Imatinib Mesylate (Gleevec®) for CML Blast Crisis
Abstract & Commentary
Synopsis: Chronic myelogenous leukemia, when it evolves beyond the accelerated phase into blast crisis, becomes refractory to treatment and meaningful responses are few. In 2 recently published reports of phase II studies of imatinib mesylate (Gleevec®) treatment of blast crisis, response rates were 50% or more in each. Furthermore, a small percentage in each study achieved a complete cytogenetic response. Nonetheless, median survival, even for those with responsive disease, remained less than 1 year. They speculate that combinations including Gleevec® and cytotoxic chemotherapy would be a worthy next step in determining optimal management of this difficult malignancy.
Sources: Sawyers CL, et al. Blood. 2002;99:3530-3539; Kantarjian HM, et al. Blood. 2002;99:3547-3553; Goldman J. Blood. 2002;99:3491-3492.
Despite recent remarkable advances in the management of chronic myelogenous leukemia (CML) during the early, chronic phase, when the disease advances to the more advanced phases, treatment successes remain few. There is no standard therapy at this point for blast crisis and treatment has been typically what is used for acute leukemia, including allogeneic bone marrow transplant. Response rates remain low and median survival is 3-6 months.1
In the current issue of Blood, there are 2 papers that report the results of phase II trials of Imatinib mesylate (STI571, Gleevec®) for patients in CML blast crisis. Although only modest improvements in patient survival were observed, there were impressive response rates, more than previously reported for combination chemotherapy.
Sawyers and colleagues describe the results of an international, multi-institutional phase II study in which 260 patients with myeloid-lineage, accelerated phase or blast crisis CML were enrolled. Of these, 239 were confirmed to have myeloid blast crisis (> 30% myeloid blasts in the marrow). Patients were treated with imatinib in daily oral doses of 400 mg or 600 mg and hematologic responses were observed in 52% and sustained hematologic responses (lasting 4 weeks) in 31%, including complete hematologic responses in 8%. For patients with sustained response, the estimated median survival was 10 months and overall median survival was 6.9 months. Nonhematologic adverse events were frequent, but generally mild or moderate.
The second report by Kantarjian and colleagues was that of a single institution’s (M.D. Anderson, Houston, Tex) experience treating CML blast crisis of both myeloid (n = 65) and lymphoid (n = 10) lineage. Doses of imatinib varied from 300 mg to 1000 mg per day.
Similar to the multi-institutional study mentioned above, the overall objective response rate was 52% (39 or 75). The cytogenetic response rate was 16% (12 patients) with 5 patients having complete cytogenetic response. The overall median survival was 6.5 months and the estimated 1-year survival, 22%. Kantarjian et al compared these results to historical controls, also treated at M.D. Anderson, mostly with cytarabine combinations and found imatinib to be both less toxic and more effective.
Comment by William B. Ershler, MD
The Philadelphia chromosome (Ph) is the hallmark of CML and it is a translocation of fragments of chromosome 9 and 22 resulting in the production of the Bcr-Abl fusion protein (p210) which is a constitutively active tyrosine kinase that mediates cellular transformation. The activation of p210 is causally related to the development of CML,2 but progression to the more advanced stages is thought to depend on the development of additional genetic changes, leading to loss of differentiation and a more problematic clinical picture. Thus, as Goldman points out in an accompanying editorial, the impressive responses observed in both studies were contrary to expectations and indicative of either a sustained importance of the Bcr fusion protein despite the accumulation of additional genetic damage, or the broader range of inhibitory activity of this previously considered, highly selective agent.
However, by whatever explanation, imatinib must now be considered an effective (perhaps the most effective) treatment for CML blast crisis. Yet, despite the impressive response rates, survival was budged only minimally. Hopefully, future trials will combine this agent with others to provide a more meaningful enhancement of survival. Also, it remains to be seen whether those treated with imatinib during chronic phase, will benefit from increased dosing or altered schedule when the blast crisis occurs. This, of course, has become a highly relevant question in light of the very common use of this agent early in the course of CML. In fact, even today, it is unlikely that patients will have progressed to blast crisis without an earlier treatment course with Gleevec®.
Dr.Ershler of INOVA Fairfax Hospital Cancer Center, Fairfax, VA, Director, Institute for Advanced Studies in Aging, Washington, D.C.
1. Gacchi S, et al. Cancer. 1999;88:2632-2641.
2. Kelliher MA, et al. Proc Natl Acad Sci USA. 1990;87: 6649-6653.