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BLOOD COMMENTARIES

CLINICAL TRIALS AND OBSERVATIONS

Treatment of relapsed/refractory hairy cell leukemia (R/R HCL) is challenging. Rogers and colleagues demonstrate efficacy of ibrutinib in a phase 2 study of 37 patients with R/R HCL, with 36-month progression-free and overall survival estimates of 73% and 85%, respectively. Interestingly, response was not predicted by loss of pERK phosphorylation, suggesting that the impact of ibrutinib may not be mediated solely by Bruton tyrosine kinase inhibition.

IMMUNOBIOLOGY AND IMMUNOTHERAPY

Martin Merinero et al delineate the molecular basis for association of mutant factor H–related protein 1 (FHR-1) with atypical hemolytic uremic syndrome (aHUS) and elucidate the interactions between factor H (CFH) and FHR-1 that regulate complement activation. CFH has a C-terminal domain that binds to cells and an N-terminal domain that facilitates degradation of activated complement. FHR-1 lacks complement-degrading activity and binds poorly to cell membranes; rare mutations allow increased cell surface binding and increase recruitment of complement C3, leading to increases in complement activation and aHUS.

LYMPHOID NEOPLASIA

Autoimmune hemolytic anemia or thrombocytopenia occurs in 5% to 9% of patients with chronic lymphocytic leukemia (CLL). Vitale and colleagues examined the impact of ibrutinib, idelalisib, and venetoclax on preexisting or emergent autoimmune cytopenias (AICs) in a retrospective analysis of 572 patients with CLL. Preexisting AIC active at the initiation of targeted drugs has a high rate of resolution, while emergent AIC during therapy is rare and largely associated with CLL with unfavorable biological features.

MYELOID NEOPLASIA

Acute myeloid leukemia (AML) cells depend on oxidative phosphorylation and fatty acid oxidation (FAO) for survival. Tcheng et al used public databases to assess differential FAO enzyme expression in normal and AML cells and identify overexpression of very long–chain acyl coenzyme A dehydrogenase (VLCAD) in AML cells. Genetic or pharmacologic inhibition of VLCAD decreases AML cell growth by interfering with mitochondrial respiration, thereby identifying a possible targeted therapeutic pathway for treatment of AML.

PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS

Xiao et al identify interleukin-19 (IL-19) produced by osteocytes as a regulator of neutrophil production. Constitutive activation of mechanistic target of rapamycin complex (mTORC1) signaling in osteocytes increases IL-19 levels and expands neutrophil numbers. Low-dose IL-19 potently reverses radiation-, chemotherapy-, and chloramphenicol-induced neutropenia, suggesting that it is a potential novel and effective new agent for treatment of neutropenia.

RED CELLS, IRON, AND ERYTHROPOIESIS

THROMBOSIS AND HEMOSTASIS

Tarasco and colleagues report prospective data for 87 patients with hereditary thrombotic thrombocytopenic purpura (TTP). The data have some surprises. Although von Willebrand factor levels rise with age, this did not lead to increased acute episodes; in fact, the majority of episodes occurred in patients less than 18 years old. In addition, prophylactic plasma as currently administered every 2 to 3 weeks does not reduce episodes, suggesting that plasma (or recombinant ADAMTS13, when available) should probably be administered weekly.

LETTER TO BLOOD

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