Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma

Abstract

To explore the role of clonal hematopoiesis (CH) on chimeric antigen receptor (CAR) T therapy outcomes, we performed targeted deep-sequencing on buffy coats collected during the 21 days before lymphodepleting chemotherapy from 114 large B-cell lymphoma patients treated with anti-CD19 CAR T cells. We detected CH in 42 (36.8%) pre-treatment samples, most frequently in PPM1D (19/114) and TP53 (13/114) genes. Grade {greater than or equal to}3 immune-effector cell-associated neurotoxicity syndrome (ICANS) incidence was higher in CH-positive patients than CH-negative patients (45.2% vs. 25.0%, p=0.038). Higher toxicities with CH were primarily associated with DNMT3A, TET2 and ASXL1 genes (DTA mutations). Grade {greater than or equal to}3 ICANS (58.9% vs. 25%, p=0.02) and {greater than or equal to}3 cytokine release syndrome (17.7% vs. 4.2%, p=0.08) incidences were higher in DTA-positive than CH-negative patients. The estimated 24-month cumulative incidence of therapy-related myeloid neoplasms after CAR T therapy was higher in CH-positive than CH-negative patients (19% [95%CI: 5.5-38.7] vs. 4.2% [95%CI: 0.3-18.4], p=0.028).

CAR T cell‐driven cerebrospinal fluid cytokine storm with confounding neurological picture in chemorefractory primary cardiac lymphoma

“…The finding that mural cells surrounding the endothelium, which are fundamental for blood–brain‐barrier integrity, express the CD19 isoform recognized by CAR T cells may also contribute to ICANS 20 . Interestingly, clonal hematopoiesis, especially that driven by mutations of the DNMT3A , TET2 , and ASXL1 genes, is associated with an increased risk of severe neurotoxicity, including ICANS, in patients with DLBCL treated with CAR T cells (axicabtagene) 21 . This is likely due to the association of clonal hematopoiesis with systemic inflammation, as confirmed by elevated IL‐6 baseline levels prior CAR T cell therapy.…”

“…20 Interestingly, clonal hematopoiesis, especially that driven by mutations of the DNMT3A, TET2, and ASXL1 genes, is associated with an increased risk of severe neurotoxicity, including ICANS, in patients with DLBCL treated with CAR T cells (axicabtagene). 21 This is likely due to the association of clonal hematopoiesis with systemic inflammation, as Other risk factors for ICANS include younger age, higher tumor burden, pre-existing neurological symptoms, preadministrated lymphodepletion agents, severe CRS, and high CSF protein level after treatment. 22 Proper management should be according to the grade of ICANS.…”

Clonal Hematopoiesis: Role in Hematologic Non-Hematologic

“… 183 CHIP-positive patients had a more frequent incidence of immune-effector cellassociated neurotoxicity syndrome (ICANS) than CHIPnegative patients (45% vs. 25%) Higher incidence of ICANS and cytokine release syndrome were observed among patients with CHIP associated with DNMT3A, TET2 and ASXL1 gene mutations. 183 In addition, the cumulative 24-h incidence of tMN was significantly higher in CHIP-positive than in CHIP-negative patients (19% vs. 4.2%, respectively).…”

“…182 Saini et al explored the occurrence of clonal hematopoiesis among 114 patients with large B-cell lymphoma treated with anti-CD19 CART cells; 36.8% of these patients displayed CHIP most frequently mutated in PPM1D and TP53 genes. 183 CHIP-positive patients had a more frequent incidence of immune-effector cellassociated neurotoxicity syndrome (ICANS) than CHIPnegative patients (45% vs. 25%) Higher incidence of ICANS and cytokine release syndrome were observed among patients with CHIP associated with DNMT3A, TET2 and ASXL1 gene mutations. 183 In addition, the cumulative 24-h incidence of tMN was significantly higher in CHIP-positive than in CHIP-negative patients (19% vs. 4.2%, respectively).…”

Klonale Hämatopoese – Bedeutung für die Zelltherapie

“…Hinsichtlich der klinischen Nebenwirkungen zeigen erste größere Kohortenanalysen eine erhöhte Rate an schweren CRS-Verläufen bei jüngeren Patient*innen < 60 Jahren mit Nachweis von CH vor CAR-T-Zell-Behandlung [ 16 ]. Auch für die immuneffektorzellassoziierte Neurotoxizität (ICANS) ist kürzlich erstmals eine Assoziation von CH und schweren Verläufen beschrieben worden [ 21 ]. Inwiefern die CH zur Pathogenese der Zytopenie nach CAR-T-Zell-Therapie beiträgt, ist noch unzureichend untersucht [ 22 , 26 ].…”