The oral targeted small-molecule inhibitors of mutant IDH1 and IDH2 appear to be active in patients with myelodysplastic syndrome (MDS) harboring these mutations, according to two phase II trials by the Groupe Francophone des Myélodysplasies (GFM) and its German colleagues in the European MDS Studies Coordination Office. Both studies were presented at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition.1,2
Somatic mutations in the genes encoding the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1/2) are found in many solid tumors. These mutations impact epigenetic regulation and cellular differentiation and ultimately help drive oncogenesis. Two inhibitors of IDH mutations—ivosidenib and enasidenib—are U.S. Food and Drug Administration–approved for adults with relapsed or refractory IDH-mutated acute myeloid leukemia (AML) who are elderly or unfit for intensive chemotherapy. The studies presented at the ASH meeting evaluated their benefit in the 10% or so of patients with IDH-mutated MDS.
Ivosidenib in the Phase II IDIOME Trial
“Ivosedinib was well tolerated in patients with myelodysplastic syndrome who had IDH1 mutations, with significant responses seen in all three cohorts. Ivosidenib was particularly effective in treatment-naive higher-risk patients, who had a 91% response rate,” said Marie Sebert, MD, PhD, of Hôpital Saint Louis, Paris.1
The findings were from a preliminary analysis of the GFM phase II IDIOME trial, which evaluated ivosidenib in three different cohorts with IDH1 mutations:
Cohort A: Patients with higher-risk MDS who failed to respond to azacitidine after six cycles but had no evidence of disease progression (n = 13)
Cohort B: Patients with untreated higher-risk MDS without life-threatening cytopenias (absolute neutrophil count < 500/mm3 or any recent severe infections and/or platelet count below 30,000/mm3 and any bleeding symptom; n = 11)
Cohort C: Patients with lower-risk MDS with anemia, not responding to erythropoietin-stimulating agents (n = 2).
The patients received 28-day cycles of ivosidenib at 500 mg daily for six cycles. In cohort B, azacitidine (75 mg/m2/d x 7 days, subcutaneously) was added to ivosidenib after three cycles in nonresponders. The primary endpoint was overall hematologic response rate at 3 and 6 months (including complete and partial responses, stable disease, and hematologic improvement) for cohorts A and B; for cohort C, the primary endpoint was safety. All responders were allowed to continue treatment until loss of response.
Dr. Sebert reported the preliminary results on the first 26 evaluable patients of 32 enrolled in the trial. Almost half the patients had a p.R132C mutation, followed by p.R132H and then p.R132G/S. Median IDH1 variant allele frequency was 15% overall.
The overall objective response rate was 69%, of which 46% were complete responses. Responses were observed in 54% of cohort A, 91% of cohort B, and 50% of cohort C. In cohort B, one patient required azacitidine after three cycles of ivosidenib, without an additional response.
With a median follow-up of 9.1 months, the median duration of response of the 18 responders was 7.4 months; 9 patients lost their response, and 2 died without loss of response. Median overall survival was 14 months in the entire cohort, 7.7 months in cohort A, and not reached in cohort C.
Of the 26 patients whose disease progressed to AML during follow-up, 4 were in cohort A, and 6 died without disease progression. The cumulative risk of evolution at 1 year was 25.1%, she reported.
Five patients experienced a serious adverse event. Four had differentiation syndrome; of these patients, one died and three experienced resolution of symptoms without sequelae. There was one case of transient febrile neutropenia.
The ongoing study will enroll up to 68 patients and will include molecular analyses.
Enasidenib in the Phase II IDEAL Trial
Lionel Ades, MD, PhD, also of the Hôpital Saint Louis, Paris, presented the interim findings from the phase II IDEAL study, which evaluated 26 patients with MDS and IDH2 mutations. “The results in terms of response seem encouraging in the different cohorts, and there was a very encouraging signal in patients with low-risk myelodysplastic syndrome,” Dr. Ades said.
Lionel Ades, MD, PhD
The three cohorts were the same subsets as evaluated in the GFM IDIOME trial. Cohort A (n = 11) and cohort C (n = 6) received enasidenib at 100 mg for six cycles; cohort B (n = 9) received enasidenib at 100 mg for six cycles (after three cycles, azacitidine could be added). Cycles were repeated every 28 days. Mean IDH2 variant allele frequency was 36% overall.
Response rates to enasidenib were as follows:
Overall: 42%, including complete responses in 23%
Cohort A (high-risk, failed to respond to hypomethylating agents): 27%, including complete responses in 18%
Cohort B (first-line, high-risk): 56%, including 11% complete responses
Cohort C (low-risk, failed to respond to erythropoietin-stimulating agents): 50%, all with complete responses.
“In cohort B, azacitidine was added to enasidenib in three patients who were primary resistant to enasidenib, and two of those patients subsequently achieved a response,” he noted.
With a median follow-up of 8.6 months, almost all responses were sustained. Among the 11 responders, 2 patients lost their response after 82 and 84 days. Median overall survival was 17.3 months; overall survival at 1 year was 80.8% in cohort A, 100% in cohort B, and 80% in cohort C. “The early death rate was low in this study, as illustrated by the 6-month death rate of 8.2%,” he said.
KEY POINTS
- The phase II IDIOME and IDEAL trials, conducted in France and Germany, indicate that for patients with myelodysplastic syndrome harboring IDH1 or IDH2 mutations, the IDH inhibitors ivosidenib and enosidenib, respectively, may be promising treatments.
- Response rates in various cohorts of patients ranged from 42% to 69%, and the median overall survival ranged from 14 to 17 months.
- The drugs were reported to be well tolerated.
Four patients evolved to AML (in cohorts A and B); the 1-year cumulative risk of evolution was 19.3% among all patients, but this risk differed across the cohorts. No patients in the low-risk cohort C group experienced disease progression.
Three patients experienced differentiation syndrome (one in cohort A and two in cohort B), which resolved without sequelae. The other most common grade 3 or 4 adverse events were nausea and diarrhea in four patients and thrombocytopenia in five patients.
“Altogether, the findings suggest that enasidenib may produce profound and durable responses in these patients,” Dr. Ades commented. Correlative studies are ongoing to assess the impact of measurable residual disease and clonal architecture on response to enasidenib.
DISCLOSURE: Dr. Sebert has received honoraria from AbbVie, Jazz, Servier, and Celgene/BMS. Dr. Ades has received honoraria from Jazz, Takeda, Celgene/BMS, Novartis, and AbbVie.
REFERENCES
1. Sebert M, Cluzeau T, Beyne Rauzy O, et al: Ivosidenib monotherapy is effective in patients with IDH1 mutated myelodysplastic syndrome: The IDIOME phase 2 study by the GFM Group. 2021 ASH Annual Meeting & Exposition. Abstract 62. Presented December 11, 2021.
2. Ades L, Dimicoli-Salazar S, Sebert M, et al: Enasidenib is effective in patients with IDH2 mutated myelodysplastic syndrome: The IDEAL phase 2 study by the GFM Group. 2021 ASH Annual Meeting & Exposition. Abstract 63. Presented December 11, 2021.
