ALBERT

Description: Background: In 1994 Severe Chronic Neutropenia International Registry (SCNIR) opened for enrollment of patients with at least 3 absolute neutrophil counts (ANC) less than 0.5 x 109/L during a three month period. At that time severe chronic neutropenia (SCN) was categorized as cyclic, congenital, autoimmune or idiopathic based largely on clinical criteria. A randomized trial had established effectiveness of treatment with granulocyte colony-stimulating factor (G-CSF), but long-term consequences of such treatment were unknown. Hypothesis: We began the SCNIR based on the hypothesis that underlying pathophysiology, natural history of patients with chronic neutropenia and benefits and risk of G-CSF therapy could only be accurately established through an international registry with long term follow-up of patients with these rare hematological disorders. Methods: SCNIR enrollment requires informed consent, ANC90%) of severe outcomes (e.g. MDS/AML, failure to respond to G-CSF, death from infections, need for stem cell transplant) often many years after SCNIR enrollment and beginning G-CSF therapy. GSD1 patients improve with G-CSF treatment, but experience splenomegaly and continued problems with infections or complications. The SCNIR through a SDS sub-registry is redefining Shwachman-Diamond syndrome; only about one-half of enrollees have “classic” presentation and a substantial number with “classic presentation” lack mutations in SBDS. The SCNIR is participating in an NIH trial of a CXCR4 antagonist for treatment of WHIM syndrome, as an example of molecularly targeted treatment for this rare disease. The SCNIR is also the key resource for discovery of genetic causes for congenital neutropenia, e.g., G6PC3, HAX1, and TCIRG1 and others, recognition of differences in frequency of autosomal dominant and recessive SCN in populations of Europe and North America and identifying congenital neutropenia cases of unknown cause. Genetic testing has also broadened the clinical spectrum of these disorders. Conclusions: Through the efforts of patients, families, physicians, nurses and investigators, and with support from the NIH, industry, and private philanthropy, chronic neutropenia is now far better understood at the genetic, molecular and cellular level than 20 years ago. Treatment responses to G-CSF are well characterized; novel therapies are emerging; and the prognosis for patients with SCN appears to be improving. The knowledge gained through the SCNIR and availability of G-CSF has redefined clinicians’ approach to chronic neutropenia. The SCNIR is a model of international research collaboration to understand rare diseases in hematology and other areas of medicine. Broad enrollment criteria, physician, patient and family participation, a dedicated staff, and continuing cooperation underlie success of the SCNIR and this model to understanding rare diseases. Disclosures Dale: Amgen: Consultancy, Honoraria, Research Funding. Boxer:Amgen: Equity Ownership. Morrow:Amgen: Employment.

Description: Background: Since 1994 the Severe Chronic Neutropenia International Registry (SCNIR) has enrolled children and adults with 〉 3 absolute neutrophil counts (ANCs) 〈 0.5 x 109/L during a 3 month period to understand the pathobiology, natural history and treatment responses for severe chronic neutropenia. We have previously reported on the frequency and risk of myelodysplasia (MDS) and acute myeloid leukemia (AML) in patients with congenital neutropenia. For this report we reviewed patterns of hematological complications and malignancies occurring in all patients enrolled through the North American office of the SCNIR. Methods: Enrollment required informed consent, and patients and their physicians provided demographic, clinical and laboratory data including bone marrow results. Genetic testing was not required. Patients were followed with annual reports on blood counts, infections, malignancies and hospitalizations. Results: From 1994 to 2018 the Seattle SCNIR office has enrolled 1672 patients in the following categories: congenital 637 (38%), cyclic 259 (15%), and idiopathic / autoimmune 776 (47%), and many have been followed now for more than 15 years. There are approximately 17,577 person years of the observational data in this Registry. The congenital category now includes patients with mutations in ELANE, SBDS, TAZ, COH1, CXCR4, SLC37A4, G6PC3, WAS, CSF3R, SRP54, GFI1, VPS45, JAGN1, HAX1 and also patients with severe neutropenia from an early date in childhood without a genetic diagnosis. Cyclic neutropenia patients have demonstrated oscillations in ANC. The idiopathic and autoimmune category includes children and adults including some with large granular lymphocytes (LGL) syndrome without recognized features of a lymphoproliferative disorder. Most patients in all categories have been treated with granulocyte colony-stimulating factor (G-CSF). Findings: MDS or AML has occurred in 70 of the 1672 patients; 99% have clinical diagnosis of a hereditary type of neutropenia: severe congenital neutropenia (55), glycogen storage disease 1b (3), congenital immunodeficiency (2), Shwachman-Diamond syndrome (SDS) (5), WHIM syndrome (1),Wiskott-Aldrich syndrome (2), cyclic neutropenia (1) and idiopathic neutropenia (1). The median age at diagnosis of AML/MDS was 15.3 years (mean 18.3, +/- 1.79 SEM [range 0.40 - 70.6]); 69 of 70 were treated with G-CSF, median dose = 7.1 mcg/kg/day (mean 7.3, +/- 1.3 SEM )(range 0.18 - 100). One Shwachman-Diamond patient never received G-CSF. Outcomes for AML/MDS patients receiving chemotherapy with HSCT before 2000 were poor with 3/17 (18%) survivors. Since 2000 there were 35/53 (66%) survivors. Five patients developed myelofibrosis (4 congenital and 1 idiopathic). Two of the congenital patients later developed AML (1 living after treatment with a HSCT, 1 deceased). The clinical diagnosis of cyclic neutropenia has a favorable prognosis with G-CSF treatment, with only one probable case in 3,833 person years of clinical observation. 1 Twelve patients developed T-cell lymphoproliferative disorder (1 autoimmune neutropenia, 3 congenital neutropenia, 8 idiopathic neutropenia (4 with LGL features)). Five of these patients are living, all in the idiopathic group, 3 of 5 living patients have features of the LGL syndrome. Ten patients have reported other hematological malignancies; CML in a congenital patient after treatment with HSCT (living), CLL in a cyclic patient (living), CMML in an idiopathic patient after treatment with a HSCT (deceased). Six of the 10 patients have developed lymphoma; cyclic neutropenia (1), idiopathic/autoimmune neutropenia (5). Only one SDS patient has developed aplastic anemia. Other cancers/non-hematological malignancies have occured mostly in older patients: breast cancer (15) colon cancer (6), dermatological malignancies (13), hepatoma (1), lung cancer (1), prostate cancer (1), thyroid cancer (1). Conclusions: The hematological consequences of severe chronic neutropenia depend on the underlying etiology. MDS and AML occur largely in patients with the congenital or hereditary neutropenias. The diagnosis of cyclic neutropenia and chronic idiopathic / autoimmune neutropenia portends a favorable prognosis, based on a total of 10482 person years of observation. Marrow failure and aplastic anemia are not expected consequences of severe chronic neutropenia. Disclosures Dale: Athelas, Inc.: Equity Ownership; Amgen: Consultancy, Research Funding; Sanofi-Aventi: Consultancy, Honoraria; Cellerant: Other: Scientific Advisory Board; Hospira: Consultancy; Prolong: Consultancy; Beheringer-Ingelheim: Consultancy; Coherus: Consultancy. Newburger:X4 Pharmaceutics: Consultancy, Honoraria; TransCytos LLC: Consultancy; Janssen Research & Development, LLC: Consultancy, Honoraria.

Description: Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome. The spectrum of cancer susceptibility in this disorder of telomere biology has not been described. There were more than 500 cases of DC reported in the literature from 1910 to 2008; the National Cancer Institute (NCI) prospective DC cohort enrolled 50 cases from 2002 to 2007. Sixty cancers were reported in 52 literature cases, while 7 occurred among patients in the NCI DC cohort. The 2 cohorts were comparable in their median overall survival (42 years) and cumulative incidence of cancer (40%-50% by age 50 years). The most frequent solid tumors were head and neck squamous cell carcinomas (40% of patients in either cohort), followed by skin and anorectal cancer. The ratio of observed to expected cancers (O/E ratio) in the NCI cohort was 11-fold compared with the general population (P 〈 .05). Significantly elevated O/E ratios were 1154 for tongue cancer and 195 for acute myeloid leukemia. Survival after bone marrow transplantation for aplastic anemia or leukemia was poor in both cohorts. The frequency and types of cancer in DC are surpassed only by those in Fanconi anemia (FA), indicating that FA and DC have similarly high risks of adverse hematologic and neoplastic events, and patients with these diseases should be counseled and monitored similarly.

Description: Severe congenital neutropenia (SCN) is a heterogeneous disorder of myelopoiesis characterized by an absolute neutrophil count (ANC) persistently below 0.50 x 109/L (500/[um]L), with maturation arrest of neutrophil precursors of the bone marrow at the promyelocyte/myelocyte stage. G-CSF treated and untreated SCN patients are at risk of developing MDS/AML. Clinicians caring for these patients must vigilantly observe for evidence of evolution to malignancy and continually consider hematopoietic transplantation as an alternative therapy. We have previously reported that SCN patients requiring higher daily doses of G-CSF treatment (〉 8 mcg/kg/day) are at an increased risk of MDS/AML, and that this risk is not predicted by pre-treatment bone marrow examinations or the pre-treatment ANC. We have reviewed clinical data for 46 patients over a 15-year period who were referred to the Severe Chronic Neutropenia International Registry (SCNIR) and developed MDS/AML. Four patients referred with a history of SCN had increased blasts on the bone marrow evaluation prior to G-CSF treatment or enrollment in the SCNIR. Blood counts were not available for two patients. For the other 40 patients, all treated with G-CSF for a median of 79 months (range 0.8 to 182 months), comparison of blood counts for the periods 12–24 months and 0–3 months before the diagnosis of MDS/AML showed: Changes in blood counts for the patient population may suggest a potential for malignant transformation. In these 40 cases, the principal clinical findings leading to the diagnosis of MDS/AML were: routine bone marrow surveillance 38%, decreased peripheral blood counts 26%, increased infections 10%, increased blasts in the blood 5%, decreased ANC with requirement for increased G-CSF dosage 2%, hepatosplenomegaly 2%, other (1 septal panniculitis and 1 leukemia cutis) 5%, and unknown 12%. The finding of mutations in the ELA2 gene in 10 of 15 cases (67%) did not influence the likelihood of MDS/AML. Previously we found that the duration and dose of G-CSF and alterations of the ANC on G-CSF therapy, suggest a high risk of transformation over time. Based on these data, the SCNIR recommends that patients with SCN have regular surveillance of blood counts every 1 to 2 months and annual bone marrow examinations with cytogenetic studies. Our findings suggest that a decline or change in blood counts of individual patients over a 3-month period may be informative in recognizing transformation to MDS/AML.