Issue Archive

How we define remission and relapse in devastating diseases helps guide clinical trials and practice to test and incorporate new therapies. In this Special Report, Cuker and colleagues propose revised outcome definitions for immune thrombotic thrombocytopenic purpura (TTP) which incorporate mechanistic insights that may better inform treatment choices of existing and novel therapeutics. The authors discuss how these guidelines are relevant to contemporary clinical practice while awaiting prospective validation.

With the explosion of data around clonal evolution in malignancy and in clonal hematopoiesis in general, it is timely to question the assumption that the "natural selection" model readily explains most patterns of clonal evolution. This Perspective challenges researchers to think beyond dogma and consider the possibility that neutral evolution may play a role in shaping the overall progression of disease, either alone or in combination with natural selection.

Pediatric practice has shown that adapting intensity of treatment for acute lymphoblastic leukemia in children according to clinical, genetic, and response depth parameters optimizes outcomes. Ribera et al extend these findings to adult patients up to age 60 with selected high-risk features. They demonstrate that depth of response, as assessed by measurable residual disease (MRD), is a strong predictive tool and that high-risk patients who achieve MRD negativity can forgo allogeneic hematopoietic transplantation without impairing long-term survival.

The discovery of mutations in calreticulin (CALR) among myeloproliferative neoplasms (MPNs) filled in a missing piece of the pathobiological puzzle for these disorders. These mutations confer cytokine independence, allowing thrombopoietin receptor–dependent transformation and identifying CALR as a potential target for therapy. Using in silico modeling and functional assays, Jia et al identified hematoxylin as an inhibitor of the glycan-binding domain of CALR, moving the field 1 step closer to drug development.

Vacuolar protein sorting 45 (VPS45) deficiency is associated with a poorly understood entity of neutropenia, myelofibrosis, and myelodysplastic syndrome. Frey and colleagues created a knockout model of VPS45, revealing a role for VPS45 in late endosome maturation, and demonstrated that VPS45 deficiency results in dysfunctional endosomal trafficking of granulocyte colony-stimulating factor receptor to the lysosome. This sets the scene for further work to define how these alterations in fundamental cell biology cause the specific hematological phenotype.

Mulder and colleagues report a population-based observational study that provides contemporary estimates of the incidence of venous thromboembolism in patients with cancer. They document a threefold rise in overall incidence and a sixfold rise in patients receiving modern anticancer therapies over the last 2 decades. They note associations with increases in treatment durations and survival as well as use of computed tomography scans. These data further inform clinicians who are treating cancer patients and considering the issue of anticoagulation as primary prophylaxis.

Kennedy et al report an investigator-initiated, randomized, placebo-controlled, double-blind trial of graft-versus-host disease (GVHD) prophylaxis. They report that adding a single dose of the interleukin-6 receptor–blocking antibody tocilizumab has a modest impact on the incidence of grade 2 but not grade 3 and 4 acute GVHD and does not appear to affect relapse or nonrelapse mortality outcomes.