Safety and Efficacy of Subcutaneous (SC) Omacetaxine Mepesuccinate in Imatinib(IM)-Resistant Chronic Myeloid Leukemia (CML) Patients (pts) with the T315I Mutation – Results of An Ongoing Multicenter Phase II Study.

Background: Omacetaxine (homoharringtonine, HHT) shows clinical activity against Ph+ CML, with a mechanism of action independent of tyrosine kinase inhibition. Currently available tyrosine kinase inhibitors (TKIs) have not demonstrated activity in CML pts harboring the T315I BCR-ABL mutation.

Study Goals: To evaluate the safety and efficacy of omacetaxine in pts with IM-resistant T315I+ Ph+ CML.

Methods: Eligible pts include adult CML with confirmed T315I BCR-ABL mutation following imatinib failure after informed consent. Presence of T315I mutation is confirmed at one of 2 central reference labs. Induction schedule consists of 1.25 mg/m² omacetaxine SC twice daily for 14 days every 28 days until complete hematologic response (CHR) or hematologic improvement (HI). Maintenance schedule may start after at least one induction cycle and after initial hematologic response. Maintenance treatment consists of 1.25 mg/m² OMA SC twice daily for 7 days every 28 days, for up to 24 months.

Study Results: To date, 50 pts have been enrolled, all having failed prior imatinib therapy, and 82% having failed 2 or more prior TKIs. Enrollment includes 26 pts in chronic phase (CP), 13 in accelerated phase (AP) and 11 in myeloid blast phase (BP). Median age: 58 yrs (19–84), 70% male. Mean baseline WBC values (/μl) were 11.51 (range 1.9–23.76) in CP, 18.88 (range 3.6– 78.2) in AP and 16.58 (range 2.4–51.5) in BP patients. Median disease duration is 58 months (range 5–285).

Efficacy: Data are available for 30 pts: 15 CP, 10 AP and 6 BP pts. In CP pts, CHR has been achieved in 80% (12/15) with a median duration of response of 8 months (range 2.7 to 13.5+). Of these 12 pts achieving CHR, 11 pts continue on study with the remaining patient achieving complete cytogenetic response (CCyR) and being removed from treatment to receive allograft transplantation. The median time to hematologic response was 1.2 months (range 0.6 to 2.5). Overall cytogenetic response in CP pts is 20% (3/15) with 13% (2/15) achieving CCyR and 1 pt achieving a minimal cytogenetic reponse. Median duration of cytogenetic response is 9.1 months (range 7.1 to 9.2+) with one pt continuing in CCyR and the second patient receiving allograft as described above. In AP pts, overall hematologic response is 60% (6/10) with 5 of these patients remaining active in treatment. Two pts have achieved CHR, 3 returned to chronic phase and 1 showed HI. Median duration of response was 2.2 months (range 1 to 4.4+). Overall cytogenetic response rate in AP patients is 21% (3/14), with 2 pts achieving major cytogenetic response and 1 pt achieving minimal response. In BP patients, overall hematologic response rate is 33% (2/6) with 1 pt achieving CHR and 1 HI. Duration of response was 3.7 and 3.9 months respectively. The T315I mutated clone has been decreased below the limit of detection in 60% of evaluable patients.

Safety: Data are available for 32 pts enrolled in all disease phases. The primary toxicity being myelosuppression which is reversible and managed by adjusting the number of dosing days received per cycle. Incidence of treatment emergent grade 3/4 events includes: thrombocytopenia 44%, neutropenia 34%, anemia 28%, febrile neutropenia 16%, and pancytopenia 9.4%. Injection site reactions have been mild with no grade 3–4 events reported. Four pts have died (3 BP, 1 AP) during the study period, all due to disease progression.

Conclusions: Omacetaxine therapy in T315I mutated BCRABL+ IM-resistant CML is well tolerated and is producing durable CHRs and cytogenetic responses in these patients.