REGULAR ARTICLE Integrative analysis of a phase 2 trial combining lenalidomide with CHOP in angioimmunoblastic T-cell lymphoma François Lemonnier, 1,2, * Violaine Safar, 3, * Asma Beldi-Ferchiou, 2,4 Anne-S ´ egol ` ene Cottereau, 5 Emmanuel Bachy, 3 Guillaume Cartron, 6 Virginie Fataccioli, 2,7 Laura Pelletier, 2 Cyrielle Robe, 2,7 Audrey Letourneau, 8 Edoardo Missiaglia, 8 Slim Fourati, 2,9 Marie-Pierre Moles-Moreau, 10 Alain Delmer, 11 Reda Bouabdallah, 12 Laurent Voillat, 13 St ´ ephanie Becker, 14 C´ eline Bossard, 15 Marie Parrens, 16 Olivier Casasnovas, 17 Victoria Cacheux, 18 Caroline R ´ egny, 19 Vincent Camus, 20 Marie-H ´ el` ene Delfau-Larue, 2,4 Michel Meignan, 21 Laurence de Leval, 8 Philippe Gaulard, 2,7 and Corinne Haioun 1,2 1 Assistance Publique–H ˆ opitaux de Paris (AP-HP), H ˆ opitaux Universitaires Henri Mondor, Unit ´ eH´ emopathies Lympho¨ ıdes, Cr ´ eteil, France; 2 Universit ´ e Paris Est Cr´ eteil, INSERM, Institut M ´ edical de Recherche Biom ´ edicale, Cr ´ eteil, France; 3 Service d’H´ ematologie Clinique, Hospices Civils de Lyon, Pierre-B ´ enite, and Universit ´ e Lyon 1, Lyon, France; 4 D´ epartement d’H´ ematologie et d’Immunologie Biologique, H ˆ opitaux Universitaires Henri Mondor, AP-HP, Cr ´ eteil, France; 5 D´ epartement de M ´ edecine Nucl ´ eaire, H ˆ opital Cochin, AP-HP, Universit ´ e Paris Descartes, Paris, France; 6 D´ epartement d’H´ ematologie Clinique, Centre Hospitalo-Universitaire de Montpellier, Unit ´ e Mixte de Recherche–Centre National de Recherche Scientifique 5535, Universit ´ e de Montpellier, Montpellier, France; 7 D´ epartement de Pathologie, H ˆ opitaux Universitaires Henri Mondor, Cr´ eteil, France; 8 Institut de Pathologie, Centre Hospitalier Universitaire Vaudois et Universit ´ e de Lausanne, Lausanne, Switzerland; 9 Service de Virologie, D ´ epartement Pr ´ evention, Diagnostic et Traitement des Infections, H ˆ opitaux Universitaires Henri Mondor, AP-HP, Cr ´ eteil, France; 10 Service d’H´ ematologie, Centre Hospitalier Universitaire, Angers, France; 11 Service d’H´ ematologie, Centre Hospitalier Universitaire, Reims, France; 12 Service d’H´ ematologie, Institut Paoli-Calmette, Marseille, France; 13 Service d’H´ ematologie, Centre Hospitalier, Chalon, France; 14 Service de M ´ edecine Nucl ´ eaire, Centre de Lutte Contre le Cancer Becquerel, Rouen, France; 15 Universit ´ e de Nantes, Center Hospitalier Universitaire Nantes, D ´ epartement de Pathologie, INSERM Centre de Recherche en Canc ´ erologie et Immunologie Nantes Angers, Nantes, France; 16 D´ epartement de Pathologie, H ˆ opital Haut-L ´ ev ˆ eque, Pessac, INSERM U1053, Universit ´ e de Bordeaux, Bordeaux, France; 17 Service d’H´ ematologie, Centre Hospitalier Universitaire, Dijon, France; 18 Service d’H´ ematologie, Centre Hospitalier Universitaire, Clermont Ferrand, France; 19 Service d’H´ ematologie, Centre Hospitalier Universitaire, Grenoble, France; 20 D´ epartement d’H´ ematologie, Centre Henri Becquerel, Rouen, France; and 21 LYSA Image, H ˆ opitaux Universitaires Henri Mondor, Cr ´ eteil, France Key Points • Lenalidomide CHOP did not improve the complete metabolic re- sponse rate compared with historical controls in previously untreated AITL patients aged 60 to 80 years. • DNMT3A mutations were present in 32% of patients and appeared to confer shorter PFS. Angioimmunoblastic T-cell lymphoma (AITL) is a frequent T-cell lymphoma in the elderly population that has a poor prognosis when treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. Lenalidomide, which has been safely combined with CHOP to treat B-cell lymphoma, has shown efficacy as a single agent in AITL treatment. We performed a multicentric phase 2 trial combining 25 mg lenalidomide daily for 14 days per cycle with 8 cycles of CHOP21 in previously untreated AITL patients aged 60 to 80 years. The primary objective was the complete metabolic response (CMR) rate at the end of treatment. Seventy-eight of the 80 patients enrolled were included in the efficacy and safety analysis. CMR was achieved in 32 (41%; 95% confidence interval [CI], 30%-52.7%) patients, which was below the prespecified CMR rate of 55% defined as success in the study. The 2-year progression-free survival (PFS) was 42.1% (95% CI, 30.9%-52.8%), and the 2-year overall survival was 59.2% (95% CI, 47.3%-69.3%). The most common toxicities were hematologic and led to treatment discontinuation in 15% of patients. This large prospective and uniform series of AITL treatment data was used to perform an integrative analysis of clinical, pathologic, biologic, and molecular data. TET2, RHOA, DNMT3A, and IDH2 mutations were present in 78%, 54%, 32%, and 22% of patients, respectively. IDH2 mutations were associated with distinct pathologic and clinical features and DNMT3A was associated with shorter PFS. In conclusion, the combination of lenalidomide and CHOP did not improve the CMR in AITL patients. This trial clarified the clinical impact of recurrent mutations in AITL. This trial was registered at www.clincialtrials.gov as #NCT01553786. Submitted 29 July 2020; accepted 2 December 2020; published online 22 January 2021. DOI 10.1182/bloodadvances.2020003081. *F.L. and V.S. contributed equally to this work. Send data sharing requests via e-mail to the corresponding author. The full-text version of this article contains a data supplement. © 2021 by The American Society of Hematology 26 JANUARY 2021 x VOLUME 5, NUMBER 2 539