubMed NCT00124748
4. CML-Study IV: Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Müller MC, Pletsch N, Proetel U, Haferlach C, Schlegelberger B, Balleisen L, Hänel M, Pfirrmann M, Krause SW, Nerl C, Pralle H, Gratwohl A, Hossfeld DK, Hasford J, Hochhaus A, Saussele S. Tolerability-adapted imatinib 800 mg/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 dosing details in manuscript PubMed NCT00055874
   1. Update: Hehlmann R, Müller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A, Proetel U, Pletsch N, Pfirrmann M, Haferlach C, Schnittger S, Einsele H, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Ehninger G, Heim D, Heimpel H, Nerl C, Krause SW, Hossfeld DK, Kolb HJ, Hasford J, Saußele S, Hochhaus A. Deep Molecular Response Is Reached by the Majority of Patients Treated With Imatinib, Predicts Survival, and Is Achieved More Quickly by Optimized High-Dose Imatinib: Results From the Randomized CML-Study IV. J Clin Oncol. 2014 Feb 10;32(5):415-23. Epub 2013 Dec 2. link to original article contains dosing details in manuscript PubMed
   2. Update: Kalmanti L, Saussele S, Lauseker M, Müller MC, Dietz CT, Heinrich L, Hanfstein B, Proetel U, Fabarius A, Krause SW, Rinaldetti S, Dengler J, Falge C, Oppliger-Leibundgut E, Burchert A, Neubauer A, Kanz L, Stegelmann F, Pfreundschuh M, Spiekermann K, Scheid C, Pfirrmann M, Hochhaus A, Hasford J, Hehlmann R. Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV. Leukemia. 2015 May;29(5):1123-32. Epub 2015 Feb 13. link to original article PubMed
   3. Update: Hehlmann R, Lauseker M, Saußele S, Pfirrmann M, Krause S, Kolb HJ, Neubauer A, Hossfeld DK, Nerl C, Gratwohl A, Baerlocher GM, Heim D, Brümmendorf TH, Fabarius A, Haferlach C, Schlegelberger B, Müller MC, Jeromin S, Proetel U, Kohlbrenner K, Voskanyan A, Rinaldetti S, Seifarth W, Spieß B, Balleisen L, Goebeler MC, Hänel M, Ho A, Dengler J, Falge C, Kanz L, Kremers S, Burchert A, Kneba M, Stegelmann F, Köhne CA, Lindemann HW, Waller CF, Pfreundschuh M, Spiekermann K, Berdel WE, Müller L, Edinger M, Mayer J, Beelen DW, Bentz M, Link H, Hertenstein B, Fuchs R, Wernli M, Schlegel F, Schlag R, de Wit M, Trümper L, Hebart H, Hahn M, Thomalla J, Scheid C, Schafhausen P, Verbeek W, Eckart MJ, Gassmann W, Pezzutto A, Schenk M, Brossart P, Geer T, Bildat S, Schäfer E, Hochhaus A, Hasford J. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017 Nov;31(11):2398-2406. Epub 2017 Aug 14. link to original article link to PMC article PubMed
5. 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 PubMed NTR674
6. SWOG S0325: Deininger MW, Kopecky KJ, Radich JP, Kamel-Reid S, Stock W, Paietta E, Emanuel PD, Tallman M, Wadleigh M, Larson RA, Lipton JH, Slovak ML, Appelbaum FR, Druker BJ. Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized phase II trial in newly diagnosed chronic phase chronic myeloid leukaemia. Br J Haematol. 2014 Jan;164(2):223-32. Epub 2013 Nov 4. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00070499

Imatinib monotherapy, intermittent therapy

Regimen

Study	Years of enrollment	Evidence
Russo et al. 2013 (INTERIM0407)	2008-NR	Phase 2

Eligible patients had been taking imatinib for at least two years and were in 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

• Patients who lost major molecular response could go back to once per day therapy after the first year

References

1. 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 contains dosing details in manuscript PubMed NCT00858806

Imatinib monotherapy, planned discontinuation

Regimen variant #1

Study	Years of enrollment	Evidence
Mahon et al. 2010 (STIM1)	2007-2009	Phase 2
Mahon et al. 2013 (STIM2)	2011-2013	Phase 2

Targeted therapy

• Imatinib (Gleevec) (dose not specified) 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	Years of enrollment	Evidence
Ross et al. 2013 (TWISTER)	2006-2011	Phase 2

Targeted therapy

• Imatinib (Gleevec) (dose not specified) 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

1. 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 PubMed NCT00478985
   1. Update: Etienne G, Guilhot J, Rea D, Rigal-Huguet F, Nicolini F, Charbonnier A, Guerci-Bresler A, Legros L, Varet B, Gardembas M, Dubruille V, Tulliez M, Noel MP, Ianotto JC, Villemagne B, Carré M, Guilhot F, Rousselot P, Mahon FX. Long-Term Follow-Up of the French Stop Imatinib (STIM1) Study in Patients With Chronic Myeloid Leukemia. J Clin Oncol. 2017 Jan 20;35(3):298-305. link to original article PubMed
2. 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 PubMed ACTRN12606000118505
3. Abstract: Francois-Xavier Mahon, MD, PhD, Franck E. Nicolini, Marie-Pierre Noël, Martine Escoffre, Aude Charbonnier, Delphine Rea, Viviane Dubruille, Bruno R. Varet, Laurence Legros, Agnès Guerci, Gabriel Etienne, Francois Guilhot, Stéphanie Dulucq, Philippe Rousselot, Joelle Guilhot. Preliminary Report Of The STIM2 Study: A Multicenter Stop Imatinib Trial For Chronic Phase Chronic Myeloid Leukemia De Novo Patients On Imatinib. Blood Nov 2013,122(21)654 link to original abstract NCT01343173

Imatinib & LoDAC

Imatinib & LoDAC: Imatinib & Low Dose Ara-C

Regimen

Study	Years 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
			2. Imatinib; 600 mg once per day	Not reported
			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

1. SPIRIT: Preudhomme C, Guilhot J, Nicolini FE, Guerci-Bresler A, Rigal-Huguet F, Maloisel F, Coiteux V, Gardembas M, Berthou C, Vekhoff A, Rea D, Jourdan E, Allard C, Delmer A, Rousselot P, Legros L, Berger M, Corm S, Etienne G, Roche-Lestienne C, Eclache V, Mahon FX, Guilhot F; SPIRIT Investigators; 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 contains dosing details in manuscript PubMed NCT00219739
   1. Post-hoc analysis: Johnson-Ansah H, Guilhot J, Rousselot P, Rea D, Legros L, Rigal-Huguet F, Nicolini FE, Mahon FX, Preudhomme C, Guilhot F. Tolerability and efficacy of pegylated interferon-a-2a in combination with imatinib for patients with chronic-phase chronic myeloid leukemia. Cancer. 2013 Dec 15;119(24):4284-9. Epub 2013 Sep 16. link to original article PubMed
   2. 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 PubMed

Imatinib & Interferon alfa

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hehlmann et al. 2011 (CML-Study IV)	2002-2012	Phase 3 (E-esc)	1. Imatinib	Not reported
			2. Imatinib; high dose	Inferior MMR rate at 12 months

Note: the manuscript does not specify a type of interferon alfa.

Targeted therapy

• Imatinib (Gleevec) 400 mg PO once per day

Immunotherapy

• Interferon alfa 1,500,000 units SC three times per week, increased up to 3,000,000 units SC three times per week as tolerated, starting after 6 weeks of imatinib monotherapy

Continued indefinitely

References

1. 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 PubMed NCT00055874
   1. Update: Hehlmann R, Müller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A, Proetel U, Pletsch N, Pfirrmann M, Haferlach C, Schnittger S, Einsele H, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Ehninger G, Heim D, Heimpel H, Nerl C, Krause SW, Hossfeld DK, Kolb HJ, Hasford J, Saußele S, Hochhaus A. Deep Molecular Response Is Reached by the Majority of Patients Treated With Imatinib, Predicts Survival, and Is Achieved More Quickly by Optimized High-Dose Imatinib: Results From the Randomized CML-Study IV. J Clin Oncol. 2014 Feb 10;32(5):415-23. Epub 2013 Dec 2. link to original article contains dosing details in manuscript PubMed
   2. Update: Kalmanti L, Saussele S, Lauseker M, Müller MC, Dietz CT, Heinrich L, Hanfstein B, Proetel U, Fabarius A, Krause SW, Rinaldetti S, Dengler J, Falge C, Oppliger-Leibundgut E, Burchert A, Neubauer A, Kanz L, Stegelmann F, Pfreundschuh M, Spiekermann K, Scheid C, Pfirrmann M, Hochhaus A, Hasford J, Hehlmann R. Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV. Leukemia. 2015 May;29(5):1123-32. Epub 2015 Feb 13. link to original article PubMed
   3. Update: Hehlmann R, Lauseker M, Saußele S, Pfirrmann M, Krause S, Kolb HJ, Neubauer A, Hossfeld DK, Nerl C, Gratwohl A, Baerlocher GM, Heim D, Brümmendorf TH, Fabarius A, Haferlach C, Schlegelberger B, Müller MC, Jeromin S, Proetel U, Kohlbrenner K, Voskanyan A, Rinaldetti S, Seifarth W, Spieß B, Balleisen L, Goebeler MC, Hänel M, Ho A, Dengler J, Falge C, Kanz L, Kremers S, Burchert A, Kneba M, Stegelmann F, Köhne CA, Lindemann HW, Waller CF, Pfreundschuh M, Spiekermann K, Berdel WE, Müller L, Edinger M, Mayer J, Beelen DW, Bentz M, Link H, Hertenstein B, Fuchs R, Wernli M, Schlegel F, Schlag R, de Wit M, Trümper L, Hebart H, Hahn M, Thomalla J, Scheid C, Schafhausen P, Verbeek W, Eckart MJ, Gassmann W, Pezzutto A, Schenk M, Brossart P, Geer T, Bildat S, Schäfer E, Hochhaus A, Hasford J. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017 Nov;31(11):2398-2406. Epub 2017 Aug 14. link to original article link to PMC article PubMed

Imatinib & Peginterferon alfa-2a

Regimen variant #1, 45 mcg

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Preudhomme et al. 2010 (SPIRIT)	2003-2007	Phase 3 (E-esc)	1. Imatinib; 400 mg once per day	Superior MMR rate at 12 months
			2. Imatinib; 600 mg once per day	Not reported
			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

Immunotherapy

• Peginterferon alfa-2a (Pegasys) 45 mcg SC once per day on days 1, 8, 15, 22

28-day cycles

Regimen variant #2, 90 mcg

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Preudhomme et al. 2010 (SPIRIT)	2003-2007	Phase 3 (E-esc)	1. Imatinib; 400 mg once per day	Superior MMR rate at 12 months
			2. Imatinib; 600 mg once per day	Not reported
			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

Immunotherapy

• Peginterferon alfa-2a (Pegasys) 90 mcg SC once per day on days 1, 8, 15, 22

28-day cycles

References

1. SPIRIT: Preudhomme C, Guilhot J, Nicolini FE, Guerci-Bresler A, Rigal-Huguet F, Maloisel F, Coiteux V, Gardembas M, Berthou C, Vekhoff A, Rea D, Jourdan E, Allard C, Delmer A, Rousselot P, Legros L, Berger M, Corm S, Etienne G, Roche-Lestienne C, Eclache V, Mahon FX, Guilhot F; SPIRIT Investigators; 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 contains dosing details in manuscript PubMed NCT00219739
   1. Post-hoc analysis: Johnson-Ansah H, Guilhot J, Rousselot P, Rea D, Legros L, Rigal-Huguet F, Nicolini FE, Mahon FX, Preudhomme C, Guilhot F. Tolerability and efficacy of pegylated interferon-a-2a in combination with imatinib for patients with chronic-phase chronic myeloid leukemia. Cancer. 2013 Dec 15;119(24):4284-9. Epub 2013 Sep 16. link to original article PubMed
   2. 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 PubMed

Interferon alfa-2a monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Talpaz et al. 1986 (DM 82-49	NR	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)	1. Busulfan 2. Hydrea	Superior 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

1. 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 PubMed
   1. 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 PubMed
2. 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 PubMed
   1. 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 PubMed
3. 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 contains dosing details in manuscript PubMed

Interferon alfa-2b monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Guilhot et al. 1997	1991-1996	Phase 3 (C)	LoDAC & Interferon alfa	Seems to have inferior OS
Kluin-Nelemans et al. 2004 (HOVON 20/MRC CML IV)	1993-2001	Phase 3 (C)	IFN alfa-2b; low-dose	Did not meet 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 MCR rate at 12 months

Immunotherapy

• Interferon alfa-2b (Intron-A)

References

1. Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau JL, Maloisel F, Bouabdallah R, Guyotat D, Cheron N, Nicolini F, Abgrall JF, Tanzer J; 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 contains dosing details in manuscript PubMed
2. 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 PubMed
3. 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 PubMed NCT00002869

Interferon alfa-n1 monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Allan et al. 1995	1986-1994	Phase 3 (E-switch-ooc)	1. Busulfan 2. Hydrea	Superior OS

Immunotherapy

• Interferon alfa-n1 (Wellferon)

References

1. 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 PubMed
2. ECOG E7995: NCT00002868

Nilotinib monotherapy

Regimen variant #1, 300 mg twice per day

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Saglio et al. 2010 (ENESTnd)	2007-2008	Phase 3 (E-RT-switch-ic)	1. Imatinib	Seems to have superior TTP
			2. Nilotinib; 400 mg twice per day	Not reported
Wang et al. 2015 (ENESTchina)	2011	Phase 3 (E-switch-ic)	Imatinib	Superior MMR rate at 12 months
Awaiting publication (CABL001J12301)	2021-2024	Phase 3 (C)	Asciminib	TBD

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

Continued indefinitely

Regimen variant #2, 400 mg twice per day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rosti et al. 2009 (CML0307)	2007-2008	Phase 2
Saglio et al. 2010 (ENESTnd)	2007-2008	Phase 3 (E-RT-switch-ic)	1. Imatinib	Superior TTP
			2. Nilotinib; 300 mg twice per day	Not reported

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

Targeted therapy

• Nilotinib (Tasigna) 400 mg PO twice per day

Continued indefinitely

Regimen variant #3, planned discontinuation

Study	Years of enrollment	Evidence
Hoghhause et al. 2017 (ENESTfreedom)	2013	Phase 2 (RT)

Note: See manuscript for exact details of the treatment timeline.

Targeted therapy

• Nilotinib (Tasigna)

Continued for at least 3 years

References

1. 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 contains dosing details in manuscript PubMed NCT00481052
   1. Update: Gugliotta G, Castagnetti F, Breccia M, Levato L, D'Adda M, Stagno F, Tiribelli M, Salvucci M, Fava C, Martino B, Cedrone M, Bocchia M, Trabacchi E, Cavazzini F, Usala E, 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 PubMed
2. ENESTnd: Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM; ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2251-9. Epub 2010 Jun 5. link to original article contains dosing details in abstract PubMed NCT00471497
   1. Update: Kantarjian HM, Hochhaus A, Saglio G, De Souza C, Flinn IW, Stenke L, Goh YT, Rosti G, Nakamae H, Gallagher NJ, Hoenekopp A, Blakesley RE, Larson RA, Hughes TP. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011 Sep;12(9):841-51. Epub 2011 Aug 17. Erratum in: Lancet Oncol. 2011 Oct;12(11):989. link to original article contains dosing details in manuscript PubMed
   2. Update: Larson RA, Hochhaus A, Hughes TP, Clark RE, Etienne G, Kim DW, Flinn IW, Kurokawa M, Moiraghi B, Yu R, Blakesley RE, Gallagher NJ, Saglio G, Kantarjian HM. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012 Oct;26(10):2197-203. Epub 2012 May 18. link to original article PubMed
   3. Update: Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, le Coutre PD, Etienne G, Dorlhiac-Llacer PE, Clark RE, Flinn IW, Nakamae H, Donohue B, Deng W, Dalal D, Menssen HD, Kantarjian HM. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016 May;30(5):1044-54. Epub 2016 Feb 3. link to original article link to PMC article PubMed
   4. 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 PubMed
3. ENESTchina: Wang J, Shen ZX, Saglio G, Jin J, Huang H, Hu Y, Du X, Li J, Meng F, Zhu H, Hu J, Wang J, Hou M, Hertle S, Menssen HD, Ortmann CE, Tribouley C, Yuan Y, Baccarani M, Huang X. Phase 3 study of nilotinib vs imatinib in Chinese patients with newly diagnosed chronic myeloid leukemia in chronic phase: ENESTchina. Blood. 2015 Apr 30;125(18):2771-8. Epub 2015 Mar 12. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01275196
4. 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 PubMed NCT01784068
   1. 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 PubMed
   2. 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 PubMed
5. CABL001J12301: contains dosing details on CT.gov NCT04971226

Radotinib monotherapy

Regimen variant #1, 300 mg twice per day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kwak et al. 2017 (RERISE)	2011-2014	Phase 3 (E-switch-ic)	1. Imatinib	Superior MMR rate at 12 months
			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	Years 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 superior MMR rate at 12 months
			2. Radotinib; 300 mg twice per day	Not reported

Targeted therapy

• Radotinib (Supect) 400 mg PO twice per day

Continued indefinitely

References

1. 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 contains dosing details in manuscript PubMed NCT01602952
2. RERISE: Kwak JY, Kim SH, Oh SJ, Zang DY, Kim H, Kim JA, Do YR, Kim HJ, Park JS, Choi CW, Lee WS, Mun YC, Kong JH, Chung JS, Shin HJ, Kim DY, Park J, Jung CW, Bunworasate U, Comia NS, Jootar S, Reksodiputro AH, Caguioa PB, Lee SE, Kim DW. Phase III clinical trial (RERISE study) results of efficacy and safety of radotinib compared with imatinib in newly diagnosed chronic phase chronic myeloid leukemia. Clin Cancer Res. 2017 Dec 1;23(23):7180-7188. Epub 2017 Sep 22. link to original article contains dosing details in abstract PubMed NCT01511289
   1. 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 PubMed

Chronic phase, relapsed or refractory

Asciminib monotherapy

Regimen variant #1, 40 mg BID

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Réa et al. 2021 (ASCEMBL)	2017-2019	Phase 3 (E-RT-switch-ooc)	Bosutinib	Superior MMR1 MMR at 96 weeks: 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 BID

FDA-recommended dose

Study	Years 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

1. 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 PubMed NCT02081378
2. 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 contains dosing details in manuscript PubMed NCT03106779
   1. Update: Réa D, Hochhaus A, Mauro MJ, Minami Y, Lomaia E, Voloshin S, Turkina A, Kim DW, Apperley JF, Cortes JE, Abdo A, Fogliatto LM, Kim DDH, Coutre PL, Saussele S, Annunziata M, Hughes TP, Chaudhri N, Chee L, García-Gutiérrez V, Sasaki K, Kapoor S, Allepuz A, Quenet S, Bédoucha V, Boquimpani C. CML-395 Efficacy and Safety Results From ASCEMBL, a Phase III Study of Asciminib vs. Bosutinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) After ≥2 Prior Tyrosine Kinase Inhibitors (TKIs): Week 96 Update. Clin Lymphoma Myeloma Leuk. 2022 Oct;22 Suppl 2:S295-S296. link to original article PubMed

Bosutinib monotherapy

Regimen

FDA-recommended dose

Study	Years 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	Inferior 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, take with food

Continued indefinitely

Dose 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

1. Study 200: Cortes JE, Kantarjian HM, Brümmendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A, Besson N, Abbas R, Wang J, Leip E, Gambacorti-Passerini C. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011 Oct 27;118(17):4567-76. Epub 2011 Aug 24. Erratum in: Blood. 2013 Oct 3;122(14):2524. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00261846
   1. Update: Khoury HJ, Cortes JE, Kantarjian HM, Gambacorti-Passerini C, Baccarani M, Kim DW, Zaritskey A, Countouriotis A, Besson N, Leip E, Kelly V, Brümmendorf TH. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012 Apr 12;119(15):3403-12. Epub 2012 Feb 27. link to original article contains dosing details in manuscript link to PMC article PubMed
   2. Update: Kantarjian HM, Cortes JE, Kim DW, Khoury HJ, Brümmendorf TH, Porkka K, Martinelli G, Durrant S, Leip E, Kelly V, Turnbull K, Besson N, Gambacorti-Passerini C. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood. 2014 Feb 27;123(9):1309-18. Epub 2013 Dec 17. link to original article contains dosing details in manuscript link to PMC article PubMed
   3. Update: Gambacorti-Passerini C, Brümmendorf TH, Kim DW, Turkina AG, Masszi T, Assouline S, Durrant S, Kantarjian HM, Khoury HJ, Zaritskey A, Shen ZX, Jin J, Vellenga E, Pasquini R, Mathews V, Cervantes F, Besson N, Turnbull K, Leip E, Kelly V, Cortes JE. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up. Am J Hematol. 2014 Jul;89(7):732-42. Epub 2014 Apr 28. link to original article link to PMC article PubMed
   4. Update: Gambacorti-Passerini C, Kantarjian HM, Kim DW, Khoury HJ, Turkina AG, Brümmendorf TH, Matczak E, Bardy-Bouxin N, Shapiro M, Turnbull K, Leip E, Cortes JE. Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors. Am J Hematol. 2015 Sep;90(9):755-68. Epub 2015 Jun 1. link to original article link to PMC article PubMed
2. 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 contains dosing details in manuscript PubMed NCT03106779
   1. Update: Réa D, Hochhaus A, Mauro MJ, Minami Y, Lomaia E, Voloshin S, Turkina A, Kim DW, Apperley JF, Cortes JE, Abdo A, Fogliatto LM, Kim DDH, Coutre PL, Saussele S, Annunziata M, Hughes TP, Chaudhri N, Chee L, García-Gutiérrez V, Sasaki K, Kapoor S, Allepuz A, Quenet S, Bédoucha V, Boquimpani C. CML-395 Efficacy and Safety Results From ASCEMBL, a Phase III Study of Asciminib vs. Bosutinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) After ≥2 Prior Tyrosine Kinase Inhibitors (TKIs): Week 96 Update. Clin Lymphoma Myeloma Leuk. 2022 Oct;22 Suppl 2:S295-S296. link to original article PubMed

BuCyTBI, then allo HSCT

BuCyTBI: Busulfan, Cyclophosphamide, Total Body Irradiation

Regimen

Study	Years of enrollment	Evidence
Fefer et al. 1979	1968-1976	Pilot, <20 pts

Chemotherapy

• Busulfan (Myleran) 5 mg/kg IV once on day -6
• Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on days -5 & -4

Radiotherapy

• TBI 920 rads on day 0

Immunotherapy

• Allogeneic stem cells transfused on day 0

One course

Immunotherapy

• Allogeneic stem cells

Stem cells transfused on day 0

References

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

Busulfan monotherapy

Regimen

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

Of historic interest.

Chemotherapy

• Busulfan (Myleran)

References

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

Cyclophosphamide & TBI, then allo HSCT

Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study	Evidence
Fefer et al. 1982	Non-randomized, <20 pts
Speck et al. 1984	Non-randomized
Goldman et al. 1986	Non-randomized
Hansen et al. 1998	Non-randomized

Details in most of the manuscripts are limited.

Chemotherapy

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

Radiotherapy

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

Immunotherapy

• Allogeneic stem cells transfused on day 0

One course

Immunotherapy

• Allogeneic stem cells

Stem cells transfused on day 0

References

1. Fefer A, Cheever MA, Greenberg PD, Appelbaum FR, Boyd CN, Buckner CD, Kaplan HG, Ramberg R, Sanders JE, Storb R, Thomas ED. Treatment of chronic granulocytic leukemia with chemoradiotherapy and transplantation of marrow from identical twins. N Engl J Med. 1982 Jan 14;306(2):63-8. link to original article PubMed
2. 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 PubMed
3. 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 PubMed
4. Hansen JA, Gooley TA, Martin PJ, Appelbaum F, Chauncey TR, Clift RA, Petersdorf EW, Radich J, Sanders JE, Storb RF, Sullivan KM, Anasetti C. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med. 1998 Apr 2;338(14):962-8. link to original article PubMed

Dasatinib monotherapy

Regimen variant #1, 70 mg twice per day

Study	Years 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	Randomized Phase 2 (E-switch-ic)	Imatinib; high-dose	Superior PFS
Shah et al. 2008 (CA180-034)	2005-2006	Phase 3 (C)	1. Dasatinib; 100 mg once per day	Non-inferior MCyR
			2. Dasatinib; 140 mg once per day	Non-inferior MCyR
			3. Dasatinib; 50 mg twice per day	Non-inferior MCyR

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. 2007_CML: Failure of standard-dose imatinib

Targeted therapy

• Dasatinib (Sprycel) 70 mg PO twice per day

Continued indefinitely

Dose 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Shah et al. 2008 (CA180-034)	2005-2006	Phase 3 (E-RT-switch-ic)	1. Dasatinib; 140 mg once per day	Non-inferior MCyR
			2. Dasatinib; 50 mg twice per day	Non-inferior MCyR
			3. Dasatinib; 70 mg twice per day	Non-inferior MCyR

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 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

1. 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 PubMed NCT00064233
2. Post-hoc analysis: Quintas-Cardama A, Kantarjian H, Jones D, Nicaise C, O'Brien S, Giles F, Talpaz M, Cortes J. Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure. Blood. 2007 Jan 15;109(2):497-9. Epub 2006 Sep 21. link to original article PubMed
3. 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 contains dosing details in manuscript PubMed
   1. Update: Hochhaus A, Baccarani M, Deininger M, Apperley JF, Lipton JH, Goldberg SL, Corm S, Shah NP, Cervantes F, Silver RT, Niederwieser D, Stone RM, Dombret H, Larson RA, Roy L, Hughes T, Müller MC, Ezzeddine R, Countouriotis AM, Kantarjian HM. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008 Jun;22(6):1200-6. Epub 2008 Apr 10. link to original article contains dosing details in manuscript PubMed
4. Kantarjian H, Pasquini R, Hamerschlak N, Rousselot P, Holowiecki J, Jootar S, Robak T, Khoroshko N, Masszi T, Skotnicki A, Hellmann A, Zaritsky A, Golenkov A, Radich J, Hughes T, Countouriotis A, Shah N. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007 Jun 15;109(12):5143-50. Epub 2007 Feb 22. link to original article contains dosing details in manuscript PubMed
5. CA180-034: Shah NP, Kantarjian HM, Kim DW, Réa D, Dorlhiac-Llacer PE, Milone JH, Vela-Ojeda J, Silver RT, Khoury HJ, Charbonnier A, Khoroshko N, Paquette RL, Deininger M, Collins RH, Otero I, Hughes T, Bleickardt E, Strauss L, Francis S, Hochhaus A. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol. 2008 Jul 1;26(19):3204-12. Epub 2008 Jun 9. link to original article contains dosing details in manuscript PubMed NCT00123474
   1. Update: Shah NP, Kim DW, Kantarjian H, Rousselot P, Llacer PE, Enrico A, Vela-Ojeda J, Silver RT, Khoury HJ, Müller MC, Lambert A, Matloub Y, Hochhaus A. Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica. 2010 Feb;95(2):232-40. link to original article link to PMC article PubMed
   2. Update: Shah NP, Guilhot F, Cortes JE, Schiffer CA, le Coutre P, Brümmendorf TH, Kantarjian HM, Hochhaus A, Rousselot P, Mohamed H, Healey D, Cunningham M, Saglio G. Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood. 2014 Apr 10;123(15):2317-24. Epub 2014 Feb 25. link to original article link to PMC article PubMed
   3. Update: Shah NP, Rousselot P, Schiffer C, Rea D, Cortes JE, Milone J, Mohamed H, Healey D, Kantarjian H, Hochhaus A, Saglio G. Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA180-034. Am J Hematol. 2016 Sep;91(9):869-74. Epub 2016 Jun 20. link to original article link to PMC article PubMed

Imatinib monotherapy

Regimen variant #1, 400 mg/day

Study	Years 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	Inferior MMR rate at 6 months
Hughes et al. 2014 (ENESTcmr)	2009-2010	Phase 3 (C)	Nilotinib	Inferior MMR rate at 24 months

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

Prior treatment criteria

• Druker et al. 2001a: Failure of interferon alfa

Preceding treatment

• ENESTcmr: 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hughes et al. 2014 (ENESTcmr)	2009-2010	Phase 3 (C)	Nilotinib	Inferior MMR rate at 24 months
Cortes et al. 2016 (LASOR)	2009-2012	Phase 3 (E-switch-ic)	Nilotinib	Did not meet primary endpoint of CCyR at 6 mo

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

Preceding treatment

• ENESTcmr: Imatinib for at least 2 years, with detectable BCR-ABL1
• LASOR: Standard-dose imatinib, with suboptimal response

Targeted therapy

• Imatinib (Gleevec) 600 mg PO once per day

Continued indefinitely

Regimen variant #3, 800 mg/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kantarjian et al. 2007CML	2005	Randomized Phase 2 (E-switch-ic)	Dasatinib	Inferior PFS
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: 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 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Petzer et al. 2010 (ISTAHIT)	2004-2006	Phase 3 (E-esc)	Imatinib; standard-dose	Superior MMR rate at 6 months

Targeted therapy

• Imatinib (Gleevec) 800 mg PO once per day for 6 months, then 400 mg PO once per day

Continued indefinitely

References

1. Phase I: Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001 Apr 5;344(14):1031-7. link to original article PubMed
2. 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 PubMed
   1. Update: Hochhaus A, Druker B, Sawyers C, Guilhot F, Schiffer CA, Cortes J, Niederwieser DW, Gambacorti-Passerini C, Stone RM, Goldman J, Fischer T, O'Brien SG, Reiffers JJ, Mone M, Krahnke T, Talpaz M, Kantarjian HM. Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment. Blood. 2008 Feb 1;111(3):1039-43. Epub 2007 Oct 11. link to original article contains dosing details in abstract PubMed
3. Kantarjian H, Pasquini R, Hamerschlak N, Rousselot P, Holowiecki J, Jootar S, Robak T, Khoroshko N, Masszi T, Skotnicki A, Hellmann A, Zaritsky A, Golenkov A, Radich J, Hughes T, Countouriotis A, Shah N. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007 Jun 15;109(12):5143-50. Epub 2007 Feb 22. link to original article contains dosing details in manuscript PubMed
4. Case series: Palandri F, Iacobucci I, Martinelli G, Amabile M, Poerio A, Testoni N, Soverini S, Castagnetti F, De Vivo A, Breccia M, Specchia G, Abruzzese E, Martino B, Cilloni D, Saglio G, Pane F, Liberati AM, Rosti G, Baccarani M; GIMEMA Working Party on CML. Long-term outcome of complete cytogenetic responders after imatinib 400 mg in late chronic phase, philadelphia-positive chronic myeloid leukemia: the GIMEMA Working Party on CML. J Clin Oncol. 2008 Jan 1;26(1):106-11. link to original article PubMed
5. ISTAHIT: Petzer AL, Wolf D, Fong D, Lion T, Dyagil I, Masliak Z, Bogdanovic A, Griskevicius L, Lejniece S, Goranov S, Gercheva L, Stojanovic A, Peytchev D, Tzvetkov N, Griniute R, Oucheva R, Ulmer H, Kwakkelstein M, Rancati F, Gastl G. High-dose imatinib improves cytogenetic and molecular remissions in patients with pretreated Philadelphia-positive, BCR-ABL-positive chronic phase chronic myeloid leukemia: first results from the randomized CELSG phase III CML 11 "ISTAHIT" study. Haematologica. 2010 Jun;95(6):908-13. Epub 2010 Feb 9. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00327262
   1. Update: Petzer AL, Fong D, Lion T, Dyagil I, Masliak Z, Bogdanovic A, Griskevicius L, Lejniece S, Goranov S, Gercheva L, Stojanovic A, Peytchev D, Tzvetkov N, Griniute R, Stanchev A, Grubinger T, Kwakkelstein M, Schuld P, Gastl G, Wolf D. High-dose imatinib induction followed by standard-dose maintenance in pre-treated chronic phase chronic myeloid leukemia patients--final analysis of a randomized, multicenter, phase III trial. Haematologica. 2012 Oct;97(10):1562-9. Epub 2012 Apr 17. link to original article contains dosing details in manuscript link to PMC article PubMed
6. ENESTcmr: Hughes TP, Lipton JH, Spector N, Cervantes F, Pasquini R, Clementino NC, Dorlhiac Llacer PE, Schwarer AP, Mahon FX, Rea D, Branford S, Purkayastha D, Collins L, Szczudlo T, Leber B. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood. 2014 Jul 31;124(5):729-36. Epub 2014 Jun 19. link to original article contains dosing details in manuscript PubMed NCT00760877
   1. Update: Hughes TP, Leber B, Cervantes F, Spector N, Pasquini R, Clementino NCD, Schwarer AP, Dorlhiac-Llacer PE, Mahon FX, Rea D, Guerci-Bresler A, Kamel-Reid S, Bendit I, Acharya S, Glynos T, Dalal D, Branford S, Lipton JH. Sustained deep molecular responses in patients switched to nilotinib due to persistent BCR-ABL1 on imatinib: final ENESTcmr randomized trial results. Leukemia. 2017 Nov;31(11):2529-2531. Epub 2017 Aug 3. link to original article link to PMC article PubMed
7. TIDEL-II: Yeung DT, Osborn MP, White DL, Branford S, Braley J, Herschtal A, Kornhauser M, Issa S, Hiwase DK, Hertzberg M, Schwarer AP, Filshie R, Arthur CK, Kwan YL, Trotman J, Forsyth CJ, Taper J, Ross DM, Beresford J, Tam C, Mills AK, Grigg AP, Hughes TP; Australasian Leukaemia and Lymphoma Group. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood. 2015 Feb 5;125(6):915-23. Epub 2014 Dec 17. link to original article contains dosing details in manuscript link to PMC article PubMed ANZCTR12607000325404
8. LASOR: Cortes JE, De Souza CA, Ayala M, Lopez JL, Bullorsky E, Shah S, Huang X, Babu KG, Abdulkadyrov K, de Oliveira JS, Shen ZX, Sacha T, Bendit I, Liang Z, Owugah T, Szczudlo T, Khanna S, Fellague-Chebra R, le Coutre PD. Switching to nilotinib versus imatinib dose escalation in patients with chronic myeloid leukaemia in chronic phase with suboptimal response to imatinib (LASOR): a randomised, open-label trial. Lancet Haematol. 2016 Dec;3(12):e581-e591. link to original article contains dosing details in abstract PubMed NCT00802841

Nilotinib monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kantarjian et al. 2006 (A2101)	2004-2005	Phase 1/2 (RT)
Hughes et al. 2014a (ENESTnd extension)	NR	Non-randomized portion of phase 3 RCT
Yeung et al. 2014 (TIDEL-II)	2007-2011	Non-randomized
Hughes et al. 2014b (ENESTcmr)	2009-2010	Phase 3 (E-switch-ic)	Imatinib	Superior MMR rate at 24 months
Cortes et al. 2016 (LASOR)	2009-2012	Phase 3 (E-switch-ic)	Imatinib; 600 mg daily	Did not meet primary endpoint of CCyR at 6 mo
Mahon et al. 2018 (ENESTop)	2012-NR	Phase 2 (RT)

Prior treatment criteria

• A2101: Failure of imatinib

Preceding treatment

• ENESTnd extension: Imatinib 400 mg once or twice per day or nilotinib 300 mg twice per day, with suboptimal response/treatment failure
• ENESTcmr: Imatinib for at least 2 years, with detectable BCR-ABL1
• TIDEL-II: Imatinib, with failure to meet molecular targets
• LASOR: Standard-dose imatinib, with suboptimal response

Targeted therapy

• Nilotinib (Tasigna) 400 mg PO twice per day

Continued indefinitely

References

1. A2101: Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006 Jun 15;354(24):2542-51. link to original article PubMed NCT00109707
   1. Update: Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, Ossenkoppele GJ, Nicolini FE, O'Brien SG, Litzow M, Bhatia R, Cervantes F, Haque A, Shou Y, Resta DJ, Weitzman A, Hochhaus A, le Coutre P. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007 Nov 15;110(10):3540-6. Epub 2007 Aug 22. link to original article contains dosing details in manuscript PubMed
   2. Update: Kantarjian HM, Giles FJ, Bhalla KN, Pinilla-Ibarz J, Larson RA, Gattermann N, Ottmann OG, Hochhaus A, Radich JP, Saglio G, Hughes TP, Martinelli G, Kim DW, Shou Y, Gallagher NJ, Blakesley R, Baccarani M, Cortes J, le Coutre PD. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011 Jan 27;117(4):1141-5. Epub 2010 Nov 22. link to original article link to PMC article PubMed
   3. Update: Giles FJ, le Coutre PD, Pinilla-Ibarz J, Larson RA, Gattermann N, Ottmann OG, Hochhaus A, Radich JP, Saglio G, Hughes TP, Martinelli G, Kim DW, Novick S, Gillis K, Fan X, Cortes J, Baccarani M, Kantarjian HM. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia. 2013 Jan;27(1):107-12. Epub 2012 Jul 5. link to original article PubMed
2. ENESTnd extension: Hughes TP, Hochhaus A, Kantarjian HM, Cervantes F, Guilhot F, Niederwieser D, le Coutre PD, Rosti G, Ossenkoppele G, Lobo C, Shibayama H, Fan X, Menssen HD, Kemp C, Larson RA, Saglio G. Safety and efficacy of switching to nilotinib 400 mg twice daily for patients with chronic myeloid leukemia in chronic phase with suboptimal response or failure on front-line imatinib or nilotinib 300 mg twice daily. Haematologica. 2014 Jul;99(7):1204-11. Epub 2014 Feb 14. link to original article link to PMC article PubMed NCT00471497
3. ENESTcmr: Hughes TP, Lipton JH, Spector N, Cervantes F, Pasquini R, Clementino NC, Dorlhiac Llacer PE, Schwarer AP, Mahon FX, Rea D, Branford S, Purkayastha D, Collins L, Szczudlo T, Leber B. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood. 2014 Jul 31;124(5):729-36. Epub 2014 Jun 19. link to original article contains dosing details in manuscript PubMed NCT00760877
   1. Update: Hughes TP, Leber B, Cervantes F, Spector N, Pasquini R, Clementino NCD, Schwarer AP, Dorlhiac-Llacer PE, Mahon FX, Rea D, Guerci-Bresler A, Kamel-Reid S, Bendit I, Acharya S, Glynos T, Dalal D, Branford S, Lipton JH. Sustained deep molecular responses in patients switched to nilotinib due to persistent BCR-ABL1 on imatinib: final ENESTcmr randomized trial results. Leukemia. 2017 Nov;31(11):2529-2531. Epub 2017 Aug 3. link to original article link to PMC article PubMed
4. TIDEL-II: Yeung DT, Osborn MP, White DL, Branford S, Braley J, Herschtal A, Kornhauser M, Issa S, Hiwase DK, Hertzberg M, Schwarer AP, Filshie R, Arthur CK, Kwan YL, Trotman J, Forsyth CJ, Taper J, Ross DM, Beresford J, Tam C, Mills AK, Grigg AP, Hughes TP; Australasian Leukaemia and Lymphoma Group. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood. 2015 Feb 5;125(6):915-23. Epub 2014 Dec 17. link to original article contains dosing details in manuscript link to PMC article PubMed ANZCTR12607000325404
5. LASOR: Cortes JE, De Souza CA, Ayala M, Lopez JL, Bullorsky E, Shah S, Huang X, Babu KG, Abdulkadyrov K, de Oliveira JS, Shen ZX, Sacha T, Bendit I, Liang Z, Owugah T, Szczudlo T, Khanna S, Fellague-Chebra R, le Coutre PD. Switching to nilotinib versus imatinib dose escalation in patients with chronic myeloid leukaemia in chronic phase with suboptimal response to imatinib (LASOR): a randomised, open-label trial. Lancet Haematol. 2016 Dec;3(12):e581-e591. link to original article contains dosing details in abstract PubMed NCT00802841
6. 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 PubMed NCT01698905

Omacetaxine monotherapy

Regimen

Study	Years 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)

Chemotherapy

• Omacetaxine (Synribo) as follows:
  • Induction: 1.25 mg/m² SC twice per day on days 1 to 14
  • Maintenance, after hematologic response is achieved: 1.25 mg/m² SC twice per day on days 1 to 7

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 cycles

References

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00375219
   1. Pooled subgroup analysis: Nicolini FE, Khoury HJ, Akard L, Rea D, Kantarjian H, Baccarani M, Leonoudakis J, Craig A, Benichou AC, Cortes J. Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors. Haematologica. 2013 Jul;98(7):e78-9. Epub 2013 Jun 10. link to original article link to PMC article PubMed
   2. Pooled update: Cortes JE, Kantarjian HM, Rea D, Wetzler M, Lipton JH, Akard L, Khoury HJ, Michallet M, Guerci-Bresler A, Chuah C, Hellmann A, Digumarti R, Parikh PM, Legros L, Warzocha K, Baccarani M, Li E, Munteanu M, Nicolini FE. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic-or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up. Cancer. 2015 May 15;121(10):1637-44. Epub 2015 Jan 13. link to original article PubMed
2. 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 PubMed NCT00462943
   1. Pooled subgroup analysis: Nicolini FE, Khoury HJ, Akard L, Rea D, Kantarjian H, Baccarani M, Leonoudakis J, Craig A, Benichou AC, Cortes J. Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors. Haematologica. 2013 Jul;98(7):e78-9. Epub 2013 Jun 10. link to original article link to PMC article PubMed
   2. Pooled update: Cortes JE, Kantarjian HM, Rea D, Wetzler M, Lipton JH, Akard L, Khoury HJ, Michallet M, Guerci-Bresler A, Chuah C, Hellmann A, Digumarti R, Parikh PM, Legros L, Warzocha K, Baccarani M, Li E, Munteanu M, Nicolini FE. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic-or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up. Cancer. 2015 May 15;121(10):1637-44. Epub 2015 Jan 13. link to original article PubMed

Ponatinib monotherapy

Regimen

Study	Years 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; may be taken either with or without food

Continued indefinitely

References

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00660920
2. PACE: Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio J, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H; PACE Investigators. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013 Nov 7;369(19):1783-96. Epub 2013 Nov 1. link to original article link to PMC article PubMed NCT01207440
   1. Update: Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Lustgarten S, Rivera VM, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes TP, Shah NP, Kantarjian HM. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018 Jul 26;132(4):393-404. Epub 2018 Mar 22. link to original article link to PMC article PubMed
3. 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 PubMed NCT02467270

Accelerated phase, first-line therapy

Imatinib monotherapy

Regimen

FDA-recommended dose

Study	Years 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

1. 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 contains dosing details in abstract PubMed

Accelerated phase, previously treated

Dasatinib monotherapy

Regimen variant #1, 70 mg twice per day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Guilhot et al. 2007 (START-A)	2004-2005	Phase 2
Kantarjian et al. 2009 (CA180-035)	2005-2006	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

Continued indefinitely

Regimen variant #2, 140 mg/day

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kantarjian et al. 2009 (CA180-035)	2005-2006	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

Continued indefinitely

References

1. 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 PubMed
2. CA180-035: Kantarjian H, Cortes J, Kim DW, Dorlhiac-Llacer P, Pasquini R, DiPersio J, Müller MC, Radich JP, Khoury HJ, Khoroshko N, Bradley-Garelik MB, Zhu C, Tallman MS. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood. 2009 Jun 18;113(25):6322-9. Epub 2009 Apr 15. link to original article link to PMC article PubMed NCT00123487
   1. Subgroup analysis: Lilly MB, Ottmann OG, Shah NP, Larson RA, Reiffers JJ, Ehninger G, Müller MC, Charbonnier A, Bullorsky E, Dombret H, Brigid Bradley-Garelik M, Zhu C, Martinelli G. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: results from a phase 3 study. Am J Hematol. 2010 Mar;85(3):164-70. link to original article contains dosing details in manuscript PubMed
   2. Subgroup analysis: Saglio G, Hochhaus A, Goh YT, Masszi T, Pasquini R, Maloisel F, Erben P, Cortes J, Paquette R, Bradley-Garelik MB, Zhu C, Dombret H. Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer. 2010 Aug 15;116(16):3852-61. link to original article link to PMC article PubMed

Nilotinib monotherapy

Regimen

Study	Years of enrollment	Evidence
Giles et al. 2010	NR	Phase 2
Nicolini et al. 2011 (ENACT)	NR in abstract	Phase 3b

Targeted therapy

• Nilotinib (Tasigna) 400 mg PO twice per day

Continued indefinitely

References

1. Giles FJ, Abruzzese E, Rosti G, Kim DW, Bhatia R, Bosly A, Goldberg S, Kam GL, Jagasia M, Mendrek W, Fischer T, Facon T, Dünzinger U, Marin D, Mueller MC, Shou Y, Gallagher NJ, Larson RA, Mahon FX, Baccarani M, Cortes J, Kantarjian HM. Nilotinib is active in chronic and accelerated phase chronic myeloid leukemia following failure of imatinib and dasatinib therapy. Leukemia. 2010 Jul;24(7):1299-301. Epub 2010 Jun 3. link to original article link to PMC article PubMed
   1. Update: le Coutre PD, Giles FJ, Hochhaus A, Apperley JF, Ossenkoppele GJ, Blakesley R, Shou Y, Gallagher NJ, Baccarani M, Cortes J, Kantarjian HM. Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results. Leukemia. 2012 Jun;26(6):1189-94. Epub 2011 Nov 11. link to original article PubMed
2. 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 PubMed NCT01126892

Omacetaxine monotherapy

Regimen

Study	Years 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)

Chemotherapy

• Omacetaxine (Synribo) as follows:
  • Induction: 1.25 mg/m² SC twice per day on days 1 to 14
  • Maintenance, after hematologic response is achieved: 1.25 mg/m² SC twice per day on days 1 to 7

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 cycles

References

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00375219
   1. Pooled subgroup analysis: Nicolini FE, Khoury HJ, Akard L, Rea D, Kantarjian H, Baccarani M, Leonoudakis J, Craig A, Benichou AC, Cortes J. Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors. Haematologica. 2013 Jul;98(7):e78-9. Epub 2013 Jun 10. link to original article link to PMC article PubMed
   2. Pooled update: Cortes JE, Kantarjian HM, Rea D, Wetzler M, Lipton JH, Akard L, Khoury HJ, Michallet M, Guerci-Bresler A, Chuah C, Hellmann A, Digumarti R, Parikh PM, Legros L, Warzocha K, Baccarani M, Li E, Munteanu M, Nicolini FE. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic-or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up. Cancer. 2015 May 15;121(10):1637-44. Epub 2015 Jan 13. link to original article PubMed
2. 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 PubMed NCT00462943
   1. Pooled subgroup analysis: Nicolini FE, Khoury HJ, Akard L, Rea D, Kantarjian H, Baccarani M, Leonoudakis J, Craig A, Benichou AC, Cortes J. Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors. Haematologica. 2013 Jul;98(7):e78-9. Epub 2013 Jun 10. link to original article link to PMC article PubMed
   2. Pooled update: Cortes JE, Kantarjian HM, Rea D, Wetzler M, Lipton JH, Akard L, Khoury HJ, Michallet M, Guerci-Bresler A, Chuah C, Hellmann A, Digumarti R, Parikh PM, Legros L, Warzocha K, Baccarani M, Li E, Munteanu M, Nicolini FE. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic-or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up. Cancer. 2015 May 15;121(10):1637-44. Epub 2015 Jan 13. link to original article PubMed

Ponatinib monotherapy

Regimen

Study	Years 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; may be taken either with or without food

Continued indefinitely

References

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00660920
2. PACE: Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio J, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H; PACE Investigators. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013 Nov 7;369(19):1783-96. Epub 2013 Nov 1. link to original article link to PMC article PubMed NCT01207440
   1. Update: Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Lustgarten S, Rivera VM, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes TP, Shah NP, Kantarjian HM. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018 Jul 26;132(4):393-404. Epub 2018 Mar 22. link to original article link to PMC article PubMed

Blast crisis

Bosutinib monotherapy

Regimen

FDA-recommended dose

Study	Years 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, take with food

Continued indefinitely

Dose 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

1. Study 200: Cortes JE, Kantarjian HM, Brümmendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A, Besson N, Abbas R, Wang J, Leip E, Gambacorti-Passerini C. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011 Oct 27;118(17):4567-76. Epub 2011 Aug 24. Erratum in: Blood. 2013 Oct 3;122(14):2524. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00261846
   1. Update: Khoury HJ, Cortes JE, Kantarjian HM, Gambacorti-Passerini C, Baccarani M, Kim DW, Zaritskey A, Countouriotis A, Besson N, Leip E, Kelly V, Brümmendorf TH. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012 Apr 12;119(15):3403-12. Epub 2012 Feb 27. link to original article contains dosing details in manuscript link to PMC article PubMed
   2. Update: Kantarjian HM, Cortes JE, Kim DW, Khoury HJ, Brümmendorf TH, Porkka K, Martinelli G, Durrant S, Leip E, Kelly V, Turnbull K, Besson N, Gambacorti-Passerini C. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood. 2014 Feb 27;123(9):1309-18. Epub 2013 Dec 17. link to original article contains dosing details in manuscript link to PMC article PubMed
   3. Update: Gambacorti-Passerini C, Brümmendorf TH, Kim DW, Turkina AG, Masszi T, Assouline S, Durrant S, Kantarjian HM, Khoury HJ, Zaritskey A, Shen ZX, Jin J, Vellenga E, Pasquini R, Mathews V, Cervantes F, Besson N, Turnbull K, Leip E, Kelly V, Cortes JE. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up. Am J Hematol. 2014 Jul;89(7):732-42. Epub 2014 Apr 28. link to original article link to PMC article PubMed
   4. Update: Gambacorti-Passerini C, Kantarjian HM, Kim DW, Khoury HJ, Turkina AG, Brümmendorf TH, Matczak E, Bardy-Bouxin N, Shapiro M, Turnbull K, Leip E, Cortes JE. Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors. Am J Hematol. 2015 Sep;90(9):755-68. Epub 2015 Jun 1. link to original article link to PMC article PubMed

Dasatinib monotherapy

Regimen variant #1, 70 mg twice per day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cortes et al. 2006 (START-B/START-L)	2004-2005	Phase 2
Kantarjian et al. 2009 (CA180-035)	2005-2006	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 Continued indefinitely

Regimen variant #2, 140 mg/day

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kantarjian et al. 2009 (CA180-035)	2005-2006	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 Continued indefinitely

References

1. START-B/START-L: Cortes J, Rousselot P, Kim DW, Ritchie E, Hamerschlak N, Coutre S, Hochhaus A, Guilhot F, Saglio G, Apperley J, Ottmann O, Shah N, Erben P, Branford S, Agarwal P, Gollerkeri A, Baccarani M. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. 2007 Apr 15;109(8):3207-13. Epub 2006 Dec 21. link to original article PubMed
2. CA180-035: Kantarjian H, Cortes J, Kim DW, Dorlhiac-Llacer P, Pasquini R, DiPersio J, Müller MC, Radich JP, Khoury HJ, Khoroshko N, Bradley-Garelik MB, Zhu C, Tallman MS. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood. 2009 Jun 18;113(25):6322-9. Epub 2009 Apr 15. link to original article link to PMC article PubMed NCT00123487
   1. Subgroup analysis: Lilly MB, Ottmann OG, Shah NP, Larson RA, Reiffers JJ, Ehninger G, Müller MC, Charbonnier A, Bullorsky E, Dombret H, Brigid Bradley-Garelik M, Zhu C, Martinelli G. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: results from a phase 3 study. Am J Hematol. 2010 Mar;85(3):164-70. link to original article contains dosing details in manuscript PubMed
   2. Subgroup analysis: Saglio G, Hochhaus A, Goh YT, Masszi T, Pasquini R, Maloisel F, Erben P, Cortes J, Paquette R, Bradley-Garelik MB, Zhu C, Dombret H. Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer. 2010 Aug 15;116(16):3852-61. link to original article link to PMC article PubMed

Imatinib monotherapy

Regimen

FDA-recommended dose

Study	Years 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

1. 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 PubMed
2. Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG, Schiffer CA, Talpaz M, Guilhot F, Deininger MW, Fischer T, O'Brien SG, Stone RM, Gambacorti-Passerini CB, Russell NH, Reiffers JJ, Shea TC, Chapuis B, Coutre S, Tura S, Morra E, Larson RA, Saven A, Peschel C, Gratwohl A, Mandelli F, Ben-Am M, Gathmann I, Capdeville R, Paquette RL, Druker BJ. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 2002 May 15;99(10):3530-9. link to original article PubMed

Response Criteria

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

Investigational agents