-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

2703 Incidence of Myeloid Malignancy in Shwachman-Diamond Syndrome: An International Cohort StudyClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 509. Bone Marrow Failure and Cancer Predisposition Syndromes: Congenital: Poster II
Hematology Disease Topics & Pathways:
Research, Bone Marrow Failure Syndromes, Inherited Marrow Failure Syndromes, Genetic Disorders, Clinical Research, Diseases, Human, Study Population
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Kasiani C Myers, MD1, Jie He, MS2*, Ben Goldberg, MS2*, Christopher R. Reilly, MD3, Yang Wan, MD PhD4*, Xiaofan Zhu, MD4,5,6, Simone Cesaro, MD7*, Marco Cipolli, MD8*, Alison A. Bertuch, MD, PhD9,10, Candelaria O'Farrell, MD11,12, Kenichiro Watanabe, MD, PhD13*, Antonis Kattamis, MD14, Polyxeni Delaporta, MD15*, Melanie Cotter, MB16, Eoghan Dunlea, MD17,18*, Taizo A. Nakano, MD19, Amy E. Geddis, MD, PHD20*, Karyn Brundige, MSN, CPNP21*, Ian Atkinson22*, Katherine Coyne21*, Sara Loveless1*, Leah Cheng21*, Edie Weller, PhD2,23*, Jean Donadieu24 and Akiko Shimamura, MD, PhD25

1Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
2Biostatistics and Research Design Center at BCH and Department of Pediatrics at Harvard Medical School, Boston, MA
3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
4Department of Pediatric Hematology and Oncology, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology& Blood Diseases Hospital, Chinese Academy of Medical Sciences& Peking Union Medical College, Tianjin, China
5Childhood Bone Marrow Failure Diseases Register of China Alliance for Blood Diseases, Tianjin, China
6Tianjin Institutes of Health Science, Tianjin 301600, China
7Pediatric Hematology-Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
8Cystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
9Department of Pediatrics, Division of Hematology/Oncology, Baylor College of Medicine, Houston, TX
10Texas Children's Hospital, Houston, TX
11Texas Children’s Hospital, Houston, TX
12Texas Children's Hospital / Baylor College of Medicine, Houston, TX
13Department of Hematology and Oncology, Shizuoka Children's Hospital, Shizuoka, SHZ, JPN
14Division of Pediatric Hematology-Oncology, First Department of Pediatrics, "Aghia Sophia" Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece
15Thalassemia Unit, First Department of Pediatrics, National and Kapodistrian University of Athens, Athens, Greece
16Trinity College, Dublin, Ireland
17Trinity College, Department of Paediatrics, Dublin, Ireland
18Children's Health Ireland, Department of Haematology, Dublin, Ireland
19Children's Hospital Colorado, Denver, CO
20Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, WA
21Department of Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA
22Dana-Farber and Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA
23Harvard Medical School, Department of Pediatrics, Boston, MA
24French Reference Center for Histiocytosis, Department of Pediatric Hematology and Oncology, Trousseau Hospital, AP-HP, Sorbonne Université, Paris, France
25Boston Children's Hospital, Boston, MA

Introduction:

Shwachman Diamond syndrome (SDS) is a genetic bone marrow failure syndrome associated with a predisposition to developing myeloid malignancies. Survival is exceptionally poor for patients who develop MDS or AML. Due to the rarity of this condition, the cumulative risk of myeloid malignancies with age is not well characterized, and this understanding is critical to guide effective clinical interventions that improve survival. The paucity of data regarding malignancy risk poses a major barrier to transplant decisions for patients with this leukemia predisposition syndrome. To address this unmet need, we conducted an international collaborative retrospective study with the primary objective of determining the cumulative incidence of myeloid malignancy as a function of age in patients with SDS.

Methods:

All patients with available reports of biallelic SBDS mutations were eligible. Data were extracted from medical records in accordance with institutional and national IRB/ethics regulations. Clinical characteristics and outcomes of patients with biallelic SBDS mutations were included for analysis from an international cohort from 7 countries, including the North American Shwachman-Diamond Syndrome Registry and the French Severe Congenital Neutropenia Registry, China, Italy, Japan, Greece, Ireland, and additional US centers (Baylor College of Medicine, Colorado Children’s Hospital and Seattle Children’s Hospital). The cumulative incidence of MDS and AML was estimated using cumulative incidence function (CIF) with competing risks. The survival curves were estimated using the Kaplan-Meier method and compared using the logrank test.

Results:
A total of 622 patients with biallelic SBDS mutations were in the study cohort. Median age at last follow up was 13.4 years (range 0-57 years) with 129 patients >age 25 years and 91 patients > age 30 years. There were 372 (59.8%) patients of male sex and 250 (40.2%) patients of female sex. MDS developed in 63 patients with a median age at diagnosis of 14.1 years (range 0-45), and AML in 42 with a median age at diagnosis of 24.2 years (range 0.5-47.3). The cumulative risk (95% confidence interval (CI)) of MDS was 2.4% (1.4-3.9) by age 5 years, 5.2% (3.5-7.4) by age 10 years, 13.4% (9.7-17.7) by age 25 years, and 32.9% (22.2-44) by age 50 years. The cumulative risk (95% CI) of AML was 0.7% (0.2-1.7) by age 5 years, 1.8% (0.9-3.3) by age 10 years, 5.1% (2.9-8.2) by age 25 years, and 28.4% (17-40.8) by age 50 years. The overall cumulative incidence (95% CI) of all myeloid malignancy was 3.2% (1.9-4.8) by age 5 years, 6.9% (4.9-9.4) by age 10 years, 16.1% (12.1-20.7) by age 25 years, and 57.2% (42.9-69.1) by age 50 years. Overall survival with age (95% CI) was 96.7% (95.3-98.2) at age 5 years, 95.8% (94.2-97.5) at age 10 years, 84.8% (80.6-89.3) at age 25 years, and 23.9% (11.8-48.6) at age 50 years.

Conclusions:

Previously, consideration of transplant timing was limited by the paucity of data on cumulative incidence of malignancy with age in SDS due to the rarity of this condition. This international collaboration analyzed data from the largest cohort of SDS patients to date, and found that SDS is associated with a very high lifetime risk of myeloid malignancy exceeding 50% by age 50 years. This study provides data to guide discussions of surveillance and early interventions, including hematopoietic stem cell transplant for SDS patients with evidence of impending malignant transformation prior to progression to malignancy. Development of optimal surveillance approaches for early diagnosis of clonal evolution and novel treatments are sorely needed to develop effective strategies to intercept malignancy and improve survival in patients with SDS.

Disclosures: Myers: Incyte: Research Funding; Elixirgen Therapeutics: Research Funding. Kattamis: Vertex Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee Membership; Vifor: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy; Novo Nordisk: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria. Shimamura: Fulcrum: Consultancy; X4 pharma: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees.

Previous Abstract | Next Abstract >>
*signifies non-member of ASH