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ABSTRACT Most brain organoids derived from human induced pluripotent stem cells (iPSCs) lack microglia and thus immune function. Microglia‐like cells (MGCs) can be differentiated from iPSCs, while the characteristics of isogenic MGC‐containing brain organoids in modeling neurodegeneration and cell‐cell communications have not been well investigated. In this study, iPSC‐derived MGCs are co‐cultured with isogenic forebrain cortical organoids (iFCo), which are stimulated with extracellular vesicles (EVs) of brain organoids differentiated from Alzheimer's disease (AD) patient‐derived iPSCs ( APOE ε4/ε4 and presenilin 1). The AD EV‐stimulated co‐culture organoids are treated with EVs from healthy MGCs or co‐culture. Differential responses of the co‐cultured organoids and the MGCs to AD EVs are demonstrated. The co‐cultured organoids mitigated pro‐inflammatory gene expressions. EVs from healthy MGCs or co‐culture reduced the expression of IL‐12β , iNOS , TREM2 , and CASS4 , which are associated with neural inflammation and degeneration, as well as showed regulation on genes involved in microglial activation and carbon metabolism. AD EV cargo analysis by proteomics and microRNA‐sequencing revealed APOE and APP proteins and microRNAs regulated pathways such as mitophagy. This study paves the way for understanding the role of microglia and brain organoids in modeling neural degeneration and the development of EV‐based cell‐free therapeutics for AD treatment.

Importance The choice of induction agent during rapid sequence intubation (RSI) of critically ill adults may affect clinical outcomes. Although ketamine and etomidate are frequently used for RSI, their comparative effectiveness remains controversial. Objective To compare the safety of etomidate vs ketamine for emergency RSI in critically ill adults. Design, Setting, and Participants This cohort study used a target trial emulation with observational data collected between March 1, 2022, and April 30, 2024, from 18 emergency departments across Brazil, with data from the Brazilian Airway Registry Cooperation. Adults who underwent RSI and received either etomidate or ketamine as a sole hypnotic agent were included; those with preintubation cardiac arrest or immediate postintubation transfer were excluded. Exposure Administration of etomidate or ketamine as the induction agent for RSI. Main Outcomes and Measures The primary outcome was 28-day in-hospital mortality. Secondary outcomes included 7-day in-hospital mortality, first-attempt intubation success, and major adverse events (new hemodynamic instability, severe hypoxemia, and cardiac arrest) within 30 minutes after intubation. Inverse probability of treatment weighting was used to adjust for confounding. Risk ratios (RRs) and risk differences (RDs) with 95% CIs were used to compare outcomes between groups. Results Among 1810 patients (median age, 64 years [IQR, 50-74 years]; 1048 men [57.9%]), 514 received ketamine and 1296 received etomidate. The median shock index was higher in the ketamine group than the etomidate group (0.81 [IQR, 0.65-1.01] vs 0.76 [IQR, 0.59-0.99]), and preintubation vasopressor use was more common in the ketamine group than the etomidate group (191 of 514 [37.2%] vs 391 of 1296 [30.2%]). Weighted 28-day mortality was higher with etomidate than ketamine (60.5% [95% CI, 57.2%-63.8%] vs 54.4% [95% CI, 45.0%-63.9%]; RR, 1.14 [95% CI, 1.03-1.27]; RD, 7.6% [95% CI, 2.0%-13.3%]). Seven-day mortality was also higher with etomidate than ketamine (35.2% [95% CI, 32.0%-38.3%] vs 30.1% [95% CI, 23.5%-36.7%]; RR, 1.19 [95% CI, 1.04-1.35]). New hemodynamic instability within 30 minutes after intubation was more frequent with ketamine (24.2% [95% CI, 20.4%-28.0%] vs 18.9% [95% CI, 16.7%-21.0%]; RR, 0.78 [0.64-0.95]). There were no statistically significant differences in the other secondary outcomes. Conclusions and Relevance In this cohort study of critically ill adults undergoing RSI, etomidate use was associated with higher in-hospital mortality at 7 and 28 days compared with ketamine. These findings highlight the need for definitive randomized clinical trials to compare both agents.

ABSTRACT Differentiated thyroid cancer (DTC) is the most common endocrine malignancy, accounting for 90%–95% of all thyroid cancers worldwide. For many years, treatment options for patients with locally advanced or metastatic radioiodine refractory disease were limited. Advances in understanding oncogenic and angiogenic signaling pathways, such as vascular endothelial growth factor receptors, fibroblast growth factor receptors, platelet derived growth factor receptor, rearranged during transfection ( RET) , and BRAF have led to the development of targeted therapies that have transformed management over the past two decades. Multikinase inhibitors such as lenvatinib, sorafenib, vandetanib, and cabozantinib have demonstrated clinical efficacy in randomized clinical trials. Most recently, mutation-specific kinase inhibitors such as selpercatinib for RET -fusion positive cancers, and the combination of dabrafenib with trametinib for BRAF V600E -mutant disease, have been approved and further expanded treatment options for these patients. In this review, we summarize the current evidence on Food and Drug Administration-approved targeted therapies for metastatic thyroid cancer and discuss their clinical impact.

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature, and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and Appendix 2 (online only) for more. PURPOSE To provide guidance on the recommended management of cancer in pregnant patients. METHODS A multidisciplinary Expert Panel convened and conducted a systematic review of the literature. RESULTS The systematic review identified 450 eligible studies. Much of the evidence consisted of observational data, case series, and case reports. RECOMMENDATIONS Management of cancer during pregnancy should be grounded in a values-based informed-consent process outlining maternal and fetal risks and anticipated benefits. Diagnostic evaluation should follow the as low as reasonably achievable (ALARA) principle, with timing of diagnostic studies individualized based on urgency of cancer detection, potential dangers of delay, and the balance of risks to both the pregnant patient and her embryo or fetus. Due to significant risk of harm to the developing embryo and/or fetus, systemic therapy should be deferred until the second trimester. Methotrexate, hormonal therapies, human epidermal growth factor receptor 2–targeted agents, vascular endothelial growth factor and poly (ADP-ribose) polymerase inhibitors, antibody-drug conjugates, and all cellular therapies are contraindicated during pregnancy, regardless of gestational age. For patients who wish to continue their pregnancy, delivery should be planned at or after 37 weeks, with the final chemotherapy dose scheduled 2-4 weeks before birth. Referral to psychosocial support services is essential to address emotional and practical challenges, reduce distress, and support shared decision making. Additional information is available at www.asco.org/survivorship-guidelines .

Abstract Patients with myeloproliferative neoplasms (MPNs) are inherently at increased risk of both thrombotic and bleeding events due to the nature of the condition. Disease management often includes anticoagulants, antiplatelet agents, and/or cytoreductive therapy to mitigate these risks. On the contrary, these therapies can also increase the risk of bleeding, presenting a clinical challenge in balancing the prevention of thrombosis with the management of bleeding complications. The relationship between treatment type, thrombotic events, and bleeding risk remains underexplored in large, real-world populations. This Swedish population-based study aimed to describe how the risk of bleeding in patients living with MPN differs by treatment strategy, and how timing of thrombotic events influences this risk. A total of 15,495 patients diagnosed with MPN between 2006 and 2021, aged 18–90, were identified through the Swedish Cancer Register and the Swedish Patient Register. Bleeding rates were estimated using Cox proportional hazards models with time-split survival data. Treatment categories were defined as follows: no therapy, anticoagulant monotherapy (e.g., warfarin, direct oral anticoagulants [DOACs]); antiplatelet monotherapy (e.g., aspirin, clopidogrel); cytoreductive monotherapy (e.g., hydroxyurea, interferon); and combination therapy, defined as any combination of at least two of the three aforementioned therapies. All treatment categories were compared to anticoagulant monotherapy. Both treatment exposure and thrombotic status were modelled as time-varying covariates, allowing individuals to contribute across multiple thrombosis and treatment combinations over time. Models were adjusted for age at diagnosis, sex, year of diagnosis, and MPN subtype. The cohort was 52% female, with a median age at diagnosis of 71 years (IQR 60–79). The most common MPN subtypes were polycythemia vera (39%) and essential thrombocythemia (38%), followed by MPN-unclassifiable (16%) and primary myelofibrosis (7%). A history of thrombosis at MPN diagnosis was present in 22% of patients, and 19% had a history of bleeding. Among the 10,487 patients receiving combination therapy, the majority included antiplatelet agents: 57% received antiplatelet + cytoreductive therapy, 12% received antiplatelet + anticoagulant therapy, and 22% received all three therapies. Only 8% received anticoagulant + cytoreductive therapy without antiplatelet agents. Patients receiving no therapy had the lowest bleeding rate overall (HR 0.63, 95% CI 0.53–0.75), likely reflecting individuals with less severe disease or contraindications to treatment. Among patients with no thrombotic event, those receiving antiplatelet monotherapy had a 35% lower rate of bleeding compared to those on anticoagulant monotherapy (HR 0.65, 95% CI 0.56–0.76). Combination therapy was associated with a reduced rate of similar magnitude (HR 0.68, 95% CI 0.59–0.78), while cytoreductive monotherapy showed no significant difference (HR 0.96, 95% CI 0.76–1.21). In patients with a prior thrombotic event, antiplatelet monotherapy remained protective (HR 0.59, 95% CI 0.43–0.79), and combination therapy was associated with a slightly lower bleeding rate compared to anticoagulant monotherapy (HR 0.78, 95% CI 0.61–0.99). The estimate for cytoreductive monotherapy in this group (HR 2.04, 95% CI 0.89–4.68) was based on a small number of patients and had wide confidence intervals, limiting interpretability. These findings suggest that bleeding risk in MPN patients is influenced by both treatment type and thrombotic history. Antiplatelet monotherapy and combination therapy were associated with lower bleeding rates than anticoagulant monotherapy, both in patients with and without prior thrombosis, though the effect was more pronounced in those without prior thrombosis. By accounting for the complete patient pathway and modelling treatment and thrombotic status as time-varying exposures, a more accurate representation of real-world treatment dynamics is presented here. Given that the majority of combination therapy regimens included antiplatelet agents, these results underscore the potential protective role of antiplatelet therapy in managing bleeding risk. These insights may support clinical decision-making, and guide personalized treatment strategies and risk assessment in patients diagnosed with MPN.

Abstract Background: Treatment of multiple myeloma (MM) has advanced dramatically over the past decade with median overall survival (OS) for newly diagnosed MM patients (pts) now exceeding 10 years. However, outcomes in pts with high-risk disease remain poor. While most pts with high-risk disease are identified through baseline cytogenetic risk stratification, presence of extramedullary disease, or R-ISS stage, there is also a population of pts who may or may not have these traditional high-risk factors who relapse earlier than expected and have similarly poor outcomes. These pts are often delineated as “functional high-risk,” but a standardized definition of this population in the era of modern myeloma therapy is lacking. Methods: Using the ASH Research Collaborative (ASH RC) Data Hub, we retrospectively searched 7,249 pts across 10 participating institutions for those with newly diagnosed multiple myeloma (NDMM) treated with a triplet or quadruplet induction regimen (with or without autologous stem cell transplant) who had response data available. We evaluated duration of response from first line therapy (PD1) on post-PD1 clinical outcomes such as: time to next treatment (TTNT), time to subsequent progression and/or death (PFS2), and OS. We also analyzed characteristics of those who did vs. did not progress at prespecified time points of interest (12-, 18-, 24-, and 36-months) from the start of induction. We utilized recursive partitioning analyses to iteratively explore all possible cutpoints and identify which one(s) provide the greatest differentiation in the risk of subsequent progression and/or death. Results: We identified 1,305 pts who met the eligibility criteria. Of these, 264 had PD1 data including 201 who had response follow-up (f/u) after PD1. Median f/u after PD1 in this population was 3.2 years, and median PFS2 f/u after PD1 (n=201) was 4.4 years. Months to PD1 was significantly associated with PFS2 (p=0.038). All prespecified time points examined showed inferior PFS2 compared to those with PD1 >36 mos, although each subgroup was not statistically significant, likely due to limited numbers in each group: PD1 <12 mos HR=1.44 (n=43; 95% CI: 0.90 – 2.30; p=0.126), PD1 12-24 mos HR=1.65 (n=30; 95% CI: 0.95 – 2.85; p=0.073), and PD1 24-36 mos HR=1.58 (n=52; 95% CI: 0.98 – 2.53; p=0.059). Similarly, timing of PD1 was also associated with OS post-PD1; pts with PD1 <12 mos had significantly lower OS compared to those with PD1 >36 mos (HR=2.35, 95% CI: 1.27 – 4.32; p=0.006). Our recursive partitioning analysis identified 30-months at the cutoff that produced the greatest differential in outcomes between those above vs. below the landmark. Approximately 23% of the pts analyzed had PD1 within 30 mos, and these pts had significantly lower OS compared to those with PD1 ≥30 mos (HR=1.99, 95% CI: 1.21 – 3.27; p=0.006). Similarly, pts who progressed within 30 mos of starting 1L therapy (n=98) had significantly shorter PFS2 (median=12.5 mos vs 22.8 mos; HR=1.55, 95% CI: 1.09 – 2.20; p=0.014) than those who did not (n=103). Those pts who progressed within 30 mos were more likely to have a higher R-ISS stage at diagnosis (p=0.048), but were not more likely to have high-risk cytogenetics (p=0.66) compared to pts with PD1 ≥30 mos. Interestingly, receiving SCT as part of 1L therapy was not significantly associated with improved PFS2 (HR=0.89, 95% CI: 0.62 – 1.29; 0.54) but was significantly associated with improved OS (HR=0.53, 95% CI: 0.31 – 0.90; 0.018) by univariate analysis. Conclusion: Our study is the first to use a large, multicenter, cohort to evaluate the definition of functional high-risk MM in the era of novel induction therapies. Our data suggest that pts who progress within 30 mos of induction on triplet or quadruplet regimens (irrespective of whether they underwent stem cell transplant) have poorer outcomes than those who progress at 30 mos or later, and that progression prior to 30 mos represents functional high-risk disease. These pts represent a clear unmet medical need, and additional focus should be taken to identify them early with the goal of designing trials to optimize their subsequent therapies.

Abstract Introduction: The prognosis of patients (pts) with histological transformation (HT) of Waldenström macroglobulinemia (WM) remains dismal with standard chemoimmunotherapy. CD19-targeted chimeric antigen receptor T-cell therapies (CAR-T) can lead to durable responses in relapsed/refractory (R/R) large B-cell lymphoma (LBCL) and are approved in the second or third line settings. Pts with HT-WM were largely excluded from CAR-T trials. We previously reported high response rates in a series of 23 pts. The aim of the present study was to evaluate a larger cohort of pts with R/R HT-WM treated with CAR-T with a longer follow-up. Methods: We performed a multicenter retrospective study of pts with biopsy-proven transformed WM/lymphoplasmacytic lymphoma treated with CAR-T in the French DESCAR-T registry (NCT04328298), 4 centers from ECWM and 4 US centers. This study includes updated data from previously published cases (Durot et al, Blood, 2024). Responses were assessed according to the Lugano 2014 criteria. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the ASTCT 2019 consensus criteria. Hematological toxicity and infections were graded according to the NCI CTCAE (version 5.0). Progression-free survival (PFS) and overall survival (OS) were calculated from the date of CAR-T infusion and estimated using the Kaplan-Meier method. Results: 50 pts were included (39 from DESCAR-T centers, 7 from US centers and 4 from ECWM centers). Median age was 60 (range: 32-72) and 68 (range: 42-82) years at WM diagnosis and CAR-T infusion, respectively. MYD88L265P and CXCR4 mutations were present in 79% (23/29) and 15% (2/13) of patients with available data, respectively. The median time from WM to HT diagnosis was 5.3 years (range: 0-32). Median prior lines of therapy was 1 (range: 0-9) for WM and 2 for HT (range: 0-4). Twenty (40%) pts previously received a BTK inhibitor for WM or HT, 12 (24%) underwent prior autologous SCT and 1 pt allogeneic SCT. 40% of pts presented primary refractory disease and 44% were refractory to last treatment before CAR-T. 40 pts (80%) received bridging therapy, of whom 17 (44%) responded (7 complete responses (CR)). 35 (70%), 10 (20%), and 5 (10%) pts received axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel), respectively. The best overall response rate (ORR) was 94%, with 44 (88%) pts reaching CR. With a median follow-up of 25.7 months (range: 1-69) from CAR-T infusion, the median PFS was 1.2 years (95% CI: 0.5-4.5) and median OS was 4.2 years (95% CI: 1.2-not reached). Median duration of response was 1.5 years (95% CI: 0.4-4.4), with a median of 4 years (95% CI: 1.5-NR) for pts still in CR at 6 months after CAR-T. 22 pts experienced relapse/progression after CAR-T, 19 related to LBCL and 3 to WM. Median survival after relapse was 7.9 months (95% CI: 3.8-25.3). At LBCL relapse after CAR-T, salvage therapy consisted of CD20xCD3 bispecific antibodies for 9 pts, lenalidomide +/- anti-CD20 or anti-CD19 antibody for 6 pts, and BTKi for 3 pts. Among 19 pts who died, 14 (74%) were due to progressive disease and 5 (26%) from infections. 37 (76%) pts experienced CRS, including 2 (4%) grade 3 events, and 22 (45%) had ICANS, with 2 (4%) ≥ grade 3 events. 17 (35%) pts presented infections, including 12 ≥ grade 3. 21 (43%) pts developed ≥ grade 3 prolonged cytopenias (ie, not resolved within 30 days post infusion). CNS involvement due to LBCL was present in 11 pts (22%) at the time of CAR-T. 6 of them had ICANS, with 1 grade 4. The best ORR was 91% (best CR 91%). Only 1 patient did not obtain a response, with stable disease at 1 month and progression at 3 months. The median PFS was 1.2 year (95% CI: 0.2-NR) and median OS was NR (95% CI: 0.5-NR). On univariate analysis, only elevated LDH was correlated with worse PFS (HR 2.5, p=0.04) and OS (HR 3.3, p=0.04). Other variables, including number of prior lines of therapy, MYD88 mutation status, primary refractory disease, refractory to last treatment, CNS involvement before CAR-T, response after bridging therapy and type of CAR-T received, were not associated with inferior PFS or OS. Conclusion: This cohort represents the largest series of pts with transformed WM treated with anti-CD19 CAR-T. We confirm the high efficacy previously reported with an acceptable safety profile, including for pts with CNS involvement due to LBCL at CAR-T infusion.

Abstract INTRODUCTION Allogeneic hematopoietic cell transplantation (alloHCT) is indicated in patients (pts) with FLT3-ITD mutated AML. The randomized BMT CTN 1506 trial (Levis et al. JCO) demonstrated that maintenance with FLT3 inhibitor gilteritinib (gilt) significantly improved relapse-free survival (RFS) among pts with detectable peri-alloHCT minimal residual disease (MRD) but was also associated with a greater degree of myelosuppression and infections. In older pts, aged >60 years, increasing post-HCT toxicity may adversely impact outcomes. On this basis, we performed a post-hoc analysis of pts aged > 60 years enrolled onto BMT CTN 1506 to examine the impact of gilteritinib maintenance in older pts. METHODS Pts ≥60 years randomized on BMT CTN 1506 (gilt=47, placebo=57; N=104) were included. The primary endpoint of this post-hoc analysis was RFS. We additionally assessed overall survival (OS), incidence of relapse, non-relapse mortality (NRM) in all pts and in pts with detectable MRD. RESULTS Baseline characteristics were balanced. Age was similar (65.2 vs 64.7 years; p = 0.12), as was prior TKI exposure, and NPM1 mutation status. Myeloablative conditioning (MAC) was used in 8 (17%) pts randomized to gilt and 18 (32%) pts randomized to placebo (p=0.08). Median f/u of survivors was 43.8 months (range:1-61 mo.). Estimated RFS and OS at 48 months were not different between groups (RFS: gilt: 57.0%, 95%CI 44.1-73.7%, placebo: 57.1%, 95%CI 45.4-71.8%; OS: gilt: 56.9%, 95%CI 42.9-46.7%, placebo: 58.4%, 95%CI 46.7-73.1%). While gilt assignment did not affect survival, several predictors of poorer survival were identified including use of reduced intensity conditioning (RIC) (HR = 3.46; p = 0.014), use of calcineurin inhibitor/MTX for graft-vs-host disease (GVHD) prophylaxis (HR = 2.29; p = 0.041), high-risk cytogenetics (HR = 2.64; p = 0.021), and MRD (+) pre-HCT (HR = 2.29; p = 0.018). Finally, relative to gilt assignment, opposing rates of relapse and NRM were observed. The incidence of relapse was lower with gilt (16%, 95%CI 6.8-28% vs 32%, 95%CI 20-45%, p=0.046) but NRM was higher (27%, 95%CI 15-41% vs 11%, 95% CI 4.3-21%, p=0.033). We next analyzed the 49 pts (gilt=22, placebo=27) with detectable peri-HCT MRD. RFS and OS again were not different (RFS: gilt: 44.4%, 95%CI 27.1-72.7%, placebo: 43.8%, 95%CI 28.4-67.5%, OS: gilt: 49.2%,95%CI, 31.3-77.4%, placebo: 55.6%, 95%CI 39.4-77.8%). The incidence of relapse trended lower in gilt pts (25%, 95%CI, 5.3-44.7% vs 45% (95%CI, 25-63%), p=0.2) while NRM trended higher (31%, 95%CI 12-52% vs 11%, 95%CI, 2.7-26%, p=0.12). Seventeen (36%) patients completed planned 2 year maintenance with gilt compared to 29 (51%) completing therapy with placebo. Median time on gilt was 13.2 months. The most common reason for discontinuation was adverse events (n=19, 40%), of which cytopenias (n=8) and infections (n=4) were most frequent. Non-relapse causes of death among gilt treated pts included infections (n=8), intracranial hemorrhage related to thrombocytopenia (n=1), second cancer (n=1), and Guillain-Barre syndrome (n=1). Most infections (n=5) were attributed to GVHD as an underlying cause. CONCLUSION Among pts aged ≥60 years, gilt maintenance did not improve RFS or OS. Gilt use was associated with reduced relapse regardless of peri-HCT MRD status demonstrating disease effect; however, higher NRM limited overall benefit. In older FLT3 mutated pts, employing strategies to mitigate HCT related toxicity, e.g. alternative GVHD prophylaxis strategies, may better accommodate use of maintenance therapy including gilt. Lower doses of gilt (particularly with azole co-use) may be worth exploring to mitigate drug AEs, improve compliance, thus further improving benefit.

Abstract Introduction Short diagnosis-to-treatment interval (DTI) is associated with aggressive disease biology and inferior outcomes in diffuse large B-cell lymphoma (DLBCL), and is recognized as a potential source of selection bias in clinical trials if not properly addressed. However, its prognostic significance in follicular lymphoma (FL) remains poorly characterized. We aimed to evaluate the prognostic significance of DTI in newly diagnosed FL patients who received frontline (1L) immunochemotherapy (IC), using a large international dataset and an independent external validation cohort. Methods For the discovery dataset, we evaluated patients diagnosed between 2002 and 2018 from ten observational cohorts as part of the FLIPI24 Consortium. External validation was conducted using data from patients enrolled in the Lymphoma Epidemiology of Outcomes (LEO) Cohort between 2010 and 2015. All patients had FL grade 1–3A and received 1L IC within 100 days of diagnosis. Patients with a concurrent DLBCL were excluded. Missing baseline laboratory values were addressed via multiple imputation. The primary endpoint was event-free survival at 24 months (EFS24); secondary endpoint was 5-year overall survival (OS), both calculated from treatment initiation. DTI was analyzed as continuous (via splines) and dichotomized variable (≤14 vs >14 days; as defined in DLBCL). Results In the discovery cohort (n=3,907), median age was 61 years (IQR 53–69), and 50% were male; 49% of patients were high-risk according to FLIPI, 26% according to PRIMA-PI, and 38% according to FLIPI24. Included patients received R-CHOP (54%), R-CVP (26%), or B-R (20%) as 1L treatment, followed by anti-CD20 maintenance in 60%. The median DTI was 30 days (IQR 17–48). Using the 14-day cut-off, 851 patients (22%) had short DTI. These patients had more adverse baseline characteristics, including B symptoms (42% vs 32%, P<0.01), ECOG performance status ≥2 (15% vs 8%, P<0.01), elevated LDH (51% vs 40%, P<0.01), hemoglobin <12 g/dL (30% vs 17%, P<0.01), and elevated β2-microglobulin (56% vs 44%, P<0.01). Prognostic indices (PIs) were also more frequently high-risk in the short-DTI group: FLIPI (56% vs 47%), PRIMA-PI (36% vs 24%), and FLIPI24 (51% vs 34%, all P<0.01). Spline modeling showed a decreasing EFS24 rate with increasing DTI, reaching a plateau at 30–40 days. In logistic regression model, each additional week of DTI improved EFS24 (OR 0.92, P<0.01). DTI attenuated but remained prognostic after adjusting for PIs (OR 0.93 for FLIPI, 0.95 for PRIMA-PI, 0.96 for FLIPI24, all P<0.01). When analyzed as a dichotomized variable, short DTI was associated with inferior EFS24: OR 1.74 adjusted for FLIPI, 1.63 for PRIMA-PI, and 1.53 for FLIPI24 (all P<0.01). The 2-year EFS of short vs long DTI groups was 71% vs 82% (HR 1.50, 95% CI 1.34–1.67, P<0.01), 5-year OS was 80% vs 86% (HR 1.38, 95% CI 1.21–1.56, P<0.01), and the 5-year cumulative risk of histologic transformation was 7.7% vs. 5.4% (P<0.01). In the validation cohort (n=516), median age was 61 years (IQR 52–69 years), 55% were male; 36% of patients were high-risk according to FLIPI; 29% according to PRIMA-PI, and 33% according to FLIPI24. Patients received B-R (59%) or R-CHOP (41%) as 1L treatment. The median DTI was 31 days (IQR 19–48), 84 patients (16%) had DTI ≤14 days. Similar patterns were observed; patients with short DTI had adverse baseline characteristics, PIs, and shorter 2-year EFS (72% vs 84%, HR 1.69, 95% CI 1.13–2.55, P=0.01). DTI remained associated with EFS24 when analyzed as a continuous variable (per week: OR 0.88 unadjusted, 0.90 with FLIPI, 0.89 with PRIMA-PI, and 0.89 with FLIPI24), and dichotomized (≤14 vs >14 days: OR 1.83 adjusted for FLIPI, 1.88 for PRIMA-PI, and 1.73 for FLIPI24). Conclusion Short DTI, defined as ≤14 days (observed in 22% of FL patients vs 46% in DLBCL), is a strong and independent predictor of inferior outcomes in newly diagnosed FL patients treated with IC. While DTI correlates with adverse baseline features and established PIs, it retains independent prognostic value. Although a 14-day threshold is reasonable for risk modeling, DTI contains greater informational value when modeled as a continuous variable. Among PIs, FLIPI24 most strongly attenuated the DTI effect, underscoring its superior discriminative power over FLIPI and PRIMA-PI. Clinical trials designs should mitigate any potential barriers to enrollment of FL patients requiring urgent therapy.

Abstract Aims BMT CTN 1506 (“MORPHO”) was a global phase 3 study of post-hematopoietic cell transplantation (HCT) maintenance with gilteritinib versus placebo for patients with FLT3-ITD-mutated AML in CR1. The study did not meet its primary endpoint of improved relapse-free survival (RFS) for post-HCT gilteritinib, but subgroup analysis indicated a benefit for participants with pre-HCT measurable residual disease (MRD). Subgroup analysis also indicated a statistically significant benefit of post-HCT gilteritinib for participants in North America, but no benefit for those in Europe or Asia. RFS for the control arms in Europe and Asia was higher than anticipated, suggesting that participants with different disease biology may have accrued to the study in these different geographic regions. In the primary analysis of the study, pre-HCT FLT3 inhibitor use and MRD across the entire study population were both found to have impacted outcomes. Time from diagnosis to HCT, a reflection of local practice patterns, is also known to impact outcomes for FLT3-ITD AML. We hypothesized that local practice patterns of pre-HCT FLT3 inhibitor use and time from AML diagnosis to HCT could have influenced the disease biology of study pts at the time of enrollment. This would be predicted to result in pre-HCT MRD levels and could provide an explanation for the regional differences observed in the study outcome. Methods We conducted a post-hoc analysis of the data focusing on days from AML diagnosis to HCT, pre-HCT FLT3 inhibitor use, and FLT3-ITD MRD assessed by a high-sensitivity assay. Eligibility requirements included FLT3-ITD-mutated AML in first remission after intensive chemotherapy and HCT occurring within 12 months of achieving remission. Patients refractory to induction therapy, or those with a history of relapse, were ineligible. Results Accrual took place in 16 different countries, with 5 countries accounting for 79.7% of the total accrual: USA 42.7%; Japan 15.7%; Korea 8.4%; UK 6.7%; Germany 6.2%; other countries 20.2%. In two countries, USA and Germany (48.9% of total enrollment), participants underwent HCT a median of 119 days after AML diagnosis, and 90.2% were treated with a FLT3 inhibitor pre-HCT. In contrast, in Japan, Korea, the UK and the other 11 countries all combined, participants underwent HCT a median of 152.5 days after AML diagnosis, and only 30.8% received any FLT3 inhibitor pre-HCT. Amongst all participants, those transplanted < 120 days from AML diagnosis and/or those treated with FLT3 inhibition pre-HCT were more likely to have improved RFS from post-HCT gilteritinib. RFS was improved with post-HCT gilteritinib in the US and Germany (HR 0.397; CI 0.220-0.718), whereas no benefit was evident in all other countries combined (HR 1.184; CI 0.685-2.048). Pre-HCT MRD levels were significantly higher (P = 0.011) in participants transplanted within 120 days from diagnosis as well as in those treated with a FLT3 inhibitor pre-HCT and also transplanted within 120 days (P = 0.019). Pre-HCT MRD was dependent on both FLT3 inhibitor use and time to HCT, as participants treated with successive courses of chemotherapy + FLT3 inhibition had successively lower MRD by the time of HCT. Conclusions The time from AML diagnosis to HCT and FLT3 inhibitor use pre-HCT both appeared to impact MRD levels immediately prior to HCT, and geographic differences in these two practice patterns likely accounted for the regional differences in benefit from post-HCT gilteritinib observed in BMT CTN 1506. Successive courses of chemotherapy without FLT3 inhibition appears to have selected a more favorable risk (e.g., MRD-lower) population for enrollment. Successive courses of chemotherapy combined with FLT3 inhibition progressively eradicated MRD, such that a majority of participants undergoing HCT after 3 or 4 courses were MRD negative and therefore unlikely to benefit from post-HCT gilteritinib. These findings have implications for clinical practice. Increasing the number of courses of chemotherapy combined with FLT3 inhibition before HCT may lower MRD sufficiently to eliminate the need for post-HCT inhibition for some patients but, alternatively, the additional delay could increase the risk of pre-HCT relapse, preventing patients from receiving HCT in first remission.