HSCT after PD-1 blockade shown to be effective in R/R lymphoma patients but with higher risk of GVHD

In January 2017, Reid W. Merryman from the Dana-Farber Cancer Institute, Harvard Medical School, Boston, and colleagues published in Blood the results of a retrospective study into the efficacy and safety of PD-1 blockade prior to allogeneic Hematopoietic Stem Cell Transplant (HSCT) in 39 patients with R/R lymphoma. The majority of the patient population (31/39pts, 78%) had Classical Hodgkin Lymphoma (cHL), and 8 pts were diagnosed with a sub-type of Non-Hodgkin Lymphoma (NHL).  

Key Highlights:

• Pts received a median of 8 anti-PD-1 treatment cycles (3–27 cycles) and a median of 4 systemic prior-treatments
• Median 62 days to HSCT after final anti-PD-1 treatment (7–260 days)
• Results: Median 12-month follow-up:
  • OS = 89% (95% CI; 74–96)
  • PFS = 76% (95% CI; 56–87)
• cHL subpopulation 12-month follow-up:
  • OS = 90% (95% CI; 71–97)
  • PFS = 74% (95% CI; 50–88)
• Safety: Cumulative incidence of GVHD after one-year:
  • Grade 2–4 = 44%
  • Grade 3–4 = 23%
  • Acute Grade 4 = 13%
• Treatment-related deaths: 4 in total, 3 due to acute GVHD within 2 weeks of HSCT, 1 due to hepatic sinusoidal obstruction syndrome (3 pts total developed hepatic sinusoidal obstruction syndrome)
• Seven pts developed prolonged febrile syndrome, 2 pts later developed fatal acute GVHD
• Pts with 8 or more doses of PD-1 blockade had significantly better PFS than those who received less than 8 doses (91% vs 54%, P=0.039)
• Time interval between final anti-PD-1 blockade and HSCT was not seen to significantly alter OS, PFS, or GVHD occurrence
• PD-1 blockade treated pts had lower total leukocyte and CD3 donor chimerism values at 100 days after HSCT than a control group: 95% vs 100% (P=0.027) and 64% vs 97% (P=0.015) respectively

In conclusion, the authors stated that despite limitations in this study (small sample size, short follow-up, retrospective rather than prospective, etc.) the reported PFS was sufficiently high, given the highly pre-treated population background. Therefore, the data in this study supports HSCT after PD-1 blockade being an effective treatment in this population, albeit with a higher risk of GVHD.

Abstract:

Anti-PD-1 monoclonal antibodies are being increasingly tested in patients with advanced lymphoma. Following treatment, many of those patients are likely to be candidates for allogeneic hematopoietic stem cell transplant (HSCT). However, the safety and efficacy of HSCT may be affected by prior PD-1 blockade. We conducted an international retrospective analysis of 39 patients with lymphoma who received prior treatment with a PD-1 inhibitor, at a median time of 62 days (7-260) before HSCT. After a median follow-up of 12 months, the one-year cumulative incidences of grade 2-4 and grade 3-4 acute graft-versus-host disease (GVHD) were 44% and 23% respectively, while the one-year incidence of chronic GVHD was 41%. There were 4 treatment-related deaths, (1 from hepatic sinusoidal obstruction syndrome, 3 from early acute GVHD). In addition, 7 patients developed a non-infectious febrile syndrome shortly after transplant requiring prolonged courses of steroids. One-year overall and progression-free survival rates were 89% (95% CI, 74-96) and 76% (95% CI, 56-87), respectively. One-year cumulative incidences of relapse and non-relapse mortality were 14% (95% CI, 4-29) and 11% (95% CI, 3-23), respectively. Circulating lymphocyte subsets were analyzed in 17 patients. Compared with controls, patients previously treated with PD-1 blockade had significantly decreased PD-1+ T cells, and decreased ratios of T regulatory cells to conventional CD4 and CD8 T cells. In conclusion, HSCT after PD-1 blockade appears feasible with a low rate of relapse. However, there may be an increased risk of early immune toxicity, which could reflect long-lasting immune alterations triggered by prior PD-1 blockade.