Dynamics and Management of CAR-T Cells Associated Cytopenias: A Single-Center Experience
Authors: Martín-Rojas Reyes María , Bailen Rebeca , Oarbeascoa Gillen , Bastos Oreiro Mariana , Gómez-Centurión Ignacio , Badiola Jon , Muñoz Cristina , Sabell Santiago , Anguita Javier , Diez-Martin Jose L. , Kwon Mi 
Published: November 2021

Abstract
* Martín-Rojas RM and Bailén R equally contributed to this work.
INTRODUCTION
CAR-T cell therapy is approved by the European Medicines Agency (EMA) and the Federal Drugs Administration (FDA) for the treatment of adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy and for children and adults up to age 25 with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Prolonged cytopenias have been reported in up to 30-60% of patients undergoing CAR-T cell therapy, but information about its pathophysiology, dynamics and clinical impact is scarce.
METHODS
We conducted a retrospective study of consecutive patients undergoing commercial CAR-T cell therapy in our center between June 2019 and March 2021. We analyzed peripheral blood cell counts pre-lymphodepletion, at admission and during the first year of follow-up. This information was correlated with clinical data and analytical parameters. This study was approved by our institutional Ethics Committee and it was performed in compliance with the Declaration of Helsinki. Data were analyzed using IBM SPSS Statistics version 24 and GraphPad Prism version 8.4.3.
RESULTS
A total of 40 patients were included, 37 with diagnosis of R/R DLBCL and 3 with B-ALL (Table 1). 6-month overall survival was 71% for patients with lymphoma and 33.3% for patients with B-ALL.
The dynamics of neutrophil and platelet counts is shown in Figure 1. Median hospitalization duration was 25 days (range: 11-241) and, during this period, 10 patients (25%) required transfusion of 5 or more red cell concentrates (18.9% lymphoma vs. 100% B-ALL; p=0.002), 11 patients (27.5%) required 5 or more platelet transfusions (21.6% lymphoma vs. 100% B-ALL; p=0.003) and 6 patients needed 5 or more doses of G-CSF (13.5% lymphoma vs. 33.3% B-ALL; p=0.3).
On day +28 post CAR-T cell therapy, 26 patients (65%) showed persistent profound cytopenias not related with marrow infiltration (absolute neutrophil counts ≤500/μL and/or platelets ≤50000/ μL): a total of 4 patients (15.4%) had neutropenia, 8 patients (31%) thrombopenia and 14 patients (54%) both. 100% of patients with B-ALL maintained aplasia at day +28, with no evidence of disease.
Due to persistent cytopenias at discharge, 22 patients (64.7%) received outpatient treatment with G-CSF (20 lymphoma vs. 2 B-ALL; p=0.41), 13 patients (38.2%) received erythropoietin (11 lymphoma vs. 2 B-ALL; p=0.16) and 12 patients (35.3%) were treated with thrombopoietin analogues (10 lymphoma vs. 2 B-ALL; p=0.13). One patient with B-ALL received a boost of selected CD34+ cells from her donor (Table 1).
On day +90 post CAR-T cell therapy, 7 patients (26.9%) showed profound cytopenias and, on day +180 it increased to 9 patients (47.4%). None of the 9 patients who were alive at one year follow-up, presented profound cytopenias at this point (Figure 2).
Profound cytopenias on day +28 were related to bridging therapy (p=0.04), bone marrow infiltration at diagnosis (p=0.05), higher lymphodepletion doses (p=0.05), evidence of a bulky mass pre-lymphodepletion (p=0.007), development of cytokine release syndrome (CRS) (p=0.012), ICU admission (p=0.07), infectious complications (p=0.008) and having less than 2000/ μL neutrophils pre-lymphodepletion (p=0.04). A multivariate analysis using logistic regression identified higher doses of lymphodepletion (OR 7.57; 95% CI 1.14-50.4; p=0.03) and bone marrow infiltration at diagnosis (OR 7.31; 95% CI 0.97-54.95; p=0.05) as the only independent predictors factors of these cytopenias.
Profound cytopenias on day +180 were related to bone marrow infiltration at diagnosis (p=0.02), having received bridging therapy (p=0.05) and lower pre-lymphodepletion lymphocyte counts (p=0.04) and folate levels (p=0.05). None of these variables reached statistical significancy on the multivariate analysis.
CONCLUSIONS
Profound cytopenias not associated with progression or relapse were a frequent complication after commercial CAR-T cell therapy, with 65% of cases on day +28, being the lymphodepletion dose and bone marrow infiltration at diagnosis independent predictors for its development. Beyond day +28, up to 47% patients showed profound cytopenias. A higher number of patients and longer follow-up are needed to confirm our findings and identify other potential prognosis factors for these cytopenias.
Figure 1 Figure 1.

Disclosures
Martín-Rojas: Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Bailen: Pfizer, Kite-Gilead, Gilead: Honoraria. Oarbeascoa: Gilead: Honoraria, Speakers Bureau. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria.