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CML Blast Crisis: Imatinib Plus Chemotherapy Effective for Some
Abstract & Commentary
By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.
Synopsis: In a series of 16 patients with CML blast crisis, treatment mitoxantrone, etoposide, and imatinib on four different schedules was studied in a phase I/II trial. The regimens were well tolerated and although median survival was only 6.4 months, all those on the more intensive schedule met criteria for hematological response and six patients ultimately received allogeneic stem cell transplant and four of these remain alive at the time of publication.
Source: Fruehauf S, et al. Cancer. 2007;109:1543-1549.
Treatment of blast crisis remains a major challenge. In the current report, Fruehauf and colleagues describe their experience in a phase I/II trial in which patients were treated with imatinib, mitoxantrone, and etoposide using four different treatment schedules. In each schedule, the mitoxantrone dose was 10 mg/m2 per day and the etoposide was 100 mg/m2 per day. The mitoxantrone and etoposide were administered on days one and two (schedule I) or days one, two, and three (schedule 2). Imatinib 600 mg per day was initiated on day 15. Schedules three and four were analogous with regard to mitoxantrone and etoposide, but the imatinib was administered from day one. After hematologic reconstitution (following the cytopenic phase) cytarabine was given at a dose of 10 mg/m2 per day in addition to the daily dose of imatinib.
There were 16 patients enrolled in this study. The majority had been treated with interferon or hydroxyurea during the chronic phase and only two had received prior imatinib. At the time of diagnosed blast crisis, the median age was 60 years (range 37 to 75 years) and the median time from diagnosis of CML diagnosis to enrollment was five months (range 1 to 23.6 months). Five patients had received prior treatment for blast crisis; each with a cytarabine-based regimen.
The treatment regimen was generally well tolerated by most patients. However, as expected, pancytopenia was commonly observed and platelet and red cell transfusions were required. The patients who received imatinib on day one (cohorts 3 and 4) had significantly longer duration of severe neutropenia. There were two treatment-related deaths; one secondary to pneumonia and the second due to intracranial hemorrhage.
The median survival was 6.4 months, comparable prior reports of imatinib used as a single agent alone for blast crisis.1 Hematologic responses with normalization of the white blood count and reduction of the bone marrow blast percentage to less than 5% was observed in six of nine patients in cohorts 1 and 2 and in seven of seven patients in cohorts 3 and 4. Two of the nine patients in cohorts one and two and four of the seven patients in cohorts three and four went on to receive allogeneic stem cell transplant. Four of the transplanted patients remained alive and in complete remission at the time of this publication (range 16 to 31 months).
The combination of mitoxantrone, etoposide, and imatinib appeared to be well tolerated in patients with blast crisis CML. Although those who received imatinib starting on day one had more profound cytopenia, they also appeared to have higher hematologic response rates. Yet, the overall median survival of 6.4 months was disappointing although four of the six transplanted patients remain alive and in remission.
The trial was initiated at the time in which imatinib was not standard of care for chronic phase CML and for most, this was their first exposure to this agent. Perhaps the success at producing hematologic response will be less on the basis of developed imatinib resistance. In this regard, the newer tyrosine kinase inhibitors, such as nilotinib2 and dasatinib3 may be more suitable for the initial blast crisis combination with mitoxantrone/etoposide or other chemotherapy agents.
Although the role for allogeneic stem cell transplant for individuals with CML in chronic phase remains controversial for those in blast crisis, if patients are suitable candidates with regard to physiological status and limited comorbidities, this approach is likely to offer the best chance for long term survival.
1. Kantarjian HM, et al. Blood. 2002;99:3547-3553.
2. Talpaz M, et al. N Engl J Med. 2006;354:2531-2541.
3. Kantarjian H, et al. N Engl J Med. 2006;354:2542-2551.