The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia

Abstract

Pinometostat (EPZ-5676) is a first-in-class small-molecule inhibitor of the histone methyltransferase disrupter of telomeric silencing 1-like (DOT1L). In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving mixed lineage leukemia () gene rearrangements () resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose-escalation cohorts (n = 26) and 2 expansion cohorts (n = 25) at pinometostat doses of 54 and 90 mg/m per day by continuous intravenous infusion in 28-day cycles. Because a maximum tolerated dose was not established in the dose-escalation phase, the expansion doses were selected based on safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady-state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remission at 54 mg/m per day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using the single agent pinometostat in leukemia patients. Administration of pinometostat was generally safe, with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as NCT01684150.

Conserved crosstalk between histone deacetylation and H3K79 methylation generates DOT1L‐dose dependency in HDAC1‐deficient thymic lymphoma

“…In MLL‐r leukemia, DOT1L recruitment to MLL target genes, such as the HoxA cluster, leads to aberrant H3K79 methylation and increased transcription (reviewed in Vlaming & Van Leeuwen, ). Although the DOT1L inhibitor Pinometostat (EPZ‐5676) has shown promising results in the laboratory and is currently in clinical development (Bernt et al , ; Daigle et al , ; Waters et al , ; Stein & Tallman, ; Stein et al , ), the cellular mechanisms and consequences of DOT1L deregulation are only just being uncovered (Vlaming & Van Leeuwen, ).…”

Single-cell epigenetics – Chromatin modification atlas unveiled by mass cytometry

“…For instance, inhibition of lysine methyltransferase DOT1L by Pinometostat reduces the bulk of H3 methylation at lysine 79 (H3K79me) 36 . Several monoclonal antibodies can identify reduced H3K79me in Pinometostat-treated cells by western blotting under denaturing conditions (Figure 1D).…”

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

“…When used in rearranged-MLL (mixed-lineage-leukemia) cells and xenograft models, 21 reduced H3K79 methylation level, decreased MLL target gene expression, and induced selective leukemia cell death. 25,26 JNJ-64619178 22 27 and GSK3326595 23 28 (Table 1) are two potent and selective PRMT5 inhibitors that induced tumor regression in solid cancers as well as in hematologic malignancies, supporting clinical testing in patients with these kinds of cancer.…”

“…Pinometostat 21 (Table ) is a picomolar inhibitor of the H3K79 methyltransferase disruptor of telomeric silencing 1‐like (DOT1L), with more than 30 000‐fold selectivity against other KMTs. When used in rearranged‐MLL (mixed‐lineage‐leukemia) cells and xenograft models, 21 reduced H3K79 methylation level, decreased MLL target gene expression, and induced selective leukemia cell death …”

“…has been conducted with the aim to evaluate the PK and the safety of this combination. [22][23][24][25][26][27][28]. AML makes the affected subjects more susceptible to fungal infections, therefore posaconazole 49 resulted effective to prevent this condition.…”