Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic‐ or accelerated‐phase chronic myeloid leukemia: Results with 24 months of follow‐up

Abstract

Background Omacetaxine, a protein synthesis inhibitor, is indicated in the US for the treatment of patients with chronic (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors. Methods This final analysis, with 24-month follow-up, includes additional efficacy and safety analyses to assess the benefit of long-term omacetaxine administration (1.25 mg/m2 bid for 14 days q 28 days followed by 7 days q 28 days) in CP- and AP-CML patients receiving >3 cycles. Results Eighteen percent of CP-CML patients achieved major cytogenetic response (MCyR) with a median duration 12.5 months (95% confidence interval [CI], 3.5-not reached [NR]); responses were maintained for ≥12 months in 3 of 14 responders and median overall survival (OS) was 40.3 months (95% CI, 23.8-not reached). In patients with AP-CML, 14% achieved or maintained major hematologic response for a median of 4.7 months (95% CI, 3.6-NR); MCyR was not achieved and median OS was 14.3 months (95% CI, 6.7–18.7). In patients with CP- or AP-CML who received >3 cycles of treatment (n=50 and 14, respectively), median OS was 49.3 months (95% CI, 23.8-NR) and 24.6 months (95% CI, 12–37.2), respectively. Grade ≥3 hematologic toxicity was the major side effect (79%/73% in CP-CML/AP-CML), with discontinuation due to toxicity in 10% of CP and 5% of AP patients. Conclusions These results suggest that long-term administration of omacetaxine is feasible with dose adjustments to manage toxicities, and that omacetaxine provides durable benefit in some patients.

Screening of Conditionally Reprogrammed Patient-Derived Carcinoma Cells Identifies ERCC3–MYC Interactions as a Target in Pancreatic Cancer

“…2A and S3B) at maximum tolerated doses [26]. Homoharringtonine, a plant alkaloid and a ribosomal inhibitor used for the treatment of chronic myeloid leukemia[30], was inactive in vivo (Fig. 2A), as was carfilzomib (Fig.…”

Overall survival with ponatinib versus allogeneic stem cell transplantation in Philadelphia chromosome‐positive leukemias with the T315I mutation

“…Ponatinib is approved in the United States and the European Union for adult patients with refractory CML or Ph+ ALL and those with the BCR‐ABL T315I mutation, and is now the only effective TKI for treating CML or Ph+ ALL in T315I‐positive patients 3, 4, 6. Recently, it was demonstrated that omacetaxine mepesuccinate, a first‐in‐class cephalotaxine, also has inhibitory activity in TKI‐resistant CML stem cells and provides a benefit to patients who have T315I‐positive chronic phase (CP)‐CML as a single agent or in combination with a TKI 7. However, omacetaxine mepesuccinate was not considered in the current analysis, which focused on a comparison between ponatinib and allogeneic stem cell transplantation (allo‐SCT).…”

Incidence and management of myelosuppression in patients with chronic- and accelerated-phase chronic myeloid leukemia treated with omacetaxine mepesuccinate

“…Despite this significant toxicity, omacetaxine treatment is feasible in many CML-CP and CML-AP patients with CML, inducing hematologic and cytogenetic responses in some patients who are able to continue treatment. In a post hoc analysis of the efficacy population from the two phase 2 studies, 11 of 50 patients (22%) with CML-CP who completed more than three cycles of omacetaxine achieved MCyR; three of these patients maintained a response for at least 12 months [15]. Rate of CHR was 94% in this subgroup and the response was durable (≥12 months) in 26% [15].…”

“…In preclinical studies, omacetaxine reduced levels of several oncoproteins, including Bcr-Abl and Mcl-1, and induced apoptosis in leukemic cells [7–10]. In clinical studies, omacetaxine produced durable hematologic and cytogenetic responses in patients with CML-CP and CML-AP, regardless of mutational status [11–15]. …”

“…In spite of this toxicity, myelosuppression is typically manageable with a combination of treatment delays, reduced dosing days per cycle, supportive care, and patient education that allows for continuation of treatment. With the exception of myelosuppression-related events such as infection, grade 3/4 nonhematologic adverse events (AEs) were infrequent; most notably, grade 3 or 4 hyperglycemia was reported in 11% of patients [2,14,15]. Here, we further examine the hematologic toxicity in the safety population composed of all CML-CP and CML-AP patients with any prior TKI treatment and who received omacetaxine in the two omacetaxine clinical trials, and describe the monitoring, management, and outcome of these events to prescribing practitioners and healthcare professionals.…”