Issue Archive

In this Blood Spotlight review, Stubbins and colleagues summarize recent data showing that the effect inflammation has on leukemic and normal myeloid cells in the marrow is pathway-, cytokine-, and cell context–dependent. They suggest how understanding this heterogeneity should influence the choice of anti-inflammatory agents for preclinical testing and clinical trials in various myeloid neoplasms.

Arruda et al review the alloimmune and autoimmune responses to procoagulant factors that cause serious bleeding and the important, unresolved problems of how to prevent and treat these conditions. They integrate the underlying pathophysiology with relevant clinical findings and outcomes with current treatment approaches while highlighting preclinical developments that are being explored and that may lead to new treatments.

Parekh et al report on secondary analyses of a frontline pediatric Hodgkin lymphoma phase 3 trial to investigate how speed of response may predict outcome and the impact of radiation therapy. They demonstrated that early positron emission tomography (PET) response after 1 cycle of chemotherapy is associated with a favorable outcome and that involved-field radiotherapy mitigates the relapse risks in those without an early PET response. These data help inform the next generation of trials in this disease.

Gout is a common inflammatory arthritis defined by NLRP3 inflammasome– and IL1β-dependent innate immune responses to monosodium urate (MSU) crystals. Agrawal et al identified clonal hematopoiesis of indeterminate potential (CHIP) as a risk factor for gout by analyzing data from 2 large biobanks. In mechanistic studies, they showed that Tet2-knockout mice experienced increased MSU-induced inflammation in an NLRP inflammasome–dependent manner due to the greater production of IL1β by macrophages. These data explain why gout is more common in people with TET2-mutant CHIP.

Bispecific antibodies that direct T-cell engagement with malignant blood cells are showing exciting potential in many relapsed hematological malignancies, but their optimal use remains undefined. Philipp et al show for the first time that continuous engagement of T cells by bispecific antibodies leads to their exhaustion, whereas including treatment-free intervals in the schedule helps preserve the fitness of immune effectors and can improve long-term results in model systems. These data call for clinical trials comparing current continuous schedules to ones that include treatment-free intervals.

Through genomic profiling, activated B-cell-like diffuse large B-cell lymphoma (DLBCL) is now recognized to have distinct subgroups that may have distinct cells-of-origin. Pindzola et al generated immunocompetent mice carrying 4 hallmark genetic alterations associated with the MYD88/CD79B-mutated (MCD) genetic subgroup. The mice showed a massive expansion of splenic germinal centers and developed DLBCL with age, revealing splenic germinal center B cells as a likely cell of origin for this subgroup.

Mild hemophilia is not always a benign disease and may present an increased bleeding risk with intense physical activities. In a randomized trial, Kumar and colleagues compared the effects of exercise versus intranasal desmopressin versus the combination of both on the rise in factor VIII:C (FVIII:C) in patients with mild hemophilia A. They demonstrated substantial rises with exercise, similar to that achieved with desmopressin, and showed that the combination generated more sustained increases in FVIII:C, with normalization in more than half the subjects.

Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplantation (HCT) is common. Ho and colleagues report that inhibition of mouse-double-minute-2 (MDM2) increases the potency of T-cell responses to AML and facilitates the “graft-versusleukemia” effect in murine models of HCT. This strategy is being tested in a clinical trial and could also be evaluated in the future in the context of targeted T-cell therapies, such as chimeric antigen receptor T cells.