Imatinib at 400 mg per day has rapidly become the standard therapy for newly diagnosed patients with chronic phase chronic myeloid leukemia (CML). In this patient population, 74% of patients achieved a complete cytogenetic response (CCR),1  but less than 5% of patients are polymerase chain reaction (PCR)–negative for BCR/ABL transcripts.2  Although relapses from a CCR have been uncommon, the presence of BCR/ABL transcripts in the majority of patients raises the concern that molecular disease persistence could translate into disease relapse. Two critical questions for the future of CML therapy are whether it is necessary to achieve lower BCR/ABL levels to affect survival and, if it is necessary, is it possible? Although it seems intuitive that lower BCR/ABL levels would be better, longer follow-up studies that correlate the level of BCR/ABL transcripts with survival are needed to determine if there is a threshold below which relapses are uncommon.

Anticipating that lower BCR/ABL transcript levels will correlate with longer survival, 2 articles in this issue of Blood address whether it is possible to obtain improved responses. The study by Chu and colleagues (page 3167) first examines the molecular mechanism of disease persistence and yields some surprising results. Ex vivo treatment of CD34+ CML cells with imatinib mesylate led, as expected, to inhibition of BCR/ABL kinase activity, but their data suggest that low levels of BCR/ABL kinase activity persisted in imatinib-treated cells. Surprisingly, they found a dose- and growth factor–dependent increase in mitogen-activated protein kinase (MAPK) activity. Although the mechanism whereby MAPK activity increased is not clear, combination treatment with imatinib and a MAPK inhibitor led to increased suppression of CML progenitor growth. If this data were confirmed using CD34+ cells from patients undergoing therapy with imatinib, it suggests a strategy to circumvent molecular persistence.

The article by Kantarjian and colleagues (page 2873) studied the effects of higher-dose imatinib in chronic phase patients and demonstrated a high rate of CCR and molecular negativity. However, the optimal dosage of imatinib is not clear. What is clear is that 800 mg per day is significantly less well tolerated than 400 mg per day, with more than one third of the patients treated with 800 mg per day requiring dose reduction. Due to technical differences in the PCR assays, the data in this report cannot be directly compared with studies in which a 5% PCR-negative rate was reported.2  What can be stated is that using historical controls, the authors found that patients treated with higher dosages of imatinib have a greater depth of molecular response. As mentioned, it is not yet clear whether improved molecular responses are necessary to achieve improved outcomes. Further, there has not been a randomized study comparing various dosages of imatinib. As such, it is not clear whether the suggestion of improved responses is worth the extra toxicity, but this data should serve as the impetus for a randomized study. In this regard, there are clinical trials that are active or soon to be activated comparing standard doses of imatinib to high-dose therapy to the combination of imatinib with interferon to imatinib with low-dose Ara-C. These studies are either designed as survival studies or use the level of molecular response at one year of therapy as endpoints. Until the results of these studies are available, treatment with 800 mg imatinib should be limited to patients in clinical trials or patients with less than optimal responses to standard dosages of imatinib. For the future, as more is learned about the mechanism of molecular persistence, even more rational strategies can be devised to eradicate this disease, and as more patients become molecularly negative, the prospect for a cure indeed seems real.

O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia.
New Engl J Med.
Hughes TP, Kaeda J, Branford S, et al, for the International Randomised Study of Interferon versus STI571 (IRIS) Study Group. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia.
N Engl J Med.
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