IDH1 Inhibitor Found Safe and Effective in Rare Precursor to Blood Malignancies

Patients with clonal cytopenias of undetermined significance (CCUS) harboring an IDH1 mutation have a heightened risk of progression to an overt myeloid neoplasm, with some studies estimating the risk to exceed 90% at 10 years.

Data from a single-arm decentralized multicenter phase 2 study suggest that early intervention with ivosidenib, an oral inhibitor of mutant IDH1, improves cytopenias characteristic of CCUS, offering the possibility of preventing progression of IDH1-mutated CCUS to myelodysplastic syndrome (MDS) and other overt myeloid neoplasms.

Overall, 14 of 17 (82%) patients in the study achieved a hematologic response, the primary endpoint of the study, including improvements in neutropenia in 88% and thrombocytopenia in 75% over a median follow-up of 16 months. Abhay Singh, MD, MPH, an associate staff physician in Cleveland Clinic Cancer Institute’s Leukemia Department, reported the findings at the American Society of Hematologic annual meeting.

“The study is a wonderful first step in the direction of blood cancer prevention, by which early incorporation of effective treatments can improve blood counts and possibly halt progression to overt myeloid neoplasm and even reverse disease in its early stages,” says study co-author Dr. Singh.

CCUS is a rare condition characterized by low blood cell counts and clonal hematopoiesis coupled with the presence of preleukemic mutations in hematopoietic stem and progenitor cells. Patients with CCUS have a high risk of progression to myeloid neoplasms (i.e., mutated acute myeloid leukemia [AML] and MDS). Ivosidenib has already been approved by the U.S. Food and Drug Administration for the treatment of IDH1-mutated AML and MDS, but has not been studied previously in CCUS, their precursor condition, which typically has a lower mutational burden compared with AML or MDS.

“Often, patients with IDH1-mutated CCUS will have a low neutrophil count and thrombocytopenia, be of older age and have at least one accompanying high-risk mutation,” says Dr. Singh.

The study was a decentralized trial (DCT) design in which patients could participate in their home with local providers using telemedicine and mobile phlebotomy services. The DCT design is intended to improve accessibility for patient populations with rare conditions, and allow rare mutations to be studied.

Long duration of hematologic response

Individuals with AML or MDS who have lower comutational burden are more likely to have a clinical response and achieve molecular remission with ivosidenib. Since CCUS is characterized by a lower mutation burden compared with AML or MDS, the investigators hypothesized that the use of ivosidenib in IDH1-mutant CCUS will result in an improved and more prolonged clinical response.

Twenty patients with unexplained cytopenias for at least six months and an IDH1 gene mutation received outpatient ivosidenib (500 mg daily) for up to 18 cycles. Almost all (95%) patients presented with neutropenia and 21% had concomitant thrombocytopenia. Patients had an average of two comutationsbeyond IDH1 prior to treatment. Of the 20 patients enrolled, 17 received at least eight weeks of treatment and were included in the efficacy analysis.

The primary endpoint was the rate of improvement in hematologic parameters based on International Working Group 2006 criteria for MDS response for erythroid, platelet and neutrophil responses through 30 days after completion of treatment. Local oncologists performed standard-of-care clinical exams supplemented by study team interviews for adverse event monitoring.

Of the 14 patients who achieved a hematologic response, the median duration of hematologic response was not reached, and 86% had a continued response at one year. Two patients progressed to MDS after four and 17 months of treatment.

A surveillance bone marrow biopsy at 18 cycles in eight responders who remained on treatment showed that none had disease progression. Nine of the 10 patients who were treated for at least 12 months had a decrease in IDH1-mutant clonal hematopoiesis variant allele frequency over time and four of the 10 had IDH1 mutation clearance with a median time to clearance of nine months.

Favorable risk/benefit profile

The researchers considered the efficacy of the therapy weighed against toxicities. There were no reported cases of differentiation syndrome, a serious potential side effect of ivosidenib that occurs due to rapid proliferation and differentiation of myeloid cells.

“When we treat early in the CCUS stage, the cells are not arrested in an immature state, so we don’t see a lot of differentiating cells. We do see benefit in reversing the clonal cells into normal cells,” says Dr. Singh.

Five patients had grade ≥3 adverse events, including one with grade ≥3 pancytopenia and rash and another with a rash.

“Ivosidenib warrants further evaluation in a larger trial in this setting based on these promising results,” says Dr. Singh.