Citations

766 Background: BASECAMP-1 (NCT04981119) is a pre-screening study to identify patients with tumor-associated human leukocyte antigen (HLA)-A*02 loss of heterozygosity (LOH) for interventional studies, such as EVEREST-2 (NCT06051695), a phase 1/2 study of logic-gated chimeric antigen receptor T-cell (CAR T) therapy for MSLN-expressing cancers. MSLN is a cell surface protein expressed in several cancer types, including mesothelioma (MESO), colorectal (CRC), non-small cell lung (NSCLC), ovarian (OVCA), and pancreatic (PANC) cancer, which can be associated with poor prognosis (1). Longitudinal clinical, genomic, and biomarker data were collected from patients enrolled in BASECAMP-1, providing a large dataset for translational discovery and propensity scoring. The aim of this analysis was to determine whether MSLN expression measured by RNAseq and IHC are correlated among patients with solid tumors. Methods: In BASECAMP-1, tumor tissue from patients with germline heterozygous HLA-A*02 is tested for HLA-A*02 LOH using an investigational next generation sequencing device codeveloped with Tempus Labs (Lozac'hmeur, et al. NPJ Precis Oncol. 2024) that detects somatic alterations, including HLA LOH, and generates RNAseq data (eg, MSLN expression). Gene-level transcripts per million read (TPM) values were determined and the log2 TPM +1 was displayed in a scatter plot (the mean and standard deviation [SD] are provided in the Table). Patients with HLA-A*02 LOH also submit tissue for IHC testing for exploratory biomarkers (eg, MSLN expression using anti-MSLN clone 5B2). Statistical significance was determined with ANOVA or t-tests. Results: As of June 1, 2024, 314 patients had been screened for BASECAMP-1 and had RNAseq results; 34 patients also had MSLN IHC results. MSLN expression by RNAseq was consistently higher in patients with PANC or OVCA vs CRC or NSCLC ( P <0.001). MSLN expression by RNAseq and IHC were correlated overall ( P <0.001), particularly among patients with PANC and OVCA. Among the 8 patients with OVCA or PANC who were IHC+ for MSLN, only 1 had an RNAseq value below 6 log2 TPM+1; this patient had mesonephric-like ovarian adenocarcinoma, which may account for the low value. The one MESO sample with both RNAseq and IHC available was IHC+ and had a high RNAseq value. Conclusions: This analysis demonstrated high correlation between RNAseq and IHC MSLN expression in tumor tissue. 1. Faust, et al. Cancers. 2022. Clinical trial information: NCT04981119 . MSLN expression by RNASeq by tumor type and IHC status. Tumor Overall (N=314) IHC data available (n=34) MSLN Positive MSLN Negative n Mean TPM a (SD) n Mean TPM a (SD) n Mean TPM a (SD) All 314 5.1 (2.3) 20 6.0 (2.1) 14 2.3 (1.7) adNSCLC 33 3.8 (2.4) 2 4.7 (1.7) 7 1.5 (1.3) sqNSCLC 4 3.1 (1.8) 0 0 MESO 4 4.5 (4.2) 1 5.7 0 CRC 148 4.4 (2.0) 8 5.1 (2.1) 7 3.1 (1.6) PANC 100 6.1 (1.8) 3 7.8 (0.6) 0 OVCA 25 7.2 (2.1) 5 6.6 (2.8) 0 a MSLN log2 transcripts per million+1. ad, adenocarcinoma; sq, squamous.

Importance Eligibility criteria for randomized clinical trials (RCTs) are designed to select clinically relevant patient populations. However, not all eligibility criteria are strongly justified, potentially excluding marginalized groups, and limiting the generalizability of trial findings. Objective To summarize and evaluate the justification of exclusion criteria in published RCTs in critical care medicine. Evidence Review A systematic sampling review of parallel-group RCTs published in the top 5 general internal medicine journals by impact factor ( The Lancet, New England Journal of Medicine, Journal of the American Medical Association, British Medical Journal, and Annals of Internal Medicine ) between January 1, 2018, and February 23, 2023, was conducted. RCTs enrolling adults in intensive care units (ICUs) and RCTs enrolling critically ill patients who required life-sustaining interventions typically initiated in the ICU were included. All study exclusion criteria were categorized as either poorly justified, potentially justified, or strongly justified, adapting previously established criteria, independently and in duplicate. Findings In total, 225 studies were identified, 75 of which were included. The median (IQR) number of exclusion criteria per trial was 19 (14-24), with 1455 total exclusion criteria. Common exclusion criteria were related to the risk of adverse reaction to interventions (302 criteria [20.8%]), followed by inability to obtain consent (120 criteria [8.2%]), and treatment limitation decisions (97 criteria [6.7%]). Most exclusion criteria were either strongly justified (1080 criteria [74.2%]) or potentially justified (297 criteria [20.4%]), whereas 5.4% (78 criteria) were poorly justified. Of the 78 poorly justified exclusion criteria, the most common were pregnancy (19 criteria [24.4%]), communication barriers (11 criteria [14.1%]), lactation (10 criteria [12.8%]), and lack of health insurance (10 criteria [12.8%]). Overall, 45 of 75 studies (60.0%) had at least 1 poorly justified exclusion criteria. Conclusions and Relevance Most exclusion criteria in critical care medicine RCTs were strongly justifiable. Across poorly justified criteria, the most common exclusions were pregnant or lactating persons, those with communication barriers, and individuals without health insurance. This highlights the need to carefully consider exclusion criteria when designing trials to minimize the inappropriate exclusion of participants and enhance generalizability.

Background: Chordoma is a rare bone cancer with limited treatment options. Clinical trials are crucial for developing effective therapies, but their success depends on including diverse patient populations. The objective of this study was to systematically evaluate the reporting of racial, ethnic, and socioeconomic diversity in United States clinical trials exploring treatment for chordoma. Methods: A literature search was conducted through PubMed/Medline, Cochrane, Epistemonikos, and ClinicalTrials.gov databases for published US chordoma trials up until 19 August 2024. The data collected included trial characteristics and racial and ethnic data, as well as socioeconomic indicators when available. Methodological Index for Non-Randomized Studies (MINORS) and Revised Cochrane Risk-of-Bias Tool for Randomized Trials (RoB2) analyses were adopted to assess the methodological quality. The N-1 Chi-squared (χ2) test was implemented to compare the reported racial and ethnic data with the most recent US Census Bureau data. Results: Five trials involving 111 patients (median age: 63 years; 34% female) were included. Four studies (80%) were single-arm non-randomized studies with one study (25%) having a high methodological quality and three (75%) having a moderate quality based on the MINORS analysis. Most patients (91%, n = 82) were White/Caucasian, representing a proportion which was significantly higher than the reported 75% in the US population (p = 0.0005). Black/African American patients (2%, n = 2) were significantly underrepresented compared to the 14% in the US population (p = 0.0015). Regarding ethnicity, Hispanic/Latino patients (7%, n = 6) were significantly underrepresented compared to the 20% in the US population (p = 0.0021). No measures of socioeconomic status were reported. Conclusions: This systematic review highlighted the need for improved racial and ethnic diversity in chordoma trials and the better reporting of socioeconomic data. The underrepresentation of minority groups may obscure potential disparities in disease incidence, treatment access, and clinical outcomes.

ABSTRACT Patients with newly diagnosed acute myeloid leukemia (ND‐AML) derive variable survival benefit from venetoclax + hypomethylating agent (Ven‐HMA) therapy. The primary objective in the current study was to develop genetic risk models that are predictive of survival and are applicable at the time of diagnosis and after establishing treatment response. Among 400 ND‐AML patients treated with Ven‐HMA at the Mayo Clinic, 247 (62%) achieved complete remission with (CR) or without (CRi) count recovery. Multivariable analysis–derived hazard ratios (HR), including 1.8 for European LeukemiaNet (ELN) adverse karyotype, 4.7 for KMT2Ar , 1.7 for TP53 MUT , 2.6 for KRAS MUT , and 2.1 for IDH2 WT were applied to develop an HR‐weighted risk model: low, intermediate, and high; respective median survival censored for allogeneic stem cell transplant (ASCT) (3‐year survival) were “not reached” (67%), 19.1 (33%), and 7.1 months (0%). In patients achieving CR/CRi, adverse karyotype, KMT2Ar , KRAS MUT , IDH2 WT predicted inferior survival, allowing for a complementary response‐stratified risk model. The model was externally validated and was shown to be superior to the ELN 2024 risk model (AIC 179 vs. 195 and AUC 0.77 vs. 0.69). Survival was inferior with failure to achieve CR/CRi or not receiving ASCT; 3‐year survival for high‐risk with or without ASCT was 42% versus 0% ( p < 0.01); intermediate 72% versus 43% ( p = 0.06); and low‐risk 88% versus 78% ( p = 0.53). The Mayo genetic risk models offer pre‐treatment and response‐based prognostic tools for ND‐AML treated with Ven‐HMA. The current study underscores the prognostically indispensable role of achieving CR/CRi and ASCT.

Background: Hypomethylating agents (HMA) with venetoclax (VEN) have shown encouraging clinical efficacy in single arm clinical trials for patients with myelodysplastic syndrome (MDS) (Garcia JS et al. ASH 2023, Zeidan AM et al. Am J Hematol. 2023). Many centers have started utilizing HMA-VEN in the clinical management of MDS due to unmet need, pending results of the ongoing phase 3 randomized clinical trial (VERONA) using this combination. However, real world studies with large sample size investigating the use of these agents in MDS, practice patterns and clinical outcomes are lacking. Methods: This is a multicenter retrospective study of 13 US academic medical centers. We included contemporary cohorts of adults (age≥18 years) with MDS who were treated with upfront combination of HMA-VEN, upfront HMA monotherapy, or VEN added after inadequate response or progression on HMA (post-HMA failure VEN). Outcomes analyzed includes clinical response, adverse events (AE) of interest, dose administration and survival. Descriptive statistics were used for baseline characteristics. Overall survival and event free survival (EFS: progression, leukemic transformation, death as events) analysis was conducted using Kaplan-Meier method. Determinants of outcomes were analyzed using multivariable regression models. All analyses were conducted at a significance level of p&lt;0.05. Results: Among 454 patients included, 258 patients received VEN in combination with HMA [upfront HMA-VEN (n=175), post-HMA failure VEN (n=83)] and 196 patients received HMA monotherapy. Median age was 69 (59-77) years and majority of patients had MDS with excess blasts (75%), high risk (31.9%) or very-high (41.8%) risk disease by IPSS-R, 23.7% had therapy related disease, 33% had deletion17p or TP53 mutation and 40.9% underwent allogeneic stem cell transplantation. VEN was predominantly started in outpatient setting (78.6%) with tumor lysis syndrome (TLS) prophylaxis and VEN doses ranged from 70-400mg, adjusted for concomitant antifungal drugs. Incidence of TLS was minimal (No TLS- 92.9%, lab-only TLS 6.2%, 1 pt with clinical TLS). Neutropenic fever was the main AE noted [upfront VEN-HMA (34.2%), HMA monotherapy (22.5%), post-HMA VEN (44.5%)]. In the upfront setting, response rate was significantly higher with HMA-VEN than HMA monotherapy (CR: 33% vs 12%; marrow CR: 40% vs 27%, p&lt;.001). VEN given in the post HMA failure setting also resulted in encouraging response rates (CR 10%, marrow CR 32%). After adjusting for covariates in multivariable analysis, patients treated with HMA-VEN in the upfront setting had significantly improved event free survival as compared to HMA monotherapy (HR 0.59, HR 0.44-0.78, p&lt;0.01), but overall survival did not reach statistical significance (overall survival HR 0.77, 95%CI 0.57-1.04, p=0.08). Conclusions: In this large multicenter retrospective analysis from US academic medical centers, we found that VEN in combination with HMA resulted in encouraging clinical outcomes and was effectively administered in the outpatient setting with minimal TLS. Infection risk management and supportive measures would be important to improve the ability to use this treatment widely, pending results of the ongoing phase 3 randomized clinical trial. Updated results with additional variables will be available at the main meeting.

Background: Therapy-related myeloid neoplasms (t-MN) occur after exposure to DNA-damaging agentsincluding cytotoxic chemo and radiation therapy and are associated with dismal outcomes. TP53 and PPM1D (protein phosphatase Mn2+/Mg2+-dependent 1D) mutations (MT) disrupt the DNA damage response and repair (DDR) pathway, are often co-mutated (25-35%), and although enriched in t-MN (20%), can also be seen in age-related clonal hematopoiesis (CH) (5-10%). While progressive genomic instability with biallelic inactivation has been described as a mechanism of MN progression with TP53 MT, similar mechanisms remain to be elucidated for PPM1D MT. We conducted this study to assess the clinical phenotype and outcomes of TP53 and PPM1D co-mutated (PPM1DTP53m) versus PPM1D MT and wild type TP53 (PPM1DTP53wt) CH and MN. Methods: After approval from the Mayo Clinic IRB, the CH and MN databases were queried and 119 pts with PPM1D MT (CH= 26, clonal cytopenia of unknown significance [CCUS]= 64, myelodysplastic syndrome [MDS]=16, myeloproliferative neoplasm [MPN]=8, acute myeloid leukemia [AML]= 5) were identified. We analyzed baseline characteristics, karyotypic changes, somatic mutations, and survival outcomes between the PPM1DTP53m (n= 22) and PPM1DTP53wt (n= 97) groups (gp). Results: Baseline characteristics The median age in years (yrs) was 68.5 (range [R], 43-89) and 71 (R,30-92) in the PPM1DTP53m and PPM1DTP53wt gp (p= 0.65). 22% vs 18% (p=0.78), 58% vs 32% (p=0.03), 9% vs 32% (p=0.01), 7% vs 4.5% (p=&gt;0.99) and 3% vs 14% (p=0.07) pts met criteria for CH, CCUS, MDS, MPN and AML in the PPM1DTP53wt and PPM1DTP53m gp, respectively. Similarly, 19% vs 18% (p=&gt;0.99), 47% vs 32% (p=0.23), 7% vs 36% (p=0.001), 2% vs 0% (p=&gt;0.99) and 2% vs 14% (p=0.04) of pts met criteria for t-CH, t-CCUS, t-MDS, t-MPN and t-AML in the PPM1DTP53wt and PPM1DTP53m gp, respectively. All PPM1D variants were truncating, located in exon 6 of the gene, with median variant allele frequency (VAF) (8% [R,1-64] vs 5.5% [R,2-24], p= 0.10) and number of PPM1D MT (1 [R,1-5] vs 1 [R, 1-3], p=&gt;0.99) being similar between the two gp. While proportion of pts with t-MN were similar between the two gps (77% vs 86%, p= 0.40), cytogenetic (CG) abnormalities (67% vs 31%, p= 0.006), including monosomies (28% vs 2%, p= &lt;0.001) and complex CG (53% vs 4%, p= &lt;0.001) were more frequent in PPM1DTP53m gp compared to PPM1DTP53wt gp, respectively. The median TP53 MT VAF was 14% (R, 1-14); 50% had multi-hit TP53 MT. Somatic mutations in PPM1D MT myeloid neoplasm with and without TP53 MT Somatic co-mutations excluding TP53 were seen in 71% of pts; 73.5% in PPM1DTP53wt and 59% in PPM1DTP53m gp (p= 0.20). Apart from CBL (0% vs 9%,p=0.03), MT involving DNMT3A (20% vs 14%, p= 0.56), TET2 (15% vs. 14%, p= &gt;0.99), IDH1 (6% vs 19%, p= 0.07), splicing factors (8% vs 14%, p=0.08), ASXL1 (11% vs 4.5%, p=0.46), and JAK2 (9% vs 0%,p=0.20) were comparable between PPM1DTP53wt and PPM1DTP53m gps, respectively. The proportion of pts with ≥ 2 somatic co-mutations excluding TP53 MT were numerically higher in PPM1DTP53wt gp (43%) compared to PPM1DTP53m gp (23%) (p= 0.09). In the PPM1DTP53wt gp, other somatic driver mutations included RUNX1 (n= 7 [7%]; CH [n=1], CCUS [n=2], MDS [n=3], MPN [n=1]), NRAS (n=1 [1%]; CCUS), BCOR (n=1 [1%]; CCUS), and PTPN11 (n=1 [1%]; CCUS). Leukemic transformation and survival With a median follow up of 6.43 months (mo) (R, 0.23-36.4), median overall survival (mOS) in mo among high-risk MDS/AML (16.4 vs 15.0, p= 0.66) and CHIP/CCUS pts (35.79 vs 26.28, p= 0.93) was similar between PPM1DTP53wt and PPM1DTP53m gps, respectively. CHIP/CCUS pts harboring multiple vs single PPM1D MT had an inferior mOS (23.9 vs 36.7 mo, p= 0.05). Three (2.5%) MDS pts underwent AML transformation; 1 (1%) and 2 (10%) in PPM1DTP53wt and PPM1DTP53m gp, respectively (p= 0.07). Conclusions In our study, 18% of pts had concurrent TP53 and PPM1D MT (82% t-MN), with the PPM1DTP53wt genotype being more frequent in CCUS, while the PPM1DTP53m genotype was more frequent in MN. The PPM1DTP53m genotype had a higher frequency of CG abnormalities, including complex CG. Survival outcome was inferior and comparable in PPM1D MT MN with or without TP53 MT. While 73.5 % of the PPM1DTP53wt gp had somatic driver MT and 31% had karyotypic abnormalities, 22% had no additional MT or CG changes (all CH/CCUS), underscoring the need to understand how PPM1D MT contribute to hematopoietic dysfunction and MN.

Background Venetoclax + hypomethylating agent (Ven-HMA) therapy results in favorable response rates (CR/CRi 66%) and overall survival (OS; median 14.7 months) in unfit patients with newly-diagnosed acute myeloid leukemia (ND-AML; N Engl J Med 2020;383). However, there is substantial heterogeneity in individual patient outcomes based on response to treatment. The objective of the current study was to develop a genetic risk model to predict survival outcome in treatment responders and non-responders, analyzed separately, and also account for allogeneic stem cell transplant (ASCT). Methods Treatment-naïve AML patients receiving Ven-HMA, outside of a clinical trial, at the Mayo Clinic, USA (MN, AZ, FL) were retrospectively recruited. Molecular studies (48-gene panel) were performed by next-generation sequencing. Response was assessed according to the 2022 European LeukemiaNet (ELN) criteria (Blood 2022;140). Standard statistical analyses were performed using JMP Pro (Version 17.0.0). Results 400 ND-AML patients (median age 73 years, 64% male, 60% de novo) received Ven-HMA. ELN cytogenetic risk included favorable 2%, intermediate 60%, or adverse 38%. Mutations involved TP53 in 26%, TET2 19%, RUNX1 19%, SRSF2 18%, ASXL1 18%, DNMT3A 15%, K/NRAS 13%, NPM1 12%, IDH2 12%, FLT3-ITD 10%, IDH1 7% and DDX41 in 4% of informative cases. 153 (38%) patients achieved CR, 94 (24%) CR with incomplete count recovery (CRi), resulting in CR/CRi in 247 (62%) patients. CR/CRi rates were higher with NPM1 (86% vs 59%), IDH2 (77% vs 60%), and DDX41 mutations (93% vs 61%) and lower with TP53 (45% vs 67%), FLT3-ITD (41% vs 64%), RUNX1 (49% vs 65%) mutations and adverse karyotype (48% vs 71%), with all retaining significance in multivariable analysis. CR/CRi rate was highest (87%) in 75 patients with one or more favorable mutations (NPM1, IDH2, DDX41) and no unfavorable mutation (TP53, FLT3-ITD, RUNX1). CR/CRi rate was lowest in 171 patients with at least one unfavorable mutation and no favorable mutation (44%; p&lt;0.01). After a median follow up of 10.5 months (0.5-66), 105 relapses (43% of patients in CR/CRi), 248 (62%) deaths and 65 (16%) ASCT were documented. Univariate analysis for transplant-censored OS disclosed superior survival in patients achieving CR/CRi (median 21 vs 3.6 months; HR 5.4, 95% CI 4.1-7.1). Among patients achieving CR/CRi, IDH2 mutation was associated with superior (median not reached vs 20.5 months) and male gender (median 17.6 vs 29.2 months), TP53 mutations (median 11.9 vs 24.3 months) and adverse karyotype (median 12.6 vs 29.4 months) with inferior survival; multivariable analysis resulted in HRs (95% CI) of 2.1 (1.3-3.4) for male gender, 2.1 (1.2-3.8) for adverse karyotype, and 2.5 (1.1-5.7) for absence of IDH2 mutations. Male gender did not show an association with karyotype, or TP53 mutations (p&gt;0.1). Accordingly, an HR-weighted genetic risk model was generated with assignment of one point each to male gender, adverse karyotype, and absence of IDH2 mutation: high risk = 3 risk factors (n=38; median 9.6 months; 3-year survival 0%); intermediate risk = 2 risk factors (n=129; median 22 months; 3-year survival 38%); and low-risk = ≤1 risk factor (n=78; median not reached; 3-year survival 69%; p&lt;0.01). In patients bridged to ASCT (n=60), post-transplant survival was inferior in the presence of ≥ 2 risk factors (n=42; median 46 months) vs. ≤1 risk factor (n=18; median not reached; p=0.1). In patients not achieving CR/CRi, risk factors for OS included male gender (median 3.4 vs 6.1 months), adverse karyotype (median 3.3 vs 4.5 months) and TP53 mutation (median 3.1 vs 4.5 months) while those with IDH2 mutations lived longer (median 8.4 vs 3.4 months). In multivariable analysis, HRs (95% CI) were 1.9 (1.3-2.9) for male gender, 2.0 (1.4-2.9) for adverse karyotype, and 2.1 (1.1-4.3) for absence of IDH2 mutations. OS was shortest for non-responders harboring 3 risk factors (n=45; median 3 months; 1-year survival 0%) and longer for those harboring two (n=80; median 6 months, 1-year OS 15%) or ≤ 1 risk factor (n=25; median 14 months; 1-year OS 56%; p&lt;0.01). Conclusion The current study describes a molecular profile for predicting response to Ven-HMA in ND-AML and also introduces a novel approach to survival prediction that considers treatment response as the starting point. In both responders and non-responders, male gender and adverse karyotype were identified as unfavorable and IDH2 mutation favorable risk factor for OS.

Background: Patients with acute lymphoblastic leukemia (ALL) receiving L-asparaginase (ASP) based induction therapy have a high risk of venous thromboembolism (VTE). Studies investigating universal thromboprophylaxis strategies have yielded sub-optimal results. Risk prediction models are needed to identify high-risk patients who would be candidates for intensification of thromboprophylaxis, and lower risk patients who are unlikely to benefit. Aims: Derive and externally validate a risk prediction model for VTE in patients with ALL receiving ASP therapy. Methods: We conducted a multicenter, international, cohort study of patients with newly-diagnosed ALL receiving ASP-based induction therapy (≥18yrs). The derivation and external validation cohorts included 306 and 97 patients without VTE prior to ASP therapy, respectively. Patients on therapeutic anticoagulation at index were excluded. Patients were followed from date of first ASP dose for 100 days post ALL diagnosis or until VTE, therapeutic anticoagulation or death. Candidate predictors were documented at ALL diagnosis and included demographics, disease and treatment characteristics, VTE history, comorbidities, thromboprophylaxis, complete blood count, fibrinogen and d-dimer. D-dimer was only analyzed within the 7 derivation cohort centers who routinely tested this at ALL diagnosis with &lt;20% missing values. Primary outcome was VTE at any site (centrally confirmed). Secondary outcomes included major bleeding by ISTH criteria. Cause-specific Cox proportional hazard regression was performed to identify VTE risk factors in the derivation cohort while treating death as a competing event. Variables with p-value &lt;0.1 on univariable analysis were included in a multivariable model and subsequently used in the risk model if p-value &lt;0.05. Lastly, the derived VTE risk prediction model was tested in the external validation cohort for association with time to VTE using cause-specific Cox proportional hazard model. All analyses were stratified by center and use of low molecular weight heparin prophylaxis (at any dose on the date of first ASP dose). Results: The cumulative incidence of VTE in the derivation cohort was 17% at 30 days (95% confidence interval [CI] 13% - 21%) and 22% at 90 days (95% CI 17% - 27%). The multivariable model included hyperlipidemia (hazard ratio [HR] 1.35; 95% CI 0.56 - 3.27), body mass index ≥ 25 kg/m² (HR 1.49; 95% CI 0.75 - 2.95), platelet count ≥ 25 x 10⁹/L (HR 1.42; 95% CI 0.67 - 3.00), increasing hemoglobin per 1 g/dL (HR 1.17; 95% CI 1.03 - 1.32) and d-dimer ≥ 1 µg FEU/mL (HR 2.68; 95% CI 1.08 - 6.66). Hemoglobin as a continuous variable and d-dimer ≥ 1 µg FEU/mL were included in the final model and used to create a risk score which was weighted by estimated log-HR sum of these risk factors. The lowest risk quartile (risk score below 2.1) successfully differentiated between a lower 30-day cumulative VTE incidence (4%, 95% CI 0.72% - 12%) compared with the other quartiles (20%, 95% CI 14% - 27%; HR 4.40, 95% CI 1.54 - 12.5) which were defined as high risk (score ≥2.1). The risk score's negative predictive value (NPV) for VTE at 30 days was 96% and positive predictive value (PPV) was 20%. The validation cohort (n=97 from 3 external cohorts with routine d-dimer measurement) included 16 (16.5%) patients in the low-risk group and 81 (83.5%) in the high-risk group, with a 30-day VTE incidence of 6.3% (95% CI 0% - 17%) and 21% (95% CI 12% - 30%), respectively (HR 6.22; 95% CI 0.85 - 45.8; p = 0.073)). The NPV (93.7%) and PPV (21%) were comparable to the derivation cohort. The 30-day incidence of major bleeding was 0% (95% CI NR - NR) in low-risk patients (HR 1.36; 95% CI 0.27 - 6.77) and 2.0% (95% CI 0.55% - 5.4%) in the high-risk group. Conclusion: Patients with ALL receiving ASP induction therapy have a 17% VTE risk at 30 days. We derived and externally validated a VTE risk prediction model based upon d-dimer and hemoglobin. This model successfully identifies at least 16.5% of patients with ALL who have a low VTE risk after ASP treatment. Using this model, novel prevention strategies which may be associated with cost and risk could now be tailored to patients with higher risk. Prospective studies are needed to validate the model's performance and role in VTE risk management.