Genetic predisposition to MDS and AML is recognized in a growing subset of patients, but data to inform medical management and outcomes are sparse. Shwachman-Diamond syndrome (SDS) is an inherited marrow failure syndrome associated with increased risk of myelodysplasia (MDS) and acute myeloid leukemia (AML). The aim of this multi-institutional retrospective study was to investigate clinical features, treatment, and outcomes of 37 patients with SDS who developed MDS or AML. Diagnosis of SDS was established by SBDS genetic testing (n=30), exocrine pancreatic dysfunction (n=5), or data were unavailable (n=2). Nine individuals presented with AML (4 male, 5 female), 26 with MDS (13 male and 13 female), one male with refractory cytopenia (RC), and one male with isolated persistent somatic TP53 mutation. Eight of 26 MDS patients, had MDS-EB1 or EB2 at diagnosis, of whom two progressed to AML. Three patients initially presenting with early MDS progressed to MDS-EB1, MDS-EB2, or AML. Median age (years) at diagnosis of early MDS was 13.8 (range 0.5-28.8), for MDS-EB1/2 was 16 (range 9-30) and for AML was 33 (range 5.5-47). Nine patients with MDS and 1 patient with AML were receiving G-CSF chronically prior to diagnosis of MDS/AML.

Complex cytogenetics, (>3 cytogenetic abnormalities per clone), were noted in 8/9 AML cases. One AML patient presented with normal cytogenetics. Complex clonal cytogenetic abnormalities were noted in 5 of 6 patients with MDS-EB1/EB2 for whom reports were available. Cytogenetic data were available for 16 MDS cases and clonal abnormalities were noted in 10. Aberrations involving chromosome 7 were most common. The patient with the somatic TP53 mutation had normal cytogenetics. Centralized bone marrow pathology review is currently ongoing.

Follow up data were available for 8 patients with AML; 6 are deceased. Six received chemotherapy with intent to proceed to hematopoietic stem cell transplant (HSCT), of whom 5 failed to achieve remission and died with disease without proceeding to transplant. One AML patient proceeded to HSCT with progressive disease post-chemotherapy, but died with relapsed disease. One patient proceeded to HSCT without prior chemotherapy and was in remission at day 30 post-HSCT. The sole long-term surviving AML patient achieved remission with chemotherapy and underwent HSCTs with 3 separate stem cell infusions due to primary graft failure after the initial two infusions. He remains alive in remission more than 4 years after diagnosis. Notably this surviving AML patient was the only AML patient with normal cytogenetics at diagnosis.

Follow up data are available for 6 of 8 patients presenting with MDS-EB1/EB2, 4 of whom are deceased. One patient who presented with MDS-EB1 is alive with relapsed disease after HSCT and one patient is in remission 100 days after HSCT.

Follow up data are available for 17 of 18 early MDS patients, 7 of whom are deceased including three who had progressed to MDS-EB1, MDS-EB2, or AML. Four of the 7 deceased patients had received a HSCT. One individual with MDS died of hepatic failure unrelated to MDS. Seven MDS patients are alive in remission after HSCT without prior chemotherapy. Treatment was not reported for an additional 2 surviving patients. One patient receiving a hypomethylating agent is alive with stable disease 4.8 years from diagnosis. The patients with RC and with a TP53 clonal abnormality are alive at 6.5 years and 1.7 years from diagnosis respectively.

In summary,prognosis is poor for patients with SDS who develop AML or MDS-EB1/2, with few long-term survivors due to resistant disease and treatment-related complications. Outcomes are better if transplanted for MDS prior to acquisition of increased blasts, with 10 of 17 (59%) subjects surviving (median follow up 6 years, range 1.5-11.2). AML often presents in adulthood highlighting the need for continued surveillance of SDS patients with bone marrow examinations including cytogenetics and FISH. These data demonstrate the importance of early detection of clonal evolution in this leukemia predisposition syndrome. Better markers for risk stratification are needed to identify patients who would benefit from early transplant prior to advanced clonal disease. Novel therapeutic strategies, such as targeted therapies, are urgently needed to improve outcomes of SDS patients with advanced MDS or AML.


DiNardo: Daiichi-Sankyo: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Norkin: Celgene: Honoraria, Research Funding. Shimamura: TransCellular Therapeutics: Other: Spouse is majority shareholder .

Author notes


Asterisk with author names denotes non-ASH members.