Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Hematology Division, Chaim Sheba Medical Center, Tel Aviv University, Ramat Gan, Israel.
Internal Medicine, University of Connecticut, Farmington, CT, USA.
Lancet Haematol. 2021 Mar;8(3):e205-e215. doi: 10.1016/S2352-3026(20)30394-X.
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.
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.
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).
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.
The Varda and Boaz Dotan Research Center for Hemato-Oncology Research, Tel Aviv University.
同种异体造血干细胞移植（HSCT）时的诊断和缓解状态是移植后总体生存的主要决定因素。我们试图开发一种当代疾病风险分层系统（DRSS），该系统考虑了移植指征的异质性。
在这项回顾性队列研究中，我们纳入了 55 种血液系统恶性肿瘤的组织学和缓解状态组合，包括急性白血病、淋巴瘤、多发性骨髓瘤、骨髓增生异常和骨髓增生性疾病。共纳入了 47065 名年龄≥18 岁、2012 年 1 月 1 日至 2016 年 12 月 31 日期间接受同种异体 HSCT 并向欧洲血液和骨髓移植协会登记处报告的成人患者。我们将 EBMT 患者分为推导（n=25534）、调整（n=18365）和地理验证（n=3366）队列。在推导队列中，对多变量 Cox 回归进行整体生存的疾病组合进行排名，对风险组的截止值进行评估，并在地理验证队列中测试选定的系统。一个来自美国的独立的单一中心队列，共 660 例患者在 2010 年 1 月 1 日至 2015 年 12 月 31 日期间接受移植，用于外部验证结果。
DRSS 模型将推导队列（中位随访时间为 2.1 年[IQR 1.0-3.2]）中的患者分为五个具有不同死亡率风险的风险组：低风险（参考组）、中 1 组（总体生存率的危险比为 1.26[95%CI 1.17-1.36]，p<0.0001）、中 2 组（1.53[1.42-1.66]，p<0.0001）、高组（2.03[1.86-2.22]，p<0.0001）和非常高组（2.87[2.63-3.13]，p<0.0001）。DRSS 水平也与调整和地理验证队列中的风险逐渐增加相关。在外部验证队列（中位随访时间为 5.7 年[IQR 4.5-7.1]）中，DRSS 方案将患者分为 4 个与死亡率风险增加相关的风险组：中 2 组风险（危险比[HR]1.34[95%CI 1.04-1.74]，p=0.025）、高风险（HR 2.03[95%CI 1.39-2.95]，p=0.00023）和非常高风险（HR 2.26[95%CI 1.62-3.15]，p<0.0001）与低风险和中 1 风险组（参考组）相比。在所有队列中，64%至 65%的患者根据以前的预后系统（即疾病风险指数[DRI]）被归类为具有中危疾病。DRSS 重新分类了这些中危 DRI 患者，在结合调整和内部地理验证队列的亚分析中，将 14041 例患者中的 855 例（6%）归类为低危，7111 例（51%）归类为中 1 组，5700 例（41%）归类为中 2 组，375 例（3%）归类为高危或非常高危。对于这 14041 例患者，DRI 预测的 2 年总生存率为 62.1%（95%CI 61.2-62.9），而 DRSS 将他们重新分类为预后更差的组，总生存率从 45.7%（37.4-54.0；高危患者）到 73.1%（70.1-76.2；低危患者）。
DRSS 是一种新的风险分层工具，包括与组织学、遗传特征和治疗反应相关的疾病特征。该模型应作为未来研究的基准。该系统有助于解释和分析具有异质队列的研究，促进更具包容性人群的试验设计。
Tel Aviv 大学的 Varda 和 Boaz Dotan 血液肿瘤学研究中心。
