Checkpoint Blockade Before Allogeneic Transplant Improves PFS, But Not OS, in Hodgkin Lymphoma

Miguel-Angel Perales, MD

Checkpoint inhibitors prior to allogeneic hematopoietic cell transplant (HCT) improved progression-free survival (PFS) and relapse incidence in patients with Hodgkin lymphoma. However, the treatment did not improve non-relapse mortality (NRM) or overall survival (OS), according to findings of a Center for International Blood and Marrow Transplant Research (CIBMTR)/EBMT (European Society for Blood and Marrow Transplantation) analysis (2020-R-03) that were presented at the EBMT 48th Annual Meeting.¹

Results showed that those who previously received a checkpoint inhibitor led to a 25% reduction in the risk of disease progression or death compared with those who did not (HR, 0.75; 95% CI, 0.59-0.95; P = .0171). The administration of checkpoint inhibitors in this setting also highlighted a lower incidence of relapse (HR, 0.53; 95% CI, 0.38-0.75; P = .00023).

However, there was no OS improvement with the prior use of checkpoint inhibition (HR, 0.96; 95%, 0.72-1.27; P = .76949), nor an improvement in NRM (HR, 1.1; 95%CI, 0.78-1.56; P = .58614).

“The bottom line is that, as we have predicted, there was a significant improvement in progression-free survival and relapse in favor of prior checkpoint inhibition, but it did not translate into a higher overall survival,” lead study author Miguel-Angel Perales, MD, a medical oncologist and chief of the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center, said in a virtual presentation during the meeting. “Patients who had prior [checkpoint inhibition] should still be referred to allogeneic transplant. We have a curative treatment. The results in our study and other studies…support very high rates of cure for these patients and that should be the strategy we adopt.”

Pembrolizumab (Keytruda) is approved for adult patients with relapsed/refractory classical Hodgkin lymphoma and pediatric patients with refractory classical Hodgkin lymphoma, or classical Hodgkin lymphoma that has relapsed after 2 or more lines of therapy. Additionally, nivolumab (Opdivo) is indicated for the treatment of patients with classical Hodgkin lymphoma that has relapsed or progressed after autologous HCT and posttransplant brentuximab vedotin (Adcetris).

While checkpoint inhibitors are used in Hodgkin treatment, it is thought that utilizing this class of agents prior to allogeneic transplant could worsen transplant complications, such as graft-vs-host disease (GVHD). These complications, therefore, are believed to lead to worse outcomes.

In the CIBMTR/EBMT study, investigators sought to examine the impact of prior checkpoint blockade on outcomes with allogeneic HCT in 1729 adults (CIBMTR, n = 403; EBMT, n = 1326) with Hodgkin lymphoma who received a first allogeneic HCT via minimal residual disease, minimal undetectable disease, or haploidentical donor from 2008 to 2009. Most patients (74%) received a reduced-intensity conditioning (RIC)/nonmyeloablative (NMA) regimen, and 20% of patients had previously received a checkpoint inhibitor.

A total 46.1% of patients who received a checkpoint inhibitor had a haploidentical donor compared with 31.8% of those who did not have an immunotherapy agent. GVHD prophylaxis comprised posttransplant cyclophosphamide, a calcineurin inhibitor (CNI), and mycophenolate mofetil (MMF) in 51.6% and 32.3% of patients, respectively, while the remaining were given CNI-based prophylaxis with MMF or methotrexate. Additionally, 81.6% and 73.7% of patients who did and did not receive a checkpoint inhibitor, respectively, had chemotherapy-sensitive disease at the time of transplantation.

The primary end point was OS.

The median follow-up was 24 months for the checkpoint inhibitor–cohort and 38 months in the arm with no checkpoint inhibitor. Additional factors that were found to impact OS included age (HR, 1.02; 95% CI, 1.01-1.02; P = .00001), sex (female vs male; HR, 0.76; 95% CI, 0.64-0.92; P = .00381), partial response (HR, 1.39; 95% CI, 1.11-1.73; P = .00367), and refractory disease (HR, 2.25; 95% CI, 1.81-2.8; P <.00001).

Myeloablative conditioning vs RIC/NMA (HR, 1.24; 95% CI, 1.02-1.5; P = .03276) and a Karnofsky performance score greater than 90 (HR, 1.45; 95% CI, 1.2-1.76; P = .00013) also had an effect on OS.

Furthermore, in patients who only received checkpoint inhibitors, PFS (HR, 0.61; 95% CI, 0.38-0.97; P = .03821) and relapse (HR, 0.43; 95% CI, 0.2-0.92; P = .03038) were improved in haploidentical donor recipients; however, this did not have an impact on OS.

Additionally, while grade 2 to 4 acute GVHD was increased with the use of checkpoint inhibitors (HR, 1.33; 95% CI, 1.03-1.71; P = .02677), there was no impact on the cumulative incidence of grade 3 to 4 acute (HR, 1.39; 95% CI, 0.94-2.05; P = .09886) and chronic GVHD (HR, 0.98; 95% CI, 0.77-1.25; P = .87631).

“Future studies are needed to identify the best donor and GVHD prophylaxis in these patients,” the authors noted.

Reference

1. Perales M-A, Awan F, Boumendil A, et al. Outcomes of allogeneic HCT in patients with Hodgkin lymphoma in the era of checkpoint inhibitors: a joint CIBMTR and EBMT analysis. Presented at: EBMT 48th Annual Meeting; March 19-23, 2022; virtual. Presidential abstract.