What Is the Role of SCT as Novel Agents Emerge for Relapsed/Refractory HL?

Phillippe Armand, MD, PhD

Pre-2010, salvage therapy plus autologous stem cell transplantation (auto-STC) had been the standard of care in patients with relapsed/refractory Hodgkin lymphoma (HL). That treatment modality is undergoing a change as emerging agents open the possibility for allogeneic stem cell transplantation (allo-SCT). Exactly how these agents will affect the use of allo-SCT remains to be seen, according to Phillippe Armand, MD, PhD. He also offered his opinion on how to frame allo-SCT’s use in historical studies that involved auto-SCT.

Postponing SCT

Although allo-SCT remains the only curative treatment for patients with relapsed/refractory HL, most patients will progress. “In studies that have been published up until a few years ago, the progression-free survival (PFS) after allo-SCT [has been] about 25% to 30%,” said Armand, director of clinical research, Lymphoma Program, Dana-Farber Cancer Institute. During a presentation at the National Comprehensive Cancer Network 13th Annual Conference: Hematologic Malignancies Armand discussed how novel agents could be used in the future either to postpone, permit, or even replace allo-SCT.Postponing SCT with novel agents may be the most valuable strategy when treating patients with relapsed/refractory HL, said Armand. “One short-term goal is to not do [SCT] yet. Patients do get sick—it’s a lot of toxicity and hassle, and it would be great not to have to do it.”

This would be possible by achieving a durable remission with HL-specific drugs. In a phase II study, 102 patients with relapsed/ refractory HL after failed auto-SCT achieved a complete response (CR) rate of 34% (95% CI, 25.2%-44.4%) and an overall response rate (ORR) of 75% (95% CI, 64.9%-82.6%) with brentuximab vedotin (Adcetris).¹The agent received accelerated FDA approval for patients with relapsed/refractory HL after auto-SCT or after failure of at least 2 prior multiagent chemotherapy regimens in patients who are not auto-SCT candidates.

Additionally, 2 phase II trials are currently investigating the importance of PD-L1 blockade in relapsed/refractory HL. “If patients have a remission of PD-L1 blockade, we know that some will be durable, especially if they have CR,” said Armand.

The CheckMate 205 study investigated nivolumab (Opdivo) in patients with relapsed/refractory HL after failed auto-SCT.²The ORR was 69% (95% CI, 63%-75%), with 16% of patients achieving a CR and 53% achieving a partial response.

Permitting SCT

KEYNOTE-087 investigated pembrolizumab (Keytruda) in patients with relapsed/refractory HL after failed auto-SCT.³The ORR was 69% (95% CI, 62.3%-75.2%) and the CR rate was 22.4% (95% CI, 16.9%-28.6%). However, Armand said that most patients treated with anti—PD-L1 therapy will progress after a median of around a year.Novel agents can also permit SCT as a therapeutic strategy, according to Armand. “If you [receive] an allo-SCT with chemotherapy-sensitive disease, it’s curative in somewhat less than half of the patients,” he said.

A phase I/II study investigated the combination of brentuximab vedotin and nivolumab as initial salvage therapy in patients with relapsed/refractory HL.⁴Among all patients treated, the ORR was 82% (95% CI, 70%-91%), and 61% (95% CI, 47%-73%) of patients achieved a CR.

Replacing SCT

“Brentuximab vedotin, if it hasn’t been used before, and [a PD-L1 blockade] are good ways to get patients into remission if you want to give them an allo-SCT,” Armand concluded. However, he also noted that the use of a PD-L1 blockade prior to allo-SCT has been the subject of debate.

Lastly, chimeric antigen receptor (CAR) T-cell therapy may even replace allo-SCT for patients with relapsed/refractory HL. In a phase I dose-escalation study, 7 patients with relapsed/ refractory HL with no prior conditioning were infused with CD30-directed CAR T cells, encoding the CD28 costimu- latory endodomain.⁵Two patients remained in CR for 2 or more years after 1 to 2 infusions. The trial is currently being redone with a lymphodepleting chemotherapy conditioning regimen to further improve responses (NCT02917083). “The results of CAR-T cell therapy in HL are immature,” said Armand. “But it may really have curative potential.”

Several trials are ongoing, including the human phase I trial investigating anti-CD30 CAR T-cell therapy (NCT0309449).⁶“Replacing allo-SCT is not a clinical endpoint right now, but in the future, it could be,” Armand said. “If some of these patients remain in long remissions and appear to be cured, it might be appetite for a trial that eliminates allo-SCT. I don’t think that we are there yet, but it is something we may be able to look forward to.”

References:

1. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentux- imab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189. doi: 10.1200/JCO.2011.38.0410.
2. Armand P, Engert A, Younes A, et al. Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multiple single-arm phase II CheckMate 2015 trial. J Clin Oncol. 2018;36(14):1428- 1439. doi: 10.1200/JCO.2017.76.0793.
3. Chen R, Zinzani PL, Fanale MA, et al; KEYNOTE-087. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol. 2017;35(19):2125-2132. doi: 10.1200/JCO.2016.72.1316.
4. Herrera AF, Moskowitz AJ, Barlett NL, et al. Interim results of brentuximab vedotin in com- bination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2018;131(11):1183-1194. doi: 10.1182/blood-2017-10-811224.
5. Ramos CA, Ballard B, Zhang H, et al. Clinical and immunological responses after CD30-spe- cific chimeric antigen receptor-redirected lymphocytes. J Clin Invest. 2017;127(9):3462- 3471. doi: 10.1172/JCI94306.
6. Wang CM, Wu ZQ, Wang Y, et al. Autologous T cells expressing CD30 chimeric antigen re- ceptors for relapsed or refractory Hodgkin lymphoma: an open-label phase I trial. Clin Cancer Res. 2017;23(5):1156-1166. doi: 10.1158/1078-0432.