BCR-ABL Derived Peptide Vaccine in Chronic Myeloid Leukemia Patients with Molecular Minimal Residual Disease During Imatinib: Interim Analysis of a Phase 2 Multicenter GIMEMA CML Working Party Trial.

Imatinib (IM) 400mg daily is the standard treatment for chronic myeloid leukemia (CML) patients and a complete cytogenetic response (CCyR) is achieved in the majority of patients within one year of treatment. In addition, a considerable number of patients reach a major molecular response (i.e BCR-ABL/ABL ratio <0.1%) but BCR-ABL transcript is still measurable in most of treated patients revealing the persistence of a minimal residual disease (MRD). In a previous small pilot study, vaccinations with p210 b3a2-derived fusion peptides in IM treated CML patients appeared to induce both a peptide specific immune response and a reduction of residual disease surviving IM. Methods: To investigate the efficacy of this immune based targeted approach in a larger cohort of patients we designed a phase 2 multicenter study (GIMEMA CML0206) employing 5 p210 b3a2-derived peptides (CMLVAX100 vaccine) in CML patients with at least 18 months of IM treatment and persistence of molecular residual disease. Each vaccination consisted of CMLVAX100 plus 2 doses of GM-CSF as immunological adjuvant. Treatment schedule included 6 biweekly vaccinations (immunization phase) followed by 3 monthly boosts (reinforcement phase) and 2 tri-monthly boosts (maintenance phase). The primary endpoint of the trial was to assess the rate of response (patients showing a reduction by at least 50% of peripheral blood BCR-ABL/ABL ratio compared to the individual prevaccine level) evaluated after immunization and reinforcement boosts (evaluation after 6 months, ) and persisting at the 9^th month (after 10^th vaccination). Secondary endpoints included the rate of undetectable transcript at any time after immunization and the rate of peptide-specific immune response induced by the vaccinations. Patients population: At present 57/69 planned patients have been enrolled and 43/57 are evaluable for response. Twentyseven are males and 16 are females with a median age of 56.5ys (range 29-78). At diagnosis, 25/43 (58%) patients presented with low, 15/43 (35%) with intermediate and 3/43(7%) with a high Sokal risk. Twenty-one out of 43 patients (49%) started standard IM treatment while in late chronic phase (CP) after a median time from diagnosis of 29 months during which they mainly received alpha interferon therapy. On the contrary 22/43(51%) patients started IM immediately after diagnosis. All patients entered the vaccination protocol after at least 18 months of IM treatment and the median time of exposure to this tyrosin kynase inhibitor before peptide vaccination was 54 months (range 23-100). All patients had obtained a CCyR before entering the study (after a median time of 6 months of IM treatment) and were still in CCyR at enrollment with a median duration of CCyR of 47 months. All patients started vaccination with persisting measurable molecular disease in peripheral blood (any level of BCR/ABL transcript).

Current interim analysis shows that vaccinations (a total of over 400 shots) were very well tolerated, with CMLVAX100-GMCSF toxicity consisting exclusively of some redness and itching at the site of injection and with only 4/43 patients (9%) experiencing a mild fever. Regarding immune response induced by vaccination, 29/43 patients (67%) showed a significant in vitro b3a2-peptide-specific CD4+ T cell proliferation. With respect to MRD response, we observed a reduction of at least 50% of pre-vaccine BCR-ABL/ABL values after 6 months of treatment (i.e. after 9 vaccinations) in 22/43 (51%) patients and the reduction was confirmed in 14/29 (48%) patients who reached the 9^th month evaluation (i.e. after 10 vaccinations); 14/43(32%) patients had at least one documented undetectable transcript during this time period. In 2/43 patients we observed a significant raise of BCR-ABL transcript level, after 3 and 18 months from starting vaccinations with subsequent loss of CCyR. Conclusions: CMLVAX100 vaccine appears to induce a reduction of long lasting molecular MRD surviving IM in about half of vaccinated CML patients, thus confirming preliminary results. If this BCR-ABL-specific immune control of MRD will have a substantial impact on the rate of BCR-ABL mutations, disease evolution and ultimately survival needs longer observation time to be determined.

Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau.