Prognostic Value of Minimal Residual Disease (MRD) Among Patients with Classical Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplantation

Background: Autologous stem cell transplantation (ASCT) can be curative for a subset of patients (pts) with relapsed/refractory classical Hodgkin lymphoma (cHL). Post-ASCT maintenance therapy with brentuximab vedotin (BV) improves progression-free survival (PFS) among pts with high-risk clinical features, and PD-1 blockade is also being investigated in this setting. Ideally, novel biomarkers could be used to guide pt selection for these post-ASCT therapies. We hypothesized that the presence of minimal residual disease (MRD), quantified using immunoglobulin-based next generation sequencing (IgNGS), could predict post-ASCT relapse. As a preliminary test of this hypothesis, we analyzed a cohort of cHL pts who had serial peripheral blood mononuclear cell (PBMC) and plasma samples collected before or after ASCT.

Methods: Samples from 2 cohorts (n=36) were analyzed. 28 pts were prospectively enrolled on a biobanking protocol and underwent ASCT at Dana-Farber Cancer Institute between 2014-2016 (biobank cohort). In addition, 8 pts underwent ASCT between 2015 and 2016 and subsequently participated in a multicenter phase II trial of post-ASCT pembrolizumab maintenance (PM) (trial cohort) (Armand, Blood 2020). Tumor tissue and serial post-ASCT plasma and PBMC samples were collected for all pts, and some pts also had pre-ASCT PB samples available for analysis. NGS of Ig receptor sequences (IgNGS) (clonoSEQ ^Ò, Adaptive Biotechnologies) was used to identify and track tumor clonotypes, as previously described (Ching, BMC Cancer 2020). MRD testing was not used for clinical decision making.

Results: The 36 enrolled pts received a median of 2 lines of therapy, and 30 pts (83%) achieved a complete response (CR) on pre-ASCT positron emission tomography (PET). In total, 19 pts received post-ASCT treatment - PM (n=8, all on trial), radiation therapy (n=5), BV maintenance (n=4), and allogeneic stem cell transplantation as part of a planned tandem transplant (n=2).

Among 36 enrolled pts, 12 (33%) had an identifiable clonotype (11/28 biobank and 1/8 trial). Higher rates of clonotype detection were seen in pts aged <32 (median) (56% vs 11%, p=0.012) and pts with primary refractory disease (56% vs 16%, p=0.030). With a median follow-up of 50 (range 4-75) months, there were no significant differences in PFS or overall survival among pts with and without a detectable tumor clonotype.

The 12 clonotyped pts had a median of 4 (range 1-13) post-ASCT plasma and 3 (range 1-17) post-ASCT PBMC samples. Among the 4 pts who relapsed, 3 had MRD detected within plasma samples with lead times of 0, 11, and 909 days (Figure 1). The pembrolizumab trial pt had detectable MRD early after ASCT which cleared within 9 weeks of starting pembrolizumab therapy, remained undetectable for the duration of pembrolizumab treatment, and became detectable again 5 months after completing PM in conjunction with clinical relapse. All pts with detectable MRD in a post-ASCT plasma sample subsequently relapsed (100% specificity). One pt relapsed without detectable MRD, but had a long interval (312 days) from last plasma sample to relapse. IgNGS testing from PBMC samples did not correlate with clinical outcomes; only two PBMC samples had detectable MRD and both were from a pt who did not relapse.

3 pts had pre-ASCT plasma samples collected concurrently with post-salvage PET scans. One pt achieved a partial response (PR) after 2 cycles of bendamustine and BV (Benda-BV), progressive disease after 4 cycles of Benda-BV, and a CR after pembrolizumab. MRD was detected after two cycles of Benda-BV (6.52 counts per million), was rising after 4 cycles of benda-BV (8.99 counts per million) and was undetectable after pembrolizumab. The pt remains in remission after a tandem transplant. Pre-ASCT samples were MRD negative in two other pts (1 CR, 1 PR) following salvage chemotherapy, both of whom remain in remission after ASCT.

Conclusions: The clonotype detection rate among pts with cHL was considerably lower than has been reported for other B-cell lymphomas, likely due to the scarcity of Reed Sternberg cells within cHL tumor samples. Novel MRD techniques for cHL should be investigated. In this pilot study, among pts with a detectable clonotype, MRD was a dynamic marker of response to different therapies and was a specific indicator of impending relapse, suggesting that additional studies of MRD in cHL are warranted.

Figure 1

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Figure 1

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