From EHA 2003

COMBINATION WITH INTERFERON-ALPHA AND LOOSENING OF THE CRITERIA FOR INTERRUPTION OF IMATINIB THERAPY IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA INDUCED HIGH RATE CYTOGENETIC AND MOLECULAR REMISSIONS

Author: T. Kyo, Hiroshima Red-Cross Hospital, Hiroshima, Japan

Co-author(s):
A. Nomura, Hiroshima Red-Cross Hospital, Hiroshima, Japan
K. Sugihara, Hiroshima Red-Cross Hospital, Hiroshima, Japan
A. Sasaki, Hiroshima Red-Cross Hospital, Hiroshima, Japan
K. Iwato, Hiroshima Red-Cross Hospital, Hiroshima, Japan
H. Asaoku, Hiroshima Red-Cross Hospital, Hiroshima, Japan
H. Dohi, Hiroshima Red-Cross Hospital, Hiroshima, Japan

Cytogenetic and molecular remission has been reported to take place at a higher rate via dose-escalation of Imatinib for Philadelphia-chromosome-positive CML patients. Likewise, combining interferon-alpha and loosening of the criteria for myelosuppression-related interruption of Imatinib therapy can be also expected to be more highly improved.

We considered the efficacy and safety of a total number of 55 patients whom we had treated in our single facility from December 2001 to September 2002. Patients' ages ranged from 19 to 85 (median: 55). Imatinib was administered to 45 patients, excluding previously untreated cases (n=10), at a daily dose of 400 mg/day for five months, and then, chromosomal analysis was performed on bone marrow specimens.

If a complete cytogenetic response (abbreviation : complete CR ) couldn’t be achieved, the dose of Imatinib was adjusted to 100 mg per 12 kg (of body weight). Filgrastim (G-CSF: 75  µg/day) was administered to patients and erythrocyte/platelet transfusion was performed if the WBC dropped below 1500/mm3, hemoglobin dropped below 8.0 g/dL and platelet counts dropped below 20,000/mm3. Imatinib therapy was paused if the WBC remained below 1500/mm3 and platelet counts remained below 20,000-30,000/mm3 consistently. Imatinib was re-administered at a daily dose of 400 mg/day if G-CSF and platelet transfusion became unnecessary.

Natural interferon-alpha was intramuscularly added to 15 of 45 patients every other day at a dose of 6 MIU in combination with Imatinib. On the other hand, Imatinib was administered to 10 previously untreated patients at a dose of 100-mg/body weight 12-kg/day from the beginning.

As a result, all 18 interferon-alpha-responders maintained complete CR and 12 of 18 patients (67%) were RT-PCR-negative. Among 27 patients who did not
respond to interferon-alpha or were intolerant of interferon-alpha, 21 patients (78%) achieved complete CR and five patients (19%) achieved partial CR. Furthermore, five patients (19%) were PCR-negative. Of a total of ten previously untreated patients, nine patients (90%) achieved complete CR. One of nine complete CR patients was PCR-negative.

Imatinib therapy was never interrupted for interferon-alpha-responders or previously untreated patients during the protocol-treatment period. Among 27 patients who did not respond to interferon-alpha or were intolerant of interferon-alpha, Imatinib therapy was interrupted at least once for 14 patients (52%) during the protocol-treatment period. Among 14 patients, eight patients achieved complete CR and five patients achieved partial CR. In contrast, all 13 patients for whom Imatinib therapy was never interrupted achieved complete CR.

It was not significantly different between Imatinib mono therapy and combination therapy with interferon-alpha for neither on cytogenetic response or on molecular response. But PCR-negative patients' rate with combination therapy tended to be higher than that of mono therapy.

Taken together, these findings indicate that it is feasible to achieve a higher rate of complete CR and molecular response than several previous reports not only via dose-escalation of Imatinib, but also via combining interferon-alpha and loosening of the criteria for myelosuppression-related interruption of Imatinib therapy, such a treatment will lead to a prospect of long-term survival for CML patients.

Anjana's Commentary

Basically, this research abstract tell us 3 things:

1. If there is myelosuppression with Gleevec therapy, transfusions
and usage of growth factors without interruption of IM leads to a higher rate of cytogenetic remission.

2. Combination of IM/IFN leads to higher rate of cytogenetic and molecular remissions but the patient base is small.

3. It is interesting that they prescribe dose of IM based on body weight. Also note that IM treatment was only interrupted if
plateletes were 20,000-30,000 consistently and ANC went below 1500.

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