ALBERT

Description: Introduction. Chronic myeloid leukemia(CML) is a very rare disease in children and adolescents. The international registry of CML in children and adolescents gives us the opportunity to assess the prognostic relevance of variant t(9 ;22) and additional cytogenetic abnormalities at diagnosis on prognosis. Patients and Methods. We used clinical and biological characteristics and outcome of 239 children and adolescents less than 18 years to assess the impact of additional cytogenetic abnormalities and variant t(9 ;22) on the rate and the time to achieve a complete cytogenetic response (CCyR). Cytogenetic analysis was performed 24 or 48 hour culture on G-banded metaphases. Results. Overall, 17/239 children (7.1%) presented with additional cytogenetic finding at diagnosis: 5/239 children (2.1%) had a variant of the t(9;22), 10 children (4.2%) had other additional cytogenetic (numerical/structural) abnormalities (ACA), and 2/239 (0.8%) had both. Characteristics of the patients and phase of the disease are reported in Table 1. In the 7 patients with variant t(9;22), one (chromosome 1 in 3 patients, chromosome 8 in 2 patients and chromosome 14 in one patient) or two further chromosomes (chromosomes 8 and 17) were involved in 6 and one patient(s), respectively. In the 12 patients with ACA, 9 patients have one type of ACA, 2 patients have 2 type of ACA and one patient have 3 type of ACA. Regarding the patients in chronic phase at diagnosis (n=219), the cumulative incidence of complete cytogenetic response at 18 months was 88% (95% CI: 82 % - 93%) and 70% (95% CI: 42% - 93%) for patients without variant t(9;22) or ACA and for those with variant t(9;22) and/or ACA (p=0.151), respectively. Three deaths were recorded (among them one patient had ACA at initial diagnosis). With a median follow up of 43 months (range 1 – 161) the probability of 3 years overall survival was 99% (95% CI: 94 % - 100%) and 88% (95% CI: 39 % - 98%) for patients in chronic phase without variant t(9;22) or ACA and for those with variant t(9;22) and/or ACA (p=0.042), respectively. Conclusion. Additional chromosomal abnormalities at diagnosis in children with CML in chronic phase may have an impact on the outcome. A larger cohort of patient and a longer follow up is needed to confirm such findings. Table 1. Cytogenetic No variant t(9;22) or ACA Variant t(9;22) ACA Variant t(9;22) and ACA Number of patients 222 5 10 2 Sex (% males) 56% 60% 50% 100% Median age, yrs (range) 12 (1-18) 14 (9-17) 12 (5-16) 6 and 17 Phase of the disease (n) chronic accelerated blastic 208 12 2 3 1 1 7 1 2 1 0 1 Acknowledgment: The I-CML Ped study is supported by an unrestricted grant from Novartis Pharmaceutical Company Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease characterized by impairment of the phagocyte NADPH-oxidase complex, resulting in deficient microbial killing and life-threatening bacterial and fungal infections. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative approach, but it can be complicated by graft failure, graft versus-host disease (GvHD) and transplant-related mortality (TRM). In order to define prognostic risk factors in this setting, the IEWP of the EBMT performed a large retrospective registry study on 600 pediatric and adult patients with CGD undergoing allo-HSCT. Patients and Methods: We analyzed the outcome of patients with CGD who received allo-HSCT in EBMT centers between 1993 and 2017. The main end-points of the study were overall survival (OS) and event-free survival (EFS; events were death and primary or secondary engraftment failure) according to patient's age, donor type, stem cell source and conditioning regimen. One patient died before allo-HSCT and was excluded from analysis. Results: We studied 536 children (aged 〈 18 years) and 63 adults (aged ≥ 18 years) affected by CGD. The median follow-up was 45.37 months (IQR 15.8-81.8). Genetic results were available for 307 patients: inheritance was X-linked (75%) or autosomal recessive (25%). Median age at transplant was 7.2 years (range: 0.12-48.56). Conditioning regimen was Busulfan/Fludarabine (n=244; 41%), Busulfan/Cyclophosphamide (n=104; 17%), Treosulfan/Fludarabine (n=76; 13%), Treosulfan/Fludarabine/Thiotepa (n=52; 9%) or other drug combinations (n=123; 20%). Donors were human leukocyte antigen (HLA) matched related (MFD, 10/10; n=211, 40%), matched unrelated (MUD, 10/10 or 6/6 in UCB; n=201; 38%), mismatched related (MMFD, ≥ 9/10; n= 27; 5%) or mismatched unrelated (MMUD, ≥ 9/10 or 5/6 in UCB; n= 83; 16%). Stem cell source was bone marrow (BM; n=408; 69%), peripheral blood (PB; n=153; 26%) or umbilical cord blood (UCB; n=27; 5%). Donor engraftment occurred in 516 evaluable patients (88%), while primary or secondary engraftment failure occurred in 68 patients (12%). Seventy-nine patients (13%) died after allo-HSCT. The 2 year Kaplan-Meier estimate of OS and EFS were 87.1% (95% CI, 84.2-89.9) and 77.8% (95% CI, 74.2-81.4), respectively (Fig A). The 2-year cumulative incidence of grade II-IV acute GvHD, chronic GvHD and extensive chronic GvHD was 18.6% (95%, 15.1-22.2), 16.2 % (95%, 18.8-19.7) and 5.5% (95%, 3.4-7.7), respectively. A univariate cox model with spline term demonstrated that older age at transplant was associated with an increased risk of death (p=0.002). Children undergoing allo-HSCT had a superior 2y OS (88.1%; 95% CI 85.2-91.0), compared to adults (78.2%; 95% CI, 67.7-88.7), p=0.03 (Fig B). Patients undergoing allo-HSCT from a MFD had a superior EFS (86.5%; 95% CI 81.5-91.4) compared to MUD (73.3%; 95% CI 66.7-79.9), MMUD (78.2%; 95% CI 69-87.5) and MMFD (59.7; 95% CI 40.4-79.1), p〈 0.001 (Fig C). Patients receiving BM grafts had superior 2y EFS (81.0%; 95% CI 76.9-85.1) compared to PB (72.5%; 95% CI 64.7-80.4) and UCB (66.7%; 95% CI 48.9-84.4), p=0.04. The pattern of disease inheritance and the choice of conditioning regimen didn't have an impact on outcome (Fig D). Fifty-three patients with graft failure underwent a second allo-HSCT and the 2y OS in this group was 82.1% (95% CI, 71.5-92.7). Year of transplantation didn't have an influence on outcome. Conclusion: This is the largest study describing the outcome of allo-HSCT in children and adults affected by CGD. We demonstrate an excellent outcome, with a low incidence of graft failure, TRM and GvHD. Older patients with CGD have reduced survival after allo-HSCT, indicating that transplant should be considered at a younger age. The use of a MMFD is associated with poorer outcome; indication to transplant in this setting should be carefully evaluated by the treating physicians. Disclosures Chiesa: Bluebird Bio: Consultancy; Gilead: Consultancy. Kalwak:medac: Other: travel grants; Sanofi: Other: travel grants. Sykora:Aventis-Behring: Research Funding; medac: Research Funding. Locatelli:Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wynn:Orchard SAB: Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Equity Ownership; Chimerix: Research Funding; Genzyme: Honoraria; Bluebird Bio: Consultancy; Orchard Therapeutics: Consultancy; Chimerix: Consultancy. Zecca:Chimerix: Honoraria. Veys:Pfizer: Honoraria; Servier: Research Funding; Novartis: Honoraria. Slatter:Medac: Other: Travel assistance.

Description: Key Points The outcome of HSCT in this large SCN cohort is acceptable. Given the TRM, a careful selection of HSCT candidates should be undertaken.

Description: Aims: To determine in children and adolescents with chronic myeloid leukemia (CML) in chronic phase (CP) treated with imatinib front line, (i) the probability of switch to a second line therapy, (ii) to characterize the reasons and the type of switch and (iii) to determine the impact of the switch on outcome. Methods: Children and adolescents (

Description: Introduction: Philadelphia-positive chronic myelogenous leukemia (CML) is a rare disease in children and constitutes approximately 3-5% of all childhood leukemias. With tyrosine kinase inhibitors (TKI), the frequency of accelerated phase (AP) or blast crisis (BC) is remarkably reduced, estimated to 1% to 1.5% per year in adults compared with more than 20% per year in the pre-TKI era. But no data are available among children. Purpose: We described the characteristics, the treatment and the outcome of 21 children with CML, who evolved in accelerated phase and/or blast crisis under TKI. Results: From 2001 to april 2015, 415 European patients were enrolled in the CML pediatric database. Twenty-one patients (5.1%), in chronic phase (CP) treated by TKI, presented AP or BC. The median age of AP/BC cohort was 13.2 years (range: 4.5-16.9 years) with a sex ratio M/F at 2. At CML diagnosis, 15 patients (71%) had high risk Sokal Score with a median score of 1,4 (range: 0,16-2,4). All patients harbored t(9;22)(q34;q11) but one had a complex translocation t(1;9;22)(q12;q34;q11) and another one presented additional inv(3)(q21q26). Imatinib was the first line TKI for all patients. Before AP or BC, only five patients (24%) obtained a complete cytogenetic response (CCyR) and three achieved MMR. For incomplete molecular response or progression to accelerated phase, 8 patients (38%) were switched to dasatinib. Median duration of TKI before AP or BC was 11 months (range: 3 months-56.5 months). Six patients evolved to AP with a median interval of 8.7 months (range: 1 months-24 months), leading to blast crisis for 4 patients with a median time of 3.5 months (range: 0.3-5.4 months). Among the 2 patients remaining in AP, imatinib was increased for one and the other was switched for dasatinib, all before hematopoietic stem cells transplantation (HSCT). One patient died of post-transplant complication and the other one is still alive in complete molecular response without TKI. Nineteen patients presented BC, including 4 after AP. Thirteen patients (62%) presented ALL, five (24%) AML and one a bi phenotypic leukemia. Central nervous system (CNS) was involved for two patients with ALL, one isolated, one combined. At AP or BC, nine patients (43%) presented new additional cytogenetic abnormalities. Eighteen patients with BC were treated according to AML or ALL protocols, combined with second generation TKI for twelve patients. Only one patient underwent preparative regimen, without intensive chemotherapy before HSCT. Ten patients reached complete remission. Four patients died before HSCT, by progressive disease for 2 and by fatal infection for 2. Overall, 15 patients in BC were transplanted. Before HSCT, median molecular response was 0.2% (range: 0-29%) and only four patients had a complete molecular response. After transplant, seven patients received second generation TKI. Four patients died, including three related to transplant toxicity. Thirteen patients were alive, but one with ALL BC relapsed 26 months post-transplant and was waiting for second HSCT. With a median follow-up of 4.4 years, 4-year overall survival was 59% (66% for ALL BC versus 40% for AML BC). Conclusion: Incidence of AP/BC after imatinib for CP CML is at 5%, in the CML pediatric database. Despite second generation TKI, combined with HSCT, outcome remains poor. Post-transplant indication of TKI is heterogenic. Recommendations would be useful for practice. Figure 1. Figure 1. Disclosures Suttorp: Novartis, Bristol Meyer Squib: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background The increased number of successfully treated pts with HSCT necessitates continuous observation focused on endocrinological complications. Significant risk factors for endocrine dysfunctions are age and nutrition state before HSCT, high dose chemotherapy HDC/T, total body irradiation (TBI), prolonged steroid therapy for GvHD and cranial irradiation (CI) given prior to the transplant maneuver. Objective The aim of this study was to evaluate the occurrence of endocrine complications, in particular disorders of growth and thyroid function, abnormal gonadal function and dysfunction in glucose metabolism in children treated with allo-, and auto-HSCT. Material and methods The investigated group consisted of : - 16 patients after auto-HSCT (7 girls, 9 boys) age at transplant maneuver 3–20 years (average 9,56±) transplanted for AML (5), NHL (3), NBL (3), embryonal cancer (2), medulloblastoma, Ewing sarcoma/PNET, HES. High dose chemotherapy (HDC/T) included: BU/MEL (7), BEAM (3). - 30 patients after allo-HSCT (20 girls, 10 boys) age at transplant manoveur 3–17 years (average 9,56±). Indications were ALL (11), AML (5), CML (6), MDS (2), NHL, JMML, SAA, Blackfan-Diamonds anaemia, SCID, RMS. According to donor availability there were MSD (13) patients, MUD (11) and HLA-mismatched related (6). The preparative regimen consisted of HDC/T usually BU/MEL (3); BU/CY/VP (6); BU/CY/ATG (5), VP/ATG/TBI (3). CI prior to grafting received 19 children: auto-HSCT (6), allo-HSCT (13) and TBI 6 patients. Prolonged high steroid doses (beyond 28 days) received 18 children: auto-HSCT (4) and allo-HSCT (14) before, and 20 after HSCT. Endocrine function was evaluated in average after 24 months in auto-setting and after 26 months in allo-setting. TSH, fT3, fT4, IGF-1, IGFBP-3, HbA1c, FSH, LH, PRL, estradiol and testosterone levels, oral glucose tolerance test, GH test, TRH test, LHRH test (LH, FSH) was performed in each patient. The University Research Committee for Bioethics did consent to this investigation protocol. Results 16 children (11girls and 5 boys) presented with abnormal puberty: 43,75% after auto- and 34,61% after allo-HSCT. Hypothyroidism occurred in 5 patients necessitating thyroid hormone substitution. Hyperthyroidism was not diagnosed. Elevated level of aTPO was noted in one child only. Impaired GH-excretion after stimulation was documented in 14 pts. Growth and maturation stature is still an ongoing observational study in this subgroup. Growth impairment was documented in 8 patients (6 girls, 2 boys) 13 to 70 months after allo- transplantation (average 36 months). Three children from above group received CI. Growth hormone substitution was instituted in 1 girl (ALL, HLA MM REL, CI). (SDS

Description: Background Preparative regimen consisting of high dose chemotherapy HDC/T and/or cranial irradiation (CI) in combination with prolonged steroid therapy may cause abnormal gonadal function. Objective Evaluate puberty disorders in children occurring after HSCT as single center experience. Material and methods The study group consisting of 21 patients (13 girls and 8 boys) age 10–20 years at grafting (median 14 years) was prospectively evaluated post grafting. The indications for HSCT were: ALL (5), AML (4), CML (5), MDS (2) and NHL, JMML, SAA, Blackfan Diamond anemia, RMS. According to donor availability 11 children had mached sib donors (MSD), 7 matched unrelated donors (MUD) and 3 patients HLA-mismatched related donors. The preparative regimens consisted of HDC/T usually BU/MEL (2pts); BU/CY/VP (5pts); BU/CY/ATG (4pts) and total body irradiation (TBI) received 3 patients with 12 Gy. CI prior to grafting was delivered to 5 children: 18 Gy (4) and 24 Gy (1). Prolonged high doses steroids (beyond day +28) received 7 children prior to- and 10 children after grafting. Endocrine function after allo-HSCT was evaluated from 10 to 42 (median 26 months). Analysis of LH, FSH, PRL, oestradiol and testosterone levels, fT3, fT4, aTPO, TRH test and LHRH test was performed in all study patients. Bone age according to Pyle-Grulich method was estimated. Results: Abnormal gonadal function was present in 12/21 children (9 girls, 3 boys) in average 28 months after HSCT Primary amenorrhea occurred in 3, secondary amenorrhea in 6 girls. Delayed bone age was documented in 2 children in average 30 mths post grafting. No significant correlation was found between children’s age during allo-HSCT and occurrence of puberty disorders. Gender of children had no effect on evalated variables. Time elapsing from HSCT did not influence the occurrence of abnormal gonadal function. No association was found between abnormal gonadal function and TBI, prolonged high doses steroids prior to- and after HSCT. Occurrence of puberty disorders was statistically significantly blunted by conditioning regimen containing Cyclophosphamide (p=0,019) and Busulfan (p=0,0179) while Melfalan did not turn out such a risk factor. PRL levels and thyroid function do not have any determination on occurrence of abnormal gonadal function after HSCT. Conclusion: Abnormal gonadal function as late effect frequently occure after HSCT. High-dose Cyclophoshamide and Busulphan tretaed children often had blunted puberty. Melfalan and TBI, however, did not cause such an effect reported by others. Endocrinological care for patients after HSCT is necessary in order to: - Discover the impaired endocrine function - Initiate correct hormonal substitution therapy - Significantly improve the quality of life after allo- HSCT and - Secondary prevent treatment related complications.

Description: BACKGROUND. Infectious complications are a significant cause of morbidity and mortality in children receiving treatment for ALL. One of the major factors increasing the risk of bacteremia is the widespread use of central venous lines (CVL). In this study we hypothesized if there are any outcome predictors during bacteremia episodes during standard chemotherapy. OBJECTIVE. The aim of the study was to analyze epidemiology and impact of bacteremia as a main cause of death during induction and consolidation therapy of ALL in children. We assessed an influence of following factors: age, sex, time to infection, duration of antibiotic treatment, and relapse on survival in ALL children with bacteremia. METHODS. We reviewed 430 medical charts of children with ALL treated in Pediatric Hematological Centers in Poland according to ALL-IC-2009 protocol between January 2012 and December 2013. The group of 110 children (71 boys, 39 girls) with ALL with at least 1 episode of bacteremia was analyzed. The median age of the children was 7.5 years. Statistical analysis was performed using chi-squared and t-test when applicable to estimate the influence of different factors (age, sex, time to infection, period of treatment) for the outcome. RESULTS. The overall incidence of bacteremia among ALL children was 110/430 (25.6%). The most common cause of bacteremia (20%) was S.epidermidis (22%) and E.Coli ESBL(+). The median time to infection (TTI) was 4.9 months . There was no significant association between TTI and outcome of the patients (p=0.07), but there was a trend towards increased death rate during consolidation therapy. The median duration of infection treatment (MDT) was 13.6 days. MDT did not influence significantly death rate (p=0.31). Among all patients, 14 (12.7%) deaths were observed. The median age of children in that group was 9.1 years. In the analyzed period 19 cases of ALL relapse were observed in this study. In the relapse group there was significantly higher mortality rate than in the group with “de novo ALL” (p

Description: PV and AL contributed equally Multiple studies from the EBMT registry and others have shown excellent survival rates after allogeneic haematopoietic stem cell transplantation (HSCT)for Wiskott-Aldrich syndrome (WAS) patients (Ozsahin et al, Blood 2008). The importance of myeloid engraftment for full disease correction has also been demonstrated (Moratto et al, Blood 2011). However, the vast majority of HSCTs in these studies were performed with (oral) busulfan/cyclophosphamide-based conditioning and in the early 2000 years or before. In 2005, the inborn errors working party (IEWP) of EBMT and ESID first recommended busulfan/fludarabine (BuFlu) or treosulfan/fludarabine (TreoFlu) based conditioning for primary immunodeficiencies such as WAS, with some centers deciding to add thiotepa (TT) to the conditioning. We performed a retrospective analysis via the EBMT and SCETIDE registries of WAS patients transplanted between 01/01/20006 and 12/31/2016 with these two regimens. The primary objective was to compare the overall (OS) and event-free survival (EFS) after HSCT with either BuFlu±TT or TreoFlu±TT conditioning. Secondary objectives included the influence of either conditioning regimen on acute and chronic GVHD, the degree of donor chimerism, incidence of secondary procedures after HSCT (2nd HSCT, stem cell boost, DLI, gene therapy or splenectomy) and rates of disease-specific complications after HSCT. At the time of this interim analysis, 174 patients were included, 92 (53%) with BuFlu±TT and 82 (47%) with TreoFlu±TT conditioning with a median age of 1.57 years (range 0.21-29.96) at HSCT and a median follow-up of 32.9 months (range 1.5-128.9). The donor was an HLA-matched sibling (MSD) in 30, a matched related donor (MRD) in 5, a matched unrelated donor (MUD, 9/10 or 10/10) in 105, a mismatched unrelated donor (MMUD, 5 years had a worse OS as compared to those 5 years or younger at HSCT (74.9% vs. 90.8%; log-rank test p=0.005). The type of donor had no influence on OS: 96.4% for MSD/MFD, 86.8% for MUD/MMUD and 87.7% for MMFD (log-rank test p=0.4). Whole blood chimerism was complete (〉90% donor) in 60/75 evaluable patients (80%) at last follow-up or before secondary procedure (if a patient had one), 39/40 (98%) in the BuFlu±TT group and 21/35 (60%) in the TreoFlu±TT group. Twenty-six patients required a secondary procedure: stem cell boost in 4 patients, donor lymphocyte infusion in 9, 2nd HSCT in 15 and splenectomy in 1. Twenty-two of these 26 (84.6%) are alive and 14 of 16 with available chimerism data have a complete donor chimerism (〉90%donor) at last follow-up. The 2-year cumulative incidence (CI) of secondary procedures was higher at 33.9% in the TreoFlu±TT versus 12.8% in the BuFlu±TT group (Gray's test p=0.017), and 2-year EFS (secondary procedure or death as event) was 61.4% in the TreoFlu±TT and 75.0% in the BuFlu±TT group (log-rank test p=0.2). Grade II-IV acute GVHD had the same incidence in both groups (100 day CI 24.4% vs. 26.3%; Gray's test p=0.849) and chronic GVHD of any grade was borderline more frequent in the TreoFlu±TT group (2 year CI 17.2% vs 6.7%; Gray's test p=0.054). The cumulative incidence of disease-specific complications occurring more than 6 months post HSCT (severe infections, bleeding, autoimmunity) was not different between the two groups (6.5% vs. 6.4%; Gray's test p=0.92). There was no malignancy reported after HSCT except for one EBV-post-transplant lymphoproliferative disorder (PTLD) 2.7 months after HSCT. In summary, HSCT with either BuFlu±TT or TreoFlu±TT conditioning reliably cures almost 90% of patients with WAS regardless of donor type. WAS-related complications are very rare events more than 6 months post HSCT. More patients required secondary procedures after treosulfan-based than busulfan-based conditioning. These data confirm the feasibility and efficacy of the regimens currently recommended by the IEWP. Disclosures Slatter: Medac: Other: Travel assistance. Chiesa:Gilead: Consultancy; Bluebird Bio: Consultancy. Kalwak:Sanofi: Other: travel grants; medac: Other: travel grants. Locatelli:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria. Sykora:Aventis-Behring: Research Funding; medac: Research Funding. Zecca:Chimerix: Honoraria. Veys:Pfizer: Honoraria; Servier: Research Funding; Novartis: Honoraria.