Outcomes in Early Relapse of Follicular Lymphoma Versus Early Histologic Transformation Following Firstline Immunochemotherapy in Follicular Lymphoma

Background: Approximately20% of patients with follicular lymphoma (FL) will experience disease progression or death within two years of years (POD24) of immunochemotherapy (IC) (Casulo et al, JCO 2015). A proportion of patients with POD24 have histologic transformation (HT), which heightens the risk of lymphoma-related death (Freeman et al, Blood 2019). To clarify the impact of HT on prognosis in POD24, we analyzed data from the Lymphoma Epidemiology of Outcomes (LEO) Consortium of Real-World Evidence (CReWE) to compare differences in outcomes among patients with POD24 with retained FL histology versus POD24 with HT.

Methods: This was a multicenter study among 8 academic cancer centers. Eligible patients hadgrade 1-3a FL at diagnosis between 2003 and 2022, with POD24 following first line IC treatment with BR, R-CHOP, or R-CVP. POD24 was defined as disease recurrence within 24 months of IC. Patients with prior lines of treatment for FL were excluded. Patients with HT at first line IC were excluded. Biopsy at POD24 was obtained at the discretion of the treating physician. Three groups of POD24 were defined: POD24 with biopsy-proven retained FL histology (POD24_FL), POD24 with biopsy-proven HT to aggressive lymphoma (POD24_HT), and POD24 either without a biopsy or indeterminate histology on biopsy (POD24_I). We evaluated second-line treatments at time of POD24. Survival probabilities from second-line treatment initiation were estimated by the Kaplan-Meier method.

Results A total of1,122 patients with FL were screened and308 patients with POD24 were identified.Median age at POD24 was 58 years (IQR 50-65).Among available data, race and ethnicity was reported as 76% non-Hispanic White, 3% non-Hispanic Black/African American, 9% Hispanic/Latino (any race), and 1% other minorities. First line therapy was R-CHOP in45% (140/308), BR in 33% (102/308) and R-CVP in 21% (66/308). Most patients (52%) had biopsy-proven retained FL at POD24 (162/308); 30% had no biopsy or indeterminate histology at POD24 (94/308), and 17% had biopsy-proven HT at POD24 (52/308). In the POD24_HT group, 52% received R-CHOP and 21% received intensive salvage chemotherapy as second line therapy. Patients with POD24_FL and POD24_I had similar rates of salvage chemotherapy (21% and 18%), BR (13% and 18%), R-CHOP (19% and 24%), and targeted therapies (8% and 5%), respectively, at second line. Consolidative autologous stem cell transplant was more common in POD24_HT patients at 21% versus 16% in POD24_FL and 6% in POD24_I.

Patients with POD24_HT had significantly worse overall survival (OS) compared to POD24_FL (ref), with a hazard ratio of 3.79 (95% confidence interval [CI] 2.46-5.84), even after adjusting for age, FLIPI score, and first-line IC treatment. At 5 years, patients with POD24_HT had OS of 31% compared with an OS of 71% for patients with POD24_FL. Patients with POD24_I had similar outcomes to those with POD24_FL (5-year OS 75% versus 71%, respectively). Event-free survival (EFS) was also significantly lower in POD24_HT compared to POD24_FL: At 2 years, EFS was 27% for POD24_FL (21-35%) and 10% for POD24 _HT (4-23%). At 5 years, lymphoma remained the leading cause of death among patients with POD24, with 20% probability of lymphoma-related death in those with POD24_FL (95% CI 14.2-27.8) compared to 53% probability of lymphoma-related death in patients with POD24_HT (95% CI 40.6-70.7).

Conclusions: In our multicenter cohort, we identified remarkable differences between the two biopsy-demonstrated entities of POD24 (i.e., with and without HT). Patients without a biopsy or indeterminate histology had similar outcomes as those with POD24_FL. Patients withearlyrelapse of FL after first-line IC remain a heterogeneous group with poor outcomes and a heightened risk of lymphoma-related mortality particularly compared with nonPOD24 groups. Even with retained FL histology, patients with POD24 had 20% probability of lymphoma-related death within 5 years of second-line treatment initiation. We demonstrate that poor survival is driven in part, but not entirely, by HT. Despite most patients receiving appropriate aggressive treatment, those with POD24_HT represent a distinctly vulnerable population warranting further study in directed prospective studies of both FL biology and clinical trials.

Casulo:Verastem: Research Funding; Gilead Sciences, Secura Bio: Research Funding; AbbVie: Consultancy, Honoraria; Genmab: Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Tsang:Novartis: Other: Advisory Board; AstraZeneca: Other: Advisory Board; AVEO: Other: Prior holder of stock options in a privately-held company; Poseida Therapeutics: Current holder of stock options in a privately-held company. Nowakowski:Segen: Consultancy; Incyte Corporation: Consultancy; Blueprint Medicines Corporation: Consultancy; Kymera Therapeutics: Consultancy; TG Therapeutics Inc: Consultancy; Daiichi Sankyo: Consultancy; Ryvu Therapeutics: Consultancy; Genentech: Consultancy; MorphoSys AG: Consultancy, Research Funding; Bantam Pharmaceutical, LLC: Consultancy; Curis: Consultancy, Research Funding; Constellation Pharmaceuticals: Consultancy; F. Hoffmann-La Roche Limited: Consultancy; Selvita Inc: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Debiopharm: Consultancy; ADC Therapeutics: Consultancy; Karyopharm Therapeutics: Consultancy; Fate Therapeutics: Consultancy; Zai Laboratory: Consultancy; AbbVie Inc.: Consultancy; MEI Pharma: Consultancy. Koff:AbbVie: Consultancy; BeiGene: Consultancy; Viracta Therapeutics: Research Funding. Chihara:SymBio pharmaceutical: Honoraria; BeiGene: Honoraria; Ono pharmaceutical: Research Funding; MorPhosys: Research Funding; Genmab: Research Funding; BMS: Research Funding. Habermann:Lilly: Other: Data Monitoring Committee. Nastoupil:BMS: Honoraria, Research Funding; Caribou Biosciences: Honoraria, Research Funding; Denovo Biopharma: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria; ADC Therapeutics: Honoraria; Genmab: Honoraria, Research Funding; Gilead Sciences/Kite Pharma: Honoraria, Research Funding; Incyte Corporation: Honoraria; Janssen: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Regeneron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Abbvie, BMS, Caribou Biosciences, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Merck, Novartis, Regeneron, Takeda: Consultancy; BMS, Caribou Biosciences, Daiichi Sankyo, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Merck, Novartis, Takeda: Research Funding; Abbvie, BMS, Caribou Biosciences, Daiichi Sankyo, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Novartis, Takeda: Honoraria. Lossos:Not specified: Patents & Royalties; University of Miami: Current Employment; ADCT: Research Funding. Martin:AbbVie, AstraZeneca, Beigene, Daiichi Sankyo, Genentech, Janssen, Merck, Pepromene: Consultancy. Kahl:Bristol Myers Squibb: Consultancy; Genentech: Consultancy; BeiGene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; AbbVie: Consultancy; Novartis: Consultancy; AstraZeneca: Consultancy, Research Funding; Kite: Consultancy; ADCT: Consultancy; Merck: Consultancy; Lilly: Consultancy. Cerhan:Genentech: Research Funding; Protagonist Therapeutics: Other: SMC; GenMab: Research Funding; BMS: Research Funding. Flowers:4D: Research Funding; Allogene: Research Funding; Xencor: Research Funding; Cellectis: Research Funding; Iovance: Research Funding; Morphosys: Research Funding; Pharmacyclics: Research Funding; Guardant: Research Funding; Sanofi: Research Funding; Amgen: Research Funding; Kite: Research Funding; Janssen Pharmaceuticals: Research Funding; Acerta: Research Funding; TG Therapeutics: Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; BeiGene: Consultancy; AbbVie: Consultancy, Research Funding; Nektar: Research Funding; Pfizer: Research Funding; Adaptimmune: Research Funding; Ziopharm National Cancer Institute: Research Funding; Novartis: Research Funding; Spectrum: Consultancy; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; EMD Serono: Research Funding; BostonGene: Research Funding; Seagen: Consultancy; Pharmacyclics / Janssen: Consultancy; N-Power Medicine: Consultancy, Current holder of stock options in a privately-held company; Karyopharm: Consultancy; Gilead: Consultancy, Research Funding; Genmab: Consultancy; Genentech/Roche: Consultancy, Research Funding; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Denovo Biopharma: Consultancy; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; AstraZeneca: Consultancy; Bio Ascend: Consultancy; Bristol Myers Squibb: Consultancy. Link:Genentech: Research Funding. Maurer:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; GenMab: Research Funding; Roche/Genentech: Research Funding; BMS: Consultancy, Research Funding.