Chronic Myeloid Leukemia (CML)

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Chronic Myeloid Leukemia (CML) Treatment Regimens

Clinical Trials: The National Comprehensive Cancer Network recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are provided only to supplement the latest treatment strategies.

These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

▶Chronic Phase CML1

Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Primary Treatment1-13

Low-risk Score

Bosutinib 400mg orally daily (Category 1).

OR

Dasatinib 100mg orally daily (Category 1).

OR

Imatinib (or generic imatinib) 400mg orally daily (Category 1).

OR

Nilotinib 300mg orally twice daily (Category 1).

Intermediate- or High-risk Score

Bosutinib 400mg orally daily (Category 1).a

OR

Dasatinib 100mg orally daily (Category 1).a

OR

Imatinib (or generic imatinib) 400mg orally daily.b

OR

Nilotinib 300mg orally twice daily (Category 1).a

3 Month Evaluation1-18

BCR-ABL1 transcripts ≤10% by QPCR (IS)

Monitor response and side effects.

Continue same tyrosine kinase inhibitor (TKI).c

BCR-ABL1 transcripts >10% by QPCR (IS)d,f-k

Evaluate patient compliance and drug interactions, consider mutational analysis, and consider bone marrow cytogenetic analysis to assess for major cytogenetic response (MCyR) at 3 months or complete cytogenetic response (CCyR) at 12 months.

Switch to alternate TKI.

OR

Continue same TKI (other than imatinib).e

OR

Increase imatinib dose to a maximum of 800mg (if primary treatment with imatinib)

AND

Consider evaluation for allogeneic hematopoietic cell transplantation (HCT).

6 Month Evaluation1-18

BCR-ABL1 transcripts ≤10% by QPCR (IS)

Monitor response and side effects.

Continue same TKI.c

BCR-ABL1 transcripts >10% by QPCR (IS)d,f-k

Evaluate patient compliance and drug interactions, and consider mutational analysis.

Switch to alternate TKI

AND

Evaluate for allogeneic HCT.

12 Month Evaluation1-16,l

BCR-ABL1 transcripts ≤1% by QPCR (IS)

Monitor response and side effects.

Continue same TKI.c

BCR-ABL1 transcripts ≤10% but >1% by QPCR (IS)f-k

Evaluate patient compliance and drug interactions, consider mutational analysis, and consider bone marrow cytogenetic analysis to assess for MCyR at 3 months or CCyR at 12 months.

Switch to alternate TKI.

OR

Continue same TKI (other than imatinb).e

OR

Increase dose of imatinib to a maximum of 800mg (if primary treatment with imatinib).

AND

Consider evaluation for allogeneic HCT.

BCR-ABL1 transcripts > 10% by QPCR (IS)f-k

Evaluate patient compliance and drug interactions, consider mutational analysis.

Switch to alternate TKI.

AND

Evaluate for allogeneic HCT.

15 Month Evaluation1-16

BCR-ABL1 transcripts ≤1% by QPCR (IS)

Monitor response and side effects.

Continue same TKI.c

BCR-ABL1 transcripts >1% by QPCR (IS)f-k

Evaluate patient compliance and drug interactions, and consider mutational analysis.

Switch to alternate TKI.

AND

Evaluate for allogeneic HCT.

Advanced Phase CML1,19-38

Accelerated phasel-o

Bosutinib 500mg orally daily (preferred).

OR

Dasatinib 140mg orally daily (preferred).

OR

Imatinib (or generic imatinib) 600mg orally daily.

OR

Nilotinib 400mg orally twice daily (preferred).

OR

Omacetaxine 1.25mg/m2 SC twice daily on days 1–14 cycled every 28 days until hematologic response, followed by omacetaxine maintenance therapy 1.25mg/m2 SC twice daily on days 1–7 cycled every 28 days until disease progression or unacceptable toxicity.

OR

Ponatinib 45mg orally daily (preferred).

Blast phase—lymphoid

Acute lymphoblastic leukemia (ALL)-type induction chemotherapy + TKI.p

OR

TKI + steroids.p

Blast phase—myeloid

Acute myeloid leukemia (AML)-type induction chemotherapy + TKI.p

OR

TKI.p

  a   Based on preliminary data from the BFORE trial and long-term follow-up data from the DASISION and ENESTnd trials, second generation TKIs (dasatinib, nitlotinib, bosutinib) are preferred by patients with an intermediate- or high-risk score, especially for young women whose goal is to achieve a deep and rapid molecular response and eventual drug discontinuation for TKI therapy for family planning purposes.

  b   Imatinib may be preferred for older patients with comorbidities such as cardiovascular disease.

  c   Discontinuation of TKI with careful monitoring is feasible in selected patients.

  d   Patients with BCR-ABL1 only slightly >10% at 3 months and/or with a steep decline from baseline, may achieve <10% at 6 months and have generally favorable outcomes. Therefore, it is important to interpret the value at 3 months in this context, before making drastic changes to the treatment strategy.

  e   Achievement of response milestones must be interpreted within the clinical context. Patients with more than 50% reduction compared to baseline or minimally above the 10% cutoff can continue the same dose of dasatinib, nilotinib, or bosutinib for another 3 months. Continuation of imatinib 400 mg is not recommended.

  f   Patients with disease that is resistant to primary treatment with imatinib should be treated with bosutinib, dasatinib, or nilotinib in the second-line setting taking into account BCR-ABL1 mutation status. The durability of these responses is frequently limited. Patients with disease that is resistant to primary treatment with bosutinib, dasatinib, or nilotinib can be treated with an alternate TKI (other than imatinib) in the second-line setting.

  g   Bosutinib is contraindicated for patients with a T315I, V299L, G250E, E317L mutation.

  h   Bosutinib has minimal activity against F317L mutation. Nilotinib may be preferred over bosutinib in patients with F317L mutation.

  i    Dasatinib is contraindicated for patients with a T315I/A, F317L/V/I/C, V299L mutation.

  j    Nilotinib is contraindicated for patients with a T315I, Y253H, E255K/V, F359V/C/I, G250E mutation.

 k    BCR-ABL1 0.1% at 12 months is associated with a very low probability of subsequent disease progression and a high likelihood of achieving a subsequent MR4.0, which is a prerequisite for a trial of treatment-free remission.

  l    Ponatinib is a treatment option for patients with T315I mutation or for patients for whom no other TKI is indicated.

m   Omacetaxine is a treatment option for patients with disease that is resistant and/or intolerant to 2 or more TKIs.

  n   Omacetaxine is a treatment option for patients with disease progression to accelerated phase CML. Omacetaxine is not a treatment option for patients that present with accelerated phase CML.

 o    Patients who present with accelerated phase at diagnosis should be treated with a TKI, followed by evaluation for allogeneic HCT.

 p    Followed by evaluation for allogeneic HCT as indicated.

References

  1. NCCN Clinical Practice Guidelines in Oncology™. Chronic Myeloid Leukemia. v 2.2020. Available at: http://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed October 4, 2019.

  2. Kantarjian HM, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;28:398–404.

  3. Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;119:1123–1129.

  4. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: The dasatinib versus imatinib study in treatment-naïve chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34:2333-2440.

  5. Hochhaus A, Kim D-W, Shah NP, et al. Four-year (yr) follow-up of patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) receiving dasatinib or imatinib: efficacy based on early response [abstract]. Blood. 2013;122:Abstract 653.

  6. Larson RA, Hochhaus A, Hughes TP, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012;26:2197–2203.

  7. Hochhaus A, Saglio G, Hughes TP, et al. 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;30:1044-1054.

  8. Hughes TP, Saglio G, Kantarjian HM, et al. Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood. 2014;123:1353–1360.

  9. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004.

10. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251–2259.

11. Cortes JE, Jones D, O’Brien S, et al. Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol. 2010;28:398–404.

12. Brummendorf TH, Cortes JE, de Souza CA, et al. 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;168:69–81.

13. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol. 2018;36:231–237.

14. Hanfstein B, Muller MC, Hehlmann R, et al. Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia. 2012;26:2096–2102.

15. Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2014;123:494–500.

16. Yeung DT, Osborn MP, White DL, et al. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood. 2015;125:915-923.

17. Kim DD, Lee H, Kamel-Reid S, Lipton JH. BCR-ABL1 transcript at 3 months predicts long-term outcomes following second generation tyrosine kinase inhibitor therapy in the patients with chronic myeloid leukaemia in chronic phase who failed imatinib. Br J Haematol. 2013;160:630–639.

18. Falchi L, Kantarjian HM, Wang X, et al. Significance of deeper molecular responses in patients with chronic myeloid leukemia in early chronic phase treated with tyrosine kinase inhibitors. Am J Hematol. 2013;88:1024–1029.

19. Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood. 2002;99:1928–1937.

20. Kantarjian HM, Cortes J, O’Brien S, et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood. 2002;99:3547–3553.

21. Kantarjian HM, O’Brien S, Cortes JE, et al. Treatment of Philadelphia chromosome- positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res. 2002;8:2167–2176.

22. Kantarjian HM, Cortes J, O’Brien S, et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood. 2002;99:3547–3553.

23. Kantarjian HM, O’Brien S, Cortes JE, et al. Treatment of Philadelphia chromosome- positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res. 2002;8:2167–2176.

24. Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 2002;99:3530–3539.

25. Palandri F, Castagnetti F, Testoni N, et al. Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: outcome of the patients alive after a 6-year follow-up. Haematologica. 2008;93:1792–1796.

26. Palandri F, Castagnetti F, Alimena G, et al. The long-term durability of cytogenetic responses in patients with accelerated phase chronic myeloid leukemia treated with imatinib 600 mg: the GIMEMA CML Working Party experience after a 7-year follow-up. Haematologica. 2009;94:205–212.

27. Silver RT, Cortes J, Waltzman R, et al. Sustained durability of responses and improved progression-free and overall survival with imatinib treatment for accelerated phase and blast crisis chronic myeloid leukemia: long-term follow-up of the STI571 0102 and 0109 trials. Haematologica. 2009;94:743–744.

28. Rea D, Etienne G, Nicolini F, et al. First-line imatinib mesylate in patients with newly diagnosed accelerated phase-chronic myeloid leukemia. Leukemia. 2012;26:2254–2259.

29. Ohanian M, Kantarjian HM, Quintas-Cardama A, et al. Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase. Clin Lymphoma Myeloma Leuk. 2014;14:155–162 e151.

30. Apperley JF, Cortes JE, Kim D-W, et al. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START A trial. J Clin Oncol. 2009;27:3472–3479.

31. Cortes J, Kim DW, Raffoux E, et al. Efficacy and safety of dasatinib in imatinib- resistant or –intolerant patients with chronic myeloid leukiemia in blast phase. Leukemia. 2008;22:2176–2183.

32. Kantarjian H, Cortes J, Kim DW, et al. 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;113:6322–6329.

33. Le Coutre PD, Giles FJ, Hochhaus A, et al. Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results. Leukemia. 2012;26:1189–1194.

34. Giles FJ, Kantarjian HM, le Coutre PD, et al. Nilotinib is effective in imatinib- resistant or –intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia. 2012;26:959–962.

35. Cortes JE, Khoury HJ, Kantarjian HM, et al. Long-term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib. Am J Hematol. 2016;91:1206-1214.

36. Sokal JE, Baccarani M, Russo D, Tura S. Staging and prognosis in chronic myelogenous leukemia. Semin Hematol. 1988;25:49–61.

37. Nicolini FE, Khoury HJ, Akard L, et al. Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors. Haematologica. 2013;98:e78–79.

38. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132:393-404.

(Revised 10/2019) © 2019 by Haymarket Media, Inc.

Hematologic Cancer Drug Monographs

Leukemias, Lymphomas, And Other Hematologic Cancers

ADCETRIS ALKERAN ALKERAN FOR INJECTION
ARRANON ARZERRA BELEODAQ
BENDEKA BEXXAR BICNU
BLEOMYCIN BLINCYTO BOSULIF
BUSULFEX CAMPATH CERUBIDINE
CLADRIBINE CLOLAR CYCLOPHOSPHAMIDE
CYTARABINE CYTOXAN INJECTION DACOGEN
DARZALEX DEPOCYT DOXIL
DOXORUBICIN HCL DOXORUBICIN HCL SOLUTION DTIC-DOME
EMPLICITI ERWINAZE EVOMELA
FARYDAK FLUDARA FOLOTYN
GAZYVA GLEEVEC GLEOSTINE
HYDREA ICLUSIG IDAMYCIN
IDAMYCIN PFS IMBRUVICA INTRON A
INTRON A SOLN ISTODAX JAKAFI
KEYTRUDA KYPROLIS LEUKERAN
MARQIBO MATULANE METHOTREXATE FOR INJECTION
METHOTREXATE INJECTION MITOXANTRONE HCL MUSTARGEN
MYLERAN NINLARO ONCASPAR
ONTAK OPDIVO PAMIDRONATE DISODIUM INJECTION
PENTOSTATIN POMALYST PURINETHOL
PURIXAN REVLIMID RITUXAN
SPRYCEL SYNRIBO TABLOID
TARGRETIN TARGRETIN GEL TASIGNA
THALOMID TREANDA TREXALL
TRISENOX UVADEX VALCHLOR
VELCADE VENCLEXTA VESANOID
VIDAZA VINBLASTINE FOR INJECTION VINBLASTINE INJECTION
VINCASAR PFS VUMON ZEVALIN
ZOLINZA ZOMETA ZYDELIG
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