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BLOOD COMMENTARIES

CLINICAL TRIALS AND OBSERVATIONS

B-cell maturation antigen (BCMA) is the target for multiple, new therapeutics in relapsed multiple myeloma (MM). Cohen and colleagues begin to address the question of sequencing by reporting a small series of patients treated with anti-BCMA chimeric antigen receptor (CAR) T cells after failure of anti-BCMA antibody-based biologicals. The authors report responses in 60% of patients and highlight the need for larger studies in this setting and a better understanding of the mechanisms of resistance to individual agents.

GENE THERAPY

Familial platelet disorder with associated myeloid malignancies (FPDMM) is due to heterozygous germline mutations in RUNX1, is manifest by a hemostatic defect, and carries a long-term risk of hematological malignancies. As such, it is a candidate disease for gene therapy. In companion articles, 2 in vivo models are reported. Using transplant models, Kiwon Lee et al found that RUNX1-deficient megakaryocytes exhibit thrombopoietic and platelet abnormalities in vivo, including decreased survival and functional defects. The authors also demonstrate that a small molecule inhibitor that blocks the transforming growth factor-beta pathway can correct the hemostatic defect in that model. In an independent approach, Byung-Chul Lee and colleagues used CRISPR gene editing to develop a rhesus macaque model and identify a barrier to corrective human gene therapy application. RUNX1-mutant stem cells have a competitive advantage over wild-type stem cells and stem cells with gene correction, indicating that further manipulation will be needed before this approach is tested on patients.

IMMUNOBIOLOGY AND IMMUNOTHERAPY

MYELOID NEOPLASIA

PLATELETS AND THROMBOPOIESIS

Familial platelet disorder with associated myeloid malignancies (FPDMM) is due to heterozygous germline mutations in RUNX1, is manifest by a hemostatic defect, and carries a long-term risk of hematological malignancies. As such, it is a candidate disease for gene therapy. In companion articles, 2 in vivo models are reported. Using transplant models, Kiwon Lee et al found that RUNX1-deficient megakaryocytes exhibit thrombopoietic and platelet abnormalities in vivo, including decreased survival and functional defects. The authors also demonstrate that a small molecule inhibitor that blocks the transforming growth factor-beta pathway can correct the hemostatic defect in that model. In an independent approach, Byung-Chul Lee and colleagues used CRISPR gene editing to develop a rhesus macaque model and identify a barrier to corrective human gene therapy application. RUNX1-mutant stem cells have a competitive advantage over wild-type stem cells and stem cells with gene correction, indicating that further manipulation will be needed before this approach is tested on patients.

RED CELLS, IRON, AND ERYTHROPOIESIS

Liver sinusoidal endothelial cells are the site for iron sensing for the body. Charlebois and colleagues identify that non–transferrin-bound iron, rather than transferrin-bound iron, is the primary driver of bone morphogenetic protein 6 (BMP6) expression in these cells during iron overload. This in turn prompts the liver to produce hepcidin, the chief iron-regulatory hormone that regulates body-iron balance.

THROMBOSIS AND HEMOSTASIS

The acute mortality of immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been markedly reduced with the use of plasma exchange, immune suppression, and caplacizumab, and it is now often a chronic disease with relapsing episodes of thrombotic microangiopathy. In this month’s CME article, Doyle et al show from UK national registry data that 40% of patients with iTTP relapse after 5-years’ follow-up and that preemptive anti-CD20 therapy is highly effective in preventing clinical relapses when ADAMTS13 levels fall.

TRANSPLANTATION

Allogeneic hematopoietic cell transplantation (HCT) is recommended by guidelines for fit patients with high-risk acute myeloid leukemia (AML). Sorror and colleagues report multi-institutional observational data with mature follow up, analyzed after adjusting for AML- and patient-specific variables, showing no benefit of HCT in older and medically infirm patients, with the exception of 2 subgroups. These data challenge the applicability of current broad guidelines for older patients and indicate the need for randomized trials on this issue in these patients, especially in the era of new induction therapies.

LETTERS TO BLOOD

BLOOD WORK

CONTINUING MEDICAL EDUCATION (CME) QUESTIONS

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