Simultaneous homoharringtonine and interferon‐α in the treatment of patients with chronic‐phase chronic myelogenous leukemia

Abstract

BACKGROUNDHomoharringtonine (HHT) has antileukemic activity in patients with Philadelphia chromosome (Ph) positive chronic myelogenous leukemia (CML). Combinations of HHT, interferon‐α (IFN‐α), and cytarabine (ara‐C) have been studied in various CML phases. The objectives of this study were to evaluate the efficacy and toxicity profiles of a combination regimen of simultaneous HHT and IFN‐α therapy in patients with chronic‐phase CML who were not exposed previously to either agent.METHODSForty‐seven patients were treated: 37 patients with early chronic‐phase CML (2 patients with clonal evolution) and 10 patients with late chronic‐phase CML. Their median age was 62 years (range, 23–73 years). HHT was given at a dose of 2.5 mg/m2 by continuous intravenous infusion over 24 hours daily for 5 days every month, and IFN‐α was given daily at a target dose of 5 × 106 units/m2 subcutaneously. Response, survival, and treatment toxicity were analyzed.RESULTSOverall, the complete hematologic response (CHR) rate was 85%; the cytogenetic response rate was 66%, with major cytogenetic responses (Ph positive in < 35% of metaphases) in 49% of patients and complete cytogenetic responses in 21% of patients. The CHR rate, cytogenetic response rate, and major cytogenetic response rate were 84%, 69%, and 52%, respectively, in patients with early chronic‐phase CML. Among the 10 patients with late chronic‐phase CML, the CHR rate, cytogenetic response rate, and major cytogenetic response rate were 80%, 50%, and 40%, respectively. Response rates in patients age > 60 years were 84%, 62%, and 49% for CHR, cytogenetic response, and major cytogenetic response. Myelosuppression was frequent but manageable: Anemia with hemoglobin < 8.0 g/dL occurred in 36% of patients, requiring dose adjustments and erythropoietin therapy. Nonhematologic toxicities were mainly fatigue, aches, and gastrointestinal disturbances. Dose reductions with multiple courses were significant and were due to myelosuppression: After 6–24 courses, the median daily IFN‐α dose was 1 MU/m2, and the median number of days on HHT per month was 2 days. With a median follow‐up of 26 months, the estimated 2‐year survival rate was 90% (95% confidence interval, 79–100%).CONCLUSIONSThe simultaneous combination of HHT and IFN‐α is safe and effective, but the dose schedules that actually were delivered were significantly lower than the planned dose schedules. With the availability of signal‐transduction inhibitor 571 (imatinib mesylate), studies of combination of HHT and IFN‐α chemotherapy in patients with CML who have disease that fails to respond to imatinib mesylate and of combinations with imatinib mesylate need to be explored. Cancer 2002;94:2024–32. © 2002 American Cancer Society.DOI 10.1002/cncr.10436

The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

“…It is currently being used as a non-first-line drug to treat acute and chronic leukemia and myelodysplastic syndrome (17)(18)(19). HHT resulted in a complete hematologic remission in 72% and cytogenetic remission in 31% of patients with late chronic-phase chronic myelogenous leukemia (CML), most of whom had not experienced a response to IFN-α therapy (20). Since the advent of imatinib, HHT was the most effective therapy for patients with CML that had not responded to IFN-α therapy.…”

“…The antitumor activity of HHT is associated with inhibition of global protein synthesis, promotion of cell differentiation, and induction of apoptosis via a caspase-3-dependent mechanism (21). Several studies have indicated that HHT is relatively non-cross-resistant to other antileukemic agents (e.g., IFN-α, cytarabine, and imatinib) and is synergistic with these drugs (20,(22)(23)(24)(25). Of note, in vitro studies revealed that HHT is effective against imatinibresistant Bcr-Abl mutants, including T315I (25).…”

Drug responses of imatinib mesylate-resistant cells: synergism of imatinib with other chemotherapeutic drugs

“…The good responses of both imatinib-sensitive and -resistant lines to HHT are particularly encouraging, since this drug has not yet been extensively used in CML. [22][23][24] Two contrasting and notable exceptions to the general trend are represented by HU and IFN-␣. Responses to HU were generally modest and complex; the behavior of LAMA84 sensitive and resistant cells in 50 M HU shows that resistance to imatinib appears to confer sensitivity (and not cross-resistance) to HU.…”

Apoptotic response to homoharringtonine in human wt p53 leukemic cells is independent of reactive oxygen species generation and implicates Bax translocation, mitochondrial cytochrome c release and caspase activation

“…6 Homoharringtonine (HHT) is a plant alkaloid with antileukemic activity which is currently being tested for treatment of acute and chronic leukemias. [7][8][9][10] The principal mechanism of action by HHT is the inhibition of protein synthesis in a doseand time-dependent manner by binding to ribosomes and inhibiting polypeptide chain elongation. 11,12 In fact, its cytotoxicity has been shown to be proportional to the extent of inhibition of protein synthesis.…”