Kelly J. Norsworthy

On December 1, 2022, the FDA approved the new molecular entity olutasidenib (Rezlidhia, Rigel Pharmaceuticals), a small-molecule inhibitor of isocitrate dehydrogenase 1, for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with a susceptible isocitrate dehydrogenase 1 mutation as detected by an FDA-approved test. The efficacy of olutasidenib was established based on complete remission (CR) + CR with partial hematologic recovery (CRh) rate, duration of CR + CRh, and conversion of transfusion dependence to transfusion independence in Study 2102-HEM-101. In the pivotal trial, 147 adult patients treated with 150 mg twice daily of olutasidenib were evaluable for efficacy. With a median follow-up of 10.2 months, the CR/CRh rate was 35% (95% confidence interval, 27%–43%), with a median duration of response of 25.9 months [95% confidence interval, 13.5–not reached]. Of the 86 patients who were transfusion dependent at baseline, 29 became transfusion independent (34%). The most common (≥20%) adverse reactions were nausea, fatigue, arthralgia, leukocytosis, dyspnea, pyrexia, rash, mucositis, diarrhea, and transaminitis. An assessment of long-term safety of olutasidenib is a condition of this approval.

PURPOSE: The US Food and Drug Administration has approved multiple new treatments for AML since 2017 based on demonstrated efficacy and safety in clinical trials. However, the uptake of new treatments and effectiveness in the routine clinical practice are largely unknown. METHODS: A retrospective observational study was conducted to examine first-line therapy in patients with AML who were treated at institutions providing data to the COTA database. Information on demographics, disease characteristics, treatments, and outcomes was collected and analyzed descriptively. RESULTS: Among the 2,516 patients eligible for inclusion in our analysis, cytarabine-based intensive chemotherapy (IC w/cytara) was the most commonly used treatment, followed by hypomethylating agents (HMA) with venetoclax (HMA+ven), HMA alone, and investigational treatment. Use of HMA+ven increased over time since its approval in 2018, whereas use of IC w/cytara and HMA alone decreased. Complete remission rates were 45% overall and highest in patients treated with IC w/cytara (61%) or investigational therapy (62%). CONCLUSION: Overall survival was highest for patients treated with IC w/cytara, although differences in baseline patient characteristics make direct comparison infeasible. Uptake of HMA+ven as a first-line treatment for patients with AML has been more rapid compared with other newly approved therapies. Outcomes for patients treated in routine practice were similar to those seen in clinical trials. Further research may be helpful in characterizing real-world effectiveness and safety in specific subpopulations and disease subtypes.

On June 6, 2024, the US Food and Drug Administration (FDA) approved imetelstat (RYTELO, Geron) for adults with low- to intermediate-1 risk myelodysplastic syndromes (MDS) with transfusion-dependent anemia requiring ≥4 red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents. The approval was based on a randomized (2:1), double-blind, placebo-controlled multicenter trial, Study MDS3001. In the protocol-specified primary analysis, the ≥8-week RBC transfusion independence (RBC-TI) rate was 39.8% (95% CI, 30.9 to 49.3) in the imetelstat group versus 15% (95% CI, 7.1 to 26.6) in the placebo group ( P < .001). This was supported by the rate of ≥24-week RBC-TI of 28% (95% CI, 20.1 to 37) in the imetelstat group versus 3.3% (95% CI, 0.4 to 11.5) in the placebo group ( P < .001). However, there was no major difference between arms regarding the key secondary end point of erythroid response (HI-E) per International Working Group 2006 criteria or secondary end points reflective of a disease-modifying effect such as complete remission rate and overall survival. The most common adverse reactions were thrombocytopenia, leukopenia, neutropenia, increased liver enzymes, fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19, and headache. The rate of grade 3 to 4 neutropenia and thrombocytopenia were 72% and 65%, respectively, in the imetelstat arm compared with 7% and 8% in the placebo arm. Despite the high incidence of neutropenia and thrombocytopenia, the FDA determined that the benefits outweighed the risks in this patient population with high unmet need. Postmarketing requirements were issued to evaluate long-term safety and to conduct a randomized trial comparing at least two dosages of imetelstat to potentially minimize risks of imetelstat treatment and improve tolerability.

Frequent Laboratory Abnormalities

On October 24, 2023, the FDA approved a supplemental application for ivosidenib (Tibsovo; Servier) for the treatment of adult patients with relapsed/refractory (R/R) isocitrate dehydrogenase 1–mutated myelodysplastic syndrome (MDS). The efficacy of ivosidenib in patients with R/R MDS was established in study AG120-C-001, an open-label, single-arm trial, based on the complete remission (CR) + partial remission (PR) rate, duration of CR + PR, and conversion of transfusion dependence to transfusion independence. With a median follow-up of 27.1 months in 18 patients with isocitrate dehydrogenase 1–mutated R/R MDS treated with ivosidenib 500 mg once daily, the CR + PR rate was 39% (95% confidence interval, 17.3–64.3; all CR responses), with a median duration of response not estimable (range, 1.9–80.8+ months). Of the nine patients with transfusion dependence at baseline, six achieved transfusion independence (67%). Serious adverse reactions in ≥5% included differentiation syndrome, fatigue, and rash. The most common (≥20%) adverse reactions were arthralgia, fatigue, cough, diarrhea, decreased appetite, mucositis, myalgia, and pruritus.