Highlighted Research Articles

Chimeric antigen receptor (CAR) T-cell therapy has recently become an alternative to allogeneic hematopoietic cell transplantation in relapsed or refractory mantle cell lymphoma (r/rMCL). In the absence of randomized clinical trials, Liebers and colleagues employed propensity score matching to compare these two treatments. Patients treated with CAR T-cell therapy brexucabtagene autoleucel (brexu-cel) in the ZUMA-2 clinical trial had higher 1-year overall survival than allogeneic transplantation patients in the EBMT patient registry. However, the long-term outcomes were comparable between the cohorts due to higher incidence of relapse after brexu-cel. Choices between transplantation and CAR T-cell therapy for r/rMCL could be informed by patient’s individual risks and benefits.See article, p. 182.Chronic B-cell receptor signaling is prevalent in primary central nervous system lymphoma (PCNSL), where it is linked to poor prognosis. In a phase II trial, 33 newly diagnosed PCNSL patients received high-dose methotrexate, ibrutinib, and temozolomide. The regimen achieved a 94% overall response rate, with 73% complete response and manageable adverse event profile. At 2 years of maintenance, progression-free survival was 58% and overall survival was 84.8%. By ctDNA profiling, tumor clearance was concordant between cerebrospinal fluid and plasma and correlated with sustained treatment response and survival. Integrating Bruton tyrosine kinase inhibitors into front-line therapy may improve outcomes.See article, p. 191.At a time of unprecedented outcomes for newly diagnosed patients with multiple myeloma, continuous drug exposure over indefinite treatment periods generates concern regarding the development of second primary malignances, which can cause cessation of therapy and significantly reduced survival. Guerrero and colleagues show that in patients with active multiple myeloma, who were treated with lenalidomide-based regimens, the presence of mutant hematopoietic progenitor cells at diagnosis did not correlate with poorer survival or the development of second primary malignances. These findings suggest that genetic screening for clonal hematopoiesis in multiple myeloma patients at diagnosis has limited use.See article, p. 203.A durable cell-cell contact between a cytotoxic lymphocyte and its target is important for efficient killing. Tin and colleagues show that SOCS1 helps acute myeloid leukemia (AML) cells avoid T-cell cytotoxicity by downregulating ICAM-1, an adhesion molecule on leukemia cells to which T cells bind. In a genome-wide CRISPR screen, the authors first identified SOCS1 as an AML-intrinsic factor of cytotoxicity resistance. In functional assays with allogeneic and CAR-engineered T cells, they reconstruct a circuit where IFNγ-elicited STAT/JAK1-ICAM1 upregulation is antagonized by leukemia cell-intrinsic SOCS1. In a clinical dataset, lower SOCS1 expression correlated with better overall survival of AML patients.See article, p. 217.MYC is a proto-oncogene often aberrantly activated in germinal center B-cell diffuse large B-cell lymphomas (GCB-DLBCL). In this study, high-throughput CRISPR-interference profiling identified a distal MYC locus enhancer, GME-1, that was selectively essential in non–MYC-rearranged GCB-DLBCL cells. GME-1 was bound and activated by trans-regulators previously associated with germinal center–specific enhancers, such as those in the BCL6 locus. In MYC-intact GCB-DLBCL patient biopsies, GME-1 was selectively acetylated, topologically interacted with the MYC promoter, and was shown to be subject to recurrent genomic copy gains. These data reveal mechanisms of MYC activation in the absence of genetic MYC rearrangement.See article, p. 233.Theory that combines intratumor and interpatient heterogeneity is needed to quantitatively understand curative treatments. The authors present a mathematical model of multidrug therapy that describes cell-to-cell and patient-to-patient heterogeneity as distributions of drug sensitivity, and they apply it to simulate curative combination therapies for diffuse large B-cell lymphomas (DLBCL). Simulated trials reproduced progression-free survival and changes in ctDNA observed under standard therapy, and accurately predicted success or failure of randomized trials of first-line combinations based on drugs’ efficacies in relapsed/refractory disease. This study suggests that predictive simulations could aid the design of new combination regimens with curative intent.See article, p. 254.