Older adults with acute myeloid leukemia (AML) who are not fit for standard chemotherapy historically have poor outcomes. Approximately 12-15% of older patients with AML harbor isocitrate dehydrogenase 2 (IDH2) gene mutations. Enasidenib is an oral inhibitor of mutant IDH2 proteins. Among 39 patients with newly diagnosed mutant-IDH2 AML who received enasidenib monotherapy in this phase I/II trial, median age was 77 years (range 58-87) and 23 patients (59%) had had an antecedent hematologic disorder. The median number of enasidenib treatment cycles was 6.0 (range 1-35). The most common treatment-related adverse events were indirect hyperbilirubinemia (31%), nausea (23%), and fatigue, decreased appetite, and rash (18% each). Treatment-related grade 3-4 cytopenias were reported for eight patients (21%); there was no treatment-related grade 3-4 infections. Twelve patients achieved a response (overall response rate 30.8% [95% CI 17.0%, 47.6%]), including seven patients (18%) who attained complete remission. At a median follow-up of 8.4 months, the median duration of any response was not reached (NR). Median overall survival for all patients was 11.3 months (95% CI 5.7, 15.1), and was NR for responders. Oral, outpatient targeted treatment with enasidenib may benefit older adults with newly diagnosed mutant-IDH2 AML who are not candidates for cytotoxic regimens.

Loss of neurofibromin 1 (NF1) leads to hyperactivation of RAS, which in turn signals through the RAF/MEK/ ERK and phosphoinositide 3-kinase (PI3K)/mTOR pathways to regulate cell growth and survival. Because NF1-deficient acute myeloid leukemias are sensitive to MEK inhibitors, we investigated here whether NF1-deficient glioblastoma multiforme (GBM) would respond to MEK inhibition. In 19 GBM cell lines, we found that treatment with the clinically available MEK inhibitors PD0325901 or AZD6244 decreased levels of phospho-ERK, the downstream effector of MEK, regardless of NF1 status. However, growth inhibition occurred only in a subset of NF1-deficient cells, in association with decreased levels of cyclin D1, increased levels of p27, and G1 arrest. As a single agent, PD0325901 suppressed the growth of NF1-deficient, MEK inhibitor–sensitive cells in vivo as well. Mechanistically, NF1-deficient, MEK inhibitor–sensitive cells were dependent upon the RAF/MEK/ERK pathway for growth and did not activate the PI3K pathway as a mechanism of acquired resistance. Importantly, NF1-deficient cells intrinsically resistant to MEK inhibition were sensitized by the addition of the dual PI3K/mTOR inhibitor PI-103. Taken together, our findings indicate that a subset of NF1-deficient GBMs may respond to MEK inhibitors currently being tested in clinical trials.

Isocitrate dehydrogenase 1 (IDH1) mutations occur in most lower-grade glioma, and not only drive gliomagenesis but are associated with longer patient survival and improved response to temozolomide (TMZ). To investigate the possible causative relationship between these events, we introduced wild-type (WT) or mutant IDH1 into immortalized, untransformed human astrocytes, then monitored transformation status and TMZ response. TMZ-sensitive parental cells exhibited DNA damage (gamma-H2AX foci) and a prolonged G2 cell cycle arrest beginning 3 days after TMZ (100μM, 3hr) exposure and persisting for greater than 4 days. The same cells transformed by expression of mutant IDH1 exhibited a comparable degree of DNA damage and cell cycle arrest, but both events resolved significantly faster in association with increased, rather than decreased, clonogenic survival. The increases in DNA damage processing, cell cycle progression, and clonogenicity were unique to cells transformed by mutant IDH1, and were not noted in cells transformed by WT IDH1 or an oncogenic form (V12H) of Ras. Similarly these effects were not noted following introduction of mutant IDH1 into Ras-transformed cells or established GBM cells. They were, however, associated with increased homologous recombination and could be reversed by the genetic or pharmacologic suppression of the homologous recombination DNA repair protein RAD51. These results show that mutant IDH1 drives a unique set of transformative events that indirectly enhance homologous recombination and facilitate repair of TMZ-induced DNA damage and TMZ resistance. The results also suggest that inhibitors of HR may be a viable means to enhance TMZ response in IDH1 mutant glioma.