Therapy-Free Remission after Interferon Alfa Maintenance with Imatinib Discontinuation in Patients with Chronic Myeloid Leukemia

Introduction: Imatinib mesylate (IM) induces sustained molecular remissions in patients with chronic myeloid leukemia (CML) but a life-long therapy is required for most of these patients. We previously reported that CD8+ memory T cells showed significant predominance over naive T cells in the patients with sustained therapy-free major molecular response (MMR), all of that had previously received IFN [1]. We have been performing a phase 2 study of treatment discontinuation after the drug change from IM to IFN (Japanese Imatinib Stop And Interferon Study; JISAS). This trial is comprised of 2 parts; the first part is to change therapy drug from imatinib to IFN and the second part is to stop IFN for therapy-free. We present here a final result of this trial.

Patients: Patients with a confirmed diagnosis of CML in 1st chronic phase (CP1) as well as in CMR (undetectable BCR-ABL transcript) following over 2 years of MMR on IM were enrolled in this pilot study after obtaining the written informed consent. All the eligible patients were recruited from September 2009 to December 2011 whether or not any therapeutic drug had been given before IM.

Evaluation and response criteria:Since a conversion factor for International scale was not available in Japan until recently, for entry to the study, BCR-ABL transcripts at a level equal to or below 100 copy/mg RNA in a real-time quantitative-polymerase chain reaction (RQ-PCR) assay or equal to or below 50 copy/assay in a highly sensitive transcription-mediated amplification (TMA) method were defined as MMR. CMR was defined as detection of no BCR-ABL transcript in RQ-PCR assay, nested reverse transcriptase-polymerase chain reaction (RT-PCR) assay, or TMA.During the study, molecular response was assessed at the baseline and every month thereafter, by determining the BCR-ABL to ABL mRNA transcript ratio isolated from the peripheral blood using RQ-PCR and RT-PCR. The BCR-ABL to ABL transcript ratio at a level below 0.001 was defined as MMR and no detectable BCR-ABL transcript in RT-PCR was defined as CMR. Molecular relapse defined as a loss of MMR was taken into account if confirmed in 2 successive assessments.

Study design and treatment: Administration of IFN is started at a dose of 3 million units 2-5 times per week within 4 weeks after IM discontinuation. IFN administration was stopped after 2 years of IFN maintenance. In case of molecular relapse, IM was resumed at 400 mg daily.

Statistical analysis: Non-parametric values or numbers were compared between the two groups using the Mann-Whitney test. Relapse-free survival was estimated using the Kaplan-Meier method.

Results: Fifteen patients were enrolled from September 2009 to December 2011. Median age was 50 years (range, 28-67 years) and male to female ratio was 1.5. Sokal score at the diagnosis was low in 13 patients and high in 2 patients. Four patients had been treated before IM. Previous therapies comprised IFN in all these patients, including 1 patient who relapsed after allogeneic stem cell transplantation (SCT). The clinical stage of this patient was amended to be accelerated phase at the time of diagnosis. Two other patients withdrew the consent. Excluding these 3 patients, the remaining 12 patients with low Sokal score were analyzed.

The average follow-up period is 1220 days (range: 797-1519 days). Four patients lost MMR (1, 3, and 6 months in IFN maintenance phase and 10 months after IFN discontinuation, respectively) and other 8 maintained CMR. Estimated molecular relapse-free survival at 1 year after discontinuation of IFN is 60%. The patients in therapy-free remission revealed significantly longer CMR period on IM (median 31 months, range 26-79 months) compared with relapsed patients (0, 9, and 14 months, respectively; p=0.0142). Molecular relapse free survival was significantly better in patients with over 2 years of CMR on IM than otherwise (80% vs 25%; log-rank test, p=0.0013). All the relapsed patients achieved MMR after 2, 2, 4, and 5 months of IM resumption, respectively.

Conclusion: IFN maintenance can provide high probability of therapy-free remission in patients with sustained molecular response of IM treatment for CML, especially with over 2 years of sustained CMR of IM treatment.

References

[1] Usuki K, et al. Leuk Res 2009; 33: e164.