Chemoresistance Can Be Reliably Overcome with High-Dose Therapy and Autologous Stem Cell Transplantation (HDT/ASCT) for Relapsed and Refractory Hodgkin's Lymphoma
Authors: Gerrie Alina S. , Power Maryse M. , Savage Kerry J. , Shepherd John D. , Connors Joseph M. 
Published: October 2019

Abstract
Abstract 2022

Background:
HDT/ASCT is the preferred treatment for relapsed and refractory HL patients (pts) with chemosensitive disease, with cure rates approximating 40–60%. The role for HDT/ASCT in chemoresistant HL is less well defined and many centers do not offer this treatment to such patients. Since 1985, HDT/ASCT has been recommended in British Columbia (BC) for all HL pts with progressive disease despite primary ABVD-type therapy, irrespective of response to salvage therapy. We sought to evaluate the long-term outcomes of HL pts whose disease was resistant to chemotherapy preceding HDT/ASCT.

Methods:
We reviewed all HL pts who underwent HDT/ASCT for primary progression (PP) or first relapse (1REL) after initial treatment with chemotherapy +/− radiation. Primary progression (PP) was defined as progression during or within 3 months of completion of initial therapy. Pts were considered to have: chemoresistant (R) disease = stable disease or progression on chemotherapy preceding HDT/ASCT; chemosensitive (S) disease = clinical and/or radiographic response to chemotherapy preceding HDT/ASCT; or untested (U) if no salvage chemotherapy was given. Clinical and laboratory data were obtained from the BC Cancer Agency Lymphoid Cancer Database, the Leukemia/BMT Program of BC Database and from hospital, clinic, and physician records.

Results:
251 pts underwent HDT/ASCT for PP (n=90 36%) or 1REL (n=161 64%) between 1985–2011: male 53%; median age at diagnosis 28 y (range 16–59 y), at HDT/ASCT 31 y (range 31–62 y). Characteristics at diagnosis were: advanced stage(stage IIB, II bulky, III or IV) 94%; stage 3–4 60%; B symptoms 57%; bulk (≥10 cm) 42%; primary therapy: ABVD/ABVD-like, 95%; MOPP-like 5%; combined modality therapy 31%. Salvage therapy prior to HDT/ASCT included MVPP (28%); COP/COPP (22%); GDP (27%); no chemotherapy (13%); other (11%). RT was given with salvage therapy in 19%: alone, 27%; with chemotherapy, 73%. Conditioning regimen was with CBV/CBVP in the majority of cases (88%); BEAM (11%); other (1%). At a median follow-up for living pts of 8 y (range 0.2 – 25 y), 136 pts (54%) were alive free of HL; 89 pts (35%) have relapsed. For all pts, median overall (OS) and progression free survivals (PFS) were 21.7 y (95% CI 16.0–27.5) and 17.3 y (95% CI 9.8–24.8), respectively. 13 pts (5%) died of complications related to or within 1 month of HDT/ASCT, 6 (2%) from secondary malignancies, 7 (3%) from unrelated causes. 199 pts (56 PP, 143 1REL) had information available regarding response to salvage therapy. Of the 56 PP pts, 14 (25%) had chemoresistant disease (PP/R); 21 (38%) did not receive salvage therapy and thus were untested (PP/U); 21 (38%) had chemosensitive disease (PP/S). 10-y PFS for PP/R, PP/U, and PP/S groups were 27%, 24%, and 40%, respectively; 10-y OS were 53%, 27%, and 53%, respectively. Of the 143 1REL pts, 26 (18%) had chemoresistant disease (1REL/R); 12 (8%) did not receive salvage therapy (1REL/U); 105 (73%) had chemosensitive disease (1REL/S). 10-y PFS for 1REL/R, 1REL/U, and 1REL/S groups were 49%, 57%, and 58%, respectively; 10-y OS were 55%, 65%, 69%, respectively. OS and PFS for the chemoresistant groups (PP/R, PP/U, 1REL/R) and 1REL/U are shown in Figures 1A and 1B respectively. To evaluate impact of chemoresistance on outcomes, PP/R (pts resistant to both primary and salvage therapy, “double-resistant”) and PP/U pts (resistant to primary therapy, “single-resistant”) were grouped together (n=35) and compared to PP/S pts. There was a significant difference in OS (P =.05) but not PFS (P =.12). When pts with 1REL/R were compared to 1REL/S, there was no significant difference in OS (P =.25) or PFS (P =.26).

Conclusion:
In this large uniformly treated cohort of HL pts with long-term follow-up, chemoresistance preceding HDT/ASCT was identified as a poor prognostic factor, particularly for PP pts; however, this poor prognostic factor could be partially overcome by HDT/ASCT, resulting in cure in 25–50% of pts across all chemoresistant groups. Importantly, even pts who were double-resistant to both primary and salvage therapy were cured in 27% of cases. HDT/ASCT should therefore be considered in all transplant eligible pts, regardless of responsiveness to salvage chemotherapy.

Disclosures:
No relevant conflicts of interest to declare.