POPULATION-WIDE INTRODUCTION OF DOSE-ADJUSTED EPOCH-R IN HIGH-GRADE B-CELL LYMPHOMA WITH MYC AND BCL2 REARRANGEMENTS WITH DLBCL MORPHOLOGY

Introduction: High-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) has poor outcomes after R-CHOP, prompting dose-intensive chemoimmunotherapy use. However, the benefit is unclear because rarity precluded randomized trials, and retrospective comparisons are confounded by variable selection of tumors for FISH testing and clinical factors influencing patient selection for intensification. In 2015, British Columbia, Canada introduced a population-based guideline to treat fit patients (pts) aged ≤ 75 years (y) with de novo HGBCL-DH-BCL2 tumors of DLBCL morphology with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) alongside routine clinical FISH testing (DA-EPOCH-R era). To assess the impact of the DA-EPOCH-R guideline, we compared the outcomes of HGBCL-DH-BCL2 with DLBCL morphology in the DA-EPOCH-R era to HGBCL-DH-BCL2 identified from a historic province-wide cohort of DLBCL morphology tumors that underwent universal FISH testing in a research setting (historic era, Alduaij et al Blood 2023), while comparing outcomes of DLBCL, NOS treated with R-CHOP as a control population (Figure 1A). We evaluated the prognostic impact of molecular subgroups within HGBCL-DH-BCL2. Given the earlier onset of progression events in HGBCL-DH-BCL2 than DLBCL, NOS after R-CHOP (Rosenwald et al JCO 2019), we compared the prognostic impact of end of treatment (EOT) PET between those entities in the DA-EPOCH-R era.

Methods: Overall survival (OS) was analyzed using Kaplan-Meier with log-rank comparisons. MYC-rearrangement partner loci were determined by breakpoint capture sequencing. DLBCL90 digital gene expression defined dark-zone signature (DZsig) status. EOT response was assessed by the Deauville criteria for positive (D4–5, POS), and negative (D1–3 or X, NEG) scans.

Results: HGBCL-DH-BCL2 versus DLBCL, NOS pts were 66 versus 627 in the DA-EPOCH-R era, and 38 versus 534 in the historic era. 71% of HGBCL-DH-BCL2 pts received DA-EPOCH-R in the DA-EPOCH-R era and 84% received R-CHOP in the historic era. Median (interquartile range) follow-up was 6.2 (5.0–7.6) y in the DA-EPOCH-R era and 15.7 (13.8–16.0) y in the historic era. OS was significantly higher in the DA-EPOCH-R era (2y: 75% versus 47%, p = 0.008, Figure 1B). No difference in 2y OS was found between eras in DLBCL, NOS (78% vs. 76%, p = 0.17, Figure 1C). Among evaluable HGBCL-DH-BCL2 tumors, 43% had IG: MYC and 77% expressed DZsig, both associated with higher 2y OS in the DA-EPOCH-R versus historic era (IG: MYC: 87% vs. 36%, p = 0.01, DZsig: 70% vs. 40%, p = 0.02). 2y OS stratified by EOT PET was similar in HGBCL-DH-BCL2 (NEG: 93% vs. POS: 62% p = 0.006) and DLBCL, NOS (NEG: 90% vs. POS: 62% p < 0.0001).

Conclusion: Introduction of a DA-EPOCH-R guideline was associated with improved real-world outcomes in HGBCL-DH-BCL2 with DLBCL morphology, particularly in IG: MYC and DZsig subgroups. EOT PET was equally prognostic in HGBCL-DH-BCL2 and DLBCL, NOS in the DA-EPOCH-R era.

Research funding declaration: This study was supported by grants from the Canadian Cancer Society Research Institute (704848 and 705288), Genome Canada (4108), Genome British Columbia (171LYM), the Canadian Institutes of Health Research (GPH-129347 and 300738), the Terry Fox Research Institute (1061 and 1043), and the British Columbia Cancer Foundation.

Keywords: aggressive B-cell non-Hodgkin lymphoma; chemotherapy

Potential sources of conflict of interest:

L. H. Sehn

Consultant or advisory role: AbbVie, Acerta, Amgen, Apbiologix, AstraZeneca, Celgene, Chugai, Gilead, Incyte, Janssen, Kite, Karyopharm, Lundbeck, Merck, Morphosys, Roche/Genentech, Sandoz, Seattle Genetics, Servier, Takeda, Teva, TG Therapeutics, and Verastem

Honoraria: AbbVie, Acerta, Amgen, Apbiologix, AstraZeneca, Celgene, Chugai, Gilead, Incyte, Janssen, Kite, Karyopharm, Lundbeck, Merck, Morphosys, Roche/Genentech, Sandoz, Seattle Genetics, Servier, Takeda, Teva, TG Therapeutics, and Verastem

Other remuneration: research funding from Roche/Genentech and Teva

J. Champagne

Honoraria: Beigene

A. Jiang

Other remuneration: named inventor on a patent describing the use of gene expression to subtype aggressive B-cell lymphomas, one of which is licensed to nanoString Technologies.

J. W. Craig

Consultant or advisory role: Bayer

Honoraria: BeiGene

K. J. Savage

Consultant or advisory role: Seagen, Roche, Abbvie, Corvus, Regeneron

Other remuneration: Research support: Bristol Myers Squibb

D. Villa

Consultant or advisory role: AbbVie, Janssen, Kite/Gilead, AstraZeneca, Roche, BeiGene, Bristol Myers Squibb/Celgene, Merck, and Zetagen

Honoraria: AbbVie, Janssen, Kite/Gilead, AstraZeneca, Roche, BeiGene, Bristol Myers Squibb/Celgene, Merck, and Zetagen

Other remuneration: Research funding (to the institution): AstraZeneca and Roche

A. S. Gerrie

Honoraria: AbbVie, AstraZeneca, Janssen, and Beigene

Other remuneration: Research funding (to the institution) from AbbVie, AstraZeneca, Janssen, Roche, and Loxo Oncology

C. L. Freeman

Consultant or advisory role: BMS, Seattle Genetics, Celgene, Abbvie, Sanofi, Incyte, Amgen, and ONK therapeutics & Janssen

Honoraria: BMS, Seattle Genetics, Celgene, Abbvie, Sanofi, Incyte, Amgen, and ONK therapeutics & Janssen

Other remuneration: Research funding from BMS, Janssen and Roche/Genentech

C. Steidl

Consultant or advisory role: Bayer and Eisai

Other remuneration: Research support: Epizyme and Trillium Therapeutics Inc.

D. W. Scott

Consultant or advisory role: AbbVie, AstraZeneca, GenMab, Incyte, Roche, and Veracyte

Other remuneration: Research funding: Janssen and Roche/Genentech; and named inventor on a patent describing the use of gene expression to subtype aggressive B-cell lymphomas, one of which is licensed to nanoString Technologies.