Combination Therapy with Entinostat (MS-275) and GM-CSF to Enhance Differentiation In Myeloid Malignancies

Histone actylases (HAC and histone deacetylases (HDAC) are two important enzymes in epigenetic control that can affect transcription of important regulatory transcription factors. Entinostat is a HDAC inhibitor that has been shown in vivo and in vitro to have anti-proliferative effects on many cancer cell types (Abujamra Leukemia Res 2009). When administered at low concentration to leukemic cell lines, entinostat induced p21-mediated growth arrest and expression of differentiation markers; higher concentrations led to marked increase in reactive oxygen species, mitochondrial damage, caspase activation and apoptosis (Rosato Cancer Res 2003). A Phase I study using entinostat as a single agent in relapsed and refractory leukemia showed in vivo differentiation potential with several patients showing significant increases in their mature granulocyte population and increased acetylation of the CD34+ blast population (Gojo Blood 2006). GM-CSF has been shown to enhance the differentiation potential of various agents such as interferon-alpha, all-trans-retinoic acid, bryostatin, and numerous other anti-neoplastic agents. The effects of combination therapy with GM-CSF and entinostat in patients with high-risk MDS or refractory and/or relapsed AML are presented here.

A Phase II study was conducted to assess the safety and efficacy of combination therapy with GM-CSF and entinostat in patients with high-risk MDS and relapsed or refractory AML who are not eligible for allogeneic bone marrow transplant (BMT). The combination of entinostat and GM-CSF was administered in 6-week (42 day) cycles for at least 2 cycles. Entinostat was originally give at 8 mg/m2 weekly but was eventually adjusted to 4 mg/m2 weekly for the first 4 out of 6 weeks due to toxicity. GM-CSF was given at a single dose of 125 micrograms/m2/day for days 1–35 in the cycles 1, 2, 4 and 6 and days 1–42 in cycles 3 and 5. Patients who tolerated two cycles of 4 mg/m2 were assessed for response through measurements of peripheral blood, bone marrow aspirate and biopsies. Transfusion requirements and adverse events (AE) were recorded on all subjects throughout the study period. Clinical responses for AML and MDS were measured according to International Working Group definitions of complete response (CR), partial response (PR), stable disease (SD), hematologic improvement, and progressive disease (PD).

A total of 24 patients met the eligibility criteria for response assessment. Median age was 71 (range 52–84) years and 15 (63%) were male. Of the 19 patients with AML, 8 had relapsed/refractory disease, 7 had AML arising from MDS, 3 had therapy-related AML, and 1 had de novo AML. The remaining 5 patients had a primary diagnosis of MDS. 10 patients (42%) completed 2 or more cycles at the 4 or 6 mg/m2 dose of MS-275. These patients completed a total of 33 cycles, 1 resulting in CR, 4 in PR, 24 in SD, and 4 in PD. In addition to these standard endpoints, improvements were also noted in peripheral neutrophil counts (p<0.019) and platelet counts (p<0.001), without an appreciable change in blast count as a result of treatment (p<0.50). These results were achieved with few toxicities at the noted dosing. A total of 38 cycles at the 4-mg/m2-dose were analyzed for Grade 3 or 4 toxicities, which included febrile neutropenia (n=3), neutropenic infection (n=3), bone pain (n=2), fatigue (n=1), pericardial effusion (n=1), and weakness (n=1).

Although treatment with entinostat and GM-CSF did not result in durable remissions, there were notable improvements in absolute neutrophil and platelet counts without negatively impacting the blast percentage. These findings suggests that therapy with entinostat and GM-CSF differentially promotes growth of mature myeloid cells and appears associated with better marrow function by minimizing the need for platelet transfusions. Such strategies may be most effective when applied to patients with low disease burdens or as maintenance therapy for patients with high risk disease in remission.

Matsui:Pfizer: Consultancy; Bristol-Meyers Squibb: Consultancy; Infinity Phamaceuticals: Consultancy, Patents & Royalties; Merck: Consultancy, Research Funding; Geron Corporation: Research Funding.