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Background The International Myeloma Working Group (IMWG) defines progression of disease (PD) in multiple myeloma by the increase in serum or urine paraprotein beyond a certain threshold. With more common use of serial bone marrow-based measurable residual disease (MRD) assessment, some patients will evolve with increase in MRD burden without meeting IMWG criteria for PD and no consensus exist on the best approach for this circumstance. Understanding the implication of increasing MRD burden is particularly relevant in patients with NDMM treated with quadruplet therapy (QUAD, consisting of a PI, an IMiD, an anti-CD38 mAb and dexamethasone) and autologous stem cell transplantation (ASCT), since most will reach MRD negativity. Methods We analyzed a large dataset of patients with NDMM patients treated with QUADs + ASCT +/- QUAD consolidation +/- single or dual-agent maintenance and monitored with serial MRD assessment by next-generation sequencing (clonoSEQ®) at end of induction, post ASCT, post consolidation and at least yearly thereafter. The dataset was built from clinical trial participants and from patients receiving standard care under an institutional guideline. MRD progression (MRD-P) was arbitrarily defined as quantitative increase in MRD burden by at least 1 log10 above the nadir. Treatment modification in the event of MRD-P without IMWG-defined PD was at discretion of treating physician. For patients with MRD-P without concomitant PD we describe cumulative incidence of PD after MRD-P. To contextualize the clinical implications of MRD-P, we describe survival free of failure of second line therapy (SFF2T), defined as time from progression event (MRD-P or PD not preceded by MRD-P) until occurrence of IMWG-defined PD or death on second line therapy, regardless of whether second line was initiated due to MRD-P or subsequent IMWG-defined PD. Results Among the 216 patients, 113 (52%) were clinical trial participants, median age was 61 years (IQR 56-68), 21% age 70 or older, 32% were non-White, 57% male, 38% had MM with 1 high risk chromosome abnormality [HRCA, gain/amp 1q, t(4;14), t(14:16), del(17p)], 15% had 2+HRCA. Median duration of follow up is 39.5 months, and 966 MRD datapoints were assessed. Overall, 83% of patients achieved sCR, 78% achieved MRD negativity at 10-5, 68% at the 10-6 threshold, and 56% ceased therapy after confirmed MRD negativity. Forty-nine patients had MRD-P(N=19) or PD not preceded by MRD-P (N=30). Patients with MRD-P or PD not preceded by MRD-P often had 1 or more HRCA (73.7% and 82.8%), International staging system III (36.8% and 30.0%), and high LDH at diagnosis (31.6% and 23.3%). Median time from onset of therapy to MRD-P was 24.4 mo (IQR 12.6-35.8) and to PD not preceded by MRD-P was 23.2 mo (IQR 18.4-29.4). Among the 19 patients with MRD-P, 12 (63%) were on observation at time of MRD-P, 2 were receiving single agent lenalidomide, 5 were receiving a QUAD, 17 (89%) had previously obtained MRD negativity at <10-5 including 10 (53%) who had also achieved MRD negativity at 10-6. Upon detection of MRD-P, 12 (63%) pts changed therapy, all to a monoclonal antibody-containing triplet or quadruplet regimen. Yet, median time from MRD-P to PD was 10.1 months. Patients with MRD-P had 1-year SFF2T of 55.6%, in contrast to 35.0% for patients with PD not preceded by MRD-P. OS 2-year from progression event was 78.0% for MRD-P and 53.9% for PD not preceded by MRD-P. Conclusions In the context of NDMM treated with QUAD + ASCT, MRD-P indicates imminent IMWG-defined PD, and is driven by a thriving plasma cell population unlikely to be controlled by reinstitution of anti-CD38 mAb-based combinations. Outcomes of patients with MRD-P are similar to those of patients with IMWG-defined PD. These findings challenge the paradigm of IMWG-defined PD and paraprotein measurability as minimal parameters for change in therapy and introduction of agents with new mechanisms of action.

Introduction: Recent efforts have shed light on the clinical and laboratory factors associated with toxicity and response to BCMA-directed CAR-T therapy in patients with relapsed/refractory multiple myeloma (RRMM). However, a major limitation of current scoring systems lies in their assessment at time of lymphodepletion. Because they are not determined before apheresis, they are ill-equipped to guide patient selection, anticipate level-of-care, or plan pre-emptive toxicity management strategies. We therefore aimed to characterize early predictors of CAR-T toxicity and response. Study Design: In this multicenter observational study, we examined demographic, clinical, and laboratory data across three distinct timepoints: indication (e.g., treatment decision), apheresis, and pre-lymphodepletion (LD). CRS and ICANS were graded according to ASTCT criteria. Hematotoxicity (ICAHT) was graded using EHA/EBMT criteria. Early infections (day 0-100) were defined based on microbiologic data or as a clinical infection syndrome, and graded per Hill et al, Blood 2018. Kaplan-Meier estimates of progression-free (PFS) and overall survival (OS) were compared by log-rank test. Cox proportional hazard models were applied to explore associations between pre-apheresis risk factors and key toxicity and survival outcomes. The CAR-HEMATOTOX (HT) score - encompassing markers of inflammation (e.g., CRP, ferritin) and marrow reserve (e.g., hemoglobin, ANC, platelet count) - was determined at each timepoint (Rejeski et al, Blood 2021). Results: We included 530 RRMM patients treated with standard-of-care cilta-cel (n=184) or ide-cel (n=346) across nine centers. Median age was 65 (range 31-88), median ECOG was 1 (IQR 0-1), and patients received a median of 5 prior lines of therapy (IQR 4-7). The median time from indication to apheresis was 16 days (IQR 7-52), while the median time from apheresis to infusion was 56 days (IQR 46-69). The proportion of high-risk patients by HT score did not change between the pre-apheresis and LD timepoints (19% vs. 20%, p=0.82). Most patients stayed either low-risk (n=388, 73.2%) or high-risk (n=68, 12.8%). However, 35 patients (6.6%) shifted from high-to-low risk, while 39 patients (7.4%) progressed from low-to-high risk - reflecting their response to bridging therapies. We noted considerable differences in morbidity and mortality based on the pre-apheresis HT score. Compared to their low-risk counterparts (score 0-2, n=427), high-risk patients (score ≥3, n=103) were hospitalized longer (12 vs. 15 days, p=0.009) and required more frequent ICU admissions (6% vs. 12%, p=0.05). They exhibited more severe early cytopenias (G3+: 8% vs. 25%, p<0.001) and late cytopenias (G3+: 7% vs. 21%, p<0.001), resulting in increased use of TPO agonists and stem cell boosts. Grade 3 or higher ICANS was also more common in HThigh patients (3% vs. 11%, p=0.006), as were severe infections (14% vs. 27%, p=0.007). We found increased non-relapsed mortality in HThigh patients (1-yr NRM 4.6% vs. 16.1%, p<0.001), but no significant difference in the occurrence of secondary malignancies (p>0.9). With a median follow-up of 12.4 months, HThigh patients showed inferior PFS (1-yr PFS 29% vs. 63%, p<0.0001) and OS (1-yr OS 49% vs. 83%, p<0.0001). Transitioning from a low-to-high score was linked to poor survival (1-yr PFS 26%), while the shift from high-to-low risk was associated with favorable outcomes (1-yr PFS 51%). In a multivariable Cox regression model of pre-apheresis features, a high HT score (aHR 2.52, p<0.0001), prior anti-BCMA therapy (aHR 1.55, p=0.04), history of extramedullary disease (aHR 1.42, p=0.02), and penta-refractoriness (aHR 1.45, p=0.02) were independently associated with PFS. Notably, the presence of more than 3 of these high-risk features defined an ultra-high-risk cohort of 28 patients (5.3%) with particularly dismal survival (1-year PFS 15%). Conclusions: Leveraging granular pre-apheresis data from a large international cohort, we identify early markers of toxicity and response in CAR-T-treated RRMM patients. The HT score - reflecting baseline inflammation and hematopoietic reserve - identified high-risk patients likely to benefit from pre-emptive toxicity mitigation strategies such as prophylactic stem cell collection. Most importantly, we characterize a small yet ultra-high-risk group of RRMM patients in need of more effective bridging and therapeutic options.

Introduction QUADs with an anti-CD38 mAb, an IMiD, a proteasome inhibitor and dexamethasone followed by autologous stem cell transplantation (ASCT) in the treatment of newly diagnosed multiple myeloma (NDMM) led to substantial improvements in depth of response, including minimal residual disease (MRD) negativity, and progression-free survival. The therapeutic success of QUAD + ASCT has reinvigorated an interest in fixed-duration therapy, yet optimal short term efficacy endpoint for treatment cessation is unknown. We used a large dataset of patients (pts) treated with QUAD + ASCT, monitored with serial MRD assessment and managed with MRD-adapted treatment duration to determine the best short term efficacy endpoint to identify pts at low risk of treatment failure. Methods We analyzed 221 pts with NDMM treated with QUAD + ASCT and monitored with serial marrow-based MRD by next-generation sequencing. Based on trial design (N=116) and institutional practice (N=105) most pts received post ASCT QUAD consolidation followed by treatment cessation if MRD<10-5 in two consecutive datapoints. Pts were monitored with MRD post induction, ASCT and consolidation, and at least yearly thereafter. We utilized Cox regression to build parallel models of predictors of disease progression or MRD resurgence utilizing the same patient and disease features and one distinct short term efficacy endpoint per model, inputted as time-varying covariate. Efficacy endpoints tested were IMWG-defined stringent complete response (sCR), MRD<10-5 (single datapoint), MRD<10-6, sustained MRD (S-MRD, two consecutive assessments at least 1 year apart) <10-5and S-MRD<10-6. Best fitting models were determined using Akaike's information criterion (AIC, lower value indicates better fitting model), an information theory approach, and Heagerty & Zheng C index. Results Median age of the 221 pts. was 61 years (IQR 55-68), 21% age 70 or older, 37% had MM with 1 high risk chromosome abnormality [HRCA, gain/amp 1q, t(4;14), t(14:16), del(17p)], 16% had 2+HRCA, 30% were non-White and 58% male. We followed pts for a median of 40.6 mo. and performed 979 MRD assessments. One hundred and eighty-three pts (83%) achieved sCR, 170(77%) MRD<10-5, 146 (66%) MRD<10-6 , 110 (50%) S-MRD<10-5 and 90 (41%) S-MRD<10-6. Average time to achieve the endpoint was 7.8 mo for sCR, 7.1 mo. for MRD <10-5, 9.4 mo. for MRD<10-6, 19.3 mo. for S-MRD<10-5 and 20.5 mo. for S-MRD<10-6. We first tested models to predict PFS among all 221 pts. Predictive models included same covariates (ISS, high LDH and number of HRCA) other than the efficacy endpoint. The best fitting model (AIC 417.2, C-stat 0.757) was based on S-MRD<10-5 (HR=0.23, 95% C.I. 0.11-0.47) and included presence of 1 HRCA (HR=2.93, 95% C.I. 1.31-6.52), 2+ HRCA (HR=7.60, 95% C.I. 3.31-17.43), high LDH (HR=1.64, 95% C.I. 0.81-3.33), ISS2 (HR 1.31, 95% C.I. 0.62-2.77) and ISS3 (HR 1.96, 95% C.I. 0.90-4.28). The model with S-MRD<10-6 had similar, but not better performance (AIC 419.4, C-stats 0.752). We subsequently analyzed the 121 (55%) pts who reached MRD-guided treatment cessation for the best fitting model to predict progression or MRD resurgence in absence of continuous therapy. Among these pts, 117(97%) achieved sCR, all (by definition) MRD<10-5, 116 (96%) MRD<10-6 , 95 (79%) S-MRD<10-5 and 81 (67%) S-MRD<10-6. The best fitting model (AIC 197.2, C-stat 0.766) was based on S-MRD<10-5 (HR 0.01, 95% C.I. 0.002-0.05) and included presence of 1 HRCA (HR=1.41, 95% C.I. 0.49-4.07), 2+ HRCA (HR=5.43, 95% C.I. 1.75-16.84), high LDH (HR=3.19, 95% C.I. 0.98-10.40), ISS2 (HR 1.25, 95% C.I. 0.53-2.96) and ISS3 (HR 0.73, 95% C.I. 0.23-2.37). The model with S-MRD<10-6 did not perform better (AIC 232.4, C-stat 0.727). Among the 94 pts who achieved S-MRD<10-5 and were monitored off therapy, the risk of MRD resurgence or progression 2.5 years after cessation of therapy was 6.1%, 15.0% and 22.2% and risk of progression was 3.0 %, 12.0% and 11.1% for patients with 0, 1 and 2+ HRCA, respectively Conclusion In the setting of QUAD therapy + ASCT, no short term conventional or MRD-based efficacy parameter negates the cumulative impact of HRCA on prognosis. S-MRD<10-5 is the best predictor of PFS and yields the best predictive models for risk of MRD resurgence or progression in the setting of fixed duration therapy. This analysis validates S-MRD<10-5 as efficacy parameter for treatment cessation in trials exploring fixed duration therapy in NDMM.

Background: C10603/RATFIY was the first AML trial to show the benefit of adding a targeted agent to intensive chemotherapy for a specific genetically determined subset (Stone R et al, NEJM 2017). The addition of the multi-kinase inhibitor midostaurin (M) to chemotherapy in previously untreated adults with FLT3-mutant AML resulted in superior event-free (EFS) and overall survival (OS) compared to placebo (P) and led to the approval of this agent in combination therapy. Subsequently, additional targeted drugs including gilteritinib for relapsed/refractory FLT3-mutant AML and quizartinib plus chemotherapy in untreated adults with AML with FLT3-ITD disease have gained approval. Long-term follow-up after reporting of the primary endpoint, especially if met, is important in oncology. Objective: We report the EFS and OS data from C10603 using 10 years of follow up to determine the persistence of a midostaurin benefit and to assess the nature of late relapses or toxicity. Methods: C10603 enrolled 717 pts (360 on the M and 357 on the P arm; median age 47.8 years (range 18-61), 398 women (55.5%) of whom 51.7% were randomized to M and 59.4% to P (p=0.04), and 89% white) from 2011-2015 with previously untreated AML who had either a FLT3-TKD or ITD mutation with allelic ratio of >0.05 to receive daunorubicin/cytarabine (3+7) induction (one reinduction permitted) followed by up to 4 consolidation cycles with cytarabine 3 g/m2 every 12h on days 1, 3 and 5. M (50 mg bid) or P was given orally on days 8-22 of each chemotherapy cycle as well as daily during one year of single-agent maintenance. Allogeneic transplantation (alloHCT) was employed at investigator's discretion; study drug was not continued post-HCT. Pts stayed on their randomized arm and were not re-randomized prior to maintenance. Pts were followed for relapse and survival after the end of protocol therapy, regardless of subsequent therapy, for 10 years. Log-rank tests, Kaplan-Meier methods, and Cox proportional hazard models were used to evaluate the treatment effect in EFS and OS, as well as the alloHCT effect. All p values are two-sided. Results: We have completed the 10-year FU on this trial and data collection has concluded. The median EFS was 8.2 months (95% CI, 5.5-11.4) on the M arm compared with 3.0 months for P (95% CI, 1.9-6.0) with a HR of 0.79 (95% CI 0.67-0.94, p=0.0067). Among the 420 CR pts who achieved complete remission (CR) by the protocol specified time of 60 days, 253 have had an event (death in 69 and relapse in 184); these events were relatively equal on each arm. OS, the co-primary endpoint, remained marginally superior for those randomized to M compared to P; the 10-year OS estimate was 43.7% (95% CI, 38.7-49.3%) vs 38.6% (95% CI, 33.6-44.4%) (p= 0.0485). The hazard ratios for OS favored randomization to M in each key biological subgroup (FLT3-ITD low or high allelic ratio or FLT3-TKD), but smaller subsets precluded statistical significance. There was a 10-year OS benefit in favor of M in men (p=0.005), but not women (p=0.9). A total of 414 transplants were performed: only 5 in the latter half of the follow-up period. Transplantation in CR1 was highly beneficial overall (10-year OS, 56% vs 35.8% without transplantation, p=0.001). Among those transplanted in CR1, randomization to M was marginally better than P (61.5% vs 49%, p=.064). After censoring for alloHCT in CR1, there was an OS trend in favor of M (51.8% v 48.0%, p=0.102). In CR1 patients who were randomized to maintenance therapy, M reduced the cumulative incidence of relapse in ELN 2017 favorable and intermediate risk pts, but not in those with adverse risk disease (HR 0.71, 0.47, and 1.01, respectively); maintenance M had no effect on OS. Only 3 pts relapsed after 5 years (all randomized to M). 25 pts randomized to M vs 13 P pts died after 5 years of follow-up. 5 pts on each arm died of a new primary cancer whereas 17 M and 5 P pts were coded as having died from treatment-related causes. None of the 3 pts who relapsed after 4 years had spliceosome mutations at diagnosis; whereas 18% (21/117) patients pts who had relapsed earlier had spliceosome mutations at diagnosis (p=0.419). Conclusions: The EFS benefit of randomization to midostaurin vs placebo when added to chemotherapy was maintained over time, although the benefit for OS was diminished, likely due in part to aging. Patient and disease factors differed between early vs late relapses, which could suggest the use of alternative therapies during distinct therapeutic stages.

Background: Myeloproliferative neoplasms (MPNs) are chronic leukemias with increased thrombotic risk. Venous thrombosis in MPN often occurs in atypical sites, such as splanchnic vein thrombosis (SVT), defined by thrombosis in the portal, hepatic, mesenteric, or splenic veins. Data to guide anticoagulation management of SVT in MPN patients is lacking. Objectives: The purpose of this study is to evaluate outcomes as well as the safety and efficacy of different anticoagulation strategies in MPN patients with SVT. Methods: A retrospective cohort study of MPN patients with SVT from 10 international centers was conducted. All centers performed systematic identification of adults with a World Health Organization 2016 diagnosis of an MPN (polycythemia vera [PV], essential thrombocythemia [ET], myelofibrosis [MF], prefibrotic MF, MPN-unclassifiable [MPN-U]) and confirmed SVT. Inclusion criteria were met if first SVT occurred after or within one year before MPN was diagnosed. The primary outcome was 1-year cumulative incidence of recurrent venous (VT) or arterial thrombosis (AT). Secondary outcomes included 1-year cumulative incidence of (1) major and clinically relevant non-major bleeding (CRNMB) by International Society on Thrombosis and Hemostasis criteria, (2) SVT recanalization; and (3) 1-year overall survival. Death as a competing risk was used for cumulative incidence analyses of recurrence and bleeding. Results: 486 MPN patients (median age at first SVT 51 years; 62.3% female) were identified. MPN diagnosis preceded SVT in 35.2% of patients (median time 4.8 years) and occurred simultaneously or within 1 year of first SVT in 64.8% of patients. 43.8% of patients had PV, 23.7% ET, 14.2% MF, 3.1% prefibrotic MF and 13.2% MPN-U. The most common driver mutation was in JAK2 (90.7%) followed by CALR (4.4%) and MPL (1.6%). SVT localization was isolated to portal (25.7%), hepatic (15.4%), mesenteric (1.9%), and splenic veins (4.3%), and in 51.2% of cases SVT occurred in multiple vessels. Prior VT or AT occurred in 8.8% and 4.1% of subjects, respectively. Cytoreduction (most commonly hydroxyurea [36.9%], interferon [9.6%] or JAK inhibitor [6.8%]) was started after SVT in 58.7% of newly diagnosed MPN patients and 40.6% of those with known MPN. 57.6% of patients were anticoagulated, 3.5% of patients were treated with an antiplatelet agent, and 11.7% were treated with both. The most common initial anticoagulants were vitamin K antagonists (VKA) (29.2%), direct oral anticoagulants (DOAC; 20.4%), and low-molecular-weight heparin (LMWH; 10.5%). DOACs were more commonly used in the USA and Asia than Europe (21.2%, 52%, and 13.5%; p<0.001). The median duration of anticoagulation was 23.9 months, with 62.8% still on anticoagulation after 3 years or at last follow-up. 1-year cumulative incidence of recurrent VT and AT was 14% (95% CI 11-18) (5.8% for recurrent SVT [95% CI 3.9-8.3]; 6.3% for other VT [95% CI 4.3-8.8]; 2.4% for AT [95% CI 1.3-4.2]), with an overall time to event 89 (IQR 34-193) days. Thrombosis incidence was similar in patients initially treated with VKA (13%), DOAC (15%) or LMWH (16%) (p=0.93); in comparison, individuals not treated with anticoagulation had 1-year thrombosis incidence of 13% (p=0.22). 1-year major and CRNMB cumulative incidence in all patients was 5.8% (95% CI 3.9-8.2) and 8.5% (95% CI 6.1-11), with median time to event 68 (IQR 13-150) days. Incidence of major bleeding was similar in VKA, DOAC, and LMWH-treated patients (5.9%, 6.6%, and 4.0%; p=0.89). 1-year cumulative incidence of SVT (partial) recanalization was 13% (95% CI 9.8-16) in all patients, with a median time to recanalization of 127 (IQR 40-323) days; recanalization rates were similar in anticoagulated and non-anticoagulated patients (p=0.76). There was a trend toward higher recanalization rates in patients treated with DOAC (26.9%) than with VKA (21.5%) or LMWH (13.6%; p=0.28). 1-year overall survival was 94.2% (95% CI 91.8-96.1) and similar between treatment groups (VKA 96.7%, DOAC 95.6%, LMWH 89.7%; p=0.11) and for no anticoagulation (82.3%; p=0.32). Conclusions: This is the largest contemporary cohort of MPN patients with SVT. MPN patients with SVT remain at risk for short-term thrombosis and bleeding complications regardless of treatment. We found no significant differences in outcomes between anticoagulation strategies, including in patients treated with DOACs compared to VKA or LMWH.

Introduction: The BMT CTN 1704 study developed and validated the CHARM that stratified risk for non-relapse mortality and overall mortality among older adults, performing better than the HCT-CI alone (Artz A et al, Blood. 2023;142:109) and equally to two machine learning models. CHARM assigns a total score for 7 health variables: increasing age, higher HCT-CI scores, lower albumin, higher C-reactive protein, higher percent of weight loss over the preceding year, lower patient-reported performance status scores, and lower cognitive score per Montreal cognitive assessment (MoCA). A CHARM calculator is available at:https://cibmtr.org/CIBMTR/OffNav/DevSandbox/CHARM-Risk-NRM-Calculator No multi-institutional prospective data exist on functional trajectories and morbidity after HCT in older patients. We now report on the association of CHARM to trajectories of secondary morbidity outcomes among allo-HCT survivors of this large, prospective study. Patients and Methods: Allo-HCT candidates, aged ≥60 years (yrs), were enrolled (n=1226) from 49 centers in the US between 2019 - 2021. The primary analysis includes 1105 patients proceeding to allo-HCT on study and secondary endpoints were assessed at day (D) 100, 180 and 365 except MoCA and organ toxicity were restricted to D100 and frailty had inadequate data for D100. A sequential multiple imputation strategy was implemented to impute endpoints for survivors at each time point with missing data. Analyses on multiply imputed datasets were conducted and the results combined using Rubin's rule. Associations between CHARM scores and secondary outcomes were analyzed using a multivariable Cox, Fine-Gray, Generalized Estimating Equations, and logistic regression model for survival, competing risks, continuous, and binary outcomes, respectively, with latter two focused on surviving patients. Models were adjusted for other variables including conditioning intensity, graft-versus-host disease (GVHD) prophylaxis regimen, disease-risk index, donor-recipient gender match, ethnicity, baseline value of the dependent variable, and visit timepoints. Results: Higher CHARM scores were associated with development of serious organ toxicities by D100 (OR: 2.05, [1.52-2.78], p<0.0001) and ≥2 worsening score on the MoCA (odds ratio (OR) 1.55 [1.16-2.1], p=0.003). Among survivors at all timepoints, higher CHARM scores were associated with greater disability by instrumental activities of daily living (IADL) (Slope -0.640 [-0.433-0.846], p<0.001) and worsening Patient-Reported Outcomes Measurement Reporting System (PROMIS) physical function (Slope -0.981 [-0.057 - -1.904], p=0.037), depression (Slope 0.763 [0.042-1.484], p=0.038) and in a lesser magnitude anxiety (Slope 0.659, p=0.076). Among survivors at D180 and D365, higher CHARM scores were associated with worse frailty (Slope 0.193 [0.081-0.305], p<0.001). CHARM scores were not associated with development of acute GVHD grades 2-4 or 3-4 but were associated with post-GVHD increased mortality (HR: 1.61, [1.25-2.08], p=0.0002). Higher CHARM scores are associated with a lower incidence of chronic GVHD (HR: 0.83, p=0.026), likely due to the effect of CHARM on the competing risk of death leaving fewer patients at risk for chronic GVHD. Conclusions: The novel primary CHARM, originally developed to predict risks of NRM, also predicts worse frailty, disability, cognitive decline, and serious organ toxicities; outcomes that are critically important to older recipients of allo-HCT. CHARM therefore informs risks of transplant morbidity, separate from risks of developing acute GVHD. Results further support adopting CHARM in practice to counsel patients, expedite HCT referrals for lower risk CHARM, and design trials for high CHARM score patients.

Background: Chromosomal rearrangements involving the KMT2A gene and mutations involving the nucleophosmin (NPM1) gene have been associated with response to menin inhibitors in multiple studies of acute myeloid leukemia (AML) patients characterized by these genetic alterations. Both alterations are more common in younger AML patients and those with NPM1 mutations historically perform better. However, the prevalence and outcomes of older (≥60 years) AML patients with these alterations who are treated with current therapies is less well understood. We present results from the Beat AML Master Trial (BAMT) that analyze the outcomes of this large, but less common subset of patients in an older AML population. Methods: Patients were consented and enrolled on this precision medicine-based Beat AML Master Trial (NCT03013998) from November 2016 to June 2024. Patients were included in this analysis if they harbor either the classic NPM1 mutation or a KMT2A rearrangement (over 10 different gene partners). Additionally, 2 patients with a NUP98 rearrangement were included with the KMT2A cohort as they are known to have similar biology in terms of menin dependence. These patients were treated with the following therapies: a sub-study specific targeted therapy for the dominant clone, venetoclax + hypomethylating agent (Ven/HMA), intensive chemotherapy (IC), alternative non-intensive therapy (NIT), or no therapy. Clinical/genetic characteristics and median overall survival (OS) were analyzed in each group separately. Overall survival (OS) was calculated from master consent and estimated using the Kaplan-Meier method. Results: Of 1096 AML patients enrolled on the BAMT, 246 patients had either an NPM1 (N=207, 18.9%) or KMT2A (N=39, 3.6%) genetic alteration. The baseline characteristics for the NPM1 cohort were median age 72 years (range: 60-92), 50% female, and ECOG performance status: 0-16%, 1-58%, 2-25% and 3-1%. Additional disease characteristics include treatment related AML at 11% and complex karyotype (≥3 abnormalities) at 3%. Median OS for the entire NPM1 cohort was 18.4 months (95% CI: 14.2-24.7). Patients were treated on a sub-study (35%), Ven/HMA (19%), IC (26%), NIT (8%) or no treatment (9%). Between treatment groups, median OS was 21 months (95% CI: 12.8-31.7) for those treated on a sub-study, 22 months (95% CI: 12.6-not reached (NR)) for Ven/HMA, 41.6 months (95% CI: 18.2-NR) for IC, and 6.3 months (95% CI: 1.3-23) for NIT, which was significantly different (p<0.0001). The baseline characteristics for the KMT2A cohort were median age 69 years (range: 60-88), 44% female, and ECOG performance status: 0-19%, 1-45%, 2-35% and 3-0%. Treatment related AML occurred in 23% of patients and complex karyotype in 31%. Median OS for the KMT2A cohort was 6.5 months (95% CI: 3.6-31.6). Patients were treated on a sub-study (38%), Ven/HMA (15%), IC (15%), NIT (15%), or no treatment (5%). Between treatment groups, median OS was 31.6 months (95% CI: 3.2-NR) for sub-study, 5.0 months (95% CI: 3.0-NR) for Ven/HMA, 12.7 months (95% CI: 4.9-NR) for IC, and 2.9 months (95% CI: 1.5-NR) for NIT, which was also significantly different (p<0.0001). Conclusions: In this cohort of older AML patients who possess NPM1 or KMT2A mutations, initial demographics and clinical characteristics upon presentation are as expected. Within each cohort and depending on the type of therapy received, there were interesting differences in survival. Median OS was the highest for the NPM1 cohort that received IC while the KMT2A cohort had the highest median OS when enrolled on a KMT2A targeted sub-study; a finding that supports precision-based medicine for this high-risk KMT2A group characterized by poor outcomes. As menin inhibitor combinations with induction chemotherapy or Ven/HMA move to the frontline setting, we anticipate seeing significant improvement in outcomes for AML patients in both of these genomic subsets. Further multivariable analysis will be performed to validate treatment effect on OS. Our analyses for these two cohorts also provide valuable outcome benchmarks for the design of future precision oncology studies that seek to improve survival in these subsets of older AML patients.

Introduction: Inotuzumab ozogamicin (INO) is an antibody targeting CD22 conjugated with a cytotoxic antitumor antibiotic (calicheamicin) approved for treatment of relapsed/refractory CD22 positive B-cell acute lymphoblastic leukemia (ALL) (Kantarjian et al. NEJM 2017). CD22 is expressed on the surface of lymphoblasts in ALL (~95%). Young adult patients (pts) 18-39 years (yrs) treated on the pediatric regimen CALGB 10403 resulted in a 3-yr event-free survival (EFS) of 59% (95% CI: 52-67%) and an estimated 3-yr overall survival (OS) of 73% (95% CI: 68-78%) (Stock et al. Blood 2019). Alliance A041501(NCT03150693), a phase 3 NCTN sponsored cooperative group trial was conducted to determine if the addition of INO to the CALGB 10403 pediatric regimen would significantly improve EFS. Methods: Eligibility included pts 18-39 years with newly diagnosed CD22 positive ALL, defined as baseline expression in > 20% of lymphoblasts by local institution. Pts with Burkitt-type ALL, BCR::ABL1 positive ALL, or Down syndrome were excluded. Eligible pts received the CALGB 10403 regimen modified to omit extended induction, include dexamethasone as opposed to prednisone as steroid backbone, cap the pegaspargase dose to 3750 units, and adding rituximab for pts with CD20 expression (> 20%). An amendment added blinatumomab for minimal residual disease (MRD) positivity. Pts achieving a complete remission (CR/CRi) or partial remission (PR) were eligible for randomization. Following a 6 pt safety run-in with INO, pts were randomized 1:1 to receive INO or continue CALGB 10403 backbone. Two cycles of INO (1.5 mg/m2/cycle) were administered following induction in the experimental arm. Pts were stratified by age, disease status post induction (M0/M1 vs M2), CD20 status, and LDA Card, which tests for the Ph-like status. The primary endpoint was to determine if the addition of INO would improve the EFS of the pediatric regimen CALGB 10403 without censoring for stem cell transplant (SCT). Key secondary endpoints included the impact of INO on disease-free survival (DFS), OS, and MRD. The Alliance Data and Safety Monitoring Board halted enrollment after 273 out of a planned 341 pts were registered because of increased grade (gr) 5 events in the INO arm compared with the control arm. Results: 273 pts were enrolled between 6/15/2018, and 5/24/2022. Median age was 27.0 yrs, 65.2% were White, 30.4% were Hispanic, and 63.4% were male. Baseline CSF analysis revealed 14% with CNS-2/3 disease. The overall CR rate was 86.8% (82.8-90.8%). 46 pts were not randomized due to death (5), withdrawal (6), ineligibility (3), toxicity (5), receipt of non-protocol therapy (8), progression (5), and other (14). 227 eligible pts were randomized 1:1 to receive INO (N=111) or not (N=116)). For randomized pts, 92.5% achieved M0/M1 marrow status, 48.9% had a positive LDA Card defining Ph-like ALL, 50.7% were CD20 positive. Only 36 pts (13%) received a SCT. With a median follow up of 28.3 months for randomized pts, 3-yr EFS was 69.0% (59.1-80.5%) for the INO arm and 66.7% (57.1-78.1%) for the control (HR=0.97; 0.58-1.63). Similarly, the 3-yr OS was 79.4% (71.0-88.7%) for the INO arm and 80.3% (71.9-89.6%) for the control (HR=1.05; 0.55-2.01). The MRD undetectable rate at Course II Day 56 was 80.6% in the INO arm and 74.2% in the control arm. Univariate analysis suggests improved EFS with INO in pts with a positive LDA card (Ph-like ALL) and of Hispanic ethnicity. There were 22 gr 5 events, 7 occurred prior to randomization. Of the 15 gr 5 events on the randomized cohort, 12 were reported in the INO arm and 3 in the control arm. Of the 12 gr 5 events in the INO arm, all occurred during intensive consolidation courses complicated by prolonged pancytopenia infection/sepsis (8), hepato-biliary in setting of infection (2), multi-organ failure (1), or post-surgical complication (1). These events occurred after INO during Course II (3), Course III (5), or Course IV (4). Conclusions: Although this trial did not meet the primary EFS endpoint for the addition of INO to the pediatric regimen CALGB 10403, these data provide compelling evidence for continued use of pediatric regimens in young adults with ALL as the EFS and OS compares favorably with prior published results. INO may still be efficacious if late toxicity can be mitigated. A pilot study is planned that will decrease INO dose, add 2 cycles of blinatumomab and strict infectious prophylaxis guidelines. Support: U10CA180821, U10CA180882

Abstract Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in the epigenetic regulation of the SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. We identified the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY) as critical for this process. Inhibiting these pathways selectively suppresses SASP without affecting cell cycle arrest, highlighting their potential as therapeutic targets for age-related inflammation. Notably, SLC25A1 inhibition reduces systemic inflammation and extends healthspan in aged mice, establishing mitochondrial metabolism as pivotal to the epigenetic control of aging.

Importance Neoadjuvant therapy (NT) is an increasingly used treatment strategy for patients with localized pancreatic ductal adenocarcinoma (PDAC). Little research has been conducted on cancer care delivery during NT, and the standards for optimal delivery of NT have not been defined. Objective To develop consensus best practices for delivering NT to patients with localized PDAC. Design, Setting, and Participants This study used a modified Delphi approach consisting of 2 rounds of voting, and a series of virtual conferences (from October to December 2023) to reach expert consensus on candidate best practice statements generated from a systematic review of the literature and expert opinion. An interdisciplinary panel was formed including 47 North American experts from surgical, medical, and radiation oncology, radiology, pathology, gastroenterology, integrative oncology, anesthesia, pharmacy, nursing, cancer care delivery research, and nutrition as well as patient and caregiver stakeholders. Main Outcome and Measures Statements that reached 75% agreement or greater were included in final consensus statements. Results Of the 47 participating panel members, 27 (57.64%) were male, and the mean (SD) age was 47.6 (8.2) years. Physicians reported completing training a mean (SD) 14.6 (8.6) years prior and seeing a mean (SD) 110.6 (38.4) patients with PDAC annually; 35 (77.7%) were in academic practice. Final consensus was reached on 82 best practices for delivering NT. Of these, 38 statements focused on pre-NT practices, including diagnosis and staging (n = 15), evaluation and optimization (n = 20), and decision-making (n = 3); 29 statements defined best practices during NT, including initiation (n = 3), delivery of therapy (n = 8), restaging practices (n = 12), and management of complications during NT (n = 6); and 15 best practices were identified to guide treatment post-NT, focusing on surgery (n = 7), pathology (n = 4), and follow-up (n = 3). Conclusions Using a modified Delphi consensus technique, best practice guidelines were developed focusing on the optimal standards for delivering NT to patients with localized PDAC. Given the prognostic importance of completing multimodality therapy, efforts to standardize and optimize the delivery of NT represent an immediate opportunity to decrease care variation and improve outcomes for patients with PDAC. Future research should focus on validating and implementing best practice standards into clinical practice.