In This Issue

Analysis of neutralizing antibodies as well as cellular immune responses in myeloma patients following booster SARS-CoV-2 mRNA vaccines revealed impaired induction of variant neutralization and CD8 T-cell responses. Patients who developed breakthrough infections after booster vaccines had lower levels of live-virus neutralizing antibodies. These data illustrate current challenges with achieving protective immunity to SARS-CoV-2 in these immunocompromised patients and suggest that they should be prioritized for emerging approaches targeting variant-specific immunity.

See article, p. 106.

Clinical use and testing of anti-BCMA chimeric antigen receptor (CAR) T cells for the treatment of multiple myeloma (MM) has so far been restricted to advanced relapsed or refractory patients who progress following multiple prior therapies. To test whether CAR T-cell therapy is a feasible strategy as an early-line therapy while disease burden is low to potentially reduce incidence of immune-related adverse effects, Garfall et al. conducted a phase I clinical trial coadministering anti-BCMA and anti-CD19 CAR T cells with immunomodulatory maintenance in high-risk MM patients who were either responding to 1-2 prior therapies or progressing after 3+ prior therapies. Their results indicate favorable safety, pharmacokinetics, and antimyeloma activity of CAR T coadministration, with durable CAR T activity associated with early maintenance.

See article, p. 118.

Poor prognosis and biallelic TP53 inactivation are hallmarks of low-hypodiploid acute lymphoblastic leukemia (LH-ALL), defined by loss of several specific chromosomes with or without genome duplication. Kim et al. tracked LH-ALL origins in adults to TP53-mutant clonal hematopoiesis, previously associated with risk of myeloid malignancies. By combining cytogenetics, copy-number variation, loss of heterozygosity, and mutational analysis of adult patients with Ph- B-cell acute lymphoblastic leukemia (B-ALL), the authors identified 80 LH-ALL cases. Within the B-ALL cohort, LH-ALL prevalence increases from 3% among patients under 40 to 32% among patients over 55 years of age and amounts to 14% of total cases. Nearly half of these cases would have been missed by cytogenetics alone, highlighting the importance of comprehensive sequencing analysis. By single-cell proteogenomics, clonal p53 alterations are seen in multiple hematopoietic lineages persisting from diagnosis to remission, tracking somatic p53 loss in a multilineage progenitor as a preneoplastic event at the origin of adult LH-ALL. These findings shed new light on TP53 clonal hematopoiesis as a precursor of adult B-ALL and identify LH-ALL as a major subtype of B-ALL in older patients.

See article, p. 134.

Current murine models of chronic lymphocytic leukemia (CLL) do not fully recapitulate the combinations of oncogenic mutations, the clonal evolution of the disease, nor the transformation of CLL into aggressive Richter syndrome (RS) characteristic of human disease. Ten Hacken, Sewastianik, Yin et al. developed a mouse model of CLL incorporating multiplexed CRISPR/Cas9-introduced mutations representing common loss-of-function mutations found in human CLL, which also exhibits phenotypes consistent with RS transformation. Leveraging the model of RS transformation, tonic PI3K signaling was found to be characteristic of human and mouse RS, with MYC/mTOR/PI3K-targeted therapeutics showing efficacy in treating RS in vivo.

See article, p. 150.