Introduction: Chimeric antigen receptor (CAR) T-cell therapy has shown high response rates and lasting remissions in some patients with relapsed and refractory lymphoid malignancies. However, severe or prolonged thrombocytopenia following CAR-T therapy remains a common adverse event. In this study, we address the question of the mechanism of prolonged thrombocytopenia, specifically hypoproduction versus shortened half-life of the platelets by immune or other mechanism(s).

Methods: We performed a retrospective analysis of 226 patients who received CD19+ targeting CAR-T therapy for lymphoma or lymphocytic leukemia between 2016 to 2025 within our institution. Baseline parameters prior to CAR-T infusion and their relation to hematologic toxicity patterns, such as thrombocytopenia, were investigated up to 1 year following CAR-T infusion. Immature platelet fraction (IPF) was investigated to assess the mechanism of thrombocytopenia following CAR-T therapy. Baseline laboratory values were captured prior to fludarabine and cyclophosphamide conditioning. Hematologic laboratory values were routinely monitored for at least 30 days, or until hematologic recovery.

Results: Mean baseline platelet count was 153 x 10^9/L (range 19-428). The mean platelet nadir was on day 26 (51 x 10^9/L, range 9-200). The platelet counts on day 30 (mean 75, range 7-282), day 60 (mean 54, range 15-127), and day 90 (mean 99.3, range 4-275).

To investigate those patients with severe thrombocytopenia (platelet count <= 30 x 10^9/L), we compared the baseline platelet counts, hemoglobin (Hgb), and absolute neutrophil count (ANC) in the patients with and without severe thrombocytopenia on days 30, 60, and 90 after CAR-T therapy.

Patients with severe thrombocytopenia at 30, 60, and 90 days had significantly lower baseline platelet counts than those without. At 30 days: with severe thrombocytopenia, baseline mean platelets 85 x 10^9/L (% CI 79-90) versus 166 x 10^9/L (CI 169-172). At 60 days: with severe thrombocytopenia, mean platelets 87 x 10^9/L (CI 77-98) versus 157 x 10^9/L (CI 144-170). At 90 days: mean platelets 84 x 10^9/L (CI 69-98) versus 166 x 10^9/L (CI 159-173).

Baseline Hgb levels also correlated with severe thrombocytopenia at 30, 60, and 90 days. Day 30: 9.2 g/dL (CI 9.1-9.3) versus 10.1 (CI 10.0-10.3). Day 60: 9.2 (CI 8.9-9.5) versus 9.8 (CI 9.6-10.1). Day 90: 9.0 (CI 8.7-9.2) versus 10.5 (CI 10.4-10.7). The baseline ANC did not correlate with severe thrombocytopenia at any time point (data not shown).

To differentiate decreased production from increased destruction, we compared the IPF among those with and without severe thrombocytopenia at the 30, 60, and 90 day time points. (Normal IPF, 1.0-5.0%). At day 30, the mean IPF was not significantly increased in the patients with severe thrombocytopenia (5.8% (CI 4.1-7.6)) compared to patients without severe thrombocytopenia (4.6% (3.4-5.8)). While the number of patients with IPF measured were low at days 60 (N=13) and 90 (N=13), the patients with severe thrombocytopenia had lower IPF values than those without.

Conclusion: Our analysis suggests severe thrombocytopenia after CAR-T infusion is typically due to a hypoproliferative process, and not increased platelet destruction or clearance. This is based on two bodies of evidence. First, baseline thrombocytopenia and anemia significantly correlated with prolonged severe thrombocytopenia after CAR-T therapy. This suggests underlying reduced bone marrow reserves. Our findings are similar to the prior findings of the CAR-HEMATOTOX model (Rejeski K, et al, Blood 2021). The non-elevated IPF further supports the hypoproductive mechanism, as IPF is elevated in patients with increased peripheral destruction of platelets (Goel G, et al, J Lab Physicians, 2021).We do not have data to address if CAR-T therapy exacerbates reduced thrombopoiesis, contributing to the severe thrombocytopenia. However, the hypoproduction is at least in large part due to underlying hematopoietic compromise. Our findings help identify a population of patients who may benefit from thrombopoietin enhancing therapy in CAR-T therapy. Our findings also suggest that immune-suppressing therapy may not be appropriate, even with severe thrombocytopenia after CAR-T therapy.

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2025
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