Combination of Dasatinib and Peg-Interferon Alpha 2b in Chronic Phase Chronic Myeloid Leukemia (CP-CML) First Line: Preliminary Results of a Phase II Trial, from the French Intergroup of CML (Fi-LMC)

Background: Combination of Pegylated-Interferon alpha (Peg-IFNa) 2a and imatinib (IM) has been reported to significantly induce higher rates of molecular responses (including undetectable BCR-ABL transcript) over IM alone, as frontline therapy for CP-CML patients (pts) in a randomized phase 3 trial (SPIRIT, Preudhomme et al, NEJM 2010). Second generation TKIs such as dasatinib (DASISION, Kantarjian et al, NEJM 2010) enhance the speed and depth of molecular response (MR) in comparison to IM. Phase II trial using nilotinib and PegIFNa2a has recently reported high rates of deep molecular response (MR4.5) within 24 months (Nicolini FE et al, Lancet Haematology 2015).

 Aims:To determine the efficacy and safety of the combination of dasatinib and Peg-IFNa2b in CP-CML frontline. (EUDRACT Number: 2012-003389-42, Dasa-PegIFN trial).

 Methods: Newly diagnosed Ph+ CP-CML pts less than 65-year-old started dasatinib 100 mg/day. At 3 months, they were assigned to receive Peg-IFNa2b associated to dasatinib when platelets (plt) > 100 X 10⁹/L, Neutrophils (ANC) > 1.5 X 10⁹/L) and lymphocytes < 4.0 X 10⁹/L counts were achieved. Otherwise, dasatinib was continued alone in the study according to the current international ELN guidelines. The maximum duration of the combination dasatinib and Peg-IFNa2b is 21 months. The primary endpoint is the cumulative rate of Molecular Response 4.5log (MR4.5 defined as BCR-ABL1/ABL1^IS≤0.0032%) at 12 months. Molecular analyses were centralized and expressed according to the international scale (IS). Secondary endpoints included efficacy (cytogenetic and molecular responses at several time-points) and safety endpoints. Preliminary results are reported here.

 Results: 81 pts were enrolled between October 2013 and July 2014. All pts will have completed the 12 months follow-up time-point in August 2015. 79/81pts were included in the analysis (1 pt died of a CML-related haemorrhage before receiving dasatinib, 1 screening failure (masked Ph)). Median age was 48 (20-65) years. 54% of pts were male. Sokal scores were low, intermediate and high in 51%, 32% and 17% of pts respectively. After the first 3 months of therapy (M3), sixty-one patients (77%) started Peg-IFNa2b at the dose of 30 microg/week in association with dasatinib.

For these pts after M3, reported hematologic adverse events (AE) were neutropenia (G3/4 n=11; G1/2 n=17), thrombocytopenia (G3/4 n=0; G1/2 n=7), anemia (G3/4 n=0; G1/2 n=7). Extra-hematologic AE were essentially of low grade (overall, G3/4 n=3; G1/2 n=113). According to NCI CTCAE V4.0, most frequent AE were infections (16%), general symptoms (15%), skin lesions (10%), hepato-biliary abnormalities (7.7%), nervous system /headache (7.7%) musculoskeletal pain (7%), psychiatric (7%), GI (6%) disorders. Eight serious AE (SAE) were reported after Peg-IFNa2b initiation: G4 neutropenia n=2, dysthyroitidis n=1, dyspnea n=1, pleural effusion n=1, lymphoid hyperplasia n=1, hemorrhoids n=1, rectal fistula (SUSAR) n=1.

Efficacy was analysed according to the intention-to-treat principle (ITT), and considering missing data as no response to avoid inflated results. Overall at M3, 85% of pts had a BCR-ABL1/ABL1 ratio ≤10%. For eligible patients who received combined therapy (n=61), rates of MMR were 16%, 51%, 70%, and 70% (pending n=5) at M3, M6, M9 and M12, including MR4.5 rates 10%, 20%, 30% at M6, M9 and M12 respectively. Eighteen pts (22.7%) were not eligible to receive Peg-IFNa2b. Reasons, according to protocol criteria, were ANC <1.5 X 10⁹/L (n=10), plt <100.0 X 10⁹/L (n=5), lymphocytes  >4.0 X 10⁹/L (n=1), absence of complete hematologic response (n=1), non compliance (n=1). Rates of MMR for these pts were 27% at M6, 50 % at M9 (missing n=2), pending data for n=6 at M12. 

 Conclusion: Peg-IFNa2b combined to dasatinib therapy in first line CP-CML induces a high rate of deep molecular response (ie MR4.5) during the first year of therapy. Despite few pending data, results at 12 months are already in line with previous data combining Peg-IFNa and TKI, expecting a potential for an increased rate in therapy cessation attempt. Preliminary data of this phase II trial indicate a manageable toxicity profile for this combination, despite an increased rate of neutropenia. Updated analyses (ITT and per protocol) will be presented for all the pts with at least 12 months follow-up.