Issue Archive

New treatment options are becoming available for people with severe sickle cell disease with the US Food and Drug Administration’s approval of 2 autologous gene therapy products. Akshay Sharma illustrates key considerations for physicians and patients in 3 informative cases. This article provides timely practical advice on candidate selection, product selection, cell collection, acute care, and long-term follow up.

Zanubrutinib is a Bruton tyrosine kinase inhibitor with lesser activity against other kinases than the first-in-class drug ibrutinib. Brown and colleagues present the final comparative analysis of an open-label randomized phase 3 trial comparing zanubrutinib with ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL). After a median follow up of >40 months, zanubrutinib therapy demonstrated a superior progression-free survival and had less cardiotoxicity, principally less emergent atrial fibrillation, but overall survival was not different. These data indicate that zanubrutinib has important advantages over ibrutinib in this patient population.

Reticular dysgenesis is 1 of the most devastating severe immunodeficiency syndromes, characterized by severe neutropenia, T- and natural killer–cell lymphopenia, and a lack of both innate and adaptive immune function. Wang et al used single cell transcriptomics to identify expanded populations of progenitor cells but relatively selective deficiency of bone marrow granulocytic precursors. The authors pinpointed deregulation of energy metabolism in maturing myeloid cells due to deficiency of adenylate kinase 2 as the cause of the severe neutropenia and increase the knowledge of the regulation of neutrophil energy production.

Human blood groups are inherited polymorphisms of erythrocyte surface proteins that can, via transfusion or pregnancy, stimulate the production of alloantibodies. Tilley and colleagues reveal their discovery of the gene underlying the inherited AnWj-negative red cell phenotype, identifying a 6646 base pair deletion at the MAL locus in 8 AnWj-negative individuals but not in AnWj-positive family members. The authors also identified that not all AnWj-negative phenotypes were inherited and that loss of expression of Mal can occur through yet unproven mechanisms. These data underpin recognition of AnWj as a blood group system and will prompt further investigation of the function of the Mal protein.

While highly potent at killing chronic lymphocytic leukemia (CLL) cells, treatment with the B-cell lymphoma-2 (BCL-2) inhibitor venetoclax does not clear all leukemic cells. Luo et al studied patients initiated on obinutuzumab-venetoclax and genetically engineered mice to describe a mechanism by which a small minority of CLL cells survived during the venetoclax ramp-up phase. B-cell depletion induced by obinutuzumab promoted the production of cytokine B-cell activating factor (BAFF), which in turn promoted CLL survival despite ongoing venetoclax therapy by increasing both mantle cell lymphoma-1 and BCL-2 expression. These data provide a strong clue to future combination therapies designed to block this BAFF-mediated adaptation.

Upregulating γ-globin gene expression to raise fetal hemoglobin is highly desirable in severe sickle cell disease and transfusion-dependent β-thalassemia. In searching for novel ways to achieve this, Wang et al identified that the orphan nuclear receptor TR4 competes with the known γ-globin repressor BCL11 transcription factor A (BCL11A) at overlapping DNA sequences in the promoter region. These data clear the way for the pursuit of new strategies to modulate fetal hemoglobin levels in patients.

Having been maintained in the fetal liver during gestation, hematopoietic stem cells (HSCs) migrate to the perinatal bone marrow to establish definitive hematopoiesis by a mechanism that has proven elusive. Lou and coauthors implicate insulin-like growth factor 1 receptor (IGF1R) signaling in this initial HSC retention by the nascent bone marrow niche, while showing that it is redundant in adult bone marrow. Mechanistically, the authors show that this signaling upregulates the chemokine CXCL12 by bone marrow stromal cells.