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In a landmark Special Report led by Buchmann, authors from among the largest international pediatric cooperative groups report on key steps towards harmonizing definitions for complete remission, treatment failure, and relapse in patients with acute lymphoblastic leukemia (ALL). By applying these modern definitions, comparisons can be made between studies in different parts of the world and international collaborations enhanced to expedite improvements in care.


Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) refractory to ibrutinib and bearing unfavourable genetics have a very poor prognosis. Siddiqi and colleagues summarize the first results of a phase 1 trial of the anti-CD19 chimeric antigen receptor T-cell (CAR T) product, lisocabtagene, in 25 such patients, reporting frequent mild cytokine release syndrome, with high-grade neurological toxicity in one-fifth of the patients. Preliminary efficacy appears promising, with 10 patients achieving complete remission and nine without detectable minimal residual disease. Mature phase 2 data are needed to assess the lasting clinical benefits from this specific CAR T approach.

Telomeres are specialized structures at the ends of chromosomes that maintain genomic stability. Niewisch et al document the clinical features, including bone marrow failure and survival outcomes associated with different germline genotypes of telomere biology disorders in 200 patients. They show that both genotype and inheritance pattern affect outcomes, thereby better informing risk stratification and clinical management of patients with these rare diseases.



Using comprehensive integrated genomic analyses in a cohort of 354 trial patients ages 15 to 64 years, Yasuda and colleagues define the landscape of adult Philadelphia chromosome–negative B-cell acute lymphoblastic leukemia (ALL). Two new high-risk subtypes not seen in pediatric populations are identified, one characterized by high CDX2 expression and the other by IDH1/2 mutations. These discoveries generate new questions about ALL biology and provide avenues for improved therapy for patients with very poor prognosis.

There is excitement about the potential for circulating tumor DNA (ctDNA) assays to better inform care of patients with diffuse large B-cell lymphoma beyond existing data from tumor biopsies, imaging, and clinical estimates. In a rigorous prospective validation, Meriranta et al report on a trial-based analysis of the prognostic utility of ctDNA in the pretreatment, on-treatment, and end-of-treatment settings beyond what can be achieved with tumor biopsies and imaging. Furthermore, they highlight the concept that ctDNA is not a single assay but rather a substrate that can be informatively assayed in different dimensions according to the clinical setting.


Interleukin-33 (IL-33) is expressed by gut epithelial cells and increases after tissue damage. Using murine models, Chen et al reveal that intestinal IL-33 enhances serotonin release, thereby activating platelets, perturbing hemostasis, and promoting platelet-dependent neutrophil recruitment during acute inflammation. This work establishes a new axis for endocrine-blood cell crosstalk linking local inflammation with systemic effects on hemostasis.


Deploying both in vivo and in silico modeling, Marar and colleagues describe that the extent of protein C (PC) activation at sites of vascular injury is determined largely by the spatial distribution of thrombin activity, in conjunction with local physical conditions. These findings provide a mechanistic basis for context-dependent contributions of activated PC anticoagulant activity and its role in the regulation of thrombin generation.

Schönborn et al report on the natural history of platelet factor 4 (PF4)-dependent platelet-activating antibodies in 65 patients who developed COVID-19 vaccine-induced thrombotic thrombocytopenia (VITT), finding that the great majority are transitory. They also report that patients with VITT receiving a subsequent mRNA-produced vaccine do not develop new thromboses or an increase in anti-PF4 antibodies, reinforcing the safety of this approach.





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