ALBERT

Description: Abstract 4816 The objective of this study was to determine the efficiency of the neonatal screening program for SCD which was implemented in 1994 in few maternities and extended in 2003 to all maternities in Brussels. It is a systematic screening performed on liquid cord blood. Affected children are referred to a specialized center. We reviewed 146 medical records of patients with SCD born in Belgium and prospectively followed from the time of their diagnosis in three Brussels' Academic Centers. The study was approved by each local ethical committee and informed consent of each patient was received. Data were collected from the time of diagnosis of SCD (either done by neonatal screening or when a clinical event led to the diagnosis) until December 31, 2007. We focused on the subgroup of patients older than 3 years of age at December 31, 2007 and those were divided into two groups: those diagnosed by the neonatal screening (NS) and those diagnosed later (no NS). The incidence of major events (first septicemia, first stroke, first episode of severe anemia, first hospitalization and its duration, and death) was compared. Among the total population studied, 89 patients were diagnosed through the NS and 57 were not (no NS). While among those older than 3 years of age at the time of evaluation, 55 (median age 6.7 year, range: 3–16) and 49 (median age 11.2 year, range: 4–27) patients were in the NS or no NS group, respectively. The median age at diagnosis for the no NS cohort is 1 year (range: 1–6). The follow-up of the NS and no NS cohort account for 301.5 and 473.8 patient-years, respectively. Most of the patients were homozygous for Hb S (Hb SS) (82% in NS group and 94% in no NS group). Incidence of a first episode of septicemia was similar in both groups (10.9% in NS group versus 12.3% in no NS group). The median age at the time of sepsis was 27.6 months and 10 months in the NS and no NS group, respectively (Table 1). All the patients from the NS group were on penicillin prophylaxis versus 40 % in the no NS group. The main pathogen remained Streptococcus pneumoniae and there were no resistant strain despite regular prophylaxis.Table 1:Data on first septicemia in the non neonatal screening groupPatientAge at diagnosisAge at septicemiaProphylaxisPathogen13 m12 mYesSt. pneumoniae226 m3 mNoSt. pneumoniae310 m16 mYesSalmonella42 m14 mNoSt. pneumoniae511 m1 dNoSt.β hemol gr A61 m26 mYesSt. pneumoniae Incidence of stroke was 1.8% (1/55; 3.2 y.o.) in the NS cohort compared to 8.2% (4/49; 2.8, 5.3, 8.0 and 18.8 y.o.) in the no NS cohort. All the patients were Hb SS. The unique patient from the NS group was previously treated with Hydroxyurea (HU) for repeated vaso-occlusive crisis. 2 were also under HU prior to stroke for the same reason. Ischemic cerebral lesions were observed on MRI for all, except for the NS group patient. There was no significant difference either in the incidence of the first episode of severe anemia or the first hospitalization defined in term of number of days of hospitalization for both groups. Two deaths occurred in the NS cohort in the very early childhood (septicemia in one and acute severe anemia for the other). These deaths are attributable to no compliance to antibio-prophylaxis in the first patient and poor follow-up in the second one. Furthermore these deaths happen in the very early period after neonatal screening has been initiated. No death occurred in the NS group since 12 years probably due to better parents' education and comprehensive care. One death was observed in the no NS group (sudden rupture of cerebral aneurysm). In conclusion, neonatal screening program is feasible, safe and appropriate to detect SCD. It enables early diagnosis and therefore early treatment, and could improve both morbidity and eventually mortality of SCD. Although the relative small size of our study and the bias due to unreported early deaths by infection or severe anemia in the no NS group before the diagnosis of SCD has been done, our results are very encouraging: neonatal screening delays the age of the first severe infection and might reduce the incidence of early neurological complications. It also underlines the better outcome with improvement of parental education and comprehensive care. These data emphasize the need to continue neonatal screening for SCD in Brussels and to extend it to all Belgian maternities. Disclosures: No relevant conflicts of interest to declare.

Description: The short-term beneficial effect of hydroxyurea (HU) in sickle cell disease (SCD) has been proven by randomized studies in children and adults. The Belgian registry of HU-treated SCD patients was created to evaluate its long-term efficacy and toxicity. The median follow-up of the 93 patients registered is 3.5 years; clinical and laboratory data have been obtained for 82 patients at 1 year, 61 at 2 years, 44 at 3 years, 33 at 4 years, and 22 after 5 years. On HU, the number of hospitalizations and days hospitalized dropped significantly. Analysis of the 22 patients with a minimum of 5 years of follow-up confirm a significant difference in the number of hospitalizations (P = .0002) and days in the hospital (P 

Description: From 06/93 to 12/99, 1395 children and adolescents were included in the FRALLE 93 protocol: group A (Very Low Risk): 182, B (Standard risk): 672 and C (High risk including T-ALL): 541. The median FU is 9.5 yr. Inclusion criterias in group B were: age between 1 and 15 yr, WBC〈 100,000, BCP phenotype and no poor-prognosis cytogenetic feature (MLL rearrangement or Ph1). Group B pts were randomised in a 2-steps schedule: at inclusion: daunorubicin (DNR: 40 mg/m2 × 2) vs idarubicin (IDA: 8 mg/m2 × 2), and at consolidation: high-dose IV methotrexate (HD-MTX): 4 × 8g/m2 at D1, D15, D29 and D42, vs low-dose po MTX (LD-MTX): 4 × 25 mg/m2; the number of triple IT was the same for both arms (N = 18). Pts with CNS leukemia were not randomized for MTX. During induction, pts were also classified on D21 bone marrow aspiration according to the level of residual blasts: M1 (〈 5%): n=555, M2 (6–25%): n=71 and M3 (〉 25%): n=41; M2/M3 pts received 1 more antracyclin infusion at D22 and M3 pts were subsequently treated according to the HR group and not randomized for MTX. Both M1 and M2 pts who reached CR were randomized for MTX. The overall group B EFS, DFS and OS were respectively 80±2, 81±2, and 91±1%. Globally there is no statistically significant impact of 1st or 2nd randomization on the outcome of patients. When we look at the outcome according to the D21 status, the EFS are very different: M1: 84±2%, M2: 63±6% and M3: 74±7%. The very poor EFS of M2 pts, who can not actually be classified as SR pts, and the fact that M1 pts represent 90% of pts randomized for MTX led us to analyse separately M1 pts. For M1 pts there is no interaction between 1st and 2nd randomization for survival, EFS and relapse rate (Gail and Simon test, p = 0.51); therefore pts were pooled for 2nd randomization analysis. Among M1 pts, 271 pts were randomized for HD-MTX and 264 for LD-MTX; there is no difference regarding age or leucocytosis between the 2 arms. Results are as follows: 5-yr EFS Relapses CI iBM relapses CI Other relapses CI 5-yr OS (EFS: event-free survival, CI: cumulative incidence, iBM: isolated bone-marrow, OS: overall survival) HD-MTX 87.82±1.99% 0.12±0.04 7.01±0.02 5.17±0.02 95.20±1.30 LD-MTX 79.92±2.47% 0.20±0.06 10.6±0.03 9.10±0.03 88.64±1.95 Test log-rank Gray Gray Gray log-rank p value 0.028 0.037 0.16 0.18 0.07 At the contrary, among M2 pts there is no difference in EFS for pts treated with HD-MTX (61±7%) and LD-MTX (65±9%) Conclusion: HD-MTX seems to benefit to pts with standard-risk BCP-ALL and good early response to chemotherapy, and the benefit is associated with a reduction in the number of relapses. No benefit is demonstrated in M2 pts with SER who have a very poor outcome and do require a more intensive treatment; the better EFS of M3 patients treated with double delayed intensification is in favour of this hypothesis.

Description: From Dec 2000 to Dec 2003, 390 children with SR-BCP-ALL (age: 1–9, WBC 10−3, or according to the exact level of positivity. Results: 1) 15% (51/336 pts) of the SR-BCP ALL have a detectable MRD at EOI 2) As expected, whatever the threshold, pts with D21 M2/M3 marrow are more likely to have a detectable MRD (p=.0017). But 43/316 M1 pts (14%) have a highly +ve (n=19;6%) or weakly +ve MRD (n=24 ; 8%). Surprisingly, only 1 out 20 M2M3 pts had a MRD 〉 10−2 while it is the case for 8 out 316 M1 pts (p=NS). If only pts receiving DNR are considered (DNR+ M1 pts and all M2/M3 pts), again pts with D21 M2/M3 marrow are more likely to have a detectable MRD (p=.0015). 3) If we compare the MRD levels in the 2 arms (DNR+ve or neg) in the 315/343 M1 pts evaluable for MRD: 136 pts in each arm had no detectable MRD; 16 and 8 have a weak positivity in the DNR− and DNR+ arm respectively while 10 and 9 have a weak positivity in the DNR− and DNR+ arm respectively: p= .29). If the exact level is considered, this absence of difference remains at all levels considered. Conclusions: 15% of the SR-BCP ALL have a detectable MRD at EOI after a three or four-drug induction. D21 M2/M3 pts are more likely than M1 pts to have a detectable MRD at EOI but 14% of the D21 M1 pts have a high (〉 10−3) or very high MRD (〉 10−2) which confirms the added value of MRD detection to classical morphology. The MRD level at EOI is not different in SR-BCP-ALL after a three or four-drug induction regimen. This is of paramount importance since EOI MRD is a surrogate marker for probability of relapse.

Description: The FRALLE 93A protocol aimed to identify a very low-risk ALL subgroup, to limit treatment morbidity and to investigate the value of intermediate dose methotrexate. Inclusion criteria were : B-cell precursor ALL, age 2-7 years, leukocyte count

Description: From December 2000 to May 2004, 433 children with SR-BCP-ALL (age: 1–9, WBC 1%). RESULTS: 1. Efficacy : no leukemic induction failure and a low incidence of patients with D21 M2/M3 marrow have been observed (5 % versus 13% in the FRALLE 93 for the same population). Only 4 out 319 evaluable pts (1.3%) have a high EOI MRD (≥ 1%) at the end of induction therapy. Five relapses have only been observed yet even if MFU is still short (31 months). 2.Toxicity: Seven cases of non leukemic deaths have been observed. Main grade III-IV toxicities were attributable to L-Aspa (CNS thrombosis: 5pts, pancreatitis: 8 cases, allergic reaction during DI °2: 35 pts). One case of secondary AML was observed (UPN98: no DNR) (25 months of CR) with translocation t(9;11) and MLL rearrangement. 3.Randomization: at this FU no difference between the DNR+ and DNR- arms is obvious neither in terms of toxicity nor efficacy. CONCLUSIONS: Most of the initial unusual toxicities mentioned where related to asparaginase even if potentially increased by the use of DEX during induction. Since most of the pancreatitis or CNS thrombosis episodes have been reported before July 2002, a potential hypothesis on the variation in the batches of the E.Coli asparaginase used in France can be made beside the classical ones (learning effect ....). Efficacy results, although preliminary, are very encouraging since at the same MFU 4 times more relapses (20 out of 410 pts) were observed in the FRALLE 93 for a comparable population.

Description: Abstract 2659 Sickle cell disease (SCD) has polymorphic manifestations, it is not well known by many physicians, and patients have often a precarious status. So despite enormous improvements in the understanding of the pathogenesis of SCD, patient care remains difficult.The objectives of this work were to create a clinical data base in order to learn the characteristics of this population, to create a network between practitioners (general, emergency and specialist practitioners), to provide state-of-the art and guidelines, it could be a tool to disseminate information, for education projects and for research; it could also represent a pilot project for other chronic diseases. A practical aspect of this data base is to improve follow-up and treatment of SCD patients by “online access from everywhere”. The SCD clinical data base was a national project and was approved by each local ethic committee; informed consent of each patient was obtained. The first step was to create the electronic database with several security measures (i.e. login, password, and separate administrators). The second step was to introduce patient's data. Patients were followed in different Academic and Secondary Care Centers. Data were collected from the initial contact until December 31, 2007. The data collection included parents' origin, hemoglobin phenotype, origin of diagnosis, clinical events, biological and radiological data, hospitalizations, and types of treatment. Up to date, we introduced 280 medical records (146 diagnosed by neonatal screening). The median age and follow-up of the cohort was 9.3 year (range, 0–44) and 6.5 year (range, 0–32), respectively. The first information provided was the predominance of patients from DR Congo (67.5 %), the occurence of severe events in 84 % of patients (Table 1), the predominance of Hb SS phenotype (90 %) and its severity, the report of septicemia which remain still very worrying (8.2 %), but also that clinical and radiological neurological events are sizeable, and that there is a good response to treatment intensification, particularly to bone marrow transplantation (BMT) and hydroxyurea. Table 1: SCD related events reported in the Belgian data base SCD related events Patients,%(n) Dactilytis 24.3 (68/280) Acute Chest Syndrome 18.9 (53/280) Recurrent Vaso-occlusive Crisis 61.8 (173/280) Anemia ≤ 6 g/dl 51.8 (145/280) Septicemia 8.2 (23/280) Splenic sequestration 7.9 (22/280) Stroke/TIA 3.9 (11/280) Osteonecrosis 5.0 (14/280) Osteomyelitis 2.5 (7/280) The main pathogen remained Streptococcus pneumoniae with no resistant strain despite regular prophylaxis. The second most common germ was Salmonella. Haemophilus influenza concerned older patients and disappeared since the introduction of the vaccination. The incidence of death was 2.86% (8/280). All of them were homozygous for Hb S. Two deaths occurred in the very early childhood due to the no compliance to antibio-prophylaxis in the first patient and poor follow-up in the second one. One death was very sudden after meningeal hemorrhage. Two other deaths happened in the adulthood, one after cerebral hemorrhage and the other one of unknown cause after going back to native country. The last three deaths were due to BMT complications (Table 2). Table 2: Causes of death reported in the national data base Patient Sex Phenotype Age at event Origin 1 F SS 18 m Cardiopulmonary arrest - Severe anemia 2 M SS 26 m Septic shock on St pmeumococcus septicaemia 3 M SS 7 y Secondary Leukemia after BMT 4 F SS 11 y 9 m Obliterans bronchiolitis/MOF* post BMT 5 M SS 14 y 3 m Meningeal hemorrhage 6 F SS 14 y 9 m Hemorrhage diathesis/MOF post BMT 7 F SS 18 y 9 m Cerebral aneurysm rupture 8 M SS 24 y 3 m Return to native country * Multiple Organ Failure In conclusion, the preliminary results confirmed the still high morbidity and mortality of SCD. It is not only a precious practical tool, but it also helps to improve clinical management of patients with SCD, it is a tool to identify risk factors and to tailor treatments. In this perspective, it constitutes a basis for prospective studies in view to validate criteria of disease severity and to adopt guidelines for adequate treatment. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Genetic counseling in sickle cell disease (SCD) allows to inform people about the genetic condition and to make informed decisions about screening and treatment opportunities. With improvement of care and follow-up of SCD and in order to provide adequate genetic counseling, the current study compared the clinical presentation of patients with hemoglobin SC disease (SC) and sickle cell anemia (SS) or SBeta°-thalassemia (Sβ°). Methods: The Belgian SCD Registry currently includes patients followed in 8 centers. Data was retrieved retrospectively from their medical charts until 2008. From 2008 till December 2012, all data (known and new cases) was prospectively entered. Data was collected either from birth, for patients diagnosed by means of the neonatal screening program (NSP) or from diagnosis following the first contact in a center and consistently until the last follow-up (FU) visit, or death. Data included genotype, demography, method and date of diagnosis, SCD-related complications, biological parameters, radiological results, treatment and hospitalizations. Results: Among the 469 patients recorded, 36 (8%) were SC. Their demographic and outcome data are given in Table 1, subgroups of SC patients detected at birth or not are given in Table 2. FU was 292 and 4749 patient-years (PY) for SC and SS/Sβ° groups respectively. Median age at diagnosis for SC and SS/Sβ° subgroups not detected at birth was 6.7 and 2.6 y. The first vaso-occlusive crisis (VOC) in SC patients occurred earlier in neonatal screened patients (5y vs 17y; P=0.004). Osteonecrosis was observed only in 6 patients diagnosed at birth but was significantly more frequent in SC individuals (P=0.02). Among the 6 SC patients treated with hydroxyurea (HU), indications for treatment were recurrent VOC (n=4), proteinuria (n=1) and osteonecrosis (n=1). Hospitalization days per 100 PY were 123 for the SC NSP cohort and 373 for the SS/Sβ° NSP cohort, with total hospitalization days significantly lower in SC patients (160 vs. 4059 days ; P=0.03). Discussion: SC patients represent 8 % of the whole cohort but asymptomatic and undiagnosed patients probably exist. Overall they are much less represented than in other Western series. They are significantly less affected by VOC, acute chest syndrome (ACS), severe anemia than SS/Sβ° patients but did not differ for occurrence of retinopathy or osteonecrosis. Several published studies confirmed these data but showed also others complications such as severe infection, stroke and death. Our data doesn’t support any impact of NSP on occurrence of major complications for SC disease. Retinopathy incidence that increases with age is as expected lower in the NSP group (younger patients at last FU when compared to no NSP group). Older age at first VOC in the no NSP group results probably from previously undiagnosed mild disease. Nevertheless several SC patients were more severely affected requiring HU treatment. Limitations of our work are linked to the small size of our SC cohort, the nature of the partial retrospective study and the unknown number of SC patients not requiring care in a specific program. In conclusion, SC patients have a lower incidence of clinical events than SS/Sβ°, excepted for osteonecrosis and retinopathy equally observed in both groups. Our data support the need of early ophthalmological FU and special awareness to detect early osteonecrosis. These Belgian data may support a dedicated genetic counseling for SC patients and affected families. Table 1. SC and SS/S β 0 patients: demographic and outcome SC SS/Sβ0 P Number of patients 36 (8%) 423 (90,2%) Male 14 (39%) 201 (48%) NS NSP 19 (53%) 142 (34%) Median age at diagnosis years (range) 0 (0-35) 1 (0-29) NS Median age at last FU years (range) 9,9 (1,4-44) 13 (1-53) NS Severe anemia 〈 60g/L 3 (8%) 208 (49%) 〈 0,01 ACS 1 (2,8%) 119 (28%) 〈 0,01 VOC 11 (31%) 253 (60%) 〈 0,05 Stroke 0 17 (4%) NS Severe infection 0 35 (8%) NS Osteonecrosis 4 (11%) 36 (8,5%) NS Retinopathy 4 (11%) 25 (6%) NS HU treatment 6 (17%) 179 (42%) 〈 0,05 Deaths 0 13 (3%) NS Table 2. SC patients from NSP vs no NSP: demographic and outcome NSP no NSP P Number of patients 19 (53%) 17 (47%) Male 10 (53%) 4 (24%) NS Median age at last FU years (range) 6 (1-14) 14 (4-44) NS Severe anemia 〈 60g/L 2 (10,5%) 1 (6%) NS ACS 0 1 (6%) NS VOC 5 (26%) 6 (35%) NS Osteonecrosis 3 (16%) 1 (6%) NS Retinopathy 0 4 (23,5%) 0,04 Disclosures No relevant conflicts of interest to declare.

Description: Abstract 135 From December 2000 to June 2010, 1201 children with SR-BCP-ALL (age: 1–9 years, WBC

Description: Key Points Patients with thalassemia major or sickle cell disease had excellent outcomes after both CBT and BMT from an HLA-identical sibling. Related cord blood transplantation is a suitable transplant option for patients with hemoglobinopathies.