Issue Archive

Roncador and colleagues trace the evolution of what we now recognize as myelodysplastic syndrome with isolated deletion 5q (MDS-5q) from its original description through being considered as a discrete clinical entity into one that includes other genetic abnormalities and whose clinical course is heavily influenced by comutations. This Special Report from a team of experts provides strong diagnostic and management principles for clinicians, clinical trialists, and researchers alike and highlights the ongoing role of lenalidomide in management and the imperative to identify patients with multihit TP53 mutations. With allogeneic transplantation remaining the only curative therapy, the precision medicine approach that they outline enables risk-based decision-making by patients and their physicians considering this option.

Acute graft-versus-host disease (aGVHD) contributes substantially to early post–allogeneic stem cell transplant morbidity and mortality, especially if there is not a prompt response to steroids. Recently, the FDA approved remestemcel-L-rknd (Ryoncil), an off-the-shelf mesenchymal stromal cell (MSC) therapy for children with steroid-refractory aGVHD. In this Blood Spotlight, Etra and colleagues highlight the preclinical data suggesting how MSCs modulate GVHD and the clinical data that underpin the approval, while posing key questions that remain unanswered about this novel approach.

Treatment of primary or secondary central nervous system (CNS) lymphoma with CD19-directed chimeric antigen receptor (CAR) T cells can be effective, but tumor inflammation–associated neurotoxicity (TIAN) is an increasingly recognized problem. Kaulen et al provide a comprehensive description of this pseudoprogression syndrome in 10 of 60 patients, revealing that it reflects local inflammation, is more common with larger CNS lesions, and is correlated with better overall responses and progression-free survival. These data enhance understanding and guide approaches to diagnosis and management.

CD99 is a marker of leukemia stem cells (LSCs). Ji et al used murine models to investigate its pathophysiological role, finding that it downregulates protein synthesis, thereby enabling maintenance of self-renewal and function of both hematopoietic stem cells (HSCs) and LSCs. These data provide novel insights into how HSCs control proteotoxic stress and highlight a potential vulnerability in LSCs that may be targetable for therapeutic benefit.

Targeting B-cell maturation antigen (BCMA) with T-cell–engaging therapies has been an important advance for treatment of multiple myeloma, but data for light-chain (AL) amyloidosis are scant. Vianna et al report 9 patients with daratumumab-refractory AL amyloidosis treated with the BCMA-targeting bispecific antibody elranatamab as monotherapy, finding rapid hematological responses and organ responses within 6 months in the majority. These encouraging preliminary data, including patients with advanced cardiac disease, warrant larger prospective trials.

In thrombopoiesis, a choreographed cytoskeletal program governs megakaryocyte maturation, polarization, and proplatelet formation. Kollotzek et al identify casein kinase 1α (CK1α) as a key regulator of these processes in both murine and human systems, uncovering its role as an important signaling molecule in megakaryocyte cytoskeletal dynamics and polarization, proplatelet formation, and polyploidization. This study expands our understanding of thrombopoiesis by identifying CK1α as a crucial gatekeeper that regulates cytoskeletal dynamics in megakaryocytes and may justify a reexamination of CK1α-targeted therapies.

Hemophilic arthropathy remains a major clinical problem despite therapeutic advances. Hawerkamp and colleagues report a new murine model that exhibits high rates of spontaneous joint bleeding and damage. They exploited it to uncover the key role of the interleukin-33 receptor, ST2, in driving bleeding-associated joint inflammation and provide compelling data to suggest that this receptor may be a therapeutic target.

Up to 30% of women who carry factor VIII (FVIII) mutations have low FVIII levels that predispose them to bleed excessively after surgery and tissue damage and to experience abnormal uterine bleeding. In this month’s CME article, using data from 361 female carriers, Guillet and colleagues identify that that the response to desmopressin in this patient group is strongly influenced by F8 variant type and body weight, with the postdesmopressin FVIII response lower at peak and inadequate in more carriers of null variants. These findings provide a strong evidence base for selection of desmopressin dosing in female carriers of hemophilia A.