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1664 Extended Follow up and Immune Alterations in Patients with Classic Hodgkin Lymphoma (cHL) Treated with Frontline Single Agent Pembrolizumab Followed By AVD Chemotherapy

Program: Oral and Poster Abstracts
Session: 624. Hodgkin Lymphomas: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Combination therapy, Clinical trials, Research, Clinical Research, Treatment Considerations, Study Population, Human
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Pamela B. Allen, MD1, Latifa Bazzi, PhD2*, Bin Zhang, MD, PhD3*, Qing Chen, MD, PhD4*, Liron Barnea Slonim, MD4*, Hatice Savas, MD5*, Ranjana H. Advani, MD6, Andrew M Evens, DO MBA MSc7, Barbara Pro, MD8, Reem Karmali, MD9, Eric Mou, MD10*, Robert Eisner, DO11, Robert Bayer, MD11*, Leo I. Gordon, MD12 and Jane N. Winter, MD13*

1Department of Hematology, Emory University School of Medicine, Decatur, GA
2Biostatistics, Northwestern, Chicago, IL
3Department of Medicine, Division of Hematology Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL
4Pathology, Northwestern, Chicago, IL
5Radiology, Northwestern, Chicago, IL
6Department of Medicine, Division of Oncology and Hematology, Stanford University, Stanford, CA
7Rutgers Cancer Institute, New Brunswick, NJ
8Lymphoma Program, Division of Hematology & Oncology, Columbia University, New York, NY
9Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL
10Division of Hematology, Oncology, and Blood & Marrow Transplantation, University of Iowa, Iowa City, IA
11Feinberg School of Medicine, Northwestern University, Chicago, IL
12Northwestern University, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL
13Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL

Background:

Hodgkin cells evade immune response through several mechanisms including overexpression of PD-L1/2, reduction of MHC expression, production of indolamine (IDO), secretion of inhibitory cytokines, and alterations to the microenvironment. We conducted a phase 2 clinical trial of sequential pembrolizumab x 3 followed by doxorubicin, vinblastine, dacarbazine (AVD) chemotherapy (4-6 cycles) for newly diagnosed early unfavorable or advanced stage cHL. Interim response to single agent anti PD-1 therapy was assessed by PET-CT and by decline in metabolic tumor volume (MTV). We report the results of changes in cytokine levels and response to PD-1 blockade and survival outcomes following extended follow up of > 5 years.


Methods:

Levels of plasma soluble cytokines and other mediators including IFN-γ, IL-10, IL-13, IL-2, IDO, LAP, PDL1, TARC (CCL17), TNF-α, and Galectin-1 were measured by Luminex using ProcartaPlex kits (ThermoFisher) according to the manufacturer’s instructions. All standards and samples were measured in duplicates pre-treatment, following single agent PEM, and after AVD. Pre-treatment diagnostic biopsy specimens were double stained for PD-L1 (E1L3N, XP Cell Signaling) and PAX5, and scored by two expert hematopathologists (QC LBS).

Response by metabolic tumor volume (MTV) was defined as complete metabolic response (CMR), ≥ 90% reduction by MTV (near CMR; nCMR), or < 90% reduction by MTV (partial response; PR). Patients were categorized as excellent responders (CMR or nCMR) versus others (PR). Changes in biomarkers were calculated as percentage change from pre-treatment to post-pembrolizumab and from post-pembrolizumab to post-chemotherapy. Percentage changes were classified as increase (≥ 25%), decrease (≤ -25%), or stable. Comparisons between patients with PR versus CMR/nCMR were calculated with Wilcoxon rank sum and Fisher’s exact tests. Additionally, we assessed levels of soluble PD-L1 as well as the relationship between baseline levels of cytokines and PDL-1 expression in Reed-Sternberg (RS) cells by H-score.

Results:

Thirty patients were enrolled from September 2017 through August 1, 2019. Response to single agent PD-1 was PR in 11 (36.7%), nCMR in 8 (26.7%), and CMR in 11 (36.7%). The updated median follow-up is 67.6 (range: 59.3-80.4) months. No patients have relapsed or died, for a PFS and OS of 100%.

Twenty-eight patients had peripheral blood available for cytokine analysis. There was no association between baseline levels of TNF‐α, IFN‐γ, TGF‐β, IL-10, IL-13, Galectin-1, IDO, TARC, or soluble PDL-1 and response to single agent pembrolizumab.

Following single agent pembrolizumab changes in cytokine levels by response (CMR/nCMR vs PR) showed that all PRs had stable or a decline in TNF‐α, IFN‐γ, TGF‐β, IL-10, IL-13, and IDO levels. In contrast, among the 18 patients with CMR/nCMR variable increase in cytokines was observed: TNF‐α increased in 1 pt (5.6%), IFN‐γ increased in 6 pts (33%), TGF‐β increased in 2 pts (11%), IL-10 increased in 3 pts (17%), and both IL-13 and IDO increased in 5 pts (28%). Following sequential chemotherapy there was no association between responses and cytokine alterations. Soluble PD-L1 was undetectable in 26/28 (93%) pts at one time point and in 18 pts at all three time points evaluated. On H-scoring there was no association with any of the cytokine’s levels at baseline and PDL-1 expression in Reed Sternberg cells.


Conclusions:

Mature data with > 5 year median follow-up confirm that sequential pembrolizumab and AVD chemotherapy remains a highly effective treatment with 100% PFS and OS. Baseline cytokine levels were not predictive of outcomes. Patients with PRs to Pembrolizumab monotherapy uniformly had a decline in cytokine levels while most with excellent responses (CMR/nCMR) had variability with most cytokines declining and some increasing. Further investigation is required to understand the implications of these findings for pembrolizumab-based therapy in cHL.

Disclosures: Allen: Kyowa Kirin: Consultancy; ADC Therapeutics: Consultancy; Secure Bio: Consultancy. Advani: BeiGene: Honoraria, Other: DSMB/Advisory Boards, Research Funding; ADCT: Honoraria, Other: DSMB/Advisory Boards; Cyteir: Research Funding; Merck: Other: Steering committee, DSMB/Advisory Boards, Research Funding; Gilead: Research Funding; Regeneron: Research Funding; Autolus: Honoraria, Other: DSMB/Advisory Boards; Seattle Genetics: Research Funding; Roche/Genentech: Honoraria, Other: Steering committee, DSMB/Advisory Boards, Research Funding. Evens: Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Pro: ONO pharma USA: Research Funding; SciTech: Research Funding; Takeda, Seattle Genetics, Celgene, Verastem, Astex: Consultancy. Karmali: Incyte: Speakers Bureau; AstraZeneca: Speakers Bureau; Ipsen: Speakers Bureau; Abbvie: Honoraria; Genmab: Honoraria; Genentech/Roche: Honoraria; BMS: Honoraria; BeiGene: Speakers Bureau. Gordon: Janssen: Other: data and safety monitoring board ; nanoparticles for cancer therapy (HDL NP As Inducers of Ferroptosis in Cancer, PCT/US2020/051549; b) Nanostructures for Treating Cancer and Other Conditions, PCT/UlllllLS2013/027431): Patents & Royalties: nanoparticles for cancer therapy (HDL NP As Inducers of Ferroptosis in Cancer, PCT/US2020/051549; b) Nanostructures for Treating Cancer and Other Conditions, PCT/UlllllLS2013/027431); Ono Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb, Kite Pharmaceuticals: Other: Advisory board.

*signifies non-member of ASH