Imatinib masylate (IM) induces sustained molecular remissions in patients with chronic myeloid leukemia (CML) but a life-long therapy is required for most of these patients. In STIM study, Mahon et al. reported that among patients with a complete molecular response (CMR) lasting at least two years, the CMR was sustained in 41% after discontinuation of IM. German study group showed that treatment with Interferon-alpha (IFN) enables IM discontinuation in most patients after prior IM/IFN combination therapy. 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 . 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). Since the aim of this study is to confirm the finding that IFN is able to maintain MMR induced by IM after its discontinuation, we present here the result of the interim analysis.
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.
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.
Administration of IFN is started at a dose of 3 million units 2–5 times per week within 4 weeks after IM discontinuation. In case of molecular relapse, IM was resumed at 400 mg daily.
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.
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 risk of Sokal score were analyzed.
The median follow-up period is 23 months (range: 6–27 months). Three patients lost MMR (1, 3, and 6 months, respectively) and other 9 maintained CMR. Molecular relapse-free survival is 74%. The sustained CMR patients had the 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). There was no difference between the relapsed and the sustained CMR patients in the duration of IM treatment. All the relapsed patients achieved MMR after 2, 4, and 5 months of IM resumption, respectively.
In conclusion, IFN monotherapy is a promising option for sustained molecular response after IM discontinuation in CML patients with CMR.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.