Cytopenias in CAR-T Cell Therapy and Use of Transfusion Resources in Adult Patients with Lymphoproliferative Disorders
Authors: Mezquita Lucía , Mingot Maria Eva , Alcalde Patricia , Sánchez-Llorca Paula , Camuña-Correa Javier , Reguera Juan Luis , Martínez-Cibrian Nuria , Blazquez-Goñi Cristina , Escamilla Gomez Virginia , Pérez-Ortega Laura , Serrano Dolores , Perez-Simon Jose A. 
Published: November 2021

Abstract
BACKGROUND AND OBJECTIVES
CD19-directed chimeric antigen receptor (CAR)-T-cell therapy is associated with early cytopenia in approx. 80% of patients and late cytopenia in 40% of patients. To date, the transfusion profile of patients undergoing these therapies has not been described. Our objectives are: To define the transfusion profile of CAR-T therapy in our setting.To evaluate clinical variables related to the intensity and duration of cytopenias.
METHODOLOGY
This is an observational, prospective, single centre study. Adult patients with lymphoproliferative disorders and acute lymphoblastic leukaemia proposed for CAR-T therapy from August 2019 to March 2021 were included.
RESULTS
68 patients were included in the CAR-T cell therapy program. Table 1 describes patients characteristics. Forty-seven received CART therapy, apheresis was not performed in 7 cases (progression n=6, withdrawal of consent n=1), product was not infused in 9 patients due to disease progression and 5 patients are awaiting infusion.
Cytokine release syndrome (CRS) occurred in 79% of patients, 25% developed grade≥2 and median time to onset was 2 days (IQR, 1-4 days). Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 33% of patients, 16% were grade≥3 and median time to onset was 7 days (IQR, 6-8 days). Median duration of hospital admission was 14 days (IQR, 12 to 21 days).
None of the 47 infused patients had neutropenia or anemia in the transfusion range prior to lymphodepletion. 94% (44/47) developed grade ≥3 neutropenia, with a median duration of 14.5 days (IQR, 9.75 to 36 days). G-CSF was administered to 21 patients, with a median time on G-CSF of 115 days (IQR, 27-258 days). A total of 239 red blood cells units (RBC) have been transfused, median 3.5 RBC/patient (IQR, 0 to 7.5 RBC / patient). 70% of this consumption occurred in the first 30 days after infusion.
Before CAR T cell infusion, 2 patients had a platelet count &lt;20x10 9/L, and 3 between 30 and 50x10 9/L, mean platelets (SD) prior to lymphodepletion was 153 (+/-106) x10 9/L. Grade ≥3 thrombocytopenia occurred in 53% of patients, median time to reach platelets &gt; 20x10 9/L was 17 days (IQR, 4-54 days) and &gt; 50x10 9/L was 39 days (IQR, 20-79 days). 62% of patients received ≤2 platelet concentrates (PC). However, 21% had long-term thrombocytopenia (&gt; 30 days). This group received a median of 15 PC (IQR, 12-27). The amount of PC used was 198, 52% were administered in the first 30 days. Eltrombopag was indicated in 9 of the 25 patients with grade ≥3 thrombocytopenia, doses never exceeded 75 mg/day. No serious bleeding (WHO grade ≥2) was observed.
Factors related to severe thrombocytopenia were female (74% vs 42%, p=0.036), CRS (61% vs 0%, p=0.019), ICANS (80% vs 43%, p=0.020) and use of steroids (92% vs 67%, p=0.003). We found no relationship with underlying disease or status, prior treatment lines, prior autologous transplantation, CAR-T product, duration of lymphopenia, time and duration of CRS or ICANS.
With a median follow-up of 167 days (IQR, 73-303 days), 26% of patients died, causes of death were infections n=2 and disease progression n=10. Three months after the procedure, there were 30 evaluable patients for response and 64% remained in remission (47% CR, 17% PR).
CONCLUSIONS
A high percentage of patients receiving CAR T cell therapy present long-term cytopenias. Reserves of irradiated blood components must be foreseen. Development of CRS and ICANS could be prognostic factors for the development of long-term grade ≥3 thrombocytopenia. Studies are needed on the use of thrombopoietin receptor agonists to reduce the duration of thrombocytopenia, although effective doses could be higher than those used in idiopathic immune thrombocytopenia.
Figure 1 Figure 1.

Disclosures
Reguera: Janssen, Kite/Gilead, Novartis: Speakers Bureau; BMS-Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees. Perez-Simon: JANSSEN, TAKEDA, PFIZER, JAZZ, BMS, AMGEN, GILEAD: Other: honorarium or budget for research projects and/or participation in advisory boards and / or learning activities and / or conferences.