Chronic myeloid leukemia

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Chronic phase, untreated

Bosutinib (Bosulif)

Regimen, Cortes et al. 2011 (BELA)

Phase III

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

given until progression of disease or unacceptable toxicity

References

1. Jorge E Cortes, Anish Maru, Carmino Antonio Antonio De Souza, François Guilhot, Ladan Duvillie, Christine Powell, Athena Countouriotis, and Carlo Gambacorti-Passerini. Bosutinib Versus Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia – BELA Trial: 24-Month Follow-up. 2011 ASH Annual Meeting Abstract 455. link to abstract
2. Carlo Gambacorti-Passerini, Jeffrey Howard Lipton, Goh Yeow Tee, Luis Felipe Casado, Andrey Zaritskey, Philipp D. le Coutre, Ladan Duvillie, Dmitri Pavlov, Athena Maria Countouriotis, Jennifer Byrne. BELA trial update: Bosutinib (BOS) versus imatinib (IM) in patients (pts) with newly diagnosed chronic phase chronic myeloid leukemia (CP CML) after 30 months of follow-up. 2012 ASCO Annual Meeting abstract 6512. link to abstract
3. Bosutinib (Bosulif) package insert

Cytarabine & Interferon alfa

Regimen, O'Brien et al. 2003; Druker et al. 2006 (IRIS)

Phase III

• Cytarabine (Cytosar) 20 mg/m2 (capped at 40 mg) SC once per day for 10 days per month
• Interferon alfa (subtype not specified) target dose 5 million units/m2 SC once per day (method of dose escalation not specified)

Continued until patient "no longer derived benefit."

References

1. O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ; IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003 Mar 13;348(11):994-1004. link to original article contains verified protocol PubMed
2. 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

Dasatinib (Sprycel)

Regimen, Kantarjian et al. 2010 (DASISION)

Phase III

• Dasatinib (Sprycel) 100 mg PO daily; dose may be escalated to 140 mg PO daily or 70 mg PO BID depending on response

References

1. Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, Moiraghi B, Shen Z, Mayer J, Pasquini R, Nakamae H, Huguet F, Boqué C, Chuah C, Bleickardt E, Bradley-Garelik MB, Zhu C, Szatrowski T, Shapiro D, Baccarani M. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2260-70. Epub 2010 Jun 5. link to original article contains protocol PubMed
2. 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 PubMed
3. 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 PubMed

Imatinib (Gleevec)

Regimen

Phase III

• Imatinib (Gleevec) 400 mg PO daily; dose may be escalated to 600 mg or 800 mg per day depending on response or decreased depending on toxicity

References

1. O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ; IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003 Mar 13;348(11):994-1004. link to original article contains verified protocol PubMed
2. 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. 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
4. de Lavallade H, Apperley JF, Khorashad JS, Milojkovic D, Reid AG, Bua M, Szydlo R, Olavarria E, Kaeda J, Goldman JM, Marin D. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol. 2008 Jul 10;26(20):3358-63. Epub 2008 Jun 2. link to original article contains protocol PubMed
5. Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM; ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2251-9. Epub 2010 Jun 5. link to original article contains protocol PubMed
6. Preudhomme C, Guilhot J, Nicolini FE, Guerci-Bresler A, Rigal-Huguet F, Maloisel F, Coiteux V, Gardembas M, Berthou C, Vekhoff A, Rea D, Jourdan E, Allard C, Delmer A, Rousselot P, Legros L, Berger M, Corm S, Etienne G, Roche-Lestienne C, Eclache V, Mahon FX, Guilhot F; SPIRIT Investigators; France Intergroupe des Leucémies Myéloïdes Chroniques (Fi-LMC). Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med. 2010 Dec 23;363(26):2511-21. link to original article contains verified protocol PubMed
7. Update: Kantarjian HM, Hochhaus A, Saglio G, De Souza C, Flinn IW, Stenke L, Goh YT, Rosti G, Nakamae H, Gallagher NJ, Hoenekopp A, Blakesley RE, Larson RA, Hughes TP. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011 Sep;12(9):841-51. Epub 2011 Aug 17. Erratum in: Lancet Oncol. 2011 Oct;12(11):989. link to original article contains verified protocol PubMed
8. 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
9. 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 PubMed

Imatinib (Gleevec), intermittent therapy

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

Regimen

Phase II

• Imatinib (Gleevec) any "standard dose" PO daily as follows:

1. 1 week on, 1 week off for weeks 1 to 4
2. 2 weeks on, 2 weeks off for weeks 5 to 12
3. 1 month on, 1 month off for weeks 13 and thereafter

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

References

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

Imatinib & LoDAC

LoDAC: Low Dose Ara-C

Regimen

Phase III

• Imatinib (Gleevec) 400 mg PO daily
• Cytarabine (Cytosar) 20 mg/m2 daily on days 15 to 28 (route not specified)

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

References

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

Imatinib & Pegylated interferon Alfa-2a

Regimen

Phase III

• Imatinib (Gleevec) 400 mg PO daily
• Peginterferon alfa-2a (Pegasys) 90 mcg (later amended to 45 mcg) SC weekly

References

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

Nilotinib (Tasigna)

Regimen, Saglio et al. 2010; Kantarjian et al. 2011; Larson et al. 2012 (ENESTnd)

Phase III

Both doses of nilotinib were superior to imatinib in terms of major molecular response. The study was not powered to detect differences between the two doses of nilotinib.

• Nilotinib (Tasigna) 300 or 400 mg PO BID

References

1. Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM; ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2251-9. Epub 2010 Jun 5. link to original article contains protocol PubMed
2. Update: Kantarjian HM, Hochhaus A, Saglio G, De Souza C, Flinn IW, Stenke L, Goh YT, Rosti G, Nakamae H, Gallagher NJ, Hoenekopp A, Blakesley RE, Larson RA, Hughes TP. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011 Sep;12(9):841-51. Epub 2011 Aug 17. Erratum in: Lancet Oncol. 2011 Oct;12(11):989. link to original article contains verified protocol PubMed
3. 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

Chronic phase, relapsed or resistant

Bosutinib (Bosulif)

Regimen

Phase II

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

given until progression of disease or unacceptable toxicity

References

1. 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. link to original article contains verified protocol--not listing the 400mg dose since this was not the dose used later in the study PubMed
2. Khoury HJ, Cortes JE, Kantarjian HM, Gambacorti-Passerini C, Baccarani M, Kim DW, Zaritskey A, Countouriotis A, Besson N, Leip E, Kelly V, Brümmendorf TH. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012 Apr 12;119(15):3403-12. Epub 2012 Feb 27. link to original article contains verified protocol PubMed
3. Bosutinib (Bosulif) package insert

Dasatinib (Sprycel)

Regimen

Phase III

• Dasatinib (Sprycel) 100 mg PO daily; dose may be escalated to 140 mg PO daily or 70 mg PO BID depending on response

Regimen #2, Kantarjian et al. 2007; Hochhaus et al. 2007; Hochhaus et al. 2008

Randomized Phase II, >20 per arm

Dasatinib (Sprycel) 70 mg PO BID

Reduction to 40 mg PO BID or escalation to 90 mg PO BID allowed under certain circumstances; see original papers for details.

References

1. Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O'Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006 Jun 15;354(24):2531-41. link to original article PubMed
2. Quintas-Cardama A, Kantarjian H, Jones D, Nicaise C, O'Brien S, Giles F, Talpaz M, Cortes J. Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure. Blood. 2007 Jan 15;109(2):497-9. Epub 2006 Sep 21. link to original article PubMed
3. Hochhaus A, Kantarjian HM, Baccarani M, Lipton JH, Apperley JF, Druker BJ, Facon T, Goldberg SL, Cervantes F, Niederwieser D, Silver RT, Stone RM, Hughes TP, Muller MC, Ezzeddine R, Countouriotis AM, Shah NP. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007 Mar 15;109(6):2303-9. Epub 2006 Nov 30. Erratum in: Blood. 2007 Sep 1;110(5):1438. link to original article contains verified protocol PubMed
4. 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
5. 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
6. Kantarjian H, Pasquini R, Hamerschlak N, Rousselot P, Holowiecki J, Jootar S, Robak T, Khoroshko N, Masszi T, Skotnicki A, Hellmann A, Zaritsky A, Golenkov A, Radich J, Hughes T, Countouriotis A, Shah N. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007 Jun 15;109(12):5143-50. Epub 2007 Feb 22. link to original article contains verified protocol PubMed
7. Update: Hochhaus A, Baccarani M, Deininger M, Apperley JF, Lipton JH, Goldberg SL, Corm S, Shah NP, Cervantes F, Silver RT, Niederwieser D, Stone RM, Dombret H, Larson RA, Roy L, Hughes T, Müller MC, Ezzeddine R, Countouriotis AM, Kantarjian HM. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008 Jun;22(6):1200-6. Epub 2008 Apr 10. link to original article contains verified protocol PubMed
8. 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 PubMed
9. Update: 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 PubMed

Imatinib (Gleevec)

Regimen

Phase III

• Imatinib (Gleevec) 400 mg PO daily; dose may be escalated to 600 mg or 800 mg per day depending on response or decreased depending on toxicity

Regimen #2 (High-Dose), Kantarjian et al. 2007

Randomized Phase II, >20 per arm

• Imatinib (Gleevec) 400 mg PO BID

References

1. 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. 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
3. Kantarjian H, Pasquini R, Hamerschlak N, Rousselot P, Holowiecki J, Jootar S, Robak T, Khoroshko N, Masszi T, Skotnicki A, Hellmann A, Zaritsky A, Golenkov A, Radich J, Hughes T, Countouriotis A, Shah N. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007 Jun 15;109(12):5143-50. Epub 2007 Feb 22. link to original article contains verified protocol PubMed
4. 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. Hochhaus A, Druker B, Sawyers C, Guilhot F, Schiffer CA, Cortes J, Niederwieser DW, Gambacorti-Passerini C, Stone RM, Goldman J, Fischer T, O'Brien SG, Reiffers JJ, Mone M, Krahnke T, Talpaz M, Kantarjian HM. Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment. Blood. 2008 Feb 1;111(3):1039-43. Epub 2007 Oct 11. link to original article contains protocol PubMed
6. Petzer AL, Wolf D, Fong D, Lion T, Dyagil I, Masliak Z, Bogdanovic A, Griskevicius L, Lejniece S, Goranov S, Gercheva L, Stojanovic A, Peytchev D, Tzvetkov N, Griniute R, Oucheva R, Ulmer H, Kwakkelstein M, Rancati F, Gastl G. High-dose imatinib improves cytogenetic and molecular remissions in patients with pretreated Philadelphia-positive, BCR-ABL-positive chronic phase chronic myeloid leukemia: first results from the randomized CELSG phase III CML 11 "ISTAHIT" study. Haematologica. 2010 Jun;95(6):908-13. Epub 2010 Feb 9. link to original article contains verified protocol PubMed
7. Update: Petzer AL, Fong D, Lion T, Dyagil I, Masliak Z, Bogdanovic A, Griskevicius L, Lejniece S, Goranov S, Gercheva L, Stojanovic A, Peytchev D, Tzvetkov N, Griniute R, Stanchev A, Grubinger T, Kwakkelstein M, Schuld P, Gastl G, Wolf D. High-dose imatinib induction followed by standard-dose maintenance in pre-treated chronic phase chronic myeloid leukemia patients--final analysis of a randomized, multicenter, phase III trial. Haematologica. 2012 Oct;97(10):1562-9. Epub 2012 Apr 17. link to original article contains verified protocol PubMed

Nilotinib (Tasigna)

Regimen

Phase II

• Nilotinib (Tasigna) 300 to 400 mg PO BID

References

1. 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
2. Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, Ossenkoppele GJ, Nicolini FE, O'Brien SG, Litzow M, Bhatia R, Cervantes F, Haque A, Shou Y, Resta DJ, Weitzman A, Hochhaus A, le Coutre P. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007 Nov 15;110(10):3540-6. Epub 2007 Aug 22. link to original article contains verified protocol PubMed
3. 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 PubMed
4. 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 PubMed
5. 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

Omacetaxine (Synribo)

Regimen

Phase II

Induction phase

• Omacetaxine (Synribo) 1.25 mg/m2 SC BID on days 1 to 14

28-day cycles, given until hematologic response is achieved

Maintenance phase

• Omacetaxine (Synribo) 1.25 mg/m2 SC BID on days 1 to 7

Supportive medications:

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

28-day cycles

References

1. Cortes J, Lipton JH, Rea D, Digumarti R, Chuah C, Nanda N, Benichou AC, Craig AR, Michallet M, Nicolini FE, Kantarjian H; on behalf of the Omacetaxine 202 Study Group. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood. 2012 Sep 27;120(13):2573-2580. Epub 2012 Aug 15. link to original article contains verified protocol PubMed
2. Omacetaxine mepesuccinate (Synribo) package insert
3. Franck E. Nicolini, Jeffrey Howard Lipton, Hagop Kantarjian, Meir Wetzler, Luke Paul Akard, Michele Baccarani, Adam Craig, Nisha Nanda, Peter D. Brown, Jorge E. Cortes. Subcutaneous omacetaxine mepesuccinate in patients with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) resistant/intolerant to two or three approved tyrosine-kinase inhibitors (TKIs). 2012 ASCO Annual Meeting Abstract 6513. link to abstract

Ponatinib (Iclusig)

Suspended by FDA on 10/31/13 because of the risk of life-threatening blood clots and severe narrowing of blood vessels. Patients who are currently taking Iclusig and responding to the drug and whose health care professionals determine that the potential benefits outweigh the risks should be treated under a single-patient Investigational New Drug (IND) application or expanded access registry program while FDA's safety investigation continues. For more information on obtaining access to treatment for your patient under an IND, please refer to this website.

Regimen

Phase II

• Ponatinib (Iclusig) 45 mg PO daily; may be taken either with or without food

given until progression of disease or unacceptable toxicity

References

1. Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, O'Hare T, Hu S, Narasimhan NI, Rivera VM, Clackson T, Turner CD, Haluska FG, Druker BJ, Deininger MW, Talpaz M. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012 Nov 29;367(22):2075-88. link to original article contains verified protocol PubMed
2. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, Dipersio J, Deangelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H; the PACE Investigators. A Phase 2 Trial of Ponatinib in Philadelphia Chromosome-Positive Leukemias. N Engl J Med. 2013 Nov 1. [Epub ahead of print] link to original article PubMed
3. Ponatinib (Iclusig) package insert

Accelerated phase

Bosutinib (Bosulif)

The references above describe results for patients with chronic phase CML. The package insert lists that it is FDA-approved for patients with "chronic, accelerated, or blast phase Ph+ chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy."

• Regimen is the same as Bosutinib (Bosulif) in chronic phase CML

Dasatinib (Sprycel)

Regimen

Phase III

• EITHER Dasatinib (Sprycel) 140 mg PO daily
• OR Dasatinib (Sprycel) 70 mg PO BID

References

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

Imatinib (Gleevec)

Regimen

Details of the regimen were not discernible from the abstract.

• Imatinib (Gleevec)

References

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

Nilotinib (Tasigna)

Regimen

Phase IIIb (non-randomized)

• Nilotinib (Tasigna) 400 mg PO BID

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 PubMed
2. 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
3. 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. link to original article PubMed

Omacetaxine (Synribo)

• Regimen is the same as Omacetaxine (Synribo) in chronic phase CML

Ponatinib (Iclusig)

Suspended by FDA on 10/31/13 because of the risk of life-threatening blood clots and severe narrowing of blood vessels. Patients who are currently taking Iclusig and responding to the drug and whose health care professionals determine that the potential benefits outweigh the risks should be treated under a single-patient Investigational New Drug (IND) application or expanded access registry program while FDA's safety investigation continues. For more information on obtaining access to treatment for your patient under an IND, please refer to this website.

• Regimen is the same as Ponatinib (Iclusig) in chronic phase CML

Blast crisis

Imatinib

References

1. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001 Apr 5;344(14):1038-42. link to original article PubMed

Lymphoid

• One of the above tyrosine kinase inhibitors PLUS acute lymphocytic leukemia (ALL) induction therapy

Myeloid

• One of the above tyrosine kinase inhibitors PLUS acute myeloid leukemia (AML) induction therapy