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BLOOD COMMENTARIES

REVIEW ARTICLE

Chimeric antigen receptor (CAR) T-cell therapy is standard for patients with large B-cell lymphoma following failure of autologous stem cell transplant (SCT). Now, 3 prospective randomized trials provide comparisons of CAR T cells with SCT as second-line therapy. Westin and Sehn review the design, key findings, and caveats for each trial and provide an insightful summary of how CAR T-cell therapy is changing our standard approach to patients when first-line therapy is not curative.

CLINICAL TRIALS AND OBSERVATIONS

Roussel and colleagues report on a large, highly anticipated randomized trial of adding bortezomib to melphalan as autologous stem cell transplantation conditioning for patients with newly diagnosed multiple myeloma. While the phase 2 data had suggested improved efficacy, no differences were observed in the rates of complete remission, minimal residual disease negativity, progression-free survival or overall survival. These data reaffirm high-dose melphalan as the standard conditioning regimen in myeloma.

HEMATOPOIESIS AND STEM CELLS

Perturbations in the gastrointestinal microflora are common following allogeneic stem cell transplants (SCTs). Miltiadous et al report on the association between early posttransplant gut microbiome and immune cell reconstitution in 894 patients post-SCT, finding fecal microbial diversity to be predictive of CD4+ T-cell counts at 3 months. Higher relative abundance of Staphylococcus in the early post-HCT period independently predicts worse CD4+ T-cell recovery, suggesting a new modifiable factor for optimization of immune recovery.

IMMUNOBIOLOGY AND IMMUNOTHERAPY

Anti-CD20 monoclonal antibodies are a mainstay of therapy for B-cell lymphomas, but efficacy is not uniform and resistance may develop. Nakamura and colleagues revealed that the SUMOylation inhibitor subasumstat is able to augment the ability of rituximab to evoke macrophage phagocytosis and natural killer cell cytotoxicity, thereby delivering improved antitumor activity in murine lymphoma models. These data highlight the potential for small molecule drugs to potentiate existing monoclonal antibody-based regimens.

MYELOID NEOPLASIA

A major cause of mortality for patients with myeloproliferative neoplasms (MPN) is progression to myelofibrosis and acute leukemia. Li et al identified that High Mobility Group A1 (HMGA1) acts as an epigenetic switch during MPN progression and that HMGA1 deficiency prevents myelofibrosis and enhances sensitivity to ruxolitinib, prolonging survival in murine models of JAK2 mutant secondary acute myeloid leukemia. These data suggest HMGA1 is a therapeutic target to treat or prevent progression.

THROMBOSIS AND HEMOSTASIS

Hereditary angioedema (HAE) is a genetic condition causing episodic bradykinin-induced swelling of skin and mucosal membranes. Dickeson and colleagues revealed a new mechanism for HAE in patients whose disease is associated with a lysine-311 to glutamic acid substitution in plasminogen. The authors' detailed biochemical studies linked fibrinolysis and bradykinin formation in this condition.

Arthropathy is the most common clinical sequela of bleeding in severe hemophilia. Magisetty et al report that an antibody that selectively inhibits the anticoagulant activity of activated protein C (APC), but not its anti-inflammatory activity, prevents bleeding-induced arthropathy in a mouse model, whereas an antibody that inhibits both APC functions does not. These data argue for the clinical development of anti-APC antibodies with highly selective actions for prevention of hemophilic arthropathy.

LETTER TO BLOOD

BLOOD WORK

ERRATA

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