Blast crisis in chronic myelogenous leukemia remains a difficult therapeutic challenge

Progression to blast crisis in patients with chronic myelogenous leukemia (CML) is an ominous development and signals the entry of the disease into an aggressive and therapy-resistant phase. It may be preceded by an accelerated phase marked by ‘B’ symptoms, progressive splenomegaly, increase in white cell counts, basophilia, therapy-resistant thrombocytosis or thrombocytopenia, and increase in the peripheral blood and marrow blast to 10 – 19% [1]. Blast crisis is usually defined by the presence of one of the following: (1) peripheral blood or bone marrow blast count 20% or 30%, (2) large foci or clusters of blasts on bone marrow biopsy, and (3) presence of extramedullary blast infiltrates (granulocytic sarcoma) [1]. About two-thirds of blast crises are myeloid and one-third lymphoid type. Progression to blast crisis appears to require additional chromosomal changes, which can be demonstrated in over 80% of the cases [2 – 4]. The commonest among these are trisomy 8, trisomy 19, duplication of Philadelphia chromosome, and isochromosome 17q. At a molecular level, 20 – 30% of the patients show deletions or rearrangements of p53 and a smaller number fusion of AML1 and EVI1. Abnormalities of methylation of M-bcr region, C-abl promoter region and the calcitonin gene have also been seen at the time of progression of CML towards blast crisis. Amplification of C-myc and deletion of RB1 are more typical of lymphoid blast crisis. Treatment of blast crisis is difficult and the prognosis poor. Imatinib, in patients without previous exposure to this agent, induces a response in 52%, with a median survival of 6.5 months and 1year survival of 22% [5]. Induction chemotherapy, usually including high dose cytarabine, produces similar results but is more toxic [6,7]. More intensive chemotherapy regimens such as mitoxantrone plus etoposide plus cytarabine (MEA) and Idarubicin plus cytarabine plus etoposide (ICE) have proven no better. With the latter two regimens, the response rate was 47% and median survival 6 months [8]. Stem cell transplant also appears to offer limited success in these patients, with disease progression/ relapse remaining a big problem. One-year survival following stem cell transplant in these patients is about 50% [8]. In this issue of Leukemia and Lymphoma, Quintas-Cardama et al. [9] report their experience in the treatment of myeloid blast crisis with a regimen that includes imatinib, low dose cytarabine, and idarubicin. The rationale for this combination came from previous reports, which showed synergy between imatinib and chemotherapeutic agents like cytarabine and idarubicin. A total of 19 patients were treated over a period of 2 years. Seventeen had previously been treated with imatinib, nine with cytarabine, and at least three with anthracyclines. Fourteen patients (74%) achieved a hematologic response, nine (47%) of which were complete. Six patients went on to undergo allogeneic stem cell transplant. But the median duration of the response was only 10 weeks and median survival 5 months. Do these results represent a significant advance in the treatment of myeloid blast crisis? The answer, alas, is a no. The total number of patients is too small. We are not told whether pretherapy bone marrows showed additional cytogenetic abnormalities and if those abnormalities had any relationship with the outcomes. Since a majority of the patients had been previously treated with imatinib, information about abl mutations associated with resistance to this agent would have been helpful. Treatment