Oral azacitidine compared with standard therapy in patients with relapsed or refractory follicular helper T-cell lymphoma (ORACLE): an open-label randomised, phase 3 study.

BACKGROUND

Follicular helper T-cell lymphomas (TFHL) harbour frequent alterations in genes that regulate DNA methylation. Preliminary reports suggest that treatment with 5-azacitidine has clinical activity in patients with relapsed or refractory TFHL. We aimed to compare the oral form of azacitidine with investigator's choice standard therapy (ICT; ie, gemcitabine, bendamustine, or romidepsin) in patients with relapsed or refractory TFHL.

METHODS

Patients older than 18 years with relapsed or refractory TFHL (angioimmunoblastic T-cell lymphoma, follicular lymphoma, or nodal T-cell lymphoma with phenotype, ie, positive with two or more markers among CD10, BCL6, CXCL13, PD1, or ICOS) based on the 2017 WHO classification of haematological neoplasms, with an Eastern Cooperative Oncology Group performance status score of 0-3, were recruited in university hospitals from five European countries and from Japan. Patients were randomly assigned 1:1 to treatment with either azacitidine given at a dose of 300 mg once a day (200 mg in Japanese patients) for 14 days in a 28-day cycle or gemcitabine, bendamustine, or romidepsin according to the investigator's choice. Random assignment was stratified by the number of previous lines of therapy and by the presence of previous or concomitant myeloid malignancy. The primary endpoint was investigator-assessed progression-free survival, presented in the intention-to-treat population. This Article is the final analysis of this trial, registered at ClinicalTrials.gov (Europe NCT03593018 and Japan NCT03703375).

FINDINGS

86 patients (median age 69 years [IQR 62-76], 50 patients were male, 36 were female) were enrolled between Nov 9, 2018, to Feb 22, 2021; 42 in the azacitidine group and 44 in the ICT group. With a median follow-up of 27·4 months (IQR 20·2-32·9), the median progression-free survival was 5·6 months (95% CI 2·7 -8·1) in the azacitidine group versus 2·8 months (1·9-4·8) in the ICT group (hazard ratio of 0·63 (95% CI 0·38-1·07); 1-sided p=0·042). Grade 3-4 adverse events were reported in 32 (76%) of 42 patients in the azacitidine group versus 42 (98%) of 43 patients in the ICT group. The most adverse grade 3 or worse adverse events were haematological (28 [67%] of 42 patients vs 40 [93%] of 43 patients), infection (8 [19%] and 14 [33%]), and gastrointestinal (5 [12%] vs 1 [2%] for azacitidine and ICT, respectively). There were two treatment-related deaths in the azacitidine group (one endocarditis and one candidiasis) and three in the ICT group (one heart failure, one COVID-19, and one cause unknown).

INTERPRETATION

Although the pre-specified primary outcome of the trial was not met, the favourable safety profile suggests that azacitidine could add to the treatment options in these difficult to treat diseases especially in combination with other drugs. Trials with combination are in preparation in a platform trial.

FUNDING

Bristol-Myers Squibb.

TRANSLATION

For the French translation of the abstract see Supplementary Materials section.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests EB reports receiving research funding from Amgen and Bristol-Myers Squibb (BMS); honoraria from Kite, Gilead, Novartis, Roche, Incyte, Miltenyi Biotech, Takeda, and Sanofi; and participation on an advisory committee for Roche, Gilead, ADC Therapeutics, Takeda, Novartis, and Incyte. FM reports receiving consultancy fees from Roche, Gilead, and AbbVie and participation on advisory committees for Roche, Gilead, Novartis, BMS, AbbVie, Genmab, Miltenyi, Allogene Therapeutics, AstraZeneca, and Janssen. GC reports receiving honoraria from Gilead, Novartis, Mylteni, Sanofi, AbbVie, Takeda, Roche, Janssen, Roche, Celgene, Novartis and participation on advisory committees for MabQi, Ownards Therapeutics, AbbVie, Roche, and BMS. NF reports receiving consultancy fees from AstraZeneca, AbbVie, Eli Lilly, HUYA, and Novartis; research funding from Bayer, BMS, Chugai Pharma, Celgene, Genmab, and Incyte; honoraria from AstraZeneca, BMS, Chugai Pharma, Dainippon Sumitomo, Eisai, Janssen, Kyowa Kirin, Nippon Shinyaku, Novartis, Ono, Sanofi, Symbio, Takeda, and Celgene. R-OC reports receiving honoraria from Roche, Takeda, Merck, BMS, Gilead and Kite, AbbVie, ADC Therapeutics, and Incyte; research funding from Takeda and Gilead and Kite; honoraria from Roche, Takeda, Merck, BMS, Gilead and Kite, AbbVie, ADC Therapeutics, Incyte and AstraZeneca; and participation on advisory committees for Roche, Takeda, Merck, BMS, Gilead and Kite, ADC Therapeutics, Janssen, and Incyte. CPF reports receiving consultancy fees from AbbVie, AstraZeneca, Atarabio, Celgene and BMS, GenMab, Gilead and Kite, Incyte, Janssen, Morphosys, Ono Pharmaceutical, Roche, and Takeda; research funding from BeiGene; and speaker bureau fees from Celgene and BMS, Gilead and Kite, Incyte, Janssen, Roche, and Takeda; and travel support from Roche. FAd’A reports receiving research funding from Servier and Nordic Nanovector. PBS reports receiving consultancy fees from Amgen, Roche, Janssen, Gilead, Incyte, Morphosys, CTI Biopharma, BMS, Celegene, AbbVie, Takeda, BMS, Beigene, and Lilly; research funding from Roche; and honoraria from Amgen, Roche, Janssen, Gilead, Incyte, Morphosys, CTI Biopharma, BMS, Celegene, AbbVie, Takeda, BMS, Beigene, and Lilly. AG and MN are current employees and stock option holders at BMS. L-MF reports receiving honoraria from Roche, AbbVie, Janssen, and AstraZeneca. M-HD-L reports receiving research funding from Roche and Celgene; honoraria from Gilead and Amgen and travel support from Mundipharma. LdL reports receiving consultancy fees from Lunaphore Technologies and Bayer and honoraria from Novartis. PG reports receiving consultancy fees from Takeda; research funding from Takeda, Innate Pharma, Alderan, and Sanofi; and honoraria from Takeda Gilead. KT reports receiving consultancy fees from Ono Pharma, Meiji Seika Pharma, Yakuruto, Solasia Pharma, Meiji Seika Pharma, and HUYABIO; research funding from Kyowa-hakko and Kirin, Meiji Seika Pharma, BMS, Byer, Daiich-Sankyo, HUYABIO, and Regeneron Pharmaceuticals; and honoraria from Chugai Pharma, Eizai, and Meiji Seika Pharma. FL reports receiving honoraria from Kiowa, Miltenyi, and BMS; research funding from Roche and BMS; and travel support from Roche and Gilead. All other authors declare no competing interests.