Assessment of Tumor Metabolic Volume (TMV) As a Predictor of Outcomes in Patients with Relapsed/Refractory Primary Mediastinal B-Cell Lymphoma (PMBCL)

Background:

PMBCL is an aggressive form of large B-cell lymphoma (LBCL) but has a unique gene expression profiling signature that more closely resembles Hodgkin's lymphoma. Treatment of relapsed/refractory (R/R) PMBCL is largely extrapolated from trials in LBCL with few PMBCL patients included. In the rituximab era, there is a paucity of data on the efficacy and outcomes of salvage therapy followed by high-dose chemotherapy and autologous stem cell transplant (HDCT/ASCT) in PMBCL. Studies have shown that patients with R/R NHL and a complete response to salvage chemotherapy have better outcomes following HDCT/ASCT; however, no studies have specifically evaluated outcomes in PMBCL, particularly in the rituximab era. Studies have also evaluated tumor metabolic volume (TMV) as a predictor of outcome in LBCL, but TMV use in PMBCL has not be explored, and a standardized approach in calculating TMV in PMBCL is yet to be established. In this analysis we report on the association of TMV and clinical outcomes in the R/R setting.

Methods:

We conducted a retrospective study of patients with R/R PMBCL, histologically confirmed at the University of Michigan, diagnosed between 2001 and 2023. Clinical and pathologic characteristics, treatment regimens, response rates and survival outcomes were collected. Pre- and post-salvage therapy PET-CT scans were analyzed using Medical Image Merge (MIM Software Inc., Cleveland, OH) to assess standardized uptake value (SUV) and TMV. Lesions were segmented using 2x liver mean SUV as well as 41% of measured lesion maximum SUV as cutoffs, in line with previously reported methodologies. The relative differences in TMV between PET-CT at diagnosis of R/R disease and PET-CT post-salvage chemoimmunotherapy were then analyzed using a cutoff of > 90% reduction. Relative reduction in TMV was then compared to EOT responses after salvage-chemoimmunotherapy or HDCT/ASCT.

Results:

16 patients were identified with R/R disease with a median time to relapse of 9.2 months after front line chemoimmunotherapy. All patients but 2 relapsed within the first 12 months from completion of first line therapy. 15 patients had evaluable post-salvage chemoimmunotherapy PET-CTs with an ORR of 53% and CR rate of 7%. 7 patients received HDT/ASCT as part of second line therapy with ORR of 85% and CR rate of 85%. 5-year PFS and OS for all patients with R/R PMBCL was 49% and 84%, respectively.

12/16 patients with R/R disease had pre- and post-salvage PET-CTs available for TMV analysis. Of the 12 patients, 7 had a PR and 1 had a CR on post-salvage scan. Of these, 5 patients proceeded to HDCT/ASCT, 3 of whom had TMV calculated by 2x liver mean SUV > median of the entire cohort and were defined as high baseline TMV. There was no correlation between pre-salvage high baseline TMV and post HDCT/ASCT response. We next employed a dynamic measurement of TMV by calculating relative reduction in TMV between pre- and post-salvage PET-CTs. A > 90% relative reduction in TMV was achieved by all 8 responding patients based on the 2x liver TMV cutoff. Of this group, 5 patients went on to receive HDCT/ASCT, all of whom achieved a CR on scans following HDCT/ASCT. When the 41% lesional TMV cutoff was applied, there was no correlation between degree of TMV reduction and outcomes of therapy. No patients who achieved a relative reduction in TMV of < 90% by the 2x liver cutoff achieved a PR or CR at the end of salvage therapy or all second line therapies.

Conclusion:

Compared to R/R DLBCL, where responses in primary refractory/early relapsed disease are poor, our data in patients with R/R PMBCL shows high response rates to salvage chemoimmunotherapy followed by HDCT/ASCT. In addition, this analysis of TMV suggests that a dynamic measurement of relative reduction in TMV of > 90% based on 2x liver cutoff on post-salvage PET-CT may be a reliable predictor of long-term outcomes. In contrast to data on DLBCL, which has shown poor outcomes when CR is not achieved with salvage therapy prior to HDCT/ASCT, our data suggest that a PR following salvage therapy, so long as it meets reduction in TMV of > 90% based on the 2x liver cutoffs, correlates with high remission rates following subsequent HDT/ASCT. As second line therapy continues to evolve for DLBCL, further studies are needed in PMBCL to determine the optimal treatment approach for this unique subset of patients as well as reliable predictors for response to guide therapy decision making.

Phillips:Xencor: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly and Company: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; ADCT: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees. Karimi:Xencor: Research Funding; Lilly/Loxo: Research Funding; AstraZeneca: Research Funding; Merck: Research Funding; Roche/Genentech: Other: Travel Expenses, Research Funding; ADC Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding.