IDH2R172 mutation in angioimmunoblastic T‐cell lymphoma: A retrospective multicenter case series

To the Editor, Angioimmunoblastic T-cell lymphoma (AITL), representing 15%–20% of all mature peripheral T-cell lymphomas (PTCLs), is a heterogeneous entity, characterized by poor outcome. Mutations affecting IDH2 gene are detected in 20% of AITL cases, but not in other PTCLs. IDH2 mutations in AITL are restricted to the R172 residue and define a TFH (T-follicular helper) phenotype, distinctive morphological features, and increased DNA hypermethylation of genes involved in TCR signaling and T-cell differentiation. We retrospectively collected data from 42 newly diagnosed consecutive AITL patients, between 2005 and 2020. Routine staging investigations and response was evaluated using the 2014 Lugano criteria The diagnosis of AITL was histologically confirmed and categorized according to the WHO classification by expert hematopathologists, and other TFH-type PTCL was not included in this analysis. No difference in pathological features (morphology and immunophenotype) was seen between IDH2 wild type (WT) and IDH2 mutant AITL. The neoplastic T cells expressed the pan-T cell antigens CD2, CD3, and CD5 and had a CD4+ T helper (Th) cell phenotype. TFH cell markers (e.g., PD1, CXCL13, BCL6, CD10) were detected in the neoplastic cells of IDH2 and IDH2 mutated, but both the extent and the intensity of staining are variable and not significant. In all the cases the presence of polymorphous inflammatory infiltrate, hyperplasia of the high endothelial venules, and extrafollicular follicular dendritic cells expansion excluded a nodal peripheral TFH lymphoma; the lack of a follicular pattern or progressive transformation of germinal center (PTGC)-like pattern rule out a nodal TFH lymphoma, follicular type. Survival analyses were performed by Kaplan–Meier method and Log-rank test was used to compare survival curves. Overall Survival (OS) was calculated from the date of diagnosis to the date of death or to the last clinical follow-up. Progression Free Survival (PFS) was defined as the time from the date of diagnosis to disease progression, relapse, or death from any cause. Cox regression model was used to estimate hazard ratios (HR) and the proportional hazard assumption was tested for all Cox models; p values <. 05 were considered significant. Baseline patients characteristics are shown in Table 1. Thirty-two patients (32/42, 76%) were IDH2, and 10 patients (10/42, 24%) were IDH2 mutated. Clinical features among the two groups were similar except that patients with IDH2 mutation more often have a positive history for prior myeloid neoplasms (p = .02) and display more frequently anemia. Thirty-one patients (75%) received anthracycline/etoposidebased therapy (9 out of 31 were IDH2 mutated) and 4 of them (4/31, 13%) were consolidated with autologous stem-cell transplantation (ASCT) in first complete remission (CR1); ASCT recipients were all IDH2. Eleven patients (11/42, 25%) received anthracycline based treatment (1 out of 11 were IDH2 mutated), without ASCT consolidation. No significant difference in treatment between the two groups was noted. At the end of first line treatment, twenty-three patients (55%) achieved a CR1. Patients with IDH2 AITL achieved CR1 in 14/32 (44%), as opposed to 9/10 (90%) of IDH2 patients (p = .018). Median follow-up was 25 months (range 1–190 months). All deaths were due to progressive disease. In univariate analysis, twoyears PFS and OS in the whole population were 40% (95% CI 25– 55) and 56% (95% CI 39–70), respectively. In univariate analysis (Figure 1), ECOG-PS > 1 (p = .04), EBV-DNA reactivation at diagnosis (p < .05), IDH2 (p = .04), not achieving a CR1 (p < .05, defined as partial response as best response), and a refractory disease Received: 6 June 2022 Revised: 20 September 2022 Accepted: 22 September 2022