Outcomes of allogeneic hematopoietic stem cell transplantation in nodular lymphocyte-predominant Hodgkin lymphoma: A registry-based study from the EBMT-LWP

Abstract INTRODUCTION Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma (HL), accounting for 5–6% of cases. Although long-term outcomes are generally favorable—with 10-year progression-free survival (PFS) rates of 70–75% and overall survival (OS) around 90%—up to 20% of patients relapse, often within 3–4 years of diagnosis. Relapsed NLPHL typically follows an indolent course, with treatment options including observation, anti-CD20 monoclonal antibodies, radiotherapy, or chemotherapy. A minority of patients, particularly those with high-risk features—such as refractory disease, early progression, or liver/bone marrow involvement—may benefit from intensified approaches such as autologous stem cell transplantation (ASCT). However, the use of allogeneic hematopoietic stem cell transplantation (alloHSCT) in NLPHL remains anecdotal, generally reserved for heavily pretreated patients, especially those relapsing after ASCT and/or experiencing histological transformation to aggressive non-Hodgkin lymphoma (NHL). This study aimed to evaluate the outcomes of alloHSCT in patients with relapsed or refractory (R/R) NLPHL. METHODS We included adult patients (>18 years) with NLPHL who underwent a first alloHSCT between January 2010 and December 2021, more than one year after diagnosis, and were reported to the EBMT registry. Patients with untreated NLPHL before alloHSCT or tandem auto-allo transplants were excluded. Patients were included based on the initial diagnosis of NLPHL; due to registry limitations, transformation to aggressive NHL prior to alloHSCT could not be excluded. The primary endpoint was 5-year PFS post-alloHSCT. Secondary endpoints included 5-year OS, cumulative incidence of relapse, and 1-year non-relapse mortality (NRM). RESULTS A total of 139 patients (27% female, 73% male) met inclusion criteria. Forty-seven percent of alloHSCTs were performed between 2010–2015, 34% between 2016–2018, and 19% between 2019–2021. Median age at alloHSCT was 35 years (IQR 27–46), and median time from diagnosis to transplant was 34 months (IQR 22–74). Prior to alloHSCT, 12% had received 1 line of therapy, 17% received 2, and 72% received ≥3. Rituximab was used in 17% of patients. Most (68%) had undergone a prior ASCT. At transplant, 60% were in complete remission (CR), 25% in partial remission (PR), and 15% had refractory or stable disease. Reduced-intensity conditioning was used in 65% of cases. Donor types included matched related (39%), unrelated (47%), and mismatched related (14%). One-year NRM was 14.7%. Acute GVHD grade II–IV and III–IV at day 100 occurred in 34.3% and 13.0%, respectively. Chronic GVHD (any grade and extensive) at 2 years occurred in 34.3% and 11.5%, respectively. With a median follow-up of 5 years (95% CI 3.9–5.9), 2- and 5-year PFS rates were 51.3% and 46.7%; OS rates were 66.2% and 63.0%, respectively. Cumulative incidence of relapse was 32.1% at 2 years and 35.5% at 5 years. GVHD- and relapse-free survival (GRFS) was 39.4% at 2 years and 34.8% at 5 years. In multivariable analysis, variables included age, sex, time from diagnosis to alloHSCT (< or >24 months), disease status at alloHSCT, and donor type. Disease status was the only significant prognostic factor for PFS. Compared to CR, patients in PR had inferior PFS (HR 1.94, 95% CI 1.06–3.55, p=0.031) and higher relapse risk (HR 3.06, 95% CI 1.44–6.49, p=0.004). Refractory/stable disease was associated with worse OS (HR 2.92, 95% CI 1.35–6.30, p=0.006), PFS (HR 2.48, 95% CI 1.22–5.04, p=0.012), and relapse risk (HR 3.52, 95% CI 1.49–8.33, p=0.004). Older age was associated with higher NRM (HR per 5-year increase 1.25, 95% CI 1.05–1.49, p=0.011) and lower OS (HR 1.14, 95% CI 1.03–1.27, p=0.014). CONCLUSIONS This is the largest reported series of patients with NLPHL undergoing alloHSCT. Unlike classical HL, the use of alloHSCT in NLPHL remains uncommon and lacks strong supporting evidence. Our results suggest that alloHSCT can offer long-term disease control in selected patients, especially those in CR at transplant. These findings provide valuable real-world evidence to guide clinical decision-making in this rare and challenging setting.