Development and validation of a disease risk stratification system for patients with haematological malignancies: a retrospective cohort study of the European Society for Blood and Marrow Transplantation registry

Background: Diagnosis and remission status at the time of allogeneic haematopoietic stem-cell transplantation (HSCT) are the principal determinants of overall survival following transplantation. We sought to develop a contemporary disease-risk stratification system (DRSS) that accounts for heterogeneous transplantation indications. Methods: In this retrospective cohort study we included 55 histology and remission status combinations across haematological malignancies, including acute leukaemia, lymphoma, multiple myeloma, and myeloproliferative and myelodysplastic disorders. A total of 47 265 adult patients (aged ≥18 years) who received an allogeneic HSCT between Jan 1, 2012, and Dec 31, 2016, and were reported to the European Society for Blood and Marrow Transplantation registry were included. We divided EBMT patients into derivation (n=25 534), tuning (n=18 365), and geographical validation (n=3366) cohorts. Disease combinations were ranked in a multivariable Cox regression for overall survival in the derivation cohort, cutoff for risk groups were evaluated for the tuning cohort, and the selected system was tested on the geographical validation cohort. An independent single-centre US cohort of 660 patients transplanted between Jan 1, 2010, and Dec 31, 2015 was used to externally validate the results. Findings: The DRSS model stratified patients in the derivation cohort (median follow-up was 2·1 years [IQR 1·0–3·2]) into five risk groups with increasing mortality risk: low risk (reference group), intermediate-1 (hazard ratio for overall survival 1·26 [95% CI 1·17–1·36], p<0·0001), intermediate-2 (1·53 [1·42–1·66], p<0·0001), high (2·03 [1·86–2·22], p<0·0001), and very high (2·87 [2·63–3·13], p<0·0001). DRSS levels were also associated with a stepwise increase in risk across the tuning and geographical validation cohort. In the external validation cohort (median follow-up was 5·7 years [IQR 4·5–7·1]), the DRSS scheme separated patients into 4 risk groups associated with increasing risk of mortality: intermediate-2 risk (hazard ratio [HR] 1·34 [95% CI 1·04–1·74], p=0·025), high risk (HR 2·03 [95% CI 1·39–2·95], p=0·00023) and very-high risk (HR 2·26 [95% CI 1·62–3·15], p<0·0001) patients compared with the low risk and intermediate-1 risk group (reference group). Across all cohorts, between 64% and 65% of patients were categorised as having intermediate-risk disease by a previous prognostic system (ie, the disease-risk index [DRI]). The DRSS reclassified these intermediate-risk DRI patients, with 855 (6%) low risk, 7111 (51%) intermediate-1 risk, 5700 (41%) intermediate-2 risk, and 375 (3%) high risk or very high risk of 14 041 patients in a subanalysis combining the tuning and internal geographic validation cohorts. The DRI projected 2-year overall survival was 62·1% (95% CI 61·2–62·9) for these 14 041 patients, while the DRSS reclassified them into finer prognostic groups with overall survival ranging from 45·7% (37·4–54·0; very high risk patients) to 73·1% (70·1–76·2; low risk patients). Interpretation: The DRSS is a novel risk stratification tool including disease features related to histology, genetic profile, and treatment response. The model should serve as a benchmark for future studies. This system facilitates the interpretation and analysis of studies with heterogeneous cohorts, promoting trial-design with more inclusive populations. Funding: The Varda and Boaz Dotan Research Center for Hemato-Oncology Research, Tel Aviv University.

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