Imatinib Mesylate Discontinuation in Patients with Chronic Myelogenous Leukaemia in Complete Molecular Remission for More Than Two Years.

Background. Imatinib mesylate (IM, Gleevec®) induces cytogenetic remission (CCR) defined as the disappearance of Philadelphia (Ph) chromosome-positive metaphases in more than 85% of patients with chronic myelogenous leukaemia (CML). However, less than 10% achieve a complete molecular response which may be defined by a minimum residual disease undetectable using polymerase chain reaction (PCR). Virtually all patients in CCR will relapse after IM interruption because of detectable residual disease. In the present study, we have discontinuated IM in patients with undetectable residual disease for more than 2 years.

Patients and method. We prospectively collected the results from 8 CML patients (median age 62 years; 41 years to 82 years) treated with IM (400 mg/day). Residual disease was quantified by RTQ-PCR and expressed as the BCR-ABL/BCR ratio. PCR negativity was controlled independently by two molecular laboratories every 4 months and patients were included in the study if they have been PCR negative during at least 2 years under IM therapy. After IM discontinuation, RTQ-PCR was monitored every month.

Results. According to Sokal’s classification, 4 patients were considered low risk, 3 intermediate risk and one high risk. All patients except one received interferon (treatment duration 3 to 72 months). One of them received an autologous stem cell transplantation for interferon failure. Median duration of IM therapy was 37 months (34 months to 40 months) and median time from CML diagnosis to IM discontinuation was 104 months (43 months to 152 months). RTQ-PCR negativity was observed during 30 months in median (24 months to 46 months) as required for the inclusion in the study. Four patients presented a molecular relapse with a detectable BCR-ABL transcript rising from 0,001% to 0,01% confirmed at least two times after 2 months (2 patients), 3 months and 4 months of IM discontinuation without detectable BCR-ABL kinase domain mutation. IM was then restarted and lead to a novel molecular remission in 2 patients and to a major molecular response in the 2 others. Four other patients are still negative with a follow up of 8, 9, 12 and 13 months after IM discontinuation. Of note, all these patients received interferon before IM therapy and one patient still have detectable serum antinuclear antibodies.

Conclusion. As we have previously reported with interferon, it is possible to stop IM in patients with CML who achieve a molecular remission as we have strictly defined. Early molecular relapses are sensitive to IM re-challenge. Interestingly, we did not observed late relapses at this point. As our patients in persistent molecular remission were previously exposed to interferon, it is possible that IM therapy combined with immune response modifiers could be responsible for a putative cure of the disease.