Pingnan Xiao

Patients with relapsed/refractory multiple myeloma (R/R MM) receiving chimeric antigen receptor (CAR) T-cell therapy are at high risk of toxicities, including cytokine release syndrome (CRS). The roles of positron emission-tomography computed tomography (PET/CT) in predicting these toxicities remain unclear. We retrospectively studied 62 patients with R/R MM who received B-cell maturation antigen (BCMA) CAR T-cell therapy at our center. Baseline metabolic tumor volume (MTV) of more than 107.2 cm³ and total lesion glycolysis (TLG) exceeding 406.5 were classified as high MTV and high TLG, respectively. Both high MTV (P = 0.008) and high TLG (P = 0.011) were identified as independent risk factors for the development of severe CRS classified as grade 3 to 4. Moreover, the administration of tocilizumab for the treatment of CRS was associated with high MTV (P = 0.005) or high TLG (P = 0.010). Notably, our multivariate Cox models that incorporated either MTV (P = 0.029) or TLG (P = 0.009) along with plasmacytoma types, high-risk cytogenetics, and high bone marrow plasma cell frequencies demonstrated strong predictive capabilities for the 5.3-year long-term OS. Therefore, baseline high MTV or TLG measured by PET/CT are recognized as adverse prognostic indicators for the incidence of severe CRS and poor outcomes in patients with R/R MM undergoing BCMA CAR T-cell therapy.

Leukemia cutis or leukemic cell infiltration in skin is one of the common extramedullary manifestations of acute myeloid leukemia (AML) and signifies a poorer prognosis. However, its pathogenesis and maintenance remain understudied. Here, we report massive AML cell infiltration in the skin in a transplantation-induced MLL-AF9 AML mouse model. These AML cells could regenerate AML after transplantation. Prospective niche characterization revealed that skin harbored mesenchymal progenitor cells (MPCs) with a similar phenotype as BM mesenchymal stem cells. These skin MPCs protected AML-initiating stem cells (LSCs) from chemotherapy in vitro partially via mitochondrial transfer. Furthermore, Lama4 deletion in skin MPCs promoted AML LSC proliferation and chemoresistance. Importantly, more chemoresistant AML LSCs appeared to be retained in Lama4−/− mouse skin after cytarabine treatment. Our study reveals the characteristics and previously unrecognized roles of skin mesenchymal niches in maintaining and protecting AML LSCs during chemotherapy, meriting future exploration of their impact on AML relapse.