Omacetaxine Mepesuccinate for Chronic Myeloid Leukemia

Chicago—Of patients with chronic myeloid leukemia (CML) who are treated with tyrosine-kinase inhibitors (TKIs), 20% to 30% develop resistance to the drugs; others are intolerant.

The FDA recently approved subcutaneous omacetaxine mepesuccinate (omacetaxine) for the treatment of CML, both chronic phase (CP) and acute phase (AP). Omacetaxine, a protein synthesis inhibitor, reduces expression of multiple oncoproteins, including Bcr-Abl, and induces apoptosis in leukemic stem cells by blocking the initial step of protein translation at the level of the ribosome. In two phase 2 trials, omacetaxine was associated with clinical activity and adequate tolerability in patients with CML.

Researchers recently pooled the results of the 2 trials to assess the efficacy and tolerability of ≥12 cycles of omacetaxine in a heavily pretreated patient population with CML-CP or CML-AP. Analysis results were reported during a poster session at the ASCO conference. The poster was titled Post Hoc Analysis of Sustained Efficacy/Tolerability of ≥12 Cycles of Omacetaxine Mepesuccinate in Chronic Myeloid Leukemia.

Male and female patients were eligible for either of the phase 2 studies if they were ≥18 years of age; were diagnosed with CML in CP, AP, or blast phase (BP); were ineligible for bone marrow transplant at the time of enrollment; and had acceptable renal and liver function. Exclusion criteria were New York Heart Association class III or IV heart disease, active ischemia, another uncontrolled cardiac condition, or myocardial infarction in the previous 12 weeks; concurrent illness that would preclude study conduct and assessment; and enrollment in another clinical investigation within 30 days of enrollment in the present study or concomitant treatment with another investigational agent.

All patients received 1.25 mg/m² of omacetaxine subcutaneously twice daily for up to 14 consecutive days every 28 days for induction and the same dosage for up to 7 days every 28 days as maintenance. If clinically indicated, the number of consecutive days of treatment per cycle and the number of days between cycles could be adjusted. In the event of febrile neutropenia, recombinant growth factor support was allowed.

There were 108 CML-CP patients and 51 CML-AP patients in the 2 trials. Of those, 29% (n=31) of the CML-CP cohort and 14% (n=7) of the CML-AP cohort received ≥12 cycles of omacetaxine as of March 31, 2012. At baseline and in the ≥12 cycle subgroups, most CML-CP patients were younger and more likely to have the T3151 mutation compared with CML-AP patients. The majority of patients had received ≥2 TKIs and prior hydroxyurea.

Of the original cohort, 9 CML-CP patients and 2 CML-AP patients continued treatment as of June 12, 2012. Of those, the CML-CP patients received a median 35 cycles and the 2 CML-AP patients received 19 and 22 cycles.

Among the CML-CP patients receiving ≥12 cycles, 9 achieved major cytogenetic response (MCyR), accounting for 38% of the patients achieving MCyR in the 2 studies overall, and 8 achieved complete cytogenetic response (CCyR), accounting for 67% of the patients achieving CCyR in the 2 studies overall. Approximately 75% maintained MCyR status during the study period. Among CML-AP patients receiving ≥12 cycles, 5 achieved MCyR.

The researchers summarized their findings by noting, “In this post hoc analysis of heavily pretreated CML-CP and CML-AP patients who had failed prior treatment with 1, 2, or 3 TKIs, approximately a third of CML-CP and a sixth of CML-AP patients received omacetaxine for ≥12 cycles. Among CML-CP and CML-AP patients, respectively, with responses of a year or more, 20 and 2 had complete hematologic response, 1 had MCyR, and 3 and 1 had CCyR. Few adverse events (AEs) emerged after ≥12 cycles of treatment; most grade 3/4 AEs were hematologic.”

This research was sponsored by ChemGenex, a wholly owned subsidiary of Teva Branded Pharmaceuticals Ltd.