Issue Archive

Saultier and Michel provide guidance on the risk-stratification, diagnosis, and clinical management principles underpinning care for the ever-increasing number of survivors of childhood leukemia. Using illustrative cases, the authors highlight the importance of early diagnosis of key long-term complications across multiple organ systems that benefit from intervention.

Caplacizumab is approved as an addition to plasma exchange (PEX) and immunosuppression for the treatment of acute autoimmune thrombotic thrombocytopenic purpura; however, it is controversial whether caplacizumab use delays recovery of ADAMTS13. Mingot-Castellano and colleagues, on behalf of the Spanish Apheresis Group and the Spanish Registry of Thrombotic Thrombocytopenic Purpura, present a retrospective study demonstrating that recovery of ADAMTS13 levels to ≥20% is similar whether caplacizumab is used or not. The early addition of caplacizumab enables earlier discontinuation of PEX.

As bispecific antibodies rapidly emerge as a new wave of immunotherapy for hematological malignancies, there are still lessons to be learned from how monoclonal antibody efficacy is influenced by interactions with immune cells. Arora and colleagues used humanized mouse models and samples from patients during therapy to show that T-cell help in the tumor microenvironment enhances rituximab-mediated natural killer (NK) cell viability, CD16 and CD25 expression, and antitumor responses. The authors’ data provide exciting clues as to how to further enhance immunotherapy design.

The first-in-class selective BCL2 inhibitor (BCL2i), venetoclax, has improved outcomes for patients with chronic lymphocytic leukemia and acute myeloid leukemia. Liu and colleagues reveal the structure and preclinical characterization of a new BCL2i, sonrotoclax, which binds with higher affinity to BCL2 than venetoclax and induces apoptosis in models of venetoclax-induced BCL2 mutations. These data suggest that sonrotoclax could find clinical applications in BCL2-dependent malignancies and underpin ongoing early-phase clinical trials with the drug.

Idiopathic multicentric Castleman disease (iMCD) encompasses several disorders with similar distinctive lymph node histological features. Half of the cases are associated with either human herpesvirus 8 infection or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome, while causation is unknown in the remaining cases. Chan et al investigated iMCD in identical twins, finding 2 potentially causative germ line mutations. Through advanced single-cell omics, the authors pinpointed nodal fibroblastic reticular cells and endothelial cells as the cells that overproduce interleukin-6, which drives the disease.

Circulating factor VIII (FVIII) levels and those of its carrier protein, von Willebrand factor (VWF), are typically correlated and their levels are largely genetically determined. de Vries and colleagues performed a massive genome-wide association study utilizing whole genome sequencing to identify several new genetic determinants of FVIII and VWF levels, including 3 loci that only modulate FVIII levels, including genes encoding modulators of FVIII release.

Minor histocompatibility antigen (MiHA) mismatch explains the persistence of severe graft-versus-host-disease in recipients of matched allogeneic hematopoietic cell transplants. Fuchs et al further our understanding of the repertoire of MiHAs, identifying many new antigens that are targeted in multiple patients. The authors’ work also suggests several new potential immunotherapy targets in the form of MiHAs that have expression restricted to blood cells.