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  • 1
    In: The Journal of Pediatrics, Elsevier BV, Vol. 160, No. 4 ( 2012-04), p. 679-683.e2
    Type of Medium: Online Resource
    ISSN: 0022-3476
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2012
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  • 2
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3206-3206
    Abstract: Abstract 3206 Poster Board III-143 BACKGROUND G-CSF therapy reduces sepsis mortality in patients with severe congenital neutropenia (SCN), but effective therapy has revealed a high syndromic predisposition to myelodysplastic syndrome and acute myeloid leukemia (MDS/AML), particularly in patients who require higher doses of G-CSF. Although the long-term risk of MDS/AML after 10 or more years on therapy remains uncertain, prior data on the limited number of patients with long-term follow-up suggested the hazard rate might be as high as 8%/year after 12 years on G-CSF. METHODS We updated prospective follow-up of 374 well-characterized patients with SCN on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry (Blood. 2006 Jun 15; 107(12):4628-35). We ascertained event-free time, deaths from sepsis, and MDS/AML events that accrued since our previous report. Follow-up was censored for patients who received a bone marrow transplant. RESULTS The update yielded 3590 person-years of follow-up versus 2043 in the prior report; among patients treated for 10 or more years, there were 849 person-years versus just 67 previously. In all, there were 61 MDS/AML events and 29 deaths from sepsis, versus prior totals of 44 and 19, respectively. After including up-to-date follow-up, the estimated annual hazard of death from sepsis remained qualitatively stable, at 0.81%/year (95% Confidence Interval, CI: 0.56 – 1.16%/year). Similarly, during the first five years after the start of G-CSF therapy, the updated estimate of the hazard curve for MDS/AML showed the same increasing trend as the previous estimate. However, in contrast to the prior estimate that showed a subsequent increasing trend over time (with a large margin of error), the updated hazard curve attained a plateau: after 10 years on G-CSF, the estimated hazard of MDS/AML was 2.3%/year (95% CI: 1.7 – 2.9%/year). Although this aspect of the natural history appears less dire than first suggested, after 15 years on G-CSF, the cumulative incidence was 10% (95% CI: 6 – 14%) for death from sepsis and 22% (95% CI: 17 – 28%) for MDS/AML. Furthermore, for the subset of patients who failed to achieve at 6 months an absolute neutrophil count at or above the median value for the cohort (2188 cells/μL) despite doses of G-CSF at or above the median (8 μg/kg/day), the cumulative incidence after 15 years on G-CSF was 18% (95% CI: 7 – 28%) for death from sepsis and 34% (95% CI: 21 – 47%) for MDS/AML. With additional follow-up, the association of G-CSF dose at 6 months with the relative hazard of MDS/AML became more strongly statistically significant (P = 0.003 versus P = 0.024; the hazard of MDS/AML increased by 1.24-fold (95% CI: 1.08-1.43-fold) per doubling of the dose of G-CSF). CONCLUSIONS For SCN patients maintained on G-CSF therapy, the hazard of MDS/AML over the long-term falls significantly below the range suggested by preliminary data. The updated hazard estimate of 2.3%/year after 10 years on G-CSF (which includes both MDS and AML events) is similar to that for other inherited bone marrow failure syndromes with a high intrinsic risk of AML, notably Fanconi anemia and dyskeratosis congenita. Nonetheless, the cumulative incidence of both MDS/AML and sepsis death rises to very high levels, and the data continue to support the hypothesis that SCN patients with higher G-CSF requirements are also at higher risk of leukemia. Disclosures Boxer: Amgen Inc.: Equity Ownership. Dale:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speaker.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 3
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 669-669
    Abstract: Background: In patients with severe congenital neutropenia (SCN), mortality from sepsis is reduced by treatment with granulocyte colony-stimulating factor (G-CSF), but myelodsyplastic syndrome and acute myeloid leukemia (MDS/AML) have been reported in treated and untreated patients. Methods: We studied 374 patients with SCN and 29 patients with Shwachman-Diamond Syndrome (SDS) on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry. Results: In SCN, mortality from sepsis was stable at 0.9%/year. The hazard of MDS/AML increased significantly over time, from 2.9%/year after 6 years to 8.0%/year after 12 years on G-CSF. After 10 years, the cumulative incidence was 8% for mortality from sepsis and 21% for MDS/AML. The hazard of MDS/AML increased with the dose of G-CSF. Twenty-nine percent of SCN patients received more than the median dose of G-CSF (≥8 μg/kg/day), but achieved less than the median absolute neutrophil count (ANC) response (ANC & lt;2188 cells/μL at 6–18 months). In these less responsive patients, the cumulative incidence of adverse events was highest: after 10 years, 40% developed MDS/AML and 14% died of sepsis, compared to 11% and 4%, respectively, of more responsive patients whose ANC was above the median on doses of G-CSF below the median. An intermediate group achieved an ANC above the median on doses of G-CSF above the median; among them, the 10 year cumulative incidence was 15% for MDS/AML and 3% for mortality from sepsis. In secondary analyses, we found that pre-treatment blood cell counts could not predict the subsequent clinical outcome. Furthermore, on therapy, patients who were less responsive vis-à-vis their neutrophil counts had similar increases in eosinophils, basophils, monocytes, and lymphocytes, and similar decreases in platelets, as other patients maintained on ≥8 μg/kg/day. Consistent with the SCN results, in SDS patients, the limited available data do not suggest that G-CSF therapy is a risk factor for MDS/AML in SDS. Conclusions: The risk of MDS/AML was similarly low in all patients who achieved an ANC above the median on any dose of G-CSF. It appears that G-CSF has reduced mortality from sepsis, and revealed the underlying leukemic predisposition of SCN.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 4
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3307-3307
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 5
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 3548-3548
    Abstract: We recently reported on the risk for death from sepsis and myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) in patients with severe congenital neutropenia (SCN) on long-term granulocyte-colony stimulating factor (G-CSF) enrolled in the Severe Chronic Neutropenia International Registry (SCNIR). (Rosenberg et al, Blood2006; 107:4628-35, and Brit J Haematol2008; 140:210-3) We found that after ten years a subgroup of SCN patients receiving more than 8 mcg/kg/day of G-CSF who achieved a median absolute neutrophil count (ANC) response of less than 2.188 × 109/L had an estimated risk of dying from sepsis of 14% and a risk of developing MDS/AML of 40%. In order to understand the risk factors for death from sepsis, we reviewed the clinical diagnosis, hematological data, G-CSF treatment, and clinical course of 9 fatalities due to infections, excluding cases with evidence of MDS or AML or occurring after hematopoietic transplantation. The 5 male and 4 female patients’ ages ranges from 1 month to 18.7 years at the time of initiation of G-CSF. All were treated with G-CSF because of severe neutropenia (ANC less that 0.5 × 109/L) and a history of recurrent fevers and infections. The pre G-CSF median ANC for the 9 patients was 0.027 × 109/L and frequent events pre-G-CSF included fevers, severe mouth ulcers, otitis, sinusitis, pneumonia, cellulitis and abscess formation, but bacteremias were infrequent. When started on G-CSF, five patients were clearly poor responders, despite steady upward titration in the G-CSF dose to 22, 45, 65, 68 and 151 mcg/kg/day, respectively. In each of these patients, the ANCs on G-CSF treatment were frequently reported as less than 0.1 × 109/L and the responses were inconsistent and quite variable. The other 4 patients also had inconsistent responses at lower G-CSF doses and the patients’ compliance with treatment was uncertain. Two are known to have had a protracted “off treatment” periods, and the septic death of one patient occurred when off therapy. Deaths were attributed to sepsis (6 cases), pneumonia (2 cases), and meningitis (1 case). These clinical data suggest that death from sepsis in SCN is usually associated with a poor response to G-CSF as reflected by the requirement for dose escalation substantially above the threshold of 8 mcg/kg/day of G-CSF associated with an increased risk of MDS/AML. Inconsistent treatment and discontinuation of treatment also lead to neutropenia and the risk of sepsis. Although impaired microbicidal function may be a contributor to infections in these patients (Donini, et al. Blood109:4716, 2007), the predominant problem is a poor ANC response; the biological basis for poor responses of some SCN patients to G-CSF is still unknown. Based on these data, we recommend careful consideration of a match related or unrelated donor hematopoietic stem cell transplant for all patients not achieving a consistent ANC 〉 1.0 × 109 with G-CSF therapy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 6
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 4786-4786
    Abstract: Abstract 4786 Pregnancy in patients with severe chronic neutropenia is associated with high risk of spontaneous abortions. Patients and physicians often ask about benefits and safety of G-CSF administration during pregnancy. We therefore conducted a telephone survey of women of child-bearing potential with the diagnoses of congenital, cyclic, idiopathic or autoimmune neutropenia who are enrolled in the North American branch of the Severe Chronic Neutropenia International Registry (SCNIR). We identified 99 women who had 214 pregnancies before and on G-CSF for this cross sectional study, expanding our previous preliminary investigation, (Boxer et al, ASH abstract 2010). In this population, 31 women had pregnancies before availability of G-CSF, 35 were on long term G-CSF at the time of their pregnancies and 33 were taking G-CSF for some, but not all, of their pregnancies. For those on G-CSF during their pregnancies, the median G-CSF dose was 1.30 mcg/kg/day (mean dose 2.2 ± 0.4 [SEM] mcg/kg/day, dose range 0.1 to 28 mcg/kg/day). Treatment was administered throughout the pregnancy in 74% (49/65) of the pregnancies. Five percent (3/65) were treated only in the 1st trimester, 11% (7/65) were treated only in the last 2 trimesters, 5% (3/65) treated for the last trimester only, and 5% (3/65) treated in 2 of 3 trimesters (2 treated in 1st and 3rd trimesters, 1 treated in the 1st and 2nd trimesters). Sixty-two women with 137 pregnancies while not on G-CSF [congenital neutropenia (CN) N=3, cyclic neutropenia (CyN) N=15, idiopathic neutropenia (IN) N=43, autoimmune neutropenia (AN) N=1] were compared with 47 women having 77 pregnancies while on G-CSF therapy [CN=9, CyN=14, IN=21, AN=3]. Pregnancies occurring in neutropenic women without G-CSF therapy had the following complications: premature labors (8), premature rupture of membranes (1), life-threatening infections (2), and minor infections (5). Patients on G-CSF during pregnancy reported no premature labors (0), no life threatening infections (0), minor infections (5), thrombocytopenia (1), placenta previa (1), abruptio placenta (1), and death following incomplete elective termination (1). By diagnostic category complications in the no G-CSF mothers occurred in 16 patients (CN=1, CyN=5, IN=9, AN=1), compared with nine in the G-CSF treated group (CN=1, CyN=4, IN=4). There were 31 spontaneous miscarriages in the women not on G-CSF (CyN=8, and IN=23) compared with 5 in the women (CyN=4, IN=1) on G-CSF. There were 93 live births from 137 pregnancies in the non G-CSF group. Thirteen of these infants had neonatal neutropenia. Other major neonatal complications in the no G-CSF group included significant infections (3) [meningitis 1, septicemias 2], minor infection (1), cerebral palsy associated with prematurity (1), respiratory distress syndrome (1), and collapsed lung (1). In the G-CSF treated group there were 65 live births from 77 pregnancies. Fifteen of these infants were neutropenic. Other complications in the G-CSF treated group included minor infections (2), abruptio placenta associated with neonatal apnea (1), and premature infants with associated complications (2). There were 2 congenital abnormalities: tracheal esophageal fistula (1) and hydronephrosis (1) in 65 live births, a frequency similar to the general population. This study showed that women with chronic neutropenia who were on G-CSF during pregnancy had a higher percentage of live births, 84% (65/77) than those not on G-CSF, 68% (93/137) (p=0.011, two tailed Fisher exact test). G-CSF therapy was associated with a lower number of spontaneous abortions, with a 6% (5/77) spontaneous abortion rate in the G-CSF treated group versus 23% (31/137) in the non G-CSF group (p=0.003, two tailed Fisher exact test). G-CSF therapy was also associated with a lower rate of serious maternal complications. Two common congenital anomalies (2/65) were observed in the offspring of the G-CSF treated mothers and no anomalies were observed in the offspring of the mothers not receiving G-CSF. Overall the newborns from the G-CSF treated mothers appeared to have fewer neonatal complications. Based on this analysis, we recommend that G-CSF therapy should be offered and continued during pregnancy in women with severe chronic neutropenia. The available data indicates that administration throughout pregnancy is well tolerated and protective of maternal health, including reducing the risk of infections and spontaneous abortions. Disclosures: Boxer: Amgen: Equity Ownership. Dale:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 7
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 502-502
    Abstract: BACKGROUND: G-CSF therapy has reduced sepsis mortality in patients with severe congenital neutropenia (SCN), revealing a syndromic predisposition to myelodysplastic syndrome and acute myeloid leukemia (MDS/AML). The MDS/AML risk appears to be higher in SCN patients who are less-responsive to therapy; however, the genetic determinants of susceptibility remain to be elucidated. METHODS: We studied 82 North American and Australian patients with SCN on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry. These patients had prospective follow-up, sufficient banked DNA for genotyping, and validated clinical data. RESULTS: Fifty-two patients (63%) were positive for germline mutations in neutrophil elastase (ELA2); the remaining 30 patients (37%) had no detectable mutations. Prior to G-CSF therapy, blood cell counts were significantly different between ELA2 positive and negative patients. Compared with ELA2 positive patients, ELA2 negative patients had significantly higher median absolute neutrophil count (ANC) values (158 versus 53 cells/uL, P=0.02), significantly lower monocyte and eosinophil counts (P & lt;0.001), and significantly lower platelet counts (P=0.002). ELA2 negative patients were maintained on significantly lower doses of G-CSF (5.2 versus 9.9 ug/kg/day, P=0.02), consistent with higher baseline ANC values. However, ELA2 negative patients were significantly less responsive to G-CSF therapy. Compared with ELA2 positive patients, on therapy, ELA2 negative patients had significantly smaller median increases in ANC values (1200 versus 2700 cells/uL, P=0.02); the difference remained significant after controlling for individual G-CSF dose (P=0.04). ELA2 negative patients had 5 MDS/AML events in 132 person-years, versus 8 MDS/AML events in 373 person-years among ELA2 positive patients. Using the Cox proportional hazards model, the hazard of MDS/AML was 3.1-fold higher in ELA2 negative patients compared with ELA2 positive patients. This association was of borderline statistical significance (P=0.08). No patient in either group died of sepsis. We found 34 distinct mutations in 52 ELA2 positive patients. The mutation sites were not clustered in the 8 ELA2 positive patients who developed MDS/AML. We found no associations of phenotype or outcome with specific ELA2 mutations; however, the numbers were limited. CONCLUSIONS: SCN patients without mutations in ELA2 constitute a clinically distinct subgroup. ELA2 negative patients are significantly less responsive to G-CSF therapy than ELA2 positive patients, and they may be at substantially higher risk of leukemia. Additional studies are needed to confirm the latter association and identify the causative gene or genes.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 8
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1490-1490
    Abstract: Abstract 1490 There are currently no established guidelines for granulocyte colony stimulating factor (G-CSF) therapy during pregnancy for women with severe chronic neutropenia. To establish treatment recommendations, we reviewed records of women with the diagnoses of congenital, cyclic, idiopathic or autoimmune neutropenia and blood neutrophil counts chronically or recurrently 〈 0.5 × 109/L who were enrolled in the North American branch of the Severe Chronic Neutropenia International Registry (SCNIR). We identified 88 women who had 183 pregnancies for this cross sectional study. We compared outcomes for women treated or not treated with G-CSF during their pregnancies. Fifty-five women [congenital neutropenia (CN) N=4, cyclic neutropenia (CyN) N=13, idiopathic neutropenia (IN) N=37, autoimmune neutropenia (AN) N=1] with 123 pregnancies while not on G-CSF therapy were compared with 41 women (CN =7, CyN=16, IN=15, AN=3) having 60 pregnancies while on G-CSF therapy. During pregnancy the patients not treated with G-CSF had the following complications: 6 premature labors, 1 premature rupture of membranes, 2 life-threatening infections, and 2 minor infections. The G-CSF treated group had no premature labors, no life threatening infections, 5 minor infections, and 1 patient developed severe thrombocytopenia. By diagnostic category the complications in the no G-CSF mothers occurred in 11 patients (IN=9, CyN=1, AN=1), compared with six in the G-CSF treated group (IN=3, CyN=2, CN=1). There were 32 spontaneous miscarriages in the women not on G-CSF (CN=1, CyN=8, and IN=23) compared with 3 in the women (CyN=3) on G-CSF. There were 82 live births from 123 pregnancies in the no G-CSF group. Thirteen of these infants had neonatal neutropenia. Other major neonatal complications in this group included 3 significant infections (1 meningitis, 2 septicemias), 1 minor infection (umbilical cord infection), 1 cerebral palsy, 1 respiratory distress syndrome, and 1 collapsed lung. In the G-CSF treated group there were 53 live births from 60 pregnancies. Twelve of these infants were neutropenic. Other complications in the G-CSF treated group included 1 umbilical cord infection (in a patient of mother with congenital neutropenia) and 1 tracheal esophageal fistula, 1 abruptio placenta associated with neonatal apnea, and 1 hydronephrosis (in infants with cyclic neutropenic mothers). The median G-CSF dose was 1.07 mcg/kg/day for all trimesters. Treatment was administered throughout the pregnancy in 62% (37/60) of the pregnancies. Seventeen percent (10/60) were treated only in the first trimester, 13% (8/60) were treated only in the last two trimesters, 3% (2/60) treated for the last trimester only, and 5% (3/60) treated in two of three trimesters (2 treated in 1st and 3rd trimesters, 1 treated in the 1st and 2nd trimesters). The two live births with congenital abnormalities occurred in G-CSF treated patients; one with tracheal esophageal fistula was exposed in the first trimester, one with hydronephrosis was exposed in all three trimesters. In summary, we found that G-CSF treatment was associated with a higher percentage of live births, 67% (82/123) without G-CSF compared with 88% (53/60) with G-CSF therapy (p=0.002, Fisher exact test). G-CSF therapy was associated with a lower number of spontaneous abortions, 26% (32/123) in the no G-CSF group versus 5% (3/60) in the G-CSF treated group (p=0.001). G-CSF therapy was associated with a lower rate of serious maternal complications. Two common congenital anomalies were observed in the offspring of the G-CSF treated mothers and no anomalies were observed in the offspring of the mothers not receiving G-CSF. Overall the newborns from the G-CSF treated mothers appeared to have fewer neonatal complications. Based on this analysis, we recommend that G-CSF therapy should be offered and continued during pregnancy in women with severe chronic neutropenia. The available data indicates that administration throughout pregnancy is well tolerated and protective of maternal health. Disclosures: Boxer: Amgen, Inc.: Equity Ownership. Dale:Amgen: Consultancy, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 9
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1484-1484
    Abstract: Abstract 1484 Low bone mineral density (BMD) is a known risk factor for fractures. Low BMD has been reported in individuals with severe chronic neutropenia (SCN), and attributed both to the diseases causing neutropenia and to G-CSF therapy. However, given the rarity of SCN, few data exist regarding associations of BMD z-scores with disease characteristics such as type of neutropenia and duration of G-CSF therapy. We present data here obtained from BMD reports collected through the Severe Chronic Neutropenia International Registry (SCNIR). We reviewed BMDs on 128 subjects [40 children ( 〈 21 years of age), 87 females] having sufficient information about lumbar spine BMD by dual-xray absorptiometry (DXA) for evaluation. For subjects with multiple BMD measurements available, the most recent one was used for analysis. Mean age was 32.0 years (range 0.6–85 years). 57 subjects had idiopathic SCN (mean age 40 years), 40 had congenital (mean age 15 years), 28 were cyclic (mean age 41 years) and 3 were autoimmune (mean age 18 years). 122 subjects had received G-CSF at the time of the BMD assessment (mean 8.8 years, range 0.1–19.9 years). 11 of the adults were on bisphosphonate therapy for low BMD at the time of the BMD assessment; no children were on anti-resorptive therapy. BMDs in these subjects were, on average, low. For the children, the BMD z-score (age matched mean ±1 standard deviation) was -1.0 ± 1.1, with 17.5% of children having BMDs that were low for age (Z-score 〈 -2.0). For the adults the BMD t-score was -1.1 ± 1.4, with 46% of adults meeting t-score criteria for osteopenia (≤ -1.0) and 9% meeting criteria for osteoporosis ( 〈 -2.5). BMDs were lowest in those with congenital neutropenia, followed by those with cyclic neutropenia. For children, BMDs were lower in those who had received longer G-CSF therapy (r= -0.506, p=0.002). This association was not seen in adults (r= 0.074, p= 0.5). The low BMDs and the correlation of lower BMD with longer G-CSF treatment in children suggests there is an association of bone loss with the childhood diseases causing SCN. The data also suggest that regular assessments of bone health should be made in SCN patients, particularly those on long-term G-CSF therapy. Disclosures: Boxer: Amgen, Inc.: Equity Ownership. Dale:Amgen: Consultancy, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 10
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2730-2730
    Abstract: 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, ANC 〈 0.5 x 109/L at least 3 times over a 3 month period, neutropenia not due to known systemic autoimmune disease (e.g., lupus, rheumatoid arthritis), cancer or cancer chemotherapy. There is a centralized enrollment process directed through offices in the US (Seattle) and Germany (Hannover). Continued enrollment requires annual follow-up information, i.e., clinical status, treatments and blood counts, and bone marrow reports for some categories of patients. Data on pregnancies, stem cell transplantation (SCT), non-hematological features and complications are also collected on standardized forms for subsets of patients. Comprehensive immunological assessments and genetic testing are encouraged but not required for enrollment. For some patient groups, e.g., Shwachman-Diamond syndrome (SDS) and Barth syndrome, the SCNIR now enrolls patients without severe neutropenia to gain perspectives on long-term outcomes for these disorders. Since 1994 the SCNIR has enrolled more than 2000 patients; 174 died, 193 resolved neutropenia, 543 withdrew or were lost to follow-up and almost all others continue in this long term observation study. The median follow-up for enrolled patients is now almost 10 years. The most common patient categories are idiopathic, cyclic (CyN) and congenital neutropenia (CN); 68% of CyN and 65% of CN patients having sequencing studies have mutations in ELANE. Some specific mutations are associated with high frequency ( 〉 90%) 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.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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