Omacetaxine Mepesuccinate for Patients with Higher-Risk MDS and CMML after Failure of Hypomethylating Agents: A Phase II Trial

Background: The outcome of patients (pts) with myelodysplastic syndromes (MDS) after hypomethylating agent (HMA) failure is poor with a median survival of 4-6 months. Omacetaxine mepesuccinate (OM) has been shown to be safe and effective in acute myeloid leukemia, including in pts who progressed from MDS. We designed a phase II trial to evaluate the safety and efficacy of OM in pts with MDS and chronic myelomonocytic leukemia (CMML) after HMA failure.

Methods: Adult pts with MDS or CMML who had not responded to, progressed on, or relapsed after HMA therapy were eligible for this study. Pts were required to be intermediate-2- or high-risk by the International Prognostic Scoring System (IPSS) or be classified as RAEB-1 (5-9% BM blasts), RAEB-2 (10-19% BM blasts) or CMML (5-19% BM blasts). Pts received OM 1.25 mg/m² SQ every 12 hours x 3 days on a 28-day cycle. The primary efficacy outcomes were overall survival (OS) and the overall response rate (ORR). Secondary outcomes included the remission duration, relapse-free survival (RFS), and the safety of the regimen.

Results: Between 6/2015 and 6/2017, 35 pts have been treated. Baseline characteristics are shown in Table 1. The median age of the cohort was 73 years (range, 61-86 years). The median BM blasts was 10% (range, 2-19%) and 15 pts (43%) had poor-risk karyotype. IPSS risk group was intermediate-1 in 8 pts (23%), intermediate-2 in 13 (57%), and high in 7 (20%). 27 pts (77%) were either high risk (n=10) or very high risk (n=17) by IPSS-R. Among 33 pts who underwent comprehensive mutation profiling, 29 (88%) had at least one mutation identified. The most frequently identified mutations were RUNX1 in 10 pts (30%), TP53 in 10 (30%), ASXL1 in 6 (18%) and TET2 in 4 (12%).

The median duration of follow-up was 17 months (range, 2-24 months), and the median number of cycles of OM received was 2 (range, 1-18). The ORR was 34%; 3 pts achieved CRp and 9 pts achieved CRi as best response. The median number of cycles to best response was 2 (range, 1-4 cycles). The response rates for pts with MDS and CMML were 41% and 0%, respectively (P=0.02). Responses were seen across cytogenetic risk groups: 5 responders were diploid, 4 had either complex cytogenetics or monosomy 7, and 3 had miscellaneous cytogenetic abnormalities. The response rate for pts with diploid and adverse-risk cytogenetics were 56% (5/9) and 27% (4/15), respectively (P=0.16).

Of the 12 responders, 4 remain on study, 5 relapsed, 2 died while in response, and 1 was lost to follow-up. To date, 24 pts (69%) have died. The median OS was 7.6 months, and the 1-year OS rate was 22% (Figure 1). The median RFS was 2.9 months, and the 1-year RFS rate was 28%. Two pts have had ongoing response ≥12 months (15.6 and 19.8 months), both of whom had MDS with diploid cytogenetics.

Treatment was overall well-tolerated. Among 26 pts who have received ≥2 cycles of OM, 2 (8%) required dose reduction during subsequent cycles. Most adverse events were grade 1-2; grade ≥3 adverse events occurred in 8 pts (23%). The most frequent non-hematologic adverse events were fatigue in 17 pts (49%), nausea in 12 (34%), mouth sores or mucositis in 6 (17%), infection in 5 (14%) and edema in 5 (14%). The 30-day and 60-day mortality rates were 11% and 14%, respectively.

Conclusions: In pts with MDS and CMML who previously failed HMA therapy, OM was safe and resulted in an ORR of 34%. Responses were seen across cytogenetic risk groups but were restricted to patients with MDS.

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