|
From ASCO 2003
Combination therapy of chronic myelogenous leukemia (CML) with imatinib and pegylated interferon 2a.
ASCO Abstract No: 2287
Author(s): A. Hochhaus, T. Fischer, T. Bruemmendorf, T. Bostel, A. Burchert, A. Neubauer, M. T. Rose, H. Gschaidmeier, R. Hehlmann; Universitaetsklinikum Mannheim der Uni Heidelberg, Mannheim, Germany; Universitaet Mainz, Mainz, Germany; Universitaet Tuebingen, Tuebingen, Germany; Universitaet Marburg, Marburg, Germany; Roche, Grenzach-Wyhlen, Germany; Novartis, Nuremberg, Germany
Abstract:
Synergistic effects of imatinib and interferoná (IFN) on CML cells were demonstrated in vitro. Imatinib selectively inhibits the proliferation of BCR-ABL+ cells, IFN has both antiproliferative and immunomodulatory properties and induces cytotoxic T lymphocytes (CTL).
To define the tolerability and efficacy of combination therapy with imatinib and pegylated IFNá2a (Pegasys), a phase I/II study was conducted in 32 Ph+ chronic phase CML patients, recruited within 6-355 days from diagnosis.
Pegasys was added on day 15 and then given once weekly, during 8 weeks. Cohorts comprised 300 or 400mg imatinib + 90 or 180ìg Pegasys. A 5th cohort of pts received 400mg imatinib for 6 weeks, 300 mg from day 43 combined with 180ìg Pegasys for 8 weeks (n=7).
Efficacy: Within phase I 30/32 pts (94%) reached a complete hematologic remission, 19 (59%) a major cytogenetic response (Ph+<35%), 8 (25%) being complete. After a maintenance phase of median 309 days major response rate was 79% with 63% complete responders. Ratios BCR-ABL/ABL determined by quantitative RT-PCR reached a median level of 0.44% (range 0.002-35).
Toxicity: Grade 3 non-hematologic adverse events were reported in 5 pts. Gr.3 leukopenia occurred in 9 pts, gr.3/4 neutropenia in 4 and 3 pts, respectively, gr.3 thrombopenia in 2 cases. Overall, gr.3/4 cytopenias was observed in 13/32 pts. Cytopenia was rare (1/7 cases) if Pegasys was commenced after 6 weeks imatinib monotherapy. Pts received 71% of the scheduled Pegasys and 95% of imatinib doses.
Since imatinib downregulates myeloblastin expression, CTLs could not be detected in 2 pts. with complete cytogenetic remission.
Conclusion:
The combination treatment of imatinib and Pegasys is feasible and results in a high rate of hematologic and cytogenetic response. Predominant dose limiting toxicities are cytopenias, which are less frequent if Pegasys therapy is commenced after >=6 weeks imatinib monotherapy in order to allow restoration of normal hematopoiesis.
Consecutive treatment with Pegasys and imatinib, or combination of imatinib, 400mg/day and Pegasys, 180ìg/week starting after 6 weeks is suggested for further studies.
|
|
