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Autologous stem cell transplantation (ASCT) in AL amyloidosis effectively produces a high overall hematological response rate, complete response rate, and durable remissions. However, it is a high-dose chemotherapy-based therapy with high morbidity which can be offered only to a subset of AL amyloidosis patients who are considered fit for this therapy. Transplant-related mortality (TRM) in AL amyloidosis has decreased over the past three decades due to improvement in patient selection. New therapeutic options question the utilization of ASCT. A model to predict TRM can improve the decision-making process, patient selection and further reduce TRM. AL amyloidosis patients (n=1718) from 9 centers globally, transplanted in the years 2003-2020 were included. Pre-ASCT variables of interest were assessed for association with Day-100 all-cause mortality, including age at ASCT (≥ 60 years), sex, light chain isotype, ECOG performance status (ECOG PS; 0, 1 and 2/3), the difference between involved and uninvolved light chains (dFLC; ≥180 mg/L), N-terminal prohormone of B natriuretic peptide (NT-proBNP; ≥1800 pg/mL) or B-type natriuretic peptide (BNP; ≥400 pg/mL), left ventricle ejection fraction (LVEF, <50%), interventricular septum (>16 mm), corrected diffusing capacity for carbon monoxide (cDLCO; ≤65% of predicted), forced expiratory volume in one second (FEV1; ≤65% of predicted), serum albumin (<2.5 g/dL), estimated glomerular filtration rate (eGFR; <30 mL/min/m2), alkaline phosphatase (>X2 upper limit of normal), and systolic blood pressure (<100 mmHg). Troponins could not be included in our modeling given the multitude of assays used across institutions and periods that could not be reconciled. A random forest (RF) classifier with 10-fold cross-validation was used to assist in variable selection. The final model variables were selected based on statistical performance and clinical relevance. The model was fitted using logistic regression. The median age at ASCT was 58, and 40% of patients were women. The most frequently involved organs were the kidneys (69%) and the heart (52%). Mayo 2004 stages I and II were collectively present in 83% of patients. Day-100 TRM occurred in 75 patients (4.4%) with the 3 main causes being shock (n=27), cardiac arrhythmia (n=26), and organ failure (n=22). Age at ASCT, sex, and light chain isotype were not predictors of Day-100 TRM. Across the other pre-ASCT variables, adverse features were present from 6.9% (LVEF <50%) to 25.8% (dFLC ≥180 mg/L) of patients. Ten factors were associated with Day-100 TRM on univariate analysis. The odds ratio of these variables ranged from 1.6 to 10.2. RF classifier using all these variables identified a model with an area under the curve (AUC) of 0.72±0.12. Using the importance hierarchy function to refine the model selection, a 4-variable model [NT-proBNP/BNP ≥1800/400 pg/mL, serum albumin <2.5 g/dL, ECOG PS 1 or 2/3, and systolic blood pressure <100 mmHg] was built with an AUC of 0.70±0.12. Based on logistic regression coefficients, ECOG PS 2/3 was assigned two points, while other adverse predictors were assigned 1-point each (model score range 0-5). We then applied the model scoring to our study population. Score distribution was as follows: 0 (n=431, 25.1% of patients), 1 (n=688,40.1%), 2 (n=413, 24.0%), and 3 and above (n=186, 10.8%). Day-100 TRM rates were 0.46%, 3.2%, 5.8%, and 14.5% for 0, 1, 2, and ≥3 points, respectively. The respective rates for the years 2003-2011 were 1.1%, 3.3%, 6.4%, and 19.2%, while for the years 2012-2020 0%, 3.1%, 5.2%, and 8.4%. We developed a simple clinical tool to predict the Day-100 TRM risk in AL patients undergoing ASCT. This tool will allow more informed decision making weighing the individual benefits and risks of ASCT compared to other therapies.

Introduction Chimeric antigen receptor T-cell therapy (CART) has revolutionized the treatment algorithm of relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). However, approximately only 40% of cases achieve long-term durable remissions. Prognostication remains important as it would allow more precise prediction of outcomes and develop a personalized treatment approach. Currently, it is unclear whether prognostic factors that have been predictive of outcomes in the pre-CART era, remain important in the current era. We conducted a single center observational study to assess the prognostic significance of extra nodal involvement (ENI) on long-term outcomes following CART in B-cell NHL. Methods The primary aim was to evaluate the prognostic significance of ENI on long-term outcomes in patients with B-cell NHL treated with CART. The second aim was to specifically evaluate the impact of gastrointestinal (GI) involvement. Continuous variables were summarized as median (range) and categorical variables were reported as frequency (percentage). Kaplan-Meier method was used to estimate freedom from events at different time points and draw corresponding survival curves. Log-rank test was used to compare freedom from events between histology groups. Results 74 patients were included in this analysis, with a median age of 62 (18-85) years. Fifty-three (72%) had evidence of ENI. Twenty-four (47%) had GI involvement as the sole site of ENI or with other sites of ENI. Forty-three (58%) patients were male and diffuse large B-cell lymphoma (DLBCL) was the most common histology (n=50 [54%]) followed by transformed follicular lymphoma (n=20 [27%]). Most patients had advanced stage disease at time of CART (n=71 [96%]) and 3 (4%) had CNS involvement at any time prior to CART. Median number of prior lines of systemic treatment were 2 (1-7) and 64 (87%) had progressive disease at time of CART. Axicabtagene ciloleucel was the most used CART product (n=68 [92%]); Grade 3-4 cytokine release syndrome was reported in 6 (8%) patients and grade 3-4 immune effector cell associated neurotoxicity syndrome was reported in 13 (18%) patients. ICU level of care was needed in 22 (30%) patients and 2 patients (3%) developed hemophagocytic lymphohistiocytosis-like syndrome. Sixty patients (87%) achieved an objective response and 34(49%) achieved a complete response. The 1-year OS was 66% (53-81) in patients who had ENI vs. 72% (54-97) in those without ENI (p=0.82); 1-year relapse rates were at 39% (20-54) vs. 36% (10-54) (p=0.95) for patients with ENI vs. those without ENI. No difference was noted between the two groups regarding progression-free survival and non-relapse mortality (NRM). No difference in outcomes was observed when patients who had GI involvement as the only site of ENI or in combination with other sites of ENI were compared to those who did not have GI involvement as one of the sites of ENI. Elevated LDH at the time of CART (HR 2.27 [95% CI 1.05-4.94], p=0.03), development of any grade ICANS (HR 2.77 [95% CI 1.27-6.04], p=0.01) and requirement for ICU level of care (HR 3.25 [95% CI 1.54-6.86], p=0.002) adversely affected OS; the impact of elevated LDH on OS remained significant in multivariate models (HR 2.34 [95% CI 1.05-5.27], p=0.04). Development of any grade CRS was associated with a decreased risk of relapse (HR 0.25 [95% CI 0.11-0.56], p=<0.001) and the requirement of ICU stay adversely affected NRM (HR 2.27 [95% CI 1.05-4.94], p=0.032). Conclusion These results suggest that ENI does not appear to be predictive of long-term outcomes in the setting of CART therapy. Patients who had ENI appeared to derive equal benefit from CART therapy. GI involvement as a site of ENI has been known to be associated with worse survival when compared to other sites of ENI but we did not observe any difference in this subgroup also. Evolving predictive models and/or biomarkers that take in account the dynamics of the interaction between the malignant and CART cells might help better inform prognostication in the current era.

Introduction: Light-chain amyloidosis (ALA) is a rare plasma cell disorder characterized by multiorgan involvement. Patients often present with non-specific symptoms, which can lead to a delay in diagnosis. This is associated with progressive organ involvement and shorter survival. Reducing the time from symptom onset to diagnosis is a critical step in improving outcomes. This study was designed to evaluate the clinical prodrome and challenges associated with the diagnosis of ALA from the patient perspective. Methods: This retrospective study surveyed patients with ALA through the online HealthTree® Cure Hub platform, which helps patients navigate their disease in a holistic way. The survey consisted of 32 questions, including 23 multiple-choice, 7 date-entry, and two free-response questions. Data on diagnosis and demographics were extracted from the electronic health record and self-reported data linked to HealthTree® Cure Hub. Results were reported as numbers and percentages, and comparisons were made by age (≥70 vs. <70 years) and sex. The following statistical methods were used: Fisher's exact test for categorical data, two-sample t-test and F-test for normally distributed continuous data, Wilcoxon rank-sum test for skewed data and Spearman correlation coefficient. Results: We surveyed 248 patients. Of those, a total of 87 patients with a self-reported diagnosis of ALA completed the questionnaire between March 12, 2023, and May 8, 2024. The median age was 66 years; 55% were female, and 91% were white. The most common initial symptoms prompting patients to seek medical evaluation were fatigue/weakness (47%), swelling (38%), shortness of breath (28%), chest pain (23%), and foamy urine (22%). Pain in hands/feet, carpal tunnel syndrome, loss of appetite, hoarseness, macroglossia, diarrhea, periorbital puffiness, nail changes, and erectile dysfunction each accounted for <10% of cases. Signs and symptoms were first detected by patients themselves in 58% of cases, by a physician in 33% and by a family member or friend for the rest. The median number of symptoms per individual was 2; 31% reported only one symptom, 37% 2-3, 18% 4-6, and 14% >6; with chest pain being the most common (39%), followed by swelling (22%), shortness of breath (13%), and foamy urine (13%); one patient reported erectile dysfunction and another reported arrhythmias as their only symptom. There was a correlation between hoarseness and nail changes (ρ=0.71), and carpal tunnel syndrome and orthostatic hypotension (ρ=0.63). Only 16% were aware of ALA as a condition prior to symptom onset. Thirty six percent presented to a general practitioner for initial evaluation; about 50% sought a specialist, including a myeloma/amyloid specialist (21%), and 14% were first evaluated in the emergency department. While most patients (45%) were diagnosed by a hematologist/oncologist, patients reported seeing a median of 3 physicians (range: 1-10) before the diagnosis was established. Among responders, 61% reported having myeloma at the time of testing. After diagnosis, about 50% were referred to a center specialized in ALA, and 72% met with a stem cell transplant specialist. Most patients reported receiving multidisciplinary care, with a median of 3 additional specialists participating in ALA care (range: 0-16). More than half of patients (59%) felt the diagnosis was delayed; among those, 42%, 24%, 24%, and 11% reported a delay of 1-6, 7-12, 13-24, and >24 months, respectively. The proportion of patients reporting >12-month delay was higher among older patients (54% vs. 27%, P=0.02). A quarter of responders felt their treatment was delayed. Half of patients felt the diagnostic delay contributed to a decrease in treatment efficacy and 48% did not feel that all medical professionals were knowledgeable about ALA. Only 38% felt the diagnostic process was simple and easy within their healthcare system. Conclusion: Most patients with AL amyloidosis initially present with non-specific symptoms, with fatigue/weakness being the most common. Over a third were evaluated first by a general practitioner, and about a third reported a diagnostic delay of >12 months. The diagnostic process is associated with high healthcare utilization, even among patients with concurrent multiple myeloma. Increasing disease awareness among patients and medical providers may shorten the time to diagnosis and contribute to improved outcomes.

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder characterized by uncontrolled terminal complement activation. Treatment with terminal complement inhibitors ravulizumab or eculizumab has led to improved clinical outcomes for patients with PNH. Evidence on real-world treatment patterns and healthcare resource utilization (HRU) in this patient population, which includes emerging data on pegcetacoplan, is limited. Objective To describe real-world drug adherence and persistence in patients with PNH receiving ravulizumab, eculizumab or pegcetacoplan, and compare HRU for patients pre- and post-ravulizumab initiation in the USA. Methods ADVANTAGE is a retrospective, longitudinal analysis using the Komodo Health Research Database, a large multi-payer US health insurance claims dataset, among patients with PNH and ≥ 1 claim for ravulizumab, eculizumab or pegcetacoplan. Patients aged ≥ 18 years at index date (defined as the date of first claim for a given complement inhibitor on/after 1 January, 2019), with ≥ 12 months enrollment prior to this date, ≥ 1 claim with an ICD-10-CM code indicating PNH prior to/at index date and no ICD-10-CM code suggesting an alternative indication, were included. Patients were followed until the end of continuous enrollment, death, or end of data availability. Adherence was assessed by proportion of days covered (PDC) and treatment duration was estimated using Kaplan-Meier analysis. The HRU analysis included patients with ≥ 12 months follow-up and compared rates of HRU per-patient per-year (PPPY) in the 12 months pre- and post-ravulizumab treatment initiation. Pre-post differences in HRU were estimated using generalized estimating equations with robust standard errors. Results The sample included 344, 342 and 97 patients with index treatments for ravulizumab, eculizumab or pegcetacoplan, respectively. Age and sex distribution of patients were similar among patients treated with ravulizumab (mean age: 44 years; 57% female), eculizumab (mean age: 44 years; 60% female), or pegcetacoplan (mean age: 45 years; 62% female). More patients in the ravulizumab cohort were complement inhibitor-naive (31%) compared with eculizumab (20%) or pegcetacoplan (24%). Mean (standard deviation [SD]) duration of follow-up was 25.3 (15.9), 33.5 (18.9) and 13 (8.0) months, and mean (SD) proportion of days covered (PDC) was 0.98 (0.05), 0.90 (0.14) and 0.77 (0.30) for the ravulizumab, eculizumab and pegcetacoplan cohorts, respectively. The percentage of patients with PDC ≥ 0.8 (a widely used threshold for treatment adherence) was 98.5% for ravulizumab, and 84.5% and 78.4% for eculizumab and pegcetacoplan, respectively. The median (interquartile range [IQR]) duration on ravulizumab treatment was 48.4 (11.5, not reached [NR]) months, compared with 7.6 (3.4, 23.3) for eculizumab and 14.6 (0.2, NR) for pegcetacoplan. Among patients with ≥ 12 months on ravulizumab treatment (n = 183), a 24.8% reduction in all-cause HRU was observed during the first 12 months of treatment compared with the prior 12 months. Statistically significant reductions were observed in mean (SD) all-cause hospitalizations (0.2 [0.6] PPPY during follow-up; % difference -44.6%, p = 0.014), outpatient visits (24.3 [17.8] PPPY; % difference -19.1%, p < 0.001) and emergency room visits (0.5 [1.3] PPPY; % difference -39.8%, p = 0.008). Similar results were observed for PNH-related HRU, including a 32.1% reduction in the overall number of visits (p < 0.001). Notably, a statistically significant reduction in PNH-related hospitalizations (0.2 [0.5] PPPY; % difference -37.8%, p = 0.044) and outpatient visits (14.3 [10.7] PPPY; % difference -22.4%, p < 0.001) was observed. Ravulizumab initiation was also associated with fewer PNH-related emergency room visits (0.2 [0.7] PPPY; % difference -32.7%, p = 0.170) and blood transfusions (0.8 [2.9] PPPY; % difference -30.7%, p = 0.277); however, these changes were not statistically significant. Conclusions In this retrospective analysis, patients demonstrated higher adherence and persistence to ravulizumab treatment compared to other complement inhibitors. HRU decreased following ravulizumab initiation, indicating an alleviated burden of disease in these patients after treatment initiation. These real-world data provide further evidence of the benefit of ravulizumab in patients with PNH.

Background An increased risk of second cancers (SC), in patients with myeloproliferative neoplasms (MPN), has been suggested by a number of population-based and cancer registry studies (Blood 2011;118:6515). Such studies often included patients belonging to a broad category of MPN entities and did not always account for history of cancer prior to the diagnosis of MPN, associated comorbidities, mutations, or treatments received, in assessing risk association and prediction (Leukemia 2019;33:1996). The current study seeks to fill knowledge gaps, in this regard, in the context of a biologically more homogeneous MPN setting, vis-ẚ-vis polycythemia vera (PV) and essential thrombocythemia (ET). Methods The present study was conducted under an institutional review board approved minimum risk protocol that allowed retrospective collection and analysis of data from Mayo Clinic patient records. Diagnostic criteria were according to the International Consensus Classification (Blood 2022; 140:1200). Documented primary cancers were annotated in 17 categories, not including pre-cancerous conditions or MPN progressions. SC was defined as any cancer that developed after 3 months from the initial diagnosis of MPN. Cox proportional hazard regression model was used for univariable and multivariable analysis. Kaplan-Meier plots were used for time-to-event assessment (considering the first in case of multiple events). Results The study population included 1,968 consecutive patients (median age 60 years; 56% females) with PV (N=1,001) or ET (N=967), seen at the Mayo Clinic between 1970 and 2024. Median follow-up was 8.6 years. The incidences of arterial/venous thrombosis were14%/12% at diagnosis and 12%/10% after diagnosis. Co-morbid conditions included diabetes (12%), hypertension (52%), tobacco use (16%), and history of autoimmune/inflammatory disease (AID; 6%); hyperlipidemia was annotated in PV cases only (51%). Non-driver mutation information was available in 620 patients: TET2 (13%), ASXL1 (7%), DNMT3A (5%), SRSF2 (3%), SF3B1 (3%) and TP53 (2%). A history of another cancer was documented in 598 (30%) patients and included cancers documented before/at (N=291; 15%) or after (N=404; 20%) the diagnosis of MPN, with only the latter being referred to as “SC”. Most frequent cancer type was non-melanoma skin cancer (NMSC), accounting for 28% of cancers diagnosed before/at MPN, and 47% of SC; other SC types included lymphoid neoplasms (10%), melanoma (10%), prostate cancer (9%), and trachea/lung/bronchial cancer (8%), as the most frequent. On multivariable analysis, cancer history, before/at or after MPN diagnosis, clustered with age >60 years (OR 2.7), male sex (OR 1.5), and history of AID (OR 1.7). History of cancer prior to MPN diagnosis, NMSC or otherwise, was associated with inferior overall survival (p<0.01); by contrast, neither myelofibrosis-free (p=0.5) nor leukemia-free (p=0.8) survival was affected. Median time from MPN diagnosis to SC was 5.7 years. In multivariable analysis including all cancers, SC-free survival was adversely affected by age>60 years (HR 2.5; p<0.01), male sex (HR 1.7; p<0.01), history of previous cancer (HR 2.5, p<0.01), and AID history (HR 1.6; p<0.01); all these 4 risk factors remained significant after excluding NMSC. Interestingly, among informative cases, SRSF2 mutation also predicted SC (HR 2.6; p=0.02), even after NMSC cases were excluded (HR 3.4; p=0.02). Pre-MPN history of cancer did not affect either arterial (p=0.9) or venous thrombosis-free survival (p=0.7), in age- and sex-adjusted analysis. Conversely, after excluding post-SC thrombotic events, venous (p=0.02) but not arterial (p=0.1) events, occurring after MPN diagnosis, were predictive of SC. This association remained significant in multivariable analysis that included age, sex, and venous thrombosis history (p=0.03). Additional observations from this study, include an independent association between SC and hyperlipidemia in PV (p<0.01) and ruxolitinib monotherapy with NMSC (HR 9; p<0.01). Conclusions The risk of SC in patients with MPN is significantly higher in older patients, men, and in the presence of pre-MPN cancer history and AID. Incidental venous, but not arterial, thrombosis was associated with subsequent SC, not NMSC. The observed association of SC with SRSF2 mutations and hyperlipidemia is noted but requires further validation.

Introduction Malignant histiocytoses (MH), encompassing histiocytic sarcoma (HS), interdigitating dendritic cell sarcoma (IDCS), and Langerhans cell sarcoma (LCS), are a group of rare, hematologic neoplasms with diverse clinical presentations and poor outcomes. There are no established or effective treatments for patients with MH. The discovery of MAPK/ERK pathway mutations in non-malignant histiocytoses have revolutionized the treatment paradigm, but it is unknown whether novel treatments are efficacious for MH. This study aimed to assess the efficacy of targeted agents (TA) and immune checkpoint inhibitors (ICI) in MH. Methods We conducted a retrospective chart review of MH patients seen at our two institutions. Only patients treated with TA and/or ICI were included. We captured the mutational status by next generation sequencing and PD-L1 expression level by immunohistochemistry, where available. We also conducted a systematic literature review using PubMed to identify additional cases of MH patients treated with TA and/or ICI. Responses were reported as complete (CR), partial (PR), or none (NR) using previously published criteria for histiocytic disorders. Results From our institutions, we identified 12 MH patients (7 HS; 4 LCS; 1 IDCS) who received 14 instances of these treatments including TA (n=9) and/or ICI (n=5). The median age at diagnosis was 55 years (range, 33-70) and 50% were males. TAs included BRAF inhibitor (vemurafenib [1]), MEK inhibitors (binimetinib [1], cobimetinib [2], trametinib [2]) and others (dasatinib [1], pazopanib [1], pexidartinib [1]), while ICIs were exclusively pembrolizumab (5). The median number of prior treatments for those who received TAs and ICIs were 4 and 2, respectively. Responses were observed in 44.4% (1 CR, 3 PRs, 5 NR) and 40% (2 CRs, 3 NRs) of patients who received TA and ICI, respectively. Only 1 patient (20%) treated with MEK inhibitor responded [DOCK8-BRAF; PR 5+ mos]. Other responders received dasatinib [PDFGRA-V608I; PR 2 mos], pexidartinib [PTPN11-A72T; PR 5 mos], and vemurafenib [BRAF-V600E; CR 10+ mos]. Two patients (40%) who received pembrolizumab responded (both CRs 12+ [10% PD-L1] and 44+ mos [40% PD-L1]). We identified 29 MH patients in the literature (27 HS; 2 LCS) treated with TAs (22) and/or ICIs (10). TAs included BRAF inhibitor only (vemurafenib [3], dabrafenib [3]), MEK inhibitor only (trametinib [5]), BRAF + MEK inhibitors (2), and others (apatinib, anlotimib, bevacizumab, daratumumab, dasatinib, imatinib, pazopanib, sorafenib, or combinations [9]), while ICIs included pembrolizumab (4), nivolumab (4), tislelizumab (1), and sintilimab (1). Responses were observed in 77% (7 CRs, 10 PRs, 5 NRs) and 100% (2 CRs, 8 PRs) of patients who received targeted agents and ICI, respectively. Most patients carrying BRAF (7/8; V600E, G596R, D594G, TRIM::BRAF) or MAP2K1 (3/3; C121S, F53I) mutations responded to treatments, irrespective of the number of mutations present. The median durations of response for ICI and targeted agents were 10.5 months (range: 1-36+) and 12+ months (range: 3-44+), respectively. After combining the datasets from our institutions and literature review, we analyzed the association between the extent of PD-L1 expression and response to ICI. Those who responded to ICI had higher PDL-1 expression (median 75% [range, 10-75] vs 25% [range, 1-30]; P=0.0097). Conclusion TAs and ICIs can be considered in the management of MH. The responses to ICI therapy may be associated with the degree of PDL1 expression

Introduction: Post-transplant cyclophosphamide (PTCy) has emerged as the new standard of care for graft-versus-host disease (GVHD) prophylaxis following reduced-intensity conditioning (RIC) allogeneic stem cell transplant (alloSCT). The BMT CTN 1703 phase III trial demonstrated superior GVHD/relapse or progression-free survival (GRFS) in patients receiving PTCy, without affecting relapse risk. The primary objective of this study was to compare the risk of relapse in high-risk myeloid neoplasms post RIC/Nonmyeloablative (NMA) transplant using PTCy vs Tacrolimus/Methotrexate (TAC/MTX) as GVHD prophylaxis (PPX). Methods: We retrospectively reviewed patients with high-risk myeloid neoplasms following RIC/NMA alloSCT who received PTCy or TAC/MTX for GVHD PPX between Jan 2018 and June 2023. Criteria for high-risk myeloid neoplasms included acute myeloid leukemia (AML) with ≥1 of the following (complex or monosomal karyotype, TP53, WT1, FLT3 ITD+/NPM1-, active disease, MRD+, secondary AML), Myelodysplastic syndrome (MDS) with ≥1 of the following (complex karyotype, monosomal karyotype, TP53, RAS pathway mutation, marrow blast of 10% or more) or chronic myelomonocytic leukemia (CMML). Kaplan-Meier and log-rank tests were used to estimate overall survival (OS) and disease-free survival (DFS). Non-relapse mortality (NRM) and relapse incidence (RI) were calculated using competing risk analysis. Factors with P<0.10 in univariate analysis were included in multivariate analysis Results: Out of 552 alloSCTs, 108 (19.5%) patients met the inclusion criteria. Seventy-two (66.6%) received TAC/MTX, and 36 (33.3%) received PTCy. The median follow-up time was 26 months (range 3-68). The median age at transplant was 65 years (range 62-69) with age comparable between the two groups (p=0.6). Haploidentical transplant accounted for 33.3% of PTCy, while the remainder had matched related or matched unrelated transplant (MRD/MUD). Compared to TAC/MTX group, the PTCy group had more frequent NRAS mutation (19.4% vs 8.3%, p=0.094), but fewer patients with hematopoietic cell transplantation-specific comorbidity index (HCT-CI) ≥ 3(41.7% vs 61.1%, p=0.056). AML MRD+ was more prevalent in the PTCy group (22.2% vs 8.3%, p=0.098). The two groups were otherwise well-balanced in terms of disease distribution, disease risk index, TP53 mutation, and complex monosomal karyotype (CK and MK). The 1-yr OS, DFS, and GRFS for PTCy vs TAC/MTX were 78.7% vs 72.8% (p=0.9), 53.6% vs 67.9% (p=0.2), 38% vs 40%, (p=0.4), respectively. The 1-yr cumulative incidence of relapse (CIR) was higher in PTCy compared to TAC/MTX (37.6% vs 11.1%, p=0.01). Both haploidentical and MRD/MUD in the PTCy group had similar 1-yr RI (34.7 vs 38.3% p=0.7). Limiting the analysis to MRD/MUD, the PTCy group had a higher risk of relapse compared to TAC/MTX (34.7% vs 10.2%, P=0.007). Sub-analysis showed a higher 1-yr-CIR in the PTCy cohort for secondary AML (40% vs 0.0%, p=0.01), TP53 mutation (44.4% vs 18.1%, p=0.02), CK/MK (71.4% vs 22.2%, P=0.008), and chromosome 17 abnormality (60% vs 10%, P=0.001), compared to TAC/MTX. Despite of the increased CIR in the PTCy group, only patients with chromosome 17 abnormality receiving PTCy had an inferior DFS compared to TAC/MTX (median 5 vs. 14 months, p=0.008). In multivariate analysis for 1-yr CIR that included TP53, chromatin modifiers mutations, complex karyotype, high/very high DRI, and PTCy, both PTCy (HR 4.56, 95% CI 1.1-18.07, p=0.031) and high/very high DRI (HR 12.745, 95% CI 1.5-103.4, p=0.017) were independently predictive of post-transplant relapse. However, these factors were not significantly associated with 1-year OS. Conclusion:In patients with high-risk MN following RIC/NMA alloSCT, those receiving PTCy as GVHD PPX had a higher risk of relapse compared to TAC/MTX, irrespective of the donor source. Notably, an inferior DFS was observed only in patients with chromosome 17 abnormality who received PTCy. Despite of the increased relapse risk in the PTCy group, OS, DFS, and GRFS were comparable to TAC/MTX, likely due to higher risk of GVHD and NRM in the latter group.

Introduction Age correlates with survival in patients (pts) with DLBCL, which has a median age at diagnosis of 67 y. Recent therapeutic advances, including bispecifics and cell therapy, have promising efficacy, but safety and accessibility continue to be limited for older pts. The randomized, global, phase 3 ECHELON-3 study (NCT04404283) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) with brentuximab vedotin (BV) + lenalidomide (Len) + rituximab (R; BV+Len+R) vs placebo+Len+R in pts with R/R DLBCL after ≥ 2 prior systemic therapies who were ineligible for hematopoietic stem cell transplant and/or chimeric antigen receptor (CAR) T-cell therapy. Here, we present safety and efficacy in pts aged ≥65 y. Methods In ECHELON-3, pts were randomized 1:1 to receive BV (1.2 mg/kg) or placebo every 3 weeks (q3w), in combination with R (375 mg/m2) q3w and Len (20 mg) once daily. Granulocyte colony-stimulating factor was required in all cycles. Efficacy was assessed by investigators per Lugano 2014 classification. The primary endpoint was OS, with key secondary endpoints of PFS and ORR. Other secondary endpoints included detailed safety and tolerability. This subgroup analysis comprises pts aged ≥65 y. P values are descriptive. Results A total of 155 pts aged ≥65 y were enrolled from April 2021 to November 2023 and randomized to BV+Len+R (n=79) or placebo+Len+R (n=76). The median age was 75 y (range, 65-89 y); 54% of pts were male, 59% were White, and 19% were Asian. Twenty-three percent and 54% had Ann Arbor stage III and IV disease, respectively, and 64% had high-intermediate or high International Prognostic Index scores (3-5) at enrollment. The most common DLBCL subtype was DLBCL not otherwise specified (58%). Twenty-nine percent of pts had transformed DLBCL. Approximately half (49%) of pts had primary refractory disease, and 81% had disease refractory to their most recent prior line of therapy. Seventy percent of pts had <1% CD30 expression via IHC; 48% of cases had germinal center B-cell origin. Prior CAR-T was reported in 21.9% of pts. At a median follow-up of 16.8 mo (95% CI, 14.3-19.5 mo), median OS was 15.9 mo (95% CI, 11.7 mo-not estimable [NE]) with BV+Len+R vs 8.5 mo (95% CI, 5.5-11.5 mo) with placebo+Len+R (hazard ratio [HR], 0.540; 95% CI, 0.351-0.830; P=.0043). Median PFS was 5.7 mo (95% CI, 4.1-12.7 mo) with BV+Len+R vs 2.8 mo (95% CI, 1.9-4.1 mo) with placebo+Len+R (HR, 0.478; 95% CI, 0.318-0.718; P=.0003). ORR was 70.9% (95% CI, 59.6%-80.6%) with BV+Len+R vs 46.1% (95% CI, 34.5%-57.9%) with placebo+Len+R (P=.0020); complete response (CR) rate was 45.6% vs 19.7%, respectively. Median time to CR was 1.61 mo with both BV+Len+R and placebo+Len+R (range, 1.2-7.3 vs 0.7-4.6 mo, respectively). Median duration of CR was 18.9 mo (95% CI, 12.4 mo-NE) with BV+Len+R vs 5.4 mo (95% CI, 2.8 mo-NE) with placebo+Len+R (HR, 0.416; 95% CI, 0.139-1.250). In total, 154 pts were evaluable for safety analysis (75 pts in placebo+Len+R group). The median number of cycles was 5 (range, 1-34) vs 3 (range, 1-31) in the BV+Len+R and placebo+Len+R groups, respectively. The percentage of pts with any treatment-emergent adverse event (TEAE) was similar between groups (97% with BV+Len+R and 99% with placebo+Len+R); grade ≥3 TEAEs occurred in 89% of pts in the BV+Len+R group and 76% in the placebo+Len+R group. Serious TEAEs and TEAEs leading to death were reported more frequently in the BV+Len+R group (62% and 13%, respectively) than the placebo+Len+R group (47% and 8%, respectively). More pts discontinued study treatment due to TEAEs in the BV+Len+R group than the placebo+Len+R group (20% vs 8%). In total, 39% of pts on BV+Len+R had a peripheral neuropathy event vs 27% of pts on placebo+Len+R; however, the majority of cases were grade 1 (22% and 17%, respectively). Additional information on older pts will be presented. Conclusions BV+Len+R demonstrated a clinically meaningful improvement in all key efficacy outcomes in pts aged ≥65 y, which is consistent with the overall ECHELON-3 population (median age 74 y; 70.5% of pts aged ≥65 y in BV+Len+R group). Differences in some safety endpoints are likely attributable to longer duration of treatment in the BV+Len+R group. No clinically meaningful safety trends in pts aged ≥65 y were identified. These results suggest that BV+Len+R may be an effective treatment option in older pts with R/R DLBCL.

Introduction Patients (pts) with progressive disease after ≥2 prior lines of systemic therapy are unlikely to derive additional benefit from current salvage immunochemotherapies, and survival declines significantly with each subsequent treatment. Pts with refractory disease following second-line therapy have worse outcomes, with reported overall response rates (ORRs) of 1% to 14% and overall survival (OS) of 5 months (Blood. 2017;130[16]:1800-1808). While chimeric antigen receptor (CAR) T-cell therapy has become a preferred strategy in the second- and third-line settings, pts with R/R disease following CAR-T experience dismal survival, with progression-free survival (PFS) and OS as low as 3 and 5 months, respectively, and no agreed standard of care post CAR-T (Blood. 2022;140[24]:2527-2529). The randomized, global, phase 3 ECHELON-3 study (NCT04404283) was conducted in pts with R/R DLBCL after ≥2 prior therapies who were ineligible for hematopoietic stem cell transplant and/or CAR-T. Here, we present subgroup analyses in pts with 2 prior lines of therapy, refractory disease, or prior CAR-T. Methods In these subgroup analyses of ECHELON-3, eligible pts had 2 prior lines of systemic therapy, disease refractory to the last prior therapy, or prior exposure to CAR-T. Pts could qualify for ≥1 subgroup and were analyzed separately. Refractory disease was defined as stable or progressive disease as best overall response to last line of treatment or relapse ≤6 months from the end of treatment. Pts were randomized 1:1 to receive brentuximab vedotin (BV; 1.2 mg/kg) or placebo every 3 weeks (q3w), in combination with rituximab (R; 375 mg/m2) q3w and lenalidomide (Len; 20 mg) once daily. Efficacy was assessed by investigators per Lugano 2014 classification. The primary endpoint was OS, with key secondary endpoints of PFS and ORR. P values are descriptive. Results In total, 230 pts were enrolled in ECHELON-3 from April 2021 to November 2023, with a median follow-up of 16.4 months (range, 0.1-31.5 months). Overall, 94 pts with 2 prior lines of systemic therapy were enrolled and randomized to BV+Len+R (n=48) or placebo+Len+R (n=46). Median OS was 16.3 months (95% CI, 12.6 months-not estimable) with BV+Len+R vs 8.5 months (95% CI, 4.1-15.8 months) with placebo+Len+R (hazard ratio [HR], 0.557; 95% CI, 0.317-0.977; P=.0388). Median PFS was 7.1 months (95% CI, 3.6-12.6 months) with BV+Len+R vs 2.7 months (95% CI, 1.4-4.0 months) with placebo+Len+R (HR, 0.462; 95% CI, 0.279-0.764; P=.0020). ORR was 68.8% (95% CI, 53.7%-81.3%) with BV+Len+R vs 43.5% with placebo+Len+R (95% CI, 28.9%-58.9%; P=.0216); complete response (CR) rate was 52.1% vs 13.0%, respectively. Additional data for pts by lines of therapy received will be presented. In total, 194 pts with disease refractory to the most recent systemic therapy were enrolled and randomized to BV+Len+R (n=98) and placebo+Len+R (n=96). Median OS was 11.7 months (95% CI, 8.8-16.3 months) with BV+Len+R vs 5.5 months (95% CI, 3.7-8.5 months) with placebo+Len+R (HR, 0.566; 95% CI, 0.396-0.808; P=.0015). Median PFS was 4.1 months (95% CI, 2.8-5.4 months) with BV+Len+R vs 1.5 months (95% CI, 1.4-2.6 months) with placebo+Len+R (HR, 0.508; 95% CI, 0.363-0.712; P<.0001). ORR was 59.2% (95% CI, 48.8%-69.0%) with BV+Len+R vs 29.2% (95% CI, 20.3%-39.3%) with placebo+Len+R (P<.0001); CR rate was 34.7% vs 11.5%, respectively. Overall, 67 pts who received prior CAR-T were enrolled and randomized to BV+Len+R (n=32) and placebo+Len+R (n=35). Median OS was 15.6 months with BV+Len+R vs 4.4 months with placebo+Len+R (HR, 0.38; 95% CI, 0.2-0.75). Median PFS was 3.0 months with BV+Len+R vs 1.4 months with placebo+Len+R (HR, 0.41; 95% CI, 0.22-0.76). ORR was 65.6% (95% CI, 46.8%-81.4%) with BV+Len+R vs 25.7% (95% CI, 12.5%-43.3%) with placebo+Len+R (P=.0014); CR rate was 37.5% vs 11.4%, respectively. Conclusions BV+Len+R demonstrated a clinically meaningful improvement in all key efficacy outcomes, including CR and OS, in pts with 2 prior lines of therapy, disease refractory to prior treatment, or prior CAR-T. This treatment benefit was generally consistent with that observed in the overall ECHELON-3 study population. Therefore, BV+Len+R has the potential to address an unmet need for effective and tolerable therapy in heavily pretreated pts, as described above.

Introduction: Myeloma response to treatment can be biochemical, pathological, or radiological, with pathological assessments being invasive. Next-generation blood flow (PBF) for assessment of circulating tumor plasma cells (CTCs) has shown promising results as a prognostic in Multiple Myeloma (MM) patients. CTC detection via PBF has a potential to serve as non-invasive method for assessing pathological burden of disease and response to treatment. Comparing CTC responses to the International Myeloma Working Group (IMWG) criteria will further help to understand PBF's utility in predicting response to therapy. Patients and Methods: The study conducted is a retrospective observational study. We included patients with MM treated at Mayo Clinic from 01/01/2011 to 12/31/2019 with CTC records available at the time of best response (BR) to frontline therapy. The CTC values were expressed as the number of plasma cell events per 150,000 Peripheral Blood Mononuclear Cells (CD38, CD138, CD19, CD45, Kappa, Lambda). The CTC levels were compared across all response(IMWG Criteria) groups at BR, and at baseline. The CTC response was expressed as % CTC decrease at BR from baseline. Time-to-event analyses utilized the Kaplan Meier method and Cox-proportional hazards models, with comparisons made using the log-rank test. Results: We identified 621 patients with CTC data at the time of BR to frontline therapy. Of these, 148 (24%) had baseline CTC data from diagnosis. The median age at diagnosis was 62.3 (27.2-83.7). The median follow-up was 66.15 months; the distribution of patients by treatment class is as follows- Alkylator: 0.8%, PI(Proteasome Inhibitor)+Cyclophosphamide: 27.4%, IMid: 12.7%, PI+IMid(Immunomodulator): 55.9%, PI+IMid+antiCD38: 3.2%; 378 patients (78.8%) underwent an autologous transplant. BR to initial therapy was sCR/stringent Complete Response (10, 1.6%), CR (230, 36.9%), VGPR/Very Good Partial Response (224, 36.1%), PR (123, 19.8%), MR/Minimal Response (12, 1.9%), SD/Stable Disease (14, 2.3%), PD/Progressive Disease (8, 1.3%). In the study, 64 patients (10.31%) had detectable CTCs at their BR. The distribution of CTCs across the different response categories was as follows: none (0%) in sCR, 3 patients (1.3%) in CR, 18 patients (8%) in VGPR, 24 patients (19.5%) in PR, 8 patients (66.7%) in MR, 6 patients (42.9%) in SD, and 5 patients (62.5%) in PD. The median CTC counts and their interquartile ranges for these categories showed significant variability: CR had a median of 46 (IQR: 28.5, 923), VGPR had 39.5 (IQR: 15.5, 111.25), PR had 47 (IQR: 22.75, 82.5), MR had 55 (IQR: 28.5, 85), SD had 96.5 (IQR: 22.25, 218.75), and PD had 317 (IQR: 57, 415). This Analysis of Variance (ANOVA) for response-wise distribution of CTC was <0.01. Response was dichotomized as PR and above for sCR, CR, VGPR, PR and less than PR for MR, SD and PD. Median Overall Survival(OS) for PR and above was 127.8 months (vs less than PR 56.7 months, p=0.01). Median OS for CTC+ at BR was 56.7 months (vs 134.8 for CTC negative, p=0.01). On multivariate analysis, presence of CTC at best response (Hazards Ratio = 2.9, n=1.1-2.9), RISS staging at diagnosis (Hazards Ratio = 2.35, n=1.5-3.05), less than PR (Hazards Ratio =1.8, 1.1-2.9) were independent predictors of inferior OS. In patients with data for CTC available at both baseline and at BR to frontline therapy (n=148), 110 had CTC detectable at diagnosis. Among patients in various response categories, a complete disappearance of CTCs was observed in sCR (n=3, 75.0%), CR (n=36, 69.2%), VGPR (n=38, 64.4%), and PR (n=14, 60.9%). CTC responses greater than 90% were noted in VGPR (n=3, 5.1%), PR (n=2, 8.7%), and SD (n=2, 40.0%). No CTC response was reported in sCR (1, 25.0%), CR (16, 30.8%), VGPR (2, 3.4% and 13, 22.0%), PR (3, 13.0% and both 2, 8.7%), SD (1, 20.0% and both 2, 40.0%), MR (1, 50.0%), and PD (1, 33.3% and 1, 50.0%, respectively). The median OS for those with a CTC response was 112.4 months vs 28.2 months for no response. (p=0.01). Conclusion: The presence of CTC at best response is an independent prognostic marker for inferior OS. Depth of response to frontline therapy correspond to a high rate of clearance of CTCs. Presence of CTC at best response provides independent prognostic value beyond the depth of response. A complete clearance of CTC at best response is associated with improved OS. CTC levels have not been corrected for WBC counts and may not be applicable in all settings.