Alternative treatment strategies, including bispecific antibodies and CAR T-cell therapies, should be investigated for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have detectable MRD in blood or apheresis stem cell (ASC) samples. So concludes Reid W. Merryman, MD, of the Dana-Farber Cancer Institute, who presented findings at the virtual 2020 American Society of Hematology Annual Meeting and Exposition showing that these patients have a significantly higher risk of relapse and inferior 5-year progression-free survival (PFS) compared with patients whose blood or ASC samples were MRD negative.

Five-year PFS for patients with detectable MRD in ASC samples – roughly a quarter of the study population – was just 13%, versus 52% for those who were MRD negative. In patients whose peripheral blood was serially analyzed after autologous stem cell transplant (ASCT), the detection of MRD in plasma reliably predicted relapse, with a median time from MRD detection to clinical relapse of about 2 months.

“These results suggest that alternative treatments, such as bispecific antibodies or CAR T-cell therapy, should be investigated for patients who are MRD positive, because these patients really don’t do well with ASCT,” Merryman said.

DLBCL is an aggressive form of non-Hodgkin lymphoma (NHL) and the most prevalent form of NHL in the United States, accounting for about 30% of mature B-cell lymphomas. Although ASCT is often curative, about 50% of patients ultimately relapse.

In the current study, Merryman and his colleagues used Adaptive Biotechnologies’ clonoSEQ^® immunoglobulin-based next-generation sequencing (IgNGS) to assess the predictive value of circulating tumor DNA (ctDNA) in ASC samples and to evaluate whether serial samples of peripheral blood mononuclear cells (PBMCs) or plasma could identify patients who were at high risk for post-ASCT relapse.

“Multiple studies in lymphoma and other malignancies have shown that tumor cells release detectable and quantifiable levels of tumor-specific DNA into the bloodstream,” Merryman told Nucleus. “In DLBCL, several investigators have tracked levels of ctDNA in response to either first-line or second-line chemoimmunotherapy and have found that a rapid reduction in ctDNA levels is associated with improved clinical outcomes. Based on these results, we hypothesized that detection of ctDNA either before or after autologous stem cell transplantation may be an indicator of increased relapse risk.”

The study involved 154 patients from three cohorts – one retrospective and two prospective – who were treated with ASCT between 2003 and 2016 at Dana-Farber and other North American cancer centers. Patients’ median age was about 58; about 63% were male. About 64% had a diagnosis of DLBCL; 29%, transformed indolent lymphoma (TIL); and 7%, primary mediastinal B-cell lymphoma (PMBCL). Patients had undergone between one and four pre-ASCT lines of therapy. Patients in the first two cohorts received no post-ASCT maintenance therapy; those in the third cohort received maintenance therapy with pembrolizumab.

ASC samples only were available for the retrospective cohort. In the second cohort, pre-treatment ASC samples and post-ASCT plasma and PMBC samples from a subset of patients were analyzed. In the third cohort, post-ASCT plasma and PBMC samples and pre-ASCT ASC samples from a subset were analyzed. IgNGS analysis was performed retrospectively and was not used to drive clinical decisions.

Median follow-up among survivors was 69 months, with a range of 13 months to 15 years. Although the cohorts were heterogeneous for both the use of maintenance therapy and the duration of follow-up – with shorter follow-up in the group that received pembrolizumab maintenance therapy – the investigators did not see significant differences in outcomes between the three groups, Merryman said, nor were there any significant differences by lymphoma type (i.e., DLBCL, PMBCL, TIL).     

“There was a non–statistically significant trend toward a higher rate of MRD detection from ASC samples for patients with TIL, 35%, compared with patients who had DLBCL, 19%,” he said. “It’s unclear if this might be due to residual indolent lymphoma cells present within the bone marrow or to some other mechanism. The population of PMBCL patients was too small to enable us to draw any firm conclusions.”

Merryman cautions that the study’s findings are not yet ready for clinical application. “They need to be tested prospectively first,” he said. “The next step – which we are now working on – would be a trial using MRD to guide therapy, with MRD-negative patients directed to ASCT and MRD-positive patients to an alternative treatment.”

The strategy of serially testing for ctDNA in plasma samples post ASCT also needs to be explored in clinical trials, he added. “Future trials should build in serial MRD testing at 1- to 2-month intervals – particularly in the early post-ASCT period, which is when patients are most likely to relapse.”

Reference

Merryman RW, Redd RA, Taranto E, et al. Prognostic Value of Circulating Tumor DNA (ctDNA) in Autologous Stem Cell Graft and Post-Transplant Plasma Samples Among Patients with Diffuse Large B-Cell Lymphoma. Abstract 531 presented 12/7/2020. 62nd American Society of Hematology Annual Meeting and Exposition.

Tags: astct, MRD, Outcomes, Patients, DLBCL