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Severe chronic neutropenia is a group of rare disorders including inborn genetic defects (congenital neutropenia;CN and cyclic neutropenia; CyN) and acquired diseases associated with severe chronic neutropenia. CN includes a variety of genetic subgroups and is well known as one of the premalignant bone marrow failure syndromes with an overall incidence of secondary leukemia of more than 10 percent. Since the availability of G-CSF for the treatment of severe chronic neutropenia patients the life expectancy and quality of life has improved significantly. Therefore, stem cell transplantation is to date limited to few indications, e. g. G-CSF treatment non-response or secondary leukemia. Here we report on the outcome of stem cell transplantations in 71 patients (70 CN, 1 CyN) documented by the SCNIR since 1994. Results Reason for SCT was myelodysplastic syndrome or secondary leukemia in 34 CN and 1 CyN patients (LEUK+), G-CSF treatment non-response in 17 CN patients and other non-malignant events (e.g. G-CSF receptor mutation) in 19 CN patients (LEUK-). In 56 of 71 patients genetic testing was available revealing 28 ELANE (11 LEUK+; 17 LEUK-), 7 HAX1 (6 LEUK+; 1 LEUK-), 7 SBDS (5 LEUK+; 2 LEUK-), 1 G6PT (LEUK+), 1 G6PC3 (LEUK-) 1 p14 (LEUK-), digenic mutation (HAX1 plus G6PC3) in 1 (LEUK-) and no gene mutation in 10 patients (6 LEUK+; 4 LEUK-). In 13 CN (7 Leuk+/6 Leuk-)and the CyN (Leuk+) patient no genetic testing was performed. For further analysis patients were divided by SCT indication (35 LEUK+ versus 36 LEUK-) and both cohorts by year of SCT (before and since 2001) to acknowledge differences in SCT outcome over time due to improved HLA-typing and concomitant treatment (e. g. GvHD prophylaxis) and a change in SCT strategy in the LEUK+ cohort by introducing a new SCT protocol in 2001. Patients are characterized as follows: LEUK+ prior to 2001 (n=11):5/6 male/female. Median age at SCT 10 years. Median follow-up of 0.54 years (max. 13.2 years). Median time between leukemia diagnosis to SCT 6.5 months. Median G-CSF dose 4.5 mcg/kg/day. LEUK+ since 2001 (n=24):9/15 male/female. Median age at SCT 12 years. Median follow-up of 4.5 years (max. 10.42 years). Median time between leukemia diagnosis to SCT 2.5 months. Median G-CSF dose 15.11 mcg/kg/day. LEUK- prior to 2001 (n=9):4/5 male/female. Median age at SCT 8 years. Median follow-up of 10.9 years (max. 27.2 years). Median G-CSF dose 24.5 mcg/kg/day. LEUK- since 2001 (n=27):15/12 male/female. Median age at SCT 5 years. Median follow-up of 3.08 years (max. 9.2 years). Median G-CSF dose 9.9 mcg/kg/day. 22 different chemo-conditioning regimens were used. Busulfan based regimens were chosen in the majority of LEUK+ and LEUK- patients independent from HLA-donor and stem cell resource. In the LEUK+ cohort before 2001 SCT was performed mainly in 2ndremission following standard chemotherapy protocols, whereas since 2001 due to the new protocol SCT was performed immediately after leukemia diagnosis without standard anti-leukemic therapy. An increase of survival rate from 27.3% (8 deaths out of 11 patients) to 83.3% (4 deaths in 24 patients) in the LEUK+ cohort is highly significant (p<0,001). In the LEUK- cohortsurvival has improved over time from 66.7% prior 2001 to 77.8% since 2001. Conclusion Secondary leukemia is the major reason for SCT in CN patients followed by G-CSF treatment non-response. Comparing SCT prior 2001 with SCT since 2001, SCT survival has improved in the LEUK- indications by 13 % independent from the conditioning regimens used for SCT and HLA match of SCT donors. These results may indicate improved HLA typing, GvHD prophylaxis and treatment for infectious episodes. In comparison, in the LEUK+ cohort a dramatic improvement was documented with an increase of survival rate from 27 % to 83% indicating the additional impact of a shortened time interval between leukemia diagnosis and SCT in combination with the avoidance of standard chemotherapy treatment prior to SCT by the new SCT protocol. Disclosures: No relevant conflicts of interest to declare.

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4722 Severe congenital neutropenia (CN) comprises a heterogeneous group of disorders with a common hematological and clinical phenotype characterized by a maturation arrest of myelopoiesis at the level of the promyelocyte / myelocyte stage with peripheral blood absolute neutrophil counts (ANC) below 0.5 ′ 109/l and early onset of bacterial infections. Current data on the molecular causes have demonstrated that CN is a multigene disorder with more than 10 genes described to date. Genetic analyses in autosomal dominant and sporadic cases of CN indicate that the majority of these cases are attributable to mutations in the elastase 2 (ELANE) gene encoding neutrophil elastase. However, mutations in the ELANE gene do not discriminate between patients with CN and patients with cyclic neutropenia (CyN). Since 1987, recombinant human Granulocyte-Colony stimulating factor (G-CSF) is available for the treatment of CN. Independent of the genetic subtype, more than 90% of patients respond well to G-CSF with sustained increase of absolute neutrophil counts and prolonged life expectancy. Since our first patients have reached adulthood the desire for parenthood arises. To-date there is only limited data on the infectious risk for affected mothers and their children due to G-CSF treatment during pregnancy. In this study we assessed the outcome of pregnancies reported to the SCNIR in Europe since 1994 with regard to:The neutropenia status in newborns of mothers and fathers with different genetic CN subtypes as an indicator for inheritance.The impact of G-CSF treatment on maternal and newborn complications in women of all neutropenia subtypes with or without G-CSF treatment during pregnancy. Since 1994 the SCNIR has collected long-term follow-up data of 510 patients with severe chronic neutropenia subtypes. 3 patients are diagnosed with congenital (71 ELANE-CN, 31 HAX1, 9 GC6PC3, 47 SDS, 117 unknown, 45 other), 66 with cyclic and 82 with idiopathic neutropenia. Adulthood was reached by 144 out of 304 CN patients. These include 38 ELANE-CN patients (male:14, female:24) and 11 ELA-CyN patients (male: 5, female:6). A total of 20 pregnancies in 12 mothers and 13 newborns by 7 fathers with different genetic subtypes of CN have been reported. Among them are pregnancies of 11 women with ELANE-CN, 8 with ELANE-CyN, 1 with SDS, 13 with an unknown genetic origin of CN (n=9) or CyN (n=4). No pregnancies were reported in patients with HAX1 or G6PC3 although 7 of these patients have reached adulthood. Data on neutropenia status was documented in 24 out of 31 live births. Neutropenia in newborns was diagnosed in 16 out of 30 live births from parents with genetic subtypes of CN. In 8 of the 16 affected newborns neutropenia was related to ELANE mutations. One mother registered with SDS delivered a healthy child. During pregnancy 17 women received G-CSF treatment (CN=11, CyN=4, IDN=2). Regardless of any cytokine treatment no major infectious complications were reported in our cohort. 24 of 31 reported pregnancies resulted in life births. 5 spontaneous terminations occurred in women with respectively without exposure to G-CSF. In addition, 2 still births were reported in women with idiopathic neutropenia, but G-CSF exposure remains unknown. Conclusion: The proportion of newborns with congenital neutropenia indicates the pattern of inheritance by their parents and reveals the need for genetic counseling. However, the acceptance of having affected children may reflect the high quality of life due to G-CSF treatment in affected parents. G-CSF treatment during pregnancy is well tolerated. In terms of G-CSF treatment, no differences in infectious complications during pregnancy in women with or without G-CSF administration were reported in our cohort. Interestingly, the proportion of women receiving G-CSF during pregnancy is highest among the CN subtype indicating the severe clinical phenotype. We therefore recommend the application of G-CSF in patients with severe chronic neutropenia during pregnancy. Disclosures: No relevant conflicts of interest to declare.

Congenital neutropenias include a heterogeneous group of diseases characterized by a decrease in circulating neutrophils and different underlying germ-line gene mutations. Since 1988 recombinant human G-CSF is available for the treatment of severe chronic neutropenia patients. In phase I/II/III studies in patients with severe congenital and cyclic neutropenia, treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) resulted in a rise in the absolute neutrophil counts (ANC) and a reduction in infections. The Severe Chronic Neutropenia International Registry collects clinical information on patients suffering from severe chronic neutropenia since 1994. 312 of 379 CN and 65 of 79 CyN patients receive long-term G-CSF treatment for a median duration of 8,26 years in CN and 9,37 in CyN. Median G-CSF doses vary by neutropenia subtype and gene mutation. Patients with congenital neutropenia revealing ELANE mutations require the highest G-CSF doses compared to other subtypes (median G-CSF dose 5 µg/kg/day in 88 patients). SCNIR follow-up data suggest that pediatric ELANE-CN patients were maintained at a particular G-CSF dose per kg body weight for longer than expected by the gain of body weight. We therefore analysed the reported yearly G-CSF doses in all treated ELANE-CN patients to evaluate the dose trend: From 88 G-CSF treated patients with ELANE-CN we excluded 16 patients with nonresponse (ANC remained below 0.5 x 109 /L) and partial response (ANC remained between 0.5 and 0.99 x 109 /L). Since the gain of body weight is highest during the first 5 years of life with and 10-fold increase we divided G-CSF good responders by age at G-CSF initiation (0-5 years vs above 6 years) and compared G-CSF doses at the end of the dose finding period with the last dose reported. 51 of the remaining 72 patients started G-CSF treatment between the first and 5th year of life with a median G-CSF treatment duration of 9.76 years. 37 of the 51 patients were treated for at least 5 years. In 21 of the 72 patients G-CSF treatment was initiated after their 10thbirthday with a median follow up of 20.45 years. 19 of the 21 patients were treated for at least 5 years. All patients with a treatment duration of less than 5 years were excluded from further analysis. In ELANE-CN patients with treatment start at an age of 0-5 years the mean G-CSF dose decreased significantly from 13.47 µg/kg/day at the time of ANC-response to 7.96 µg/kg/day at the last report (median G-CSF dose decreased from 6.85 µg/kg/day to 4.42 µg/kg/day) during a treatment duration of at least 5 years. In summary, a significant decrease in the individual G-CSF doses could be observed in ELANE-CN patients who started G-CSF treatment during the first five years of their lives suggesting an age dependent alleviation of the severity of the disease as judged by the response to G-CSF. Disclosures No relevant conflicts of interest to declare.