Issue Archive

Pemmaraju and colleagues of the North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium summarize the latest biological insights, the importance of an accurate diagnosis, and the data on the activity of targeted agents. The front-line tagraxofusp, a conjugate of the diphtheria toxin and interleukin-3, and venetoclax are among these agents. The investigators also emphasize the role of central nervous system prophylaxis and outline challenges in developing optimized regimens to treat this rare and difficult malignancy.

Measurable residual disease (MRD) status after initial therapy for multiple myeloma is a proven surrogate for progression-free survival (PFS), but its value during maintenance is uncertain. Paiva et al report that serial monitoring of MRD during maintenance treatment captures dynamic conversion between MRD-negative and -positive states and robustly anticipates PFS. This shows the feasibility of longer term MRD monitoring and provides a rationale for trials that investigate intervention prior to frank relapse or shortening of maintenance for those who remain MRD negative.

Retinoids and their family of receptors play a role in the maintenance of quiescent hematopoietic stem cells (HSCs). Analyses of retinoid X receptor (RXR) conditional knockout mice by Menéndez-Gutiérrez and colleagues identifies MYC pathway activation in RXR-deficient HSCs. This leads to a decreased quiescent HSC pool, stem cell exhaustion, myeloid cell/megakaryocyte differentiation, and myeloproliferative-like disease.

Newman and colleagues examined whether household poverty and neighborhood influence access and outcomes of young patients treated with chimeric antigen receptor (CAR) T cells for relapsed/refractory acute lymphoblastic leukemia. Referral patterns differ for patients with high-disease burden and suggest reduced access for patients with household poverty. However, when CAR T-cell treatment is received, patients with household poverty have similar complete remission rates and survival outcomes to patients without household poverty, highlighting the importance of achieving equitable access.

The BH3 mimetic venetoclax improves outcomes for older, unfit patients with acute myeloid leukemia (AML) when combined with azacytidine or low-dose cytosine arabinoside, but relapse is common. Moujalled et al identified loss-of-function BAX mutations in 17% of AML samples from patients relapsing after venetoclax, providing a novel explanation for resistance that also applies in vitro to other BH3 mimetics. In contrast, these mutations are uncommon after intensive chemotherapy, reinforcing the case for exploration of venetoclax–chemotherapy combinations.

Little is known about how to optimally sequence allogeneic stem cell transplants (allo-HCT) and CAR T-cell therapy. Using murine models, Patterson et al demonstrate that allo-HCT with posttransplantation cyclophosphamide can be combined effectively with allogeneic CD19 CAR T-cell treatment. The authors highlight that CAR T cells given just before or shortly after cyclophosphamide graft-versus-host disease prophylaxis exert stronger antileukemic effects than CAR T cells administered later, suggesting a strategy to leverage the complementary antileukemic effects of polyclonal alloreactive T cells and antigen-specific CAR T cells.

Using 2 global postmarketing surveillance databases, Goldman and colleagues report that progressive multifocal leukoencephalopathy (PML), a viral disease associated with profound immunosuppression, occurs in approximately 0.9 cases per 1000 recipients of CD19-directed CAR T-cell therapy. The risk of PML appears higher with CAR T-cell therapy than other cancer therapies, but its precise role cannot be distinguished from antecedent therapies that these patients receive.