The development of imatinib mesylate (Gleevec), a tyrosine kinase inhibitor targeted against the causative Bcr-Abl protein in chronic myeloid leukemia (CML), has resulted in hematologic and cytogenetic remissions in all phases of CML. Following imatinib treatment, more than 90% of patients obtain complete hematologic response, and 70% to 80% achieve a complete cytogenetic response. With 5 years of follow-up, the data are very encouraging, exhibiting a major change in the natural history of the disease. The understanding of at least some of the mechanisms of resistance to imatinib has led to a rapid development of new agents that may overcome this resistance. Combination strategies are currently being investigated in preliminary clinical studies and may prove to be useful. Overall, there are an increasing number of treatment options now available for patients with CML.
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, imatinib mesylate (Gleevec) therapy improves survival and prevents leukemic transformation in chronic phase CML. Among 553 newly diagnosed cases, the complete cytogenetic remission rate was 69% at 1 year and 87% at 5 years. 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. 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.
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. Allogeneic stem cell transplant (ASCT) remains a viable salvage therapy for imatinib failures. 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.
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. 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.
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. 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. 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.
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. In another preliminary study, dasatinib therapy was also shown to overcome in vivo nilotinib resistance. Therefore, we believe it is currently reasonable to consider early intervention with dasatinib in imatinib failures with chronic phase CML.
Although kinase inhibitor therapy has dramatically improved the outlook for patients with CML, certain challenges remain: the potential need for lifelong therapy, emergence of BCR-ABL mutations (eg, BCR-ABLT315I) that are resistant to all three aforementioned kinase inhibitors, improving but still inadequate treatment outcomes for accelerated or blast phase disease,[19,20] sudden blastic transformation from imatinib-induced complete cytogenetic remission, and drug side effects that are not trivial.
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. Other adverse events associated with imatinib treatment include grade 3/4 neutropenia (17%), thrombocytopenia (9%), anemia (4%), and elevated liver enzymes (5%). Despite recent concerns, 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.
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%). 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. 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.
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