AUTHORS
Gloria Iacoboni, MD, Peter Borchmann, MD2, Tom Van Meerten, MD, PhD3, Pierre Bories, MD4, Peter Dreger, Prof. Dr. med.5, Laszlo Gopsca, MD6, Pim G.N.J. Mutsaers, MD7, Matthias Edinger, MD8, Lajos Gergely, MD9, Bastian von Tresckow, MD10, Peter Neumeister, MD11, Normann Steiner, MD12, Ulrich Jaeger, MD13, Ana Triguero14, Laimonas Griškevicius, MD15, François Lemonnier Sr, MD, PhD16, Jaap A. Van Doesum17, Marie Jose Kersten, MD18, Nirav N. Shah, MD, MS19, Stefan Miltenyi, PhD20, Toon Overstijns, MD21, Corinne Brillant, MD22, Wael Nasri, MD23, Pearl Van Heteren, MD24, Silke Holtkamp, PhD25, Peter Vandenberghe, MD, PhD26
AFFILIATIONS
1 Vall d'Hebron University Hospital, Barcelona, Spain
2 University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne Lymphoma Working Group, Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, Germany
3 University Medical Center Groningen, University of Groningen, Groningen, Netherlands
4 University Cancer Institute Toulouse Oncopole, Toulouse, France
5 University Hospital Heidelberg, Heidelberg, Germany
6 South-Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
7 Erasmus University Rotterdam, Rotterdam, Netherlands
8 University Hospital Regensburg, Regensburg, Germany
9 University of Debrecen, Debrecen, Hungary
10 Department of Hematology and Stem Cell Transplantation, West German Cancer Center and German Cancer consortium (DKTK partner site Essen), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
11 Medical University Graz, Graz, Austria
12 Medical University Innsbruck, Innsbruck, Austria
13 Medical University of Vienna, Vienna, Austria
14 Hospital Clínic De Barcelona, Barcelona, Spain
15 Vilnius University Hospital Santaros Klinikos and Vilnius University, Vilnius, Lithuania
16 CHU Mondor, Créteil, France
17 University Medical Center Groningen, Groningen, Netherlands
18 Amsterdam University Medical Center, Amsterdam, Netherlands
19 Medical College of Wisconsin, Milwaukee, Wisconsin, United States
20 Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany
21 Miltenyi Biomedicine, Bergisch Gladbach, Germany
22 Miltenyi Biomedicine, Bergisch Gladbach, Germany
23 Miltenyi Biomedicine, Bergisch Gladbach, Germany
24 Miltenyi Biomedicine, Bergisch Gladbach, Germany
25 Miltenyi Biomedicine, Bergisch Gladbach, Germany
26 University Hospital Leuven, Leuven, Belgium
ABSTRACT
Background
Zamtocabtagene autoleucel (zamto-cel) is an autologous, tandem CD20-CD19-directed CAR-T cell therapy. In DALY 2-EU, a randomized, open-label study, zamto-cel demonstrated superior efficacy compared with chemoimmunotherapy (CIT) in second-line large B-cell lymphoma (LBCL) patients who were ineligible for autologous stem cell transplantation. Here, we characterize short- and long-term hematologic and immune recovery, together with infections, following zamto-cel treatment. Exploratory assessments of immune effector cell-associated hematotoxicity (ICAHT; neutropenia [N-ICAHT] and thrombocytopenia [T-ICAHT]) and CAR-HEMATOTOX scoring will be further detailed during ASH, representing, to our knowledge, the first report of these toxicity metrics for a dual CD20-CD19-directed CAR-T cell therapy.
Methods
A total of 168 adults with transplant-ineligible LBCL and relapsed/refractory disease ≤24 months after initiation of first-line therapy were randomized to zamto-cel (n=82) or CIT with R-GemOx or Pola-BR (n=86). Of the 82 patients randomized to zamto-cel, 76 received the study treatment (target dose of 2.5×106 CAR-T cells/kg body weight). The primary endpoint was IRC-assessed EFS. Safety endpoints comprised AEs, serious AEs, and AESIs, as well as hospitalizations, intensive care unit (ICU) days, and requirements for transfusions, antimicrobial therapy, and immunoglobulin substitution. The CAR-HEMATOTOX score and ICAHT grading were determined retrospectively as exploratory post hoc analyses.
Results
Baseline characteristics of the zamto-cel arm were representative of an elderly population with high tumour burden (median age 74 years, 30.5% ECOG 2, 57.3% IPI 3-5, 67.1% stage III-IV). Median follow-up from CAR T-cell infusion was 21 months.
In this treatment arm (n=76), any-grade neutropenia occurred in 100% of patients, with Grade ≥3 in 89.4%. The highest rates occurred in the early post-zamto-cel period, peaking at week 3 after leukapheresis with Grade ≥3 events in 55.3% of patients. Neutropenia subsequently improved, with Grade ≥3 events declining to 9.2% at week 5 and 7.9% at week 6 after leukapheresis. Severe neutropenia was uncommon beyond week 8. Overall, 39 (42.7%) patients received growth factors for neutropenia. No apparent association between CAR-HEMATOTOX score and N-ICAHT was observed in this exploratory analysis.
Any-grade anaemia occurred in all patients and was predominantly grade 1 or 2 (26.3% and 55.3%, respectively). Grade 3 anaemia occurred in 14 (18.4%) patients; no grade ≥4 anaemia was reported. Any-grade thrombocytopenia occurred in 68 (89.5%) patients and was predominantly grade 1 or 2 (57.9% and 9.2%, respectively). Grade ≥3 thrombocytopenia occurred in 17 (22.4%) patients. A total of 28 (37%) patients received red blood cell or platelet transfusions within 12 months of zamto-cel infusion. Use of erythropoiesis- and thrombopoiesis-stimulating agents was rare (one patient each). Prior to zamto-cel, all patients had CD8+ and CD4+ T-cell lymphopenia (<200 cells/μL); by week 16 post-leukapheresis, 81% and 19% of patients with available values had recovered CD8+ and CD4+ T cells, respectively.
At baseline, B-cell aplasia (<5 B cells per μL) was present in 74 (94.7%) patients. Median time to recovery was 8.4 months; by week 16 after leukapheresis, 11.1% of patients with available values had recovered B cells. Hypogammaglobulinemia (IgG <4 g/L) was uncommonly reported at baseline (3 patients; 4%), peaked at week 8 after leukapheresis (25.4%), and declined thereafter; 3 patients (4%) received immunoglobulin substitution per institutional guidelines.
Grade ≥3 treatment-emergent infections occurred in 14 (18%) patients. COVID-19 was the most common infection-related TEAE (6 [8%] patients). ICU admissions within 7 months of randomization (excluding prophylactic ICU surveillance) were reported in 6 (8%) patients, with a median duration of 8 days; infection was the leading cause of admission in 2 cases (one COVID-19 pneumonia and one necrotizing fasciitis). Treatment-related deaths occurred in two (3%) patients (CRS and haemophagocytic lymphohistiocytosis).
Conclusion
In the DALY 2-EU study, grade ≥3 cytopenias occurred predominantly in the early post-infusion period and resolved rapidly in most patients. The need for transfusions and growth-factor support was limited, and the incidence of grade ≥3 infections remained low. These findings support the use of zamto-cel in elderly, transplant-ineligible LBCL patients.
DISCLOSURES
Gloria Iacoboni, MD: Gilead Sciences/Kite Pharma, AstraZeneca, AbbVie, Miltenyi - Other (including travel support); AbbVie, AstraZeneca, Bristol-Myers Squibb, Kite/Gilead, Miltenyi, Sobi, Roche, Lilly - Honoraria; Bristol-Myers Squibb, Kite/Gilead, Janssen, Miltenyi, Abbvie, MSD, Regeneron, Autolous - Consultancy (Includes expert testimony)