Prognostic Value of Minimal Residual Disease (MRD) Among Patients with Classical Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplantation
Authors: Taranto Eleanor , Redd Robert A. , Jeter Erin , McHugh Kristin M , Brown Jennifer R , Crombie Jennifer L. , Davids Matthew S. , Fisher David C. , Freedman Arnold S. , Jacobsen Eric D , Jacobson Caron , Kim Austin I. , LaCasce Ann S. , Lampson Benjamin L. , Ng Samuel Y. , Odejide Oreofe O. , Parry Erin Michelle , Dahi Parastoo B. , Nieto Yago , Joyce Robin M. , Chen Yi-Bin , Herrera Alex F. , Armand Philippe , Merryman Reid W 
Published: November 2021

Abstract

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 &lt;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 Figure 1.

Disclosures
Brown: Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding; Invectys: Other: Data Safety Monitoring Committee Service; Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy. Crombie: Roche: Research Funding; Incyte: Consultancy; Karyopharm: Consultancy; Merck: Research Funding; Abbvie: Research Funding; Bayer: Research Funding. Davids: TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Takeda: Consultancy; Surface Oncology: Research Funding; AbbVie: Consultancy; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy. Jacobsen: Takeda: Consultancy; Syros: Consultancy; Janssen: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding. Jacobson: Lonza: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau; Nkarta: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Humanigen: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel support. LaCasce: Bristol-Myers Squibb Company.: Other: Data Safetly and Monitoring. Dahi: Kite / Gilead: Membership on an entity's Board of Directors or advisory committees. Chen: Gamida: Consultancy; Incyte: Consultancy. Herrera: ADC Therapeutics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Tubulis: Consultancy; Kite, a Gilead Company: Research Funding; Seagen: Consultancy, Research Funding; Takeda: Consultancy; Gilead Sciences: Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm: Consultancy; Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Armand: IGM: Research Funding; Tensha: Research Funding; Roche: Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Regeneron: Consultancy; Epizyme: Consultancy; Enterome: Consultancy; Daiichi Sankyo: Consultancy; Miltenyi: Consultancy; Tessa Therapeutics: Consultancy; GenMab: Consultancy; C4: Consultancy; Kite: Research Funding; Pfizer: Consultancy; Infinity: Consultancy; Otsuka: Research Funding; Sigma Tau: Research Funding; Morphosys: Consultancy; Celgene: Consultancy; ADC Therapeutics: Consultancy; Adaptive: Consultancy, Research Funding; Affimed: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding.