Issue Archive

Outcomes for patients with paroxysmal nocturnal hemoglobinuria have been markedly improved by the introduction of complement inhibitors; however, breakthrough hemolysis remains a persistent challenge in a significant minority of patients. Fattizzo et al reviewed the published rates of breakthrough hemolysis for each of the marketed anticomplement agents and summarized clinical factors associating with episodes. The authors provide advice on management of this problem in routine practice for physicians and patients.

Cytokine release syndrome (CRS) is a major toxicity of chimeric antigen receptor T-cell therapy (CAR-T). Frigault and colleagues report a 2-part phase 2 trial, including randomization against placebo, of the Janus kinase 1 inhibitor itacitinib as prophylaxis against CRS during CAR-T for lymphoma. The authors’ results suggest that itacitinib significantly reduced severe CRS without compromising efficacy and may also reduce immune cell–associated neurotoxicity syndrome. Larger formal phase 3 trials are required to confirm these very encouraging observations and to exclude any unexpected safety signals.

As new therapies against acute leukemias are deployed, unusual mechanisms of resistance can become prominent. Lineage switching from B-cell acute lymphoblastic leukemia (B-ALL) to myeloid leukemia is an increasingly common cause of relapse after immunotherapies such as blinatumomab and chimeric antigen receptor T-cell therapy. In an international retrospective study of lineage switching after immunotherapy, Silbert and colleagues revealed that this typically occurs early after therapy (median <2 months), often despite achieving molecular remission, and is most prevalent in B-ALL with KMT2A rearrangement. As outcomes are dismal, new strategies are needed for early intervention.

Other than well-defined intrinsic genetic changes in myeloma cells, why do some patients with multiple myeloma do well in the long term? Kim et al identified that higher CD4⁺/CD8⁺ T-cell ratios associate with better outcomes and analyzed the CD4⁺ T-cell compartment in the bone marrow using single-cell RNA sequencing coupled with single-cell T-cell receptor sequencing. The authors revealed the presence of a subset of helper CD4⁺ T cells with the capacity to recognize and kill autologous myeloma cells and showed how cytotoxicity can be downregulated by blockade of the cell surface receptor NKG2D, providing at least a partial explanation for the original clinical observation.

The efficacy of the anti-CD22 antibody calicheamicin drug conjugate inotuzumab ozogamicin (InO) in B-cell acute lymphoblastic leukemia (B-ALL) is variable for unknown reasons. Escherich and colleagues used patient samples and preclinical models to demonstrate that InO sensitivity in B-ALL depends on the stage of B-cell developmental arrest and identified CD22 as a direct transcriptional target of early B-cell factor 1 (EBF1). The authors showed that B-ALL samples exhibiting gene-regulatory profiles resembling those of normal pre-pro-B cells prior to EBF1 activation have reduced responsiveness to InO, providing strong clues to the mechanisms underpinning interpatient heterogeneity in response.

Jak2 V617F gain-of-function mutation in hematopoietic stem cells (HSCs) drives myeloproliferation, but factors determining whether this manifests clinically as polycythemia vera, essential thrombocytosis, or myelofibrosis remain incompletely understood. Using precise gene modification in murine models with high clinical fidelity, Papadopoulos et al delineated how specific phenotypes were dependent or independent of signaling from myeloproliferative leukemia (Mpl), the thrombopoietin receptor. As HSC expansion in particular is Mpl-dependent, these findings underscore the potential for therapeutic modulation of Mpl signaling in selected Jak2 V617F myeloproliferative neoplasms.

In addition to vaccine-induced thrombotic thrombocytopenia (VITT), adenovirus vector-based COVID vaccines have been associated with increased risk of thrombotic events, including cerebral venous thrombosis, ischemic stroke, and myocardial infarction. In a microfluidic study mimicking arterial flow, Chen et al identified a novel shear-dependent platelet aggregation mechanism induced by the binding of platelet integrin α_IIbβ₃ to the arginine-glycine-aspartate sequence of the viral capsid, distinct from VITT. These results help explain the excess thrombotic events without thrombocytopenia.

Our understanding of blood group antigens is evolving but has been limited by the need for structural studies to define changes in protein structure. Howe and Stack explored the predicted structural changes introduced by amino acid substitutions and how they link to the immunogenicity of clinically relevant blood group antigens. The authors’ findings indicate that many blood group antigens are buried or partially buried in rigid, ordered protein regions.