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Multicenter Study
. 2026 Feb 10;10(3):593-603.
doi: 10.1182/bloodadvances.2025017862.

Derivation and external validation of a venous thromboembolism risk prediction model in asparaginase-treated ALL

Daniela R Anderson  1 , Radhika Gangaraju  2 , Wafik George Sedhom  3 , Eva N Hamulyák  4   5 , Tzu-Fei Wang  6 , Kristin O'Dwyer  7 , Brian J Carney  8 , Chandrasekar Muthiah  9 , Michaela Liedtke  10 , Talha Badar  11 , Shai Shimony  12 , Renana Robinson  13   14 , Kristen Sanfilippo  15 , Andriy Derkach  16 , Shira Dinner  3 , Bart J Biemond  4 , David Nemirovsky  16 , Leah A Goldberg  17 , Anjani D Kapadia  18 , Hannah Levavi  19 , Michal Bar-Natan  20 , Grace Van Hyfte  21 , Karan Bansal  2 , Marc Carrier  6 , Jill Fulcher  6 , Anke M Gerrits  22 , Mark R Litzow  23 , Selina Luger  24 , Guru Subramanian Guru Murthy  9 , Marlise Luskin  12 , Ofir Wolach  13   14 , William Shomali  25 , Jeffrey I Zwicker  26   27 , Wendy Stock  28 , Avi Leader  26   27
Affiliations
Multicenter Study

Derivation and external validation of a venous thromboembolism risk prediction model in asparaginase-treated ALL

Daniela R Anderson et al. Blood Adv. .

Abstract

The incidence of venous thromboembolism (VTE) in patients with acute lymphoblastic leukemia (ALL) receiving asparaginase-based induction is high despite primary thromboprophylaxis. Our aim was to derive and externally validate a VTE risk prediction model in patients with ALL receiving asparaginase-based induction. We conducted a multicenter retrospective cohort study of patients (aged ≥18 years) with newly diagnosed ALL receiving asparaginase-based induction. The derivation and external validation cohorts included 306 and 94 patients, respectively. Primary outcome was VTE at any site. A cause-specific Cox proportional hazards model stratified by thromboprophylaxis and center was performed to identify VTE risk factors in the derivation cohort. A risk prediction model for VTE at 30 days was derived using variables with P value < .05 in the multivariable model and was tested in the validation cohort. VTE risk factors on multivariable analysis in the derivation cohort included D-dimer ≥1 μg fibrinogen equivalent unit per mL (hazard ratio [HR], 2.64; 95% confidence interval [CI], 1.07-6.5) and hemoglobin (HR for each 1 g/dL increment, 1.19; 95% CI, 1.06-1.34) at ALL diagnosis. A VTE risk score based on these variables distinguished between a 4% (95% CI, 0.72-12) and 20% (95% CI, 14-27) 30-day cumulative incidence of VTE in the derivation cohort, with similar findings in the validation cohort (area under the curve, 0.56). The negative predictive value for VTE at 30 days was 96% and 93% in the derivation and validation cohorts, respectively, and the positive predictive value was 20% in both. We derived and validated a model using D-dimer and hemoglobin, which stratifies VTE risk in patients with ALL receiving asparaginase-based induction.

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Conflict of interest statement

Conflict-of-interest disclosure: R.G. reports consultancy fees and research funding from Sanofi. T.-F.W. reports honoraria from Servier and Valeo; and research funding from Leo Pharma. B.J.C. reports honoraria from, and serves on board of directors or advisory committees for, Sanofi. M. Liedtke reports research funding from Biomea Fusion, Seagen, Bristol Myers Squibb (BMS), Caelum/Alexion, Gilead Science, Janssen, AbbVie, and Allogene; and serves on board of directors or advisory committees for Kite, Nexcella, BMS, Janssen, and AbbVie. T.B. serves on an advisory board for Takeda, Amgen, and Syndax; and reports research funding from Takeda and MorphoSys. S.D. reports consultancy fees from Rigel, Pfizer, and Kite. H.L. reports consultancy fess from Sobi; and serves on advisory board for Sobi and Takeda. M.B.-N. reports research funding from Incyte, BMS, and Amgen. M.C. reports consultancy fees for Sanofi, Regeneron, Anthos, Servier, Bayer, BMS, Pfizer, and Leo Pharma; and grants paid to the institution from Pfizer and Leo Pharma. J.F. reports honaraia from Pfizer, Amgen, AbbVie, Gilead Science, Jazz Pharmaceuticals, and Novartis. S.L. serves on board of directors or advisory committees for AbbVie, Daiichi Sankyo, Novartis, Amgen, and Marker Therapeutics; reports research funding from Takeda; and consultancy fees from Novartis, Amgen, and Astella. B.J.B. reports research funding from Novartis, Pfizer, and BMS; and honoraria from Pfizer, BMS, Celgene, Novo Nordisk, and Sanofi. M.R.L. reports research funding from AbbVie, Actinium, Amgen, Astellas, Pluristem, and Sanofi; has served on speakers bureaus for Amgen and BeiGene, and DSMB:BioSight. G.S.G.M. has served on advisory boards for BMS, Syndax, Pfizer, BeiGene, Autolus, and Gilead Sciences/Kite; on speakers bureaus for Stemline, Rigel, and Amgen; reports research funding from Zentalis Pharmaceuticals, Merck, Loxo/Lilly, BeiGene, Schrödinger, Gilead Sciences/Kite; and consultancy fees from Amgen. M. Luskin reports honoraria from Pfizer, Jazz Pharmaceuticals, Novartis, and Kite; and research funding from AbbVie and Novartis. O.W. reports consultancy fees from AbbVie, Janssen, and Pfizer; honoraria from AbbVie, Janssen, Teva, Medison, Astellas, and Amgen; research funding from AbbVie and Janssen; and serves on the advisory board for Pfizer. W. Shomali reports research funding from Blueprint Medicines, Incyte Inc, Ajax Therapeutics, and Merck; and consultancy fees from Incyte Inc. J.I.Z. reports patents and royalties from UpToDate; research funding from Quercegen Pharmaceuticals and Incyte Corporation; and consultancy fees from Med Learning Group, Calyx, BMS, Regeneron, and Parexel. W. Stock reports consultancy fees and honoraria from Adaptive, Kura, Servier, Newave, Adaptive, Jazz Pharmaceuticals, and Asofarma; research funding from Kura; and serves on the board of directors or advisory committees for Kura, Servier, Newave, Adaptive, Jazz Pharmaceuticals, and Asofarma. A.L. reports honoraria from Leo Pharma; royalties from UpToDate; and consultancy fees from Pfizer. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
The 90-day cumulative incidence of VTE. This figure shows the cumulative incidence of VTE in the derivation (A) and validation (B) cohorts with death as a competing event. The shading around the curve represents the 95% CI. The index day was the first day of asparaginase treatment. ASP, asparaginase.
Figure 2.
Figure 2.
The 90-day cumulative incidence of VTE stratified by LMWH thromboprophylaxis†. This figure shows the cumulative incidence of VTE among patients receiving LMWH thromboprophylaxis† (red curve) and not receiving LMWH thromboprophylaxis† (blue curve) in the derivation cohort, with death as a competing event. The shading around the curve represents the 95% CI. The index day was the first day of asparaginase treatment. †LMWH thromboprophylaxis was defined as the use of LMWH prophylaxis at any dose on the date of the first asparaginase dose. ASP, asparaginase.
Figure 3.
Figure 3.
Cumulative incidence of VTE stratified by predicted VTE risk†. This figure shows the cumulative incidence of VTE among patients with low (blue curve) and high predicted VTE risk† (red curve) in the derivation (A) and validation (B) cohorts, with death as a competing event. The index day was the first day of asparaginase treatment. †Predicted VTE risk was determined using the ENTHRALL VTE risk prediction model, which stratified patients by low (score of <2.1) or high (score of ≥2.1) VTE risk. The ENTHRALL VTE risk prediction model uses D-dimer (μg FEU per milliliter) and hemoglobin (gram per deciliter) at ALL diagnosis to generate risk scores. The risk score for patient i was defined as Ri= 0.175 × Hbi+ 0.971 × I(D-dimeri≥ 1). ASP, asparaginase.
See this image and copyright information in PMC

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