Safety and Efficacy of a Combination of Imatinib and Pegylated Interferon α2a (Pegasys®) in Newly Diagnosed Patients with Chronic Myelogenous Leukemia - A Phase II Cohort Study.

Imatinib (IM) and interferon α (IFN) are active in the treatment of CML patients (pts); synergistic effects of both drugs were demonstrated in vitro. To define efficacy and tolerability of a combination therapy with IM and pegylated IFNα2a (PEG-IFN), a phase II cohort study was performed in 40 newly diagnosed Ph+ chronic phase CML pts (25 m, 15 f; median age 52 yrs, range 22–74). Treatment was commenced at a median of 0.7 mo (0.1–2.5) after diagnosis. 18 pts (45%) were of low, 21 pts (53%) of intermediate, and 1 patient (2%) of high risk according to Hasford. Objectives were to determine efficacy and safety of PEG-IFN (sc) given in different combination schedules with IM (po) and to explore myeloblastin (proteinase 3, PR3) expression and its correlation with PR3-specific T-cells (PR3-CTL) as a putative surrogate marker for IFN response. After cytoreduction with hydroxyurea, pts in cohort I (n=20) received PEG-IFN-monotherapy (6 wks), then IM monotherapy (6 wks), followed by the combination. Cohort II pts (n=20) started with IM monotherapy (6 wks), followed by the combination. Target dose for IM was 400 mg/d, for PEG-IFN 180 μg/week during mono- and 135 μg/week during combination therapy. Dose and schedule were adjusted according to hematological and non-hematological side effects. After 48 and 96 wks, 28 (70%) and 35 pts (88%) achieved a complete (CCR), 6 and 1 pts a partial cytogenetic remission, respectively. In 5 pts, treatment was stopped due to side effects (n=4) or lack of efficacy (n=1). Thus, 33/40 pts (83%) actually had CCR at 96 wks. Major molecular response (MMR; BCR-ABL ratio of ≤0.1% according to the international scale) was achieved in 21 (53%) and 26 pts (65%) after 48 and 96 wks, respectively. Non-hematologic grade 3 toxicity included exanthema (n=4), increased transaminases (n=3), flu-like symptoms (n=1), and depression (n=1). Grade 3 leukocytopenia occurred in 10 pts, grade 3/4 thrombocytopenia in 5 and 1 pts, respectively. Overall, pts received 42% of the scheduled PEG-IFN and 87% of IM doses. Expression levels of PR3 mRNA were determined in 264 samples from 19 pts by a quantitative PCR assay. Median ratios PR3/glucose-6-phosphate dehydrogenase (in %, range) were 16 (0.068–1700) at baseline, 6.1 (0.26–840) after 6 wks PEG-IFN mono, 0.093 (0.0088–1.4) after 6 wks IM mono, 0.054 (0.02–150) and 0.091 (0.007–250) after 48 and 96 wks of the combination therapy, respectively. PR3 expression was significantly reduced by IM, but not by upfront PEG-IFN (p=0.001). PR3-CTL were prospectively monitored by a PR3 specific tetramer assay in 113 peripheral blood samples from 17 HLA-A2+ pts. Autoreactive PR3-CTL were detected at baseline in 2/14 pts (0.18 and 0.23%), after PEG-IFN monotherapy in 3/6 pts (0.04, 0.11, and 0.35%), and during combination therapy in 7/16 pts (peak levels median 0; range 0–1.5%). PR3-CTL increased after initial PEG-IFN, decreased after commencement of IM and were associated with a higher PR3 antigen load. In conclusion, the combination treatment of IM and PEG-IFN is well tolerated and results in a high rate of CCR and MMR. However, IM may modify PEG-IFN immunotherapy, for example by inhibition of autoantigen expression. Consecutive vs simultaneous treatment schedules may affect efficacy of IM/PEG-IFN combination therapies.