HHT [USAN/INN designation - omacetaxine mepesuccinate] is an ester of cephalotaxine with activity in CML independent from tyrosine kinase (TK) inhibition. HHT is also active against Ba/F3 cell lines transfected with various BCR-ABL kinase domain (KD) mutants, including the T315I mutation. BCR-ABL positive cells with the T315I mutation are resistant, both in vitro and in vivo, to IM, as well as 2nd generation TK inhibitors (TKIs), such as dasatinib, nilotinib and bosutinib. Given the lack of active agents in this unique patient (Pt) population, we are conducting a multicenter open-label phase II trial evaluating safety and efficacy of SC HHT in Pts with IM-resistant T315I+ CML in all phases of the disease. The presence of T315I is confirmed at 2 reference labs. Peripheral blood BCR-ABL transcript levels are determined during HHT therapy by qRT-PCR and BCR-ABL KD mutation analyses. Induction consists of repeated cycles of HHT, 1.25 mg/m2 twice daily SC for 14 consecutive days every (q) 28 days until complete hematologic response (CHR) or hematologic improvement. Pts can receive maintenance HHT, 1.25 mg/m2 twice daily SC for 7 days q 28 days, until progression or for up to 24 mo. To date, 19 Pts with Ph+ CML with T315I have been enrolled, 11 in chronic (CP), 4 in accelerated (AP), 4 in blast (BP) phase. Median age is 56 yrs (23 to 79). Pts have failed a median 2 (1 to 8+) prior therapies, including IM (19), dasatinib (10), nilotinib (8), MK-0457 (3), ara-C (5), anthracyclines (3), interferon (2). Median T315I transcript level at baseline is 50% (20–100%). All Pts have completed at least one induction course of HHT, 10 Pts completed 2 courses, 2 Pts 3, and 1 Pt 4. Five Pts are on maintenance HHT (1–7+ mo). SC HHT is well tolerated; no Pt has discontinued treatment due to toxicity. Hyperglycemia, cardiac arrhythmia, and hypotension have not been reported, and local injection reactions are uncommon. One Pt experienced acute coronary syndrome due to HHT-induced anemia. Cycle 2 treatment delays due to neutropenia and/or thrombocytopenia have occurred in 7 of 14 Pts (1–41 days). 4 Pts have experienced progressive disease [1 in CP (splenomegaly, ↑BCR-ABL), 1 AP, 2 BP] after 1–2 induction cycles and were taken off study. T315I transcript levels are no longer detectable in 1 AP and 4 CP Pts, 2 of whom have achieved CHR (1 recently achieved, 1 maintained 7+ mo). In summary, current data from this phase II trial indicate that HHT has an acceptable safety profile and activity in Pts with IM-resistant CML. The SC route offers a convenient dosing format for self administration. Additional enrollment and longer follow-up will determine whether HHT provides a therapeutic option in highly-resistant CML Pts with T315I BCR-ABL KD mutation who have failed one or more TKIs.

Author notes

Disclosure:Employment: Annie-Claude Benichou, M.D. is an employee of Stragen, France. Consultancy: Hagop Kantarjian, MD, Jorge Cortes, M.D., and Richard Schwartz, M.D. are consultants to ChemGenex, Pharmaceuticals, Inc. Ownership Interests:; Annie-Claude-Benichou, M.D. and Richard Schwartz, M.D. own stock in ChemGenex Pharmaceuticals, Inc. Research Funding: H Jean Khoury, M.D., Dan Jones, M.D., Ph.D., Andreas Hochhaus, M.D., Hagop Kantarjian, M.D., Jorge Cortes, M.D. have received research funding from ChemGenex Pharmaceuticals, Inc. Membership Information: Hagop Kantarjian, M.D. is a clinical advisor and a member of Chemgenex Pharmaceuticals, Inc.’s Scientific Advisory Board. Jorge Cortes, M.D. is a clinical advisor to ChemGenex Pharmaceuticals, Inc.