Oral Epigenetic Therapy Demonstrates Hematologic Responses in Leukemia

An analysis of three phase 1/2 studies evaluating the oral therapy CC-486 in patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML) who received prior epigenetic hypomethylating agents (HMA), showed positive results.

The findings were presented at the 58^th American Society of Hematology Annual Meeting in San Diego, CA.

In the analysis, there were 35 patients who received prior HMA therapy, 22 with MDS, 2 with CMML, and 11 with AMML. They received 120 to 600 mg of CC-486 over 7 days following a single sub-cutaneous azacitidine (AZA) cycle (75 mg/m2/d x7d), or 300 mg QD, once daily, or 200 mg BID, twice daily) of CC-486 14 days or 21days, with no initial SC AZA cycle.

Before receiving CC-486, eleven patients (31%) failed more than 1 prior injectable HMA course. A majority of patients (57%) received more than 4 HMA therapy cycles. There were 5 AML patients who received prior HMAs during treatment for MDS.

Of the 25 patients in whom outcomes with prior HMAs were known, 14 patients relapsed, and 11 were refractory to the injectable HMA, according to the press release. The median number of CC-486 cycles was 5, and ranged from 1 to 60.

The overall response rate (ORR) in the study included complete remission (CR), partial remission, CR with incomplete hematologic recovery (Cri; AML patients only), hematologic improvement, and transfusion independence.

The results of the study showed that for all patients treated with CC-486, the ORR was 38%. Marrow CR (mCR) was assessed in MDS patients with ≥5% bone marrow blasts at baseline. Of the 11 patients who were refractory prior to HMAs, 4 patients (36%) responded, including 1 AML patient who attained CR with CC-486. Out of the 14 patients who relapsed during or after prior HMA therapy, 5 (35%) responded. Patients who received at least 6 prior cycles of HMA therapy, the ORR was 33%.

The most frequent (≥10%) grade 3-4 hematologic adverse events (AEs) were anemia, thrombocytopenia, and neutropenia, while the most frequent grade 3-4 gastrointestinal AEs were diarrhea and vomiting.

“The results of this analysis suggest that prior HMA exposure does not preclude the future response to CC-486,” said Dr Guillermo Garcia-Manero, chief, Section of Myelodysplastic Syndromes at MD Anderson Cancer Center. “The extended dosing and hypomethylation may also differentiate CC-486 and induce these responses. As we look toward new options for patients with MDS, CMML, and AML, this oral epigenetic therapy deserves further evaluation.”