Issue Archive

Light-chain amyloidosis (AL amyloidosis) is a clonal plasma cell disorder causing fatal organ dysfunction due to light-chain deposition and toxic fibril formation. Wechalekar and Sanchorawala provide this Blood Spotlight review of daratumumab-based regimens in this disease, highlighting their ability to achieve deep clonal remissions and improve outcomes.

Ruggeri et al identify a novel mechanism by which donor natural killer (NK) cells in an allograft accelerate posttransplant immune reconstitution. Using murine models, they demonstrate that donor NK cells kill recipient-type dendritic cells in the first days after transplantation, releasing β-2-microglobulin that enhances immune reconstitution by sustaining the proliferation of thymic epithelial cells. These intriguing data may lead to new therapies to enhance T-cell reconstitution in HLA-mismatched allogeneic transplant recipients.

Combining Bruton tyrosine kinase inhibitors with the BCL2 inhibitor venetoclax increases efficacy in patients with relapsed chronic lymphocytic leukemia but with increased toxicity and cost. Scarfò and colleagues report on the prospective IMPROVE trial evaluating a minimal residual disease (MRD)-driven approach to individualized treatment, commencing with venetoclax and only adding ibrutinib if MRD persists while discontinuing all therapy after a fixed duration if MRD is undetectable. These phase 2 data provide proof-of-concept and encourage randomized trials to define the optimal ways to combine these drugs.

Most acute promyelocytic leukemia (APL) are highly sensitive to retinoic acid (RA), with variant APL bearing the PLZF-RARA fusion oncoprotein being a notable exception. Using murine transgenic models, Poplineau and colleagues identify an RA resistance network involving the E2F-EZH2 axis, with the nonenzymatic activity of EZH2 critically involved. Targeting pan-EZH2 activity significantly improves survival in mice reconstituted by RA-resistant PLZF-RARA leukemia cells, suggesting a potential new avenue for therapy.

The causative role of a disturbed microbiome in the generation of acute graft-versus-host disease (aGVHD) is now accepted but remains ill understood. Burgos da Silva and colleagues describe features of the intestinal microbiome that associate with organ-specific GVHD and clinical outcomes in patients undergoing allogeneic hematopoietic cell transplantation. These data suggest that microbiome-derived biomarkers and prophylactic interventions could be developed for aGVHD treatment.

Refractoriness to platelet transfusion is a major problem in a small group of patients, and large-scale manufacturing of clinical grade functional platelets ex vivo has remained an elusive goal. Sugimoto et al report on the results of the first clinical trial of an autologous transfusion of induced pluripotent stem cell (iPSC)-derived platelets in a patient who had severe aplastic anemia but no compatible platelet donor. Using methodology described in a complementary article in Blood Advances, the results provide proof-of-principle and illustrate the challenges to be faced in taking this approach further.