Management and Outcomes of Nodular Lymphocyte Predominant Hodgkin Lymphoma: A Retrospective Study By the Lymphoma Study Association
Authors: Lazarovici Julien , Brice Pauline , Obéric Lucie , Gaillard Isabelle , Hunault-Berger Mathilde , Broussais Florence , Bologna Serge , Gyan Emmanuel , Sebban Catherine , Touati Mohamed , Delarue Richard , Orsini-Piocelle Frédérique , Stamatoullas Aspasia , Dartigues Peggy , André Marc PE , Casasnovas Olivier , Mounier Nicolas , Fermé Christophe 
Published: November 2019

Abstract
Introduction
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare entity with distinct clinico-pathological features accounting for 5% of all Hodgkin lymphomas. Its optimal management is still debated, including the place of therapeutic abstention, and the role of rituximab. With the aim to report the management of the disease in a large series of patients (pts), we performed a retrospective study describing the characteristics of NLPHL at diagnosis, the therapeutic strategies, outcomes and the risk of late complications, including secondary malignancies.
Methods
We retrospectively analyzed adult pts with NLPHL treated in the Lymphoma Study Association (LYSA) centers between 1974 and 2012. Survival analysis were made according to the log-rank regression model. We also performed a competing risk analysis in order to better assess the risks of death, progression and secondary malignancies.
Results
314 pts, out of a total of 366 were retained for further analysis. Median age at diagnosis was 38 years. Most pts (82.5%) presented with localized, Ann Arbor stage I-II disease. Watchful waiting (WW) was the most frequent attitude at diagnosis, and concerned 114 pts (36%), mainly with localized disease (104 pts). 200 pts received a treatment, which comprised chemotherapy +/- rituximab for 68 pts (34% of pts with treatment), radiotherapy for 63 pts (31.5%), combined modality treatment (CMT, chemotherapy +/- rituximab followed by radiotherapy) for 40 pts (20%), and rituximab alone for 28 pts (14%). Among 155 pts with localized disease who received initial treatment, radiotherapy alone was delivered to 62 pts (42 with stage I, 20 with stage II disease), mainly on the cervical, supra-clavicular or axillar areas. The radiotherapy fields included the mediastinum in 7 localized pts treated by CMT. Among 55 pts with disseminated disease receiving initial treatment, chemotherapy +/- rituximab was administered to 32 pts. Most of them received anthracycline-based chemotherapy, and ABVD-derived chemotherapies were the preferred regimens with 19 pts; 8 pts received CHOP-like regimens.
With a median follow-up of 55.8 months, 112 pts relapsed or progressed. Among them, 37 pts (33%) received chemotherapy +/- rituximab, 27 pts (24%) radiotherapy alone, 19 pts (17%) rituximab alone, 7 pts (6%) CMT, and 2 pts rituximab + radiotherapy. WW concerned 19 pts (17%) at first relapse/progression.
The overall response rate (ORR) for the whole population was 83%, with 200 pts (79%) reaching CR or CRu, 3 months after diagnosis. The CR/CRu rate according to the different treatment modalities were 95% for radiotherapy alone, 89% for rituximab alone, 87% for chemotherapy +/- rituximab and 91% for CMT, respectively. In localized disease, 40 pts had persistent CR/CRu after radiotherapy alone. In disseminated disease, 45 pts who attained CR/CRu after chemotherapy +/- rituximab did not subsequently relapse.
The median PFS for the whole population was 112.1 months. There was no impact of Ann Arbor stage on PFS, but the attitude at diagnosis had a powerful impact. Compared to WW, the risk of progression was significantly reduced for pts treated by radiotherapy alone (Hazard ratio: 0.345 [95% CI: 0.196; 0.610], p = 0.0002), chemotherapy +/- rituximab (HR: 0.476 [0.266; 0.855], p = 0.0129), or CMT (HR: 0.292 [0.148; 0.577], p = 0.0004), but not with rituximab alone. The risk reduction remained significant for pts who had complete surgical resection of the initial lesions and received any additional treatment vspts who were just watched after surgery (HR: 0.344 [0.122; 0.974], p = 0.0444).
The estimated OS at 72 months is 96.9%. OS was not different according to the attitude at diagnosis, including WW. 10 pts died, 1 due to lymphoma progression, 5 of secondary malignancies and the remaining 4 of accident or unknown causes.
The competing risk analysis model confirmed that the risk of relapse/progression was significantly reduced with radiotherapy in stage I-II pts (HR : 0.474 [0.277; 0.812]), and with a treatment combining chemotherapy +/- rituximab +/- radiotherapy in the whole population (HR: 0.388 [0.234; 0.643]).
Conclusion
Our study supports the use of radiotherapy in localized disease, and of treatments combining chemotherapy +/- rituximab +/- radiotherapy, to improve disease control in adult patients with NLPHL.

Disclosures
No relevant conflicts of interest to declare.