Citations

Abstract The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to optimize and validate biomarkers for clinical trials while sharing all data and biofluid samples with the global scientific community. ADNI has been instrumental in standardizing and validating amyloid beta (Aβ) and tau positron emission tomography (PET) imaging. ADNI data were used for the US Food and Drug Administration (FDA) approval of the Fujirebio and Roche Elecsys cerebrospinal fluid diagnostic tests. Additionally, ADNI provided data for the trials of the FDA‐approved treatments aducanumab, lecanemab, and donanemab. More than 6000 scientific papers have been published using ADNI data, reflecting ADNI's promotion of open science and data sharing. Despite its enormous success, ADNI has some limitations, particularly in generalizing its data and findings to the entire US/Canadian population. This introduction provides a historical overview of ADNI and highlights its significant accomplishments and future vision to pioneer “the clinical trial of the future” focusing on demographic inclusivity. Highlights The Alzheimer's Disease Neuroimaging Initiative (ADNI) introduced a novel model for public‐private partnerships and data sharing. It successfully validated amyloid and Tau PET imaging, as well as CSF and plasma biomarkers, for diagnosing Alzheimer's disease. ADNI generated and disseminated vital data for designing AD clinical trials.

Abstract The antiapoptotic protein, myeloid cell leukemia-1 (Mcl-1), contributes to the pathophysiology of acute myeloid leukemia (AML) and certain B-cell malignancies. Tumor dependence on Mcl-1 is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase (CDK) inhibitor targeting CDK9, indirectly decreases Mcl-1 protein expression and synergizes with venetoclax in preclinical models. This dose escalation study evaluated voruciclib in patients with previously treated hematologic malignancies. Initially, voruciclib was administered daily, continuously, on a 28-day cycle (group 1). After 2 patients with prior allogeneic stem cell transplantation had a dose-limiting toxicity (DLT) of interstitial pneumonitis at 100 mg, voruciclib administration was changed to days 1 to 14 of a 28-day cycle (group 2). Forty patients, 21 with AML and 19 with B-cell malignancies, were enrolled. Patients had a median of 3 prior lines of therapy (range, 1-8). Dose escalation in group 2 was stopped at 200 mg, a dose that achieved plasma concentrations sufficient for target inhibition, without DLTs observed. The most common adverse events were diarrhea (30%), nausea (25%), anemia (22%), fatigue (22%), constipation (17%), dizziness (15%), and dyspnea (15%). In AML, 1 patient achieved a morphologic leukemia-free state, and 2 had stable disease. Voruciclib treatment led to a decrease in MCL1 messenger RNA expression, downregulation of myelocytomatosis (MYC) and NF-κB transcriptional gene sets, and reduced phosphorylation of RNA polymerase 2. Voruciclib on intermittent dosing was well tolerated, with no DLTs, paving the way for evaluation of the combination of voruciclib with venetoclax for patients with previously treated AML. This trial was registered at www.clinicaltrials.gov as #NCT03547115.

Indications for and implications of germline genetic testing (GGT) in patients with prostate cancer have expanded over the past decade, particularly related to precision therapies and management. GGT has become the standard of care for many cancers such as breast, ovarian, colorectal, pancreatic, and metastatic prostate cancer, and it is imperative that patients be offered timely and equitable access to testing as it can inform patient-physician shared decision making for management of the current cancer as well as anticipatory guidance for disease progression. Additionally, GGT guides screening for and prevention of secondary malignancies for the patient and cascade testing for at-risk family members. Here, we present data supporting the notion that clinicians should offer all patients with prostate cancer the opportunity to undergo comprehensive GGT for pathogenic germline variants known to be associated with familial cancer and/or known to have implications for treatment and management.

Abstract Aims We aimed to perform a retrospective cohort study using the Centers for Disease Control and Prevention’s (CDC’s) Wide-Ranging Online Data for Epidemiologic Research (WONDER) database to analyse the trends in cardiovascular disease (CVD)–related mortality in patients with myeloproliferative neoplasms (MPNs) from 1999 to 2020. Methods and results We analysed the death certificate data from the CDC WONDER database from 1999 to 2020 for CVD with co-morbid myeloproliferative disorders in the US population. Age-adjusted mortality rates (AAMRs) and 95% confidence intervals (CIs) were computed per 1 million population by standardizing crude mortality rates to the 2000 US census population. To assess annual national mortality trends, we employed the Joinpoint regression model, calculating the annual per cent change in AAMR and corresponding 95% CIs. A total of 15 269 deaths related to CVD occurred in patients with co-morbid MPNs from 1999 to 2020. Overall, there was a decreasing trend in CVD-related AAMRs throughout these years. Males contributed to 51% of total deaths, and their AAMR was persistently higher than women throughout the study. Non-Hispanic (NH) Whites had the highest overall AAMR, followed by NH Blacks, NH American Indians or Alaska Natives, Hispanics or Latinos, and NH Asian or Pacific Islanders. Conclusion Our findings indicate a significant decline with notable gender, racial/ethnic, and regional differences in CVD-related mortality among patients with MPN over the past two decades. We emphasize the importance of a collaborative approach between oncologists and cardiologists in managing these patients, highlighting the potential benefits of integrating cardio-oncology services to enhance patient outcomes.

Background/Objectives: Spino-plastic surgery describes a specialized, multidisciplinary approach to addressing various spinal pathologies. The field is the innovative product of a multidisciplinary collaboration between plastic and reconstructive, orthopedic, and neurosurgery. Over the last few decades, this collaboration has borne promising surgical techniques and treatment plans geared toward restoring form, function, and aesthetics in patients with a variety of spinal conditions, including failed fusions, pseudoarthrosis, and the need for oncologic reconstruction. This paper explores the application of spino-plastic surgery in the context of post-sarcoma resection reconstructions, focusing on the efficacy in addressing the unique challenges posed by extensive tissue loss and structural deformities. Methods: Our study reviews a series of cases wherein spino-plastic techniques were utilized in patients with sarcomas of the spine and adjacent structures. We also discuss the technical considerations, including preoperative planning, intraoperative challenges, and overall patient care, that are crucial for the success of spino-plastic procedures. Results: The outcomes demonstrate significant improvements in patient mobility, pain reduction, and overall quality of life. Most notably, spino-plastic surgical techniques help facilitate the restoration of functional anatomy by leveraging vascularized bone grafts and muscle flaps, thereby enhancing long-term stability and reducing the risk of complications such as nonunion or infection. Conclusions: Spino-plastic collaboration represents a pivotal advancement in oncologic treatment, spinal care, and reconstructive surgery, offering new hope for patients undergoing post-sarcoma reconstruction. Further research and refinement of the techniques will only expand their application and improve outcomes for a broader range of patients in the future.

Introduction: Although not formally approved for the treatment of multiple myeloma (MM), the BCL2 inhibitor venetoclax (ven) has shown promising activity in patients (pts) with MM whose disease harbors t(11;14). The randomized BELLINI trial (VenVd vs Vd in unselected MM pts, Kumar Lancet Oncol 2020) demonstrated improved PFS, especially in the 35 patients with t(11;14) [HR 0.11], although worse OS in the intention to treat population due to increased treatment related mortality. The subsequent CANOVA trial (Vendex vs Pomdex in MM pts with t(11;14), Mateos IMS 2023) failed to show a PFS benefit (median PFS 9.9 mo vs 5.8 mo, p=0.237), leaving an uncertain future for ven in myeloma, despite the biological rationale and clinical activity. We therefore analyzed real world physician practice patterns using off-label ven for MM in the US. Methods: This retrospective observational study used data from the US nationwide Flatiron Health electronic health record (EHR)-derived de-identified longitudinal database. The Flatiron Health database contains structured and unstructured data curated via technology-enabled abstraction from approx. 280 cancer clinics and 800 unique sites of care. We included all patients in the Flatiron Health database with multiple myeloma (ICD-9 203.0x or ICD-10 C90.0x, confirmed with clinical review) who had received ven as part of any line of MM treatment. This included patients who commenced ven between 2016-2024. The primary endpoint was time to next treatment or death (TTNT) from ven initiation, with overall survival (OS) from ven initiation as the key secondary endpoint, both of which were estimated using the Kaplan-Meier method. Outcomes were compared using Cox proportional hazards model, using R v 4.3.0. Results: We included 208 patients who received ven for MM. They had a median of three prior lines of therapy (range 0-12), a median age of 67 years (Range 34-85 yrs), and 59% were male. Race/ethnicity breakdown was: Non-Hispanic White: 136 pts (72.7%), Black 36 (19.3%), Hispanic 10 (5.3%), Asian 5 (2.7%), other/unknown 21 (10.1%). Most had commercial insurance (188 pts, 91.3%) and 108 pts (52%) were cared for in academic settings while 100 (48%) were in community settings. ECOG performance status was 0 in 50 pts (24%), 1 in 80 pts (38.5%), ≥2 in 31 pts (14.9%) and unknown in 47 (22.6%). ISS Stage was I in 42 pts (20.2%), II in 43 pts (20.7%), III in 52 pts (25.0%) and unknown in 71 (34.1%). 148 pts had t(11;14) (71.2%), while 25 pts did not (12%) and 35 pts had unknown t(11;14) status (16.8%). Most pts received ven as part of a triplet combination (106 pts, 51%), followed by doublets (39, 18.8%; 21 ven+dex and 18 ven+non-dex doublet), quads (38, 18.3%), as a single agent (17, 8.2%) or in other combinations such as with multi-agent cytotoxic chemotherapy or in addition to quadruplet therapy (8, 3.9%). Most common first ven-containing regimens used were VenDd (34 pts), VenKd (31), VenVd (25), Vendex (21), VenDVd (13), VenDKd (7). Ven was used as part of ≥2 different regimens in 20 patients, in 10 of whom those regimens were non-consecutive. Median TTNT was 10.2 months (mo) in all comers, 12 mo in pts with t(11;14), 3.4 mo in pts without t(11;14) and 7.6 mo in pts with unknown t(11;14) status. Median OS was 27.6 mo in all comers, 30.5 mo in pts with t(11;14), 8.1 mo in pts without t(11;14) and 27.9 mo in pts with unknown t(11;14) status. Pts with t(11;14) receiving ven had a significantly longer TTNT than those without t(11;14) [median 12 mo vs 3.4 mo, HR 0.59, 95%CI 0.42-0.84, p=0.003]. and a significantly longer OS [median 30.5 mo vs 8.1 mo, HR 0.58, 95% CI 0.38 - 0.89, p=0.012]. Discussion: We evaluated US ven prescribing patterns in 208 pts with MM in the largest real world study of ven in MM to date. While it was mostly used in pts with t(11;14) (71%), there was occasional use in pts without t(11;14), and it was used in a wide variety of combination regimens. Ven achieved meaningful TTNT in some patients and both TTNT and OS were greater in pts with t(11;14) than those without. This suggest that despite mixed data from clinical trials, clinicians are using ven for MM patients in practice and further data is required to optimize its use and understand its best combination treatment partners in MM.

Fetal hemoglobin (HbF) is anti-sickling and elevated HbF ameliorates sickle cell disease (SCD) manifestations. BEAM-101 is an investigational cell therapy comprised of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) that are base edited ex vivo to introduce naturally occurring A-to-G substitutions into the promoters of the HBG1/2 genes that encode γ-globin to disrupt BCL11A transcriptional repressor binding sites, leading to increased HbF production. We previously demonstrated in pre-clinical studies that base editing potently induced HbF (>60%) and proportionately reduced sickle hemoglobin (HbS) (<40%) without relying on double-stranded DNA breaks. We present initial data from BEACON (NCT05456880), a Phase 1/2, single-arm, open-label study evaluating the safety and efficacy of a single dose of BEAM-101 in patients with SCD with severe vaso-occlusive crises (VOCs). Patients 18-35 years diagnosed with SCD and ≥4 severe VOCs in the 2-year period prior to screening per trial criteria were eligible. After plerixafor mobilization, autologous CD34+ HSPCs were collected by leukapheresis/isolation and genetically modified with an adenine base editor. After myeloablative conditioning with pharmacokinetically adjusted busulfan, patients received a single infusion of BEAM-101 (≥3.0 × 106 viable CD34+ cells/kg) and are monitored for neutrophil and platelet engraftment, adverse events (AEs), total hemoglobin (Hb), Hb fractions, % F-cells, hemolysis markers, peripheral blood editing, and VOCs for 24 months. As of July 2, 2024, >20 patients are enrolled and BEAM-101 has been manufactured for 8 patients, of whom 6 patients have been dosed. One patient not included in this analysis discontinued during the mobilization/collection period prior to BEAM-101 treatment for non-medical reasons. Baseline demographics were as follows: 5/6 patients βS/βS, 1/6 patients βS/β0, all self-reported Black/African American, 50% female, aged 19-27 years. Of the 6 patients, half (n=3) required only a single mobilization cycle and the other half required 2. Patients received a mean BEAM-101 dose of 11.9 × 106 (5.2-23.4) viable CD34+ cells/kg. Excepting safety data that include all patients dosed (n=6), the following data are from patients dosed with ≥1 month of follow up (n=4; 6, 5, 2, and 1 month[s] post-treatment, each). All 4 patients with ≥1 month of follow up achieved neutrophil and platelet engraftment at a median of 17 (15-19) and 20 (11-34) days, respectively. One patient died due to respiratory failure, likely related to busulfan conditioning, 4 months after infusion. In all patients dosed (n=6), there have been no ≥Grade 3 AEs or serious AEs related to BEAM-101. Using the central laboratory data, patients' total Hb increased from baseline (mean 9.3 [7.9-10.9] g/dL) to 17.9, 18.2, 11.0, and 11.8 g/dL at last time point (LTP) available for P1, P2, P3, and P4, respectively. No signs/symptoms or interventions were undertaken for high total Hb. All patients achieved >60% HbF of non-transfused Hb (total Hb − HbA) at Month (M) 1 and sustained this elevation to the LTP available. By M1, HbS% in non-transfused blood dropped to ≤36% in all 4 patients and was sustained through LTP. In total blood, % F-cells were 99.6% in P1 at M6, 94.4% in P2 at M4, 52.0% in P3 at M2, and 13.3% in P4 at M1 with all patients having >19 pg HbF/F-cell at LTP available. Peripheral blood editing in nucleated cells, measured in P1 (at M6) and P2 (at M3), was 69.9% and 76.1%, respectively. Markers of hemolysis (lactate dehydrogenase, indirect bilirubin, haptoglobin, and reticulocyte counts) have normalized or improved for all patients. No VOCs have been reported by investigators following BEAM-101 treatment. These initial data show a safety profile for BEAM-101 consistent with busulfan conditioning and autologous HSCT. Treatment with BEAM-101 resulted in rapid engraftment, improvement in hemolysis markers, and marked improvement of anemia in all 4 dosed patients. We observed rapid and robust HbF induction consistent with pre-clinical data by M1 (>60%) and corresponding HbS reduction (≤36%) in non-transfused blood in all post-treatment assessments. No VOCs were reported by investigators post-treatment. These initial data support base editing of the HBG1/2 promoters as an effective therapeutic modality for the treatment of SCD and will continue to be investigated in the ongoing BEACON study. Updated data to be presented.

Background: Polatuzumab vedotin (Pola) is an antibody drug conjugate targeting CD79b that incorporates the microtubule disrupting monomethyl auristatin E payload. Pola was approved in 2023 for the upfront treatment of diffuse large B cell lymphoma (DLBCL) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (polaRCHP) based on the POLARIX trial. However, the activity of pola appears to vary based on DLBCL cell of origin (COO) subtype, with greater efficacy in activated B cell (ABC) DLBCL compared to germinal center B cell (GCB) DLBCL (Russler-Germain Blood 2023). When outcomes in POLARIX are stratified by COO, polaRCHP demonstrated progression free survival (PFS) and overall survival (OS) benefits over RCHOP in patients with ABC but not GCB subtype DLBCL (PFS HR 0.34 ABC vs 1.03 GCB, OS HR 0.27 ABC vs 1.64 GCB; Morschhauser ASH 2023 and FDA data). Most prospective studies of pola used gene expression to assess COO, which is not readily clinically available. This study aims to examine if COO subtype by Hans algorithm (based on CD10, BCL6, and MUM1 expression by immunohistochemistry) is predictive of pola responses and outcomes in patients with large B cell lymphoma (LBCL). Methods: We conducted a retrospective, multicenter observational study of adults with LBCL who received pola (monotherapy or in combination) from 2015-2024 with Hans algorithm COO data and response assessment available. Patients were stratified by receipt of pola in the frontline vs relapsed/refractory (R/R) setting. The primary endpoint was overall response rate (ORR) to pola-based treatment in GCB vs non-GCB subtypes. Secondary endpoints included complete response rate (CRR), PFS, and OS. For time to event endpoints, patients responding to pola who received CAR T or stem cell transplantation prior to progression were censored at time of cellular therapy. Demographics were summarized by descriptive statistics. Comparative and survival analyses used Chi squared/Fischer exact tests and Kaplan Meier analysis. Data cutoff was July 1, 2024. Results: 718 patients were included. Median follow-up was 15 months (interquartile range [IQR] 8-32). Median age at LBCL diagnosis was 66 years (IQR 56-74); 62% were men; 69 (10%) had double hit lymphoma (DHL); 129 (18%) had underlying low grade lymphoma. Pola was used in the frontline setting in 293 (41%) patients, of whom 139 (47%) had GCB vs 154 (53%) non-GCB COO. Of the 426 patients receiving pola for R/R LBCL (including one patient receiving pola retreatment), 224 (53%) had GCB vs 202 (47%) non-GCB COO. Among patients receiving pola-based regimens in the R/R setting (GCB vs non-GCB: pola monotherapy = 7% vs 4%, pola + R = 26% vs 26%, pola + BR = 55% vs 61%, pola + other = 12% vs 9%; p = 0.44), the ORR in GCB vs non-GCB LBCL was 36% vs 61% (p < 0.001), while CRR in GCB vs non-GCB was 17% vs 36% (p < 0.001). COO remained a significant component of logistic multivariate regression models of ORR (p < 0.001) and CRR (p < 0.001) when incorporating IPI at original LBCL diagnosis, histology, DHL status, and refractory status to frontline therapy. Despite this, no significant PFS or OS differences by COO were seen, potentially due to approximately 1/4 patients being censored due to receiving subsequent cellular therapy (e.g. CAR T) prior to progression. In patients receiving frontline pola-based regimens (of which 275 [94%] included an anthracycline), ORR and CRR were similar in GCB vs non-GCB (ORR 89% vs 88% p > 0.5; CRR 76% vs 77% p > 0.5). While PFS and OS were similar between COO groups in the frontline cohort, follow-up and cohort size were limited. Conclusion: Based on this real-world evidence, COO classification by Hans algorithm is a strong predictor of the activity of pola-containing therapy in R/R LBCL, with significantly higher ORR and CRR in patients with non-GCB compared to GCB COO LBCL. This aligns with the cumulative existing evidence. ORR and CRR to pola-containing therapy in the frontline setting did not differ significantly by COO subtype, but longer follow-up of larger cohorts is needed to clarify the predictive role of COO by Hans algorithm in this setting, especially considering the PFS advantage with polaRCHP in POLARIX was not associated with significant differences in ORR or CRR. Overall, clinicians should consider factoring COO subtype into treatment decisions regarding pola-containing regimens, and studies of pola-based therapies should stratify patients and report outcomes by COO subtype.