Enasidenib for Patients with Clonal Cytopenias of Undetermined Significance

Individuals with cytopenia (low blood cell counts) and clonal hematopoiesis (hee-MA-toh-poy-EE-sis), who do not meet the criteria for a hematologic malignancy, have an entity called clonal cytopenias of undetermined significance (CCUS). These patients have an 82% and 95% chance at 5 years and 10 years, respectively, of developing either acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Although the overwhelming majority of patients inevitably develop a hematologic malignancy, there are no established preventative therapies for patients with CCUS. Studies have shown that AML and MDS originate from stem cells carrying pre-leukemic mutations such as IDH1/2 mutations. IDH1/2 mutations occur in 19% of AML patients and roughly 5% of patients with MDS. Furthermore, individuals with clonal hematopoiesis containing the IDH1/2 mutations are 28 times more likely to develop AML than those without IDH mutations.

 

With the support of Gateway, Dr. Bolton has a decentralized trial utilizing ivosidenib in IDH-1 mutant CCUS that is near completion. Early results suggest that ivosidenib was well-tolerated, induced durable hematologic remissions in 15/18 (83%) patients, allowing them to become transfusion independent, reduced clonal burden in 9/10 (90%) patients, and cleared the mutation in 4/10 (40%) patients. While data collection is still ongoing for the current trial, Dr. Bolton would like to expand this methodology to IDH-2 mutant CCUS patients. This phase II study will assess if enasidenib, an oral IDH-2 inhibitor approved for relapsed/refractory AML, can improve blood cell counts in patients with CCUS who have the IDH-2 mutation. While only 2% of CCUS patients harbor the IDH-2 mutation, Dr. Bolton will utilize a decentralized clinical trial model to reach this rare population in all 50 U.S. states. If successful, Dr. Bolton will pursue FDA approval and seek to have this treatment included in clinical guidelines for patients with IDH-2 mutated CCUS.