Issue Archive

Bird and Pawlyn review what we know about resistance to a critical class of drugs for the treatment of multiple myeloma: immunomodulatory imide drugs (IMiDs). This class includes thalidomide, lenalidomide, and pomalidomide, all identified initially by empiric means, as well as the cereblon E3 ligase modulators, such as iberdomide and mezigdomide, identified after the mechanism of action of this class of drug was discovered. The authors highlight mechanisms of resistance that directly interfere with the targeting of cereblon, as well as other mechanisms, and discuss potential options to overcome this resistance.

Zinzani and colleagues present long-term follow-up data demonstrating that pembrolizumab, a PD-1 inhibitor, is safe and effective in patients with relapsed/refractory primary mediastinal B-cell lymphoma (PMBCL). Of the 22 of 53 patients (41.5%) enrolled achieving response during up to 2 years of therapy, the estimated freedom from progression at 4 years exceeds 80%. Eleven patients (21%) have sustained complete response without further therapy at 4 years of follow-up, providing compelling evidence that some patients with relapsed PMBCL may be cured with checkpoint blockade alone.

Autologous CD19 chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of pediatric relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). del Bufalo et al report on their experience using donor-derived CAR T cells in patients unsuitable for an autologous approach. Using T cells from either their prior allogeneic stem cell donor or from a designated donor transduced with a second-generation CD19-CAR, the authors report expansion and persistence of CAR T cells and complete remission without measurable residual disease in 13 patients. Eight remain in remission after a median follow-up of 12 months. These exciting results warrant further prospective study.

Children with Down syndrome (DS) have a 20 times higher risk of developing acute lymphoblastic leukemia (ALL). Li et al report on comprehensive genomic and transcriptomic analyses of 295 patients with DS-ALL, identifying 15 distinct molecular subtypes, 3 of which have a much higher frequency in DS-ALL compared to ALL in children without DS. For a common specific subset of BCR::ABL1-like ALL, patients with DS have inferior outcomes to children without DS. These data highlight unexpected genomic heterogeneity and reinforce opportunities for use of targeted therapies.

Iron overload is a common feature in both β-thalassemia major and intermedia due to increased erythropoietic demand, suppression of hepcidin expression, and increased gastrointestinal absorption, with or without transfusions. Yu et al explore the mechanisms of iron homeostasis in β-thalassemia during pregnancy in murine models of these diseases. The authors found that hyperferremia in thalassemic pregnant mice precipitates placental and fetal iron loading, which potentiates development of placental hypertrophy and intrauterine growth restriction. These data help explain some of the increased risk for adverse outcomes of pregnancy in patients with β-thalassemia.

Using single-particle cryo-electron microscopy, Childers and colleagues report on the first structure of factor VIII (FVIII) bound to a recombinant derivative of an anti-C1 domain antibody inhibitor previously isolated from a patient with severe hemophilia A. The inhibitor targets positively charged amino acids on the C1 domain to block FVIII binding to von Willebrand factor, phospholipid membranes, and lipoprotein receptor–related protein 1, which drives FVIII hepatic clearance and antigen presentation in dendritic cells. These data help explain the in vivo consequences of this inhibitor and may assist future engineering of FVIII with a longer half-life due to reduced clearance.