IMPORTANCE Allogeneic hematopoietic stem cell transplantation is the standard intervention for childhood cerebral X-linked adrenoleukodystrophy. However, the pretransplant conditions, demyelination patterns, complications, and neurological outcomes of this therapy are not well characterized. OBJECTIVES To identify the risks to stable neurocognitive survival after hematopoietic stem cell transplantation and to describe subgroups of patients with distinct clinical long-term outcomes. DESIGN, SETTING, AND PARTICIPANTS This case series analyzed the treatment and outcome of a cohort of 36 boys who underwent hematopoietic stem cell transplantation at Charite Universitatsmedizin Berlin, Germany, between January 1, 1997, and October 31, 2014. Case analysis was performed from January 1, 2016, through November 30, 2017. During this retrospective review, the adrenoleukodystrophy-disability rating score and the neurological function score were used. Demyelinating lesions in the brain were quantified by the Loes score. MAIN OUTCOMES AND MEASURES Overall survival, survival without major functional disabilities, and event-free survival were analyzed. Patients' clinical symptoms, demyelination patterns, and stem cell source were stratified. RESULTS Of the 36 boys who underwent hematopoietic stem cell transplantation, the median (range) age was 7.2 (4.2-15.4) years; 18 were presymptomatic and 18 were symptomatic. Twenty-seven patients (75%) were alive at a median (interquartile range [IQR]) follow-up of 108 (40-157) months. Sixteen of 18 presymptomatic patients (89%) survived, and 13 (72%) had an event-free survival with a median (IQR) survival time of 49 (37-115) months. Among the symptomatic patients, 11 of 18 (61%) survived, but only 1 was an event-free survival (6%) (median [IQR] time, 9 [3-22] months). Of the 9 patients who received a bone marrow transplant from a matched family donor, all survived. Among the 36 patients, 6 disease-related deaths (17%) and 3 transplant-related deaths (8%) occurred. Deaths from disease progression (n = 6) occurred only in patients with demyelination patterns other than parieto-occipital. In total, 18 patients (SO%) displayed limited parieto-occipital (Loes score <9) or frontal (Loes score <4) demyelination before transplant (favorable). None of these patients died of progressive disease or developed major functional disabilities, 15 of them were characterized by stable neuroimaging after the transplant, and event-free survival was 77% (95% CI, 60%-100%). In contrast, the other 18 patients with more extended parieto-occipital demyelination (n = 6), frontal involvement (n = 4), or other demyelination patterns (n = 8) progressed (unfavorable): 13 patients developed epilepsy and 10 developed major functional disabilities, and their event-free survival was 0%. This newly defined neuroimaging assessment correlated best with neurocognitive deterioration after transplant (hazard ratio, 16.7; 95% CI, 4.7-59.6). CONCLUSIONS AND RELEVANCE All patients with favorable neuroimaging who received matched bone marrow remained stable after transplant, while some of the other patients developed major functional disabilities. Newborn screening for the disease and regular neuroimaging are recommended, and patients who lack a matched bone marrow donor may need to find new therapeutic options.

Hematopoietic stem cell transplantation (HSCT) has become a standard procedure to reconstitute a malignant or defective hematopoietic system for a series of indications, especially when other therapy options are not feasible. Indications are typically malignant transformation within the hemopoietic system, as leukemia or lymphoma, but can, especially by pediatric patients, also comprise non-malignant indications like severe immune defects, hemoglobinopathies, metabolic disorders, or neurometabolic diseases. So far, most studies comprise only adult patients or cohorts where children are included, in a malignant indication for HSCT.

A substantial number of individuals with Fanconi anemia (FA) develop bone marrow failure and are treated with androgen therapy in order to increase blood counts. The authors retrospectively identified 70 patients who received androgen therapy any time between July 1976 and September 2014. Among these patients, 37 had medical records for analysis. Twenty-five of the 37 (68%) patients had response in hemoglobin level (n = 25), platelet count (n = 21), and/or absolute neutrophil count (n = 13). The median rise in hemoglobin was 6.5mg/dL, platelet count 70,000/mm(3), and absolute neutrophil count (ANC) 1530/mu L. The majority of patients (n = 22) had a response in 2 or more blood parameters. Reasons for discontinuation of therapy included development of cytogenetic aberrations (n = 9), lack of response (n = 7), hepatic adenoma (n = 6), progression to myelodysplastic syndrome/acute myeloid leukemia (n = 3), stabilization of blood parameters (n = 3), resolution of cytopenia secondary to mosaicism (n = 1), virilization (n = 1), development of anogenital carcinoma (n = 1), inaccessibility of medication (n = 1), and unknown (n = 1). Four patients at last follow-up remain on androgen therapy. These results highlight that androgen therapy can significantly improve blood counts for many FA patients, but progression of underlying bone marrow disease and development of liver adenomas requires careful monitoring.

Allogeneic hematopoietic stem cell transplantation is required as rescue therapy in about 20% of pediatric patients with acute lymphoblastic leukemia. However, the relapse rates are considerable, and relapse confers a poor outcome. Early assessment of the risk of relapse is therefore of paramount importance for the development of appropriate measures. We used the EuroChimerism approach to investigate the potential impact of lineage-specific chimerism testing for relapse-risk analysis in 162 pediatric patients with acute lymphoblastic leukemia after allogeneic stem cell transplantation in a multicenter study based on standardized transplantation protocols. Within a median observation time of 4.5 years, relapses have occurred in 41/162 patients at a median of 0.6 years after transplantation (range, 0.13–5.7 years). Prospective screening at defined consecutive time points revealed that reappearance of recipient-derived cells within the CD34+ and CD8+ cell subsets display the most significant association with the occurrence of relapses with hazard ratios of 5.2 (P=0.003) and 2.8 (P=0.008), respectively. The appearance of recipient cells after a period of pure donor chimerism in the CD34+ and CD8+ leukocyte subsets revealed dynamics indicative of a significantly elevated risk of relapse or imminent disease recurrence. Assessment of chimerism within these lineages can therefore provide complementary information for further diagnostic and, potentially, therapeutic purposes aiming at the prevention of overt relapse. This study was registered at clinical.trials.gov with the number NC01423747.

Background Levetiracetam is increasingly used as antiepileptic drug (AED) of choice in children as well as in adults with complex diseases due to its lack of interactions and a large spectrum of action. Secondary graft failure, i.e. loss of donor cells after initial engraftment, is a relatively uncommon but serious and life-theatening complication after pediatric hematopoietic stem cell transplantation. Methods and results We report a case of secondary graft failure after hematopoietic stem cell transplantation for treatment-related myelodysplastic syndrome during antiepileptic treatment with levetiracetam. Exclusion of all other possible etiologies left levetiracetam as the most likely cause of the imminent complete secondary graft failure after hematopoietic stem cell transplantation. Furthermore, the blood cell count improved just a few days after cessation of levetiracetam medication. Conclusion Thus, we recommend that in case of secondary graft failure after hematopoietic stem cell transplantation, all possible causes should carefully be excluded, including adverse events through new generation AED agents. Switching to different AEDs with less harming effect on bone marrow function should strongly be considered.

PURPOSEAlthough hematopoietic stem-cell transplantation is widely performed in children with high-risk acute lymphoblastic leukemia (ALL), the influence of donor types is poorly understood. Thus, transplantation outcomes were compared in the prospective multinational Berlin-Frankfurt-Muenster (BFM) study group trial: ALL-SCT-BFM 2003 (Allogeneic Stem Cell Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia).PATIENTS AND METHODSAfter conditioning with total-body irradiation and etoposide, 411 children with high-risk ALL received highly standardized stem-cell transplantations during the first or later remissions. Depending on donor availability, grafts originated from HLA-genoidentical siblings or from HLA-matched unrelated donors who were identified and matched by high-resolution allelic typing and were compatible in at least 9 of 10 HLA loci.RESULTSFour-year event-free survival (± standard deviation [SD]) did not differ between patients with transplantations from unrelated or sibling donors (0.67 ± 0.03 v 0.71 ± 0.05; P = .405), with cumulative incidences of nonrelapse mortality (± SD) of 0.10 ± 0.02 and 0.03 ± 0.02 (P = .017) and relapse rates (± SD) of 0.22 ± 0.02 and 0.24 ± 0.04 (P = .732), respectively. Among recipients of transplantations from unrelated donors, no significant differences in event-free survival, overall survival, or nonrelapse mortality were observed between 9/10 and 10/10 matched grafts or between peripheral blood stem cells and bone marrow. The absence of chronic graft-versus-host disease had no effect on event-free survival. Engraftment was faster after bone marrow transplantation from siblings and was associated with fewer severe infections and pulmonary complications.CONCLUSIONOutcome among high-risk pediatric patients with ALL after hematopoietic stem-cell transplantation was not affected by donor type. Standardized myeloablative conditioning produced a low incidence of treatment-related mortality and effective control of leukemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated donors became a common practice during the last years to rescue children and adolescents with high risk acute lymphoblastic leukaemia (ALL) who lack an HLA identical sibling donor (MSD). However, heterogeneous approaches in donor selection and transplantation methods hamper the interpretation of available data. Therefore we compared the influence of donor source under standardized methods. Twenty-nine centres participated in the prospective trial to evaluate whether the results of HSCT from HLA matched donors (MD) are comparable to those of HLA identical siblings in patients with high risk ALL. 118 patients (age 0.5-18 years, med. 10.2) underwent MSD-HSCT and 313 MD-HSCT. 218 pts were in first and 213 beyond 1st remission. Unrelated donors were compatible for at least 9/10 matches with allelic typing. GvHD-prophylaxis consisted of CSA only after MSD-HSCT and of CSA/MTX/ATG after MD-HSCT. Patients older than 2 years received total body irradiation and etoposide as conditioning regimen. The stem cell source was for 82% of the MSD-group bone marrow (BM), 10% received peripheral blood stem cells (PBSC) and some received cord blood (CB). In the MD-cohort, 66% received BM, 28% PBSC and the remaining CB or combinations. After a median follow up of 4.2 years, the 4-year disease free survival (DFS) is 0.70±0.04, the overall survival (OS) 0.77±0.04 after MSD-HSCT and after MD-HSCT DFS is 0.66±0.03, OS 0.73±0.03 (n.s.); 4-years relapse-incidence is 0.22±0.04 after MSD-HSCT and 0.23±0.02 after MD-HSCT (n.s.). Non-relapse mortality at 4 years is 0.06±0.02 for MSD and 0.10±0.02 for MD (p-value 0.228). In multivariate analysis the only significant impact on OS and DFS was 1st remission compared to 2nd or 3rd remission with a Hazard ratio of 1.71. However, engraftment was significantly better after MSD-HSCT: the median day to reach ANC >1000/μl/lymphocytes >100/μl/platelets >50.000/μl was 17/14/22 after MSD-HSCT and 22/23/32 after MD-HSCT (p < 0.001). This resulted in significant less severe infections ( ≥ grade 3 CTA 3.0) –18% vs. 40% (p < 0.01) and less severe pulmonary complications: 10% vs. 19% (p = 0.034). We conclude that despite excellent outcome with low GVHD-incidence and low NRM after HSCT from MD in children with high risk ALL the HSCT von MSD results in faster engraftment and immunoreconstitution and less severe infections and justifies the use of minor sibling donors.

Die Transfusion von Erythrozyten ist essentieller Bestandteil der modernen Medizin. Sie ist die am schnellsten wirksame Therapie der lebensbedrohlichen anämischen Hypoxie. Der Einsatz von Erythrozytenkonzentraten (EK) muss jedoch dem Gebot einer rationalen Indikation folgen. Die Indikation zur Erythrozytentransfusion wird maßgeblich davon bestimmt, wie es dem Patienten möglich ist, einen anämisch bedingten Sauerstoffmangel zu kompensieren. Bei Unterschreiten eines kritischen Sauerstoffangebots treten klinische Symptome der anämischen Hypoxie auf. Diese „physiologischen Transfusionstrigger“ sind streng genommen die definitiven Indikatoren zur Erythrozytentransfusion. Sie sind jedoch unspezifisch und unter klinischen Bedingungen nicht immer eindeutig zu bestimmen. Daher müssen bei der Indikationsstellung zur Erythrozytentransfusion die aktuelle Hämoglobinkonzentration, der Allgemeinzustand und Begleiterkrankungen (z. B. koronare oder zerebrovaskuläre Gefäßerkrankungen), welche die individuelle Fähigkeit des Patienten, eine Anämie zu kompensieren, limitieren, mitbeachtet werden. Aktuelle klinische Studien belegen, dass bei moderater Anämie (Hämoglobin [Hb] 8–10 g/dl) die meisten Patienten hinsichtlich ihrer Langzeitprognose nicht von Erythrozytentransfusionen profitieren. Eine restriktive Indikationsstellung zur Gabe von Erythrozytenkonzentraten wird daher empfohlen.

AIMS Intra-myocardial transplantation of CD133(+) bone marrow stem cells (BMC) yielded promising results in clinical pilot trials. We now performed the double-blinded, randomized, placebo-controlled CARDIO133 trial to determine its impact on left ventricular (LV) function and clinical symptoms. METHODS AND RESULTS Sixty patients with chronic ischaemic heart disease and impaired LV function (left ventricular ejection fraction, LVEF <35%) were randomized to undergo either coronary artery bypass grafting (CABG) and injection of CD133(+) BMC in the non-transmural, hypokinetic infarct border zone (CD133), or CABG and placebo injection (placebo). Pre-operative LVEF was 27 ± 6% in CD133 patients and 26 ± 6% in placebo patients. Outcome was assessed after 6 months, and the primary endpoint was LVEF measured by cardiac magnetic resonance imaging (MRI) at rest. The incidence of adverse events was similar in both groups. There was no difference in 6-min walking distance, Minnesota Living with Heart Failure score, or Canadian Cardiovascular Society (CCS) class between groups at follow-up, and New York Heart Association class improved more in the placebo group (P = 0.004). By cardiac MRI, LVEF at 6 months was 33 ± 8% in the placebo group and 31 ± 7% in verum patients (P = 0.3), with an average inter-group difference of -2.1% (95% CI -6.3 to 2.1). Systolic or diastolic LV dimensions at 6 months were not different, either. In the CD133 group, myocardial perfusion at rest recovered in more LV segments than in the placebo group (9 vs. 2%, P < 0.001). Scar mass decreased by 2.2 ± 5 g in CD133(+) patients (P = 0.05), but was unchanged in the placebo group (0.3 ± 4 g, P = 0.7; inter-group difference in change = 2 g (95% CI -1.1 to 5)). By speckle-tracking echocardiography, cell-treated patients showed a better recovery of regional wall motion when the target area was posterior. CONCLUSION Although there may be some improvements in scar size and regional perfusion, intra-myocardial injection of CD133(+) BMC has no effect on global LV function and clinical symptoms. Improvements in regional myocardial function are only detectable in patients with posterior infarction, probably because the interventricular septum after anterior infarction is not accessible by trans-epicardial injection. CLINICAL TRIAL REGISTRATION This trial was registered at http://www.clinicaltrials.gov under NCT00462774.

BACKGROUND:Establishing Total Body Irradiation (TBI) using Helical Tomotherapy (HT) to gain better control over dose distribution and homogeneity and to individually spare organs at risk. Because of their limited body length the technique seems especially eligible in juvenile patients.PATIENTS AND METHODS:The cohort consisted of 10 patients, 6 female and 4 male, aged 4 - 22 y with acute lymphoblastic- (ALL) or acute myeloic leukemia (AML). All patients presented with high risk disease features. Body length in treatment position ranged from 110-180 cm. Two Gy single dose was applied BID to a total dose of 12 Gy. Dose volume constraint for the PTV was 95% dose coverage for 95% of the volume. The lungs were spared to a mean dose of [less than or equal to] 10 Gy. Patients were positioned in a vac-loc bag in supine position with a 3-point head mask.RESULTS:Average D95 to the PTV was 11.7 Gy corresponding to a mean coverage of the PTV of 97.5%. Dmean for the lungs was 9.14 Gy. Grade 3-4 side effects were not observed.CONCLUSIONS:TBI using HT is feasible and well tolerated. A benefit could be demonstrated with regard to dose distribution and homogeneity and the selective dose-reduction to organs at risk.

Aims: Results of intramyocardial injection of autologous CD133+ bone marrow stem cells (BMC) during coronary artery bypass graft (CABG) surgery in non-randomized, non-blinded pilot trials were promising. The Cardio133 trial was performed as a double-blinded, randomized, placebo-controlled trial to determine its impact on global and regional left ventricular (LV) function and heart failure symptoms.

Background To date, allogeneic stem cell transplantation (SCT) is the only curative approach for patients with Fanconi anemia (FA) and myeloid malignancy (AML). No data exist on whether cytoreductive chemotherapy prior to SCT impacts outcome. Methods We retrospectively analyzed data retrieved from the AML-BFM database (Germany) regarding children with FA and AML. Results Between January 1993 and May 2013 14 patients were identified, in whom AML was diagnosed at a median age of 11.6 yrs \[0.9-19.6\] (n=13). In 10 patients (4 not available) the diagnosis FA preceded the occurrence of AML by a median of 32.3 months [0-161]. Six of 14 patients underwent SCT achieving a 5 year overall survival of 42%. Median time to transplant after the diagnosis of AML was 2 months. One patient died after relapse, one due to severe graft versus host disease (GvHD), another of unknown cause. Of the three surviving patients two had chronic GvHD (one limited, one extended). All three surviving patients received a radiation free preparative regimen (1. fludarabine (Flu) and cyclophosphamide (Cy); 2. busulfan (Bu) and Flu; 3. Bu, Flu and Cy.) including antibodies for intensive GVHD prophylaxis. In all three cases a high cell dose of either PBSC (30.1 x 10e6 CD34+) or BM (2.13 and 3.43 x 10e8 MNC) was infused. Two surviving patients received low dose cytoreductive therapy (thioguanin and cytarabin) to bridge time to SCT. The remaining patient did not receive pre-transplant therapy. Eight of 14 patients did not receive a SCT. Median survival for these children was 40 days. Three of 8 patients received low intensity chemotherapy (thioguanin and/or cytarabin). Two were treated with more intensive combinations (e.g. cytarabin, adriamycin and etoposide). The latter all died of complications from long lasting aplasia. Additionally to the 14 patients described above, another patient was identified, in whom AML developed 14 months after successful SCT for bone marrow failure. Blasts were of recipient origin and the patient died of progressive disease. Conclusion The data presented are subject to selection bias. Three of 14 patients survived and 2/3 surviving patients received low dose cytoreductive therapy for disease control before going to transplant. None of them achieved complete remission (CR) before SCT. Graft failure and chronic GVHD were the main complications after transplantation. FA patients with AML should proceed to SCT. Mild cytoreductive therapy with thioguanine and cytarabine may be useful. Achieving CR pre transplant might not be necessary for OS. Disclosures: No relevant conflicts of interest to declare.

Allogeneic hematopoietic stem-cell transplantation (HSCT) from HLA identical sibling donors is standard of care for children with high-risk acute lymphoblastic leukemia (ALL). However, transplant-related mortality remains a serious problem, especially after transplantation from unrelated or HLA-mismatched donors. Heterogeneity regarding patient selection, transplantation procedures and study endpoints hamper the interpretation of the available data. We therefore initiated a prospective trial to evaluate the results of HSCT in a standardised setting. From September 2003 through September 2010, 471 children with ALL in first, second or subsequent remission (229 in CR1, 242 ≥ CR2) received an allogeneic HSCT from an HLA-matched sibling (MSD), an HLA-matched family/unrelated donor (MD) or, for patients with very high-risk disease, an HLA-mismatched donor (MMD) after conditioning with total body irradiation (TBI) and etoposide or a chemotherapy-only regimen. Two high risk groups with indication for an HSCT were defined according to results with conventional chemotherapy: "high relapse risk group" (HRR) and "very high relapse risk group" (VHRR). HRR was defined by response to front line chemotherapy, amount of minimal residual disease (MRD), phenotype of leukemia and/or time and site of relapse At a median observation time of 3 years, the 4-year probability of disease-free survival (pDFS) after MD-HSCT was equivalent to that of MSD-HSCT (68% vs. 71%; n.s.). Transplant-related mortality (TRM) after 3 years was 5% for MSD and 10% for MD HSCT (n.s.). Acute GvHD grade I/II occurred in 274 pts (58%) with no difference between MSD and MD or MMD, 117 evaluable pts did not develop any acute GvHD (24%). Grade III and IV aGvHD occurred in 10% of all patients with no difference according to donor type, stem cell source, patient's age or gender matching. Forty percent of 439 evaluable patients developed cGVHD. The 2-year cumulative incidence of extensive chronic GvHD was 16% after MSD and 2% after MD HSCT (P < .001). After MSD-HSCT, age >10 years (29% vs. 4%), transplantation of PBSC compared to BM (50% vs. 14%) and remission status > CR1 (21% vs. 11%) negatively influenced the 2 years cumulative incidence of extensive cGVHD. Gender match of donor/recipient, year of HSCT, phenotype, and CMV status did not influence the incidence and severity of cGVD after MSD-HSCT. After MD-HSCT, the 2 year cumulative incidence of cGVHD was only 5% with no difference between BM and PBSC or HLA disparities (9/10 or 10/10 matches). The 3-year cumulative incidence of relapse was 21% after MSD-HSCT, and 19% after MD-HSCT (n.s.). For patients with VHRR the results for MD/MSD HSCT (n=232) were significantly superior to those of MMD HSCT (n=46) (3-year pDFS 65% vs. 31%; P < .001; 3-year incidence of TRM 10% vs, 26%; P < .001). Allogeneic HSCT from HLA-matched donors is equivalent to HSCT from HLA-identical sibling donors in children with ALL.

Objectives: CD133pos cells are currently evaluated for use in cardiac cell therapy.We hypothesized that they exert their beneficial effects in a paracrine manner and investigated this in a cell culture ischaemia model.Furthermore, we checked whether purified CD133pos cells perform better than non-fractionated mononuclear cells (MNC).Methods: CD133pos cells were isolated from bone marrow MNC and conditioned medium was prepared from CD133pos and non-fractionated MNC.HL-1 cardiomyocytes were subjected to simulated ischaemia in the respective conditioned media or in control medium.After treatment, total remaining cells, apoptotic cells and nuclear shrinking were quantified using an automated imaging system.Furthermore, metabolic activity and phosphorylation of kinases Akt, Erk1/2, GSK3b and transcription factor Stat3 were investigated.Results: After simulated ischaemia, the rate of detached dead cells was lowest in CD133pos conditioned medium (26 ± 6%) and highest in control medium (36 ± 6%).In CD133pos conditioned medium, the fraction of nonapoptotic cells was most enhanced and nuclear shrinking as a consequence of apoptosis was reduced.Cell viability was also highest in CD133pos conditioned medium (109.4 ± 8.8% in relation to control).In both conditioned media, phosphorylation of Akt, Erk1/2, and GSK3b was lower than in control medium.Stat3 phosphorylation was sustained on the level of control.Conclusions: Factors released from purified CD133pos bone marrow cells exhibit more pronounced protective effects on HL-1 cardiomyocytes under simulated ischaemia than from non-fractionated MNC.These effects are not associated with the phosphorylation of cell survival promoting kinases Akt, Erk1/2, GSK3b and transcription factor Stat3.Although the molecular mechanism of cardioprotection by CD133pos cells requires further investigation, our results reinforce the advantage of enriching CD133pos cells for cardiac cell therapy.

Pediatric patients with SCID constitute medical emergencies. In the absence of an HLA-identical hematopoietic stem cell (HSC) donor, mismatched related-donor transplantation (MMRDT) or unrelated-donor umbilical cord blood transplantation (UCBT) are valuable treatment options. To help transplantation centers choose the best treatment option, we retrospectively compared outcomes after 175 MMRDTs and 74 UCBTs in patients with SCID or Omenn syndrome. Median follow-up time was 83 months and 58 months for UCBT and MMRDT, respectively. Most UCB recipients received a myeloablative conditioning regimen; most MMRDT recipients did not. UCB recipients presented a higher frequency of complete donor chimerism (P = .04) and faster total lymphocyte count recovery (P = .04) without any statistically significance with the preparative regimen they received. The MMRDT and UCBT groups did not differ in terms of T-cell engraftment, CD4+ and CD3+ cell recoveries, while Ig replacement therapy was discontinued sooner after UCBT (adjusted P = .02). There was a trend toward a greater incidence of grades II-IV acute GVHD (P = .06) and more chronic GVHD (P = .03) after UCBT. The estimated 5-year overall survival rates were 62% ± 4% after MMRDT and 57% ± 6% after UCBT. For children with SCID and no HLA-identical sibling donor, both UCBT and MMRDT represent available HSC sources for transplantation with quite similar outcomes.

We report a novel allele HLA-DQB1*06:49 with a G→T transversion, most closely resembling HLA-DQB1*06:02:01.

Abstract Abstract 2780 Introduction: Refractory cytopenia in childhood (RCC) is the most common subtype of myelodysplastic syndrome (MDS) in children. Differential diagnosis from inherited bone marrow failure (IBMF) such as Fanconi anemia (FA) remains an intriguing challenge, because most patients with RCC have a hypocellular bone marrow (BM) and dysplastic features in haematopoiesis are observed in both RCC and IBMF. Moreover the spectrum of phenotypic findings in FA is extremely wide. Some FA patients have a mild phenotype without malformation. The purpose of this study is to estimate the incidence of FA in an RCC cohort without a full clinical feature of FA, but subsequently diagnosed by chromosome breaking test. Patients and Methods: Between 01/2007 and 12/2010 reference pathologists of the European Working Group of MDS in Childhood (EWOG-MDS) provided a morphological report consistent with RCC in 137 children studied in Germany. Seventeen patients with hypercellular BM or abnormal karyotype, 2 patients, in whom dyskeratosis congenital was diagnosed after initial inclusion and one patient, in whom chromosome breaking test was not performed, were excluded. Results: Seven of remaining 117 patients had facial and/or skeletal anomalies typically noted in FA and one patient had a brother with FA. In these 8 patients, FA had been suspected by their local physicians (group FA-1). Nine patients (8.3%) without these typical anomalies were subsequently diagnosed of FA by chromosome breakage test (group FA-2). The diagnosis of RCC was finally made in the remaining 100 patients with negative chromosomal breakage test (group RCC). The clinical features of patients in each group are summarized in the Table. The mean corpuscular volume of red cells (MCV) was elevated (> +2SD) for ages in all patients with FA, but only 42 % in patient with RCC. In some children of group FA-2 additional non-haematological abnormalities were also observed. However, they were not evident and or typical to prompt the treating physicians to suspect FA. A few patients in the group RCC also had some physical anomalies, not specific for any of the known IBMF disorders. Possibly that other known or not yet described IBMF disorders remain uncovered in children with “de novo” RCC. Conclusion: Our results illustrate that the same haematological features and congenital anomalies can be noted in FA and RCC. More importantly, they indicate that the exclusion of FA by a chromosomal breakage test or other methods is mandatory in all patients prior to diagnosis RCC. Chromosomal breakage analysis may identify patients with FA in 8% of patients with a morphological description of RCC without a full clinical picture of FA. Disclosures: No relevant conflicts of interest to declare.

The new DQB1*03:02:05 differs from DQB1*03:02:01 by two nucleotide exchanges in exon 2.

infant's lymphoma using 2 independent methods: FISH and microsatellite analysis.Procedures were carried out according to the Declaration of Helsinki and with the informed consent of the family.As a result, the infant's tumor cells were found to be of maternal origin (Figure 1A-B).Although HLA loss in the tumor tissue is one of the escape mechanisms for evading the immune surveillance system, tumor cells losing HLA-C antigens are recognized and removed by NK cells.Recently, Villalobos et al demonstrated that the uniparental disomy of the HLA-C locus as well as the loss of mismatched HLA-A and -B alleles were associated with leukemic relapse after HLA-haploidentical transplantation. 7 We could not precisely determine whether the tumor tissue lost noninherited maternal HLA alleles in the present study (supplemental Table 1).However, it was crucial that the maternal leukemic cells transmigrated into the paratesticular area, a sanctuary from the immuno-surveillance system, where they were engrafted and proliferated.