Subcutaneous (SC) Homoharringtonine (HHT) for Patients (pts) with Chronic Myelogenous Leukemia (CML) in Chronic Phase (CP) after Imatinib Mesylate Failure.

HHT is a cephalotaxus alkaloid obtained from an evergreen tree that inhibits the synthesis of proteins leading to apoptosis. HHT by intravenous (IV) administration has demonstrated significant activity in pts with CML after failure to interferon (IFN) therapy, with cytogenetic (CG) responses in 30% of cases. A phase I study of SC HHT previously reported in pts in accelerated or blast phase (before imatinib was available), demonstrated efficacy (5 of 10 responses) and adequate tolerance at the same doses used IV. We thus started a phase II study to determine the activity of SC HHT in pts with CML in late CP after imatinib failure. Therapy with HHT consisted of an initial IV loading dose of 2.5 mg/m² over 24 h, followed by 1.25 mg/m² SC twice daily for 14 days every 28 days. Six pts have been treated and 5 are evaluable (1 pt lost to follow-up after 1 cycle). Best response to prior imatinib therapy for a median of 64 weeks (range, 12 to 96) was: complete hematologic response (CHR) in 3 pts and complete CG response (CG CR) in 2, and primary resistance in 1 pt. All 5 evaluable pts had also failed IFN, and other therapies: Ara-C (n=2), farnesyl transferase inhibitors (n=2). At the time HHT was started, all had lost CHR. Median age was 52.5 years (range, 36 to 66), time from diagnosis to treatment 58 months (18 to 164), WBC 24.35 x 10⁹/L (6/4 to 43), platelets 308 x 10⁹/L (147 to 536), and peripheral basophils 4/5% (3% to 17%). Mutations of the BCR-ABL kinase domain were identified in 2 pts (2 mutations each: G250E and Y253H in one, D276G and F359I the other). Pts received a median of 4.5 courses of SC HHT (range, 1 to 5). CHR was achieved in all 5 evaluable pts. Of these, 1 achieved a CG CR and a minor CG response (lowest Ph 80% and 90%, respectively). The pt that achieved CG CR had D286G and F359I mutations before therapy with HHT. Interestingly, this pt developed extramedullary blast disease (bones) that required radiotherapy while remaining in CG CR in peripheral blood and bone marrow. All pts developed myelosuppression and 3 had their HHT dose reduced due to prolonged neutropenia. Grade 3–4 non-hematologic toxicity included neutropenic fever (n=1), and fatigue (n=1). We conclude that SC HHT is well tolerated and may have clinical activity in pts with CML after imatinib failure. This study was terminated because of drug availability from this source; a new trial will be conducted obtaining HHT from a different sponsor.