ALBERT

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: 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 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: Abstract 4689 Familial Platelet Disorder with Predisposition to Acute Myeloid Leukemia (FPD/AML) has been attributed to abnormalities of the RUNX1 gene, located at human chromosome 21q22. The protein product of this gene forms a critical component of the core binding factor (CBF) complex, which is required for normal hematopoiesis. Truncating mutations and deletions of RUNX1 (particularly in exons 3, 4, and 5, encoding the DNA binding and CBF-beta interaction domains) that result in haploinsufficiency or dominant-negative activity have been identified as the genetic mechanisms underlying FPD/AML. Clinically, these patients present with mild to moderate thrombocytopenia, platelet dysfunction, bleeding, and about a 35% risk of developing AML. We report on three unrelated families who share histories of autosomal dominant thrombocytopenia over two to five generations, bleeding, platelet aggregation defects, and development of myelodysplastic syndrome, AML or intriguingly, chronic myeloid leukemia (CML). Detailed genetic interrogation of the RUNX1 locus in the proband from each family, including complete sequencing of all 8 exons, flanking 50 base pair regions, and P1 and P2 promoters, as well as gene dosage studies, failed to demonstrate a causative lesion in the RUNX1 gene. Our findings strongly suggest that genetic loci other than RUNX1 are involved in some cases of autosomal dominant thrombocytopenia with a predisposition to both AML and CML. Identification of the disease-causing genes in these families will allow for prospective testing of family members, appropriate surveillance and early intervention in affected individuals, and potentially new molecular insights into leukemogenesis. We have broadened the genotype-phenotype correlation in FPD/AML beyond the RUNX1 gene and suggest that this syndrome may be more genetically heterogeneous than initially described. Disclosures: No relevant conflicts of interest to declare.

Description: Polycythemia vera (PV), is a myeloproliferative disease (MPD) originating in a hematopoietic stem cell resulting in clonal expansion of erythroid progenitors. It is associated with thromboses and malignant transformation. Recently the V617F alteration arising from a mutation in JAK2 has been identified in greater than 90% of cases of PV in adults. PV is rare in children and the frequency of the common JAK2 mutation is significantly lower than in adult patients, indicating that alternative genetic events are involved in the pathogenesis of this disease. We have identified a child diagnosed with PV at the age of 15 months, the youngest described in the literature to date. Initial laboratory values demonstrated a WBC of 33 x109/L, hemoglobin 181 g/L, and platelet count of 579 x109/L. Bone marrow cytogenetics were normal. Erythroid colony forming units demonstrated erythropoietin-independent growth. Peripheral blood, buccal swab and saliva analysis revealed the presence of the common JAK2 V617F mutation, but a B lymphocyte cell line and skin-fibroblast-culture from this patient were negative, indicating that the JAK2 mutation was somatic. Peripheral blood from her parents and older brother demonstrated normal blood counts and wild type JAK2 status. This child was also diagnosed with Neurofibromatosis type 1 (NF1) based on meeting NIH consensus diagnostic criteria diagnostic criteria, having the requisite number of appropriately sized café-au-lait macules and Lisch nodules. NF1 and PV have no previously known association, however NF1 is associated with another MPD, juvenile myelomonocytic leukemia (JMML). Patients with NF1 and JMML demonstrate loss of heterozygosity (LOH) at the NF1 locus while 60% of JMML patients without NF1 alternatively demonstrate somatic mutations in NRAS, KRAS2 or PTPN11. Taken together, these genetic lesions result in hyperactivation of the RAS/MAPK pathway. Low density single nucleotide polymorphism arrays performed on peripheral blood from this patient failed to demonstrate obvious LOH at the NF1 locus. NF1 gene sequencing failed to identify the cause of the NF1 phenotype. Mutations were not identified in the commonly mutated regions of NRAS, KRAS2 or PTPN11. This case reveals the presence of the most commonly acquired somatic JAK2 mutation in a young child with PV and indicates that buccal swabs and saliva are unreliable sources of unaffected tissue for assessing the presence of germline mutations in PV patients. Moreover, it suggests that some patients with clinical NF1 are at risk for developing other MPDs besides JMML. For this patient, a novel unidentified genetic abnormality resulting in the clinical phenotype of NF1 may serve as a predisposing genetic event accounting for the unusually young age of presentation. The investigation of rare children with PV has the potential to provide valuable insight into the molecular interactions underlying the pathogenesis of MPDs.

Description: Offering to provide research results to study participants is gaining increasing support based, in part, on the principle of respect for persons. The frequency and means of this practice is unknown in national and international research communities. All investigators who presented oral abstracts involving human research at the American Society of Hematology Annual Meeting (December 2003) were surveyed. Responses were received from 197 (42%) of 472 eligible investigators. Nonrespondents did not differ in study type or country of origin. Only 30% (n = 48) of those who completed the survey had a formal plan for the return of research results; 40% of these would return both a summary plus individual level results. Of the respondents, 69% (n = 109) supported or strongly supported the practice; only 3% opposed the practice. The most commonly cited reasons for not returning results were: did not consider it (38%), anticipated contact difficulties (32%), and participant difficulty understanding results (26%). Only 11 (7%) indicated that their institutional review board (IRB) mandates the offer to provide results to all participants; this did not vary significantly by country. Given the high level of support in the international research community, evaluation of well-planned interventions for offering to provide research results to participants should be a priority.