Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of T-cell lymphoma that manifests with a broad array of neoplastic and paraneoplastic manifestations, including generalized lymphadenopathy, hepatosplenomegaly, systemic symptoms, rash and hypergammaglobulinemia. AITL accounts for approximately 20% of T-cell lymphomas and 1–2% of all non-Hodgkin lymphomas (NHL). Median survival among patients with AITL is less than 3 years, although the course of illness varies widely. Histologic examination of AITL characteristically demonstrates proliferation of high endothelial venules and a polymorphic infiltrate, malignant cells that resemble CD4+ follicular helper T-cells and occasional EBV-positive lymphoid cells. The genetics of AITL remain almost completely undefined, in part because of the low tumor cell fraction and the abundance of non-malignant bystander cells. We reasoned that targeted sequencing of selected genes of interest would increase coverage and thereby enable the detection of low frequency variants present with malignant AITL cells.
To define a targeted mutational landscape of AITL, we performed exon capture and next-generation sequencing of all coding exons of 197 genes known to be recurrently altered in cases of NHL. Single nucleotide variants (SNVs) and insertions/deletions were confirmed by manual review of sequencing reads and a subset was validated by Sanger sequencing of tumor and germline tissue. Twenty-six cases collected from three sites in the USA had adequate tumor specimens available and resulted in high-quality reads (median depth of coverage∼300). Median age among the 26 cases was 66.5 years (range 30–89). Twelve (46%) patients were male. Among 21 cases with adequate clinical annotation, all 21 had advanced stage disease (11 stage 3, 10 stage 4), 13 (62%) had B-symptoms and 19 (90%) had an ECOG performance score of 0–2. Ten patients received CHOP-like regimens, 4 received non-anthracycline containing chemotherapy regimens, 5 received prednisone monotherapy, 2 received cyclosporine monotherapy, and one patient underwent allogeneic stem cell transplantation after cytoreduction with alemtuzumab. Among the 17 patients with staging after first-line treatment, 8 (47%) achieved a complete response, 3 (18%) achieved a partial response, 1 (6%) had stable disease and 5 (29%) had progression of disease. Median overall survival among the 26 patients was 420 days with a median follow-up of 426 days (range 21–3532).
Recent studies have identified both TET2 and DNMT3A mutations in a small number of AITL samples as well as hematopoietic stem cells from the same patients. From the 26 cases, we identified 28 TET2 mutations (13 frameshift, 8 nonsense, 5 missense, 2 splice site) in 17 (65.4%) cases, including 5 cases with 2 TET2 mutations and 2 cases with 3 TET2 mutations. Among the latter, the fractions of mutant reads suggested that one mutation was present within all tumor cells and the other 2 mutations were present in subclones. Six of 17 cases with TET2 mutations also harbored mutations in DNMT3A, compared with 0 of 9 cases that lacked TET2 mutations (p=0.06). Median age for patients with wild-type TET2 was 56 years (range 30–83), 68 years for patients with one TET2 mutation (range 55–89), and 77 years for patients with 2 or 3 TET2 mutations (range 59–84; p<10−4). Median age for patients with wild-type DNMT3A was 64 years (range 30–84) and 75.5 years for patients with mutated DNMT3A (range 64–89; p=0.03).
Known gain-of-function mutations were identified at JAK3 V722I (n=2) and IDH2 R172K (n=1). Frame-shift mutations were recovered in ABCA7 (n=1), ARID1B (n=1), CREBBP (n=2), GNAS (n=1), IKZF2 (n=2), PRDM1 (n=2), SMARCA2 (n=1), and TNFRSF14 (n=1). Nonsense mutations were recovered in ALPK2 (n=1), CCND3 (n=2), and CHD8 (n=2). Only 2 cases harbored TP53 mutations (M133R, S261_splice). Additional missense variants were identified across a large number of genes, including several previously described in the COSMIC database.
In conclusion, the genetics of AITL vary broadly across cases, with a small number of genes previously associated with NHL harboring recurrent mutations. Mutations of DNMT3A commonly occur in combination with one or more mutations in TET2. Mutation of either locus is associated with advanced age, supporting the hypothesis that the mutations are acquired over time within hematopoietic stem cells.
Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc.: Research Funding. Weinstock:Novartis: Consultancy, Research Funding.
Asterisk with author names denotes non-ASH members.