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Background Diffuse intrinsic pontine glioma (DIPG) remains a clinico-radiologic diagnosis without routine tissue acquisition. Reliable imaging distinction between DIPG and other pontine tumors with potentially more favorable prognoses and treatment considerations is essential. Methods Cases submitted to the International DIPG registry (IDIPGR) with histopathologic and/or radiologic data were analyzed. Central imaging review was performed on diagnostic brain MRIs (if available) by two neuro-radiologists. Imaging features suggestive of alternative diagnoses included nonpontine origin, Results Among 286 patients with pathology from biopsy and/or autopsy, 23 (8%) had histologic diagnoses inconsistent with DIPG, most commonly nondiffuse low-grade gliomas and embryonal tumors. Among 569 patients with centrally-reviewed diagnostic MRIs, 40 (7%) were classified as non-DIPG, alternative diagnosis suspected. The combined analysis included 151 patients with both histopathology and centrally-reviewed MRI. Of 77 patients with imaging classified as characteristic of DIPG, 76 (99%) had histopathologic diagnoses consistent with DIPG (infiltrating grade II-IV gliomas). Of 57 patients classified as likely DIPG with some unusual imaging features, 55 (96%) had histopathologic diagnoses consistent with DIPG. Of 17 patients with imaging features suggestive of an alternative diagnosis, eight (47%) had histopathologic diagnoses inconsistent with DIPG (remaining patients were excluded due to nonpontine tumor origin). Association between central neuro-imaging review impression and histopathology was significant (p < 0.001), and central neuro-imaging impression was prognostic of overall survival. Conclusions The accuracy and important role of central neuro-imaging review in confirming the diagnosis of DIPG is demonstrated.

Resume Nous rapportons le cas d’une volumineuse tumeur renale gauche avec remaniements necrotiques et hemorragiques chez un enfant de 7 mois, suggerant cliniquement et radiologiquement un nephroblastome. Il s’agissait d’une tumeur nodulaire de 8 cm, qui occupait les deux tiers du rein et presentait des plages necrotico-hemorragiques. Il n’etait constate ni rupture capsulaire, ni infiltration du sinus renal. Le parenchyme renal adjacent apparaissait macroscopiquement normal. A l’examen histologique, la tumeur presentait une architecture uniquement tubulopapillaire avec de nombreux psammomes. Le diagnostic differentiel principal retenu etait celui d’un nephroblastome epithelial pur. Toutefois, certaines caracteristiques histologiques et immuno-histochimiques ont permis d’infirmer cette hypothese et de retenir le diagnostic d’adenome metanephrique. L’adenome metanephrique est une tumeur renale benigne exceptionnelle chez l’enfant. Le pathologiste se doit d’y penser car le seul traitement necessaire est la chirurgie.

There is no standard of care for cerebrospinal (CSF) diversion in children with diffuse intrinsic pontine glioma (DIPG), nor understanding of survival impact. We evaluated CSF diversion characteristics in children with DIPG to determine incidence, indications and potential impact on survival. Data was extracted from subjects registered in the International DIPG registry (IDIPGR). IDIPGR team personnel obtained clinical and radiographic data from the registry database and when appropriate, abstracted additional data from individual medical records. Univariable analyses were performed using the Fisher’s exact test or Wilcoxon rank sum test. Survival was estimated using the Kaplan-Meier method. Evaluable patients (n=457) met criteria for DIPG diagnosis by central radiology review. Ninety-two patients (20%) had permanent CSF diversion. Indications for permanent diversion were hydrocephalus (41%), hydrocephalus and clinical symptoms (35%), and clinical symptoms alone (3%). Those with permanent diversion were significantly younger at diagnosis than those without diversion (median 5.3 years vs 6.9 years, p=0.0002), otherwise no significant differences in gender, race, or treatment were found. The progression-free and overall survival of those with permanent CSF diversion compared to those without permanent diversion was 4.5 and 10.9 months vs 6.9 and 11.2 months, respectively (p=0.001, p= 0.4). There was no significant difference in overall survival in patients with or without permanent CSF diversion among a large cohort of DIPG patients. Patients without permanent diversion had significantly prolonged progression free survival compared to those with permanent diversion. The qualitative risks and benefits of permanent CSF diversion need to be further evaluated.

INTRODUCTION The role of diagnostic biopsy in diffuse intrinsic pontine glioma (DIPG) remains in question. Distinguishing radiographically between DIPG and other pontine tumors with more favorable prognosis and different therapy is critically important. METHODS Cases submitted to the International DIPG registry with histopathologic data were analyzed. Central imaging review was performed by two neuro-radiologists; all cases with imaging features or histopathology suggestive of alternative diagnoses were re-reviewed. Imaging features suggestive of alternative diagnoses included non-pontine origin, RESULTS Among 297 patients with pathology from biopsy and/or autopsy available, 27 (9%) had histologic diagnoses not consistent with DIPG, commonly embryonal tumors (n=9) and pilocytic astrocytomas (n=11). 163 patients had diagnostic MRI available for central neuroimaging review. Among 81 patients classified as characteristic of DIPG, 80 (99%) had histopathology consistent with DIPG (diffuse midline glioma, H3K27M-mutant, glioblastoma, anaplastic astrocytoma, diffuse astrocytoma). Among 63 patients classified as likely DIPG, but with unusual imaging features, 59 (94%) had histopathology consistent with DIPG. 19 patients had imaging features suggestive of another diagnosis, including 13 with non-pontine tumor origin; the remaining 6 all had histopathology not consistent with DIPG. Association between central imaging review and histopathology was significant (p CONCLUSIONS The important role and accuracy of central neuroimaging review in diagnosing or excluding DIPG is demonstrated. In patients with pontine tumors for which DIPG is felt unlikely radiographically, biopsy may be considered to guide diagnosis and treatment.

Diffuse intrinsic pontine glioma (DIPG) is aggressive brainstem tumor with median survival of < 1 year. We queried data from the International DIPG Registry to define clinical, radiological, histological, and molecular characteristics of DIPG patients who survived < 3 months from diagnosis. Among 909 patients enrolled on the registry, 59 (6.5%) had overall survival (OS) of < 3 months. Median age at diagnosis was 5.8 years (range 0–13 years), and 12 (20%) were age < 3 years at diagnosis. Most presented with short duration of symptoms (< 6 weeks, 50/58; 86%) and at least one cranial nerve palsy, cerebellar sign, and/or pyramidal tract sign (52/54; 96%). Twenty-two (41%) presented with hydrocephalus, including 10 who required CSF diversion. All had extra-pontine extension on diagnostic imaging. Less than half of patients (25/56, 45%) received therapy; of these, 11 received radiation (RT) only, 12 received RT and chemotherapy, and 2 received chemotherapy only. Most received steroids (48/52; 92%), including 27 who received palliative steroids at the end of life. Biopsy and autopsy were performed in 11/57 (19%) and 13/58 (22%) cases, respectively. Of 22 for whom histology was known, 19 represented high-grade glioma subtypes, 2 low-grade gliomas, and 1 embryonal tumor. Six were molecularly characterized, and 3 harbored H3K27M mutations. Ongoing work will aim to further characterize the molecular features of these tumors with exceptional poor outcomes despite therapy.

Background Pediatric low-grade gliomas (LGG) represent 30-50% of central nervous system pediatric tumors. Over the last decades, the combination of carboplatin and vincristine (CV) has become the first line of treatment in most centers. In a large clinical trial where the efficacy of CV was compared to another regimen, 19% presented grade III neurotoxicity. Despite the fact that CV therapy is widely used for pediatric patients with LGG, no study has reported detailed neurological adverse events and outcome with this treatment regimen. The purpose of this retrospective study is to better understand neurotoxicity associated with CV. Procedure We conducted a retrospective study to better evaluate the incidence and evolution of neurotoxicity associated with CV in patients with LGG. Results Twenty-one pediatric patients were treated with CV at our single institution over 16 years. Most patients had optic glioma. Peripheral neuropathy was present in most patients (86%). Eight patients (38%) had a dose reduction of vincristine due to grade III toxicity (three motor neuropathies, three sensory neuropathies, one constipation, and one dysphagia). Most neurotoxicity occurred during induction or the first maintenance cycle. No ototoxicity was observed during treatment or follow-up. Conclusions In our study, neurotoxicity with vincristine occurred two times more frequently than in previously published literature. Careful neurological assessment is important to detect neurotoxicity, especially during induction. The high incidence of neurotoxicity should be considered when selecting a chemotherapy regimen for pediatric LGG.

Background Optic pathway gliomas (OPGs) occur sporadically or in patients with neurofibromatosis type 1 (NF1). The purpose of this study was to evaluate the clinical presentation at diagnosis and at progression of patients with OPGs. Methods We conducted a chart review of patients with OPGs diagnosed in a single center over a period of 15 years. Demographic data including age, sex, NF1 status, clinical presentation, and outcome were collected. Results Of the 40 patients who were identified, 23 had sporadic tumors (57.5%) and 17 had NF1-related tumors (42.5%). Among the children with NF1, there was a significant overrepresentation of girls (82.3%) ( P = 0.02), while among the children without NF1, there were slightly more boys (56.5%) than girls (43.5%). The presence of nystagmus was strongly associated with sporadic optic pathway gliomas. Poor visual outcome was related to tumor affecting both optic pathways, hydrocephalus at diagnosis, and optic nerve atrophy. Of the 40 patients, five died of OPG complications (12.5%) and all had sporadic tumors. Conclusions Our cohort is one of the largest with OPGs and a detailed description of the clinical presentation both at diagnosis and at progression. We observed a significant difference between sporadic and NF1 optic pathway gliomas in terms of demographics, clinical presentation, and outcome.

Background The combination of vinblastine and mammalian target of rapamycin (mTOR) inhibitor sirolimus inhibits the growth of neuroblastoma xenografts through pro-apoptotic and anti-angiogenic mechanisms. This phase I study aimed to explore the safety and toxicity of this combination in pediatric patients with advanced solid tumors. Procedure Patients ≤21 years of age with recurrent/refractory solid tumors (including CNS) were eligible. Sirolimus was administered daily by mouth or nasogastric (NG) tube, with doses adjusted to achieve a target trough concentration of 10–15 ng/ml, with weekly intravenous vinblastine (dose escalated 4–6 mg/m2/dose according to 3 + 3 phase I design). Results Fourteen patients were enrolled (median age 8.7 years; range 2.3–19) of whom 12 were evaluable for toxicity and 11 for response. One patient experienced a dose-limiting toxicity (grade 3 mucositis) at the highest vinblastine dose level. Myelosuppression was the most common toxicity. Dose-adjusted sirolimus trough concentrations were significantly lower in patients receiving drug via NG tube (1.50 ± 0.75 ng/ml/mg vs. 2.25 ± 1.07 ng/ml/mg for oral administration). Correlative biomarker analysis demonstrated a significant reduction in serum concentration of soluble vascular endothelial growth factor receptor (sVEGFR2) at 28 days compared to baseline consistent with inhibition of angiogenesis. One patient had a partial response and three had stable disease for more than 3 months. Conclusions The combination of mTOR inhibitor and vinblastine given over an extended continuous schedule is safe, associated with a reduction in circulating angiogenic factor (CAF) VEGFR2 and resulted in clinical responses. Future studies using the intravenously administered mTOR inhibitor temsirolimus are planned. Pediatr Blood Cancer 2014;61:128–133. © 2013 Wiley Periodicals, Inc.

Background Pracinostat (SB939) is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDAC). The adult recommended phase II dose (RP2D) is 60 mg po three times per week (t.i.w.) for 3 weeks every 4 weeks. This study assessed the toxicities and pharmacokinetics of pracinostat and determined the RP2D in children with refractory solid tumors. Methods Pediatric patients with refractory solid tumors were treated with oral pracinostat t.i.w. for 3 consecutive weeks, followed by 1 week off dosing. Three dose levels—25, 35, and 45 mg/m2 were evaluated using a standard 3 + 3 cohort design. Pharmacokinetic (PK) studies were optional. Results Twelve patients were enrolled. The most common diagnosis was Ewing sarcoma. Most adverse events (AEs) were hematological with five (40%) patients experiencing grade 3 neutropenia. Non-hematological AEs were generally grade 1. No dose limiting toxicities occurred. More hematological and non-hematological AEs occurred at 45 mg/m2: Two of five patients experienced Grade 3 neutropenia and one each Grade 3 thrombocytopenia and leucopenia, Grade 1 fatigue and anorexia occurred in three. The RP2D was declared to be 45 mg/m2 (comparable to an adult dose of 80 mg). One patient had a best response of stable disease (duration of 2.9 months). Three patients on 25 mg/m2 and one each on 35 and 45 mg/m2 participated in the PK study. No dose related changes in Cmax or AUC occurred. Conclusions Pracinostat is reasonably well tolerated in children with refractory solid tumors. The RP2D is 45 mg/m2. Pediatr Blood Cancer 2013;60:1868–1874. © 2013 Wiley Periodicals, Inc.

Combining mammalian target of rapamycin (mTOR) inhibitors and vinca alkaloids has shown therapeutic synergy in xenograft models of pediatric cancers. This phase I study assessed safety and toxicity of temsirolimus in combination with vinblastine in children. Procedure Patients ≥ 1 and ≤ 18 years with recurrent/refractory solid or CNS tumors were eligible. Vinblastine (4 mg/m2 ) and temsirolimus (15 mg/m2 ) were administered i.v. weekly, with planned dose escalation of vinblastine using a rolling six phase I design. Pharmacokinetic and pharmacodynamic data were collected. Results Seven patients with median age 12 years (range, 8-18 years) were enrolled; all were evaluable for toxicity and six for response. At dose level 1, four of six patients developed grade 3 mucositis, of which one met duration criteria for dose-limiting toxicity (DLT). Four patients required dose omissions for grade 3 or 4 hematologic toxicity, including one prolonged neutropenia DLT. A subsequent patient was enrolled on dose level -2 (temsirolimus 10 mg/m2 , vinblastine 4 mg/m2 ) with no protocol-related toxicity > grade 1, except grade 2 neutropenia. Two serious adverse events (SAE) occurred-an allergic reaction to temsirolimus (grade 2) and an intracranial hemorrhage in a CNS tumor patient (grade 3)-unlikely related to study therapy. Soluble VEGFR2 was reduced at cycle 1, day 36 in keeping with inhibition of angiogenesis. Four patients achieved prolonged stable disease for a median of 5.0 months (range, 3.1-8.3 months). Conclusion The combination of weekly temsirolimus (15 mg/m2 ) and vinblastine (4 mg/m2 ) exceeds the maximum tolerated dose in children, with frequent oral mucositis and hematologic toxicity.

OBJECTIVE. Unclassified inherited bone marrow failure syndromes are a heterogeneous group of genetic disorders that represent either new syndromes or atypical clinical courses of known inherited bone marrow failure syndromes. The relative prevalence of the unclassified inherited bone marrow failure syndromes and their characteristics and the clinical and economic challenges that they create have never been studied. METHODS. We analyzed cases of inherited bone marrow failure syndrome in the Canadian Inherited Marrow Failure Registry that were deemed unclassifiable at study entry. RESULTS. From October 2001 to March 2006, 39 of the 162 patients enrolled in the Canadian Inherited Marrow Failure Registry were registered as having unclassified inherited bone marrow failure syndromes. These patients presented at a significantly older age (median: 9 months) than the patients with classified inherited bone marrow failure syndrome (median: 1 month) and had substantial variation in the clinical presentations. The hematologic phenotype, however, was similar to the classified inherited bone marrow failure syndromes and included single- or multiple-lineage cytopenia, severe aplastic anemia, myelodysplasia, and malignancy. Grouping patients according to the affected blood cell lineage(s) and to the presence of associated physical malformations was not always sufficient to characterize a condition, because affected members from several families fit into different phenotypic groups. Compared with the classified inherited bone marrow failure syndromes, the patients with unclassified inherited bone marrow failure syndromes had 3.2 more specific diagnostic tests at 4.5 times higher cost per evaluated patient to attempt to categorize their syndrome. At last follow-up, only 20% of the unclassified inherited bone marrow failure syndromes were ultimately diagnosed with a specific syndrome on the basis of the development of new clinical findings or positive genetic tests. CONCLUSIONS. Unclassified inherited bone marrow failure syndromes are relatively common among the inherited bone marrow failure syndromes and present a major diagnostic and therapeutic dilemma.

Purpose A significant increase in the incidence of neuroblastoma occurred among a 5-year birth cohort (May 1989 to April 1994) during an active urinary screening program for its early detection. We examined the postscreening incidence of neuroblastoma in the subsequent 5-year birth cohort (May 1994 to April 1999), with follow-up to 2002, to determine whether the incidence remained increased. Patients and Methods We reviewed institutional records of patients diagnosed with neuroblastoma during the period from 1994 to 2002 who were born in 1994 to 1999 in the province of Quebec, as well as in the state of Minnesota and the province of Ontario, regions that had served as controls during the screening interval. We calculated and compared incidence rates during the 1994 to 2002 time period. Results For the 5-year birth cohort as a whole, the rate of newly diagnosed neuroblastoma was higher in Quebec than in the control populations of Minnesota and Ontario (standardized incidence ratio, 1.34; 95% CI, 1.03 to 1.70). However, in years 4 and 5 of the interval, population-based incidence declined to the same levels as those seen in the control areas. Conclusion The institution of a urinary screening program for neuroblastoma led to increased awareness of the diagnosis and an elevated rate of diagnosis even after the completion of the screening evaluation. However, this halo effect was transient, with diagnostic rates subsequently decreasing within the range seen in control populations.

Purpose The Québec Neuroblastoma Screening Program was put in place to investigate the possibility of decreasing mortality from high-risk neuroblastoma through early screening. We assess treatment complications in the patients diagnosed during this screening program. Patients and Methods A total of 476,603 patients born during the screening period were eligible. Parents of 425,838 children (89%) agreed to participate in the 3-week screening, and 73% agreed to participate in the 6-month screening. Forty-five patients had neuroblastoma. We reviewed the medical and research charts for all patients diagnosed by screening. Follow-up was available from 8 to 13 years after screening. Results Forty-five patients were diagnosed by screening. All patients were treated according to the Pediatric Oncology Group recommendations of the time. All patients had surgery, and 29 patients received chemotherapy. No patient died from neuroblastoma. Eleven patients suffered complications from treatment. Two patients had life-threatening complications. Conclusion In view of the lack of impact of screening programs on neuroblastoma mortality, evidence that many of the tumors detected through screening can be observed without treatment and the serious complications that may arise from therapy, we do not support neuroblastoma screening programs for children.

Doxorubicin chemotherapy is very effective in children with acute lymphoblastic leukemia (ALL) but also injures myocardial cells. Dexrazoxane, a free-radical scavenger, may protect the heart from doxorubicin-associated damage.To determine whether dexrazoxane decreases doxorubicin-associated injury of cardiomyocytes, we randomly assigned 101 children with ALL to receive doxorubicin alone (30 mg per square meter of body-surface area every three weeks for 10 doses) and 105 to receive dexrazoxane (300 mg per square meter) followed immediately by doxorubicin. Serial measurements of serum cardiac troponin T were obtained in 76 of 101 patients in the doxorubicin group and 82 of 105 patients in the group given dexrazoxane and doxorubicin. A total of 2377 serum samples (mean, 15.1 samples per patient) were obtained before, during, and after treatment with doxorubicin. Troponin T levels were evaluated in a blinded fashion to determine whether they were elevated (0.01 ng per milliliter)--the primary end point--or extremely elevated (0.025 ng per milliliter).Elevations of troponin T occurred in 35 percent of the patients (55 of 158). Patients treated with doxorubicin alone were more likely than those who received dexrazoxane and doxorubicin to have elevated troponin T levels (50 percent vs. 21 percent, P0.001) and extremely elevated troponin T levels (32 percent vs. 10 percent, P0.001). The median follow-up was 2.7 years. The rate of event-free survival at 2.5 years was 83 percent in both groups (P=0.87 by the log-rank test).Dexrazoxane prevents or reduces cardiac injury, as reflected by elevations in troponin T, that is associated with the use of doxorubicin for childhood ALL without compromising the antileukemic efficacy of doxorubicin. Longer follow-up will be necessary to determine the influence of dexrazoxane on echocardiographic findings at four years and on event-free survival.

Childhood cancer is a group of heterogeneous complex diseases. Although 80% of these children are cured with conventional therapies, it remains the first cause of death among children in Western countries. A significant number of refractory/relapse patients will eventually succumb to their disease and the lack of therapeutic advances for these patients is even more worrisome. Indeed, no significant progress has been noted over the last decade for these patients, urging the need for new and more effective therapeutic approaches. Precision medicine and more effective personalized targeted therapies (PTT) are a major breakthrough leading to increased cure rates and decreased treatment-related morbidity and mortality for the patients with refractory or relapsed tumors. To address this challenge, the TRICEPS study was initiated on April 2014 at the Sainte-Justine UHC (Montreal, Canada) with an overreaching goal to explore the feasibility of performing genomic-driven targeted therapy in pediatric and adolescent (aged 0-21 years) patients with relapsed or refractory childhood cancer. This study offers in-depth genomic and transcriptomic investigation of patient’s tumoral material to identify patient-specific alterations and actionable driver mutation(s) that can be targeted with approved targeted drug and within a reasonable clinically relevant timeframe to assess the feasibility of going from biopsy to a detailed tumor analysis report. Over a period of 30 months, 44 relapsed/refractory cancer patients were recruited. Twenty-two of them underwent extensive genomic investigation (exomic and transcriptomic sequencing) within a median timeframe of 9.7 weeks from patient enrolment to return of results. Patient screen failures occurred due to benign/necrotic tumor biopsies or low tumor purity resulting in suboptimal DNA/RNA quantity or quality for genomic analysis. In all 22 patients, we have identified clinically relevant genomic alterations (SNVs, indels, fusions, CNAs) and relapse-specific mutations influencing patient management and providing options for personalized interventions. We assessed the functional impact of some of these cancer-specific alterations. This was the case of a novel relapse-specific rearrangement, identified on relapsed childhood ETP-ALL, and leading to asparagine synthetase (ASNS) up-regulation through a promoter exchange. The expression of this fusion was associated with reduced apoptosis following l-asparaginase treatment. This study shows that PPT based on next generation sequencing technology is a powerful approach that could be implemented in the clinic within a foreseeable future to guide treatment of hard-to-treat childhood cancers and to further improve patient care and outcomes. Citation Format: Fida Khater, Stephanie Vairy, Sylvie Langlois, Jasmine Healy, Sophie Dumoucel, Mathieu Lajoie, Thomas Sontag, Pascal St-Onge, Henrique Bittencourt, Dorothée Dal Soglio, Anne-Sophie Carret, Sonia Cellot, Josette Champagne, Michel Duval, Maja Krajinovic, Jean-Marie Leclerc, Valerie Larouche, Natalie Patey, Sébastien Perreault, Nelson Piché, Yvan Samson, Pierre Teira, Monia Marzouki, Daniel Sinnett. Identification of actionable targets for refractory/relapsed childhood cancer leading to personalized targeted therapy (TRICEPS Study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4885. doi:10.1158/1538-7445.AM2017-4885

An 8-month-old girl underwent surgical resection of a cervical mass with histologic diagnosis of a primitive myxoid mesenchymal tumor of infancy (PMMTI). More than 5 years after the initial surgical intervention, the tumor recurred locally, with numerous distant metastases. The histologic morphology of this tumor was compatible with a diagnosis of an undifferentiated high-grade sarcoma. PMMTI is a recently described poorly differentiated fibroblastic soft-tissue tumor of infancy, of at least borderline biological behavior, characterized by local recurrence and a potential to metastasize. We present here the first case of a transformation of a PMMTI into an undifferentiated high-grade sarcoma.

MB-23. RECURRENT SHH/TP53 MUTANT MEDULLOBLASTOMA TREATED WITH A COMBINATION OF LITHIUM AND RADIATION THERAPY Anne-Sophie Carret1, Louis Crevier2, Yvan Samson1, Benjamin Ellezam3, and Anne-Marie Charpentier4; Department of Pediatrics, Division of Hematology-Oncology, CHU Sainte-Justine/Universite de Montreal, Montreal, QC, Canada; Department of Neurosurgery, CHU Sainte-Justine/ Universite de Montreal, Montreal, QC, Canada; Department of Pathology, CHU Sainte-Justine/Universite de Montreal, Montreal, QC, Canada; Department of Radiation Oncology, Centre Hospitalier de l’Universite de Montreal, Montreal, QC, Canada INTRODUCTION: TP53 mutations remain a poor prognotic factor and account for a high proportion of the treatment failure in SHH subgroup medulloblatoma. Poor survival of patients with P53 mutant medulloblastoma may be related to radiation/chemotherapy resistance. Lithium, an activator of the WNT pathway, sensitizes TP53 mutant medulloblastoma to radiation. CASE REPORT: a 12-yo boy presented with left localized hemispheric medulloblastoma. After a complete excision of the tumour he was randomized and treated according to COGACNS0331 and received a standard-dose craniospinal radiation with a boost to the entire posterior fossa, followed by maintenance chemotherapy. Patient was considered in complete remission. 15 months post-end of treatment, MRI showed a local recurrence. After 2 cycles of temozolomide, irinotecan and bevacizumab chemotherapy, patient had tumor progression. He then underwent a complete resection of the tumour. Pathology showed anaplastic type, SHH/TP53 mutant medulloblastoma. Due to the expected poor survival and the lackof known and consensual curative treatment, the patient was treated with a combination of therapeutic dose of lithium and focal radiation therapy to a dose of 54 Gy. One year later, the patient remains asymptomatic and, in complete remission. CONCLUSION: Lithium combined to radiation therapy may represent an interesting therapeutic avenue for higher risk groups of medulloblastoma in a context of a pilot study. Neuro-Oncology 18:iii97–iii122, 2016. doi:10.1093/neuonc/now076.21 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

In Canada, about 1500 pediatric cancers are diagnosed each year. Despite improvements in risk-stratified treatments, around 20% of childhood cancer patients do not respond to current therapies and ultimately succumb to their disease, urging the need for new and more effective therapeutic approaches. Personalized targeted therapy (PTT) based on next generation sequencing (NGS) may be a key component to increase cure rates and decrease treatment-related morbidity and mortality. To assess the feasibility of performing PTT clinical trials in the context of childhood cancers, a pilot study is currently underway at the Sainte-Justine UHC, Montreal, where 30 relapsed or refractory cancer patients (aged 0-21 years) are being recruited over a 2 year period and offered in-depth genomic and transcriptomic investigation to identify patient-specific alterations. This pilot study will allow us to determine the number of children with cancer who are suitable candidates for targeted therapy, to determine the number and type of driver mutation(s) found in the recurrent or refractory childhood cancers, to determine the number of cancer patients who harbor actionable driver mutation(s) that can be targeted with a Health Canada/FDA approved targeted drug and to assess the feasibility of going from biopsy to a detailed tumour analysis report within a clinically-relevant timeframe. Thus far, sixteen patients have been recruited in this study between April 2014 and July 2015. Study subject accrual has been successful with 100% compliance. Eight patients have undergone extensive genomic investigation in a real-time manner. We identified clinically relevant genomic alterations (singe nucleotide variants or structural variations) that can be used to inform clinical management for 8/8 of these patients. Patient screen failures occurred due to benign tumor biopsies, necrotic tumor tissue or low tumor purity, resulting in suboptimal DNA/RNA quantity or quality for NGS. Identified relapse-specific mutations allowed follow up of minimal residual disease, particularly post-transplant for relapsed leukemia cases, influenced patient management and revealed alternative therapeutic options for future personalized targeted therapy. This feasibility study shows that PTT based on NGS technology is a useful approach that could be implemented in the clinic within a foreseeable future to guide treatment of relapsed or refractory childhood cancer patients. The following step toward translating our results into novel personalized therapeutic approaches will be the development of phase II clinical trials to evaluate the efficacy of these targeted therapies in terms of therapeutic response, survival, and overall quality of life. Our overreaching goal is to be able to offer personalized targeted therapy options to all patients upon primary diagnosis of their cancer. Citation Format: Sylvie Langlois, Jasmine Healy, Mathieu Lajoie, Sophie Dumoucel, Fida Khater, Thomas Sontag, Pascal St-Onge, Patrick Beaulieu, Henrique Bittencourt, Dorothée Dal Soglio, Anne-Sophie Carret, Sonia Cellot, Josette Champagne, Michel Duval, Maja Krajinovic, Jean-Marie Leclerc, Natalie Patey, Nelson Piché, Yvan Samson, Pierre Teira, Monia Marzouki, Daniel Sinnett. TRICEPS: A feasibility study of personalized targeted therapy in relapsed/refractory childhood cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A41.

Our knowledge of the phenotypes of inherited bone marrow failure syndromes (IBMFSs) derives from case reports or case series in which only one IBMFS was studied. However, the substantial phenotypic overlap necessitates comparative analysis between the IBMFSs. Shwachman-Diamond syndrome (SDS) is an IBMFS that the appreciation of what comprises its clinical phenotype is still evolving. In this analysis we used data on 125 patients from the Canadian Inherited Marrow Failure Study (CIMFS), which is a prospective multicenter population-based study. Thirty-four cases of SDS patients were analyzed and compared to other patients with the four most common IBMFSs on the CIMFS: Diamond Blackfan anemia, Fanconi anemia (FA), Kostmann/severe congenital neutropenia and dyskeratosis congenita (DC). The diagnosis of SDS, FA and DC was often delayed relative to symptoms onset; indicating a major need for improving tools to establish a rapid diagnosis. We identified multiple phenotypic differences between SDS and other IBMFSs, including several novel differences. SBDS biallelic mutations were less frequent than in previous reports (81%). Importantly, compared to patients with biallelic mutations, patients with wild type SBDS had more severe hematological disease but milder pancreatic disease. In conclusion, comprehensive study of the IBMFSs can provide useful comparative data between the disorders. SBDS-negative SDS patients may have more severe hematological failure and milder pancreatic disease.

Purpose Survival rates for paediatric diffuse intrinsic brainstem glioma (DIBSG) are dismal. Metronomic dosing of temozolomide (TMZ) combined with standard radiotherapy may improve survival by increasing the therapeutic index and anti-angiogenic effect of TMZ. This study aimed to evaluate the safety and efficacy of this regimen in paediatric DIBSG patients. Methods Children aged 18 years or younger with newly diagnosed DIBSG were treated with standard radiotherapy and concomitant metronomic TMZ at 85 mg/m 2 /day for 6 weeks, followed by metronomic TMZ monotherapy at the same dose. Treatment was continued until tumour progression or unacceptable toxicity occurred. Primary endpoints included overall survival and toxicities. For patients who consented, plasma and urine samples were collected at diagnosis, post-induction and prior to each course of maintenance therapy for the quantification of angiogenesis markers. Results Fifteen eligible patients were enrolled, with a median age of 6.4 years. The most common toxicities were myelosuppression, most notably prolonged lymphopaenia and thrombocytopaenia. The only dose-limiting toxicity was thrombocytopaenia. Intratumoural haemorrhage was confirmed in one patient. Median time to progression was 5.13 months (95% CI = 6.4, 10.8) and median overall survival (OS) was 9.8 months (95% CI = 6.4, 10.8). Six-months OS was 80% ± 10.3%, with a 1-year OS of 20% ± 10.3%. Serum levels of both VEGF and endoglin tended to decrease during the first two cycles of therapy. Conclusion Chemoradiotherapy with metronomic dosing of TMZ showed similar toxicity to previous TMZ regimens, and does not appear to improve survival in paediatric DIBSG.

Purpose Dexrazoxane is a drug used to prevent anthracycline-induced cardiotoxicity. A recent report found an association between the use of dexrazoxane and the risk of developing secondary malignant neoplasms (SMNs) in children with Hodgkin's disease. We report the absence of an association of SMNs in children with acute lymphoblastic leukemia (ALL) treated on Dana-Farber Cancer Institute ALL Consortium Protocol 95-01. Patients and Methods Two hundred five children with high-risk (HR) ALL were randomly assigned to receive doxorubicin alone (n = 100) or doxorubicin with dexrazoxane (n = 105) during the induction and intensification phases of multiagent chemotherapy. We compared incidence of SMNs in these two groups. Results With a median follow-up of 6.2 years, no differences in the incidence of SMNs were noted between the group that received dexrazoxane and the group that did not (P = .66). One SMN (a melanoma located outside of the cranial radiation field) occurred in a patient who was randomly assigned to doxorubicin alone. No SMNs were observed in patients randomly assigned to receive dexrazoxane. Conclusion Dexrazoxane was not associated with an increased risk of SMNs in children treated for HR ALL. Given the potential importance of dexrazoxane as a cardioprotectant, we recommend that dexrazoxane continue to be used and studied in doxorubicin-containing pediatric regimens.

BACKGROUND. Surgical removal and radiation therapy are associated with significant risk for morbidity in the pediatric population with craniopharyngioma. Intracystic therapies have been utilized in some centers to potentially decrease morbidity associated with cystic craniopharyngioma. The aim of the study was to review the Canadian experience with intracystic bleomycin therapy (ICB). METHODS. All centers in the Canadian Pediatric Brain Tumor Consortium (CPBTC) were invited to participate in a retrospective review of this treatment. A questionnaire was sent to each center. The data were analyzed at British Columbia's Children's Hospital. RESULTS. In all, 6 of 17 centers utilized ICB and submitted data. A total of 17 of 19 patients with the intention to treat received bleomycin. Twelve were treated at the time of diagnosis, and 5 at the time of recurrence. Five patients achieved a complete response, 6 achieved a partial response, and 5 achieved a minor response to bleomycin. One patient was stable for 2.8 years. At the time of last follow-up, 8 patients have not required further intervention. Complications included transient symptomatic peritumoral edema (2 patients), precocious puberty (1 patient) and panhypopituitarism (2 patients). The median follow-up was 4 years (range, 0.5–10.2 years). The median progression-free survival was 1.8 years (range, 0.3–6.1 years). One patient died of a massive infarct secondary to radiation-induced moyamoya syndrome. CONCLUSIONS. ICB was found to be well tolerated in this group of children. ICB may be a feasible and effective therapy for certain children with craniopharyngioma. Bleomycin may delay the need for aggressive surgery or radiation therapy for several years. Prospective multiinstitutional clinical trials are required to further evaluate the feasibility, effectiveness, and dose schedules of this treatment. Cancer 2007. © 2007 American Cancer Society.

Purpose Historically, adolescents with acute lymphoblastic leukemia (ALL) have had inferior outcomes when compared with younger children. We report the outcome of adolescents treated on Dana-Farber Cancer Institute (DFCI; Boston, MA) ALL Consortium Protocols conducted between 1991 and 2000. Patients and Methods A total of 844 patients aged 1 to 18 years, with newly diagnosed ALL were enrolled onto two consecutive DFCI-ALL Consortium Protocols. We compared outcomes in three age groups: children aged 1 to 10 years (n = 685), young adolescents aged 10 to 15 years (n = 108), and older adolescents aged 15 to 18 years (n = 51). Results With a median follow-up of 6.5 years, the 5-year event-free survival (EFS) for those aged 1 to 10 years was 85% (SE, 1%), compared with 77% (SE, 4%) for those aged 10 to 15 years, and 78% (SE, 6%) for those aged 15 to 18 years (P = .09). Adolescents were more likely to present with T-cell phenotype (P < .001) and less likely to have the TEL-AML1 fusion (P = .05). The incidence of pancreatitis and thromboembolic complications, but not asparaginase allergy, was higher in patients ≥ 10 years of age compared with those younger than 10 years. However, there was no difference in the rate of treatment-related complications between the 10- to 15-year and 15- to 18-year age groups. Conclusion Adolescents were more likely to present at diagnosis with biologically higher risk disease (T-cell phenotype and absence of the TEL-AML1 fusion) and more likely to experience treatment-related complications than younger children. However, the 5-year EFS for older adolescents was 78% ± 6%, which is superior to published outcomes for similarly aged patients treated with other pediatric and adult ALL regimens. Based on this experience, we currently are piloting our regimen in patients aged 18 to 50 years.

Despite all recent advances in cancer's treatment, 18% of children will die from their cancer. New tools that enable better individual tumor characterization and classification are required to improve patient care and outcomes on children. Personalized targeted therapy has proven to be a promising strategy for first line treatment in adult cancer. Given the high heterogeneity in childhood cancers, access to histopathology-based clinical trials for targeted therapy is challenging and facilitated by the capacity to sequence individual childhood tumors in real time. A feasibility study is currently underway at the CHU Sainte-Justine, Montreal, where 30 relapse or refractory cancer patients between 0 and 21 years, are being offered in-depth genomic and transcriptomic investigation to identify patient-specific alterations that may be targetable with alternative therapies. This pilot study will allow us to address the following questions: 1) determine the number of children with cancer who are suitable candidates for targeted therapy at our institution each year, 2) determine the number and type of driver mutation(s) found in our population of recurrent or refractory cancers, 3) determine the number of cancer patients who harbour actionable driver mutation(s) that can be targeted with a Health Canada approved targeted drug, 4) assess the feasibility of obtaining high quality/quantity biospecimen, performing genomic sequencing and data analysis, identifying a drug based on the genomic data and offering this information to the medical team, the patient and the family within a 10-week time frame. The following step toward translating our results into novel personalized therapeutic approaches will then be the development of phase II clinical trials to evaluate the efficacy of these targeted therapies in terms of therapeutic response, survival, and overall quality of life. Our overreaching goal is to be able to offer personalized targeted therapy options to all patients upon primary diagnosis of their cancer.

The Dana-Farber Cancer Institute (DFCI) Childhood ALL Consortium Protocol 95-01 was designed to minimize therapy-related morbidity for children with newly diagnosed ALL without compromising efficacy. Patients participated in randomized comparisons of (1) doxorubicin given with or without dexrazoxane, a cardioprotectant (high-risk patients), (2) intensive intrathecal chemotherapy and cranial radiation (standard-risk patients), and (3) Erwinia and Escherichia coli asparaginase (all patients). Between 1996 and 2000, 491 patients (aged 0-18 years) were enrolled (272 standard risk and 219 high risk). With a median of 5.7 years of follow-up, the estimated 5-year event-free survival (EFS) for all patients was 82% ± 2%. Dexrazoxane did not have a significant impact on the 5-year EFS of high-risk patients (P = .99), and there was no significant difference in outcome of standard-risk patients based on type of central nervous system (CNS) treatment (P = .26). Compared with E coli asparaginase, Erwinia asparaginase was associated with a lower incidence of toxicity (10% versus 24%), but also an inferior 5-year EFS (78% ± 4% versus 89% ± 3%, P = .01). We conclude that (1) dexrazoxane does not interfere with the antileukemic effect of doxorubicin, (2) intensive intrathecal chemotherapy is as effective as cranial radiation in preventing CNS relapse in standard-risk patients, and (3) once-weekly Erwinia is less toxic than E coli asparaginase, but also less efficacious.

To determine the incidence and characteristics of pediatric patients with central nervous system (CNS) germ cell tumors (GCT) in Canada.A national retrospective review of hospital charts was done on all patients with CNS GCT diagnosed between 1990 and 2004. Patients had to be under age 18 years at the time of diagnosis of a CNS germ cell tumor and be a resident of Canada. Information extracted included age and year of diagnosis, pathological diagnosis, location of tumor, evidence of disseminated disease at time of diagnosis and biological markers.One hundred and twenty-one cases were identified (83 germinoma; 38 non-germinoma germ cell tumor). The mean annual incidence of CNS GCT was 1.06 per million children (0.7 per million for germinoma; 0.3 per million for NGGCT). Though yearly incidences varied, there was no clear trend to increased incidence. Male predominance was noted (2.4:1 for germinoma; 11:1 for NGGCT). The primary locations were the pineal and suprasellar regions. At the time of diagnosis, disseminated disease was not uncommon (22% germinoma; 32% NGGCT). Beta human gonadotrophin was elevated in the serum, cerebrospinal fluid (CSF) or both in 7% of patients with germinoma and 36% of patients with NGGCT. Elevation of alpha-fetoprotein in serum, CSF or both was seen in 34% of patients with NGGCT.The incidence of CNS germ cell tumors in Canadian children is similar to that observed in other Western countries.

Background:. Inherited bone marrow failure syndromes (IMFSs) are genetic disorders characterized by defective single-lineage or multi-lineage hematopoiesis. IMFS patients are at risk for severe cytopenias, development of marrow cytogenetic abnormalities (MCA), myelodysplasia (MDS), and malignancy. The rate of disease progression and proportion of patients at risk for these complications is currently unclear. We examined recently diagnosed IMFS patients to determine distribution of diagnoses, disease progression and development of significant outcomes. Methods:. The CIMFR is a prospective multi-center study established in 2001 to register all IMFS patients in Canada. Analysis was restricted to patients diagnosed after November 30, 1997. Summary statistics were used to depict the study population while survival was described using the Kaplan‐Meier method. Results:. 74 CIMFR patients were considered recently diagnosed. Median age at diagnosis was 2.7 years (range, birth to 40.6). Annual follow-up data were available for 53 (72%) patients. The five most prevalent diagnoses were Fanconi anemia (FA), Shwachman‐Diamond syndrome (SDS), Diamond‐Blackfan anemia (DBA), dyskeratosis congenita (DKC), and Kostmann’s neutropenia (KS). Eighteen (24%) patients were unclassifiable. Twenty-eight (53%) follow-up patients had disease progression as indicated by new or worsening cytopenias, new marrow changes, or initiation of transfusion support and/or medical therapy. Fourteen (19%) fulfilled minimal diagnostic criteria for myelodysplasia. Eleven patients had hematopoietic stem cell transplantation (HSCT) by first follow-up. Five patients have died. Survival at 36 months is 89.8 � 5.7%. Conclusions:. IMFS patients are often diagnosed at a young age. The relative distribution of diagnoses is similar to previous reviews of published cases; however, 25% of patients are currently unclassifiable. Disease progression has occurred in approximately 50% of follow-up patients. Early mortality is noted. Continued prospective observation of these patients is warranted. Pediatr Blood Cancer 2006;47:918‐925. 2006 Wiley-Liss, Inc.

Purpose: To report the clinical course of adolescents with medulloblastoma, with specific emphasis on prognosis and pattern of relapse. Methods and Materials: We retrospectively studied the clinical course and outcomes of children aged 10–20 years with medulloblastoma, treated at centers throughout Canada between 1986 and 2003. To better assess time to relapse, a cohort of patients aged 3–20 years at diagnosis was generated. Results: A total of 72 adolescents were analyzed. Five-year overall survival and event-free survival rates were 78.3% ± 5.4% and 68.0% ± 6.2%, respectively. Late relapses occurred at a median of 3.0 years (range, 0.3–6.8 years). In univariate analysis, conventional risk stratification and the addition of chemotherapy to craniospinal radiation did not have prognostic significance. Female patients had improved overall survival ( p = 0.007). Time to relapse increased with age in a linear fashion. After relapse, patients faired poorly regardless of treatment modality. Patients who did not receive chemotherapy initially had improved progression-free survival at relapse ( p = 0.05). Conclusions: Our study suggests that adolescents with medulloblastoma might have a unique prognosis and pattern of relapse, dissimilar to those in younger children. They might benefit from different risk stratifications and prolonged follow-up. These issues should be addressed in future prospective trials.

BACKGROUND Most reported data of chemoradiotherapy protocols for the treatment of medulloblastoma describe children who were treated in the first decade of life. To consider the feasibility of this approach in adolescents, the authors studied their clinical course with specific emphasis on toxicity, tolerability, and prognosis. METHODS In this retrospective study, the authors examined the toxicity profiles and outcomes of children age 10–20 years with medulloblastoma who were treated at centers throughout Canada between 1986 and 2003. Detailed toxicity data from 2 chemotherapy protocols were collected for teenagers and were compared with data from a group of control patients age 5–10 years. RESULTS In total, 72 teenagers were analyzed. Grade ≥ 2 ototoxicity and neurotoxicity occurred in 45% and 71% of chemotherapy-treated patients, respectively. Grade 3–4 hematotoxicty occurred in 95% of patients. Toxicity resulted in delay of treatment for 73% of patients and dose modification in 75% of patients, including protocol discontinuation in 25% of patients. Weight loss > 10% was encountered in 73% of patients and required intervention in 45% of patients. Teenagers had significantly more hematotoxicity and neurotoxicity compared with controls on both chemotherapeutic protocols. Ototoxicity was similar in both age groups. Toxicity resulted in significantly more treatment delays and dose modifications in teenager patients compared with controls. The 5-year overall and event-free survival rates (± standard deviation) were 78% ± 6% and 70% ± 6%, respectively. The mean time (± standard deviation) to disease recurrence was 3.2 ± 2.2 years. CONCLUSIONS The increased toxicity rate and high incidence of treatment modifications in this study suggested that current pediatric protocols may require modifications for teenagers with medulloblastoma. The results highlighted several issues that should be addressed in future prospective trials. Cancer 2005. © 2005 American Cancer Society.

Purpose: We evaluated the long-term effects of treatment on height and weight in children with acute lymphoblastic leukemia (ALL) treated with one of the following three different CNS therapies: intrathecal therapy alone, intrathecal therapy with conventional cranial radiation, or intrathecal therapy with twice-daily radiation. Patients and Methods: Between 1987 and 1995, 618 children treated on two consecutive Dana-Farber Cancer Institute Consortium protocols for ALL were measured for height and weight at diagnosis, and approximately every 6 months thereafter. Patient height, weight, and body mass index (BMI) were converted to z scores for age and sex using the 2000 Centers for Disease Control and Prevention growth charts for the United States. Results: Children younger than 13 years at diagnosis had a statistically significant decrease in their height z scores and an increase in their BMI z scores, regardless of whether they had received cranial radiation. Young age at diagnosis and increased chemotherapy intensity were major risk factors. Unexpectedly, there was no significant difference in long-term height between children who received radiation and those who did not. Conclusion: Final height is compromised in survivors of ALL. The detrimental effects on height occur during therapy without the ability for long-term catch-up growth. Although patients became overweight for height, this seemed to be a result of relative height loss with normal weight gain rather than accelerated weight gain. The type of CNS treatment received did not affect changes in height, weight, or BMI.

The Dana-Farber Cancer Institute (DFCI) ALL consortium has been conducting clinical trials in childhood acute lymphoblastic leukemia (ALL) since 1981. The treatment backbone has included intensive, multi-agent remission induction, early intensification with weekly, high-dose asparaginase, cranial radiation for the majority of patients, frequent vincristine/ corticosteroid pulses during post-remission therapy, and for high-risk patients, doxorubicin during intensification. Between 1981 and 1995, 1,255 children with newly diagnosed ALL were evaluated on four consecutive protocols: 81-01 (1981-1985), 85-01 (1985-1987), 87-01 (1987-1991) and 91-01 (1991-1995). The 5-year event-free survival (EFS) rates (+/- standard error) for all patients by protocol were as follows: 74 +/- 3% (81-01), 78 +/- 3% (85-01), 77 +/- 2% (87-01) and 83 +/- 2% (91-01). The 5-year EFS rates ranged from 78 to 85% for patients with B-progenitor phenotype retrospectively classified as NCI standard-risk, 63-82% for NCI high-risk B-progenitor patients, and 70-79% for patients with T cell phenotype. Results of randomized studies revealed that neither high-dose methotrexate during induction (protocol 87-01) nor high-dose 6-mercaptopurine during intensification (protocol 91-01) were associated with improvement in EFS compared with standard doses. Current studies continue to focus on improving efficacy while minimizing acute and late toxicities.

We report a case of childhood acute lymphoblastic leukemia with the simultaneous occurrence of a t(2;8)(p12;q24) typically associated with mature B cell or Burkitt leukemia, and a t(12;21)(p13;q22) exclusively associated with pre-B cell ALL. The lymphoblasts were characterized as L2 morphology by the French–American–British classification. However, there were atypical morphologic findings for L2 ALL, including vacuolization in some cells. The lymphoblasts were periodic acid-Schiff positive and myeloperoxidase negative. Immunophenotypic analysis revealed that the majority of lymphoblasts were TdT+, CD10+, CD19+, CD20−, and cytoplasmic μ+. These features were consistent with an immature pre-B cell leukemia phenotype with some characteristics of a mature B-cell leukemia. A t(2;8)(p12;q24)(p12;q24), characteristic of mature B-cell leukemia or Burkitt type leukemia, was detected by conventional cytogenetics with no other cytogenetic abnormalities. However, diagnostic peripheral blood and bone marrow specimens demonstrated simultaneous occurrence of a cryptic t(12;21)(p13;q22) by both FISH and RT-PCR. The simultaneous occurrence of these translocations in a pediatric patient have implications for the pathogenesis of leukemias with t(2;8)(p12;q24) as well as t(12;21)(p12;q22). Analysis of additional cases of leukemia with translocations involving the MYC locus on 8q24 will be required to determine the frequency of association with the cryptic t(12;21)(p13;22), and the prognostic significance of the simultaneous occurrence of the translocations.

Abstract 1266 Introduction: Inherited bone marrow failure syndromes (IBMFSs) are a group of rare, genetic disorders with a risk of clonal and malignant myeloid transformation including clonal marrow cytogenetic abnormalities, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The clinical characteristics and outcome of IBMFS-related clonal and malignant myeloid transformation are unclear, particularly in cases of early transformation such as isolated clonal marrow cytogenetic abnormalities. Objectives: The aims of this study were to determine the risk and clinical outcome of IBMFS-related clonal and malignant myeloid transformation using data from the Canadian Inherited Marrow Failure Registry (CIMFR). Methods: The CIMFR is a multicenter collaborative study which is intended to enroll all patients with IBMFSs in Canada. The registry was approved by the Institutional Ethics Board of all the participating institutions, and includes 15 of 16 pediatric tertiary care centers across all provinces in Canada. We estimate that these centers care for >95% of the eligible pediatric IBMFS population in Canada. The CIMFR is population-based as >90% of the patients in this study are from centers who enrolled >80% of the patients in their institutions. Clonal and malignant myeloid transformation was defined as having either clonal marrow cytogenetic abnormalities or prominent bi-lineage morphologic dysplasia or increased percentage of marrow blasts (≥5%) or a combination of the above. Results: Among 327 IBMFS patients enrolled on the CIMFR, 45 (13.8%) developed clonal and malignant myeloid transformation. In these 45 patients, the three most common IBMFS diagnoses were Fanconi anemia (31.1%), Shwachman-Diamond syndrome (20.0%) and unclassifiable IBMFSs (28.9%). Clonal marrow cytogenetic abnormalities were identified in 38/45 (84.4%) patients, while 5/45 (11.1%) patients had constitutional cytogenetic changes, 1/45 patients had AML with no cytogenetic abnormalities and 1/45 patients had no cytogenetic abnormalities. Two out of the 5 patients with constitutional cytogenetic abnormalities developed a clonal marrow cytogenetic abnormality later in their disease course. The most common clonal marrow cytogenetic abnormality was monosomy 7, which was found in 14/38 (36.8%) patients. Cytology in the majority of patients 20/45 (44.4%) was consistent with refractory cytopenia. Eight out of the 45 patients developed AML and 2 of these patients had monosomy 7. Twenty-two out of 45 (48.9%) patients with clonal and malignant myeloid transformation underwent hematopoietic stem cell transplantation due to severe cytopenia, excess blasts or leukemia. Fourteen out of the 22 (63.6%) transplanted patients are alive at last follow-up. Out of 8 patients who had AML, 3 received transplant and are alive at last follow-up. The 5 remaining AML patients died; 3 while awaiting transplant, 1 did not achieve remission and 1 refused transplant. Overall mortality in the group of patients with clonal and malignant myeloid transformation was 15/45 (33.3%) at a median follow-up of 10 months from diagnosis with clonal and malignant myeloid transformation. Overall mortality in those 282 patients on CIMFR without clonal and malignant myeloid transformation is 6.4%. Conclusion: Despite short-term follow-up of patients on the CIMFR, a relatively high prevalence of clonal and malignant myeloid transformation was found. Clonal marrow cytogenetic abnormalities are associated with a high risk of progression into advanced MDS or AML and death. Disclosures: No relevant conflicts of interest to declare.