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Targeting mutant IDH2 in angioimmunoblastic T-cell lymphoma

Dr. Epstein-Peterson

Zachary Epstein-Peterson


Memorial Sloan Kettering Cancer Center

Project Term: July 1, 2023 - June 30, 2026

Angioimmunoblastic T-cell lymphoma is a rare, aggressive form of T-cell lymphoma associated with poor clinical outcomes in response to current therapeutic approaches. Recurrent oncogenic mutations in isocitrate dehydrogenase 2 (IDH2) have been identified in patients with angioimmunoblastic T-cell lymphoma and this represents a targetable lesion in other malignancies. However, comprehensive investigations of mutant IDH2 inhibition in angioimmunoblastic T-cell lymphoma are lacking, and this may represent a new therapeutic avenue for a patient population in need of newer treatments

Lay Abstract

Peripheral T-cell lymphomas (PTCL) are a varied group of aggressive cancers that comprise ~10-15% of non-Hodgkin lymphomas (NHL). In contrast to B-cell NHL, our understanding of PTCL remains poor, and, besides few specific examples, clinical outcomes for PTCL are poor, with 5-year overall survival rates of <30% in response to standard therapies and especially poor outcomes for patients with disease that relapses following therapy or does not respond to begin with. Angioimmunoblastic T-cell lymphoma (AITL), one of the most common subtypes of PTCL, frequently harbors mutations in the IDH2 gene, which normally functions in cell nutrient processing. Cancer-associated IDH2 mutations gain the ability to produce high levels of a metabolite called 2HG, which in a different type of blood cancer has been shown to lock IDH2-mutant cancer cells in an stem cell-like state. In clinical trials involving patients with acute myeloid leukemia, the mutant IDH2 enzyme inhibitor enasidenib induced a response in ~40% of patients, leading to FDA approval for this indication.

We treated two patients with IDH2-mutated AITL that had relapsed after chemotherapy with enasidenib at our institution. When starting this therapy, each patient had an extensive burden of lymphoma, and each experienced a quick response within 1-2 weeks of initiating treatment. However, the lymphoma later became unresponsive to enasidenib. In both instances, however, preliminary evidence suggests that the AITL itself may have responded to the enasidenib, but with concurrent outgrowth of a of B-cell NHL, which has been previously described in patients with AITL.

Based on supporting evidence for the role of IDH2 mutations in the underlying biology of AITL and observations from our two-patient experience, we hypothesize that IDH2 inhibition may offer an effective new therapeutic strategy to treat patients with IDH2-mutant AITL. To test this hypothesis, we will execute a multicenter prospective clinical trial testing enasidenib in this patient population. Besides determining the safety and preliminary effectiveness of enasidenib, we will also seek to better understand the underlying disease biology of AITL and IDH2 mutations in this disease. We hope that this trial and the accompanying scientific studies will enable the further clinical development of mutant IDH2 inhibitors as well as other targeted treatments for patients facing AITL, with the ultimate goal of individualizing and improving outcomes for patients with this challenging disease.

Academic Clinical Trials Program (ACT)
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