Leukemia Treatment Regimens: Chronic Myeloid Leukemia (CML)

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LEUKEMIA TREATMENT REGIMENS: Chronic Myeloid Leukemia (CML)

Clinical Trials: The NCCN 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 health care 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 chronic myeloid leukemia (CML) cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These chronic myeloid leukemia (CML) cancer treatment regimens are provided only to supplement the latest treatment strategies.

These Cancer Treatment Guidelines are a work in progress that may be refined as often as new significant data become 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.

(Revised 2/2017)

© 2017 by Haymarket Media, Inc.

Chronic Phase CML1

Primary Treatment1

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

REGIMEN

DOSING

Low-risk Score2-9a

Imatinib 400mg orally daily (Category 1)

OR

Nilotinib 300mg orally twice daily (Category 1)

OR

Dasatinib 100mg orally daily (Category 1).

Intermediate- or High-risk Score2-9a

Dasatinib 100mg orally daily (preferred)

OR

Nilotinib 300mg orally twice daily (preferred)

OR

Imatinib 400mg orally daily.

3 Month Evaluation1

BCR-ABL1 transcripts ≤10% by QPCR (IS)2-9b

Continue same tyrosine kinase inhibitor (TKI).

BCR-ABL1 transcripts >10% by QPCR (IS)9-12c-j

Evaluate patient compliance and drug–drug interactions, consider mutational analysis and bone marrow cytogenetics

Switch to alternate TKI (other than imatinib)

OR

Continue same TKI

OR

Dose escalation of imatinib to a maximum of 800mg (if primary treatment with imatinib)

AND

Evaluate for hematopoietic cell transplantation (HCT) depending on response to TKI therapy.

6 Month Evaluation1

BCR-ABL1 transcripts ≤10% by QPCR (IS)2-9b

Continue same TKI.

BCR-ABL1 transcripts >10% by QPCR (IS)13c, e-j

Evaluate patient compliance and drug–drug interactions, consider mutational analysis and bone marrow cytogenetics

Change therapy to alternate TKI (other than imatinib) and evaluate for HCT depending on response to TKI therapy.

12 Month Evaluation1

BCR-ABL1 transcripts <1% by QPCR (IS)2-9b

Continue same TKI.

BCR-ABL1 transcripts ≤10% but 1% by QPCR (IS)10d-j

Evaluate patient compliance and drug–drug interactions, consider mutational analysis and bone marrow cytogenetics

Switch to alternate TKI

OR

Continue same TKI

OR

Dose escalation of imatinib to a maximum of 800mg (if primary treatment with imatinib)

AND

Evaluate for HCT depending on response to TKI therapy.

BCR-ABL1 transcripts > 10% by QPCR (IS)10c,e-j

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

Change therapy to alternate TKI (other than imatinib) and evaluate for HCT depending on response to TKI

Evaluations Beyond 12 Months1

BCR-ABL1 transcripts <0.1% by QPCR (IS)2-9b

Continue same TKI.

BCR-ABL1 transcripts <1% but no less than 0.1% by QPCR (IS)10d-j

Evaluate patient compliance and drug–drug interactions, consider

mutational analysis and bone

marrow cytogenetics

Change therapy to alternate TKI (preferred) (other than imatinib)

OR

Continue same TKI

OR

Dose escalation of imatinib to a maximum of 800mg (if primary treatment with imatinib)

AND

Evaluate for hematopoietic cell transplantation (HCT) depending on response to TKI therapy.

BCR-ABL1 transcripts >10% by QPCR (IS)10c, e-j

Evaluate patient compliance and drug–drug interactions, consider

mutational analysis and bone

marrow cytogenetics

Change therapy to alternate TKI (other than imatinib) and evaluate for HCT depending on response to TKI therapy.

Advanced Phase CML1

Accelerated phase15-32k

Imatinib 600mg orally daily

OR

Dasatinib 140mg orally daily (70mg twice daily)

OR

Nilotinib 400mg orally twice daily

OR

Bosutinib 500mg orally daily

OR

Ponatinib 45mg orally daily

OR

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

Blast phase—lymphoid15-32

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

OR

TKI + steroids.

Blast phase—myeloid15-32

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

OR

TKI.

a Preliminary data suggest that patients with an intermediate- or high-risk Sokal or Hasford score may preferentially benefit from dasatinib or nilotinib.

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

c 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.

d 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 or nilotinib for another 3 months.

e Patients with disease that is resistant to primary treatment with imatinib should be treated with nilotinib, dasatinib, or bosutinib in the second-line setting. Patients with disease that is resistant to primary treatment with nilotinib or dasatinib could be treated with an alternate TKI (other than imatinib) in the second-line setting.

f Dasatinib is a treatment option for patients with a Y253H, E255K/V, or F359V/C/I mutation

g Nilotinib is a treatment option for patients with F317L/V/I/C, T315A, or V299L mutation

h Bosutinib is a treatment option for patients with E255K/V, F317L/V/I/C, F359V/C/I, T315A, or Y253H mutation

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

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

k 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

References

1. NCCN Clinical Practice Guidelines in Oncology™. Chronic Myeloid Leukemia. v 2.2017. Available at: http://www. nccn.org/pro fessionals/physician_gls/pdf/cml.pdf. Accessed February 23, 2017.

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. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. Yeung DT, Osborn MP, White DL, et al. Early switch to nilotinib does not overcome the adverse outcome for CML patients failing to achieve early molecular response on imatinib, despite excellent overall outcomes in the TIDEL II trial [abstract]. Blood. 2012;120:Abstract 3771.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.

26. 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.

27. 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.

28. 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.

29. Gambacorti-Passerini C, Cortes JE, Khoury HJ, et al. Safety and efficacy of bosutinib in patients with AP and BP CML and ph+ ALL following resistance/intolerance to imatinib and other TKIs: Update from study SKI-200 [abstract]. J Clin Oncol. 2010;28(15_suppl):Abstract 6509.

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

31. 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.

32. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. Long-term follow-up of ponatinib efficacy and safety in the phase 2 PACE trial [abstract]. Blood. 2014;124:Abstract 3135.


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

Data provided by the Monthly Prescribing Reference (MPR) Hematology/Oncology Edition.

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