BACKGROUND Data to inform surveillance and treatment for leukaemia predisposition syndromes are scarce and recommendations are largely based on expert opinion. This study aimed to investigate the clinical features and outcomes of patients with myelodysplastic syndrome or acute myeloid leukaemia and Shwachman-Diamond syndrome, an inherited bone marrow failure disorder with high risk of developing myeloid malignancies. METHODS We did a multicentre, retrospective, cohort study in collaboration with the North American Shwachman-Diamond Syndrome Registry. We reviewed patient medical records from 17 centres in the USA and Canada. Patients with a genetic (biallelic mutations in the SBDS gene) or clinical diagnosis (cytopenias and pancreatic dysfunction) of Shwachman-Diamond syndrome who developed myelodysplastic syndrome or acute myeloid leukaemia were eligible without additional restriction. Medical records were reviewed between March 1, 2001, and Oct 5, 2017. Masked central review of bone marrow pathology was done if available to confirm leukaemia or myelodysplastic syndrome diagnosis. We describe the clinical features and overall survival of these patients. FINDINGS We initially identified 37 patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia. 27 patients had samples available for central pathology review and were reclassified accordingly (central diagnosis concurred with local in 15 [56%] cases), 10 had no samples available and were classified based on the local review data, and 1 patient was excluded at this stage as not eligible. 36 patients were included in the analysis, of whom 10 (28%) initially presented with acute myeloid leukaemia and 26 (72%) initially presented with myelodysplastic syndrome. With a median follow-up of 4·9 years (IQR 3·9-8·4), median overall survival for patients with myelodysplastic syndrome was 7·7 years (95% CI 0·8-not reached) and 0·99 years (95% CI 0·2-2·4) for patients with acute myeloid leukaemia. Overall survival at 3 years was 11% (95% CI 1-39) for patients with leukaemia and 51% (29-68) for patients with myelodysplastic syndrome. Management and surveillance were variable. 18 (69%) of 26 patients with myelodysplastic syndrome received upfront therapy (14 haematopoietic stem cell transplantation and 4 chemotherapy), 4 (15%) patients received no treatment, 2 (8%) had unavailable data, and 2 (8%) progressed to acute myeloid leukaemia before receiving treatment. 12 patients received treatment for acute myeloid leukaemia-including the two patients initially diagnosed with myelodysplastic who progressed- two (16%) received HSCT as initial therapy and ten (83%) received chemotherapy with intent to proceed with HSCT. 33 (92%) of 36 patients (eight of ten with leukaemia and 25 of 26 with myelodysplastic syndrome) were known to have Shwachman-Diamond syndrome before development of a myeloid malignancy and could have been monitored with bone marrow surveillance. Bone marrow surveillance before myeloid malignancy diagnosis was done in three (33%) of nine patients with leukaemia for whom surveillance status was confirmed and 11 (46%) of 24 patients with myelodysplastic syndrome. Patients monitored had a 3-year overall survival of 62% (95% CI 32-82; n=14) compared with 28% (95% CI 10-50; n=19; p=0·13) without surveillance. Six (40%) of 15 patients with available longitudinal data developed myelodysplastic syndrome in the setting of stable blood counts. INTERPRETATION Our results suggest that prognosis is poor for patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia owing to both therapy-resistant disease and treatment-related toxicities. Improved surveillance algorithms and risk stratification tools, studies of clonal evolution, and prospective trials are needed to inform effective prevention and treatment strategies for leukaemia predisposition in patients with Shwachman-Diamond syndrome. FUNDING National Institute of Health.

中文翻译：

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Shwachman-Diamond综合征和骨髓增生异常综合征或急性髓性白血病的患者的临床特征和结局：一项多中心，回顾性队列研究。

背景技术用于监测白血病易感综合症的监视和治疗的数据很少，并且推荐主要基于专家意见。这项研究的目的是调查患有骨髓增生异常综合症或急性髓性白血病和Shwachman-Diamond综合征的患者的临床特征和结局，Shwachman-Diamond综合征是一种遗传性骨髓衰竭疾病，具有发展为骨髓恶性肿瘤的高风险。方法我们与北美Shwachman-Diamond综合征注册中心进行了一项多中心，回顾性队列研究。我们审查了来自美国和加拿大的17个中心的患者病历。具有Shwachman-Diamond综合征的遗传（SBDS基因双等位基因突变）或临床诊断（血细胞减少和胰腺功能障碍）的患者，发展为骨髓增生异常性综合征或急性髓性白血病，无附加限制。在2001年3月1日至2017年10月5日之间对病历进行了审查。如果可以确认是否患有白血病或骨髓增生异常综合症，则对骨髓病理学进行蒙面的中央回顾。我们描述了这些患者的临床特征和总体生存率。结果我们最初确定了37例Shwachman-Diamond综合征和骨髓增生异常综合征或急性髓性白血病患者。27例患者的样本可用于中央病理学检查，并据此进行了重新分类（15例[56％]病例接受中央诊断，其中局部诊断为同意），10名患者没有可用的样本，并根据当地的回顾数据进行了分类，并且在此阶段将1名患者排除为不合格。分析包括36例患者，其中10例（28％）最初表现为急性髓细胞性白血病，26例（72％）最初表现为骨髓增生异常综合症。中位随访期为4·9年（IQR 3·9-8·4），骨髓增生异常综合症患者的中位总体生存期为7·7年（95％CI 0·8-未达到）和0·99年（95％CI 0·2-2·4）用于急性髓细胞性白血病患者。白血病患者3年总生存率为11％（95％CI 1-39），骨髓增生异常综合征患者为51％（29-68）。管理和监督各不相同。26例骨髓增生异常综合征患者中有18例（69％）接受了前期治疗（14例造血干细胞移植和4例化学疗法），4例（15％）的患者未接受治疗，2例（8％）的数据不可用，2例（8％）在接受治疗前发展为急性髓细胞性白血病。12例接受了急性骨髓性白血病治疗的患者-包括两名最初被诊断为骨髓增生异常的患者，其中2例（16％）接受了HSCT作为初始治疗，另外10例（83％）接受了化疗以进行HSCT。已知36名患者中的33名（92％）（白血病10例中的8例，骨髓增生异常综合征中的25例中的25例）在发生髓样恶性肿瘤之前患有Shwachman-Diamond综合征，可以通过骨髓监测进行监测。在确诊为监视状态的九名白血病患者中，三名（33％）进行了骨髓恶性肿瘤诊断之前的骨髓监视，以及24例骨髓增生异常综合症患者中的11名（46％）。接受监测的患者3年总生存率为62％（95％CI 32-82; n = 14），而没有监测的患者为28％（95％CI 10-50; n = 19; p = 0·13）。15例具有纵向数据的患者中有6例（40％）在稳定血球计数的情况下发生了骨髓增生异常综合症。解释我们的结果表明，由于抗药性疾病和与治疗有关的毒性，Shwachman-Diamond综合征和骨髓增生异常综合征或急性髓细胞性白血病的患者预后较差。改进的监视算法和风险分层工具，克隆进化研究，需要进行前瞻性试验来告知Shwachman-Diamond综合征患者白血病易感性的有效预防和治疗策略。资助国立卫生研究院。