When ImmunoTx Fails, HL Patients Should Get Timely Allo-HCT

Helen Leask, PhD

April 18, 2022

Physicians treating Hodgkin lymphoma should not delay potentially curative allogeneic hematopoietic cell transplantation (allo-HCT) over fears of checkpoint inhibitor (CPI)–related graft-versus-host disease (GVHD), said a speaker at the annual meeting European Society for Blood and Bone Marrow Transplantation.

In fact, prior treatment with PD-1–directed therapies nivolumab (Opdivo) and pembrolizumab (Keytruda) appears to improve outcomes in allo-HCT patients, said Miguel-Angel Perales, MD, chief of the adult bone marrow transplant service at Memorial Sloan Kettering Cancer Center in New York.

"The use of allogeneic HCT is decreasing for Hodgkin even though it is a curative option, and we see patients referred after they have had multiple lines of therapy," Perales said in an interview. "The lymphoma MDs have a perception that outcomes are poor, and therefore don't refer."

To illustrate his point, Perales shared data from the EBMT database. In 2014, the registry accrued approximately 450 allo-HCT cases; by 2021 this had fallen to fewer than 200 procedures.

Ironically, this declining enthusiasm for transplantation coincides with a steady improvement in transplant outcomes following PD-1 blockade, Perales noted. For example, an analysis, published in Nature, yielded an 82% overall survival (OS) at 3 years in patients who underwent allo-HCT after CPI treatment (n =209).

"Results of allo-HCT in patients with Hodgkin show a remarkable cure rate," said Perales. "Part of that is probably driven by lower relapse due to enhanced graft-versus-lymphoma effect due to long CPI half-life." (The half-lives of pembrolizumab and nivolumab are 22 and 25 days, respectively.)

At the EBMT meeting, Perales presented a new retrospective analysis that tested the hypothesis that CPIs might actually improve outcomes for allo-HCT patients. An international team of clinicians from EBMT and the Center for International Blood and Marrow Transplant Research (CIBMTR) compared allo-HCT outcomes with (n = 347) and without (n = 1,382) prior treatment with a checkpoint inhibitor.

They found that prior CPI therapy was, indeed, associated with lower relapse (hazard ratio, 0.53; P = .00023) and longer progression-free survival (PFS) (HR, 0.75; P = .0171).

However, prior PD-1 drugs provided no survival advantage, Perales said. "The easiest explanation for a study showing a difference in PFS/relapse, not OS, is that we have good treatments that can treat patients who relapse and so their overall survival ends up being the same."

The researchers also confirmed previous reports that patients who received PD-1 inhibitors prior to transplant had a higher incidence of GVHD. Prevalence of acute grades 2-4 GVHD was significantly higher (P = .027); however, acute grades 3-4 GVHD and chronic GVHD were not significantly different between the two groups.

Perales speculated that the use of posttransplant cyclophosphamide for GVHD prophylaxis would mitigate the risk of GVHD associated with PD-1 inhibitors, "we have not yet proven that formally ... [we] are still analyzing our data."

Commenting on the results of the new analysis, Perales expressed concern that patients are being recruited to early-phase clinical trials after failing on a checkpoint inhibitor, instead of being offered allo-HCT – a potentially curative treatment – because treaters are misinformed about the safety of transplant after these drugs.

The NIH clinical-trials database backs up Perales' worries. In the United States, for example, there are currently 19 trials recruiting for relapsed/refractory Hodgkin lymphoma patients prior to transplant. Of these, 15 studies permit enrollment of patients who have failed on CPIs, and 8 are phase 1 or 2 studies.

"The good news is that new drugs, including CPIs, have dramatically changed outcomes in this disease and that fewer patients now need an allo-HCT," said Perales. And if a transplant is needed, "it is safe to perform allo-HCT in patients treated with prior CPI."

However, time is of the essence. "Patients with Hodgkin lymphoma should be referred to allo-HCT if they are not responding or tolerating CPI, rather than go on a series of phase 1 trials," Perales said. "Median age is 32, and we should be going for a cure, nothing less."

Perales reported receiving honoraria from numerous pharmaceutical companies; serving on the data and safety monitoring boards of Cidara Therapeutics, Medigene, Sellas Life Sciences, and Servier; and serving on the scientific advisory board of NexImmune. He has ownership interests in NexImmune and Omeros, and has received institutional research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.


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