Towards Stopping Imatinib Therapy under the Umbrella of Interferone: Alpha-Interferone Improves Molecular Response in CML Patients with Imatinib Induced Complete Cytogenetic Remission: An Early Observation from a Study of Pegylated Interferone in the Set up of Minimal Residual Disease.

The therapy with Imatinib mesylate (Ima) is related with a high rate of response in both newly diagnosed and previously treated CML patients (pt’s). However only 5% of treated pt’s achieve complete molecular remission (CMR) as defined by repeated negative nested PCR or RT-PCR studies, and discontinuation of therapy usually results in a rapid disease progression. The later phenomenon is related with the reduced activity of Ima on early Ph+ progenitor cells (LTCIC). Two recent reports suggests that, unlike the pt’s with less then CMR, in about half of the pt’s with CMR on Ima, discontinuation of therapy do not result in disease progression. Alpha interferone (IFN) was shown to be highly active in suppressing Ph+ LTCIC. Indeed, in patients achieving durable complete cytogenetic remissions (CCyR) with IFN, therapy can be discontinued. It was also shown that IFN therapy induces significantly higher response rate when applied in the set up of minimal residual disease (MRD, i.e. in CCyR after high dose chemotherapy), then at diagnosis. We therefore initiated a clinical trial that aims to suppress the Ph+ stem cells remaining active at the MRD set-up after Ima therapy, by the addition of IFN at that stage, to facilitate discontinuation of therapy in Ima responding pt’s. We report on an early observation in the first cohort of patients.

Materials and methods. CML pt’s that achieved a durable CCyR (> 1 year of negative classical cytogenetic and FISH studies) are eligible. After randomization, Pegylated alpha-2A interferone (Peg-IFN, Pegasys, Hoffmann - La Roche), 180 mcg/week, is added to therapy (basic Ima dose unchanged) in the study arm, and given for 12 months. Ima is discontinued after 9 months of Peg-IFN therapy following BM study that indicates maintained CCyR. Tight follow up of BM studies is than applied as it was shown that re-induction of response was feasible in all documented progressions caused by discontinuation of Ima. Pt’s on the control arm continue Ima therapy until progression.

Results. To date, seven pt’s in the study arm completed 4 months of therapy. One patient chose to stop Peg-IFN therapy after two weeks due to side effects. He had a base line CMR that was unchanged in the 4 month’s study. The other six pt’s are 5 males and one female age 24 to 59 (median 36) years, with a disease duration of 34–98 (median 49) months. Five of the six failed (3) or lost response (2) to IFN therapy in the past. One patient underwent an autologous BMT which induced reversibility of resistance to IFN seven years ago. Two pt’s required dose reduction of Peg-IFN (to 90 mcg/week). All six pt’s continued their base line Ima dose. After 4 months of Peg-IFN therapy, four pt’s that started with a positive RT-PCR study (0.2%, 0.9%, 0.07% and 0.1%) achieved a CMR (zero bcr/abl transcripts in RT-PCR study). One patient reduced his MRD from 0.8% to 0.01%, and one patient kept a CMR that was documented prior to therapy.

An updete of all pt’s completing 4 month of therapy in this study will be presented.

Conclusions. The addition of Peg-IFN to CML patients with a durable Imatinib induced CCyR, improves molecular response and can induce CMR. This observation is an encouraging mile stone in the attempt of using IFN as a platform to facilitate discontinuation of Imatinib therapy in responding patients.