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3090 DA-EPOCH-R for High Grade B-Cell Lymphoma Patients with MYC and BCL2 and/or BCL6 Rearrangements: Clinical Results of the Induction Phase of the HOVON-152 Trial

Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphomas: Prospective Therapeutic Trials: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, adult, Lymphomas, non-Hodgkin lymphoma, Non-Biological therapies, Clinical Research, B Cell lymphoma, Chemotherapy, Diseases, aggressive lymphoma, Therapies, Lymphoid Malignancies, Adverse Events, Monoclonal Antibody Therapy, Study Population, Human
Sunday, December 10, 2023, 6:00 PM-8:00 PM

A. De Jonge1,2*, Marie José Kersten, MD, PhD1,3, Erik van Werkhoven, MSc4,5*, Marjolein van der Poel, MD PhD6*, Koen de Heer, MD7*, Clara Klerk, MD PhD8*, Yorick Sandberg, MD PhD9*, Rozemarijn S Van Rijn, MD, PhD10*, Rob Fijnheer, MD PhD11*, Pim Mutsaers, MD12*, Vibeke Vergote, MD13*, Djamila Issa, MD PhD14*, Aart Beeker, MD15, Yavuz M. Bilgin, MD PhD16*, Lara H. Böhmer, MD17*, Laurens Nieuwenhuizen, MD PhD18*, Wendy Stevens, MD19*, Roel JW van Kampen, MD PhD20, Rogier Mous, MD PhD21*, Marc Durian, MD22*, Tjeerd Snijders, MD23*, Joost S.P Vermaat, MD, PhD, MSc24, Otto Visser, MD PhD25*, Josée M. Zijlstra, MD, PhD26,27, Henk Hofwegen5*, Helma G.J.M. Zanders5*, Liping P. Fu28*, Daphne De Jong, MD PhD29*, Marcel Nijland, MD PhD30* and Martine E.D. Chamuleau, MD PhD1,2

1Cancer Biology and Immunology, Cancer Center Amsterdam, Amsterdam, Netherlands
2Department of Hematology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, Netherlands
3Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
4Department of Hematology, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands
5HOVON foundation, Rotterdam, Netherlands
6Department of Internal Medicine, Division of Hematology, Maastricht University Medical Center, Maastricht, Netherlands
7Department of Internal Medicine, Flevoziekenhuis, Almere, Netherlands
8Department of Internal Medicine, Dijklanderziekenhuis, Hoorn, NLD
9Department of Internal Medicine, Maasstad Hospital, Rotterdam, Netherlands
10Department of Hematology, Medical Center Leeuwarden, Leeuwarden, Netherlands
11Department of Internal Medicine, Meander Medisch Centrum, Amersfoort, Netherlands
12Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
13Department of Hematology, University Hospitals Leuven, Leuven, BEL
14Department of Internal Medicine, Jeroen Bosch Hospital, Den Bosch, Netherlands
15Spaarne Ziekenhuis, Hoofddorp, Netherlands
16Department of Internal Medicine, Adrz, Goes, Netherlands
17Department of Hematology, Haga Teaching Hospital, The Hague, Netherlands
18Department of Internal Medicine, Máxima Medisch Centrum, Eindhoven, Netherlands
19Department of Hematology, Radboud University Medical Center, Nijmegen, Netherlands
20Department of Internal Medicine, Zuyderland Medical Center, Sittard-Geleen, Netherlands
21Department of Hematology, University Medical Center Utrecht, Utrecht, Netherlands
22Department of Internal medicine, Elisabeth-TweeSteden Ziekenhuis, Tilburg, NLD
23Department of Internal medicine, Medisch Spectrum Twente, Enschede, Netherlands
24Leiden University Medical Center, Leiden, Netherlands
25Department of Hematology, Isala Hospital, Zwolle, Netherlands
26Cancer Center Amsterdam, Imaging, Amsterdam, Netherlands
27Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
28Department of Pathology, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, Netherlands
29Department of Pathology, Amsterdam UMC Location Vrije Universiteit, Amsterdam, Netherlands
30Department of Hematology, University Medical Center Groningen, Groningen, Netherlands


Patients (pts) with high grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 gene rearrangements (double hit and triple hit (DH/TH)) have poor outcomes to standard R-CHOP. Retrospective studies reported improved disease-free survival (DFS) through intensification with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). This regimen was studied in a small prospective trial including 24 DH/TH and 19 single MYC rearranged (SH) lymphomas (Dunleavy, Lancet Haematol 2019). No prospective studies evaluating DA-EPOCH-R exclusively for pts with DH/TH HGBL have been reported.

The HOVON-152 trial aimed to improve outcomes in untreated DH/TH HGBL pts by investigating the efficacy of the immune checkpoint inhibitor nivolumab as consolidation treatment in pts achieving complete metabolic response (CMR) after DA-EPOCH-R induction. Here, we present the efficacy and safety profile of the induction phase with DA-EPOCH-R.


HOVON-152 is a prospective, multi-center, single arm phase II trial. Inclusion criteria were pts with newly diagnosed HGBL-DH/TH (according to the WHO 2016 classification), age ≥ 18 years, WHO performance status (PS) 0-3 and Ann Arbor stage II-IV. During the screening period for rearrangement status, pts could receive 1 cycle of R-CHOP or DA-EPOCH-R, followed by 5 cycles of DA-EPOCH-R. All pts received intrathecal CNS prophylaxis.

All diagnostic lymphoma samples were centrally reviewed. PET-CT scans were performed at diagnosis, after 3 cycles and at end-of-induction (local review, central review will be reported at the conference). Pts in CMR after induction treatment (Deauville 1-3 or a negative lymphoma biopsy in case of Deauville 4) proceeded to nivolumab consolidation (480 mg every 4 weeks for one year).

The HOVON-152 aimed to improve 12 months DFS of pts in CMR after induction from an expected 70% to 85% with nivolumab consolidation. Secondary objectives included evaluation of response rates, overall survival (OS) and safety. With a power of 0.90 a sample size of 97 pts was calculated.

Here, we report efficacy (CMR rate) and safety of DA-EPOCH-R induction treatment. Logistic univariate analysis is used to analyze baseline characteristics associated with response. Adverse events (AEs) were defined according to the common terminology criteria for adverse events (CTC AE 5.0), counted by the highest grade per system organ class per patient.


From August 2018 - March 2022, 97 pts have been enrolled (study inclusion completed). One patient was excluded due to CNS localization. The median age was 62 years (range 35-79); 90 (83%) pts had stage III-IV disease and 52 (54%) had (intermediate-)high international prognostic index (IPI) (Table 1). Central pathology review confirmed DH/TH in all pts. 65 pts (67%) had a BCL2 DH, 11 (12%) a BCL6 DH and 16 (17%) a TH.

Dose adjustments were performed conform protocol. The maximum dose-level (DL) achieved was DL1 in 41 (43%), DL2 in 22 (23%), DL3 in 25 (25%), DL4 in 7 (7%) and DL5 in 1 (1%) of the pts. Vincristine dose was reduced in 28/81 (35%) pts.

After DA-EPOCH-R induction, 63/96 (66%, 95% CI 55-75%) pts achieved CMR. WHO PS 2-3 (odds ratio (OR) 0.15, 95% CI 0.03-0.85, p=0.03), elevated LDH (OR 0.24, 95%CI 0.10-0.59, p=0.002) and bulky disease defined as ≥10 cm mass (OR 0.23, 95%CI 0.09-0.56, p=0.001), were significantly associated with a lower chance of achieving CMR.

During treatment, 7 (7%) pts experienced a grade 5 AE (ileus, intestinal perforation, multi-organ failure/sepsis). Thereof, 4 patients died during DA-EPOCH-R and 3 patients died after DA-EPOCH-R. 31 (32%) experienced a grade 4 AE (e.g. sepsis, perforation, hemorrhage, thrombocytopenia and neutropenia), 21 (22%) a grade 3 AE (e.g. anemia, mucositis, infections and electrolyte disturbances) and 16 (17%) pts a grade 2 AE.


We report the largest prospective series of DH/TH HGBL patients treated with DA-EPOCH-R. DA-EPOCH-R induction was feasible, with toxicity and dose adjustments as previously described. The observed CMR rate of 66% was lower than previously reported in a prospective cohort of mixed DH/TH and SH patients (74%).

For patients achieving CMR, the nivolumab consolidation phase is ongoing. Translational side studies investigating predictive factors to identify patients not achieving CMR are ongoing. For these patients, novel strategies to improve first-line treatment are warranted.

Disclosures: Kersten: Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support; Miltenyi Biotech: Consultancy, Honoraria, Other: travel support; Adicet Bio: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; BeiGene: Other: Travel support; Galapagos: Research Funding. Mutsaers: AstraZeneca: Research Funding; GlaxoSmithKline: Consultancy. Vergote: Beigene: Other: Consultancy / advisory board; Cellgene: Other: Consultancy / advisory board; Gilead: Other: Consultancy / advisory board, travel support; Roche: Other: Consultancy / advisory board; Lilly Oncology: Other: Consultancy / advisory board; Abbvie: Other: Consultancy / advisory board, travel support; Amgen: Other: Travel support; Janssen: Other: Speaker fee. Chamuleau: BMS/Celgene: Honoraria, Research Funding; Genmab: Research Funding; Gilead: Research Funding; Roche: Honoraria; Abbvie: Honoraria; Novartis: Honoraria.

OffLabel Disclosure: Nivolumab to prolong disease free survival in DH/TH high grade B-cell lymphoma

*signifies non-member of ASH