iMTSS: An Integrated Framework for Biology- and Patient-Driven Prognosis in Myelofibrosis Undergoing Transplantation

Allogeneic hematopoietic cell transplantation is the only curative treatment for myelofibrosis, but failure occurs by two mechanistically distinct routes: relapse of the neoplasm, which reflects its underlying genetics, and nonrelapse mortality, which reflects whether the patient and graft tolerate the procedure. Established prognostic systems either lack molecular granularity or were derived in the nontransplant setting, and all collapse these two routes into a single survival estimate. None can indicate why an individual patient is at risk or which class of intervention might reduce that risk. To determine why an individual patient is at risk and to develop and validate an integrated framework that quantifies biology- and patient-driven prognosis. We analyzed 1550 adults undergoing first allogeneic transplantation for primary or secondary myelofibrosis across international centers, the largest genomically annotated transplant cohort in this disease. The cohort was split into development (n = 930) and validation (n = 620) sets. Overall survival was modeled by Cox regression; relapse and nonrelapse mortality were modeled as competing events by Fine-Gray subdistribution-hazard regression at 2 yr. Discrimination was assessed by the concordance index with bootstrap confidence intervals. The molecular contribution was quantified by variance decomposition of, and robustness to the analytic choices was examined by resampling. A genetically defined disease-intrinsic axis, including TP53 allelic state, RAS pathway mutations, ASXL1 and driver genotype, blasts, and blood counts, predicted 2-yr relapse incidence (validation concordance 0.69, 95% CI 0.63 to 0.74), whereas a nonoverlapping host and structural axis, including portal vein thrombosis, donor type, patients' performance status, and age, predicted 2-yr nonrelapse mortality (0.63, 95% CI 0.59 to 0.68). The two scores shared only 3.4% of their variance, indicating that a patient's disease genetics carried almost no information about nonrelapse mortality. Variance decomposition showed that TP53 allelic state alone accounted for 30% of the relapse score. Recombined, the framework discriminated overall survival (concordance 0.640, 95% CI 0.616 to 0.662) better than every established prognostic system. For proof of concept, three risk groups separated in the validation cohort, with 5-yr survival of 72%, 58%, and 39% (P < .001), and the models were well calibrated. Relapse and nonrelapse mortality after transplantation for myelofibrosis are governed by distinct dimensions. Estimating both outcomes independently with genetic and clinical information, in addition to overall survival, establishes an individualized basis for transplant decision-making. The calculator is openly available (https://imtss-calculator.com).