Platelet transfusion is important in the prevention and treatment of bleeding in patients with acute myeloid leukemia (AML) after receiving intensive chemotherapy. However, platelet transfusion refractoriness (PTR) is an intractable clinical issue occurred in these patients. And its clinical and immunological features remain largely unknown. The potential causes and clinical features of PTR were retrospectively analyzed in 560 patients who were diagnosed as de novo AML in Tongji Hospital from June 2012 through June 2018. A high‐throughput antibody screening for the detection of human leukocyte antigen (HLA) and its serotypes was performed in 133 newly diagnosed AML patients. PTR occurred in 11.8% of the de novo AML patients. The median age for patients with PTR was 46 years (range, 15‐70). It frequently manifested in female patients and in patients with splenomegaly, M4 subtype, c‐Kit gene mutation, and rearrangements of RUNX1‐RUNX1T1 or CBFB‐MYH11, commonly referred to as core binding factor AML (CBF‐AML). Notably, CBF‐AML was independently associated with the occurrence of PTR. PTR predominantly developed in patients who had CBF‐AML (P < .001) and in patients who further had better minimal residual disease (MRD) reduction (≥3‐log) before the second consolidation chemotherapy (P = .007). HLA‐I antibodies were detected in the serum of 9.0% of AML patients and markedly enriched in patients with PTR (P < .001) and in patients with CBF‐AML (P = .018). HLA‐B was the most frequently identified serum epitope in PTR patients. Patients with CBF‐AML had higher tendency to develop HLA‐I antibodies and PTR, which depicted novel features of PTR in AML and might provide insights into its efficient managements.

Poly(ADP-ribose) polymerase inhibitors (PARPis) are a class of agents targeting DNA damage repair that have become standard therapy for epithelial ovarian cancer (EOC) and multiple other solid tumors. In addition to targeting DNA damage repair, PARPis actively modulate antitumor immune responses, with efficacy being partially dependent on T cell activity. Here, we found that patient T cells sustain DNA damage during PARPi treatment, which reduces treatment efficacy. Leveraging paired pre- and posttreatment tumor samples from a clinical trial of patients with EOC treated with neoadjuvant niraparib as monotherapy, we showed that the PARPi caused DNA damage, slowed proliferation, and increased apoptosis in T cells, which we validated both in vitro and in mouse models. A genome-wide CRISPR (clustered regularly interspaced short palindromic repeats) knockout screen in primary human T cells identified PARP1 as the principal mediator of PARPi-induced T cell death. T cell–specific deletion of PARP1 or mutating Parp1 at its binding sites in transgenic mice led to reduced T cell DNA damage during PARPi treatment, resulting in improved efficacy of PARPis, alone or in combination with immune checkpoint inhibition. We then engineered PARPi-tolerant CAR T cells using cytosine base editing, which decreased PARPi-induced PARP1 trapping and led to reduced PARPi-induced DNA damage, resulting in superior antitumor efficacy in xenograft models compared with parental CAR T cells. This study highlights the relevance of PARPi-induced DNA damage to T cells and suggests opportunities to improve the efficacy of PARPis as monotherapy or in combination with immunotherapy.

(1) Background: The combination of CAR-T with ASCT has been observed to enhance the efficacy of CAR-T cell therapy. However, the impact of this combination on adverse reactions is still uncertain. (2) Methods: Between January 2019 and February 2023, 292 patients diagnosed with r/r B-cell lymphoma received either CAR-T therapy alone or in combination with ASCT at our institution. We evaluated the incidence of CRS and CRES and utilized a logistic regression model to identify factors contributing to severe CRS (grade 3–4) and CRES (grade 3–4). (3) Results: The overall incidence of CRS and CRES was 78.9% and 8.2% in 147 patients receiving CAR-T alone, and 95.9% and 15.2% in 145 patients receiving CAR-T combined with ASCT, respectively. The incidence of overall CRS (p < 0.0001) and mild CRS (grade 1–2) (p = 0.021) was elevated in the ASCT combined with CAR-T group. No significant difference was observed in severe CRS and CRES between the groups. Among the 26 cases of lymphoma involving the central nervous system (CNS), 96.2% (25/26) developed CRS (15.4% grade 3–4), and 34.6% (9/26) manifested CRES (7.7% grade 3–4). Female patients had a lower incidence of severe CRS but a higher incidence of severe CRES. Lymphomas with CNS involvement demonstrated a higher risk of CRES compared to those without central involvement. (4) Conclusions: The combination of ASCT with CAR-T demonstrated a preferable option in r/r B-cell lymphoma without an increased incidence of severe CRS and CRES.