SUMMARY: The FDA on December 1, 2022, approved REZLIDHIA® (Olutasidenib) capsules for adult patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) with a susceptible IDH1 mutation, as detected by an FDA-approved test. The FDA on the same day also approved the Abbott RealTime IDH1 Assay to select patients for REZLIDHIA®.
The American Cancer Society estimates that for 2022, about 20,050 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,540 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior Myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone. AML mainly affects older adults and the median age at diagnosis is 68 years. A significant majority of patients with AML are unable to receive intensive induction chemotherapy due to comorbidities and therefore receive less intensive, noncurative regimens, with poor outcomes.
Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites, by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression, thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle.
Approximately 20-25% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic Cholangiocarcinoma, 30% of patients with Angioimmunoblastic T-Cell Lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations. IDH2 mutations are more common than IDH1 mutations, occurring in approximately 15% to 20% of patients with AML. The presence of IDH mutations has both prognostic and predictive value. Patients with an IDH mutation and a Nucleo¬phosmin (NPM1) mutation usually have a better prognosis whereas patients with mutations in IDH and FMS-like tyrosine kinase 3 (FLT3) do not. Further IDH mutations predict response to specific IDH1 and IDH2 inhibitors in the Relapsed and Refractory setting. The presence of an IDH mutation is therefore not only prognostic, but also predictive of response to certain therapies.
The two IDH inhibitors presently available in the US include IDHIFA® (Enasidenib), approved for the treatment of patients with Relapsed or Refractory AML with IDH2 mutation and TIBSOVO® (Ivosidenib), approved for AML patients with the IDH1 mutation who have Relapsed/Refractory disease, as well as monotherapy for newly diagnosed AML patients 75 years or older with comorbidities that preclude the use of intensive induction chemotherapy. IDHIFA® can be associated with indirect hyperbilirubinemia, which is of no clinical consequence, whereas with TIBSOVO® there is a small risk of QT interval prolongation. Both agents can lead to Differentiation Syndrome in 10-15% of patients which requires systemic steroids and hemodynamic monitoring for at least 3 days.
REZLIDHIA® is a potent, selective, oral, brain-penetrant, small molecule inhibitor of mutant IDH1, that has exhibited favorable tolerability and clinical activity in high-risk AML patients in a Phase 1 trial (Watts JM, et al. Blood 2019). The present FDA approval was based on the Phase 1/2 Study 2102-HEM-101 trial (NCT02719574), which included 147 adult patients with Relapsed or Refractory AML with an IDH1 mutation, confirmed using the above now approved assay. Enrolled patients had pathologically proven AML, except those with Acute Promyelocytic Leukemia with the t(15;17) translocation, or intermediate high, or very high-risk MDS as defined by the WHO criteria or Revised International Prognostic Scoring System. REZLIDHIA® 150 mg was given orally, twice daily, until disease progression, unacceptable toxicity, or Hematopoietic Stem Cell Transplantation. The median treatment duration was 4.7 months. Sixteen (11%) patients underwent Hematopoietic Stem Cell Transplantation following treatment with REZLIDHIA®. The Primary end points included the rate of Complete Remission (CR) plus Complete Remission with partial hematologic recovery (CRh). Secondary end points included time to response, Duration of Response, Event-Free Survival, Overall Survival, and Relapse-Free Survival.
The Complete Remission plus Complete Remission with partial hematologic recovery rate with REZLIDHIA® was 35%, with 32% CR and 2.7% CRh. The median time to CR+CRh was 1.9 months and the median duration of CR+CRh was 25.9 months. Among the 86 patients who were Red Blood Cell (RBC) and/or platelet transfusions dependent at baseline, 34% became RBC and platelet transfusion independent during any 56-day post-baseline period. Of the 61 patients who were RBC and platelet transfusions independent at baseline, 64% remained transfusion independent during any 56-day post-baseline period. The most common adverse reactions were nausea, diarrhea, constipation, mucositis, fatigue/malaise, arthralgia, fever, rash, leukocytosis, dyspnea, and transaminitis. Health care professionals and patients should be aware of the risk of Differentiation Syndrome, which can be fatal.
REZLIDHIA® is the third IDH inhibitor currently approved for the treatment of Acute Myeloid Leukemia.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olutasidenib-relapsed-or-refractory-acute-myeloid-leukemia-susceptible-idh1-mutation.
