Improved Outcomes for Primary Refractory Classical Hodgkin Lymphoma: A Retrospective Analysis
Authors: Santarosa Alayna M. , Ganesan Nivetha , Chang Tiffany , Hannigan Kelly , Casper Ellie , Shah Gunjan L. , Boardman Alexander P. , Caron Philip , David Kevin A. , Dogan Ahmet , Epstein-Peterson Zachary D. , Falchi Lorenzo , Ghione Paola , Hamlin Paul A. , Horwitz Steven , Intlekofer Andrew M. , Johnson William T. , Krivisky Ariel , Kumar Anita , Lue Jennifer Kimberly , Luttwak Efrat , Noy Ariela , Owens Colette , Palomba Maria Lia , Salles Gilles , Schoder Heiko , Steiner Raphael E. , Stuver Robert , Torka Pallawi , Vardhana Santosha A. , Yahalom Joachim , Zelenetz Andrew D. , Moskowitz Craig H. , Moskowitz Alison 
Published: December 2024

Background: While most pts with classical Hodgkin Lymphoma (cHL) are cured following frontline therapy, up to 10% develop relapsed (rel) disease and 5-10% have primary refractory (ref) disease. Standard of care for pts with rel/ref disease is salvage therapy followed by autologous stem cell transplantation (ASCT). We previously reported 5-year overall survival (OS) of 60% for 192 ref pts treated on sequential clinical trials from 1994 through 2015 (Shah Br J Haematol. 2016). The approval of brentuximab vedotin (BV) and checkpoint inhibitors (CPI) has significantly impacted cHL treatment, likely leading to improved outcomes for rel/ref pts. We aimed to characterize outcomes for pts with ref cHL treated with modern therapies.
Methods: We identified consecutive pts age 18 and older with biopsy-confirmed ref cHL from 01/01/2010 to 12/31/2023. Ref disease was defined as never achieving complete response (CR) following completion of frontline therapy. Overall survival (OS) was calculated from C1D1 of first salvage therapy to date of death or last follow-up (FU). Progression free survival (PFS) was calculated from C1D1 of first salvage therapy. When analyzing pts who underwent ASCT, OS and PFS were calculated from date of transplant. Log rank tests were used to assess for differences in survival stratified by prognostic factors and treatment categories. Treatment was categorized as chemotherapy-based therapy (without BV or CPI), BV-based therapy (without CPI), and CPI-based therapy.
Results: Among 215 pts identified, the median age at diagnosis was 34 years (range:19-79), 49% were male, and 74% identified as White, 10% Black, 4% Asian, 12% not reported. At time of diagnosis, 55% had advanced stage disease (stage III: 23%, IV: 32%), 47% had extra-nodal involvement, and 56% had B-symptoms. At frontline, 75% received ABVD-based therapy, 14% BV-based therapy, 3% BEACOPP-based therapy, 2% CPI-based therapy, and the remaining 6% received alternative curative combination therapy. Upon confirming ref disease, 44% had advanced stage disease (stage III: 12%, IV: 32%), 39% had extra-nodal involvement, and 18% had B-symptoms. For first salvage, 37% received chemotherapy-based therapy, 32% BV-based therapy, and 31% CPI-based therapy. Response to first salvage included CR (47%), PR (30%), SD (5%), progression of disease (11%), and unknown (7%). Responses were assessed using Lugano criteria (Cheson 2014). 165 (77%) pts underwent ASCT of whom 123 (75%) were PET-negative prior to transplant. The median number of salvage treatment lines prior to transplant was 1 (range: 1-8). 36% received peri-transplant radiation and 25% received BV maintenance therapy.
After a median FU among survivors of 52 months (range: 0.2-143), 4-year OS was 86% (95CI: 81-92), and 4-year PFS was 61% (95CI: 53-69). Presence of stage IV disease (p=0.003) and B-symptoms (p=0.004) were associated with shorter survival for all pts, and both remained prognostic by multivariate analysis. For pts treated with CPI-based salvage, only presence of stage IV disease was predictive for inferior survival (p=0.016) and was associated with 4-year OS of 70% vs 94% for pts with or without stage IV disease.
Among the 165 pts who received ASCT, median FU after transplant was 43 months (6-72), 4-year OS was 91% (95CI: 85-96), and 4-year PFS was 70% (95CI: 63-78). By univariate analysis, factors predictive for poor PFS following transplant included stage IV disease (p&lt;0.001) and lack of CR before transplant (p=0.013). Receipt of PD1-based salvage any time before transplant significantly improved PFS (4-year PFS 85% vs 65%, p=0.020). By multivariate analysis, only stage IV disease and receipt of CPI-based salvage remained significant. Pts with 0, 1, or 2 risk factors (stage IV disease at time of ref disease and/or no receipt of CPI as salvage) had 4-year PFS of 96%, 78%, and 44%, respectively (p&lt;0.001).
Conclusion: This report represents one of the largest series of refractory cHL cases treated with modern therapy. 4-year OS was 86%, which compares favorably to prior series. For pts who received ASCT, stage IV disease and receipt of CPI-based salvage significantly impacted post-transplant PFS adversely and favorably, respectively, whereas CR before transplant was no longer prognostic. Primary refractory cHL no longer appears to be a negative prognostic factor for pts treated with CPI-based salvage, especially for those with stage I-III disease.