ALBERT

Description: Recent work has established that heterozygous germline GATA2 mutations predispose carriers to familial myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), “MonoMAC” syndrome, and DCML deficiency. Here, we describe a previously unreported MDS family carrying a missense GATA2 mutation (p.Thr354Met), one patient with MDS/AML carrying a frameshift GATA2 mutation (p.Leu332Thrfs*53), another with MDS harboring a GATA2 splice site mutation, and 3 patients exhibiting MDS or MDS/AML who have large deletions encompassing the GATA2 locus. Intriguingly, 2 MDS/AML or “MonoMAC” syndrome patients with GATA2 deletions and one with a frameshift mutation also have primary lymphedema. Primary lymphedema occurs as a result of aberrations in the development and/or function of lymphatic vessels, spurring us to investigate whether GATA2 plays a role in the lymphatic vasculature. We demonstrate here that GATA2 protein is present at high levels in lymphatic vessel valves and that GATA2 controls the expression of genes important for programming lymphatic valve development. Our data expand the phenotypes associated with germline GATA2 mutations to include predisposition to primary lymphedema and suggest that complete haploinsufficiency or loss of function of GATA2, rather than missense mutations, is the key predisposing factor for lymphedema onset. Moreover, we reveal a crucial role for GATA2 in lymphatic vascular development.

Description: Hodgkin’s Disease (HD) is the most common lymphoma affecting young adults and teenagers. Bone marrow involvement is rare but if present, infers Stage IV disease and an inferior outcome. Adult studies have suggested that bone marrow examination (BME) may not be necessary unless certain risk factors are present. However, some pediatric centers continue to perform BME routinely on all children with HD. BME is invasive and generally performed under conscious sedation in children. We validated and administered an internet-based survey to examine the practice of all Canadian pediatric oncologists regarding BME in children with HD. We also retrospectively evaluated the impact of routine BME on the HD patients treated at our institution over the past 27 years. Forty-three percent of eligible physicians (n=93) completed the survey and 16 of a total of 17 Canadian pediatric oncology centers were represented. BME universally consisted of bilateral bone marrow aspirates and trephine biopsies. Routine BME for Stage III and IV disease was consistently practised nationally (by 92% and 97% of respondents, respectively). By contrast, 54% and 70% of respondents reported performing routine BME in low stage (Stage I and II) disease, respectively. Respondents were more likely to report performing routine BME in low stage patients, if their pediatric hematology/oncology training was entirely outside Canada (p=0.04 for Stage I and p=0.07 for Stage II) and if they practiced at smaller centers (p=0.05 for Stage I and p=0.03 for Stage II). There were no differences in practice regarding BME associated with the number of years in practice or the number of patients seen annually by the respondent. If not part of routine staging for all patients, BME was more likely performed if there were “B” symptoms, cytopenias, and/or bulky disease. Most respondents (95%) would proceed with BME following a positive PET scan. In the review of local institutional practice, 62 patients with HD and BME were eligible for analysis. Only 4 patients (6.5%) had a positive BME. No patient with otherwise low stage disease was found to have bone marrow involvement. Two patients, who would have been assigned as Stage III disease, were upstaged to Stage IV due to their BME. Comparison of staging with and without BME demonstrated no significant difference. Hemoglobin level was found to be the to be the only significant risk factor for marrow involvement based on univariate analysis(put in statisticp=0.006). Age, gender, histologic subtype, presence of “B” symptoms, and other blood parameters (white count, platelets, ESR and transaminases) were not significant factors. Practice regarding BME in children with low stage HD is highly variable across Canada. Bone marrow examination in pediatric patients with low stage HD should be abandoned, unless there is a specific indication to do so (for example positive PET scan or unexplained anemia). Moreover, BME does not appear to add any additional therapeutic direction for higher stage patients.

Description: Background Four key challenges have been identified for the informed consent process in pediatric Bone Marrow Transplantation (BMT): 1. The information disclosed is complex, 2. parents are often under significant emotional duress, 3. life or death circumstances are perceived, and 4. there is often significant time pressure. The purposes of this study were A. to survey parental perceptions of the validity of the informed consent provided for their child’s BMT, B. to determine if the quality of the consent influenced hope, guilt, anxiety or stress. Methods An information package and informed consent document were mailed to 67 English-speaking parents whose children underwent BMT and were prepared for transplant by one physician using a standardized template at the IWK Health Centre (Halifax, Nova Scotia, Canada) between 1998 and 2002. These parents represented the guardians of 36 children who had undergone BMT. Semi-structured interviews were conducted by phone or in person and audiotaped. Transcripts were independently analyzed for common themes by 2 reviewers. Results Twenty parents (12 mothers and 8 fathers) of 12 children consented to participate in the study. Participants did not differ from eligible non-participants in indication for transplant, donor source, major complications, or death rates. Elements of consent: (A) Freedom to Choose. All parents reported feeling personally compelled to consent, but denied external pressure to do so. All participants, including those whose children had died (n=5), would consent to BMT again. No parent reported questioning the validity of the informed consent for BMT. (B) Capacity to Understand. A minority of parents (n=5, 25%) reported diminished ability to understand the process, usually related to emotional duress at the time of consent. (C) Adequacy of Information. Most parents (n=15, 75%) stated directly that they felt fully prepared for the potential side effects of BMT. However, there were four reports of unexpected severity of side effects of therapy [excess hair growth (n=1), bleeding (n=1), and fatigue (n=2)] and 1 of an unexpected side effect (pneumonitis). Emotional impact: 7 parents (35%) reported marked hopelessness during the disclosure process, although all parents expressed that they did not want false hope. 14 parents reported a direct relationship between hope and objective test results (ie daily complete blood count). Parents (n=18) reported peak stress leading up to BMT and the first 6 months post BMT. 18 parents noted ongoing, significant, stress at the time of the study, despite length of time from BMT (median 39 months). One parent reported experiencing guilt. All parents denied experiencing second thoughts with respect to the decision to consent. 8 parents reported heightened health vigilance for their child and increased stress with the appearance of minor health concerns (ie mosquito bites, bruises), or at the time of recheck, despite length of time post BMT. In addition to geographic isolation, all parents reported social isolation, sometimes severe, at the time of, and following BMT. Conclusions Despite significant barriers to informed consent, no parent reported questioning the validity of the consent for BMT for their child. Hopelessness, social isolation and continuing high levels of stress related to the health of their child are frequently reported. Consent conferences and ongoing follow up should proactively address these issues for parents of children undertaking BMT.

Description: Background: Offering research results to study participants is increasingly considered an ethical obligation founded on the principle of respect for persons. This practice acknowledges the importance of the participant’s contribution in the study and, in some instances, enables the participant to benefit directly from the health information derived from the research. Recent studies have established that there is growing support for this practice among investigators and study participants in highly selected populations. The frequency and means of this practice is unknown in the broader national and international research community. Methods: We pilot-tested a questionnaire, which we designed for this study. It had a high content validity. The questionnaire was designed to document the frequency with which researchers offer return of results to research participants, the means by which researchers offer results, the role of Research Ethics Boards (REBs) in the return of research results, and the demographics of the study participants. We classified all 887 abstracts presented at the American Society of Hematology Annual Meeting in December 2003 according to study type. Only those abstracts involving human subjects were included. Of the 478 eligible abstracts, email addresses for 472 (98.7%) first or senior authors were found using public web sites. The investigators were sent the 4–5 minute survey by email. Two reminders were sent to non-respondents. Responses were downloaded to a secure server and analyzed by descriptive and Chi squared techniques. Results: Interim results were obtained 11 days after initiating the survey. Complete responses were received from 84 of the 471 (18%) investigators. Most responders were physicians (n=68; 81%) and almost half (n=40; 47%) received Research Ethics Board (REB) approval for their study in the United States. Only 23 (27%) investigators had a formal plan for the return of results to study participants. No clear preference for any one means of returning research results was indicated. The majority (n=18; 78%) indicated that they would provide the participant with a choice of whether or not to receive research results and most (n=14; 61%) indicated that they would provide an overall summary of results rather than an overall summary plus individual level results. Reasons for not returning research results included: did not consider it (n=25), contact difficulties (n=22), and participant difficulty in understanding results (n=19). Cost and concern for the patient regarding adverse effects of receiving results were infrequently cited. Only 2 (2%) of investigators reported that their REB mandated the offer of return of research results to all participants. 55 researchers (66%) supported or strongly supported the return of results to participants, 27 (32%) were neutral, and only 2 (2%) opposed or strongly opposed this practice. Updated data and further analyses will be reported at the annual meeting. Conclusion: Investigators in the international research community infrequently offer to return results to research participants, and REBs rarely mandate this practice. Our study reaffirms the findings of other studies that indicate a high level of support for this practice among researchers. Further work is needed to assess participant needs and concerns, and how to bridge the gap between the expressed attitudes of researchers and actual practice.

Description: Asparaginase (ASP) therapy is associated with depletion of antithrombin (AT) and fibrinogen (FG). Potential toxicities include central nervous system thrombosis (CNST) and hemorrhage. Historical practice at the Izaak Walton Killam Health Centre (IWK) involves measuring AT and FG levels after ASP administration and transfusing fresh-frozen plasma (FFP) or cryoprecipitate (CRY) to prevent thrombotic and hemorrhagic complications. To determine whether this reduced these complications in children with acute lymphoblastic leukemia (ALL), incidence, outcome, and clinical characteristics of ASP-related CNST in ALL patients at IWK were compared with a similar cohort from BC Children's Hospital (BCCH), where prophylaxis was not performed. Costs associated with preventative versus expectant management were estimated. From 1990 to 2005, 240 patients were treated at IWK and 479 at BCCH. Seven BCCH patients developed venous CNST (1.5%), compared with none at IWK. CNST occurred exclusively during induction. Six patients received anticoagulation and continued ASP. All 7 patients remain in remission. National Cancer Institute high-risk ALL predicted CNST risk (P = .02), whereas sex, age, race, and body mass index did not. Neither FFP nor CRY protected against CNST, suggesting prophylaxis is unwarranted for unselected ALL patients. However, prophylactic replacement for HR patients in induction may be cost-effective.

Description: Abstract 4471 Chronic myeloid leukemia (CML) is associated with the reciprocal t(9;22)(q34;q11) translocation, which generates the BCR-ABL fusion oncogene and is the most common myeloproliferative disease affecting adults. The clinical outcome in this disease has been revolutionized with the use of imatinib mesylate (Gleevec), a targeted tyrosine kinase inhibitor, and molecular surveillance, with the development of quantitative PCR (qPCR) approaches to measure BCR-ABL transcript levels. A number of guidelines outlining follow-up strategies for patients with chronic phase CML on imatinib therapy have been established. Once a patient is stable, a typical recommendation includes peripheral blood (PB) monitoring by qPCR of BCR-ABL levels every 3–6 months to determine response or relapse, with consideration of annual bone marrow (BM) examinations to assess for cytogenetic evolution. At the Queen Elizabeth II Health Sciences Centre and IWK Health Centre in Halifax, Nova Scotia, 34 patients with chronic phase CML on imatinib were identified from 2006 to 2008, with 36 paired samples, where transcript levels were assessed in both PB and BM within one week of each other. In 24 of the cases, the BCR-ABL transcript levels in PB and BM were within 0.5 log values of each other. In the remaining 12 cases, BCR-ABL transcript levels differed by greater than 0.5 log. Three cases had higher BM levels, but surprisingly, 9 patients had a higher BCR-ABL transcript level in the PB. In all cases, BCR-ABL levels were assessed by Q-RT-PCR using the ABI7500 instrument and primers and probe designed to detect p210 and p190 breakpoints. Results were recorded as a ratio of %BCR-ABL to GAPDH that was amplified as an internal control. There was no significant difference in clinical, morphological or laboratory parameters between these patients and others who had comparable PB and BM BCR-ABL levels. These findings highlight the need to compare BCR-ABL transcript levels derived from the same tissue during longitudinal monitoring. Moreover, while potentially due to stochastic factors, the striking observation of higher PB BCR-ABL transcript levels raises the question of which tissue represents the most accurate source for monitoring of BCR-ABL transcript levels and whether there is value in confirming a significant change in PB transcript level with BM evaluation. The discrepant levels in PB and BM could not be attributed to technical issues; the timing of sample processing from collection and quality of mRNA were comparable and no variability was observed in GAPDH levels to account for the difference. Without a technical explanation, the mechanism underlying this phenomenon remains uncertain. We speculate that it may reflect CML stem cell geography with one possibility being that the CML niche may be located external to the BM. Further studies are needed to confirm these observations. If corroborated, then revision of surveillance approaches for chronic phase patients may be indicated. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4954 Background. The SLC25A38 gene has recently been identified to play a role in the pathogenesis of congenital sideroblastic anemia (CSA). The erythroid specific mitochondrial carrier family protein SLC25A38 is important for the biosynthesis of heme. The ALAS2 gene is also frequently mutated in CSA. Refractory anemia with ringed sideroblasts (RARS) is an acquired myelodysplastic condition characterized by lineage dysplasia with an excess number of ringed sideroblasts in the marrow. A genetic cause for the expression of ringed sideroblasts in RARS or other myleodysplasias has not been clearly determined. We examine whether loss of function mutations in SLC25A38 or ALAS2 genes are associated with acquired myelodysplastic syndromes (MDS) with ringed sideroblasts. Methods. Participants had to have adequate banked DNA or bone marrow from diagnosis and meet WHO 2001 criteria of MDS and a high percentage of ringed sideroblasts. Medical records were retrospectively examined for patient demographics and outcomes. All diagnostic bone marrows were reviewed to confirm the diagnosis and the percentage of ringed sideroblasts and blasts was recorded. Cytogenetic findings were also recorded. DNA was extracted as needed by standard techniques. Coding exons and exon/intron boundaries of SLC25A38/ALAS2 were PCR-amplified using primers designed with Primer3 (http://frodo.wi.mit.edu/) from each affected individual. These products were then sequenced using the ABI 3130 xl electrophoresis instrument (Applied Biosystems). Sequence chromatograms were interpreted using the MutationSurveyor program from SoftGenetics, Inc., with gene annotations from GenBank looking for mutations predicted to result in loss of function. Results. 12 samples were identified from patients diagnosed between 2003 and 2008. The diagnosis by WHO 2001 classification of myelodysplastic syndrome was refractory anemia with ringed sideroblasts [RARS] (n=7), refractory cytopenia with multilineage dysplasia (RCMD-RS] (n=4) and refractory anemia with ringed sideroblasts with thrombocytosis [RARS-T] (n=1). The median age at diagnosis was 82 years (range 58–94 years). Participants were males (n=9) and females (n=3). The clinical status was as follows: Remission (n = 1), Active Disease (n = 7), and Unknown (n = 4). Treatment provided to patients included transfusion supportive care only (n =2), erythropoietin (n= 3) and MDS directed drug therapy (n=1) and unknown (n=5). For those with blood counts available at diagnosis, the median white blood cell count was 8 × 109/L (range 4.7–10.9), the hemoglobin was 94 g/L (range 85–112) and the platelets were 327 × 109/L (range 3–951). The absolute neutrophil count was 5.3 × 109/L (range 3.1–7) and the absolute lymphocyte count was 1.9 × 109/L (range 0.7 – 2.2). The median percentage ringed sideroblast count in the diagnostic bone marrow was 51% (range 15–81%). Conventional G-banding cytogenetics showed a definitive abnormality in only one of the 12 patients. Mutations predicted to result in complete loss of function occurred in 0/12 in the SLC25A38 gene and 0/12 in the ALAS2 gene. One previously unreported variant of unknown significance at SLC25A38 E03 (cDNA position #239C〉G; 80T〉R) was identified in homozygous form in a patient with RARS and normal cytogenetics. Conclusions. Variations in the coding regions of SLC25A38 or ALAS2 genes were not obviously associated with mutations predicted to result in complete loss of function in this cohort of patients with acquired myelodysplastic syndromes with ringed sideroblasts. We did identify one unique variant in homozygous form but its significance is uncertain. We plan to expand this study to confirm these findings. Whilst loss of complete function of these genes does not appear to be associated with acquired ringed sideroblasts, we have not ruled out a contribution of functional mutations resulting in reduced expression of these genes. Further examination of this question may clarify the physiological understanding of ringed sideroblasts in acquired MDS, which in turn may represent a target for therapy. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 69 Background. Ethical challenges associated with tissue banking in pediatric populations include consent, privacy and confidentiality, conflicts of interest, return of summary and individualized results and logistical issues. A gap in the literature exists in applying theoretical claims because of a paucity of empirical evidence with respect to parental attitudes towards tissue banking for their children. The purpose of this study was to investigate parental attitudes to ethical issues in tissue banking while acting as surrogate decision-makers for pediatric malignant hematology and oncology populations. Methods. A validated questionnaire was developed through literature review, an expert content validity exercise and a pilot study. The final questionnaire and 2 reminders with return postage were sent to parents of 104 consecutively diagnosed, pediatric oncology patients treated at the IWK Health Centre in Halifax, Nova Scotia, from January 2006 to December 2007. The questionnaire examined ethical domains related to consent, tissue acquisition for banking and subsequent use, as well as patient and parent demographics. Results. Fifty four parents (including 10 of 16 parents of children who were deceased) completed the questionnaires. The majority of the respondents were Caucasian (98%, n=53) and primarily spoke English (83%, n=45). 35% of patients were diagnosed with acute lymphoid leukemia or acute myeloid leukemia at an average age of approximately 8 years old. Most respondents (n=46, 85%) stated that they would agree to have tissue obtained in order to classify the cancer. 48 parents (89%) reported that they would agree to have their child's tissue sent anywhere in the world for research purposes. If a severe underlying health condition existed, 98% of parents (n=53) would want genetic research to be done if it might improve the immediate or future health of their child. 45 respondents (83%) stated that they would want genetic research to be done, if it might improve their personal health, and 76% of parents (n=41) agreed that they would still want genetic research to be undertaken, even if it would not improve their child's health. In a situation where a child is refusing a very painful procedure strictly for research purposes, 41% of parents said that they would not go through with the procedure, while 15% said they would do so regardless of the child's dissent. 54% of parents (n=29) feel that they should be asked for consent if previously stored tissue is to be used for a new research purpose. When a patient reaches the age of majority, 98% of parents agree that their child should be given the opportunity to confirm consent and 71% feel that the now mature child should be able to then withdraw consent. Only 2% of respondents believe stored tissue should be destroyed in the event that a patient (who is now the age of majority) cannot be contacted to confirm consent. 40 parents (74%) believed that they have few or no rights to any money gained as a result of research using their child's tissue; and 83% believed that the money should be used to fund childhood cancer research. In the setting where approximately two thirds of children would be offered research participation, 26% of respondents (n=14) cannot remember if their child was offered research participation, and 30% of parents (n=16) cannot recall if they provided consent. 3 parents reported that they did not understand the consent forms and 30% of parents (n=16) felt that they were not given adequate time to read the forms. While most parents agree that all their research participation questions were thoroughly addressed, 35% reported (n=19) that more time would have been helpful. Conclusions. Most parents are willing to participate in tissue research providing the child is not exposed to extra pain. Most parents felt that they had sufficient information to provide consent but a significant minority would like more time. Parents generally do not feel a right to monetary gains from tissue research or express concerns about sending tissue internationally for research purposes. In addition, parents are not apprehensive about genetic research being conducted on banked tissues, even if it cannot directly help the health of their child or themselves. This information may help Institutional Review Boards in assessing parentally perceived risks of research participation, and researchers in providing consent elements that parents require to make fully informed choices. Disclosures: No relevant conflicts of interest to declare.

Description: Background and Objectives. Phenotypic overlap among the inherited bone marrow failure syndromes (IBMFSs) frequently limits the ability to establish a diagnosis based solely on clinical manifestations. Since a large number of IBMFS genes (〉70) have been identified, genetic testing is often prolonged and costly. Correct diagnosis, care and counseling often depend on identifying the mutated gene. Thus time-efficient and cost-effective strategies for genetic testing are essential. The aims of this study were to develop and evaluate the application of a next generation sequencing (NGS) IBMFS Gene Panel assay for genetic testing of patients with previously characterized categories of IBMFSs (e.g. Fanconi anemia and Diamond Blackfan anemia) but unknown genotype, as well as patients with unclassified IBMFSs. Methods. We designed a NGS assay to test a comprehensive panel of 72 known IBMFS genes. Genomic DNA from patients enrolled on the Canadian Inherited Marrow Failure Registry was analyzed using the Haloplex technology and Illumina Seq2000 platform. The average gene coverage was 99.12%. SureCall program was used to align, map, and identify variants. Polyphen, Sift and MutationTaster were used to predict the effect of variants on the protein. Human Splicing Finder program was used to analyze effect of splicing. The assay was validated by detecting all 50 mutations and polymorphic variants that were previously found by Sanger sequencing in 31 patients. Results. A total of 158 patients with unknown mutations were studied. Among 75 patients with known categories of IBMFSs but unknown genotypes, we found deleterious mutations in 43 patients (57.3%). These categories included Diamond Blackfan anemia, Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, TAR syndrome, familial thrombocytopenia and Kostmann/severe congenital neutropenia. Among 83 patients with unclassified IBMFSs, we found deleterious mutations and established the diagnosis in 16 patients (19.2%). Established diagnoses included dyskeratosis congenita, Diamond-Blackfan anemia, myelokathexis, GATA2-associated familial MDS, WAS-associated severe congenital neutropenia, G6PC3-associated severe congenital neutropenia, MYH9-associated disorder, MASTL-associated disorder and Wiskott-Aldrich syndrome. All identified mutations were validated. The assay allowed identification of mutant genes that had not been previously reported to be associated with the patient phenotypes in two cases. The assay led to amendment of established diagnoses in two other cases. The assay results directed a change in clinical care in multiple cases, including implementation of cancer surveillance program and consideration for prenatal diagnosis. The cost of the NGS was $470/patient compared to $4643/patient among those who underwent genetic testing by Sanger sequencing during the tenure of the study. Conclusion. Our novel assay is a rapid, accurate, and cost saving strategy for genetic investigation of patients with IBMFSs. It can identify mutations in classified and unclassified IBMFSs with high level of sensitivity and precision. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 1705 Background: Outcomes in acute lymphoblastic leukemia (ALL), the most common childhood malignancy, have improved significantly due to risk-based multi-agent chemotherapy strategies derived from diagnostic advances in cytogenetics and molecular biology. Characterization of recurrent genetic lesions has enabled further prognostic stratification on recent clinical trials. Abnormalities involving the short arm of chromosome 9 are well-documented in pediatric ALL. Three critical tumor suppressors: CDKN2a (p16INK4a), CDKN2b (p15INK4b) and p14ARF have been localized to band 9p21. While 9p21 abnormalities have been reported in 10% of childhood ALL, their prognostic significance remains uncertain and may depend on which of these genes are lost/inactivated. Moreover, 9p deletions may be cryptic and/or not readily identified by standard G-banding techniques. We investigated the incidence and prognostic significance of 9p21 abnormalities identified retrospectively in pediatric ALL patients. Methods: A total of 76 children were diagnosed with ALL at the IWK Health Centre in Halifax, Nova Scotia from 2000–2005. Cell pellets were available for analysis on 48 patients. Chart review was conducted retrospectively. Approval was obtained by the IWK Research Ethics Board. 9p21 abnormalities were assessed by two modalities: 1) fluorescence in-situ hybridization (FISH) using a commercial p16 probe; and 2) methylation specific multiplex ligation-dependent probe amplification (MS-MLPA), using SALSA MLPA kit ME024-A1 9p21 CDKN2A/2B region (MRC Holland). Results: Of the 48 samples studied by FISH, 18 (38%) had a 9p21 deletion, only 4 of which were previously identified by G-banding. MLPA was performed on 40 samples and identified a total of 18 (45%) patients with a 9p21 deletion, 5 of which were not identified by FISH. Aberrant methylation at CDKN2b (p15INK4b) was found by MLPA in 19 patients (46%). Overall, 32 of 48 (67%) patients were determined to have an abnormal 9p21, representing a substantially greater frequency than previously reported. The detection rate for deletions at 9p21 between FISH and MLPA, was not statistically different (p=0.31). Interestingly, all patients with T-cell disease (n=5) had an abnormal 9p21, suggesting an association between this immunophenotype and 9p21 abnormalities (p=0.02). Overall, 9p21 abnormalities were associated with National Cancer Institute (NCI) high risk criteria (p=0.04), specifically white blood cell count 〉50,000/μL at diagnosis (p=0.019) and a higher percentage of leukemic blasts in the peripheral blood (p=0.016). Only four B-cell lineage patients in our cohort relapsed, three of which had 9p21 abnormalities and one of these ultimately died of disease. Conclusions: Using FISH and MLPA, our study has revealed a much higher incidence of 9p21 abnormalities in childhood ALL than has previously been described. Moreover, our findings demonstrate an association with high risk features and possibly inferior prognosis. It is possible that the lack of consistent reports linking 9p21 abnormalities to prognosis are related to suboptimal ascertainment. A small sample size in our study prevents the conclusive determination of an independent prognostic impact. However, our results justify the need for a larger multi-center investigation to evaluate how 9p21 abnormalities might affect ALL outcome and possibly influence future risk stratification for determining treatment. Disclosures: No relevant conflicts of interest to declare.