Evaluation of incidence and outcomes of transformed nodular lymphocyte predominant Hodgkin lymphoma in the United States: A population based cohort study

Abstract Background: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare indolent B-cell lymphoma that is biologically distinct from classic Hodgkin lymphoma. Most patients present with limited-stage disease, and late relapses are common. The standard of care has evolved over the past decade with increasing use of rituximab-based chemotherapy regimens (Fanale, et al. Blood. 2017). NLPHL can transform into diffuse large B-cell lymphoma (DLBCL), however the incidence of histologic transformation (HT) and survival outcomes of transformed cases in the US population are unknown. The objective of this study was to describe the cumulative incidence and outcomes of transformed NLPHL in the US. We hypothesized that patients with transformed NLPHL would have significantly lower survival rates compared to de novo DLBCL. Method: We performed a population-based cohort study using data from the Surveillance, Epidemiology, and End Results (SEER) program. We used the SEER-17 database, which captures cancer incidence and survival data representing 26.5% of the US population. We included patients aged 18-84 years old and diagnosed with NLPHL between 2010-2022. We identified patients with HT by following patients from diagnosis of NLPHL until their subsequent diagnosis of DLBCL. All patients had biopsy-confirmed HT. The study outcomes were relative survival (RS), overall survival (OS), lymphoma-specific survival (LSS), and the cumulative incidence of death from lymphoma (CIF). The lymphoma-specific CIF was used to account for the competing risk of death from other causes. The study covariates were age, sex, race, stage, B symptoms, prior receipt of chemotherapy, and prior receipt of radiation therapy. The study outcomes were modeled using flexible parametric survival models. Results: There were 1,700 patients with NLPHL included in the study. The median age at diagnosis was 46 years (interquartile range, 32-59), and most patients were male (n=1,118, 66%). After a median follow-up of 5.58 years, the cumulative incidence of HT was 2.59% (n=44/1700). The 5-year RS for patients without a history of HT was 97% (95% CI, 96-98%) compared to 88% (95% CI, 73-95%) for patients who subsequently transformed. Similarly, the other survival outcomes were also numerically worse for patients with HT (5-year OS, 93% vs 86%; 5-year LSS 97% vs 89%; and 5-year CIF 3% vs 11%). Next, we compared transformed NLPHL (n=44) with denovo DLBCL (n=61,784) diagnosed during the same time period. We found no significant difference in any of the study outcomes in the multivariable analysis. Using de novo DLBCL as the reference, the hazard ratios (95% CI) for transformed NLPHL were 0.53 (0.19-1.46) for RS, 0.55 (0.21-1.44) for OS, 0.57 (0.20-1.59) for LSS, and a subdistribution hazard ratio of 0.64 (0.26-1.58) for lymphoma-specific death. Conclusion: HT in NLPHL is an uncommon occurrence that is associated with a relatively good prognosis. In our study, patients who developed HT had similar 5-year survival rates compared to patients who never transformed. In addition, there was no significant difference in the outcomes of patients with transformed NLPHL and de novo DLBCL. Future studies will be needed to determine the impact of prior anthracycline-based chemotherapy on the outcomes of patients with transformed disease.