Lenalidomide in Combination with CHOP in Patients with Angioimmunoblastic T-Cell Lymphoma (AITL): Final Analysis of Clinical and Molecular Data of a Phase 2 Lysa Study
Authors: Lemonnier Francois , Safar Violaine , de Leval Laurence , Cottereau Anne Ségolène , Pelletier Laura , Robe Cyrielle , Bachy Emmanuel , Cartron Guillaume , Moles Marie-Pierre , Letourneau Audrey , Missiaglia Edoardo , Delmer Alain Jacques , Bouabdallah Reda , Voillat Laurent , Parrens Marie , Casasnovas Olivier , Cacheux Victoria , Gressin Remy , Tilly Herve , Delfau Marie-Helene , Meignan Michel , Gaulard Philippe , Haioun Corinne 
Published: October 2019

Abstract
Introduction: AITL, one of the most common peripheral T-cell Lymphoma portends a poor prognosis. AITL is characterized by neoplastic T cells with a follicular helper immunophenotype, frequent mutations in epigenetic regulators TET2, IDH2, DNMT3A and in RHOA, and a prominent tumor microenvironment that could contribute to lymphomagenesis. Aiming to target this microenvironment and given the promising activity of lenalinomide (Len) in a relapsed setting (PMID: 23731832), we postulated that AITL patients (pts) might benefit from a treatment with Len combined with a classical CHOP regimen. This multicenter, open label, phase 2 trial (NCT01553786) investigates this treatment in previously untreated elderly pts.
Patients and methods: Patients older than 59 years were treated with 8 cycles of Len + CHOP 21 (Len 25 mg/day (d), d1 to 14) and received intrathecal methotrexate prophylaxis. Thromboprophylaxis with low molecular weight heparin was mandatory. PET CTs at diagnosis and at the end of treatment were centrally reviewed. The primary objective was to evaluate the complete metabolic response rate according to the Lugano 2014 Classification. Secondary endpoints were safety, progression-free (PFS) and overall survival (OS). Mutations in TET2, IDH2, DNMT3A, RHOA, CD28, PLCG1, STAT3 and STAT5B were analyzed by deep sequencing (1000X) using DNA extracted from formalin-fixed paraffin-embedded tumor samples by PGM technology and were correlated to clinical parameters.
Results: Between November 2011 and March 2017, 80 pts were enrolled, and 78 were evaluable. Central pathology review confirmed the diagnosis of AITL in 72 cases (92%). Median age was 69 (59-80), 52 % were female, 68% had a performance status of 0 to 1, 94% an Ann Arbor stage ≥III, 82% IPI≥3. Forty-five patients (58 %) completed the 8 planned cycles (mean number of cycles delivered, 5.9). Of the 624 planned treatment cycles, 458 (72 %) were completed. Treatment was stopped in 8 pts because of progressive disease, and in 15 because of adverse events. Toxicity was within the range expected of R-CHOP therapy with 70% grade 4 neutropenia and 31 % thrombocytopenia. Deep vein thrombosis occurred in 8 pts. Four secondary primary malignancies were reported. Five patients died from toxicity (4 from infection). Len dose reductions or interruptions were applied in 37 (5%) and 59 (9%) cycles, respectively, related to toxic effects. The median dose of Len per patient was 2275 mg (IQR 95-2825)-i.e. 81% of the planned dose of 2800 mg. Doxorubicin and cyclophosphamide were administrated at 98% and 97% of the planned dose. Complete metabolic response was observed in 34 patients (43.6%) (90%CI = [34.0%; 53.5%]), partial metabolic response in 3 (3.8%), no metabolic response in 2 (2.6%) and progressive metabolic disease in 16 (20.5%), the other being not evaluated because of progression (N=20) or death (N=3). With a median follow-up duration of 31.5 months (95%CI = [23.0; 43.7]) at the time of the cut-off, 2-year PFS is 42.3% (95%CI = [30.9%; 53.2%]) and 2-year OS is 60.1% (95%CI = [47.4%; 70.7%]). IPI was strongly associated with the survival (figure 1A). Mutational status was successfully determined in 64 pts with confirmed AITL diagnosis. TET2 mutations were detected in 49 cases (77%), with 28 (43%) pts bearing ≥2 TET2 mutations. RHOAG17V mutations in 34 pts (53%), DNMT3A mutations in 20 (31%) pts, including 6 with the DNMT3AR882X variant and IDH2 mutations in 14 (22%). CD28, PLCCG1 and STAT mutations were detected in less than 10% of pts (figure 1B). TET2 mutations correlated to age>65 years (p=0.006) and IPI 3-5 (p=0.007). Interestingly, DNMT3A mutations were associated with a decreased response rate (p=0.003), a shorter PFS (p=0.04) and a trend toward a shorter OS (0.08). It is noteworthy that none of the 6 pts with the DNMT3AR882X mutant had response, suggesting that the resistance to anthracycline reported in DNMT3AR882X mutated acute myeloid leukemia (PMID: 27841873) could also occur in DNMT3AR882X mutated AITL. No correlation between other detected mutations and outcome was observed (table 1C).
Conclusion
A combination of 25 mg of Len for 14 days with CHOP cycles gives acceptable toxicity in AITL elderly pts. However, response rate and outcome appear similar to previous studies. We also confirmed in a prospective study the frequency of mutations in epigenetic regulators and RHOA in AITL and clarified their prognostic impact.
Figure Figure.

Disclosures
Bachy: Gilead Sciences: Honoraria; Sandoz: Consultancy; Janssen: Honoraria; Roche: Research Funding; Takeda: Research Funding; Amgen: Honoraria; Celgene: Consultancy. Cartron:Celgene: Consultancy, Honoraria; Sanofi: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria. Casasnovas:Merck: Honoraria; Takeda: Honoraria; Roche: Honoraria; Gilead Sciences: Research Funding; Roche: Research Funding; Janssen: Consultancy; Gilead Sciences: Consultancy; MSD: Consultancy; merck: Consultancy; takeda: Consultancy; Roche: Consultancy; Janssen: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; MSD: Honoraria. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees. Gaulard:Celgene: Research Funding; Roche: Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Haioun:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.