Retreatment with R-CHOP-like Therapy Is Active with Durable Responses in Patients with Late Relapse of Diffuse Large B-Cell Lymphoma

Background

Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, relapses after >2 years in 10% of patients (pts) defined as late-relapse (LR DLBCL) and is often treated with high dose immunochemotherapy (HD ICP) followed by stem cell transplant (SCT). LR DLBCL may be genetically distinct from the initial DLBCL, and thus potentially chemotherapy naïve (PMID: 37319384). Retreatment with first-line (1L) regimen with curative intent may be feasible while avoiding HD ICP toxicity. We aimed to retrospectively analyze outcomes of LR DLBCL retreatment in a single-institution cohort.

Methods

We evaluated 199 pts diagnosed with LR DLBCL between 01/2010 and 12/2023 at MD Anderson Cancer Center and included 21 pts that received second- or third- line (2L, 3L) rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-like therapy. Parameters included age, gender, stage, IPI score, cell of origin (COO), BCL-2, BCL-6, and MYC by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), therapies, and response. Primary endpoints were complete remission (CR) rate, 2-year progression-free survival (PFS) and 2-year overall survival (OS) after 2L R-CHOP-like therapy, using Kaplan-Meier method and the univariable Cox regression analysis (UVA). Missing data were handled with complete case analysis.

Results

Among 21 pts, median age was 62 (54-80), 9 (43%) were female and 13 (62%) non-Hispanic white. At initial presentation 12 pts (63%) had stage III-IV, 19 (95%) PS ECOG 0-1, 12 (67%) extranodal involvement (ENI), 7 (58%) high LDH, 4 (33%) high IPI (3-5), 7 (54%) germinal center B-cell (GCB) subtype, 5 (26%) transformed, 1 (5%) high-grade B-cell lymphoma (HGBCL). By IHC, 9 (82%), 9 (75%), and 2 (67%) were BCL2, BCL6, MYC positive, respectively. By FISH, 3 (75%), 2 (50%) and 1 (11%) were BCL2, BCL6, MYC positive, respectively. For 1L therapy, 12 (57%) pts received R-CHOP, 5 (24%) R-EPOCH, and 1 each (5%) R-CHOP+Bortezomib, R-CEOP, R-CVP and R-Cytoxan/Gemzar/Vincristine, with the median number of cycles of 6 (3-8). All pts achieved 1L CR, which included consolidative radiation (5 pts, 24%) and autologous SCT (1 pt, 5%).

The median time from initial DLBCL to LR DLBCL was 87.5 months (25.1-148.9). The median age at LR DLBCL diagnosis was 70 (58-88), 16 pts (76%) had stage III-IV, 20 (100%) PS ECOG 0-1, 11 (54%) ENI, 14 (67%) high LDH, 11 (55%) high IPI, 11 (65%) GCB subtype, 7 (35%) transformed, 2 (12%) HGBCL. By IHC, 15 (88%), 15 (94%), and 9 (64%) were BCL2, BCL6, and MYC positive, respectively. By FISH, 3 (43%), 5 (71%) and 3 (23%) were BCL2, BCL6, and MYC positive, respectively. Change between initial DLBCL and LR DLBCL occurred for COO in 4 pts; BCL2, BCL6 and MYC by IHC in 2 pts each; MYC by FISH in 1 pt; transformation in 3 pts. For LR DLBCL therapy, 6 pts (29%) received R-CHOP or R-EPOCH for 2-4 cycles followed by R-CEOP; 3 (14%), 4 (19%), and 4 pts received R-CHOP, R-CEOP and R-EPOCH only, respectively; 1 pt (5%) each received R-EPOCH for 2 cycles followed by R-CHOP, Polatuzumab-R-CHP for 2 cycles followed by R-CEOP, and R-CHOP + novel agent. One pt (5%) received R-CEOP with ibrutinib and lenalidomide in 3L. The median number of cycles was 5 (2-6). 2 pts (10%) had consolidative radiation and 1 pt (5%) had autologous SCT.

The CR rate for retreatment was 85.7% (95% CI: 64-97%). At a median follow up of 30.5 months (17.4-51.5), the estimated 2-year PFS was 54% (95% CI: 35-81%) with median not reached and the 2-year OS was 68% (95% CI: 48-96%). 1 pt (5%) had a relapse ~2.5 years after retreatment and 2 pts (10%) had central nervous system relapse. 6 pts (29%) received CAR T-cell therapy in 3L. 2 pts (12%) developed grade I diastolic dysfunction and none developed leukemias. Deaths after 2 years were not lymphoma related.

By UVA, involvement of >1 EN site and high IPI at retreatment were associated with inferior PFS (HR= 2.52, p=0.01 and HR=2.03, p=0.04, respectively).

Conclusion

Pts with LR DLBCL retreated with an R-CHOP-like regimen have outcomes comparable to historic 1L R-CHOP therapy (PMID: 16754935), including CR rates and response durability. This supports the hypothesis that LR DLBCL may represent a genetically distinct and therapy naïve disease, potentially allowing for avoidance of HD-ICP toxicity. R-CHOP-like retreatment followed by response assessment after 2 cycles, and continuation if CR or CAR T-cell therapy if progression of disease, should be further evaluated in larger studies.

Chihara:Ono pharmaceutical: Research Funding; MorPhosys: Research Funding; BMS: Research Funding; Genmab: Research Funding; BeiGene: Honoraria; SymBio pharmaceutical: Honoraria. Ahmed:Bristol Myers Squibb: Research Funding; Merck: Research Funding; Nektar: Research Funding; Xencor: Research Funding; Myeloid Therapeutics: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Research Funding; ADC Therapeutics: Consultancy. Iyer:Yingli: Membership on an entity's Board of Directors or advisory committees, Research Funding; Secura Bio: Membership on an entity's Board of Directors or advisory committees; Legend: Research Funding; Salarius: Consultancy; IMPaRT.AI: Other: Stock, Founder; Crispr: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acrotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate: Research Funding; Ono: Research Funding; Trillium: Research Funding; Merck: Research Funding; Seagen/Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; JCO-CCI: Other: Editor. Neelapu:Fosun Kite: Consultancy; GlaxoSmithKline: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Sellas Life Sciences: Consultancy; Synthekine: Consultancy; Sana Biotechnology: Consultancy, Research Funding; Caribou Biosciences: Consultancy; MorphoSys: Consultancy; Takeda: Consultancy; Allogene: Consultancy, Research Funding; Anthenex: Consultancy; Janssen: Consultancy; Incyte: Consultancy; bluebird bio: Consultancy; Adicet Bio: Consultancy, Research Funding; Athenex: Consultancy; Orna Therapeutics: Consultancy; Merck: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; ImmunoACT: Consultancy; Chimagen: Consultancy; Carsgen: Consultancy; Astellas Pharma: Consultancy; Appia Bio: Consultancy; Precision Biosciences: Research Funding; Cargo Therapeutics: Research Funding; Longbow Immunotherapy: Current holder of stock options in a privately-held company. Fayad:Roche/Genentech: Research Funding; M.D. Anderson Cancer Center: Current Employment. Wang:MSC National Research Institute of Oncology: Honoraria; Merck: Consultancy, Honoraria; Physicians Education Resources: Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Nurix: Honoraria; NIH: Honoraria; MJH Life Sciences: Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Genmab: Honoraria, Research Funding; Dava Oncology: Honoraria; Catamount Medical Education: Honoraria; Research to Practice: Honoraria; Scripps: Honoraria; Studio ER Congressi: Honoraria; South African Clinical Hematology Society: Honoraria; WedMD: Honoraria; ADC Therapeutics: Consultancy; Amphista Therapeutics Limited: Consultancy; bE Biopharma: Consultancy; InnoCare: Consultancy, Research Funding; Deciphera: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Lilly: Consultancy, Research Funding; Miltenyi Biomedicine: Consultancy; Oncternal: Consultancy, Research Funding; Praxel: Consultancy; Pepromene Oncology: Consultancy; Juno Therapeutics: Research Funding; CAHON: Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; BioInvent: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Strati:Sobi ADC Therapeutics: Consultancy, Other: Travel, accommodations, expenses, Research Funding; Kite, a Gilead company: Consultancy, Research Funding; Roche-Genentech: Consultancy; ALX Oncology: Research Funding; Ipsen: Consultancy; Hutchison MediPharma: Consultancy; TG Therapeutics: Consultancy; Acerta-Astrazeneca: Consultancy, Research Funding; Abbvie-Genmab: Consultancy. Vega:Geron Corporation: Research Funding; Caribou: Research Funding; Allogene: Research Funding. Flowers:TG Therapeutics: Research Funding; Bristol Myers Squibb: Consultancy; Sanofi: Research Funding; Bio Ascend: Consultancy; Ziopharm National Cancer Institute: Research Funding; BostonGene: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; 4D: Research Funding; Acerta: Research Funding; Adaptimmune: Research Funding; Allogene: Research Funding; Amgen: Research Funding; Cellectis: Research Funding; Guardant: Research Funding; Iovance: Research Funding; Janssen Pharmaceuticals: Research Funding; Kite: Research Funding; Morphosys: Research Funding; Nektar: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Takeda: Research Funding; Xencor: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; EMD Serono: Research Funding; AstraZeneca: Consultancy; BeiGene: Consultancy; Celgene: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Genentech/Roche: Consultancy, Research Funding; Genmab: Consultancy; Gilead: Consultancy, Research Funding; Karyopharm: Consultancy; N-Power Medicine: Consultancy, Current holder of stock options in a privately-held company; Pharmacyclics / Janssen: Consultancy; Seagen: Consultancy; Spectrum: Consultancy; Bayer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Westin:AstraZeneca: Consultancy, Research Funding; Morphosys/Incyte: Consultancy, Research Funding; Allogene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Kite/Gilead: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Nurix: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy; Regeneron: Consultancy; Novartis: Consultancy, Research Funding; AbbVie/GenMab: Consultancy.