Shwachman-Diamond Syndrome: Development of a North American Registry to Assess Long-Term Outcomes, Risk of Leukemia and Other Complications.

Abstract Abstract 1363 Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, bone marrow failure, pancreatic dysfunction, and skeletal abnormalities. Its clinical manifestations are variable and there are no reliable clinical or molecular predictors for patient outcomes. In collaboration with the Severe Chronic Neutropenia International Registry (SCNIR), we have established a North American Shwachman-Diamond Registry (NASDSR) to understand the molecular basis, phenotype, natural history and treatment responses of patients with SDS. In this report, we summarize findings related to severe neutropenia and the risk of severe infections or leukemia in 26 patients [12 adults (6 female, 6 male) and 14 children (5 female and 9 male, less than 18 years of age)] observed for up to 12 years (median 3, range 1 to 12), initially enrolled through the SCNIR. 21 of 26 patients were neutropenic prior to enrollment, median absolute neutrophil count (ANC) 0.476 × 109/L, range 0.070 × 109/L to 0.935 × 109/L. Five patients have never received G-CSF. Of the twenty-one patients (ages 4 to 47) who received G-CSF continuously or intermittently, (median dose 1.88 mcg/kg/day, range 0.00 mcg/kg/day to 17.50 mcg/kg/day), 18 are doing well with stable neutrophil responses while on treatment, after a median treatment period of 3 years. Three deaths and outcomes for two other patients are of particular interest. Patient #1 (8 months, female) was hospitalized for infections for most of her life and died at the age of 8 months due to sepsis with multi-organ system failure. This patient received G-CSF only during the final month of life. Patient #2 (age 21, female) developed AML with del(3p)(7)(21)[7] and died in relapse 25 days after starting G-CSF at a dose of 6.0 mcg/kg/day for treatment of severe neutropenia. Patient #3 (age 8, female) received G-CSF (median dose of 8.25 mcg/kg/day) for nearly 6 years, i.e., from age 16 months until developing a cytogenetic abnormality 45,XX,t(6;13)(q21;q32), -7 [3]/46,XX[47] at age 7 years. She underwent a bone marrow transplant 7 months later and died of sepsis after failing to engraft. Patient #4 (age 14, male) received a transplant after developing a cytogenetic abnormality 46,XY[15];46,Xydel(7)(q22q34)[5], 5 years after starting G-CSF at a median dose of 5 mcg/kg/day. Patient #4 is currently 28 years old. Patient #5 (age 7, male) received a matched sibling transplant because of mild marrow dysplastic changes without cytogenetic abnormalities after receiving G-CSF (1.3 mcg/kg/day) with good neutrophil response for 8 years. He is doing well at 3 years after transplantation. All of the enrolled patients have other manifestations of SDS including steatorrhea due to pancreatic insufficiency, hepatomegaly, splenomegaly, and osteopenia. None has developed non-hematological malignancies. The SCNIR-NASDSR seeks to enroll additional patients in North America to build an accurate database for molecular studies and clinical recommendations for this important disease. Disclosures Dale: Amgen: Consultancy, Research Funding, Speaker; Merck: Research Funding.

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