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Checkpoint inhibitors may have role posttransplant for aggressive B-cell lymphoma
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SALT LAKE CITY — Preliminary data have suggested the potential role for immune checkpoint inhibitors in the posttransplant setting among patients with relapsed/ large B-cell lymphomas, according to a presenter at the BMT Tandem Meetings.
Immune checkpoint inhibitors that target CTLA-4, PD-1 or its ligand PD-L1 have shown tremendous promise in the treatment of solid tumors, particularly advanced lung cancer, renal cell carcinoma and melanoma. However, their role in certain hematologic malignancies has been less clear.
“In lymphomas in general, and aggressive lymphomas in particular, the data are much more limited. We are a little late to the game,” John Sweetenham, MD, FRCP, FACP, senior director of clinical affairs and executive medical director of Huntsman Cancer Institute at The University of Utah and HemOnc Today’s Chief Medical Editor for Hematology, said during his presentation.
Outcomes for patients with relapsed/refractory B-cell lymphoma have generally improved over time, but still remain poor. Outcomes improve slightly if patients are able to get to transplant.
“The question is, what can we do to improve outcomes for both of these groups?” Sweetenham said. “One conclusion you might draw is we can try to introduce new agents to try to get patients to transplant. If we can get them to transplant, what can we do in the immediate peritransplant setting and posttransplant setting that might modify the course of the disease thereafter?”
An earlier trial from Moskowitz and colleagues, which evaluated pembrolizumab (Keytruda, Merck) among patients with Hodgkin lymphoma, showed 89% of responses were ongoing at the time of analysis and motivated future research of PD-1 inhibition for patients with lymphoma, Sweetenham said.
There have been a few trials that specifically evaluated checkpoint inhibitors in diffuse large B-cell lymphoma.
These include an analysis of ipilimumab (Yervoy, Bristol-Myers Squibb) by Ansell and colleagues, which included 18 patients with DLBCL and showed one patient achieved complete response for a duration that exceeded 31 months.
Also, Lesokhin and colleagues showed 18% complete and partial response rates and a 27% stable disease rate among patients with DLBCL treated with nivolumab (Opdivo, Bristol-Myers Squibb).
Zinzani and colleagues showed a 6% complete response rate and 31% partial response rate among patients with relapsed/refractory primary mediastinal B-cell lymphoma treated with pembrolizumab.
“These results are very encouraging, but the only caveat being that primary mediastinal B-cell lymphoma shares characteristics with Hodgkin lymphoma,” Sweetenham said. “So, what we may be seeing in this very distinct subtype of large B-cell lymphoma may not be representative of what we expect to see among a broader group of patients with large B-cell lymphoma.”
There have been some data in the pretransplant period showing activity with checkpoint inhibitors, especially emerging data showing combining these drugs with standard salvage chemotherapy and radiotherapy regimens used for relapsed disease may enhance the efficacy.
However, in the posttransplant period, there is even greater rationale for checkpoint inhibitors, Sweetenham said.
These reasons include that the postautologous transplant period is characterized by minimal residual disease, “so there is a window of opportunity to eradicate remaining chemotherapy-refractory cells during that time,” Sweetenham said.
There also is immune remodeling that occurs during this period, especially during the first 6 months, as well as dominance of subsets of cells that are likely targets of PD-1 blockade up to 6 months following transplant.
Skarbnik and colleagues presented preliminary safety and efficacy data from an ongoing phase 1 study of ipilimumab and nivolumab following autologous HSCT for patients with high-risk hematologic malignancies in December at the ASH Annual Meeting and Exposition.
After a median follow-up of 24 weeks, researchers reported a 92% OS rate and 88% PFS rate among 25 patients. All patients with primary refractory DLBCL were in complete response.
There also were no new safety signals.
“These are extremely preliminary data, but they certainly represent the safety of the approach and we’ll have to wait over time to see more of the efficacy,” Sweetenham said.
There are a number of other studies ongoing in this setting, including a phase 2 study of pembrolizumab following autologous HSCT for patients with relapsed/refractory Hodgkin lymphoma, DLBCL and peripheral T-cell lymphoma.
“Overall, at the moment the data are extremely preliminary, but they do demonstrate the potential of the use of checkpoint inhibition in this disease, particularly in the posttransplant setting,” Sweetenham said. “The rationale for that is strong, based on minimal residual disease and the remodeling of the immune system.
“The potential advantage that these new agents may have over some of the other immune approaches is that immune checkpoint inhibitors have been well studied in other populations with poor performance status, such as those patients with advanced melanoma and lung cancer,” Sweetenham added. “Although data right now are very limited, this approach is more likely to have broad applicability than some of the other strategies being used for these very difficult patients to treat.” – by Alexandra Todak
References:
Sweetenham J. Checkpoint inhibitors in the pre- and post-autologous transplant setting for aggressive B-cell lymphomas. Presented at: BMT Tandem Meetings; Feb. 21-25, 2018; Salt Lake City.
Ansell SM, et al. Cli Cancer Res. 2009;doi:10.1158/1078-0432.CCR-09-1339.
Lesokhin AM, et al. J Clin Onol. 2016;doi:10.1200/JCO.2015.65.9789.
Moskowitz CH, et al. Abstract 290. Presented at: ASH Annual Meeting and Exposition; Dec. 5-9, 2014; San Francisco.
Skarbnik AP, et al. Abstract 340. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Zinzani PL, et al. Blood. 2017;doi:10.1182/blood-2016-12758383.
Disclosure: Sweetenham reports no relevant financial disclosures.