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Non-Hodgkin Lymphoma
Hematopoietic recovery and immune reconstitution after axicabtagene ciloleucel in patients with large B-cell lymphoma
Paolo Strati,1 Ankur Varma,2,4 Sherry Adkins,1 Loretta J. Nastoupil,1 Jason R. Westin,1 Fredrick B Hagemeister,1 Nathan H Fowler,1 Hun J. Lee,1 Luis E. Fayad,1 Felipe Samaniego,1 Sairah Ahmed,1 Yiming Chen,1 Sandra Horowitz,1 Sara Arafat,1 Swapna Johncy,1 Partow Kebriaei,2 Victor Eduardo Mulanovich,3 Ella Ariza Heredia3 and Sattva S. Neelapu1
1Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX; 2Department of Stem Cell Transplantation,The University of Texas MD Anderson Cancer Center, Houston, TX; 3Department of Infectious Disease, The University of Texas MD Anderson Cancer Center, Houston, TX, and 4Division of Hematology, Oncology and Cellular Therapy, Rush University, Chicago, IL, USA
ABSTRACT
Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 may be associated with long-term adverse effects such as cytope- nia and immune deficiency. In order to characterize these late events, we analyzed 31 patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel at our institution on two clinical trials, ZUMA-1 (clinicaltrials gov. Identifier: NCT02348216) and ZUMA-9 (clinicaltrials gov. Identifier: NCT03153462). Complete blood counts, lymphocyte subsets, and immunoglobulin levels were measured serially until month 24 or progression. Fifteen (48%) patients had grade 3-4 cytopenia, including anemia (five, 16%), neutropenia (nine, 29%), or thrombocytopenia (13, 42%) at day 30. Cytopenia at day 30 was not sig- nificantly associated with later diagnosis of myelodysplasia. Among patients with ongoing remission, grade 3-4 cytopenia was observed in one of nine (11%) at 2 years. While peripheral CD8+ T cells recovered early, CD4+ T-cell recovery was delayed with a count of <200/mL in three of nine (33%) patients at 1 year and two of seven (29%) at 2 years. Immunoglobulin G levels normalized in five of nine (56%) patients at 2 years. Thirteen (42%) patients developed grade 3-4 infectious complica- tions, including herpes zoster and Pneumocystis jiroveci pneumonia. These results suggest the need for prolonged monitoring and prophylaxis against opportunistic infections in these patients, to improve the long- term safety of axicabtagene ciloleucel therapy.
Introduction
Chimeric antigen receptor (CAR) T-cell therapies targeting CD19, such as axi- cabtagene ciloleucel (axi-cel), have significantly improved the outcome of patients with refractory large B-cell lymphoma (LBCL).1-4 While acute toxicities, such as cytokine release syndrome (CRS) and neurotoxicity, have been well reported, late adverse effects, such as cytopenia and immune deficiency, have not been well characterized.5-7
Cytopenias lasting beyond day 30 post infusion have been observed with most CAR T-cell products, suggesting a class effect rather than a complication of condi- tioning chemotherapy.1,3,8-10 In addition, prolonged B-cell aplasia is a known on-tar- get off-tumor effect of anti-CD19 CAR T-cell therapies.2 It is unclear at this time how long it takes for cytopenias to resolve and at what point these patients should be worked up for myelodysplastic syndrome (MDS). It is also unknown what the timing of T-cell immune reconstitution is after axi-cel therapy and whether these patients are at short or long-term risk of infectious complications.
Ferrata Storti Foundation
Haematologica 2021 Volume 106(10):2667-2672
Correspondence:
SATTVA S. NEELAPU
sneelapu@mdanderson.org
Received: March 30, 2020. Accepted: July 14, 2020. Pre-published: July 30, 2020.
https://doi.org/10.3324/haematol.2020.254045 ©2021 Ferrata Storti Foundation
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