Angioimmunoblastic Versus Non-Angioimmunoblastic Nodal T-Follicular Helper Cell Lymphomas: Single Center Retrospective Analysis on 208 Cases
Authors: Sordi Benedetta , Eren Ozgur Can , Ganesan Nivetha , Iyengar Varun , Stuver Robert , Johnson William T. , Moskowitz Alison , Ghione Paola , Galasso Natasha , Casper Ellie , Chang Tiffany , Hancock Helen , Davey Theresa , Boardman Alexander P. , Caron Philip , David Kevin A. , Falchi Lorenzo , Hamlin Paul A. , Intlekofer Andrew M. , Kumar Anita , Luttwak Efrat , Noy Ariela , Owens Colette , Palomba Maria Lia , Salles Gilles , Steiner Raphael E. , Torka Pallawi , Vardhana Santosha A. , Dogan Ahmet , Horwitz Steven , Epstein-Peterson Zachary D. 
Published: December 2024

Introduction: Nodal-T follicular helper lymphomas (nTFHLs) now include three histologic subtypes: angioimmunoblastic-type (AITL), follicular-type (nTFHL-F), and nTFHL not otherwise specified (nTFHL-NOS). Differences in terms of clinical, phenotypic, genetic variables, and outcome between AITL and non-AITL nTFHLs remain to be established. In this study, we report a retrospective analysis of nTFHLs comparing histologic variants, clinical and biologic features.

Materials and methods: Patients (pts) diagnosed with nTFHLs and PTCL-NOS from 10/2012 to 12/2023 were identified from Memorial Sloan Kettering (MSK) registry. Inclusion criteria were: nTFHL confirmation by histopathological review and a follow up of at least 6 months (mo) or progression/death. Pts treated at our center from 1st line (cohort 1L) with curative or non-curative intent (palliative/deintensified chemotherapy) were evaluated for median (m) progression-free and overall survival (PFS, OS) and prognostic impact of molecular and clinical variables. A 2nd line analysis (cohort 2L) was conducted in pts with refractory/relapsed disease, either treated from 1st line or referred for 2nd line. Kaplan-Meier with 95% confidence intervals and Cox regression methods were used to assess survival outcomes and perform univariate/multivariate analysis. Molecular profiling was performed with MSK IMPACT.

Results: Of 460 cases investigated, 208 nTFHL pts were eligible. Most pts had advanced-stage disease (92%) and extranodal sites (n=116; 56%) including bone marrow in 72% (n=84). Low (0-1), intermediate (2-3) and high IPI (4-5) were 14%, 58% and 13%, respectively (missing 15%). AITL was the most common variant (n= 182; 87.5%), followed by nTHFL-NOS (n=25; 12%) and nTHFL-F (n=1; 0.5%). TFH markers were expressed as follows: CD4 (208/208), PD-1 (207/207) in 100%, ICOS in 99% (84/85), CXCL13 in 85% (121/143), BCL6 in 75% (111/148), and CD10 in 67% (135/201) of cases. EBER was expressed in 69% (141/205).

Molecular profiling was available on 137 pts: the most frequent mutations (mut) were TET2 (88%, n=120), RHOA (55%, n=76), DNMT3A (34%, n=47) and IDH2 (23%, n=31). Non-AITL were similar to AITL with exceptions including higher incidence of extranodal sites (p=0.03, specifically skin/subcutaneous, p=0.02), a less frequent CD10 expression (p=0.002), and presence of TET2 (p=0.02) and RHOA (p=0.03) mut.

Median OS of the overall population was 60 mo (52-73). In cohort 1L, there were 100 efficacy-evaluable pts treated with curative intent. Treatments included: CHOEP (n=33), clinical trial (n=22), BV-CHP (n=18), CHOP (n=18), EPOCH (n=6), and others (n=3); autologous stem cell transplantation was performed as consolidation of initial response for 53 pts. The overall response rate and complete response rate to first-line therapy was 90% and 79%, respectively. The mPFS was 20 mo (14-35) and the mOS was 71 mo (59-NR).

73 pts were included in 2L cohort. Therapies were as follows: PI3K inhibitor (PI3K) alone or combination [PI3K +/-combo, n=25, including with histone deacetylase inhibitor (HDAC)]; HDAC alone or combination (HDAC +/-combo, n=12, excludes PI3K + HDAC); chemotherapy/radiotherapy (ch/rt, n=13); other treatments (n=23). Of those, the longest mPFS [19.0 mo (8.6-NR)] and mOS [32.3 (17.1-NR)] was observed with PI3K (+/-combo), with significantly improved mPFS over HDAC +/-combo (p=0.01) and ch/rt (p=0.0002).

Among cohort 1L, irrespective of curative intent, no significant difference in outcome was seen in AITL vs non-AITL: mPFS 14 (10-25) and 15.3 mo (6.1-NR); mOS 71 (59-110) and 66 mo (35-NR) respectively. DNMT3A mut showed an adverse impact on PFS in univariate analysis (p=0.01). Significant factors associated with reduced OS included: IPI Score 4-5 (p=0.05), mut IDH2 (p=0.004), mut DNMT3A (p=0.002) in univariate analysis; mut IDH2 and DNMT3A (p=0.01 and p=0.04, respectively) remained significant on multivariate analysis. Additionally, combined or isolated IDH2 and DNMT3A mut adversely impact PFS and OS (all p&lt;0.01) compared to the absence of both IDH2/DNMT3A mut.

Conclusions: Our single center analysis confirmed AITL as the most common variant of nTFHL. AITL and non-AITL appear similar regarding clinical presentation, molecular profile, and outcomes. DNMT3A adversely impact outcomes, as previously reported. Our findings warrant confirmation in larger cohorts to refine understanding of nTFHL subtypes and inform management.