Prevalence and variation of CHIP in patients with aggressive lymphomas undergoing CD19-directed CAR T-cell treatment

Abstract

Inflammation plays an important role in CAR-T-cell therapy, especially in the pathophysiology of cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Clonal hematopoiesis of indetermined potential (CHIP) has also been associated with chronic inflammation. The relevance of CHIP in the context of CAR-T-cell treatment is currently widely unknown. We longitudinally evaluated the prevalence of CHIP, using a targeted deep sequencing approach in a cohort of patients with r/r B-NHL before and after CAR-T-cell treatment. The aim was to define the prevalence and variation of CHIP over time and to assess the influence on clinical inflammation syndromes (CRS/ICANS), cytopenia and outcome. Overall, 32 patients were included. CHIP was found in 11 of 32 patients (34 %) before CAR-T-cell therapy. CHIP progression was commonly detected in the later course. Patients with CHIP showed a comparable response rate to CAR-T-cell treatment but had an improved OS (not reached vs. 265 days, p=0.003). No significant difference was observed in terms of the occurrence and severity of CRS/ICANS, therapeutic usage of tocilizumab and glucocorticosteroids, paraclinical markers of inflammation (except ferritin) or dynamics of hematopoietic recovery. CHIP is commonly observed in patients undergoing CD19-directed CAR-T-cell therapy and is not associated with an inferior outcome.

Fatal Progression of Mutated TP53-Associated Clonal Hematopoiesis following Anti-CD19 CAR-T Cell Therapy

“…The impact of genotoxic stress on the hematopoietic system associated with the cytokine and/or microenvironmental changes post-CAR-T cell therapy remain to be elucidated and the observation periods of most studies are still limited. Based on our observation together with other publications [9][10][11][12], we advocate for an early screening as well as thorough and extended follow-ups of CH with TP53 alterations in patients receiving CAR-T cell therapy.…”

“…In three retrospective cohorts of non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM) patients treated with different CAR-T constructs, CH was detected in 34% to 48% prior to CAR-T treatment. However, CH was not associated with differences in progression-free or overall survival [9][10][11]. The most commonly affected genes were DNMT3A, ASXL1, TET2, and TP53, reflecting the findings of individuals that were not treated with CAR-T cell therapy [9,19,20].…”

“…Early and late onset cytopenia represent common side effects of chimeric antigen receptor (CAR)-T cell therapy, to which lymphodepleting preparative therapy, prior lines of chemo-or radiotherapy, and severe cytokine release syndrome (CRS) may contribute [1][2][3][4][5][6][7][8]. Clonal hematopoiesis (CH) is frequently found in lymphoma and myeloma patients undergoing CAR-T cell therapy and has not been associated with adverse outcomes in published retrospective studies across current genetic markers for CH [9][10][11][12]. However, due to the low patient numbers in these studies, the implications of specific CH-associated genetic alterations remain unclear.…”

Klonale Hämatopoese – Bedeutung für die Zelltherapie

“…Die bisher existierenden Daten zu dieser Thematik zeigen eine durchgängig hohe Prävalenz von CH vor einer CAR-T-Zell-Therapie (34–48 %), was unter anderem auf die intensive Vorbehandlung dieser Patient*innen zurückgeführt werden kann. Darüber hinaus fand sich in einer longitudinalen Analyse von Patient*innen nach CAR-T-Zell-Therapie häufig eine klonale Progression im Langzeitverlauf, was in diesem Kontext für die Entwicklung sekundärer myeloischer Neoplasien von Bedeutung sein könnte [ 26 ]. 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 ]. Im Gegensatz zur autologen Transplantation scheint das Vorliegen einer CH im Rahmen einer CAR-T-Zell-Therapie bisher nicht mit einem schlechteren Überleben assoziiert zu sein.…”