Issue Archive

Regimens combining intensive chemotherapy with tyrosine kinase inhibitors have improved outcomes for adults with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph⁺ ALL). In this month’s CME article, a retrospective analysis incorporating propensity matching, Ghobadi and colleagues find that in patients achieving complete molecular remission by 90 days, elective allogeneic transplant in first remission reduces the risk of relapse at the expense of transplant-related morbidity and mortality, providing no survival benefit. These data argue for reserving allogeneic transplant for salvage in such patients.

Two complementary articles shed new light on resistance to venetoclax in lymphoid malignancies. Thijssen et al use single-cell studies to reveal the multilayered nature of the mechanisms underpinning the recurrence of chronic lymphocytic leukemia in patients on long-term venetoclax, identifying a range of recurring genetic and epigenetic changes in apoptotic regulators. Overlying this heterogeneity, heightened expression of MCL1 driven by NF-κB is ubiquitous but reversible upon drug discontinuation. Thomalla and colleagues use B-lineage cell lines and patient samples to elegantly demonstrate how methylation and silencing of PUMA, a pro-apoptotic, causes failure of venetoclax. Both articles provide clinically applicable suggestions for circumventing emergent resistance to venetoclax.

Two complementary articles shed new light on resistance to venetoclax in lymphoid malignancies. Thijssen et al use single-cell studies to reveal the multilayered nature of the mechanisms underpinning the recurrence of chronic lymphocytic leukemia in patients on long-term venetoclax, identifying a range of recurring genetic and epigenetic changes in apoptotic regulators. Overlying this heterogeneity, heightened expression of MCL1 driven by NF-κB is ubiquitous but reversible upon drug discontinuation. Thomalla and colleagues use B-lineage cell lines and patient samples to elegantly demonstrate how methylation and silencing of PUMA, a pro-apoptotic, causes failure of venetoclax. Both articles provide clinically applicable suggestions for circumventing emergent resistance to venetoclax.

Bhat and colleagues evaluate the incidence of symptomatic ventricular arrhythmias in a large-case series of acalabrutinib-treated patients. Although lower than the rate reported with ibrutinib, the occurrence in nearly 3% of acalabrutinib-treated patients is an estimated 8-fold higher than similar untreated control subjects. Their data suggest that ventricular arrhythmias may be a class-effect of Bruton tyrosine kinase inhibitors and increase impetus for time-limited treatment regimens.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare but potentially life-threatening condition in pregnancy that can lead to intracranial bleeding in the fetus or neonate. Zhi et al describe that prophylactic administration of a human polyclonal or monoclonal antihuman platelet antigen (HPA)-1a in a preclinical and alloantigen-specific mouse model of FNAIT can rapidly clear HPA-1a–positive platelets from the circulation, thereby preventing alloimmunization and the onset of FNAIT. This finding provides the rationale for this preventative approach to be tested in clinical trials.

Cerebral cavernous malformation (CCM) lesions are leaky, prone to rupture, and cause neurological complications. Globisch et al investigate the role of coagulation in CCM, studying murine and human samples to investigate pro- and anticoagulant proteins in the lesions, through high-quality imaging and transcriptomics. The authors found CCM lesions display vascular heterogeneity with procoagulant and anticoagulant regions and that stable clots are associated with cerebral hypoxia. Their data supports the idea that antithrombotic therapy may be beneficial.

Luspatercept is an approved therapy for selected patients with lower risk myelodysplasia requiring transfusion despite erythropoiesis-stimulating agents, based on the early results of a randomized trial against placebo. Zeidan and colleagues report that after a median of 26 months follow-up, 27% of patients commencing luspatercept were continuing therapy. Their updated analyses confirm that a significant minority (45%) of eligible patients can achieve transfusion independence, with a median durability of 30 weeks. These longer follow-up data better quantify the incremental benefit of luspatercept over placebo.