A Phase II Study of Intravenous (IV) Homoharringtonine (HHT) and Imatinib (IM) in Patients (pts) with Chronic Myeloid Leukemia (CML).

HHT is a cephalotaxine ester that inhibits cell growth, inhibits protein synthesis, and increases the turnover of the antiapoptotic protein myeloid cell leukemia-1 (Mcl-1). A prior phase II study of subcutaneous HHT in late chronic phase (CP) CML after IM failure demonstrated efficacy (complete hematologic response [CHR] in 5 of 5 evaluable pts, cytogenetic response in 3) and adequate tolerance. HHT has proved synergistic with IM in CML cell lines including some resistant to imatinib. Thus a “sequential blockade” strategy was designed with HHT to inhibit Bcr-Abl protein synthesis, and imatinib to inhibit its kinase activity. Accordingly, we initiated a clinical trial of IV HHT and IM (HHT+IM) in pts with CML in all phases. Pts with CP had to be refractory or resistant to prior IM therapy. Therapy consisted of HHT 2.5 mg/m (daily continuous 24-hour infusion) on days 1–5 every 4 weeks and IM 400 mg daily (for pts in CP) or 600 mg daily (for pts in AP or BP). Twelve pts have been treated: 2 in CP, 4 in accelerated (AP), and 6 in blast (BP) phase. Pts had failed a median of 3 prior therapies (range, 0 to 4), including IM (n=9) administered for a median of 24 mo (range 2–57) and others (dasatinib 5, interferon-α 4, nilotinib 3, allogeneic stem cell transplant 2). Two pts (BP) were therapy-naïve at study entry. Median age was 59 yrs (range 21–77) and time from CML diagnosis to HHT+IM 36 mo (range 1–141). Mutations of the BCR-ABL kinase domain were identified in 4 (33%) pts (T315I, F359V, Q252H, and F317L). Pts have received a median of 2+ courses of HHT+IM (range, 1+ to 5+) for a total of 29 cycles administered. Median cycle duration was 28 days (range, 6 to 71). After a median follow-up of 8.5 weeks (range, 3 to 19), 5 (42%) pts had a hematologic response: 3 had CHR (1 AP, 2 BP), and 2 had hematologic improvement (HI; 1 AP, 1 BP). In addition, 1 AP pt who had a transient HI achieved a minor cytogenetic (CG) response. Two of the 3 pts in CHR achieved a complete CG response: 1 AP who had failed IM (both as single-agent and combined with lonafarnib) and 1 BP who also achieved undetectable Bcr-Abl transcripts after having failed allo-SCT. The third pt who achieved CHR (BP) was therapy-naïve at HHT+IM start and has achieved a partial CG response (10% Ph+). In addition, 2 of 3 pts who had failed IM, nilotinib, and dasatinib had normalization of their platelet count (baseline >1000x10⁹/L). Among responders, Abl kinase domain mutations were detected at baseline in the pt who achieved a minor CG response (Q252H). Seven pts are still on HHT+IM, including the 3 pts in CHR. Grade 3–4 neutropenia, thrombocytopenia, and anemia were observed in 10 (83%), 9 (75%), and 10 (83%) pts each and was prolonged (>35 days) in 5 pts. Grade 3–4 non-hematologic toxicity included infection (n=3), dizziness (n=3), renal failure (n=2), fatigue (n=1), pain (n=1), and nausea/vomiting (n=1). The actions of HHT on total protein levels and phosphorylated forms of Bcr-Abl and its substrate, Crkl, are being investigated in vitro and during therapy. We conclude that the combination of IV HHT and IM is well tolerated and has clinical activity in pts with CML in all phases, including in some who have failed prior therapy with IM and other tyrosine kinase inhibitors. Studies of HHT in pts who failed prior therapy with 1–3 tyrosine kinase inhibitors, including those with T315I, are ongoing.