Derivation and External Validation of a Venous Thromboembolism Risk Prediction Model in Patients with Acute Lymphoblastic Leukemia Receiving Asparaginase Therapy

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 <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 <0.1 on univariable analysis were included in a multivariable model and subsequently used in the risk model if p-value <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.

Gangaraju:Alexion: Consultancy; Bayer: Consultancy; Takeda: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding. Wang:Servier: Honoraria; Leo Pharma: Research Funding; Valeo: Honoraria. Carney:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Liedtke:Biomea: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Nexcella: Membership on an entity's Board of Directors or advisory committees; Seagen: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Caelum/Alexion: Research Funding; Gilead: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Allogene: Research Funding. Badar:Morphosys: Other: Advisory Board; Takeda: Other: advisory board ; pfizer: Other: Advisory board. Dinner:Rigel: Consultancy; Pfizer: Consultancy; Kite: Consultancy. Levavi:Sobi: Consultancy, Other: Advisory Board. Bar-Natan:Incyte: Research Funding; BMS: Research Funding; Amgen: Research Funding. Carrier:Sanofi: Consultancy; Regeneron: Consultancy; Anthos: Consultancy; Servier: Consultancy; Bayer: Consultancy; BMS: Consultancy; Pfizer: Consultancy, Other: Grants paid to institution; Leo Pharma: Consultancy, Other: Grants paid to institution. Fulcher:Pfizer: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Gilead: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria. Luger:AbbVie: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Astellas: Consultancy. Guru Murthy:BMS: Other: Advisory Board; Stemline: Speakers Bureau; Zentalis: Research Funding; Syndax: Other: Advisory Board; Rigel: Speakers Bureau; Pfizer: Other: Advisory board; Merck: Research Funding; Amgen: Consultancy, Speakers Bureau; LOXO/Lilly: Research Funding; BeiGene: Other: Advisory board, Research Funding; Autolus: Other: Advisory board; Schrodinger: Research Funding; Gilead Sciences/Kite: Other: Advisory board, Research Funding. Luskin:Pfizer: Honoraria; Jazz: Honoraria; AbbVie: Research Funding; Novartis: Honoraria, Research Funding; KITE: Honoraria. Wolach:Abbvie, Janssen,: Consultancy, Honoraria, Research Funding; Teva: Honoraria; Pfizer: Honoraria; Medison: Honoraria; Astellas: Honoraria; Amgen: Honoraria. Shomali:Blueprint Medicines: Research Funding; Incyte Inc: Consultancy, Research Funding. Zwicker:UpToDate: Patents & Royalties; Quercegen: Research Funding; Med Learning Group: Consultancy; Calyx: Consultancy; BMS: Consultancy; Regeneron: Consultancy; Parexel: Consultancy; Incyte Corporation: Research Funding. Stock:Adaptive: Consultancy, Honoraria; Kura: Research Funding; Kura, Servier, Newave, Adaptive, Jazz, Asofarma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Leader:Leo Pharma: Honoraria.