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Background: Chimeric Antigen Receptor T-cells targeting CD19 (CART-19) have shown promising efficacy for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The ELIANA trial leading to market authorization of tisagenlecleucel excluded prior therapy with monoclonal antibodies. Blinatumomab prior to CART-19 seems associated with a higher risk of early failure (Pillai, Blood Advances 2019). Inotuzumab ozogamicin (InO) is an anti-CD22 antibody conjugated to calicheamicin. InO as bridging therapy to CART-19 (n=11) was associated with a shorter overall survival (OS) (Dourthe, Leukemia 2021). InO given prior to leukapheresis might impact on the quality of T-cells collected and, when used as bridging, could result in insufficient CD19 positive (CD19+) antigen load and affect CAR T-cell expansion. We report on a cohort of children and young adults with R/R BCP-ALL treated with InO prior to CART-19 infusion. Methods: Data of patients (pts) treated with CART-19 after InO given at any time before and/or after apheresis, irrespective of other anti-leukemic treatments, were collected using a standardized Case Report Form. The study was approved by the ethics committee of the UMC Utrecht (MvdL/is/21/500393) Results: Thirty-nine pts were treated in 10 centers and received CART-19 between July 2016 and April 2021. Thirty-four received commercial tisagenlecleucel and 5 academic products. Median age was 13 years (range 1-23); 25 were male. Four pts (10.3%) had received a prior CART-19 infusion and 15 (38%) blinatumomab, 18 (46%) had been previously transplanted. All pts received at least two doses of InO (range 2-12); 12 before apheresis only (median time 48 days (range 13-560) between last InO dose and apheresis); 27 as bridging therapy (median time 52 days (range 16-257) from last InO dose to CART-19 infusion), including 5 who had also received InO before apheresis. At time of the infusion, 22 pts were in complete remission (CR) ( At day 28 (d28) post infusion 35/39 were in CR (89.7%), of whom 31 (88.6%) were also MRD negative. Four pts (10.3%) did not achieve CR: 3/4 were not in CR at the time of the infusion; all of them received InO as bridging within 2 months before the infusion. With a median follow-up of 12.5 months (range 1-50) after CART-19 infusion, 12-month event free survival (EFS) was 59% (95% confidence interval (CI) [42.0-76.0]) and OS was 79.5% (95% CI [64.6-94.4]). There was no significant difference in OS/EFS between pts who received blinatumomab and InO prior to CART-19 infusion (n=15) and those who received InO only (n=24) (p=0.61 and p=0.37, respectively). Sixteen pts (45.7%) relapsed at median 163 days (range 28-655) after CART-19 infusion; 7/16 (43.8%) had a CD19+ relapse (median 287 days; range 28-655), 8/16 (50.0%) had a CD19 negative (CD19-) relapse (median 163 days; range 136-273) (1 status unknown). There was no significant difference in 12-month OS/EFS between pts who received InO before apheresis or as bridging (OS 83.3% vs 77.8%, p=0.50; EFS 58.3% vs 59.3%, p=0.62); and no difference in d28 MRD response (p=0.57) or incidence of CD19+ or CD19- relapses (p=0.48) between the 2 groups. Twelve of the 35 pts in CR at d28 (34.2%) lost BCA, median 92 days after CART-19 infusion (range 29−294) (1 data not available); 7/12 relapsed, 5/7 with CD19+ relapse. Among the 35 responders, 5/12 pts who received InO before harvesting lost BCA (1 data not available) vs 7/23 pts who received InO as bridging. There was no significant difference in 12-month EFS between pts who received CART-19 with low CD19 burden at start of lymphodepletion chemotherapy (MRD Conclusion: InO as a bridging strategy to CAR T-19 does not seem to result in inferior response when EFS/OS are compared to published data (Maude, NEJM 2018; Pasquini, Blood Adv, 2020). The ITCC/IntReALL-059 study will treat very high risk first relapsed BCP-ALL pts (very early relapse or presence of TP53 mutation and/or deletion, hypodiploidy, t(1;19)/t(17;19), KTM2A/AF4) with InO reinduction followed by CART, given the poor prognosis with current strategies. Disclosures O'Brien: Jazz: Honoraria; Pfizer: Honoraria, Research Funding. Jacoby: NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Zwaan: SANOFI: Consultancy; NOVARTIS: Consultancy; ROCHE: Consultancy; INCYTE: Consultancy; PFIZER: Consultancy, Research Funding; JAZZ: Other: travel funding, Research Funding; BMS: Research Funding; Abbvie: Research Funding.

Introduction: CML is a rare disease in children and adolescents, accounting for 2-3% of leukemia cases in this population. Pediatric CML is more frequent in the 2 nd decade of life but data on adolescents are limited. Only response to treatment has been analyzed in few studies and seems to be poorer in this age cohort. The International Registry of Childhood Chronic Myeloid Leukemia gave us the opportunity to analyze the characteristics and outcome in a large cohort of adolescents. Aims and objectives: To report on clinical features and response to treatment in adolescents (15-18 years of age at diagnosis) with CML in chronic phase (CML-CP). Material and methods: The International Registry of Childhood CML (I-CML-Ped Study, registered at www.clinicaltrials.gov NCT01281735) enrolled patients less than 18 years of age at diagnosis of CML in all phases according to the criteria of the European Leukemia Net (ELN). Data from this registry collected from Jan 2011 - Mar 2021 into the I-CML-Ped Study (Poitiers, France) were retrospectively analyzed. Results: Out of 614 patients (pts) registered in the I-CML-Ped Study, we identified 144 (23.4%) adolescents (15-18 years of age at diagnosis) with sufficient available data. Among them, according to the ELN criteria, 132 (92%), 7 (5%), and 5 (3%) pts presented with CML-CP, accelerated phase (AP), and blastic phase (BP), respectively. The median age of the cohort comprising 132 adolescents with CML-CP was 16.2 years [range, 15-18]. Ratio male/female was 1.75. Splenomegaly was reported in 66% of the pts with a median spleen size of 11.5 cm below the costal margin [range, 1-32]. Hepatomegaly was reported in 31% of the pts with a median liver size of 2.5 cm below the costal margin [range, 1-19]. Pain, asthenia and weight loss were the most frequent symptoms at diagnosis in 35%, 33%, and 20% of pts, respectively. The performance status according to the OMS and Karnofsky scores were 0 and 100% in 81% and 57% of the pts, respectively. At diagnosis, median leukocyte count was 181 G/L [range, 7-820]; median platelet count was 516 G/L [range, 102-2619], and median hemoglobin level was 10.45 g/dL [range, 4-17]. BCR-ABL1 transcript type b3a2 was present in 53% of the assessable pts. Additional chromosomal abnormalities and variants were found in 5% of the pts. 9% and 40% of pts were considered at high-risk according to the ELTS score and to the Sokal score (for pts less than 45 years), respectively. The majority of pts (97%) were treated with imatinib as first line treatment. After 12 months of treatment, in pts with data available, rate of complete cytogenetic response (CCyR) was 74/109 (68%) pts with imatinib first line. Overall, rate of CCyR was 101/109 (93%) pts with imatinib first line [88/109 (81%) pts receiving imatinib only, 13/109 (12%) pts after switching to another TKI, 8/109 (7%) pts did not achieve CCyR]. Median time to achieve CCyR was 8.2 months [range, 2.7-106.7]. The cumulative rate of MMR at month 12 was 40/111 (36%) pts. Overall rate of MMR was 91/111 (82%) pts [72/111 (65%) pts with first line imatinib only; 19/111 (17%) pts with another TKI]. Median time to achieve first MMR was 14.5 months [range, 0.9-63.1]. Out of all patients on first line imatinib, 11/123 (9%) pts progressed: 3/11 pts progressed to AP and 8/11 pts to BP. Further progress to BP was observed in 2 of the 3 pts with AP. BP phenotype was myeloid in 5/10 pts, lymphoid in 3/10 pts and bilineage in 1/10 pts (no data for 1/10 pts). With imatinib first line, deaths occurred in 5/123 (4%) pts, among them 4/5 due to complications associated with hematopoietic stem cell transplantation. With a median follow up of 37 months [range, 0.9-231], the overall survival rate was 89.2% [83.6%; 94.7%] for pts treated with imatinib first line (N = 123). Conclusion: Our results are in line with publications describing adolescents and young adults (AYAs) as a risk population for a poorer treatment outcome: when comparing AYAs (15-29 yrs) to adults (>30 yrs), CCyR and MMR were inferior in AYAs (cumulative CCyR 84% vs 93%, cumulative MMR 75% vs 86%, respectively) [Pemmaraju N et al., Haematologica 2012] and rates of progression to AP and BP were 8.7% in AYAs (16-29 yrs) but only 5.3% and 6.1% in adults (45-59 yrs and >60 yrs, respectively) [Kalmanti L et al. , Ann Hematol. 2013]. Additional research is required in adolescents with CML to shed light on the cause(s) for the observed differences and to further improve the outcome. Disclosures No relevant conflicts of interest to declare.

Pearson marrow pancreas syndrome (PS) is a multisystem disorder caused by mitochondrial DNA (mtDNA) deletions. Diamond-Blackfan anemia (DBA) is a congenital hypoproliferative anemia in which mutations in ribosomal protein genes and GATA1 have been implicated. Both syndromes share several features including early onset of severe anemia, variable nonhematologic manifestations, sporadic genetic occurrence, and occasional spontaneous hematologic improvement. Because of the overlapping features and relative rarity of PS, we hypothesized that some patients in whom the leading clinical diagnosis is DBA actually have PS. Here, we evaluated patient DNA samples submitted for DBA genetic studies and found that 8 (4.6%) of 173 genetically uncharacterized patients contained large mtDNA deletions. Only 2 (25%) of the patients had been diagnosed with PS on clinical grounds subsequent to sample submission. We conclude that PS can be overlooked, and that mtDNA deletion testing should be performed in the diagnostic evaluation of patients with congenital anemia.

Chronic granulomatous disease (CGD) can be cured by allogeneic hemopoietic stem cell transplantation (HSCT). Complications include graft failure, graft-versus-host disease (GVHD), infection, and transplant-related mortality; therefore, reduced-intensity conditioning regimens are being used to improve outcomes. In this retrospective study, the aim was to determine the outcome of treosulfan-based conditioning in HSCT for pediatric patients with CGD. The following data were collected: risk features pre-HSCT, additional conditioning agents, donor type and stem cell source, toxicity, engraftment, GVHD, chimerism, viral reactivation, post-HSCT complications, length of follow-up, and outcome. Seventy patients (median age, 107 months; interquartile range [IQR], 46-232 months) from 16 centers worldwide were transplanted between 2006 and 2015. Ninety-one percent had high-risk features. Fifty-seven HLA-matched donors, 12 HLA-mismatched donors, and 1 CD3(+)TCR ??/CD19 depleted parental haploidentical transplants were performed. No major toxicity was reported. Median times to neutrophil and platelet engraftment were 17 (IQR, 15-35) and 16 (IQR, 13-50) days. At a median follow-up of 34 months (IQR, 13-102 months), the overall survival was 91.4%, and event-free survival was 81.4%. The cumulative incidence of acute grade III-IV GVHD was 12%. Nine patients developed chronic GVHD. When split cell chimerism was available, 95% or more myeloid donor chimerism was documented in 80% of surviving patients. Secondary graft failure occurred in 12% of patients. Treosulfan-containing conditioning regimens can be used safely in HSCT for children with CGD and high-risk clinical features, achieving excellent survival with high myeloid chimerism. Further studies are needed to compare with other regimens and evaluate the long-term outcome, particularly on fertility.

Introduction: CML is rare in the first two decades of life comprising only 3% of pediatric and adolescent leukemias. The overall annual incidence is approximately 1 per million children and adolescents and it increases with age (median: 12 yrs, range: 1-18) resulting in an extreme rarity of children affected in the first years of life. Data regarding the clinicopathologic characteristics and response to therapy of childhood CML diagnosed at age Aims and objectives: We studied the epidemiologic and clinical features of patients(pts) with CML Material and Methods: Data from pediatric CML pts (age at diagnosis 0-18 yrs) registered from 2010 until 2017 into the International Pediatric CML Registry (Poitiers, France) under the umbrella of the I-BFM Study Group were retrospectively analyzed. Characteristics and treatment outcome of pts Results: 22/479 pts (4.6%, ratio male/female: 14/8) were enrolled with a median age of 22 months (10-34) and a median weight and height were 9.3 kg (8.1-15.5) and 78 cm (73-98), respectively. The median time period from the first symptoms until final diagnosis was 21 days (2-182). Median spleen size was 12 cm (2-20) and median liver size was 3 cm (2-6) below the costal margins. Major complains and symptoms comprised asthenia (30%), fever (30%), abdominal pain (20%), extramedullary signs (14%), hemorrhage (5%), and weight loss (5%). Median WBC, Hb and platelet counts were 154 600/µl (23 000-892 000), 8.7 g/dl (5,6-11,5) and 311 000/µl (51 000-1 820 000), respectively. All pts underwent BM aspiration but, BM biopsy was performed only in 8/22 children. Philadelphia chromosome and BCR-ABL1 gene rearrangement were detected by cytogenetic and/or molecular techniques (FISH and RQ-PCR). In only 2 (9%) children, additional chromosomal abnormalities were detected by cytogenetics classifying one patient in accelerated phase. Overall 19/22 (86%) children were diagnosed in chronic phase and the remaining 3 pts were in advanced phase (CML-AP: n= 2, CML-BP: n= 1). Median follow-up of the cohort was 78 months (7-196). Treatment: 21/22 pts initially received imatinib at the recommended dose of 260-300 mg/sqm/day while one child received IFN + ARA-C. Imatinib was changed to either dasatinib (n= 5) or nilotinib (n= 1) in 6 children (29%). Thus, 15 pts continued on imatinib. During follow-up, 9/22 (41%) pts underwent HSCT including 2 pts after switching to dasatinib. Molecular response: Major molecular response (MR) was achieved in 10/21 (48%) children on TKI. One child (1/21) on TKI was not followed for MR, but he developed complete cytogenetic remission 4 mo after imatinib treatment. The remaining cohort (6/22; 27%) is alive on TKI without major MR with a median follow-up of 77 m (7-186) and 5/22 (23%) achieved complete MR following HSCT. Adverse effects (AE): 194 AE episodes were reported in 18/22 (82%) pts. Most frequently observed AEs were hematologic (20%), gastrointestinal (16%), infectious (14%), musculoskeletal (14%), skin (12%), metabolic (6%), and HSCT-related (GvHD, 5%). Less frequently AEs comprised psychological (3%), edema (3%), tooth development delay (2%), allergic (2%), neurologic (PRESS syndrome,1%), and renal colic (1%). At last follow up, assessment of puberty status revealed that the majority of children were in Tanner stage 1 or 2 (17/22, 77%). Among these, 7 were >10 years old and showed puberty delay, while pubertal development was normal in the remaining 5/22 pts. Data on growth and development was available in 15/22 (68%) children. The majority had experienced decline of height (93%) and weight (73%). In 4 (27%) and 2 (13%) pts, respectively, measurements were found below the 3rd-10th percentiles. Delta z-score analysis for height and weight revealed that the z-scores in total 3 pts were below -2. Survival: 21/22 (95%) children are alive while one patient died of GvHD. Two pts' last molecular status is unknown. 7/19 pts (37%) are in molecular CR following HSCT and the other 12/19 (63%) are still on TKI. Out of these, 3/12 pts achieved durable CMR with TKI (PCR negative) while the remaining 9/12 pts show either fluctuating (n= 3 ) or no major MR (n= 6). Conclusion: This report demonstrates for the first time the efficacy and long term side effects of upfront imatinib in the so far largest cohort of children with CML diagnosed at very young age. Disclosures Kalwak: Sanofi: Other: travel grants; medac: Other: travel grants.

BACKGROUND: Recent EBMT analysis showed that infections are responsible for 21% of deaths after allo-HCT and 11% after auto-HCT. However, the risk, types and outcome of infections vary between age groups. The aim of the study is the direct comparison of risk factors of incidence and outcome of infections in children and adults. PATIENTS AND METHODS: We analyzed risk factors for the incidence and outcome of bacterial, fungal, and viral infections in 650 children and 3200 adults who received HCT between 2012-2015. The risk factors were determined by multivariable logistic regression analysis. RESULTS: A total number of 395/650 (60.8%) children and 1122/3200 (35.0%) adults were diagnosed for microbiologically confirmed infection, including 345/499 (69.1%) and 679/1070 (63.5%), respectively after allo-HCT, and 50/151 (33.1%) and 443/2130 (20.8%) respectively, after auto-HCT. At 2 years after HCT, the incidences of microbiologically documented bacterial infection were 36.0% and 27.6%, (p21d) hematological recovery (HR=3.3; p21 days (HR=1.4; p=0.038) were associated with increased risk of death from infection. Among patients with bacterial infections, the risk was higher in G- infections (HR=1.6; p=0.031). Among auto-HCT patients, no child died of infection. In adults, the risk of death was higher if duration of treatment of infection was >21 days (HR=1.7; p CONCLUSIONS: The profile of infections and related deaths varies between children and adults. MMUD transplants, diagnosis of acute leukemia, chronic GVHD, CMV reactivation and prolonged infection are relative risk factors for death from infection after HCT. Disclosures Kalwak: Sanofi: Other: travel grants; medac: Other: travel grants.

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.

Introduction Using the EBMT registry, we retrospectively analyzed outcomes for 373 pediatric patients who underwent second allogeneic transplant for relapsed acute leukemia at 120 centers in 32 countries, between the years 2004 and 2013, in an attempt to assess relapse, survival, GVHD and other outcomes, as well as identify factors correlating with prognosis in this cohort of patients. To our knowledge, this is the largest analysis of pediatric patients undergoing second allogeneic HSCT for relapsed acute leukemia to date. This allowed for an independent analysis of each disease, including 214 patients with ALL and 159 with AML. Patients and Methods Centers received a questionnaire completing data already available in the ProMISe database on patients between 0-18 years of age treated between 2004 and 2013. Results A total of 387 patients received a second SCT after relapse. 373 have been included in the analysis, 214 for ALL and 159 for AML. Detailed data were available for 201 patients from 48 centers; for the remainder, analysis was based on the registry. For the entire cohort overall survival (OS) at 2 and 5 years were 38% and 29%, and leukemia free survival (LFS) 30% and 25% respectively. ALL: With a median follow up from 2nd SCT of 36.4 months, OS at 1 and 5 years were 47% and 28% respectively. LFS was 39% and 28% respectively. NRM at 2 years was 22%. In multivariate analyses favorable prognostic factors for both OS and LFS were: CR prior to 2nd SCT (p=0.0001), interval > 12 months between transplants (p=0.0007), use of myeloablative conditioning (p=0.039) and the presence of cGvHD after the first SCT (p=0.0001). Good prognostic factor for low NRM was interval of more than 12 months between transplants (p=0.0002). AML: With a median follow up from 2nd SCT of 50 months, OS at 1 and 5 years were 44% and 15% respectively. LFS was 28% and 15% respectively. NRM at 2 years was 18%. In multivariate analyses, favorable prognostic factors for OS as well as LFS were: CR prior to 2nd SCT (p=0.031;0.044 respectively), interval > 6 months between transplants (p=0.0003;0.0001 respectively), and having cGvHD after the first SCT (p=0.0001). Most patients experience disease relapse or NRM within the first year after their second transplant. This observation seems to be more consistent in patients transplanted for ALL, with more changes over time in patients with AML. For ALL in particular, the 2-year incidences of relapse, NRM and LFS were not different from those at 5-years. Even in the relapse setting, survival rates for patients with ALL remain superior to patients with AML, consistent with the prognostic differences at diagnosis. Our findings, consistent for the AML and ALL subgroups, suggest that cGHVD prior to second HSCT is associated with better outcome. The identification of cGHVD prior to second transplant has not been heretofore described as a favorable prognostic factor. This strong correlation merits further study, specifically as to the underlying biology for this association. Conclusion Children with relapsed acute leukemias have a substantial chance to become long term survivors following a second SCT. CR prior to second SCT, longer interval between transplants and the presence of cGvHD after the first transplant, are favorable prognostic factors for ALL and AML. Our findings may help physicians in discussing the risk-benefit of a second transplant. These results are particularly relevant in an era where an explosion of new therapies, specifically targeted therapies and those that modulate the immune response, behoove us to carefully identify subpopulations of patients for whom specific therapies are appropriate. Novel approaches are needed to minimize relapse risk as well as short and long term morbidity in these pediatric patients while considering a second SCT for relapsed acute leukemia. Disclosures Corbacioglu: Jazz Pharmaceuticals: Consultancy, Honoraria. Bader: Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding.

The Sokal score for patients less than 45 years can be used for the prognostic discrimination in the pediatric population. Limited data are available regarding the utility of the EUTOS score in the pediatric population (Gurrea Salas et al, Ann Hematol 2015). Recently, a new EUTOS score, the EUTOS Long Term Survival (ELTS) score was validated in the adult population (Pfirrmann et al, Leukemia 2016). The international registry for chronic myeloid leukemia (CML) in children and adolescents (I-CML- Ped Study registered at www.clinicaltrials.gov as NCT01281735) gave us the opportunity to test this score in this population. Aim: The aim of this analysis was the comparison of risk groups allocations and outcome between the Sokal ( Patients and Methods: As of June 1, 2016, 462 children and adolescents less than 18 years old were enrolled in the I-CML-Ped study between January 2011 and April 2016. Among them, 350 patients diagnosed with CML in chronic phase according to the ELN definition and treated with imatinib (+/- hydroxyurea or anagrelide) as first line treatment were eligible for analysis. For progression free survival (PFS) analyses, events of interest included progression to accelerated phase or blast crisis and deaths irrespective of its cause, whichever came first. For survival analyses, the event of interest was death from CML, deaths from other causes being considered as competing events, as initially designed in the ELTS score model. Estimates were compared by the log-rank test and Gray test respectively. Level of significance was 0.05. Results: The median follow up of the 350 patients was 3 years (range 1 month to 6 years). Progression and/or death (whichever came first) occurred in 23 patients. For the entire cohort of patients the 5-year PFS was 92% (95% CI: 88%-94%) and the 5-year survival accounting for CML death was 97% (95% CI: 94%-99%). Of the 308 patients allocated to low (n=54), intermediate (n=118) and high (n=136) risk groups by the Sokal ( Conclusion: ELTS score showed better differentiation regarding progression free survival than Sokal ( Figure 1. Figure 1. Disclosures Suttorp: Novartis, Bristol Meyer Squib, Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Biondi:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Cellgene: Other: Advisory Board.

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.

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 ( Results: The I-CML-Ped study enrolled 301 children and adolescents with CML in CP treated with imatinib front line. Among them 112 patients subsequently switched to a second line therapy (median duration of imatinib treatment before the switch: 16 months [range: 1-111]).The probability of switch at 38 months was 50% (95% CI: 29-60). Primary resistance was the cause of switch in 47% of the patients: failure to achieve complete hematologic response (CHR, 1%), complete cytogenetic response (CCR, 20%) or major molecular response (MMR, 24%); not detailed (2%). A loss of response (CHR loss [2%] or CCR loss [4%] or MMR loss [13%]) or progression were the cause of switch in 19% and 4% of the patients, respectively. Occurrence of non hematologic toxicity (mainly muscle-skeleton pain) was the cause of switch in 10% of the patients. The reason of switch was the physician's choice in 20% of the patients (switch to hematopoietic stem cell transplantation [HSCT] while the patients were in MMR or deeper molecular response). The second line therapy consisted of second generation tyrosine kinase inhibitors (63%), chemotherapy (4%) or HSCT (33%). With a median follow up of 38 months (range: 2-150), overall, 8 deaths were recorded among switching patients: all were patients transplanted for acute phase (4 patients), hematologic resistance (1 patient), loss of hematologic response (1 patient) or physician's choice (2 patients). The causes of death were treatment related mortality (7 patients) and relapse (1 patient). One death only was recorded among the non switching patients. The probability of overall survival at 48 months was 90% (95% CI: 81% - 95%) for switching patients and 98% (95% CI: 89% - 100%) (p=0.005) for the non switching patients. Conclusion: Treatment failure is the main reason for a switch to a second line therapy in children and adolescents treated with imatinib front line. Efficacy of second line therapy still needs improvement. Disclosures No relevant conflicts of interest to declare.

Aims: An international registry (I-CML-Ped Study)was established to assess epidemiology, management and outcome of CML in the pediatric population. Methods: All national pediatric study groups were invited to include newly diagnosed children and adolescents less than 18 years with CML diagnosed later than January 2000. Results: Since January 2011, 351 patients from 12 countries have been registered. Clinical and biological data at initial diagnosis are available in 278 patients.There was a male preponderance (57%). The median age at diagnosis was 12.4 years (range, 9 months -17.5 years); 6% of the patients were younger than 4 years. At time of diagnosis 92% of the children were in chronic phase, 8% in accelerated phase and 1% in blastic phase according to the European Leukemia Net criteria. The Sokal risk group distribution was: 18% low, 31% intermediate and 51% high risk. The majority of the patients showed a Lansky score of 100 (59%) or 90 (21%). Splenomegaly was present in 76% of patients. The median of the spleen size below the costal margin was 11 cm (range: 1 to 25 cm). The median of the leukocyte count was 235x109/L (range: 5 to 1038). Additional chromosomal abnormalities in Ph-positive cells were observed in 6 % of the patients. The BCR-ABL transcript type was available in 227 patients: b3a2 54%, b2a2 38%, b3a2-b2a2 6% and b2a3 2%. The median follow-up time is 39 months (range, 0.5-161). Eight deaths were recorded. The estimated overall survival rate at 60 months is 95% (95%CI 89-97). Irrespective of treatment and follow-up, 124 (73%) of 169 assessable patients for cytogenetic response achieved complete cytogenetic response (CCyR). Exploratory analyses were performed in newly diagnosed patients regarding clinical and biological factors influencing the achievement of CCyR 12 months after starting imatinib. In univariate analyses, the Eutos score, the spleen size, the hematocrit level, the lymphocyte count and immature cells in peripheral blood, the percentage of granulocytes and monocytes in the marrow were identified as potential prognostic factors. However, only the percentage of the granulocytes in the marrow was identified as independent factor of achievement of CCyR at 12 months in multivariate analysis. Data collection and quality control regarding molecular assessment are ongoing. Conclusion: The data indicates that children and adolescents with CML presented with clinical and biological differences compared to adult patients with CML. Identification of prognostic factors is needed to optimize the strategy in the pediatric population. Acknowledgment: The I-CML Ped study is supported by an unrestricted grant from Novartis Pharmaceutical Company Disclosures No relevant conflicts of interest to declare.

Pearson marrow pancreas syndrome (PS) is a congenital multisystem disorder characterized by sideroblastic anemia, pancreatic insufficiency, metabolic acidosis, and other defects, and is caused by mitochondrial DNA (mtDNA) deletions. Diamond Blackfan anemia (DBA) is a congenital hypoproliferative anemia with associated physical malformations, and in which mutations in ribosomal protein (RP) genes and GATA1 have been implicated. The clinical presentation of both of these bone marrow failure (BMF) syndromes shares several features including early onset of severe anemia, sporadic genetic inheritance, variable penetrance and manifestations, and episodes of spontaneous hematologic improvement. PS is less frequently occurring than DBA, with estimated incidences of < 1/1,000,000 versus 1/100,000 respectively, and therefore less often encountered by hematologists. We hypothesized that some patients in whom the leading clinical diagnosis is DBA actually have PS. To test this hypothesis, we retrospectively evaluated DNA samples from a cohort of patients that were submitted to a research study for DBA genetic testing. The study cohort consists of clinical samples and/or data from 362 patients, with a primary inclusion criterion of known or suspected congenital anemia. Prior genetic studies from this cohort have yielded the novel identification or confirmation of mutations and deletions in several genes implicated in DBA (e.g. RP genes, GATA1), which are to date identifiable in 175/362 samples (48%), a proportion consistent with that found in independent DBA registries. We screened peripheral blood DNA samples available from 173 genetically uncharacterized patients using a long PCR strategy, and found that 8 samples (4.6%) contained large mtDNA deletions. Deletion mapping and Southern blot analysis on DNA from these 8 patients confirmed the presence of a single deletion event within each patient, ranging in size from 2.3 - 7.0 kb of the 16.6 kb mitochondrial genome, existing as monomer or multimer mtDNA species, and in a proportion ranging from 55-80% of total mtDNA, all of which are consistent with the molecular diagnosis of PS. Follow-up with referring providers in the 1 month to 8 year time span since sample submission revealed that 2 of the 8 patients (25%) were subsequently diagnosed with PS. Of the remaining 6 undiagnosed patients, 2 had died from complications of bone marrow transplantation, performed for worsening cytopenias and concern for myelodysplasia; one patient died from bacterial sepsis; and 3 were alive with the provisional diagnosis of DBA. One of the 3 patients had become transfusion-independent. Review of bone marrow examinations revealed that the pathological hallmarks of ringed sideroblasts and/or vacuolization of precursors described in PS were inconsistently present or reported in the diagnostic evaluation. We conclude that PS is frequently overlooked in the diagnostic evaluation of children with congenital anemia. Establishing the diagnosis of PS, as distinct from DBA and other BMF disorders, holds important implications for patient management and family counseling. mtDNA deletion testing should be performed in the initial genetic evaluation of all patients with congenital anemia. Disclosures: Szczepanski: Octapharma AG: Investigator Other.

Abstract 3741 Background: CML is a very rare disease in children and adolescents accounting for less than 5% of all CML cases. Only scant data is available regarding epidemiology, presenting features and outcome of CML in this age range. Aims: An international registry (I-CML-Ped Study) was established to assess epidemiology, management and outcome of CML in the pediatric population. The main objectives of the study are the following: i) to describe the clinical and biological characteristics of CML in a large cohort of patients less than 18 years of age, ii) to identify prognostic factors in this age-group in order to optimize individual treatment choices iii) to determine side effects and long term effects of treatments, mainly the tyrosine kinase inhibitor effect, on growth and development of a pediatric cohort. Methods: All national pediatric study groups were invited to participate. All newly diagnosed children and adolescents less than 18 years diagnosed later than January 2000 has to be notified and collection of the follow- up data is planned. The study is strictly observational and informed consent from the patient and/or the legal guardians is required for enrollment. The study was started in January 2011. Results: As of July 2012, 200 patients (pts) from 9 countries have been registered. There was a male preponderance (59%). The median age at diagnosis was 11.6 years (range, 8 months −18 years); 8% of the patients were younger than 4 years. Clinical and biological data at initial diagnosis so far is available in 150 pts. At time of diagnosis 92% were in chronic phase, 6% in accelerated phase and 2% in blastic phase according to the European Leukemia Net criteria. The Sokal risk group distribution was: 13% low, 33% intermediate and 55% high risk. The majority of the patients showed a Lansky score of 100 (67%) or 90 (16%). Splenomegaly was present in 76% of patients. The median of the spleen size below the costal margin was 8 cm (range: 0 to 25 cm). The median of the leukocyte count was 250×109/L (range: 5 to 1037). Additional chromosomal abnormalities in Ph-positive cells were observed in 2.3 % of the patients. The BCR-ABL transcript type was available in 100 patients: b3a2 51%, b2a2 40%, b3a2 plus b2a2 7% and b2a3 2%. The median follow-up time is 28 months (range, 2–138). Five deaths were recorded. The estimated overall survival rate at 42 months is 97% (CI 95%, 91–99). Forty seven (63%) of 75 assessable patients for cytogenetic response achieved complete cytogenetic response 12 months after the start of the treatment (imatinib: 43 pts, switch to dasatinib after imatinib failure: 3 pts, interferon + cytosine arabinoside: 1pt). Data collection regarding molecular assessment is ongoing and will be presented. Conclusion: This is the largest study reporting on children and adolescents with CML. The data indicates that children and adolescents with CML presented with clinical and biological differences compared to adult patients with CML. Whether these differences translate into a different outcome still remains to be determined. Acknowledgment: The I-CML Ped study is supported by an unrestricted grant from Novartis Pharmaceutical Company Disclosures: No relevant conflicts of interest to declare.

Abstract 664 Severe combined immune deficiency (SCID) diseases, as well as other severe T-cell deficiencies like Omenn syndrome, are considered pediatric emergencies. To date, hematopoietic stem cell transplantation (HSCT) is the only curative therapy for these children. Considering the urgency of these transplants, for patients lacking an identical sibling donor, the use of mismatched related donors (MMRD) and unrelated umbilical cord blood (UCB) are important alternatives. In a retrospective study, we compared the outcomes of 175 children with severe T-cell deficiencies (SCID=152, Omenn syndrome=23) receiving MMRD transplants and 74 (SCID=52, Omenn syndrome=15) receiving UCB transplants, reported to the SCETIDE and Eurocord databases, from 1995 to 2005. MMRD transplants were performed in 12 different centers and UCB transplants were distributed among 30 different centers. Only 5 centers performed the two techniques. The median age at transplant was 6.4 months for the UCB group and 6.5 months for the MMRD group (p=0,87). Median time elapsed between diagnosis and transplant was 47 days for MMRD (range 4-485) and 55 days (range 17-526) for UCB transplants (p=0.06). There were no statistically significant differences between the two groups regarding gender and incidence of failure to thrive, chronic diarrhea or respiratory impairment before transplant. Patients receiving UCB had more often B-negative phenotype (61% UCB vs. 41% MMRD; p=0.009), while patients receiving MMRD had a greater incidence of viral infections prior to transplant (59% MMRD vs. 36% UCB; p=0.004). The year of transplantation also differed between the two groups, as more patients receiving UCB were transplanted between 2000-2005 (65%) compared to MMRD (50%) (p=0.014). Regarding HLA (considering HLA-A,B-low resolution and DRB1-high resolution), in the UCB group, 67% of patients had 0 or 1 disparities while 33% had 2 or 3 disparities. In the MMRD group, 10% had 1 disparity and 90% had 2 or 3 disparities. Seven patients receiving UCB (16%) transplants and 30 patients receiving MMRD (17%) did not receive any preparative regimen prior to graft infusion. Conditioning regimen was non-myeloablative in 45% of MMRD transplants and 30% of UCB transplants. The remaining received myeloablative regimens. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine A-based in the majority of the UCB transplants (n=71). T-cell depletion was used in all transplants with MMRD and 52 patients received immunosuppressants, mostly cyclosporine A. The median follow-up time was 84 months for patients given a MMRD and 59 months for UCB transplants recipients. Sixty-one patients receiving UCB transplants engrafted (82%), all with full donor chimerism in CD3+ cells. On the CD3- compartment 75% had full donor, 5% mixed and 20% had recipient chimerism. In MMRD group, 130 patients engrafted (74%), 98% with full donor chimerism in CD3+ cells. On CD3- cells, 33% had full donor chimerism, 48% were mixed and 19% recipient chimerism. Forty-six patients in the MMRD group and 7 patients in the UCB group needed to receive second transplants. The cumulative incidence of acute GVHD had no statistically significant difference between groups (33% UCB vs. 23% MMRD; p=0.13). However, patients receiving UCB transplants had more chronic GVHD (22% UCB vs. 11% MMRD; p=0.04). In a univariate analysis, 5-year overall survival was 62 ± 4% for MMRD and 58% ± 6% for UCB transplants (p=0.83). In a multivariate analysis adjusting for differences between the two groups, 5-year overall survival was not statistically different (p=0.54). Regarding T-cell reconstitution, we analyzed the total lymphocyte, CD3+ and CD4+ cell numbers and there were no statistically significant differences between the two groups comparing absolute numbers at 6, 12 and 24 months after transplantation. In conclusion, both unrelated cord blood and mismatched related donors are choices for transplants in severe T-cell deficiencies lacking an HLA-identical sibling donor. The choice of donor type will depend on centre's strategy regarding the possibility of efficiently deplete MMRD grafts of T-cells, or find a rapidly available UCB unit. Disclosures: No relevant conflicts of interest to declare.

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.

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 Conclusions Early endocrinological care of children treated with both auto-, as well as allo-HSCT is necessary due to a significant risk for hormonal disorders. Early diagnosis of impaired endocrine function together with early substitution therapy will significantly improve the quality of life after HSCT.

The aim of the study was to analyze the correlation between the number of transplanted CD34+ cells and CD3+ cells and the incidence of severe Graft versus Host Disease (GvHD) in children undergoing allogeneic hematopoietic cell transplantation from HLA-matched or mismatched unrelated donors. 115 patients (median age 11.4, range 0.7 – 31.6; ALL n=41, AML n=22, CML n=21, MDS/JMML n=10, NHL/HD n=4, SAA/FA n=13, SCID/WAS n=4) underwent unmanipulated allogeneic BMT (n=34) or PBSCT (n=81) from unrelated donors between 1999 and 2005. There were 88 matched- and 27 mismatched donor-recipient pairs, respectively (acc. to ALL SZT - BFM 2003 protocol). Among 88 matched pairs, 51 were 10 out of 10 HLA-allele matched (High Resolution Class I and II typed), whereas in another 37 cases 9 out of 10 alleles were matched. In the mismatched group there were 22 pairs with a 8 out of 10 allele-match and 5 pairs with 7 out of 10 allele-match, respectively. No single DRB1* mismatch was accepted. A distinct correlation between the degree of HLA-match and the risk of grades III-IV aGvHD was found (p=0.05), which occurred in 11 out of 27 pts in the mismatched group (40.7%) and in 19 out of 88 pts in the matched group (21.6%). No difference between the 2 groups was observed with regard to the incidence of extensive cGvHD. No correlation was found between the number of transplanted CD34+ cells/kg or CD3+ cells/kg and the incidence of aGvHD grades III–IV or extensive cGvHD. Median numbers of transplanted CD34+ cells/kg and CD3+ cells/kg were 7.7 × 106 (10.9 × 106) and 2.6 × 108 (3.3 × 108) respectively in the group of patients with grades III–IV aGvHD (extensive cGvHD) and 9.3 × 106 (8.8 × 106) and 3.4 × 108 (3.1 × 108) respectively in the group without these complications. Pts in the mismatched group were given slightly higher numbers of CD3+ cells/kg (4.9 vs 3.0 × 108 in the matched group) and similar numbers of CD34+ cells/kg (median 8.1 vs 8.9 × 106 in the matched group). Despite a higher incidence of severe aGvHD in the mismatched group, probability of 5-year survival was in contrast slightly better in the mismatched group (pS = 0.59 vs pS = 0.48 in the matched group, p=NS). Seventeen from 27 pts in the mismatched group remain alive (62.9%). Median follow-up of all 63 surviving pts (55%) is 21 months (range 6 – 69). Neither degree of HLA match, nor the source of stem cells (PB vs BM), nor number of transplanted CD34 (less or more than 8 × 106/kg) or CD3 cells/kg had an impact on survival. In conclusion, there seems to be no correlation between the numbers of transplanted CD34+ cells/kg and/or CD3+ cells/kg and the incidence of severe GvHD in the unrelated donor setting in children. It is safe and feasible to perform allogeneic transplants from unrelated mismatched donors, provided a detailed selection of more than 1 HLA-allele-mismatched donors is performed. This conclusion remains in contrast with the ALL SZT-BFM 2003 protocol, which requires extensive T-cell depletion in case of mismatched donor-recipient pairs. High number of transplanted CD34+ cells seems to be a positive factor influencing engraftment and survival in this constellation. There seems to be not necessary to limit the number of transplanted CD34+ cells to 6 or 8 × 106/kg, which had been previously suggested by studies performed in Europe or USA in adults.