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Background. Early allograft dysfunction (EAD) affects outcomes in liver transplantation (LT). Existing risk models developed for deceased-donor LT depend on posttransplant factors and fall short in living-donor LT (LDLT), where pretransplant evaluations are crucial for preventing EAD and justifying the donor’s risks. Methods. This retrospective study analyzed data from 2944 adult patients who underwent LDLT at 17 centers between 2016 and 2020. We developed a logistic regression model to predict EAD based on this development cohort. We used data from 1020 patients at the King Faisal Transplant Center for external validation. Results. In the development cohort, 321 patients (10.9%) experienced EAD. These patients had poorer health status, more liver decompensation, and higher requirements of hospitalization than those without EAD. Multivariable logistic regression identified independent pretransplant predictors of EAD: laboratory Model for End-Stage Liver Disease score (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.06-1.09), the necessity for hospitalization at the time of transplant (OR, 2.58; 95% CI, 2.00-3.30), and graft weight in kilogram (OR, 0.27; 95% CI, 0.17-0.45). Using these predictors, we developed the model for EAD after LDLT, which demonstrated strong discriminative ability in the development cohort with an area under the curve (AUC) of 0.71 (95% CI, 0.68-0.74). The model maintained high discrimination during internal validation (AUC, 0.70; 95% CI, 0.67-0.73) and showed a modest reduction in discriminative power in external validation (AUC, 0.65; 95% CI, 0.61-0.68). Conclusions. EAD post-LDLT is influenced by the recipient’s pretransplant health condition and the graft weight. Integrating the model for EAD after LDLT into the pretransplant process of pairing donors and recipients can enhance the safety and efficacy of LDLT.

Introduction: GOLCA is a potential first-in-class CELMoDTM agent for the treatment of lymphoma, purposefully designed to target the proteins Ikaros/Aiolos to produce dual immunomodulatory and anti-tumor activity, with preferential distribution to lymphoid organs. Pharmacodynamic data in pts with R/R FL show that, combined with RTX, the immunomodulatory effects of GOLCA are significantly increased (Chavez et al, EHA 2024, #1132). GOLCA as monotherapy (mono) and + RTX has been shown to be well-tolerated and effective in pts with R/R DLBCL (Chavez et al, ASH 2023, #4496) and R/R FL (Chavez et al, EHA 2024, #1132). Here, we report 30 mo follow up of pts with R/R FL who received GOLCA mono, and updated safety/efficacy of GOLCA + RTX from the ongoing Phase 1/2 CC-99282-NHL-001 study (NCT03930953). Methods: Pts with R/R FL with ≥ 2 prior lines of therapy (L) received GOLCA mono at different dosing schedules during part A (dose exploration) and GOLCA ± RTX at 0.2 mg or 0.4 mg days (d) 1-14 every 28 d (q28d) in part B (dose expansion). Total treatment duration with GOLCA was up to 2 years or until progressive disease or unacceptable toxicity, whichever occurred first. The efficacy-evaluable population consisted of pts completing ≥ 1 cycle of GOLCA and having baseline tumor assessment and ≥ 1 post-baseline tumor assessment or clinical progression or disease-related death. Results: As of May 31, 2024, 63 pts with R/R FL have enrolled: GOLCA mono (n = 19) at various dosing schedules and GOLCA + RTX at 0.2 mg (n = 22) or 0.4 mg (n = 22) on d1-14 q28d schedule. The median time from diagnosis to first dose of GOLCA was 68 mo (range, 23-136) and 59 mo (range, 15-309) in GOLCA mono and + RTX cohorts, respectively. The median number of prior therapies received was 4 (range, 2-11), and 3 (range, 1-12) in GOLCA mono and + RTX cohorts, respectively. In the GOLCA mono and + RTX cohorts, 9/19 (47%) and 13/43 (30%) pts had received prior lenalidomide (len)-based therapy, with 5/9 and 7/13 having len-refractory disease, respectively. In the GOLCA + RTX cohort, 10/43 (23%) had prior CAR T cell therapy and 6/43 (14%) had prior anti-CD20xCD3 bispecific antibody with or without CAR T cell therapy. In the GOLCA + RTX-treated safety population (n = 43), the incidence of treatment emergent adverse events (TEAEs) was similar across 0.2 and 0.4 mg dose levels (DL). The most frequent grade (G) 3+ TEAEs were neutropenia (44%) and anemia (12%). The incidence of febrile neutropenia was 7%. Serious adverse events occurred in 30% of pts, with febrile neutropenia and pneumonia being the most common, in 2 pts (5%) each, as well as pulmonary embolism in 1 pt. Neutropenia led to GOLCA dose interruption in 4 pts (9%) and dose reduction in 1 pt (2%). No pts discontinued treatment because of GOLCA-related TEAEs. Non-hematological TEAEs (e.g., GI toxicity, rash, fatigue) were all low-grade (except 1 pt with G3 fatigue). There were no new safety signals identified for GOLCA mono (part A) at the 30-mo follow up period. In the efficacy-evaluable population, at a median follow up of 6 mo (range 3-18), the ORR and CRR in the GOLCA + RTX cohort (n = 29) were 57% and 29% at 0.2 mg dose (n = 14) and 93% and 67% at 0.4 mg dose (n = 15), respectively. The median time to response was 2 mo (first response assessment). At the 0.4 mg DL of GOLCA + RTX, consistent responses were seen in pts at 2L/3L and 4L+, including in those with prior exposure to len-based therapies and/or T-cell-redirecting therapy. At the 0.4 mg DL, 12/14 (86%) pts remained in response at the time of data cut-off. In pts receiving GOLCA mono across different dose schedules in part A (n = 12), ORR and CRR were 67% and 42%, respectively. Responses were durable, with median DOR of 22 mo (range, 2-51) at a median follow up of 30 mo. 33% of pts (4/12) have completed 2 yrs of protocol defined GOLCA treatment and remain in response at the 1 yr post-treatment follow-up period, without requiring any intervening treatment. Conclusions: GOLCA 0.4 mg + RTX was well tolerated and highly active in heavily pre-treated pts with R/R FL, including those with prior exposure to len-based therapies and/or T-cell-redirecting therapies. Treatment with fixed-duration GOLCA mono led to durable responses including a subset of pts remaining treatment free, without progression at extended follow up. These data further support development of GOLCA + RTX as a fixed-duration, chemotherapy-free, outpatient treatment option in pts with R/R FL, and also pts with newly diagnosed advanced stage FL (NCT06425302).

Introduction: Treatment for R/R MCL has evolved with the use of cBTKi monotherapy. Previously, we reported differences in RW time to next treatment (rwTTNT) and overall survival (rwOS) among patients (pts) treated with ibrutinib (ibr), acalabrutinib (acala), and zanubrutinib (zanu), but reasons for the differences were unknown (Phillips et al. EHA 2024). Our objectives were to re-evaluate trends in rwTTNT and rwOS; assess treatment patterns of cBTKis, including switching; describe reasons for cBTKi discontinuation; and compare RW effectiveness of ibr, acala, and zanu monotherapy. Methods: This retrospective cohort study included adult pts diagnosed with R/R MCL who initiated second-line (2L) or third-line (3L) first cBTKi treatment 01/2018-11/2023 and were followed until loss to follow-up or death using the US nationwide Flatiron Health EHR deidentified database. Patient characteristics and survival estimates based on Kaplan-Meier (KM) analyses were summarized. Adjusted analysis using a multivariate Cox model was applied to assess rwTTNT and rwOS. Key model variables were age, sex, POD24 (2L start ≤24 mo from first-line start), and number of prior lines of therapy. Reasons for discontinuation were abstracted from documentation in notes and included non-mutually exclusive categories. Results: This study included 698 pts who received cBTKi monotherapy in 2L or 3L for MCL. The median age at cBTKi start was 73 (range, 34-85 yrs); the majority of pts were male (74%) and White (White 78%, Black 3.2%, Asian 1.3%, Other Race 7.6%, Unknown 10%) and non-Hispanic/Latino (non-Hispanic/Latino 74%, Hispanic/Latino 6.0%, Unknown 20%). Patients varied by socioeconomic status (Yost index 1 [12%], 2 [16%], 3 [19%], 4 [24%], 5 [19%], Unknown [10%]). Patients also varied by baseline ECOG performance status, Ki67, comorbidities, and LDH. Most pts had stage III/IV at diagnosis (75%). Among pts who received a cBTKi at 2L or 3L index therapy, 135 received zanu (2L [79%], 3L [21%]), 342 received acala (2L [76%], 3L [24%]), and 221 received ibr (2L [75%], 3L [25%]). Follow-up time (median [IQR]) from start of 2L/3L for each cBTKi were zanu 15 mo (10, 25), acala 36 mo (20, 52), and ibr 57 mo (35, 67). Among the overall 2L/3L cBTKi monotherapy cohort, median rwTTNT was 11.5 mo (95% CI 10.0, 13.5) and median rwOS was 30.4 mo (24.7, 36.1). For each cBTKi therapy in unadjusted KM analyses, median rwTTNT for zanu was 16.8 mo (95% CI 11.1, 23.2), acala 11.9 mo (9.2, 14.6), and ibr 9.8 mo (7.6, 13.1); median rwOS was 28.8 for zanu (95% CI 23.7, not reached), acala 29.2 mo (22.9, 36.5), and ibr 29.3 mo (21.2, 39.1). Adjusted multivariate model showed a trend of longer rwTTNT with zanu compared to ibr (HR 0.76 [95% CI 0.57, 1.01]; P=.06) and acala (0.88 [0.67, 1.16]; P=.40), and significantly longer rwOS for zanu compared to ibr (0.67 [0.46, 0.98]; P=.04) but a nonsignificant trend in rwOS favoring zanu compared to acala (0.73 [0.51, 1.05]; P=.09). Forty-seven pts (6.7%) who received cBTKi monotherapy in 2L or 3L switched to another cBTKi; 31 (4.4%) switched from ibr to acala or zanu, 12 (1.7%) from acala to zanu, and <5 (0.1%) from zanu to acala. Reasons for discontinuation (~60% documented in cohort) varied by cBTKi monotherapy use. The most common documented reasons for discontinuation were disease progression (30% overall; zanu [24%], acala [35%], ibr [26%]) and toxicity (11% overall; zanu [7%], acala [10%], ibr [17%]). Among pts who switched from one cBTKi to another, the most documented reason for discontinuation was toxicity for ibr to acala or zanu (61%) and for acala to zanu (58%). Other reasons included financial (1%), non-cancer-related medical issue (4%), cancer-related symptoms not due to therapy (2%), and pt request (1%). Conclusions: Among RW pts with R/R MCL who received cBTKi monotherapy, zanu had a longer rwOS compared to ibr, and a trend of longer rwTTNT and rwOS compared to acala. Reasons for discontinuation were most commonly disease progression and toxicity. Among pts who switched cBTKis, the most common reason for switching was toxicity, which provides a broader scope of reasons for differences in rwTTNT that are not exclusive to disease progression.

Background: Despite recent major advances, multiple myeloma (MM) remains incurable using therapies that are currently available to patients. There are no available/approved targeted therapies for MM that allow for individualized therapeutic approaches to the disease. Fifteen to 20% of newly diagnosed MM patients have a translocation of chromosomes 4 and 14 [t(4;14)]. This translocation puts transcription of the gene encoding Multiple Myeloma SET domain-containing protein (MMSET or NSD2), a histone 3 lysine 36 methyltransferase, under the control of the IgH super enhancer. The super enhancer drives the overexpression of MMSET resulting in an abnormal histone code that promotes myelomagenesis. Presence of t(4;14) is associated with poor clinical prognosis (Caro Am Soc Clin Oncol Educ Book 2021). KTX-1001 is a first-in-class, selective and potent small molecule inhibitor of MMSET, and is the first investigational drug that targets the t(4;14) MM patient population. Methods: This Phase 1, first-in-human open-label study (NCT05651932) is designed to assess the safety, tolerability, and initial clinical activity of KTX-1001 in relapsed/refractory MM (RRMM) and has two parts: dose escalation (Part A) and dose expansion (Part B). In Part B, only t(4;14)+ MM patients will be evaluated in single agent and combination expansion cohorts. Patients with RRMM who have received ≥3 prior lines of therapy, including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 antibody are eligible for the dose escalation part. The primary objective of the study is to determine a recommended phase 2 dose (RP2D) and schedule of KTX-1001. Secondary and exploratory objectives include pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of KTX-1001, and assessment of preliminary efficacy. KTX-1001 is administered orally until disease progression, unacceptable toxicity, or patient withdrawal from the study. A Safety Review Committee (SRC) reviews all data prior to each dose escalation decision and on a regular basis. Results: As of June 14, 2024, 17 patients (pts) have been treated with KTX-1001 in Part A across 6 dose levels (SRC reviewed). Dose Level 7 has been reached with no dose limiting toxicities (DLTs). Ten of these patients are t(4;14) positive. Patients have received a median of 5 prior lines of therapy (range: 3-17), including 7 pts with prior BCMA CAR-T, 6 pts with prior BCMA bispecific and/or ADC, 5 pts with prior non-BCMA bispecific, and 12 pts with prior transplant. Patient demographics include a median age of 68 years (range: 50-83), 10 male/ 7 female, 13 white, 2 black or African American, 2 as other identified race, and 3 Hispanic or Latino pts. Six pts remain on treatment. KTX-1001 shows excellent tolerability to date, with treatment emergent AEs (TEAEs) (CTCAEv5.0) predominantly of grade 1 and 2 severity. Most frequently observed TEAEs suspected to be related to KTX-1001 include fatigue (35%), diarrhea (24%), and constipation (24%), for which no grade 3 or 4 events have been observed. Frequency and/or severity of TEAEs have not increased with escalating doses nor treatment duration, and no patients have discontinued due to an AE. Two heavily pre-treated patients [one known to be t(4;14)+] have demonstrated long-lasting stable disease and clinical benefit at 10 and 7 months respectively. Both patients have been intra-patient dose escalated. For PK and PD data collected to date, drug exposure and steady-state concentration of KTX-1001 (at C1D15, when steady state concentration has been reached) appear to be dose-proportional. PD data indicate a dose-dependent decrease in the H3K36me2 mark on treatment versus baseline across dose levels 1 through 6, suggesting that the RP2D may be reached by year end. Updated results will be presented at the congress. Conclusions: Dose escalation of KTX-1001 is ongoing with an excellent tolerability profile to date and demonstration of on-target pharmacodynamics that will inform the determination of the RP2D(s). These PD data support the targeted mechanism of action of KTX-1001 to selectively inhibit MMSET and break the t(4;14) histone code. Given KTX-1001's promising safety profile, single-agent and combination expansion cohorts with standard-of-care MM agents/classes will begin in 2025 to further optimize doses and provide proof of concept in Part B of the Phase 1 study.

Background Follicular lymphoma (FL) is a generally indolent disease where a watch and wait strategy is standard in asymptomatic patients (pts) with a low tumor-burden. Harnessing antitumor immunity through an anti-tumor immunization strategy at this stage may delay or avoid the subsequent need for more toxic and complex therapies. EO2463 is a therapeutic vaccine designed from non-self protein sequences, derived from gut bacteria, including 4 HLA-A2 synthetically produced 9-mer CD8 cytotoxic T cell epitopes, exhibiting molecular mimicry with specific epitopes on the B cell markers CD20, CD22, CD37, and CD268 (BAFF-receptor). Additionally, EO2463 contains a CD4 helper epitope UCP2 derived from hTERT. The compound expands pre-existing memory CD8 T cells recognizing the non-self protein sequences from gut bacteria which can then cross-react with the selected B cell antigens on tumor cells. EO2463 is being used to drive anti-tumor immunity against B cell malignancies, and has demonstrated long-lasting, specific CD8-memory T cell responses and clinical activity in relapsed/refractory FL and marginal zone lymphoma (MZL) [J Clinical Oncol 2024, 42 (S16), 7058]. Furthermore, CD8 T cells expanded from samples of patients treated with EO2463 can kill HLA-A2 expressing lymphoblastoid cell lines presenting the B cell targets [Hematological Oncol 2023, 41 (S2), 581-582]. Methods The current report describes Cohort 2 of trial EONHL1-20/SIDNEY (NCT04669171) and includes pts with newly diagnosed, previously untreated FL, grade 1-3A, HLA-A2, and not in need of treatment. Pts receive EO2463 (300μg/peptide) SC with adjuvant Montanide ISA 51 VG, q2 weeks (w) x 4, then q4w, for a total of 12 doses (39w; PET-CTs at w6, w19, and w42). Planned accrual for this cohort is 25 pts. Immune responses were assayed on thawed pt peripheral blood mononuclear cells by flow cytometry and EO2463 peptide specific tetramers or by IFN-γ ELISPOT (assaying responses against 9-mer peptides from CD20, CD22, CD37, and CD268; and from peptides of EO2463) without any proceeding in vitro stimulation (ex vivo). Results As of June 2024, 15 pts had started study treatment. Median age was 62 (range 55-66) year, 7 male and 6 female, 2 pts Ann Arbor stage I/II, 5 stage III, and 8 stage IV. Ten of 15 pts were still on treatment; median treatment duration was 18.4 weeks (range 5-39 w) for all pts. Among 13 evaluable pts, best responses by PET-CT using Lugano criteria were 1 pt CR, 5 pts PR (46% objective responses (OR)), 3 pts SD, and 4 pts PD. Of those with PD per Lugano, 2 had isolated increases in FDG-uptake without increase in lesion size/number at w6 and both remain on treatment (per protocol based on LYRIC criteria). OR was first noted w6 in 3 pts and w19 in 3 pts; duration of response is not evaluable at this time due to short follow-up. The pt with CR had isolated increases in FDG-uptake at w6, PR at w19, and CR at w35. Anti-EO2463 immune responses were observed in 4 of 5 tested pts at the 1st testing timepoint (w5) and onwards (currently longest tested up until w31). In an exploratory analysis, the percentage of EO2463 peptide specific CD8 T cells measured by tetramers seemed linked to clinical response (OR 3 pts vs non-OR 2 pts; 2-sided T-test, p=0.02; range of percentages in pts with OR 0.85%-1.39% of all CD8 T cells in peripheral blood, range in pts with non-OR 0.17%-0.27%). Functionality and cross-reactivity of responses were shown by IFN-γ ELISPOT using 9-mer peptides corresponding to the B cell targets in 4 tested pts. Expanded antigen-specific CD8 T cells displayed a memory phenotype; effector/memory (TEM), and terminally differentiated effector memory CD8 T cells (TEMRA). The most common related AEs were grade 1 (7 pts) and grade 2 (5 pts) local administration site reactions (mainly erythema, pruritus, and induration). Other related AEs in > 1 pt were grade 1 headache (2 pts) and grade 1-3 fatigue/asthenia (3 pts). Asthenia lasting 2 days was the only related grade 3 adverse event (AE). Conclusions EO2463 monotherapy is associated with a very manageable safety profile and appears to demonstrate meaningful single-agent efficacy in FL. Consistent with the preclinical hypothesis, expansion of specific CD8 memory T cells may be associated with response. Results will be expanded at the meeting. Study EONHL1-20/SIDNEY also includes cohorts, not covered in this abstract, exploring EO2463 plus rituximab for 1st line FL/MZL, and EO2463 plus lenalidomide/rituximab in relapsed FL/MZL.

Background Follicular and marginal zone B cell lymphoma (FL; MZL) demonstrate an indolent course with heterogeneous outcomes and a potential for spontaneous remissions indicating immune system intervention. T cell-based therapeutic approaches are therefore an attractive proposition in FL and MZL. EO2463 peptide immunotherapy expands pre-existing memory CD8 T cells recognizing non-self-protein sequences from gut bacteria which cross-react with B cell antigens. The compound includes 4 HLA-A2 synthetically produced epitopes which exhibit molecular mimicry with the B cell markers CD20, CD22, CD37, and CD268 (BAFF-receptor), as well as a the CD4 helper-epitope UCP2 derived from hTERT. EO2463 is being used to drive anti-tumor immunity against B cell malignancies, and has demonstrated long-lasting, specific CD8-memory T cell responses and clinical activity in relapsed/refractory FL and MZL [J Clinical Oncol 2024, 42 (S16), 7058]. Furthermore, CD8 T cells expanded from samples of patients (pts) treated with EO2463 can kill HLA-A2 expressing lymphoblastoid cell lines presenting the B cell targets [Hematological Oncol 2023, 41 (S2), 581-582]. Methods The current report describes testing of a possible biomarker in the phase 1 portion of the ongoing EONHL1-20/SIDNEY trial (NCT04669171).This part of the trial (“Cohort 1”) included pts (n=9) with relapsed (at least 1, no limit, prior treatments) FL and MZL, stage 1-3A, confirmed to be positive for HLA-A2. Pts received EO2463 (150 [n=3] or 300μg/peptide [n=6]) SC with adjuvant Montanide ISA 51 VG q2 weeks (w) x 4, then q4w, for a max of 12 months; at w7 lenalidomide (20 mg/day for 21/28 days up to 12 cycles) was added (EL), and if no complete remission (CR) at w19, rituximab (375 mg/m IV, q1w x 4, then q4w x 4) was also added (ER2). Immune responses and clinical outcomes of Cohort 1 were previously reported [J Clinical Oncol 2024, 42 (S16), 7058]. To assess a possible biomarker, tetramers were used to specifically detect CD8 T cells recognizing the 4 epitopes in the EO2463 compound (derived from gut bacterial proteins exhibiting molecular mimicry with the B cell markers CD20, CD22, CD37, and CD268). The tetramers were all marked with phycoerythrin. Thawed samples of peripheral blood mononuclear cells taken at start of w5 (after 2 administrations of EO2463 monotherapy, each followed by 2w observation) were stained ex vivo (without any in vitro stimulation) with the tetramers and assayed by flow cytometry. Results are presented as percentage of EO2463 specific CD8 T cells among all CD8 T cells in the peripheral blood of the pt. Results Among the 9 treated pts, PET-CT at w6 (after 3 administrations of EO2463 monotherapy) suggested possible clinical activity in 4/9 pts (1 PR, 1 pt size reduction 15%, 1 pt 20% reduced tracer uptake, 1 pt 5/6 target lesions reduced metabolic activity). By PET-CT at w42 (after 12 administrations of EO2463 monotherapy, 11 cycles of lenalidomide, and rituximab treatment) the Lugano response assessment was complete response in 6/9 pts. A positive biomarker response was assessed in 5/9 pts (percentage of specific CD8 T cells ranged from 0.2-2.1%). EO2463 monotherapy PET-CT activity at w6 (n=4/9 pts): 4 of 4 pts with clinical activity were biomarker positive and 1/5 of the other pts was also positive; this pt had an isolated increase in FDG-uptake at w6, followed by a CR at w19. Four further other pts were biomarker negative. In this limited sample, the biomarker had sensitivity 100% and specificity 80%. EO2463 in combination with lenalidomide/rituximab PET-CT CR at w42 (n=6/9): 5 of 6 pts with CR were biomarker positive and 1 pt with CR was negative; the pt with a negative test had no objective tumor response until after rituximab. In this limited sample, the biomarker showed sensitivity 83% and specificity 100%. Conclusions The current preliminary assessment indicates that direct ex vivo tetramer staining for specific CD8 T cells after short term (5 w) treatment with EO2463 monotherapy could be a possible biomarker for clinical response, both for EO2463 monotherapy response, and for response to EO2463 in combination with lenalidomide/rituximab. We plan to validate these findings in the ongoing study cohorts of the trial; expansion phase 2 cohorts, exploring EO2463 monotherapy in the “watch & wait” setting, EO2463 plus rituximab for 1st line FL/MZL, and EO2463/lenalidomide +/- rituximab in relapsed FL/MZL.

Background. Study of myeloid neoplasms (MN) has been rapidly transformed by genome characterization. Gene mutations have been reported to influence disease phenotype and risk of disease progression, and the evaluation of mutational status can provide valuable insights to improve the decision-making process. In this international study, we evaluated the clinical impact of mutational screening in patients with CMML, which is characterized by significant clinical and genomic heterogeneity, including a substantial proportion of patients with poor outcomes and unmet needs. Currently, only limited molecular information has been incorporated into CMML classification and prognostication. Methods. We retrospectively collected 3182 CMML patients. We used MOSAIC, an AI-based framework for multimodal analysis in rare cancers (PMID: 38875514) to develop innovative, molecular-based tools for classification and prognostication. An independent validation of the results on 516 prospectively collected patients was performed. Results. Bayesian Networs and Hierarchical Dirichlet Processes were used to identify genomic associations and define a CMML molecular classification. We identified 11 clusters with distinct clinical and genomic features, including splicing machinery, signal transduction and tyrosine kinase pathways aberrations, and high-risk molecular signatures (i.e., AML-like and TP53 mutations). Up to 15% of patients showed clear genomic overlap with other MN. Importantly, extensive multi-color flow cytometry on T lymphocytes, NK and myeloid cells (BD FACSymphony A5 Cell Analyzer) revealed specific immunologic and inflammation signatures associated with molecular subgroups. We then integrated molecular and clinical information to build an international CMML Prognostic Scoring System (iCPSS). We assessed the performance of different statistical and AI-based methods; L1-penalized Cox Model resulted as the best performing method. Selected features included hematological parameters (WBC, Hb, PLT and marrow blasts), cytogenetic abnormalities, and mutations in 10 genes (ASXL1, DNMT3A, EZH2, NRAS, RUNX1, SETBP1, STAG2, TET2, TP53, U2AF1). By Bayesian thresholds optimization, we identified 5 risk classes (i.e., very-low, low, intermediate, high and very-high) with median overall survival (OS) ranging from 99 to 9 months (P<.001), and median leukemia-free survival (LFS) ranging from 210 to 18 months (P<.001). iCPSS provided better patient discrimination across all clinical endpoints compared to currently available prognostic tools, with a Concordance Index (CI) for OS of 0.75 versus 0.62-0.64, respectively. Notably, compared to available scoring systems, up to 40% of patients were reassigned to higher or lower risk classes by the iCPSS. External validation on an independent prospective cohort confirmed that the performance of iCPSS is superior to existing prognostic models (CI for OS 0.71 vs 0.54-0.61, respectively) To demonstrate the clinical utility of iCPSS, we focused on 753 patients who underwent allogeneic stem cell transplantation (HSCT). In multivariable analysis, iCPSS stratified the probability of OS post-HSCT (P<.001) and identified groups of patients with different probabilities of disease relapse, ranging from 9% to 62% (P<.001). We employed a clinical- and genomic-based decision support system (PMID: 38723212) to determine the optimal timing of HSCT. Preliminary analyses indicated that higher-risk patients according to iCPSS (i.e., intermediate, high, and very high) benefit from an immediate HSCT strategy. Lower-risk patients (i.e., very low and low) had life expectancy maximized with delayed HSCT. Modeling decision analysis using iCPSS compared to conventional scores, resulted in a change in transplantation policy for a significant proportion of patients (up to 25%). Conclusion. Molecular information significantly improves the classification of CMML patients, providing a basis for refining diagnostic boundaries with other MN and for a more rational inclusion of patients in clinical trials. The iCPSS demonstrated superior performance over currently available scoring systems and improved HSCT decision making process.

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 Both radiation and temozolomide (TMZ) have meaningful single-modality anti-tumor activity against low-grade gliomas. ECOG-ACRIN E3F05 tested whether combined therapy with radiation and temozolomide is more effective than radiation alone in patients with grade II gliomas. METHODS Patients with grade II gliomas (central pathology review performed post hoc), no prior radiation/chemotherapy, and either age > 40, uncontrolled symptoms/seizures, or progression after initial observation were randomized 1:1 to radiation 50.4 Gy alone in 28 fractions (Arm A) versus radiation 50.4 Gy with concomitant and 12 four-week cycles of post-radiation TMZ (Arm B). Randomization was stratified by 1p/19q codeletion status, age, KPS, pre-operative tumor diameter, and contrast enhancement. The primary endpoint was progression-free survival (PFS); overall survival (OS), quality of life, cognition, severe toxicities, and impact of codeletion status were secondary objectives. RESULTS The trial opened 1/09. Accrual was stopped in 1/14 after RTOG 9802 reported benefit from the addition of PCV chemotherapy to radiation in grade II gliomas. A total of 172 subjects were enrolled. Median age was 44 (range 19-78) and 54% male. 1p/19q codeletion was present in 44%. NCI CTCAE (version 4) grade 3+ toxicity was more common in participants treated with TMZ: thrombocytopenia (11%) and neutropenia (5%) versus none in the radiation alone arm. With a median follow-up of 117 months, OS was superior in Arm B (HR 0.54, 95% CI 0.31-0.95, stratified log-rank p value 0.03). OS HRs were 0.56 and 0.53 for subjects with and without 1p/19q codeleted tumors, respectively. PFS did not differ between Arms A and B (HR 0.76, 95% CI 0.44-1.28, p = 0.30). Five and ten-year OS were 78% and 70% in Arm B versus 70% and 47% in Arm A. CONCLUSION The addition of temozolomide to radiation improves overall survival in both co-deleted and non-co-deleted grade II gliomas.