Jonathon Vallejo

The list of preferred terms included in grouped terms used for safety analysis in ASCEMBL

Specific dose modification strategies for concomitant use of asciminib with other drug products

The list of preferred terms included in grouped terms used for safety analysis in X2101 trial

Select laboratory abnormalities (≥ 10%) that worsened from baseline in patients with Ph + CML in CP, previously treated with two or more tyrosine kinase inhibitors in ASCEMBL

Select laboratory abnormalities (≥ 10%) that worsened from baseline in patients with Ph + CML in CP with the T315I mutation in X2101 trial

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.

On October 29, 2021, FDA granted accelerated approval to asciminib (SCEMBLIX; Novartis), a tyrosine kinase inhibitor (TKI), for the treatment of adult patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP), previously treated with two or more TKIs, and granted traditional approval to asciminib for adult patients with Ph+ CML in CP with the T315I mutation. The first indication was approved based on major molecular response (MMR) at 24 weeks in the ASCEMBL study, a randomized trial comparing asciminib with bosutinib in patients who had failed two or more TKIs. This indication was ultimately granted traditional approval on October 12, 2022, based on safety data and MMR rate at 96 weeks of 38% [95% confidence interval (CI), 30–46] in the asciminib arm versus 16% (95% CI, 8–26) in the bosutinib arm (P value: 0.001). The second indication was approved based on MMR rate by 96 weeks of 49% (95% CI, 34–64) in the single-arm CABL001X2101 study. The most common (≥20%) adverse reactions included upper respiratory tract infections, musculoskeletal pain, headache, fatigue, nausea, rash, and diarrhea. The most common (≥20%) laboratory abnormalities were thrombocytopenia, neutropenia, anemia, lymphopenia, hypertriglyceridemia, hyperuricemia, and increases in creatine kinase, alanine aminotransferase, aspartate aminotransferase, lipase, and amylase. This manuscript describes the basis for approval of these indications.

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.