Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients

TY - JOUR

T1 - Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients

AU - Panagiota, Victoria

AU - Kerschbaum, Johanna Franziska

AU - Penack, Olaf

AU - Stein, Catarina M

AU - Arends, Christopher M

AU - Koenecke, Christian

AU - Strzelecka, Paulina M

AU - Kloos, Arnold

AU - Wiegand, Laura

AU - Lasch, Alina

AU - Altwasser, Robert

AU - Halik, Adriane

AU - Gabdoulline, Razif

AU - Thomson, Julia

AU - Weibl, Konstantin

AU - Franke, Georg-Nikolaus

AU - Berger, Carolina

AU - Hasenkamp, Justin

AU - Ayuk, Francis

AU - Na, Il-Kang

AU - Beutel, Gernot

AU - Keller, Ulrich

AU - Bullinger, Lars

AU - Wulf, Gerald Georg

AU - Kröger, Nicolaus

AU - Vucinic, Vladan

AU - Heuser, Michael

AU - Damm, Frederik

N1 - Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.

PY - 2023/10

Y1 - 2023/10

N2 - Recent evidence revealed important interactions between clonal hematopoiesis (CH) and cellular therapies established for the treatment of hematologic malignancies. The impact of CH on safety, efficacy, and outcome of chimeric antigen receptor (CAR) T-cell therapy is currently under investigation. We analyzed 110 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (n = 105) or acute lymphoblastic leukemia (ALL) (n = 5), treated with Axicabtagene-Ciloleucel (39%), Tisagenlecleucel (51%), or Brexucabtagene autoleucel (10%). Using error-corrected targeted sequencing, a high CH prevalence of 56.4% (variant allele frequency [VAF] ≥1%) at the time of CAR T-cell infusion was detected. The most frequently mutated gene was PPM1D followed by DNMT3A, TET2, ASXL1, and TP53. Variant allele frequencies were significantly lower in B and T cells compared with monocytes and granulocytes. CH did not increase the risk of CAR T-related toxicities. The incidences of cytokine release syndrome and immune effector-cell-associated neurotoxicity syndrome were similar between CHpos and CHneg patients, regardless of clone size, age, or CAR T product. Prolonged cytopenias were not associated with CH. Best overall response rates (ORRs) were numerically but not significantly higher in CHpos patients (ORR 76.7% versus 62.2%; P = 0.13). Furthermore, CH status did not predict progression-free survival or overall survival. Lastly, sequential analysis showed a modest VAF increase of 1.3% and acquisition of novel mutations within 100 days postinfusion. CH was frequent in large B-cell lymphoma/ALL patients receiving CAR T-cells but did not affect toxicity nor treatment response or outcome.

AB - Recent evidence revealed important interactions between clonal hematopoiesis (CH) and cellular therapies established for the treatment of hematologic malignancies. The impact of CH on safety, efficacy, and outcome of chimeric antigen receptor (CAR) T-cell therapy is currently under investigation. We analyzed 110 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (n = 105) or acute lymphoblastic leukemia (ALL) (n = 5), treated with Axicabtagene-Ciloleucel (39%), Tisagenlecleucel (51%), or Brexucabtagene autoleucel (10%). Using error-corrected targeted sequencing, a high CH prevalence of 56.4% (variant allele frequency [VAF] ≥1%) at the time of CAR T-cell infusion was detected. The most frequently mutated gene was PPM1D followed by DNMT3A, TET2, ASXL1, and TP53. Variant allele frequencies were significantly lower in B and T cells compared with monocytes and granulocytes. CH did not increase the risk of CAR T-related toxicities. The incidences of cytokine release syndrome and immune effector-cell-associated neurotoxicity syndrome were similar between CHpos and CHneg patients, regardless of clone size, age, or CAR T product. Prolonged cytopenias were not associated with CH. Best overall response rates (ORRs) were numerically but not significantly higher in CHpos patients (ORR 76.7% versus 62.2%; P = 0.13). Furthermore, CH status did not predict progression-free survival or overall survival. Lastly, sequential analysis showed a modest VAF increase of 1.3% and acquisition of novel mutations within 100 days postinfusion. CH was frequent in large B-cell lymphoma/ALL patients receiving CAR T-cells but did not affect toxicity nor treatment response or outcome.

U2 - 10.1097/HS9.0000000000000957

DO - 10.1097/HS9.0000000000000957

M3 - SCORING: Journal article

C2 - 37799345

VL - 7

SP - e957

JO - HEMASPHERE

JF - HEMASPHERE

SN - 2572-9241

IS - 10

ER -