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Introduction: Understanding patient preferences and decision-making processes is crucial in managing relapsed multiple myeloma (RRMM). Shared decision-making has become a key element of patient-centered care, allowing patients to collaborate with healthcare providers in choosing treatments that align with their health and quality of life goals. This study examines how the perceived severity of treatment side effects influences patient decision-making autonomy and communication patterns, providing insights into decision-making practices in hematology. Methods: A survey was conducted with 784 RRMM patients as of January 1, 2024, using HealthTree Cure Hub (PMID: 35271305). Among the participants, 333 experienced a relapse and responded to the question about how side effect severity affected their treatment choices. Of these, 54% (n=181) considered side effects to be very or extremely influential (VE), whereas 46% (n=152) regarded them as somewhat, slightly, or not influential at all (SSN). Participants evaluated these factors on 5-point Likert scales: 1 (very poor) to 5 (very good); 0 (not at all influential) to 4 (extremely influential). The survey assessed patient involvement in final treatment decisions, discussions with fellow patients, family or caregivers, and the time allocated and used for decision-making. Results: Patients in the VE group reported a better understanding of the likely side effects of treatment options compared to the SSN group (VE: 3.9±1.0; SSN: 3.6±1.0, p<0.05), with a higher proportion reporting a very good understanding (VE: 31%, n=45; SSN: 18%, n=29, p=0.036). A weak relationship confirmed VE patients engaged in additional side effect education before making a change in treatment decisions (r=0.164, p=0.004). VE patients also reported a better understanding of the balance between effectiveness and potential side effects of treatments than SSN patients (VE: 3.8±1.0; SSN: 3.5±1.1, p<0.05), with more VE patients reporting a very good understanding (29%, n=41 vs. 15%, n=24, p=0.006). A weak relationship confirmed that VE patients more closely evaluated the trade-offs of treatment options when choosing a new treatment regimen (r=0.197, p<0.001). Likely to achieve a better understanding, more VE patients talked with fellow patients (VE: 19%, n=24; SSN: 7%, n=11, p = 0.003) and rated these conversations as more influential than SSN (VE: 1.5±1.5; SSN: 1.1±1.4, p<0.05). Additionally, VE patients were more likely to discuss treatment options with family or caregivers before making a final decision (VE: 49%, n=61; SSN: 29%, n=43, p<0.05). Moreover, VE patients reported greater involvement in their doctor-patient communication approach (VE: 3.2±0.8; SSN: 2.8±0.8, p<0.05), with scores ranging from 1 (“...follow the doctor's suggestions”) to 4 (“...we discuss my preferences... and I make the final decision”). Furthermore, VE patients reported more self-determination in the treatment decision-making process than SSN patients, with more VE patients making the final treatment decision themselves rather than having their doctor decide (“I made the final decision” - VE: 66%, n=93; SSN: 52%, n=81; “My doctor made the final decision” - VE: 34%, n=47; SSN: 46%, n=72, p=0.013). VE patients reported being provided 1.5 more weeks of time to make a treatment decision than the SSN (4.8±8.9 v. 3.3±6.0 wks, p<0.05). Subsequently, VE patients reported using 79% more time than SSN patients to arrive at a final decision (VE: 2.5±6.0; SSN: 1.4±1.9 wks, p<0.05), likely attributed to time spent gaining a better understanding, having more conversations with patients and family, more shared decision making and self-determination in their treatment decision. Conclusion: The study highlights that RRMM patients who consider side effects to be very or extremely influential in their treatment decisions report being more proactive in understanding and discussing their treatment options. These patients engage more with healthcare providers, peers, and family members and are granted more time to make informed decisions. This emphasis on understanding and communication underscores the importance of personalized patient education and shared decision-making in the treatment of RRMM, especially for patients who are highly influenced by potential side effects. Together, these findings underscore the ongoing need for patient-centered care and education to optimize treatment choices.

Introduction Peripheral T-cell lymphoma (PTCL) encompasses a heterogeneous group of clinically aggressive entities. ~30% of cases cannot be further classified and are designated as PTCL - not otherwise specified (NOS). We delineated two novel molecular subgroups among PTCL-NOS with distinct clinical and biological features: PTCL-GATA3 which is characterized by high expression of GATA3, a master regulator of T-helper-2-cell (TH2) differentiation, and its target genes (i.e., CCR4, IL4, IL13) and PTCL-TBX21 which is characterized by high expression of TBX21, a master regulator of TH1 differentiation, and its target genes (i.e., CXCR3, IFNG), with the GATA3 subtype showing significantly worse clinical outcomes (overall survival). Nonsense mutations in CCR4 are found predominately in PTCL-GATA3, often within the cytoplasmic domain and gain-of-function in nature. Methods Mutation and copy number data were generated from whole exome sequencing (TFH phenotype excluded following LLMPP pathology review; n = 153). Single nucleotide variants were determined using Mutect2 and Varsvan2 using in-house filtering. Copy number (CN) profiles were generated using CNVkit. Four CCR4 cytoplasmic domain mutants and controls (cytoplasmic domain knockout [CDKO], wild-type CCR4 overexpression (CCR4-WT), and empty vector [EV]) were transduced into healthy-donor CD4+ T cells (n = 2). Polarization studies were generated using TH1- or TH2-associated cytokine exposure. Surface plasmon resonance was used to determine the binding affinity of CCR4 proteins to CCL17 and CCL22. In silico docking studies were done through Schrödinger's BioLuminate. Antibody-dependent cell-mediated cytotoxicity (ADCC) assay was performed through co-incubation of NK92 (CD16 and CD56) and CCR4 edited primary CD4+ T-cells (stained with calcein AM) for 2 hours at a 5:1 NK:T cell ratio by 7-AAD flow cytometry. Results PTCL-GATA3 had a higher frequency of CN aberrations (e.g. TP53, PTEN CN loss) and a more aberrant genome (p < 0.001) than PTCL-TBX21, including mutations with genes associated with DNA repair and damage (TP53, ATM) and T-cell differentiation (CCR4). CCR4 mutations were virtually mutually exclusive with TP53 mutations, and these cases showed higher CCR4 mRNA and protein expression than CCR4-WT cases (p < 0.05). Primary CD4+ T-cells with ectopic expression of the CCR4 variants, especially CCR4-Q330X, did not require CD3/CD28 for proliferation, bypassing CD3/CD28 ligation for T-cell activation. In addition, proliferation rates were similar between TH2-conditional media and normal media, but proliferation and TBX21 expression in TH1-conditional media were inhibited, implying a novel role of CCR4 in T-cell receptor (TCR) activation and TH-differentiation. CCR4 variant proteins showed higher binding affinity for their natural ligands, CCL22 and CCL17, with mutants exhibiting tighter binding to both ligands (1.5- to 3-fold decrease in KD) by surface plasmon resonance and in silico modeling studies. The in silico models demonstrated mutant CCR4 bound mogamulizumab tighter than CCR4-WT, consistent with a higher ADCC-induced apoptosis rate, highest with CCR4-Q330X mutation. CCR4-Y331X exhibited a worse docking score compared to CCR4-WT and a lower ADCC-induced apoptosis rate. Conclusions Our findings reveal distinct genetic characterizations including aberrant TP53 and PI3K signaling and CCR4 mutations in PTCL-GATA3. These CCR4 mutations are shown to have a key role in PTCL-GATA3 pathogenesis by dysregulating TH-differentiation and aberrantly activating the TCR. CCR4 mutation promotes the TH2 phenotype by blocking TH1 differentiation. CCR4 mutant proteins demonstrated an increased binding affinity towards its known ligands, CCL17 and CCL22, and mogamulizumab, consistent with previous studies exhibiting mogamulizumab efficacy against CCR4 mutations. However, the most frequent CCR4 mutant, Y331X, showed worse binding compared to other CCR4 mutants or CCR4-WT, a mutation that showed Mogamulizumab-resistance in a prior CTCL study as well as in an in vitro ADCC assay. The results emphasize aberrant pathways implicated by genomic and clinical evaluation of two novel PTCL subtypes, as well as support the novel role of mutant CCR4 in enhancing T-cell lymphomagenesis and T-helper differentiation, highlighting multiple therapeutic targets.

Background: Cure rates for children, adolescents, and young adults with cHL are high, but patients with a slow early response (SER) to front-line chemotherapy are at an increased risk of relapse compared with patients who have a rapid early response (RER). To avoid long-term toxicity while optimizing outcomes, treatment for pediatric cHL is now shifting to a response-adapted approach. KEYNOTE-667 (NCT03407144) is an open-label phase 2 study designed to evaluate the efficacy and safety of pembrolizumab plus chemotherapy consolidation with or without radiotherapy (RT) followed by pembrolizumab maintenance in patients with cHL and SER to front-line chemotherapy. The study includes 2 groups of patients: those with low-risk cHL (stage IA, IB, and IIA without bulky disease) and those with high-risk cHL (stage IIEB-IVB cHL). Prior analysis of the low-risk group showed that consolidation with pembrolizumab plus doxorubicin, vinblastine, and dacarbazine (AVD) and RT followed by maintenance pembrolizumab had manageable safety and promising antitumor activity in patients with low-risk cHL and SER to front-line doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). We present updated results for patients with low-risk cHL and SER to ABVD. Methods: Patients eligible for the low-risk group were aged 3-25 years and had newly diagnosed stage IA, IB, or IIA cHL without bulky disease, measurable disease, and a Lansky Play-Performance Scale score of ≥50 (aged <16 years) or a Karnofsky Performance Status score of ≥50 (aged ≥16 years). All patients in the low-risk group received 2 cycles of ABVD followed by early response assessment (PET and CT/MRI). Patients with a RER (ie, Deauville score [DS] 1-3) received nonstudy therapy. Patients with SER (ie, DS 4 or 5) received consolidation with pembrolizumab 2 mg/kg up to 200 mg (aged 3-17 years) or 200 mg (aged 18-25 years) IV Q3W plus 2 cycles of AVD. Patients then underwent late response assessment (LRA; PET and MRI/CT). All patients with SER received involved-site RT: 21.6 Gy for complete PET response (ie, DS 1-3) or 30.6-36 Gy for partial PET response (ie, DS 4 or 5). All patients received maintenance pembrolizumab for up to 17 cycles. The primary end point was objective response rate (ORR) by blinded independent central review (BICR) per Cheson 2007 IWG criteria. Secondary end points included PET negativity after consolidation and safety. Results: 78 patients with low-risk cHL received front-line ABVD. As of the data cutoff date (February 29, 2024), 10 of 78 patients had SER to ABVD and received consolidation with pembrolizumab plus AVD; 4 had completed consolidation and maintenance, 1 was continuing to receive treatment, and 5 had discontinued because of complete response (CR). Median time from allocation to data cutoff was 19.9 months (range, 5.6-44.8). Patients had received a median of 11.5 doses of pembrolizumab (range, 5-17) and the median time on pembro was 7.4 months (range, 3.5-11.3). The median age of patients was 16 years (range, 7-20), 6 (60%) were male, and 8 (80%) had Ann Arbor stage II disease. Of 10 patients who received consolidation, all (100%) had an LRA. The ORR was 100% (95% CI, 69-100; 9 CR and 1 partial response). Six patients (60%) were PET negative by BICR. Seven patients (70%) were PET negative by investigator review, all of whom received a reduced dose of RT. During consolidation, treatment-related adverse events (AEs) were reported in 8 patients (80%); grade 3 or 4 treatment-related AEs occurred in 4 patients (40%). No patients discontinued or died due to treatment-related AEs. Seven patients (67%) had pembrolizumab-related AEs, 3 of whom (30%) had a grade 3 event (vomiting, lymphocyte count decreased, white blood cell count decreased). Immune-mediated AEs occurred in 3 patients (30%; all grade 1 or 2 hypothyroidism). Conclusion: After additional follow-up, consolidation withpembrolizumab plus AVD and RT followed by pembrolizumab maintenance continued to demonstrate promising activity and manageable safety in patients with low-risk cHL and SER to ABVD. Of patients with a LRA, 60% were PET negative by BICR; 70% of patients were PET negative by investigator review and received a reduced dose of RT. These results support further evaluation of pembrolizumab plus AVD consolidation as a treatment option for patients with low-risk CHL and SER to front-line ABVD.

Introduction: Based on a donor versus no-donor analysis, UKALLXII/E2993 showed a survival benefit for adults with acute lymphoblastic leukemia (ALL) who underwent allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR1) compared to consolidation/maintenance chemotherapy alone. The follow-up phase 3 E1910 trial (NCT02003222) randomized BCR::ABL1-negative B-lineage ALL patients (pts) aged 30-70 years in measurable residual disease (MRD)-negative CR1 after intensification to conventional chemotherapy (CC) +/- blinatumomab (blin) and demonstrated significantly improved overall survival (OS) with blin (Litzow, NEJM 2024). The current exploratory subgroup analysis evaluates outcomes of MRD-negative pts randomized on E1910 who underwent alloHCT on trial. Methods: Among pts enrolled on E1910, pts in MRD-negative CR1 by 6-color flow cytometry after intensification who were randomized to CC +/- blin and subsequently underwent alloHCT were identified. We compared baseline characteristics, MRD status post induction, relapse-free survival (RFS) and OS using the Kaplan-Meier method and the two-sided log-rank test and Cox model. A multivariable analysis was performed with alloHCT included as a time-varying covariate as well as a landmark analysis comparing the outcome of pts with unfavorable risk on the CC + blin arm who underwent alloHCT versus those who did not. Results: Of 224 MRD-negative randomized pts, 44 underwent alloHCT on trial: 22 in each arm. The median time from randomization to transplant was 3.2 months (mos). The median follow-up from initial registration was 57.8 mos. Baseline demographics including age (median 55 years), gender (53% male), race (89% white) and ethnicity (89% non-Hispanic/Latino) were equally distributed. Compared to CC + blin, the median peripheral blood white cell (WBC) count and blast percentage at diagnosis were higher in the CC arm at 6,640 vs 3,740/uL and 55 vs 9%, respectively, while median marrow blast percentage and overall unfavorable risk as defined in E1910 (55% vs 64%) were similar. Of the 44 MRD-negative pts who proceeded to alloHCT on study, 77% in the CC arm and 64% in the CC+ blin arm were MRD-negative after induction. Myeloablative conditioning was given to the majority of pts (68% CC arm and 73% CC+blin arm) and the most common graft versus host disease prophylaxis was tacrolimus-based on both arms. Among the 44 pts who underwent alloHCT, the observed hazard ratio (HR) comparing relative risk of death between pts randomized to CC+blin or CC only was 0.59 (95% CI: 0.12-2.11) with a 3-year OS rate of 82% versus 71% and the HR comparing relative risk of relapse/death was 0.52 (CI: 0.15-1.79) with a 3-year RFS rate of 82% versus 67%. For patients with unfavorable risk, 3-year OS and 3-year RFS in each treatment arm were both 71% versus 65%. Among 50 pts with unfavorable risk in MRD-negative CR after intensification who were randomized to CC + blin, a landmark analysis performed at 5 mos post randomization showed 3-year OS and RFS rates of 71% versus 90% and 71% versus 86% between the 14 pts who underwent alloHCT and those who did not, respectively. Receipt of alloHCT was a time-varying covariate in a multivariable analysis with gender, WBC count, platelets, hemoglobin, peripheral blood blasts, bone marrow blasts, performance status, and combined molecular risk category. Age, CD20 status, rituximab use, and intention to receive alloHCT were used as stratification factors. In the entire cohort of MRD-negative pts who were randomized, there was a significant association between improved OS and the receipt of CC+blin vs CC alone (HR 0.46, 95% CI: 0.26 - 0.82; p=0.009), better performance status of 0-1 vs ≥2 and favorable vs unfavorable risk ALL. In contrast, the receipt of alloHCT had no significant effect on OS (HR 1.00, 95% CI: 0.49 - 2.01). Conclusions: Within the constraints of small numbers, this exploratory subgroup analysis demonstrates that in pts with newly diagnosed BCR::ABL1-negative B-ALL treated on E1910 who achieved MRD-negativity after intensification, alloHCT outcomes did not appear to be different with or without blin in consolidation. In a multivariate analysis of all MRD-negative pts, receipt of blin but not alloHCT was associated with improved OS. Further investigation is warranted to characterize the relative benefit of blinatumomab in pts receiving alloHCT in frontline consolidation.

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: Light chain (AL) amyloidosis is a rare and understudied plasma cell disorder. It is caused by abnormal misfolding of monoclonal immunoglobulin light chains, leading to extracellular deposition of amyloid, ultimately resulting in organ dysfunction and death. Since AL amyloidosis is uncommon, therapies are adapted from the more common plasma cell disorders like multiple myeloma. Daratumumab, a monoclonal antibody targeting CD38, was first tested in several prospective and retrospective studies in AL patients with relapsed refractory disease. The ANDROMEDA study (Kastritis E et al, NEJM 2021) established daratumumab in combination with CyBorD (Cyclophosphamide-Bortezomib-Dexamethasone) followed by daratumumab maintenance as the new standard of care compared to CyBorD alone for newly diagnosed patients. Consequently, daratumumab maintenance has become universally offered to all newly diagnosed AL amyloidosis patients. Notably, there was no second randomization before the initiation of maintenance therapy in ANDROMEDA. Hence, a critical question that remains is whether the superior efficacy observed in the investigational arm of the ANDROMEDA trial is solely a result of the addition of daratumumab during the induction phase or if the maintenance phase contributed to the favorable outcomes in the investigational arm. We hypothesize that a shorter duration of maintenance would prove non-inferior to the standard duration of daratumumab maintenance in patients with AL amyloidosis that have responded to Daratumumab-CyBorD induction. To answer this question we are conducting a pragmatic phase 2 randomized trial assessing the optimal duration of daratumumab maintenance in patients with AL amyloidosis who have responded to Daratumumab-CyBorD induction. Study Design, Patients and Methods: We use broadened eligibility criteria consistent with pragmatic trial design. The estimated total enrollment is up to 96 patients. The main eligibility criteria are patients with biopsy-proven AL Amyloidosis who have completed 6 cycles of Dara-CyBorD-based induction treatment and achieved an adequate response to induction (defined as hematological complete response (CR), hematological very good partial response (VGPR), or hematological partial response (PR) with at least one organ response). Patients in whom bortezomib and/or cyclophosphamide were omitted from induction due to toxicity concerns or adverse effects are allowed. The major exclusion criteria are patients who were concomitantly diagnosed with multiple myeloma based on International Myeloma Working Group (IMWG) criteria. This phase II, open-label, multicenter trial (NCT05898646) randomizes patients who have attained an adequate response to 6 cycles of Dara-CyBorD-based induction in a 1:1 ratio, using a dynamic allocation procedure that balances the marginal distributions of the stratification factors (age, cardiac stage, and t(11;14) status). Randomization is to either single-agent daratumumab maintenance of 6 cycles duration (experimental arm) or 18 cycles of daratumumab maintenance (control arm) (cycle = 28 days). Treatment is allowed to be given at a local facility After completing maintenance treatment, patients will follow up every 3 months for up to 36 months from registration. The primary endpoint of the trial is to evaluate the non-inferiority of a shorter (6 cycles) daratumumab maintenance measured by event-free survival (EFS) compared to the standard maintenance of 18 cycles in newly diagnosed AL amyloidosis who receive 6 cycles of daratumumab-CyBorD based induction. EFS in this study is defined as time from registration to any of the following events: hematological progression, organ progression, subsequent anti-plasma cell therapy in the absence of hematological progression but with persistent organ dysfunction or death, whichever occurs first. Secondary endpoints are depth of hematological and organ response, bone marrow measurable residual disease negativity rate, duration of response, quality of life, and survival. By investigating whether a shorter duration of maintenance is non-inferior to the standard duration, we aim to inform clinical practice and potentially reduce the toxicities associated with prolonged maintenance therapy, including hypogammaglobulinemia, recurrent infections, the need for intravenous gammaglobulin replacement, and financial toxicity.

Introduction Establishment of reference intervals (RI) for quantitative assays requires a minimum of 120 qualified normal donor (ND) samples for each partition of an analyte. Based on CLSI EP28 A3C guideline [CLSI. Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline-Third Edition. CLSI document EP28-A3c. Wayne, PA: Clinical and Laboratory Standards Institute; 2008.], verification of previously established and/or published RI can be performed with a minimum of 20 NDs, especially given complexities of finding qualified NDs. Reagent manufacturers typically provide adult RI, thus facilitating RI verification as a viable option. NDs for the Pediatric (Peds) (<18 years of age) population are difficult to obtain, published RIs are performed with sample cohorts less than the suggested number or only performed with specific instrument/reagent combinations. Herein, we report our experiences with Peds RI. Methods After IRB approval, healthy pediatric outpatients ages 0-18yrs were recruited and consented. Plasma obtained from umbilical cord, finger/heel/ear stick, or venipuncture blood samples (no more than 50 mL or 3 mL per kg) and collected in 3.2% sodium citrate. Assays included Protein (P) C antigen (PCAG) and chromogenic activity (PCFX); P S total (PST), free (PSF) antigen, and functional (SFX); antithrombin antigen (ATAG) and chromogenic activity (ATFX); plasminogen (PLGN) and alpha-2-plasmin inhibitor (A2PI). Assay kits were PCFX - HemosIL® (Werfen, Beford, MA) Protein C, PST - LIATEST® (Diagnostica Stago S.A.S., Asnières sur Seine, France) Protein S, PSF - HemosIL® Free Protein S, SFX - HemosIL® Protein S Activity, ATAG - LIATEST® AT III , ATFX - HemosIL® Liquid Antithrombin, PLGN - HemosIL® Plasminogen, and A2PI - HemosIL® Plasmin Inhibitor performed on the ACL TOP 700 (Werfen) instrument. PCAG - REAADS® Protein C Antigen Test Kit (Corgenix, Inc. Broomfield, CO) was performed on the Janus G3 liquid handler (Revvity, Waltham, MA) and Synergy Neo2 microplate reader (Agilent, Santa Clara, CA). Assay mean and range were calculated. Results Insufficient numbers of patients <1yr were collected. Type of assay, age range in yr and number of samples (n), assay mean in % and range results respectively were as follows: PCAG 1-5 (n=15) 87(46-146); 5-10 (n=82) 81 (45-158); 10-15 (n=169) 84 (44-157); 15-18 (n=107) 91 (57-149). PCFX 1-5 (n=20) 97 (56-140); 5-10 (n=84) 89 (62-135); 10-15 (n=188) 91 (55-140); 15-18 (n=124) 96 (54-138). PST (males): 1-5 (n=10) 120 (96-145); 5-10 (n=46) 108 (75-150); 10-15 (n=91) 111 (80-168); 15-18 (n=63) 113 (72-184). PST (females): 1-5 (n=9) 104 (67-146); 5-10 (n=37) 111 (81-159); Ages 10-15 (n=94) 107 (78-153); 15-18 (n=63) 101 (65-148). PSF (males): 1-5 (n=10) 94 (74-109); 5-10 (n=47) 101 (66-141); 10-15 (n=93) 101 (69-151); 15-18 (n=62) 111 (74-187). PSF (females): 1-5 (n=9) 78 (9-124); 5-10 (n=37) 107 (79-137); 10-15 (n=95) 99 (63-138); 15-18 (n=63) 97 (60-132). SFX (males): 1-5 (n=9) 100 (85-128); 5-10 (n=48) 104 (66-144); 10-15 (n=93) 103 (66-168); 15-18 (n=59) 109 (72-157). SFX (females): 1-5 (n=8) 94 (18-121); 5-10 (n=37) 107 (81-143); 10-15 (n=90) 101 (65-147); 15-18 (n=60) 97 (53-135). ATAG 1-5 (n=19) 104 (80-121); 5-10 (n=83) 104 (78-121); 10-15 (n=188) 104 (66-126); 15-18 (n=126) 101 (67-126). ATFX 1-5 (n=20) 112 (94-135); 5-10 (n=84) 107 (87-123); 10-15 (n=188) 105 (84-138); 15-18 (n=126) 101 (84-129). PLGN 1-5 (n=17) 96 (76-124); 5-10 (n=85) 88 (65-125); 10-15 (n=183) 90 (49-151); 15-18 (n=119) 94 (64-151). A2PI: 1-5 (n=17) 134 (118-151); 5-10 (n=85) 126 (107-139); 10-15 (n=183) 121 (104-140); 15-18 (n=118) 116 (91-143). Conclusions Based on CLSI EP28 A3C criteria for verification, no more than 10% of results should fall outside of established/published RI, for example adult RI. Thus, compared to the SCL adult RI, PLGN assay meets criteria in all age ranges and no additional ND are needed. For the remaining assays, additional ND for ages 1-5 are needed. For ages 5-18 criteria for verification are satisfied for all analytes except PCAG. PCAG has 27, 61, and 19 patients falling below lower RI for ages 5-10, 10-15, and 15-18, respectively.

Background: In TRANSCEND CLL 004 (NCT03331198),monotherapy with liso-cel, an autologous, CD19-directed CAR T cell product (100 × 106 CAR+ T cells [dose level (DL) 2]), resulted in 43% ORR and 18% CR/CR with incomplete marrow recovery (CRi) rate per IRC in pts with third-line or later R/R CLL/SLL who had PD on Bruton tyrosine kinase inhibitor (BTKi) and failed venetoclax (Siddiqi T, et al. Lancet 2023). Ibr + other CAR T cell therapies has shown high ORR and reduced cytokine release syndrome (CRS) severity in pts with R/R CLL/SLL. In the phase 1 dose-escalation ibr combination cohort, DL2 was the recommended dose of liso-cel for expansion (Wierda WG, et al. Blood 2020). Here, we report results of liso-cel + ibr in pts with R/R CLL/SLL from TRANSCEND CLL 004. Methods: Eligible pts ≥ 18 y of age with CLL/SLL had ≥ 1 of the following: 1) receiving BTKi with PD at entry, 2) high-risk disease and < CR after ≥ 6 mo on BTKi, 3) BTK/PLCγ2 mutation ± ibr PD, 4) prior BTKi with no contraindications to ibr, and 5) (per amendment) PD on BTKi and received prior venetoclax. At enrollment, pts started or continued ibr (420 mg daily or less for toxicity) through leukapheresis and for up to 90 d (or longer per investigator [inv]) after liso-cel (target dose of 50 × 106 CAR+ T cells [DL1] or DL2). Response was per inv by 2018 iwCLL criteria. Primary endpoint was CR/CRi rate at DL2; secondary endpoints included safety, ORR, duration of response (DOR), duration of CR/CRi (DOCR), time to response, time to CR/CRi, PFS, OS, and undetectable MRD (uMRD) rate in blood. Cellular kinetics was exploratory. Efficacy analyses were at DL2 and safety at DL1 + DL2. Treatment-emergent AEs (TEAE) occurred the latter of ≤ 90 days after liso-cel or ≤ 30 days of ibr completion. Liso-cel-treated pts who completed or withdrew from study could enroll in a separate long-term follow-up (LTFU) study (NCT03435796) for safety and OS ≤ 15 y after liso-cel. Results: A total of 65 pts underwent leukapheresis; 56 received ibr + liso-cel (DL1, n = 5; DL2, n = 51). At data cutoff (01/12/2024), 28 of 56 (50%) pts had discontinued the study, 11 (20%) completed the study, and 17 (30%) were ongoing; 5 of 28 (18%) eligible pts enrolled in LTFU. Median (IQR) on-study follow-up (including LTFU) was 24.8 mo (14.2-34.6). Median (range) age was 65 y (44-77); 55 (98%) pts had high-risk cytogenetics, such as del(17p) (n = 25), TP53 mutation (n = 24), and unmutated IGHV (n = 39); 43% had LDH ≥ ULN; and median (range) SPD was 27 cm2 (1-218). Pts had a median (range) of 5 (1-13) prior therapies (≤ 2, n = 13 [23%]). Median (range) time from leukapheresis to liso-cel availability was 25 d (17-79). Median (range) ibr exposure was 34 d (15-188) before and 94.5 d (6-1517) after liso-cel. At DL2, ORR (95% CI) was 86% (73.7-94.3), median (range) time to first response was 1.0 mo (0.9-6.0), and median (95% CI) DOR was 41.4 mo (23.3-not reached [NR]). CR/CRi rate (95% CI; primary endpoint) was 45% (31.1-59.7), median (range) time to first CR/CRi was 3.1 mo (0.9-12.1), and median (95% CI) DOCR was NR (26.6-NR). Median (95% CI) PFS and OS was 31.4 mo (20.1-NR) and NR (27.5-NR), respectively. uMRD rate (95% CI) in blood and marrow was 86% (73.7-94.3) and 84% (71.4-93.0), respectively. Grade (gr) ≥ 3 TEAEs occurred in 48 (86%) pts (most commonly neutropenia [52%] and anemia [41%]) with no gr 5 TEAEs. Liso-cel-related gr ≥ 3 TEAEs occurred in 32 (57%) pts and ibr-related gr ≥ 3 TEAEs in 24 (43%) pts including cardiovascular events of hypertension (7%) and atrial fibrillation (2%). Any-gr CRS occurred in 45 (80%) pts (gr ≥ 3, n = 2 [4%]) and any-gr neurological events (NE) in 23 (41%) pts (gr ≥ 3, n = 6 [11%]). Eight (14%) pts had gr ≥ 3 infections and 5 (9%) had second primary malignancies. Twenty-five (45%) pts had prolonged cytopenias (gr ≥ 3 at D30); most recovered to gr ≤ 2 by D90. Sixteen pts died after infusion (PD, n = 6; unknown, n = 6; COVID-19, n = 3; mixed septic/cardiogenic shock, n = 1). Liso-cel showed rapid expansion (median tmax, 10 d) and was detected up to 42 mo after infusion. Conclusions: Combined liso-cel + ibr demonstrated substantial efficacy with deep remissions (86% ORR, 45% CR rate, and 86% blood uMRD rate) and manageable safety in pts with R/R CLL/SLL. Though comparisons should be made with caution and there were differences in disease characteristics between cohorts, liso-cel + ibr showed a numerically higher ORR/CR rate and lower gr ≥ 3 CRS/NE rates vs liso-cel monotherapy, supporting the combination as a promising new therapeutic strategy for pts with R/R CLL/SLL.

The Canadian Consortium on Neurodegeneration in Aging (CCNA) was created by the Canadian federal government through its health research funding agency, the Canadian Institutes for Health Research (CIHR), in 2014, as a response to the G7 initiative to fight dementia. Two five-year funding cycles (2014–2019; 2019–2024) have occurred following peer review, and a third cycle (Phase 3) has just begun. A unique construct was mandated, consisting of 20 national teams in Phase I and 19 teams in Phase II (with research topics spanning from basic to clinical science to health resource systems) along with cross-cutting programs to support them. Responding to the needs of researchers within the CCNA teams, a unique sample of 1173 deeply phenotyped patients with various forms of dementia was accrued and studied over eight years (COMPASS-ND). In the second phase of funding (2019–2024), a national dementia prevention program (CAN-THUMBS UP) was set up. In a short time, this prevention program became a member of the World Wide FINGERS prevention consortium. In this article, the challenges, successes, and impacts of CCNA in Canada and internationally are discussed. Short-term deliverables have occurred, along with considerable promise of impacts in the longer term. The creation of synergy, networking, capacity building, engagement of people with lived experience, and economies of scale have contributed to the considerable success of CCNA by all measures. CCNA is evidence that an organized “centrally-organized” approach to dementia research can catalyze important progress nationally and yield significant and measurable results.

Abstract Background The phase III RxPONDER trial has affected treatment for node-positive (1-3), hormone receptor-positive, HER2-negative breast cancer with a 21-gene recurrence score (RS) less than 26. We investigated how these findings apply to different racial and ethnic groups within the trial. Methods The trial randomly assigned women to endocrine therapy (ET) or to chemotherapy plus ET. The primary clinical outcome was invasive disease-free survival (IDFS), with distant relapse-free survival (DRFS) as a secondary outcome. Multivariable Cox models were used to evaluate the association between race/ethnicity and survival outcomes, adjusting for clinicopathological characteristics, RS, and treatment. Results A total of 4048 women with self-reported race/ethnicity were included: Hispanic (15.1%), non-Hispanic Black (NHB) (6.1%), Native American/Pacific Islander (0.8%), Asian (8.0%), and non-Hispanic White (NHW) (70%). No differences in RS distribution, tumor size, or number of positive nodes were observed by race/ethnicity. Relative to NHWs, IDFS was worse for NHB participants (5-year IDFS 91.6% vs 87.1%, HR = 1.37; 95% CI = 1.03 to 1.81) and better for Asians (91.6% vs 93.9%, HR = 0.64; 95% CI = 0.46 to 0.91). Relative to NHW, DRFS was worse for NHB participants (5-year DRFS 95.8% vs 91.0%, HR = 1.65; 95% CI = 1.17 to 2.32) and better for Asians (95.8% vs 96.7%, HR = 0.59; 95% CI = 0.37 to 0.95). Adjusting for clinical characteristics, particularly body mass index, diminished the effect of race on outcomes. Chemotherapy treatment efficacy did not differ by race/ethnicity. Conclusions NHB women had worse clinical outcomes compared with NHWs in the RxPONDER trial despite similar RS and comparable treatment. Our study emphasizes the persistent racial disparities in breast cancer outcomes while highlighting complex interactions among contributing factors. Trial Registration ClinicalTrials.gov: NCT01272037.