Results of triple therapy with interferon‐alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in early chronic phase

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Abstract
BACKGROUND: Before the discovery of imatinib mesylate, a Bcr‐Abl selective tyrosine kinase inhibitor, three agents, interferon‐alpha (IFN‐α), cytarabine (ara‐C), and homoharringtonine (HHT), had demonstrated activity against Philadelphia chromosome (Ph)‐positive chronic myelogenous leukemia (CML) as single agents and in couplet combinations. The goals of the current study were to evaluate the efficacy of the triple combination regimen with IFN‐α, ara‐C, and HHT in newly diagnosed Ph‐positive CML and to assess the impact of the added sequential therapy with imatinib on overall prognosis.METHODS: Ninety patients with Ph‐positive CML in early chronic phase received the triple regimen. Therapy consisted of 5 million units (MU)/m2 IFN‐α subcutaneously (s.c. daily, ara‐C 10 mg s.c. daily, and HHT 2.5 mg/m2 by continuous infusion over 24 hours daily × 5 every month. After a median duration of 16.5 months of therapy, 78 patients had their therapy changed to 400 mg orally administered imatinib daily.RESULTS: With the triple regimen, 85 patients (94%) achieved complete hematologic response and 67 patients (74%) had a cytogenetic response (Ph suppression to ≤ 90%) which was complete (Ph 0%) in 20 patients (22%) and major in 42 patients (46%). Myelosuppression was significant, resulting in considerable reductions in the dose schedules. After 12 months of therapy, the median IFN‐α dose was 1.6 MU/m2 daily, the median ara‐C dose was 1.85 mg daily, and the median number of HHT days was 2 every month. Only three patients developed blastic phase while receiving the triple regimen. With the change to imatinib therapy, currently 57 patients (63%) are in complete cytogenetic response and 69 patients (76%) in major cytogenetic response. With a median follow‐up time of 46 months for the total study group, the estimated 5‐year survival rate was 88%, and only 8 patients (9%) to date have developed blastic phase.CONCLUSIONS: The sequence of IFN‐α, ara‐C, and HHT followed by imatinib (imposed by the discovery of the latter drug) resulted in an estimated 5‐year survival rate of 88%. This finding suggests that imatinib combination regimens may improve the prognosis in CML. Cancer 2003;98:888–93. © 2003 American Cancer Society.DOI 10.1002/cncr.11620