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BLOOD COMMENTARIES

PLENARY PAPER

Despite strong evidence of genetic predisposition to childhood precursor B-cell acute lymphoblastic leukemia (pB-ALL), fewer than 1% of genetically predisposed carriers develop disease, and infectious exposures are thought to provide a “second hit” for leukemia development. In a Plenary Paper, Vicente-Dueñas and colleagues, using mouse models of pB-ALL, make the remarkable observation that mutation carriers have an distinct gut microbiome and that its disruption through antibiotics or changing environment is sufficient to promote ALL without infection.

REVIEW ARTICLE

The authors provide an up-to-date review of hepatosplenic T-cell lymphoma, including new insights into its genetic landscape and therapeutic approaches to this rare poor-prognosis malignancy.

CLINICAL TRIALS AND OBSERVATIONS

Two papers in this issue report on the efficacy of zanubrutinib, a novel selective BTK inhibitor, in Waldenström macroglobulinemia (WM). The first reports the 3-year follow-up of patients with WM treated with zanubrutinib, demonstrating deep and durable responses, albeit very few complete responses; progression-free survival was over 80%. The second decribes a phase 3 trial comparing ibrutinib to zanubrutinib in WM and reports excellent responses to both drugs; there was no significant difference in response rates, but zanubrutinib was associated with less toxicity, especially cardiac toxicity.

Two papers in this issue report on the efficacy of zanubrutinib, a novel selective BTK inhibitor, in Waldenström macroglobulinemia (WM). The first reports the 3-year follow-up of patients with WM treated with zanubrutinib, demonstrating deep and durable responses, albeit very few complete responses; progression-free survival was over 80%. The second decribes a phase 3 trial comparing ibrutinib to zanubrutinib in WM and reports excellent responses to both drugs; there was no significant difference in response rates, but zanubrutinib was associated with less toxicity, especially cardiac toxicity.

MYELOID NEOPLASIA

In primary myelofibrosis (PMF), bone marrow fibrosis is driven by normal stromal cells in the context of hematopoietic stem cells (HSCs) that carry myeloproliferative neoplasm (MPN)–related mutations. The authors investigated the cross talk between mutant stem cells and normal stromal cells that drives fibrosis in several mouse models of PMF. They demonstrate that CXCL4 is markedly upregulated in MPN stem cells and increased expression in both stem cells and stromal cells is associated with increasing fibrosis; furthermore, they show that knockout of CXCL4 ameliorates fibrosis.

PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS

Clearance of monoclonal antibody (mAb)–opsonized cells by macrophages, or macrophage antibody-dependent cellular phagocytosis (ADCP), is the cytotoxic mechanism mediating tumor lysis in response to rituximab and other therapeutic antibodies. The authors demonstrate that rapid uptake of opsonized cells is followed by a period of markedly reduced phagocytosis (hypophagia) that may limit therapeutic effect.

THROMBOSIS AND HEMOSTASIS

Yu et al demonstrate that SARS-CoV-2 spike protein subunits activate the alternative pathway of complement in vitro, suggesting that many clinical manifestations of COVID-19, such as microangiopathy, renal injury, and thrombophilia may be driven by complement activation.

BLOOD WORK

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