Effect of early granulocyte-colony-stimulating factor administration in the prevention of febrile neutropenia and impact on toxicity and efficacy of anti-CD19 CAR-T in patients with relapsed/refractory B-cell lymphoma

Raphaël Liévin,Catherine Thieblemont,Miryam Mebarki,Eric De Kerviler,Nathalie Parquet,Sylvie Chevret,Florence Morin,Romain De Jorna,Eugenio Galli,Laetitia Vercellino,Sophie Caillat-Zucman,Roberta Di Blasi,Isabelle Madelaine,Vincent Allain,Jerome Larghero

doi:10.1038/s41409-021-01526-0

Abstract

Chimeric Antigen Receptor T cells (CAR-T) are an outbreaking treatment option for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the most common specific toxicities, while severe neutropenia and infections are often observed as well. From March 2020, early G-CSF prophylaxis at day (D) two post-infusion was systematically proposed. We then compared patients treated before that date who did not receive G-CSF or who received late (after D5) G-CSF as control group. Patients administered with early G-CSF had similar duration of grade 4 neutropenia but significantly decreased incidence of febrile neutropenia (58% versus 81%, p = 0.018). Similar rate of toxicities was observed, including overall and grade 3-4 CRS (p = 0.93 and p = 0.28, respectively), and overall and grade 3-4 ICANS (p = 0.62 and p = 0.88, respectively). We observed no difference in the quality of CAR T-cells expansion (p = 0.79, %Cmax), nor in response rate (best ORR, 57.6% vs 61.8%, p = 0.93), nor survival even in a group of patients adjusted by a propensity score. In conclusion, early G-CSF administration was safe and effective in reducing febrile neutropenia without impact on toxicities nor on anti-lymphoma activity of CAR-T.

Highlights

In recent years, consistent progress was made in treating relapsed/refractory diffuse large B-cell lymphomas (R/R DLBCL) [1–4]
The objective of the present study was to evaluate the efficacy of the G-CSF with an early and prophylactic administration at day 2 after the CAR T-cells infusion on the duration of severe neutropenia, the incidence of febrile neutropenia, and the prevalence of early infections in patients with R/R LBCL treated with CAR-T: with this aim, we compared the group of patients receiving the G-CSF at day 2 to the group of patients without G-CSF before March 2019, and the group of patients with G-CSF between March 2019 and March 2020 treated with late G-CSF after Day 5, as control group
In this report, we observed that in a series of patients with R/R DLBCL treated with CAR-T, early administration of G-CSF was associated with reduced febrile neutropenia without any impact on the toxicities, Cytokine release syndrome (CRS) or neurotoxicities, as well as on the efficacy and expansion of CAR-T in term of response

Summary

Introduction

Consistent progress was made in treating relapsed/refractory diffuse large B-cell lymphomas (R/R DLBCL) [1–4]. CAR-T cells are autologous T-cells with an engineered T-cell receptor, which artificially targets surface tumoral antigen. This approach is on active use since June 2018 in Europe for R/R B-cell malignancies, after pivotal Phase I-II studies of anti CD19 CAR-T cells were published [1–3]. Besides CRS, ICANS is the other described complication, possibly involving an endothelial toxicity and causing variable neurologic signs, from slightly impaired cognitive function to coma or fatal seizures [6]. Both CRS and ICANS have been objected of a consensus for harmonizing gradings [7]. The first nadir of cytopenias seemed to be related to effects of lymphodepletion and activity of CRS, possibly mediated by macrophages; this could

Objectives

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Conclusion