Treatment of Stage IA Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL): An Analysis from the German Hodgkin Study Group (GHSG)

Introduction: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity accounting for about 5% of all HL cases. As compared with classical HL (cHL), NLPHL is characterized by the absence of CD30 and the consistent expression of CD20 on the malignant lymphocyte predominant (LP) cells. Given a more indolent clinical course, especially early-stage NLPHL is often treated less aggressive than classical HL (cHL). In stage IA patients, radiotherapy (RT) alone is applied at most institutions. However, this clinical practice is not based on data from prospective clinical trials with sufficient follow-up. To shed more light on the optimal treatment of stage IA NLPHL, we performed an analysis including patients with long-term follow-up treated within German Hodgkin Study Group (GHSG) clinical trials.

Patients: A total of 256 stage IA NLPHL patients treated within 7 prospective GHSG studies between 1988 and 2009 were included in the analysis. Treatment consisted of combined-modality treatment (CMT) (n=72), extended-field RT (EF-RT) (n=49), involved-field RT (IF-RT) (n=108) or four weekly doses of the anti-CD20 antibody rituximab (n=27).

Results: The median age at NLPHL diagnosis was 38.5 years (range: 17-75); 194/256 (75.8%) patients were male and 62/256 (24.2%) patients were female. Median follow-up for the whole patient group was 91 months (98 months for CMT, 118 months for EF-RT, 87 months for IF-RT, 49 months for rituximab). All patients responded to treatment irrespective of the treatment modality applied. At 8 years, progression-free survival (PFS) and overall survival (OS) rates were 88.5% and 94.5% for CMT, 84.3% and 95.7% for EF-RT and 91.9% and 99.0% for IF-RT; 4-year PFS and OS rates for patients treated with rituximab were 81.0% and 100%. Seventeen patients developed a second malignancy in the course of follow-up (8 after CMT, 3 after EF-RT, 4 after IF-RT, 2 after rituxmab). Nine of these second malignancies were solid tumors (4 after CMT, 2 after EF-RT, 1 after IF-RT, 2 after rituximab) and 8 were hematologic malignancies (4 after CMT, 1 after EF-RT, 3 after IF-RT, none after rituximab). A total 12 deaths occurred. The most common cause of death was cardiac failure (n=3). Only one patient died from NLPHL.

Conclusion: Based on this large analysis with long-term follow-up, IF-RT should be the standard of care for stage IA NLPHL. Treatment with single agent rituximab is associated with an increased event rate when compared with IF-RT and should therefore not be routinely used in stage IA NLPHL patients. However, given the shorter follow-up in comparison with CMT, EF-RT and IF-RT, final conclusions regarding rituximab especially in terms of treatment-related late sequelae cannot yet be drawn. Addition of chemotherapy does not improve the excellent outcome achieved with RT alone.