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2943 Quantitative Baseline Circulating Tumor DNA Levels Correlate with GM-CSF Response to Idiotype Vaccine in Untreated Mantle Cell Lymphoma

Lymphoma Biology—Non-Genetic Studies
Program: Oral and Poster Abstracts
Session: 622. Lymphoma Biology—Non-Genetic Studies: Poster II
Sunday, December 4, 2016, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Mark Roschewski, MD1, Kieron Dunleavy, MD1, Sattva S. Neelapu, MD2, Stefania Pittaluga, MD, PhD3, Christopher Joseph Melani, MD4, Elaine S. Jaffe, MD3, Margaret Shovlin, RN1*, Beryl Crossley, BS5*, Katie Kong, BS6*, Allison Jacob, MD5*, Larry Kwak7* and Wyndham H. Wilson, MD, PhD1

1Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
2Department of Lymphoma and Myeloma, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX
3Laboratory of Pathology, Clinical Center, National Cancer Institute, National Institutes of Health, Bethesda, MD
4Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
5Adaptive Biotechnologies, Seattle, WA
6Adaptive Biotechnologies, South San Francisco, CA
7Department of Hematology and Hematopietic Cell Transplantation, City of Hope, Duarte, CA

Background: Mantle cell lymphoma (MCL) is an incurable lymphoma that responds to various forms of immunotherapy. Previously, we reported that specific anti-idiotype tumor responses as measured by GM-CSF levels after vaccine were associated with overall survival (OS) and time to next treatment (TTNT) following DA-EPOCH-R in untreated MCL at 11 years of follow-up (Dunleavy ASCO 2012). Levels of GM-CSF prior to idiotype vaccine also were correlated with post-vaccine GM-CSF levels suggesting that pre-existing anti-tumor immune response predict idiotype vaccine responsiveness. High-throughput DNA sequencing methods can detect and quantify circulating tumor-specific DNA (ctDNA) in peripheral blood of MCL patients prior to therapy and can be monitored for clearance after therapy. We hypothesized that pre-treatment ctDNA levels may be a surrogate marker for ongoing host anti-tumor immunity. Here, we analyzed the relationship of pre- and post-treatment levels of ctDNA to predict GM-CSF response and clinical outcomes in untreated MCL.

Methods: DA-EPOCH-R was administered x 6, followed by 5 cycles of Id-vaccine beginning at least 12 weeks later in untreated MCL. Id protein was produced by hybridoma technology, conjugated to keyhole limpet hemocyanin (KLH), and administered together with GM-CSF x 5 over 6 months. Pre- and post-vaccine samples were tested in parallel to assess humoral and cellular immune responses. Pre-treatment formalin-fixed paraffin embedded tissue specimens were de-identified and sent for identification of tumor-specific clonotypes. Tumor DNA was amplified using locus-specific primer sets for the immunoglobulin heavy-chain locus (IGH) complete (IGH-VDJH), IGH incomplete (IGH-DJH), and immunoglobulin k locus (IGK). Amplified products were sequenced and tumor-specific clonotypes were quantitated in peripheral blood mononuclear cells before treatment as ctDNA and after treatment as MRD.

Results: Characteristics of all 26 pts: median age 57 (r 22-73), male sex 73%, PS 1 (0-2), MIPI (low-65%; interm-16%; high-19%), and blastoid 15%. Responses to DA-EPOCH-R: CR-92%, PR-8%. Immune analyses were performed in 24 pts; vaccine not produced in 1 pt and 1 pt progressed before immune analyses. Baseline tumor was available for clonotype calibration in 20 patients. With a potential follow-up of 14 years, the median OS of the entire cohort is 9.0 years and 10/26 (38%) patients are still alive. Pre-treatment levels of ctDNA were inversely correlated with normalized antitumor GM-CSF response (r=0.49, p=0.035) but not with white blood cell count (r=0.18, p=0.46), LDH (r=0.21, p=0.39) or MIPI scores (r=22, p=0.37). Patients with low pre-treatment ctDNA levels had longer OS than patients with high levels of ctDNA, but this did not reach statistical significance (11.01 y vs. 5.71 y, p=0.67). Eight of 20 of patients (40%) were MRD positive after DA-EPOCH-R despite achieving CR/CRu. Patients who achieved MRD-zero had a trend towards improved OS (NR vs. 8.2 years, p=0.15).

Conclusions: Lower pre-treatment ctDNA levels correlate with normalized GM-CSF response to idiotype vaccine and may be a surrogate marker of ongoing host anti-tumor immunity. In this small study, ctDNA levels did not correlate with traditional markers of tumor proliferation. There is a trend towards improvement in OS in patients who achieve MRD-zero. Future studies are underway to explore the biologic significance of pre- and post-treatment ctDNA levels in MCL.

This work was supported by the Intramural Research Program of NCI at NIH and Adaptive Biotechnologies, Inc.

Disclosures: Crossley: Adaptive: Employment, Equity Ownership. Kong: Adaptive: Employment, Equity Ownership. Jacob: Adaptive: Employment, Equity Ownership. Kwak: Celltrion, Inc.: Consultancy.

*signifies non-member of ASH