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Bhatt and colleagues discuss the necessity for more focused research on the process for determining fitness in older adults for intensive treatment of acute myeloid leukemia. Geriatric assessment tools have been advanced to determine fitness for therapy, but the authors call for a prospective study to validate the criteria for fitness and to determine whether geriatric assessment-based fitness are in fact superior to other criteria for assessment of fitness. They propose end points for these assessments based on early or nonrelapse mortality, decline in function of quality of life, and necessity for modifying drug dosage.


Giovanni Tonon reviews the factors contributing to genomic instability in multiple myeloma cells, describing a precarious balance between oxidative stress and dependence on the proteosome to protect from proteostatic toxicity against the intrinsic genomic instability of myeloma plasma cells. He proposes that these factors underlie the sensitivity of myeloma cells to DNA damaging agents, which remain a component of antimyeloma therapy.


Neelapu et al report on long-term outcomes from ZUMA-5, a trial of axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, for relapsed/refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL). At a median follow-up of 41.7 months, the overall response rates were 94% in FL and 77% in MZL, similar to what was seen in earlier reported results at 17.5 months. Median progression-free survival was 40.2 months in FL and not yet reached in MZL; median overall survival was not reached in either group. Clinical outcomes were worse following recent bendamustine therapy and for patients with high-tumor volume. After 3 years, axi-cel demonstrates durable responses with few relapses beyond 2 years.


Chimeric antigen receptor (CAR) T-cell therapy targeting acute myeloid leukemia (AML) is challenging because of the overlap of expression of surface proteins on normal myeloid stem cells and leukemic blasts, risking severe myelosuppression. Dao and colleagues present preclinical studies of a novel CAR T-cell platform that combines antibody specificity to a common myeloid antigen (CD33) with specificity for Wilms tumor 1 protein, which is expressed preferentially in AML blasts. This construct confers cytotoxic activity against AML blasts while sparing normal myelomonocytic cells.


Heger et al report on a novel risk stratification schema for patients with central nervous system lymphoma (CNSL) using ultrasensitive circulating tumor DNA (ctDNA) sequencing in 67 patients at baseline and after therapy. Undetectable plasma ctDNA predicts favorable outcomes while persistence of peripheral residual disease following therapy predicts for relapse. The authors developed a molecular prognostic index for CNSL that could improve standard risk stratification and allow for more individualized treatment.


Ningtyas and colleagues demonstrate that platelets play a central role in the clearance of senescent erythrocytes by forming platelet–red blood cell (P-RBC) complexes. Through a series of elegant experiments, the authors confirmed that P-RBC complexes form preferentially with senescent red cells, leading to their selective clearance in the spleen. Patients with immune thrombocytopenia or those who are postsplenectomy have increased circulating senescent red cells, possibly contributing to thrombotic risk.


Kim et al demonstrate that megakaryocytes can cause contraction of plasma clots. Using sophisticated microscopy, the authors showed that megakaryocytes derived from induced pluripotent stem cells cause clot shrinkage through contraction of fibrin-attached plasma membrane protrusions.



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