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658 Recent Bendamustine Treatment before Apheresis Has a Negative Impact on Outcomes in Patients with Large B-Cell Lymphoma Receiving Chimeric Antigen Receptor T-Cell Therapy

Program: Oral and Poster Abstracts
Type: Oral
Session: 705. Cellular Immunotherapies: Results from CD19-Directed CAR T in treating Aggressive B-cell Lymphomas
Hematology Disease Topics & Pathways:
Research, Biological therapies, Lymphomas, Clinical Research, B Cell lymphoma, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, real-world evidence, Therapies, Lymphoid Malignancies
Sunday, December 11, 2022: 5:15 PM

Gloria Iacoboni, MD1*, ANA Africa Martin Lopez2*, Katarzyna Aleksandra Jalowiec3*, Mi Kwon, MD, PhD4*, Kai Rejeski, MD5, Víctor Navarro Garcés6*, Paula Amat, MD PhD7*, Juan Luis Reguera, MD8*, Laura Gallur, MD1*, Sara Gutierrez-Herrero9*, Claire Roddie3*, Gillen Oarbeascoa10*, Ana Benzaquén, MD7*, Cecilia Carpio, MD1*, Lucía López Corral, MD2*, Rafael Hernani, MD7*, Mariana Bastos-Oreiro, MD, PhD10*, Marion Subklewe, MD11, Maeve O'Reilly3*, Lourdes Martín9* and Pere Barba, MD1*

1Vall d’Hebron University Hospital, Barcelona, Spain
2Hematology Department, Hospital Clínico Universitario de Salamanca (CAUSA/IBSAL), Salamanca, Spain
3University College London Hospital NHS Foundation Trust, London, United Kingdom
4Department of Hematology Institute of Health Research Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain
5Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
6Oncology Data Science (ODysSey) Group, Vall d’Hebron Institute of Oncology (VHIO), BARCELONA, Spain
7Hospital Clínico Universitario de Valencia, Valencia, Spain
8Hospital Universitario Virgen del Rocío, Sevilla, Spain
9Cancer Research Center, Salamanca, Spain
10Gregorio Marañon General University Hospital, Madrid, Spain
11Department of Medicine III (Hematology/Oncology), LMU University Hospital Munich, Muenchen, Germany

Introduction: Since chimeric antigen receptor (CAR) T-cells are produced from circulating autologous T-lymphocytes, the final composition of each product is highly dependent on the number and fitness of these T-cells. A potential deleterious effect of prior bendamustine (benda) on CAR T-cell production has been proposed due to its lymphotoxic effect. Based on this, consensus documents suggest avoiding benda in potential CAR-T candidates. However, there is scarce data regarding the impact of previous benda exposure on T-cell kinetics and clinical outcomes in patients treated with CD19-targeted CAR T-cell therapies.

Methods: We conducted a retrospective, multicenter, international study including patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) treated at 7 sites with commercially available CAR T-cell products until June 2022. We analyzed the baseline characteristics, response rates and survival outcomes. A univariate logistic regression model was carried out to study the association between different variables with previous benda therapy. Progression-free survival (PFS) and overall survival (OS) were calculated from time of infusion. The maximum log-rank method was used to select the best cutoff for the time between last bendamustine dose and apheresis with an impact on OS. Finally, we carried out an analysis of circulating CAR T-cells by flow cytometry in benda-treated patients from 2 centers (n=15) and compared them with benda-naïve matched controls (1:1) based on IPI score (0-2 vs 3-5), age (±10 years) and type of construct (axi-cel vs. tisa-cel).

Results: We included 370 patients, of which 74 (20%) had received bendamustine-containing regimens before apheresis. The median time between last benda dose and apheresis was 226 days (IQR 67-606) and median total dose was 1050 mg (IQR 277-1800). Regarding baseline characteristics, patients in the benda group were older (median years, 66 vs 61) and had a higher ECOG score (ECOG >1, 16% vs 4%) than benda-naïve patients. Median follow-up from infusion was 19.4 months (CI95% 13.7 - 30.8 months).

First, we analyzed the impact of previous benda on several parameters at apheresis and after treatment. Patients with prior exposure to benda had lower median absolute lymphocyte counts (0.7 x109/L vs 1.0 x109/L, p=0.004), CD3+ cells (0.5 x109/L vs 0.7 x109/L, p=0.006) and platelets (125 x109/L vs 179 x109/L, p=0.004) at apheresis than benda-naïve patients. Patients without previous benda exposure showed better response rates (overall, complete – CR-) to CAR T-cell therapy than those in the benda group (72%, 51% vs 57%, 41%), respectively (p=0.018). Median PFS for the full cohort was 4.4 months, 3.2 and 4.9 months in the benda and benda-naïve cohorts, respectively (p=0.3). Median OS was 18.6 months for the full cohort, 20.1 and 18.6 months in the benda and benda-naïve cohorts, respectively (p=0.31). There were no differences in the incidence or severity of cytokine release syndrome (CRS) and neurotoxicity after infusion.

Regarding CAR-T characterization, patients with prior benda showed a lower (14.4 vs 28.6 cells/mL) and more delayed (17 vs. 13 days) absolute CAR T-cell peak expansion after infusion than benda-naïve controls. Regarding CAR T-cell subpopulations, there was a higher proportion of central memory and effector memory CAR+ T-cells in the benda-naïve group, compared with the benda group (Figure 1).

Given the wide variability in the time from last benda dose to apheresis, we then focused our analysis on patients receiving benda within the last 9 months before T-cell collection (benda<9m), as described in Methods. The values of CD3+ lymphocytes and platelets at apheresis were similar between benda <9m and benda >9m patients. The overall (CR) response rate was lower in the benda <9m than in the benda >9m group: 45% (33%) and 67% (50%), respectively (p=0.0071) (Figure 2). Similarly, patients in the benda <9m cohort had a lower median PFS than those in the benda >9m (1.5 vs. 7.1 months, p=0.02). Probability of OS and incidence of CRS and neurotoxicity were similar, irrespective of the time from last benda dose.

Conclusions: Bendamustine-containing regimens before CAR T-cell therapy may have a negative impact on T-cell numbers and composition at apheresis and on CAR T-cell expansion. LBCL patients with recent exposure (<9 months) to benda have worse outcomes after CAR T-cell therapy than patients with an earlier exposure.

Disclosures: Iacoboni: NOVARTIS, KITE/GILEAD, BMS/CELGENE: Consultancy; NOVARTIS, KITE/GILEAD, BMS/CELGENE, ASTRAZENECA, ROCHE, ABBVIE, JANSSEN, MILTENYI: Honoraria. Jalowiec: Kite Gilead: Honoraria. Kwon: Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Gilead: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; BMS: Consultancy. Rejeski: Novartis: Honoraria; Kite/Gilead: Other: Travel Support, Research Funding. Roddie: Kite Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Carpio: Takeda: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy; BMS: Honoraria; Novartis: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria. Bastos-Oreiro: Roche: Consultancy, Research Funding, Speakers Bureau; KITE/GILEAD: Consultancy, Honoraria; NOVARTIS: Speakers Bureau; INCYTE: Consultancy, Speakers Bureau; JANSSEN: Speakers Bureau. Subklewe: MorphoSys: Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Seagen: Research Funding; Miltenyi Biotech: Consultancy, Research Funding; Roche: Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; AvenCell: Consultancy; CDR-Life: Consultancy; Ichnos: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; BMS/Celgene: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Incyte: Consultancy; Molecular Partners: Consultancy. Barba: Amgen: Honoraria; Gilead: Honoraria; BMS: Honoraria; Novartis: Honoraria; Pfizer: Honoraria.

*signifies non-member of ASH