Citations

Abstract Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), 2 B-cell maturation antigen (BCMA)–directed chimeric antigen receptor T-cell (CAR-T) therapies, have transformed outcomes for relapsed/refractory multiple myeloma; however, the 6 to 8 weeks manufacturing time risks disease progression or death in up to 10% of patients. Talquetamab, a G-protein–coupled receptor, family C, group 5, member D (GPRC5D)–targeting bispecific antibody, represents a promising option. We performed a multi-institutional retrospective analysis across 20 centers (18 United States, 2 Germany) evaluating talquetamab as a bridging therapy prior to cilta-cel or ide-cel. Among 134 patients receiving talquetamab, 119 proceeded to CAR-T (n = 98 cilta-cel, n = 21 ide-cel). Reasons for not proceeding (n = 15) included progression (n = 7), manufacturing failure (n = 6), or patient decision (n = 2). Median age was 65 years and had median 5 prior lines of therapy. Notably, 85% would not have met CARTITUDE-1/KarMMa eligibility criteria. Talquetamab was administered for a median 23 days. Toxicity was manageable: no grade ≥3 cytokine release syndrome (CRS), 2% grade 3 immune effector cell–associated neurotoxicity syndrome (ICANS) and grade 1 to 2 talquetamab unique toxicities (70% oral, 38% skin, and 17% nail; 60% resolved). Talquetamab achieved 71% response rate. After CAR-T, 88% responded (54% complete response), with low-grade toxicities (2 grade ≥3 CRS, 1 grade 3 ICANS, and 5% grade ≥3 infections). Two cases of facial palsy and 1 acute myeloid leukemia occurred. Talquetamab correlated with sustained soluble BCMA decline and peak CAR-T expansion around day 14. Talquetamab bridging appears safe, enabling the majority of difficult-to-treat patients to successfully proceed to BCMA CAR-T therapy.

Abstract Epcoritamab and glofitamab are CD20-directed bispecific antibodies (BsAbs) approved in the United States for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Limited data exist for patients treated outside of trials. Patients with R/R DLBCL receiving commercial epcoritamab or glofitamab between 1 January 2023 and 15 October 2024 were collected from 21 United States institutions. Among 245 patients, 156 received epcoritamab and 89 received glofitamab, 113 were refractory to front-line therapy, 40 had MYC and BCL2 and/or BCL6 rearrangements, 147 received prior chimeric antigen receptor T-cell therapy, and 174 patients would have been ineligible for registrational trials. The overall response rate (ORR) for epcoritamab and glofitamab was 51% (23% complete response, [CR]) and 53% (30% CR), respectively. Median progression-free survival (PFS) was 2.6 months (95% confidence interval [CI], 2.0-3.8 months), and median overall survival (OS) was 7.8 months (95% CI, 6.2-11.0 months). The 6-month PFS was 36% (95% CI, 30-44) and the 6-month OS was 60% (95% CI, 54-67). Both trial ineligibility and undetectable CD20 pre-BsAbs portended shorter PFS and OS. Of 17 individuals with paired biopsies, 15 (88.2%) lost CD20 expression after BsAbs with a median time to progression of 3.7 months. This analysis including patients with R/R DLBCL shows the ORR to CD3/CD20 BsAbs was comparable to pivotal trials, although PFS and OS were lower. Baseline undetectable levels of CD20 were associated with poor outcomes. These results demonstrate the activity of BsAbs in R/R DLBCL, and underscore the importance of target antigen expression.

Abstract Teclistamab is an anti-CD3-/B-cell maturation antigen (BCMA) bispecific antibody approved for use in relapsed/refractory multiple myeloma. We undertook a retrospective study of post-approval, real-world outcomes with teclistamab in the US Multiple Myeloma Immunotherapy Consortium. Among 509 patients, 89% would have been ineligible for the MajesTEC-1 trial, primarily due to prior BCMA-directed therapy, cytopenias, or diminished performance status. Cytokine release syndrome occurred in 54% (1.4% grade ≥3) and immune effector cell–associated neurotoxicity syndrome in 11% (2.2% grade ≥3), with no fatal events. Infections occurred in 42% and contributed to death in 5%. Partial response (PR) or better was achieved in 53% and very good PR or better in 45%. With 10.1 months of median follow-up, the estimated median progression-free survival (PFS) was 5.8 months and 12-month overall survival was 61%. Independent predictors of less than very good PR and shorter PFS included BCMA-directed chimeric antigen receptor T-cell therapy in the previous 9 months, high disease burden, lymphopenia, and elevated ferritin. Significance: T cell–engaging bispecific antibodies such as teclistamab represent an important new treatment modality for multiple myeloma and other blood cancers. This study evaluates the real-world safety and efficacy of teclistamab, including its activity in populations not represented in the initial phase I/II study, and identifies clinical variables associated with treatment response. See related commentary by Zweegman et al., p. 542

Abstract Overall response (OR) that combines complete (CR) and partial responses (PR) is the conventional end point for acute graft-versus-host disease (GVHD) trials. Because PR includes heterogeneous clinical presentations, reclassifying PR could produce a better end point. Patients in the primary treatment cohort from the Japanese Society for Transplantation and Cellular Therapy (JSTCT) were randomly divided into training and validation sets. In the training set, a classification and regression tree algorithm generated day 28 refined response (RR) criteria based on symptoms at treatment and day 28. We then evaluated RR for primary and second-line treatments, using the area under the receiver operating characteristic curve (AUC) and negative predictive value (NPV) for 6-month nonrelapse mortality as performance measures. RR considered patients with grade 0/1 at day 28 without additional treatment as responders. RR for primary treatment produced higher AUCs than OR with small improvement of NPVs in both validation sets: JSTCT (AUC, 0.73 vs 0.69 [P < .001]; NPV, 92.0% vs 89.6% [P < .001]) and the Mount Sinai Acute GVHD International Consortium (MAGIC; AUC, 0.71 vs 0.68 [P = .032]; NPV, 90.9% vs 89.8% [P = .009]). RR for second-line treatment produced similar AUCs but much higher NPVs than OR in both validation sets of JSTCT (AUC, 0.64 vs 0.63 [P = .775]; NPV, 74.5% vs 66.0% [P < .001]) and MAGIC (AUC, 0.67 vs 0.64 [P = .105]; NPV, 86.8% vs 76.1% [P = .004]). Classifying persistent but mild skin symptoms as responses and residual lower gastrointestinal GVHD as nonresponses were major drivers in improving the prognostic performance of RR. Our externally validated day 28 RR would serve as a better end point than conventional criteria in future first- and second-line treatment trials.

Importance SARS-CoV-2 infection has been linked to neurotoxic effects and cognitive deficits. Objective To determine whether decreases in cognitive function were accelerated after SARS-CoV-2 infection compared with individuals not infected. Design, Setting, and Participants Multicenter, prospective cohort study from 2016 to 2022 among 3525 participants alive on March 1, 2020, and enrolled in The Atherosclerosis Risk in Communities (ARIC) study and the Collaborative Cohort of Cohorts for COVID-19 Research study who completed a prepandemic cognitive assessment and a pandemic-era assessment of SARS-CoV-2 infection. Final analyses performed in November 2024. Exposure SARS-CoV-2 infection determined via self-report of a positive SARS-CoV-2 test or health care professional diagnosis of COVID-19, a positive SARS-CoV-2 antinucleocapsid antibody response, or presence of an administrative code for COVID-19 on medical records. Main outcomes and measures A neuropsychological battery assessed multiple cognitive domains, and a cocalibrated confirmatory factor analysis generated factor scores for global cognitive function. The primary outcome was the rate of excess change in cognitive function. Results The 3525 eligible participants had a mean (SD) age of 80.8 (4.7) years, 2085 (59.1%) were female, 752 (21.4%) were Black, and 2773 (78.6%) were White. SARS-CoV-2 infection was detected among 307 participants (8.7%), 103 of whom (33.6%) were hospitalized. Among uninfected participants, the mean annualized change in cognitive function was −0.09 (95% CI, −0.13 to −0.04). Compared with this rate, change was faster (β = −0.06; 95% CI, −0.09 to −0.02) among participants hospitalized for infection, but not different from participants who were infected but not hospitalized (β = 0.00; 95% CI, −0.02 to 0.03). The association among participants hospitalized for infection was evident in the cognitive domains of memory and executive function, but not language. Conclusions and relevance This cohort study of older participants found accelerated decreases in cognition among individuals hospitalized for SARS-CoV-2 infection, but not nonhospitalized infection, in comparison with individuals not yet infected.

Abstract Severe aplastic anemia (SAA) is a rare and life-threatening bone marrow failure disorder. Immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine has long been a frontline treatment option in SAA; however, its limited durability and risk of long-term complications such as secondary malignancies remain a drawback in this treatment modality. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative option with significantly improved outcomes over the long term, particularly with HLA-matched related donors. However, the use of alternative donors, such as haploidentical, mismatched, or matched unrelated donors, has previously been limited due to increased transplant-related morbidity, particularly graft-versus-host disease (GVHD). HCTs have therefore been limited to young recipients and those with HLA-matched related donors, creating significant disparity for older adults and those who lack matched donor options. Nevertheless, more recent advances in HCT, such as posttransplant cyclophosphamide for GVHD prophylaxis, have led to improved outcomes of HCT with alternative donors; however, alternative donor HCT remains underused as up-front therapy, in part because of limited multicenter trial data. This review discusses current SAA treatment approaches, including both IST and HCT, and highlights remaining gaps. It also discusses how ongoing clinical trials such as CureAA and TransIT could help address these gaps. Furthermore, we discuss the importance of stakeholder engagement and implementation science in the integration of research-based evidence into clinical practice. Bridging these gaps is necessary for achieving equitable access for patients historically excluded from frontline HCT, including older adults and racially or ethnically diverse populations.

Objective: Diabetes is a defining disease of the 21st century because of its rising prevalence, association with obesity, and enormous health impact. Abundant evidence shows that lifestyle interventions can delay or prevent type 2 diabetes (T2D) in adults, offer relief, and sometimes achieve complete remission. Despite this empowering message, there are no clinical practice guidelines that focus primarily on lifestyle interventions as first-line management of prediabetes and T2D. Our objective, therefore, is to offer pragmatic, trustworthy, and evidence-based guidance for clinicians in using the 6 pillars of lifestyle medicine—nutrition, physical activity, stress management, sleep, social connectedness, avoidance of risky substances—for managing adults with T2D and in preventing T2D in adults with prediabetes or a history of gestational diabetes mellitus. Methods: We used well-established, peer-reviewed guideline methodology to develop evidence-based key action statements (recommendations) that facilitate quality improvement in clinical practice. The guideline development group included 20 members representing consumers, advanced practice nursing, cardiology, clinical pharmacology, behavioral medicine, endocrinology, family medicine, lifestyle medicine, nutrition and dietetics, health education, health and wellness coaching, sleep medicine, sports medicine, and obesity medicine. Recommendation strength was based on the aggregate evidence supporting a key action statement plus a comparison of associated benefits vs harms/costs. Multiple literature searches, conducted by an information specialist, identified 8 relevant guidelines, 118 relevant systematic reviews, and 112 randomized clinical trials. The guideline underwent extensive internal, external, and public review and comment prior to publication. Results: We developed 14 key action statements and associated evidence profiles, each with a distinct quality improvement goal in the context of lifestyle interventions for T2D. Strong recommendations were made regarding advocacy for lifestyle interventions; assessing baseline lifestyle habits; establishing priorities for lifestyle change; prescribing aerobic and muscle strength physical activity; reducing sedentary time; identifying sleep disorders; prescribing nutrition plans for prevention and treatment; promoting peer/familial support and social connections; counseling regarding tobacco, alcohol, and recreational drugs, and establishing a plan for continuity of care. Recommendations were made regarding identifying the need for psychological interventions and for adjusting (deprescribing) pharmacologic therapy. We include numerous tables and figures to facilitate implementation, a plain-language summary for consumers, and an executive summary for clinicians as separate publications. Conclusions: There is robust research evidence supporting the efficacy of lifestyle interventions in preventing, treating, and achieving remission of T2D in adults. Our multidisciplinary guideline development group successfully synthesized this evidence into 14 key action statements that can be used by clinicians and other healthcare professionals to improve quality of care for adults with, or at-risk for, T2D. Despite the research gaps and implementation challenges we highlight in the guideline we believe strongly that our recommendations have immediate relevance and can help raise awareness and shift the paradigm of T2D management towards optimal use of lifestyle interventions.

This executive summary highlights evidence-based recommendations for using lifestyle interventions in the treatment and remission of type 2 diabetes (T2D) and prediabetes in adults. The summary and guideline are intended for any clinician or healthcare professional in a community or non-inpatient healthcare setting involved in managing non-pregnant adults with T2D, prediabetes or a history of gestational diabetes mellitus (GDM). The purpose of this executive summary is to provide a succinct overview of the key action statements (recommendations) from Lifestyle Interventions for Treatment and Remission of Type 2 Diabetes and Prediabetes in Adults: A Clinical Practice Guideline from the American College of Lifestyle Medicine. This is the first diabetes guideline to emphasize lifestyle interventions as the foundation of management and is also the first to focus on all six pillars of lifestyle medicine (plant-predomination nutrition, regular physical activity, restorative sleep, stress reduction, social connectedness, and avoiding risky substances), including behavior change strategies. This summary is not intended to substitute for the full guideline, which should be read before taking the recommended actions. The guideline on which this summary is based was developed with a priori methodology that has been previously published, refined, and used in over 20 multidisciplinary, trustworthy, and evidence-based national guidelines. The guideline development group included 20 members representing consumers, advanced practice nursing, cardiology, clinical pharmacology, behavioral medicine, endocrinology, family medicine, lifestyle medicine, nutrition and dietetics, health education, health and wellness coaching, sleep medicine, sports medicine, and obesity medicine. We developed 14 key action statements and associated evidence profiles, each with a distinct quality improvement goal in the context of lifestyle interventions for T2D. Strong recommendations were made regarding advocacy for lifestyle interventions; assessing baseline lifestyle habits; establishing priorities for lifestyle change; prescribing aerobic and muscle strength physical activity; reducing sedentary time; identifying sleep disorders; prescribing nutrition plans for prevention and treatment; promoting peer/familial support and social connections; counseling regarding tobacco, alcohol, and recreational drugs, and establishing a plan for continuity of care. Recommendations were made regarding identifying the need for psychological interventions and for adjusting (deprescribing) pharmacologic therapy. We include numerous tables and figures to facilitate implementation, a plain-language summary for consumers, and an executive summary for clinicians as separate publications. Although not a substitute for the full clinical practice guideline, this executive summary can provide insight into the key guideline recommendations, to whom they apply, and to how they might alter care. These recommendations offer detailed, explicit, and evidence-based strategies for successful lifestyle behavior change, making them relevant not only to our guideline but to other guidelines and standards that advocate for lifestyle change in managing adults with T2D.