Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic‐phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors

Abstract

Omacetaxine mepesuccinate (omacetaxine) is a first-in-class cephalotaxine with a unique mode of action, independent of BCR-ABL, that has shown promising activity in patients with chronic myeloid leukemia (CML). This multicenter, noncomparative, open-label phase 2 study evaluated the efficacy and safety of subcutaneous omacetaxine in CML patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs); results in patients in chronic phase are reported here. Patients received subcutaneous omacetaxine 1.25 mg/m2 twice daily days 1–14 every 28 days until hematologic response (up to a maximum of six cycles), then days 1–7 every 28 days as maintenance. Primary endpoints were rates of hematologic response lasting >8 weeks and major cytogenetic response (MCyR). Forty-six patients were enrolled: all had received imatinib, 83% had received dasatinib, and 57% nilotinib. A median 4.5 cycles of omacetaxine were administered (range, 1–36). Hematologic response was achieved or maintained in 31 patients (67%); median response duration was 7.0 months. Ten patients (22%) achieved MCyR, including 2 (4%) complete cytogenetic responses. Median progression-free survival was 7.0 months [95% confidence interval (CI), 5.9–8.9 months], and overall survival was 30.1 months (95% CI, 20.3 months—not reached). Grade 3/4 hematologic toxicity included thrombocytopenia (54%), neutropenia (48%), and anemia (33%). Nonhematologic adverse events were predominantly grade 1/2 and included diarrhea (44%), nausea (30%), fatigue (24%), pyrexia (20%), headache (20%), and asthenia (20%). Subcutaneous omacetaxine may offer clinical benefit to patients with chronic-phase CML with resistance or intolerance to multiple TKI therapies.

Chronic Myeloid Leukemia in Adolescents and Young Adults: Patient Characteristics, Outcomes and Review of the Literature

“…Standard therapy with upfront TKI, whether first-generation TKI (imatinib) [22] or second-generation TKI (dasatinib [23], nilotinib [24]) should be offered to AYA patients and older adults alike. Salvage therapy in second-line settings and beyond for AYA patients should again include all therapies available to older patients with CML, with no known age restrictions for younger patients in the AYA group, including the other TKI therapies not yet used from frontline setting, several newer CML drugs recently Food and Drug Administration approved (ponatinib [25], bosutinib [26], omacetaxine [27]), enrollment in a clinical trial or allogeneic stem cell transplantation (SCT). With particular attention for the AYA group, as compared to the older group of CML patients (especially those aged 70 and above), allogeneic SCT has historically been put forward to represent a more readily available option in some younger patients' cases (especially those with molecular mutations such as the T315I mutation) in appropriately selected CML patients [28,29].…”

Current Management Approaches of Chronic Myeloid Leukemia

“…And also median PFS and OS were 7 months and 30 months respectively [73]. Among evaluated 62 patients with CP CML enrolled in the first study CHR, MCgR and CCgR were seen in 77%, 23%, and 16% of patients respectively.…”

“…Accelerated approval was based on the safety and efficacy results from two phase II trials enrolling patients with CP or AP CML (one study involving 202 patients who had failed one or more TKIs and a T315I mutation; the second study involving 203 patients who had failed treatment with two or more TKIs) [73,74].…”

“…MHR rates were also 32%, 40% and 50% respectively for patients with any BCR-ABL mutations, multiple mutations and T315I mutation at base line. These results were based on pooled analysis of 41 patients with AP CML [73,75].…”

Novel homobarringtonie‑containing therapy for the treatment of patients with primary acute myeloid leukemia that are resistant to conventional therapy

“…HBT also prevents DNA synthesis and targets the G1/G2 phases of the cell cycle (14,15). Following the demonstration of the therapeutic efficacy of omacetaxine mepesuccinate (a type of synthetic HBT) for chronic myeloid leukemia (CML) (16,17), the United States Food and Drug Administration approved its use as a tyrosine kinase inhibitor for the treatment of resistant chronic phase or accelerated CML (18). Previous Chinese studies have added HBT as the third drug to the conventional inductive therapy for AML (19)(20)(21)(22), and these studies demonstrated that the treatment of HBT combined with aclarubicin and Ara-c resulted in a complete remission (CR) rate of 83%.…”