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

Abstract

We present the case of a 64-year-old man diagnosed with large B-cell lymphoma who relapsed twice after standard-of-care therapy. Due to persisting cytopenia, Next generation sequencing analysis was performed, revealing a small TP53-mutated clone. As a third-line therapy, the patient was treated with CAR-T cells, which resulted in complete remission. However, this treatment also led to the expansion of the TP53-mutated clone and therapy-related myelodysplasia with a complex aberrant karyotype. This case may serve as a paradigmatic example of clonal hematopoietic progression in a patient undergoing CAR-T cell therapy, especially in the context of a TP53-mutated clone.

Hematopoiesis and immune reconstitution after CD19 directed chimeric antigen receptor T‐cells (CAR‐T): A comprehensive review on incidence, risk factors and current management

“…CD8+ T‐cells and CD56+ natural killer (NK) cells fully recovered in all patients by 1 year, while reconstitution of CD4+ T cells was delayed, with normalization in only 67% of patients at 1 year. Similarly, in 39 CAR‐T recipients with R/R, the absolute counts of CD4+, CD8+, and CD16/56+ lymphocytes decreased significantly after lymphodepleting chemotherapy: while CD8+ and CD16/CD56+ cell counts rapidly recovered in all patients at a median time of 21 days, 7–10,12–15,17,21,22,24–64,66–92 a slower recovery was observed for CD4+, which recovered within 60 days in only 5 (23.81%) of patients 71 …”

“…17,52,53,59 Although the presence of a CH prior to CAR-T cell therapy does not appear to affect survival, it might predict increased response, higher risk for clinically significant CRS and higher risk for myeloid neoplasm in presence of TP53. 52,53,60 With regards to CHIP occurring after CAR-T cell therapy, it has been shown that patients with preexisting CHIP, may acquire new mutations or expanded their previous VAF during follow-up. 53 The cumulative incidence of t-MN at 24 months appeared significantly higher for patients with preexisting CHIP as compared to CAR-T cell recipients without prior CHIP (19% vs. 4.2%).…”

“…The nadir of IgG was reached in median at day 44 (range 7-153) and recovery occurred in 28.5% of patients at a median of 184 days. 73 In the cohort of pediatric pts with B-ALL, Deyà-Martinez et al, observed that 71% of patients developed undetectable IgM levels at a median of 71 days after infusion 9,11,14,[16][17][18][19][20][21][22]36,[50][51][52][53][54][55][56][57][58][59][60][61][62][63][64] ; IgA levels decreased in 13% of patients to undetectable levels at 185 days after infusion . Patients with undetectable IgM, showed a longer CAR-T persistence (373.5 vs. 60 days; p: <.001).…”

“…It is difficult to consider CAR‐T therapy as causative of clonal hematopoiesis (CH), and this can be excluded when a CH already existed before CAR‐T cell infusion 17,52,53,59 . Although the presence of a CH prior to CAR‐T cell therapy does not appear to affect survival, it might predict increased response, higher risk for clinically significant CRS and higher risk for myeloid neoplasm in presence of TP53 52,53,60 . With regards to CHIP occurring after CAR‐T cell therapy, it has been shown that patients with preexisting CHIP, may acquire new mutations or expanded their previous VAF during follow‐up 53 .…”

“…In the cohort of pediatric pts with B‐ALL, Deyà‐Martinez et al, observed that 71% of patients developed undetectable IgM levels at a median of 71 days after infusion 9,11,14,16–22,36,50–64,66–98 ; IgA levels decreased in 13% of patients to undetectable levels at 185 days after infusion (11–308). Patients with undetectable IgM, showed a longer CAR‐T persistence (373.5 vs. 60 days; p : <.001).…”