Allogeneic Stem Cell Transplant and CD30 Directed CART Cell Therapies Are Associated with Improved Survival in Classical Hodgkin Lymphoma Refractory or Intolerant to Brentuximab Vedotin and Anti-PD-1 Therapy: Real World Analysis from 14 U.S. Academic Centers
Authors: Voorhees Timothy , Grover Natalie S. , McLaughlin Eric , Florindez Jorge A , Moyo Tamara K. , Reves Heather , Sumransub Nuttavut , Deshpande Saarang , Rose Ashley , Duarte Cassandra , Faisal Muhammad Salman , Hamid Showkat , Subbiah Suki , Ayyappan Sabarish R. , Shea Lauren Kelly , Cortese Matthew J , Patel Krish , Major Ajay , Saeed Hayder , Svoboda Jakub , Desai Sanjal H. , Ramakrishnan Geethakumari Praveen , Torka Pallawi , Epperla Narendranath 
Published: December 2023

Background: Patients (pts) with classical Hodgkin Lymphoma (cHL) who become refractory to both BV and anti-PD-1 therapies (double refractory, DR) or intolerant (INT) of BV and anti-PD-1 therapies have limited treatment options. There is limited information regarding optimal treatment approaches in these pts. Rechallenging with BV or anti-PD-1 therapies has been previously described in small cohorts with variable success. Allogeneic stem cell transplantation (alloSCT) remains the only curative approach in multiply relapsed/refractory cHL. This study aims to assess practice patterns and outcomes in a large cohort of pts with DR or INT cHL.
Methods: We conducted a retrospective study of adult pts with cHL from 14 U.S. academic medical centers who developed DR or INT cHL between Jan 2011 and Dec 2021. DR was defined as treatment failure (evidence of progression by imaging or biopsy) while on therapy or within 3 months of the last dose of both BV and anti-PD-1 therapy. INT was defined as having toxicity limiting further cycles of BV or anti-PD-1 therapy. Pts with INT were either intolerant to both BV and anti-PD-1 or intolerant and refractory to BV or anti-PD-1. The co-primary endpoints were progression free survival (PFS) and overall survival (OS) in pts with DR/INT cHL. Time-to-event analyses were evaluated by Kaplan-Meier methods and log-rank tests.
Results: A total of158 pts were eligible. Clinical characteristics at diagnosis included median age 33 years (yrs, range 16-89), 61% male, 77% white race, 66% nodular sclerosing subtype, 47% stage 4, and 60% primary refractory. DR cHL was observed in 119 pts (75%), while 39 pts (25%) were INT.
The median OS from the time of DR/INT was 7.4 yrs (95%CI 4.1-NR). There was no difference in OS by DR and INT pts (log-rank p=0.33). The majority (87%, n=137) received subsequent lines of therapy after DR/INT (median 2, range 0-14). Next line of therapy after DR/INT was BV or anti-PD-1 rechallenge (with or without combination therapy) in 39 pts (29%), conventional cytotoxic chemotherapy in 62 pts (45%), immunomodulatory based therapy (lenalidomide, everolimus) in 16 pts (12%) or other in 20 pts (15%). Any line of therapy after DR/INT included alloSCT in 29 pts (18%) and CD30 directed chimeric antigen receptor T-cell (CART) therapy in 24 pts (15%).
Forty pts (25%) were rechallenged with BV based therapies. The majority (88%) were previously refractory to BV. The median time from DR/INT to BV rechallenge was 348 days (range 14-1186). The objective response rate (ORR) was 63%, complete response rate (CRR) was 33%, and median PFS was 183 days (95%CI 108-273). Fifty-nine pts (37%) were rechallenged with anti-PD-1 based therapies. The majority (88%) were previously refractory to anti-PD-1 therapy. The median time from DR/INT to anti-PD-1 rechallenge was 233 days (range 3-1409). The ORR was 54%, CRR was 27%, and median PFS was 182 days (95%CI 127-357). There was no difference in PFS comparing BV and anti-PD-1 rechallenge (p=0.50) and no OS benefit of either BV or anti-PD-1 rechallenge, p=0.19 and 0.80 respectively.
In 29 pts treated with alloSCT, the median time from DR/INT to alloSCT was 220 days (range 27-1971). AlloSCT was associated with longer OS compared to pts not treated with alloSCT (p&lt;0.001), Figure 1. 3-year OS estimate was 96% (95%CI 75-99%) with alloSCT and 56% (95%CI 46-65%) without alloSCT. In 24 pts treated with CD30 directed CART, the median time from DR/INT to CART was 255 days (range 76-1600). CD30 directed CART was associated with longer OS compared to pts not treated with CART (p=0.009), Figure 2. 3-year OS estimate was 86% (95%CI 62-95%) with CART and 60% (95%CI 50-69%) without CAR-T. Only 2 pts were treated with both alloSCT and CART after DR/INT indicating that OS benefit was independent of cross over treatment.
Conclusion: To our knowledge, this is the largest cohort analyzing treatment outcomes in pts refractory to, or intolerant of BV and anti-PD-1 therapy. Additionally, this study represents one of the largest evaluations of BV or anti-PD-1 rechallenge after prior DR or INT. BV and anti-PD-1 rechallenge were effective with high ORR, but median PFS with rechallenge was less than a year, indicating that rechallenge could be considered as a therapeutic bridge. There was no OS benefit of BV or anti-PD-1 rechallenge. AlloSCT and CD30 directed CART were highly effective and associated with longer OS. Pts with DR/INT cHL should be considered for alloSCT or CD30 directed CART.