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3019 Ibrutinib in Combination with R-Gemox-D in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: Phase II Clinical Trial of the Geltamo Group

Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Poster III
Hematology Disease Topics & Pathways:
Biological, antibodies, Diseases, Combinations, Therapies, Non-Hodgkin Lymphoma, DLBCL, immunotherapy, Lymphoid Malignancies
Monday, December 7, 2020, 7:00 AM-3:30 PM

Beatriz Rey Búa1*, Ana Jiménez Ubieto, MD PhD2*, Jose Javier Sanchez Blanco3*, Pau Abrisqueta, MD, PhD4*, Antonio Gutierrez5*, Angel Ramirez Payer6*, Eva Giné, MD, PhD7, Izaskun Cebeiro Sr.8*, Maria Jose Terol9*, Fatima De la Cruz, MD10*, Rafael Andreu11*, María José Ramírez Sánchez12*, Adolfo de la Fuente13*, Ma Cruz Viguria14*, Maria Jesús Peñarrubia15*, Carlos Grande16*, Dolores Caballero, MD, PhD17 and Alejandro Martin Garcia-Sancho, MD, PhD18*

1Hospital Universitario de Salamanca Hematología. Instituto de investigación biomédica de Salamanca (IBSAL), Salamanca, Spain
2Hematología y Hemoterapia, Hospital 12 de Octubre, Madrid, Spain
3Hospital Morales Messeguer, Murcia, Spain
4Department of Hematology, University Hospital Vall d’Hebron, Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain
5Hematology Department, Son Espases University Hospital/IdISBa, Palma, Spain
6H. C. Asturias, Oviedo, Asturias, Spain
7Hematology Department, Hospital Clinic of Barcelona. IDIBAPS. University of Barcelona, Barcelona, Spain
8H. de Donostia, Donostia, Donostia, Spain
9Hospital Clínico Universitari de València, Valencia, Spain
10Hospital Universitario Virgen del Rocio, Seville, ESP
11Hospital Universitario La Fe de Valencia, VALENCIA, ESP
12H. Especialidades Jerez de la Frontera, Jerez, Jerez, Spain
13MD Anderson Cancer Center, Madrid, Spain
14Complejo Hospitalario de Navarra, Navarra, Spain
15Hospital Clinico Universitario de Valladolid, Valladolid, Spain
16Hospital 12 De Octubre, Madrid, ESP
17Department of Hematology, Hospitalario Universitario de Salamanca (HUS/IBSAL) and CIBERONC, Salamanca, Spain
18Department of Hematology, Hospital Clínico Universitario de Salamanca (CAUSA/IBSAL), Salamanca, Spain


Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), non-candidates for autologous stem-cell transplantation (ASCT), have few treatment options. Ibrutinib is an oral Bruton’s tyrosine kinase inhibitor that has shown increased antitumor activity in patients with DLBCL of different subtype from germinal center B-cell like (non-GCB). In the present phase II clinical trial (NCT02692248), we investigated the efficacy and toxicity of the combination of Ibrutinib with the R-GEMOX-D regimen (rituximab, gemcitabine, oxaliplatin and dexamethasone), in patients with non- GCB DLBCL.


We included patients with histological diagnosis of non-GCB DLBCL (according to Hans algorithm), with relapsed or refractory disease after at least 1 line of immunochemotherapy and non-candidates for ASCT. Patients received an induction treatment consisting of 6 (in case of complete remission [CR] after cycle 4) or 8 (in case of partial response [PR] or stable disease after cycle 4) cycles of R-GEMOX-D at standard doses every 2 weeks, in combination with ibrutinib (560 mg daily), followed by a maintenance treatment with ibrutinib for a maximum of 2 years. The primary objective was to evaluate the overall response rate (ORR) after 4 cycles, and the secondary objectives were: CR rate, progression-free survival (PFS), overall survival (OS) and toxicity. Analyses were performed in the intention to treat population (data cut-off 10th April 2020).


Sixty-four patients (59.4% male) were included between March 2016 and November 2018. Median age was 67 (25-84) years. Patients had received a median of 2 previous lines of treatment; 56.3% were refractory (<PR) to the last regimen, whereas 43.7% had relapsed disease after a previous CR. Eleven (17.2%) patients had received a previous ASCT. IPI at study entry was 0-1, 2-3, and 4-5 in 9.4%, 67.2%, and 20.3% of patients, respectively (missing data in 2 patients).

Of the 64 patients who started study treatment, 44 and 35 patients, respectively, were evaluated for response after 4th cycle and at the end of induction. Twenty-four (37%) patients started maintenance with ibrutinib, 7 of whom continue or have completed it. Causes of withdrawal from the trial (n=57) were progression (n=40), adverse event (n=6), transplantation (n=5), withdrawal of consent (n=3) and other causes (n=3).

ORR and CR rate after 4th cycle were 53.2% and 35.9%, respectively. Patients with relapsed disease had significantly higher ORR (67.9% vs 41.7%, p=0.037) and CR rate (57.1% vs 19.4%, p=0.002) than patients with refractory disease. At the end of induction, ORR and CR rate were 35.9% and 29.7%, respectively.

After a median follow-up of 22 months (range: 1 to 39 months), the estimated 2-year PFS and OS were 21% and 25%, respectively (Figure 1A and 1B), being significantly better in patients with relapsed disease (Figure 1C and 1D). In the multivariate analysis, status of lymphoma at study entry significantly influenced PFS (HR 0.45; 95% CI 0.25-0.82; p=0.009) and OS (HR 0.51; 95% CI 0.27-0.94; p=0.0031) independently from the IPI and the number of previous treatment lines.

The most frequent adverse events (AE) (present in at least 20% of patients) were thrombocytopenia (67.2%), diarrhea (51.6%), neutropenia (46.9%), anemia (37.5%), fatigue (34.4%), nausea (29.7%) and paresthesia (20.3%). The most frequent grade 3-5 AE (present in at least 10% of patients) were thrombocytopenia (46.9%), neutropenia (35.9%), diarrhea (15.6%) and anemia (14.1%). Three patients presented a grade 5 AE, two of them related (aspergillosis and pneumonia, respectively) and one unrelated (heart failure).


The combination of ibrutinib with R-GEMOX-D as salvage therapy for patients with non-GCB DLBCL is associated with high response rates, especially in relapsed patients. The vast majority of refractory patients progress very early, so this regimen could be considered as a bridge to other consolidation therapies. Biological studies analyzing cell of origin by gene expression profiling, minimal residual disease and mutational spectrum are in progress.

Disclosures: Abrisqueta: Roche: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau. Giné: Janssen: Research Funding; Gilead: Research Funding; Roche: Research Funding. Grande: Janssen: Research Funding. Caballero: Roche: Other: travel; Gilead: Other: travel; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel; BMS: Other: travel; Takeda: Other: travel; Kite: Membership on an entity's Board of Directors or advisory committees. Martin Garcia-Sancho: Roche, Celgene, Janssen, Servier, Gilead: Honoraria; Celgene, Eusa Pharma, Gilead, iQuone, Kyowa Kirin, Roche, Morphosys: Consultancy.

OffLabel Disclosure: Off-label use of a new combination in the context of a clinical trial. New combination (Ibrutinib + R-GEMOX)

*signifies non-member of ASH