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Chronic Phase Chronic Myeloid Leukemia: More Drugs, More Lives Saved, New Challenges

Chronic Phase Chronic Myeloid Leukemia: More Drugs, More Lives Saved, New Challenges

In this issue of ONCOLOGY, Jabbour, Cortes, and Kantarjian provide an "owners manual" for chronic myeloid leukemia (CML) drug therapy, in which they elegantly discuss practical issues of management.

Although not curative,[1] imatinib mesylate (Gleevec) therapy improves survival and prevents leukemic transformation in chronic phase CML.[2] Among 553 newly diagnosed cases, the complete cytogenetic remission rate was 69% at 1 year and 87% at 5 years.[2] Complete cytogenetic remission is defined as the complete eradication of karyotypically apparent Philadelphia chromosome (Ph)-positive metaphases. Among such patients, major molecular remission, defined as 3-log reduction in mutant allele burden, occurred in 53% at 1 year and 80% at 4 years.[2] The 5-year overall survival rate was 89%; progression to either accelerated or blast phase CML occurred in only 6% of the study population; cytogenetic (from complete cytogenetic remission) or hematologic relapse occurred in 5% and 3% of patients, respectively.[2]

Expert Panel Guidelines

With this and other[3-7] similar kind of information, it is not surprising that almost 90% of practicing physicians choose drug therapy with imatinib as first-line treatment even for transplant-eligible patients.[8] Allogeneic stem cell transplant (ASCT) remains a viable salvage therapy for imatinib failures.[9] The same international survey indicated that physicians choose 400 mg/d as the starting dose, which is in line with the recently published recommendations from a CML expert panel.[10]

Once treatment has commenced, the expert panel recommends peripheral blood monitoring of molecular remission every 3 months and bone marrow cytogenetic examination every 6 months until complete cytogenetic remission is demonstrated and every 12 months thereafter.[10] However, we are not convinced about the outcome-relevant value of annual bone marrow examination after achievement of complete cytogenetic remission in chronic phase CML. We would also point out that neither cytogenetic nor molecular tests are indicated in the absence of complete hematologic remission, which is defined by normal complete blood count, leukocyte differential, and no palpable spleen.

Imatinib Failure

The aforementioned CML expert panel defines suboptimal imatinib response as follows: (1) no complete hematologic remission at 3 months, (2) no partial cytogenetic remission (ie, 1%-35% Ph-positive metaphases) at 6 months, (3) no complete cytogenetic remission at 12 months, or (4) no major molecular remission at 18 months.[10] We find these particular guidelines reasonable. What then is next for patients with either suboptimal response to imatinib, drug intolerance, or loss of molecular, cytogenetic, or hematologic response?

In a recent study, chronic phase CML patients who were imatinib-intolerant or -refractory continued to benefit from other kinase inhibitor therapy (dasatinib [Sprycel] or nilotinib [Tasigna]) and experienced a 3-year survival that was not inferior to that of ASCT.[11] This observation is in line with earlier studies that showed the efficacy of both dasatinib and nilotinib as salvage therapy for chronic phase CML after initial treatment with imatinib has failed.[12,13] For example, among 186 chronic phase CML patients with imatinib-resistant or imatinib-intolerant disease, dasatinib at 70 mg twice daily induced 90% complete hematologic remission and 52% durable major cytogenetic remission (complete plus partial cytogenetic remission) at a median follow-up of 8 months.[14]

Similarly, for patients with suboptimal response to conventional doses of imatinib (400-600 mg/d), switching to dasatinib was shown to be more effective than increasing the dose of imatinib further.[15] In another preliminary study, dasatinib therapy was also shown to overcome in vivo nilotinib resistance.[16] Therefore, we believe it is currently reasonable to consider early intervention with dasatinib in imatinib failures with chronic phase CML.

Remaining Challenges

Although kinase inhibitor therapy has dramatically improved the outlook for patients with CML, certain challenges remain: the potential need for lifelong therapy,[17] emergence of BCR-ABL mutations (eg, BCR-ABLT315I) that are resistant to all three aforementioned kinase inhibitors,[18] improving but still inadequate treatment outcomes for accelerated or blast phase disease,[19,20] sudden blastic transformation from imatinib-induced complete cytogenetic remission,[21] and drug side effects that are not trivial.[22]

Reported imatinib side effects occurring in more than one-third of treated patients include edema, muscle cramps, diarrhea, nausea, musculoskeletal pain, rash, abdominal pain, fatigue, and headaches.[2] Other adverse events associated with imatinib treatment include grade 3/4 neutropenia (17%), thrombocytopenia (9%), anemia (4%), and elevated liver enzymes (5%).[2] Despite recent concerns,[23] the risk of potentially imatinib-related congestive heart failure is estimated to be < 1%.[2,24] Physicians should also be aware of imatinib-associated hypophosphatemia and altered bone metabolism.[25]

Adverse events seen in dasatinib-treated chronic phase CML patients include moderate to severe myelosuppression in more than one-third of the patients, pleural effusion (19%), edema (18%), elevated bilirubin (14%), elevated transaminases (> 50%), dyspnea (27%), diarrhea (30%), headache (34%), fatigue (28%), and rash (22%).[14] Adverse events reported in at least 4% of nilotinib therapy recipients included myelosuppression, rash, pruritus, dry skin, gastrointestinal symptoms, fatigue, and increased serum lipase, amylase, transaminase, and/or bilirubin levels.[12] Last but not least, these drugs are not cheap!

—Ayalew Tefferi, MD
—Mark Litzow, MD

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References

1. Barnes DJ, Melo JV: Primitive, quiescent and difficult to kill: The role of non-proliferating stem cells in chronic myeloid leukemia. Cell Cycle 5:2862-2866, 2006.

2. Druker BJ, Guilhot F, O'Brien SG, et al: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408-2417, 2006.

3. Kantarjian HM, O'Brien S, Cortes J, et al: Imatinib mesylate therapy improves survival in patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia in the chronic phase: comparison with historic data. Cancer 98:2636-2642, 2003.

4. Kantarjian HM, Talpaz M, O'Brien S, et al: Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. Blood 108:1835-1840, 2006.

5. Cortes J, Talpaz M, O'Brien S, et al: Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate. Clin Cancer Res 11:3425-3432, 2005.

6. Kantarjian H, Talpaz M, O'Brien S, et al: Survival benefit with imatinib mesylate therapy in patients with accelerated-phase chronic myelogenous leukemia-comparison with historic experience. Cancer 103:2099-2108, 2005.

7. Kantarjian H, Talpaz M, O'Brien S, et al: High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood 103:2873-2878, 2004.

8. Kantarjian HM, Cortes J, Guilhot F, et al: Diagnosis and management of chronic myeloid leukemia: A survey of American and European practice patterns. Cancer 109:1365-1375, 2007.

9. Jabbour E, Cortes J, Kantarjian HM, et al: Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure. Blood 108:1421-1423, 2006.

10. Baccarani M, Saglio G, Goldman J, et al: Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 108:1809-1820, 2006.

11. Kantarjian H, O'Brien S, Talpaz M, et al: Outcome of patients with Philadelphia chromosome-positive chronic myelogenous leukemia post-imatinib mesylate failure. Cancer 109:1556-1560, 2007.

12. Kantarjian H, Giles F, Wunderle L, et al: Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354:2542-2551, 2006.

13. Talpaz M, Shah NP, Kantarjian H, et al: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354:2531-2541, 2006.

14. Hochhaus A, Kantarjian HM, Baccarani M, et al: Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 109:2303-2309, 2007.

15. Kantarjian H, Pasquini R, Hamerschlak N, et al: Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: A randomized phase-II trial. Blood 2007 (epub ahead of print).

16. Quintas-Cardama A, Kantarjian H, Jones D, et al: Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure. Blood 109:497-499, 2007.

17. Cortes J, O'Brien S, Kantarjian H: Discontinuation of imatinib therapy after achieving a molecular response. Blood 104:2204-2205, 2004.

18. Giles FJ, Cortes J, Jones D, et al: MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood 109:500-502, 2007.

19. Cortes J, Rousselot P, Kim DW, et al: Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 109:3207-3213, 2006.

20. Guilhot F, Apperley J, Kim DW, et al: Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 2007 (epub ahead of print).

21. Jabbour E, Kantarjian H, O'Brien S, et al: Sudden blastic transformation in patients with chronic myeloid leukemia treated with imatinib mesylate. Blood 107:480-482, 2006.

22. Atallah E, Kantarjian H, Cortes J: Emerging safety issues with imatinib and other abl tyrosine kinase inhibitors. Clin Lymphoma Myeloma 7(suppl 3):S105-S112, 2007.

23. Kerkela R, Grazette L, Yacobi R, et al: Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12:908-916, 2006.

24. Atallah E, Kantarjian H, Cortes J: In reply to 'Cardiotoxicity of the cancer therapeutic agent imatinib mesylate.' Nat Med 13:14; author reply 15-16, 2007.

25. Berman E, Nicolaides M, Maki RG, et al: Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med 354:2006-2013, 2006.

 
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