The phase III DUO trial of PI3K inhibitor duvelisib versus ofatumumab in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: final analysis including overall survival.

Not available.

Prognostic impact of chronic lymphocytic leukemia comorbidity index in a young population: a real-world evidence study of a national gulf region cohort.

In chronic lymphocytic leukaemia (CLL), comorbidities assessed by the CLL comorbidity index (CLL-CI) have been associated with outcomes in Western cohorts. We conducted a retrospective analysis of an unselected Middle Eastern cohort of newly diagnosed CLL patients seen at the Kuwait Cancer Control Center (n = 300). Compared to Western studies, these Middle Eastern patients were diagnosed at a younger age (median of 59) and had a higher comorbidity burden (69% non-low risk CLL-CI). A higher CLL-CI score was independently associated with significantly shorter event-free survival and greater risk of death. Our analysis demonstrates that CLL-CI is a valuable tool for comorbidity assessment and prognostic influence in (relatively young) Middle Eastern CLL patients.

T-bet suppresses proliferation of malignant B cells in chronic lymphocytic leukemia.

The T-box transcription factor T-bet is known as a master regulator of T-cell response but its role in malignant B cells is not sufficiently explored. Here, we conducted single-cell resolved multi-omics analyses of malignant B cells from patients with chronic lymphocytic leukemia (CLL) and studied a CLL mouse model with genetic knockout of TBX21. We found that T-bet acts as a tumor suppressor in malignant B cells by decreasing their proliferation rate. NF-κB activity induced by inflammatory signals provided by the microenvironment, triggered T-bet expression which impacted on promoter proximal and distal chromatin co-accessibility and controlled a specific gene signature by mainly suppressing transcription. Gene set enrichment analysis identified a positive regulation of interferon signaling, and a negative control of proliferation by T-bet. In line, we showed that T-bet represses cell cycling and is associated with longer overall survival of CLL patients. Our study uncovers a novel tumor suppressive role of T-bet in malignant B cells via its regulation of inflammatory processes and cell cycling which has implications for stratification and therapy of CLL patients. Linking T-bet activity to inflammation explains the good prognostic role of genetic alterations in inflammatory signaling pathways in CLL.

Comparison of Comorbidity Models Within a Population-Based Cohort of Older Adults With Non-Hodgkin Lymphoma.

PURPOSE: Compare the association of individual comorbidities, comorbidity indices, and survival in older adults with non-Hodgkin lymphoma (NHL), including in specific NHL subtypes. METHODS: Data source was SEER-Medicare, a population-based registry of adults age 65 years and older with cancer. We included all incident cases of NHL diagnosed during 2008-2017 who met study inclusion criteria. Comorbidities were classified using the three-factor risk estimate scale (TRES), Charlson comorbidity index (CCI), and National Cancer Institute (NCI) comorbidity index categories and weights. Overall survival (OS) and lymphoma-specific survival, with death from other causes treated as a competing risk, were estimated using the Kaplan-Meier method from time of diagnosis. Multivariable Cox models were constructed, and Harrel C-statistics were used to compare comorbidity models. A two-sided P value of <.05 was considered significant. RESULTS: A total of 40,486 patients with newly diagnosed NHL were included. Patients with aggressive NHL had higher rates of baseline comorbidity. Despite differences in baseline comorbidity between NHL subtypes, cardiovascular, pulmonary, diabetes, and renal comorbidities were frequent and consistently associated with OS in most NHL subtypes. These categories were used to construct a candidate comorbidity score, the non-Hodgkin lymphoma 5 (NHL-5). Comparing three validated comorbidity scores, TRES, CCI, NCI, and the novel NHL-5 score, we found similar associations with OS and lymphoma-specific survival, which was confirmed in sensitivity analyses by NHL subtypes. CONCLUSION: The optimal measure of comorbidity in NHL is unknown. Here, we demonstrate that the three-category TRES and five-category NHL-5 scores perform as well as the 14-16 category CCI and NCI scores in terms of association with OS and lymphoma-specific survival. These simple scores could be more easily used in clinical practice without prognostic loss.

Glofitamab stimulates immune cell infiltration of CNS tumors and induces clinical responses in secondary CNS lymphoma.

Although CD20xCD3 bispecific antibodies are effective against systemic B-cell lymphomas, their efficacy in CNS lymphoma is unknown. Here, we report the CD20xCD3 bispecific, glofitamab, penetrates the blood-brain barrier, stimulates immune-cell infiltration of CNS tumors, and induces responses in CNS lymphoma.

Impact of race and social determinants of health on outcomes in patients with aggressive B-cell NHL treated with CAR-T therapy.

ABSTRACT: Chimeric antigen receptor (CAR) T-cell (CAR-T) immunotherapy is an effective therapy for relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). However, data are limited on the impact of the convergence of race and social determinants of health on outcomes for patients treated with CAR-T therapy. We examined the impact of interactions between race and insurance type on health care use and outcomes in patients treated with CAR-T therapy for aggressive B-NHL. Adult patients with r/r B-NHL treated with CD19 CAR-Ts were identified between 2015 and 2021 across 13 US academic centers. Insurance type, demographic, and clinical data were collected and analyzed. In total, 466 adult patients were included in our analysis. Median follow-up after CAR-T therapy was 12.7 months. Median progression-free survival (mPFS) was longer for Caucasians (11.5 months) than for African Americans (3.5 months; hazard ratio [HR], 1.56 [1.03-2.4]; P = .04) or Asians (2.7 months; HR, 1.7 [1.02-2.67]; P = .04). Differences in median overall survival (mOS) were not significant. For Medicare (n = 206) vs Medicaid (n = 33) vs private insurance (n = 219) vs self-pay (n = 7): mPFS was 15.9 vs 4.2 vs 6.0 vs 0.9 months (P < .001), respectively; and mOS was 31.2 vs 12.8 vs 21.5 vs 3.2 months (P < .001), respectively. Our multicenter retrospective analysis showed that race and insurance status can affect outcomes for patients treated with CAR-T therapy.

CGRP receptor antagonists (gepants).

Small molecule calcitonin gene-related peptide (CGRP) receptor antagonists are commonly referred to as gepants. The first generation of gepants provided the first line of evidence of CGRP-mediated antimigraine medication in 2004-2011. However, further development was halted due to either lack of oral availability or concerns of hepatotoxicity. More than 15 years later, the first second generation of gepants, ubrogepant and rimegepant, are now approved for the acute treatment of migraine with or without aura. Furthermore, a novel and promising third-generation gepant, zavegepant, has recently been approved as well. In this chapter, we review the evidence supporting the effectiveness, safety, and tolerability of gepants for the acute treatment of migraine. Furthermore, we discuss the potential limitations and future directions of this class of migraine-specific medication.

Outcomes of patients with secondary central nervous system lymphoma following CAR T-cell therapy: a multicenter cohort study.

Chimeric antigen receptor T-cell therapy (CAR-T) has been successful in treating relapsed/refractory B-cell lymphomas. However, its role in the treatment of diseases involving the central nervous system (CNS) is not well studied. We performed a multicenter retrospective cohort study to evaluate the outcomes of patients with secondary CNS lymphoma (SCNSL) who received CAR-T. Eligibility required active CNSL at the time of apheresis. The objectives included evaluation of overall survival (OS), progression-free survival (PFS), identification of predictors of complete response (CR) post-CAR-T, and assessment of risk factors for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Sixty-one patients were included in the analysis. The overall response rate was 68% with a CR rate of 57%. In the multivariable analysis, patients who experienced any grade CRS had higher odds of achieving CR (OR = 3.9, 95% CI = 1.01-15.39, p = 0.047). The median PFS was 3.3 months (95% CI = 2.6-6.0 months) with 6- and 12-month PFS rates of 35% and 16%, respectively. The median OS was 7.6 months (95% CI = 5.0-13.5 months) with 6- and 12-month OS rates of 59% and 41%, respectively. Any grade CRS and ICANS were 70% (n = 43) and 57% (n = 34), respectively with grade ≥ 3 CRS and ICANS rates of 16% and 44%. Factors associated with increased risk of CRS and ICANS included receiving axi-cel or having leptomeningeal ± parenchymal + CNS involvement, respectively. Despite achieving high response rates, most patients experience early relapse or death following CAR-T in SCNSL. The current study provides a benchmark for future trials exploring novel therapeutic options in SCNSL.

Influence of treatment intensity and medical comorbidities in older adults with peripheral T cell lymphoma.

We conducted a population-based study of patients >65 years, diagnosed 2008-2017, with peripheral T-cell lymphoma (PTCL) using SEER-Medicare. Associations between PTCL subtype, treatment regimen, comorbidity, and mortality were assessed using the Kaplan-Meier method and multivariable Cox regression. Amongst the 2,546 patients, the median age was 77 years (interquartile range, 71-83). 5-year overall survival (OS) ranged from 22.2% to 37.3% depending on PTCL subtype. The most common frontline regimen was cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). 5-year OS rate was 47.0% for patients treated with etoposide + CHOP (N = 67; CHOEP), 33.7% for those treated with CHOP (N = 732), and 23.8% for patients treated with non-anthracycline-containing regimens (N = 105; p < 0.001). In patients without comorbidities, CHOEP remained independently associated with improved OS (HR 0.52, 95% CI,0.30-0.91). Median OS was 1.2 years from initiation of second-line therapy (N = 228) independent of treatment regimen. Frontline but not second-line treatment regimen is associated with OS in older patients with PTCL.

Cyclin-dependent kinase-9 in B-cell malignancies: pathogenic role and therapeutic implications.

Cyclin-dependent kinases (CDK) regulate cell cycle and transcriptional activity. Pan-CDK inhibitors demonstrated early efficacy in lymphoid malignancies, but also have been associated with narrow therapeutic index. Among transcriptional CDKs, CDK7 and CDK9 emerged as promising targets. CDK9 serves as a component of P-TEFb elongation complex and thus is indispensable in mRNA transcription. Selective CDK9 inhibitors demonstrated pre-clinical efficacy in in vitro and in vivo models of B-cell non-Hodgkin lymphoma. CDK9 inhibition results in transcriptional pausing with rapid downmodulation of short-lived oncogenic proteins, e.g. Myc and Mcl-1, followed by cell apoptosis. Early phase clinical trials established safety of CDK9 inhibitors, with manageable neutropenia, infections and gastrointestinal toxicities. In this review, we summarize the rationale of targeting CDK9 in lymphoid malignancies, as well as pre-clinical and early clinical data with pan-CDK and selective CDK9 inhibitors.

T Cell-intrinsic Immunomodulatory Effects of TAK-981 (Subasumstat), a SUMO-activating Enzyme Inhibitor, in Chronic Lymphocytic Leukemia.

Novel targeted agents used in therapy of lymphoid malignancies are recognized to have complex immune-mediated effects. Sumoylation, a posttranslational modification of target proteins by small ubiquitin-like modifiers (SUMO), regulates a variety of cellular processes indispensable in immune cell activation. Despite this, the role of sumoylation in T-cell biology in context of cancer is not known. TAK-981 (subasumstat) is a small-molecule inhibitor of the SUMO-activating enzyme (SAE) that forms a covalent adduct with an activated SUMO protein. Using T cells derived from patients with chronic lymphocytic leukemia (CLL), we demonstrate that targeting SAE activates type I IFN response. This is accompanied by largely intact T-cell activation in response to T-cell receptor engagement, with increased expression of CD69 and CD38. Furthermore, TAK-981 decreases regulatory T cell (Treg) differentiation and enhances secretion of IFNγ by CD4+ and CD8+ T cells. These findings were recapitulated in mouse models, suggesting an evolutionarily conserved mechanism of T-cell activation regulated by SUMO modification. Relevant to the consideration of TAK-981 as an effective agent for immunotherapy in hematologic malignancies, we demonstrate that the downstream impact of TAK-981 administration is enhancement of the cytotoxic function of CD8+ T cells, thus uncovering immune implications of targeting sumoylation in lymphoid neoplasia.

Perspectives on Neuronutrition in Prevention and Treatment of Neurological Disorders.

The term neuronutrition has been proposed as part of nutritional neuroscience, studying the effects of various dietary components on behavior and cognition. Other researchers underline that neuronutrition includes the use of various nutrients and diets to prevent and treat neurological disorders. The aim of this narrative review was to explore the current understanding of the term neuronutrition as the key concept for brain health, its potential molecular targets, and perspectives of its nutritional approach to the prevention and treatment of Alzheimer's and Parkinson's diseases, multiple sclerosis, anxiety, depressive disorders, migraine, and chronic pain. Neuronutrition can be defined as a part of neuroscience that studies the influence of various aspects of nutrition (nutrients, diet, eating behavior, food environment, etc.) on the development of nervous disorders and includes nutrition, clinical dietetics, and neurology. There is evidence that the neuronutritional approach can influence neuroepigenetic modifications, immunological regulation, metabolic control, and behavioral patterns. The main molecular targets in neuronutrition include neuroinflammation, oxidative/nitrosative stress and mitochondrial dysfunction, gut-brain axis disturbance, and neurotransmitter imbalance. To effectively apply neuronutrition for maintaining brain health, a personalized approach is needed, which includes the adaptation of the scientific findings to the genetic, biochemical, psycho-physiological, and environmental features of each individual.

Thinking "outside the germinal center": Re-educating T cells to combat follicular lymphoma.

There have been significant advancements in the management of follicular lymphoma (FL), the most common indolent lymphoma. These include immunomodulatory agents such as lenalidomide, epigenetic modifiers (tazemetostat), and phosphoinotiside-3 kinase inhibitors (copanlisib). The focus of this review is T cell-engager therapies, namely chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies, have recently transformed the treatment landscape of FL. Two CAR T cell products, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), and one bispecific antibody, mosunetuzumab, recently received FDA approvals in FL. Several other new immune effector drugs are being evaluated and will expand the treatment armamentarium. This review focuses on CAR T-cell and bispecific antibody therapies, details their safety and efficacy and considers their evolving role in the current treatment landscape of FL.

METTL3-Mediated m6A Modification Controls Splicing Factor Abundance and Contributes to Aggressive CLL.

RNA splicing dysregulation underlies the onset and progression of cancers. In chronic lymphocytic leukemia (CLL), spliceosome mutations leading to aberrant splicing occur in ∼20% of patients. However, the mechanism for splicing defects in spliceosome-unmutated CLL cases remains elusive. Through an integrative transcriptomic and proteomic analysis, we discover that proteins involved in RNA splicing are posttranscriptionally upregulated in CLL cells, resulting in splicing dysregulation. The abundance of splicing complexes is an independent risk factor for poor prognosis. Moreover, increased splicing factor expression is highly correlated with the abundance of METTL3, an RNA methyltransferase that deposits N6-methyladenosine (m6A) on mRNA. METTL3 is essential for cell growth in vitro and in vivo and controls splicing factor protein expression in a methyltransferase-dependent manner through m6A modification-mediated ribosome recycling and decoding. Our results uncover METTL3-mediated m6A modification as a novel regulatory axis in driving splicing dysregulation and contributing to aggressive CLL. SIGNIFICANCE: METTL3 controls widespread splicing factor abundance via translational control of m6A-modified mRNA, contributes to RNA splicing dysregulation and disease progression in CLL, and serves as a potential therapeutic target in aggressive CLL. See related commentary by Janin and Esteller, p. 176. This article is highlighted in the In This Issue feature, p. 171.

Pharmacologic targeting of Nedd8-activating enzyme reinvigorates T-cell responses in lymphoid neoplasia.

Neddylation is a sequential enzyme-based process which regulates the function of E3 Cullin-RING ligase (CRL) and thus degradation of substrate proteins. Here we show that CD8+ T cells are a direct target for therapeutically relevant anti-lymphoma activity of pevonedistat, a Nedd8-activating enzyme (NAE) inhibitor. Pevonedistat-treated patient-derived CD8+ T cells upregulated TNFα and IFNγ and exhibited enhanced cytotoxicity. Pevonedistat induced CD8+ T-cell inflamed microenvironment and delayed tumor progression in A20 syngeneic lymphoma model. This anti-tumor effect lessened when CD8+ T cells lost the ability to engage tumors through MHC class I interactions, achieved either through CD8+ T-cell depletion or genetic knockout of B2M. Meanwhile, loss of UBE2M in tumor did not alter efficacy of pevonedistat. Concurrent blockade of NAE and PD-1 led to enhanced tumor immune infiltration, T-cell activation and chemokine expression and synergistically restricted tumor growth. shRNA-mediated knockdown of HIF-1α, a CRL substrate, abrogated the in vitro effects of pevonedistat, suggesting that NAE inhibition modulates T-cell function in HIF-1α-dependent manner. scRNA-Seq-based clinical analyses in lymphoma patients receiving pevonedistat therapy demonstrated upregulation of interferon response signatures in immune cells. Thus, targeting NAE enhances the inflammatory T-cell state, providing rationale for checkpoint blockade-based combination therapy.