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Cytopenias after CAR T-cell therapy
survival not reached.1,2 Major acute side effects of chimeric antigen receptor T (CAR T)-cell therapy include cytokine release syndrome (CRS) and neurologic toxicities, which are treated with anti-IL-6 receptor blockade and/or corticosteroids.
In the ZUMA-1 trial, grade 3 or higher cytopenias were common in the first 30 days following CAR T-cell therapy, and this is typically attributed to fludarabine and cyclophosphamide given for lymphodepletion prior to CAR T-cell infusion.3,4 However, cytopenias may persist, and at 3 months or later, 17% of ZUMA-1 patients expe- rienced one or more grade 3 or higher cytopenia, including 11% with neutropenia, 7% with thrombocytopenia, and 3% with anemia.1 Late cytopenias were seen without evi- dence of marrow dysplasia or relapse. In addition, B-cell aplasia occurred due to on-target elimination of CD19-expressing normal B cells, with resultant hypogam- maglobulinemia, and use of intravenous immunoglobulins (IVIG) in 31%. Overall, 28% of patients had ≥grade 3 infections on the ZUMA-1 trial.
The presence of early and late cytopenias, corticosteroid treatment for CRS and neurotoxicity, and reconstitution of B and T lymphocytes after CAR T therapy may put patients at risk of infection. This study aimed to character- ize immune reconstitution after axi-cel therapy and iden- tify early and late infections in patients with R/R LBCL receiving treatment with axi-cel. We examined cytope- nias, lymphocyte reconstitution, and infection data up to 1 year following infusion of axi-cel.
Methods
Patients and data collection
We retrospectively reviewed data from the medical records of patients with R/R LBCL who were treated with axi-cel at the Moffitt Cancer Center between February 1, 2016, and February 28, 2019. This study was approved by the Institutional Review Board. Data extracted from the electronic medical record included patient demographics, prior therapies, baseline disease status, CAR T-cell product, dates of treatment and disease progression or last follow-up, occurrence and grade of CRS and neurotoxicity, complete blood counts (CBC), immunoglobulin levels, infection data, pathology reports, and drug administration. B-, T- and natu- ral killer-lymphocyte subsets were quantified from fresh peripher- al blood samples using a validated flow cytometry panel in the clinical lab. All data was censored at date of progression, develop- ment of a new malignancy requiring systemic treatment, death, or last follow-up, in order to understand the effect of axi-cel therapy independent of disease progression. Immunoglobulin levels were censored after a patient was treated with IVIG. Adverse events were graded per the Common Terminology Criteria for Adverse Events (CTCAE) v4.03. CRS was scored based on modified Lee grading system.5 Neurologic toxicity was scored based on CAR- related encephalopathy syndrome/CAR T toxity (CRES/CAR- TOX) grading system or individual terms for CTCAE neurotoxic- ity.6 Disease status at apheresis was defined as: primary refractory, never achieving end of treatment CR; refractory, not primary refractory and no response to the most recent therapy; relapsed, responded to most recent therapy and progressed. Bridging thera- py was defined as any lymphoma-specific therapy administered after leukapheresis and before conditioning chemotherapy. Cyclophosphamide and fludarabine conditioning followed by axi- cel infusion were performed as in ZUMA-1. Prophylaxis policies were adapted from our institution’s autologous stem cell trans-
plant procedures. Our institutional standard for antimicrobial pro- phylaxis includes starting antibacterial prophylaxis with a fluoro- quinolone and antifungal prophylaxis with fluconazole on the morning of axi-cel infusion or earlier if the patient is neutropenic, with discontinuation in afebrile patients free of infection after neu- trophil recovery. The standard empiric treatment for neutropenic fever included cefepime or piperacillin/tazobactam. Pneumocystis jiroveci pneumonia (PJP) prophylaxis is started on day 30 following axi-cel infusion and included sulfamethoxazole-trimethoprim in patients without cytopenias, with inhaled pentamidine, dapsone or atovaquone prophylaxis used in cytopenic patients. Duration of PJP prophylaxis was physician dependent and was typically pro- vided for 6-12 months, or until recovery of CD4 count over 200 cells/mL. Varicella zoster virus (VZV) reactivation prophylaxis is provided for a minimum of 12 months, typically using acyclovir. Herpes simplex virus (HSV) 1/2 immunoglobulin G (IgG) testing was by ARUP laboratories (Salt Lake City, UT).
Definition of infection
An episode of infection was defined as a viral, bacterial, or fun- gal finding based on microbiological data or a clinical syndrome, which was found based on retrospective chart review. Severe infection was defined as an infection which required intravenous (IV) antibiotics or hospitalization. Standard follow-up at our insti- tution includes clinic appointments on days 30, 90, 180, 270, and 360. Patients were expected to call if they developed any infec- tious symptoms in the interim.
Statistical analysis
Patient characteristics were summarized using descriptive sta- tistics including median and range for continuous measures and proportions and frequencies for categorical measures. Chi-square test or Fisher exact test was used to explore the association between categorical variables. Dunnett’s test was used to make pairwise comparisons with Day 0, and Kruskal-Wallis test has been used to compare total white blood cells (WBC), neutrophils (N), CD3 positive cells, CD56 positive cells, CD8 positive cells, CD4 positive cells, CD19 positive cells, and IgG levels up to 1 year following axi-cel. When comparing characteristics to infection/severe infection, the associations between categorical variables were evaluated using c2 tests or Fisher’s exact tests when the expected frequency was less than 5. In addition, infection inci- dence per 1,000 person-days at day 30, 90, 180, 270, and 360 was computed to incorporate the multiple infections per patient. The cumulative incidence of first infection was estimated by compet- ing risk approach, where death or progression were considered as competing events. The association between continuous variables and infection were assessed using Wilcoxon tests. Categorical variable levels for overall survival (OS) were compared using the Log-rank test. Kaplan-Meier curves were used to show progres- sion free survival (PFS) and OS for all patients in the study. Statistical significance was defined as two-sided P-value of <0.05.
Results
The majority of acute toxicities are known to resolve before day 30 after CAR T, which also is the time of first disease assessment.7 Therefore, we separately analyzed immune reconstitution and infections prior to day 30 and after day 30 after axi-cel infusion. Further, in order to focus on survivorship we censored patients from the analysis at the time of lymphoma relapse. Of 85 infused patients, we censored 11 for analysis beyond day 30 due to early pro- gressive disease or death, and an additional 4 patients
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