[Chemotherapy-induced nausea and vomiting in pediatric oncology patients: 2023 recommendations from the Supportive Care Committee of the French Society of Cancer in Children and Adolescents]. / Nausées et vomissements chimio-induits en oncohématologie pédiatrique : actualisation 2023 des recommandations du comité soins de support de la SFCE.

Chemotherapy-induced nausea and vomiting (CINV) are frequent and dreaded side effects in cancer treatments. CINV has a major impact on patient's condition and quality of life. Prophylaxis is tailored to patient's profile and the emetogenic level of their chemotherapy. The aim of this study is to update the recommendations for CINV prevention and management in pediatric onco-hematology for use in France, by adapting the guidelines of the Pediatric Oncology Group of Ontario (POGO). Clinical practice guideline adaptation is a recognized method for tailoring existing clinical practice guidelines to local context. A multidisciplinary French-speaking panel was formed to discuss about POGO guideline recommendations for the acute and delayed phases, breakthrough, refractory and anticipatory CINV and the evidence supporting them. Panel members were asked whether they wanted to adopt, modify or reject each of the POGO guideline recommendations. Panel members translated each recommendation and adapted recommendations for an implementation in France. Their acceptance required agreement at least 80 % of panel members. Algorithms and tables were created, listing all the recommendations and providing a better overview for decision-making process adapted to the patient's profile. These recommendations should be reviewed for implementation at French institutions caring for pediatric cancer patients and once implemented, the rates of adherence to recommendations and CINV control should be reported.

[SFCE harmonization workshops: Neonatal acute myeloid leukemia]. / Orientation et prise en charge de la leucémie aiguë myéloïde néonatale : recommandations du comité leucémies de la SFCE.

Neonatal acute myeloid leukemias (AML) occurred within the first 28 days of life and constitute only a small proportion of all AL. They are distinguished from leukemias of older children by their clinical presentation, which frequently includes cutaneous localizations ("blueberry muffin rash syndrome") and a leukocytosis above 50 ×109/L. This proliferation may be transient, causing a transient leukemoid reaction in a background of constitutional trisomy 21 ("Transient Abnormal Myelopoieseis" or TAM) or Infantile Myeloproliferative Disease in the absence of constitutional trisomy 21 ("Infantile Myeloproliferative Disease" or IMD). In cases of true neonatal AML, the prognosis of patients is poor. Overall survival is around 35 % in the largest historical series. This poor prognosis is mainly due to the period of onset of this pathology making the use of chemotherapy more limited and involving many considerations, both ethical and therapeutic. The objective of this work is to review this rare pathology by addressing the clinical, biological, therapeutic and ethical particularities of patients with true neonatal AML or transient leukemoid reactions occurring in a constitutional trisomy 21 (true TAM) or somatic background (IMD).

Symptomatic osteonecrosis in French survivors of childhood and adolescent leukemia: a clinical and MRI study of LEA cohort.

Osteonecrosis (ON) is a known complication of acute leukemia (AL) management, affecting 1%-10% of young patients and resulting in long-term morbidity. Widespread access to MRI over the past decade has allowed earlier detection and more accurate assessment. This study investigated clinical and MRI features of the 129 (2.5%) patients with symptomatic ON retrospectively recruited from the French LEA (Leucémies de l'Enfant et de l'Adolescent, or child and adolescent leukemias) cohort (n = 4,973). We analyzed data concerning ON risk factors, multifocal involvement, severe lesions detected by MRI, and patient quality of life (QoL). ON patients tended to be >10 years old at the time of AL diagnosis (odds ratio [OR]: 22.46; p < 10-6), female (OR: 1.8; p = 0.002), or treated for relapse (OR: 1.81; p = 0.041). They more frequently suffered from other sequelae (p < 10-6). Most necroses involved weight-bearing joints, and they were multifocal in 69% of cases. Double-blinded review of MRIs for 39 patients identified severe lesions in 14, usually in the hips. QoL of adolescents and adults was poor and permanently impacted after onset of ON. In conclusion, age >10 at time of AL diagnosis, female sex, and relapse occurrence were risk factors for multifocal ON; MRI revealed severe ON in a third of the patients considered; and ON was associated with persistently poor QoL affecting multiple domains. Future studies should include prospective data addressing ON management and seek to identify genetic markers for targeted screening enabling early ON detection and treatment.

[Antineoplastic drug-induced nausea and vomiting in pediatric onco-hematology: 2022: Guidelines from the supportive care committee of the French Society of Childhood Cancer (SFCE)]. / Nausées-vomissements induits par les traitements anticancéreux (NVITAC) en onco-hématologie pédiatrique : recommandations 2022 du Comité soins de support de la SFCE.

Nausea and vomiting induced by cancer treatment (CINV) remain one of the most common and feared side effects in children despite the use of new drugs to prevent them. The existing recommendations for the prophylaxis and treatment of CINV are based on adult patients in Anglo-Saxon societies. Based on a recent review of the literature, we focused on specific pediatric issues in order to offer recommendations validated by the supportive care committee of the French society for childhood cancer.

[Prevention and management of pegaspargase associated-toxicities (excluding coagulation abnormalities). Recommendations of the French Society of Children and Adolescent Cancers (Leukemia committee)]. / Prise en charge des toxicités de la pégaspargase (hors anomalies de la coagulation). Recommandations du comité leucémie de la Société française de lutte contre les cancers de l'enfant et de l'adolescent.

Pegaspargase (Oncaspar®), a pegylated form of native Escherichia Coli-derived L-asparaginase is an essential component chemotherapy used in the treatment of acute lymphoblastic leukemia (ALL) in pediatric and adult patients. Its particular toxicity profile requires a specific management to improve safety and tolerability and optimize treatment outcome and therefore survival. Within the framework of workshops of practice harmonization of the French Society of Children and Adolescent Cancers, diagnostic and management of the most commonly occuring toxicities (excluding coagulation abnormalities) during Pegaspargase treatment were reviewed according to the analysis of published studies.

Novel Insights into Pediatric Acute Lymphoblastic Leukemia Ophthalmic Relapses from a Nationwide Cohort Study.

Ten to fifteen percent of children with acute lymphoblastic leukemia (ALL) relapse following treatment. Of these, less than 2% display ophthalmic relapses, which owing to their scarcity, are largely undocumented, leaving clinicians with few diagnostic and therapeutic recommendations, despite serious functional sequelae. We conducted a French multicenter retrospective study to collect all clinical, radiological, biological, and therapeutic data, and outcomes for children with ALL ophthalmic relapses. From 2000 to 2020, 20 ophthalmic relapses occurring after first-line therapy performed before January 1st, 2017 were included in our study: 14 B-ALL and 6 T-ALL. Fifteen patients (75%) had concomitant involvement of the central nervous system, and 11 (55%) a combined bone marrow relapse. Only 1 had an isolated ophthalmic relapse. Eight children (40%) died, 7 from a refractory disease and 1 from toxic death, and 4 patients relapsed. With a median follow-up of 63.1 months, 8 patients are currently alive in continuous complete remission with only 2 displaying severe ophthalmic sequelae. Although rare, ophthalmic relapse could have a significant impact on the functional prognosis of survivors. Their management must be multidisciplinary, with a central role given to ophthalmologists.

[Supportive care in pediatric oncology: Considering children and AYA's special needs]. / Soins de support en oncologie pédiatrique ou le respect des besoins fondamentaux des enfants et adolescents.

Organization of health care of a patient followed in pediatric oncology is not limited to cancer treatment. It includes a whole range of supportive care. Some are common to the supportive care offered in adult oncology, such as pain management and nutritional support. However, there are pediatric specificities. Others are more peculiar to children, such as education and information for young patients, and require a specific framework and innovative tools. The young age of patients and the improvement in survival rates in pediatric oncology also lead to questioning the temporality of supportive care by considering access to supportive care beyond the active phase of the disease. This review explains some of these different specificities: information and communication to the patient and his parents, assessment and management of pain, nutritional support but also schooling, long-term follow-up and screening sequelae induced by the disease and its treatments.

Effect of Child Position on Pain Experience During Lumbar Puncture: A Prospective Pilot Study.

BACKGROUND: This study aimed to evaluate the impact of patient's position on pain and anxiety during lumbar puncture (LP). MATERIALS AND METHODS: A randomized controlled trial included children between 2 and 18 years old receiving at least 2 therapeutic LPs. They were randomly assigned to undergo lateral decubitus position or sitting position LP. Primary outcome was the maximum LP-induced pain, secondary endpoint the maximum LP-induced anxiety score. RESULTS: Twenty-eight patients were randomized. For patients under 6 years old, mean of Face, Leg, Activity, Cry, and Consolability were 2.8/10±3.0 (median=1) at first time and 1.5±1.7 (median=1) at second time. For patients 6 to 18 years old, mean of visual analog scale were 2.2±2.2 (median=1.5) at first time and 3.2±2.8 (median=3) at second time. There was no significant differences according to position on anxiety among children. CONCLUSIONS: Results did not demonstrate whether lateral decubitus position could generate less pain and anxiety than sitting position.

Discontinuation of Imatinib in Children with Chronic Myeloid Leukemia: A Study from the International Registry of Childhood CML.

Within the International Registry of Childhood Chronic Myeloid Leukemia (CML), we identified 18 patients less than 18 years old at diagnosis of CML who were in the chronic phase and exhibiting a sustained deep molecular response (DMR) to imatinib defined as BCR-ABL1/ABL1 < 0.01% (MR4) for at least two years followed by discontinuation of imatinib. Before discontinuation, the median duration of imatinib was 73.2 months (range, 32-109) and the median duration of MR4 was 46.2 months (range, 23.9-98.6). Seven patients experienced loss of major molecular response (MMR) 4.1 months (range, 1.9-6.4) after stopping and so restarted imatinib. The median molecular follow-up after discontinuation was 51 months (range, 6-100) for the nine patients without molecular relapse. The molecular free remission rate was 61% (95% CI, 38-83%), 56% (95% CI, 33-79%) and 56% (95% CI, 33-79%) at 6, 12 and 36 months, respectively. Six of the seven children who experienced molecular relapse after discontinuation regained DMR (median, 4.7 months; range, 2.5-18) after restarting imatinib. No withdrawal syndrome was observed. In univariate analysis, age, sex, Sokal and ELTS scores, imatinib treatment and DMR durations before discontinuation had no influence on treatment free remission. These data suggest that imatinib can be safely discontinued in children with sustained MR4 for at least two years.

Childhood ovarian nonseminomatous germ cell tumors: A highly curable disease with few long-term treatment-related toxicities-Results of the French TGM95 study.

We report survival and late effects analysis of TGM95 study for childhood (≤18 years) ovarian nonseminomatous germ cell tumors (NS-GCT). Patients with localized tumors (FIGO-stage IA) had no adjuvant treatment (low-risk, LR). Patients with advanced-stage received 3-5 VBP (vinblastin-bleomycin-cisplatin) in intermediate-risk group (IR: FIGO-stage IC-II-III and AFP < 15 000 ng/mL) or 4-6 VIP (etoposide-ifosfamide-cisplatin) in high-risk group (HiR: metastatic or AFP ≥ 15 000 ng/mL). Seventy-seven patients were included (median age = 12 years): 14 LR (13 FIGO-stage IA, 1 retrospectively IC), 26 IR (12 IC, 12 II-III, 2 not-available) and 37 HiR (2 IA with AFP ≥ 15 000 ng/mL, 27 II-III, 8 IV). After a median follow-up of 13.4 years, 12 events (eight relapses) and six deaths (two GCT-related, two due to acute myeloid leukemia and two noncancer related) occurred. All relapses (6 LR, 1 IR) occurred within 2 years. Four contralateral mature teratomas were observed within 8 years. Five-year EFS and OS were 88.2% (95%CI = 79-94%) and 94.6% (95%CI = 87-98%). Seven patients (9%) had bilateral gonadectomy. Among 51 survivors at 2 years aged >15 years (median = 26 years) with remaining ovarian tissue, all had developed spontaneous puberty and 21 (41%) had at least one pregnancy (including two with infertility treatment). Among 69 patients treated with platinum-based chemotherapy, chronic-kidney-disease was diagnosed in four patients (three after VIP) and significant ototoxicity occurred in three (all grade-2). Childhood ovarian NS-GCTs have an excellent prognosis with few late effects. The low-intensive etoposide-free VBP regimen could be an alternative in children with IR disease especially in cases of tumor rupture. The risk of contralateral mature teratoma needs regular monitoring of the remaining ovary.

[Chemo-induced mucositis in pediatric oncology: Perspectives?] / Mucites chimio-induites en oncologie pédiatrique : quelles perspectives ?

Mucositis is defined as inflammatory and/or ulcerative lesions of the oral and/or gastrointestinal tract. It occurs in approximately 40% to 50% of adults patients receiving conventional chemotherapy and up to 75% of patients receiving high dose chemotherapy as conditioning for hematopoietic stem cell transplantation. It is a toxic side effect, which strongly impairs quality of life and leads to refractory pain, increasing risk of infection and even therapeutic modifications. Despite improvements made, the management of mucositis remains a challenge and is still not consensual. A multicentric survey of practices concerning the preventive and curative management of chemo-induced mucositis in pediatric oncology department in France was carried out using a standardized questionnaire. Results confirm heterogeneous practices and the small progress made during the last decade. This national survey and an analysis of the recent literature leads to propose guidelines for the prevention and treatment of oral mucositis in children receiving treatment for cancer.

Testosterone deficiency in men surviving childhood acute leukemia after treatment with hematopoietic stem cell transplantation or testicular radiation: an L.E.A. study.

We included 255 patients from the L.E.A. French long-term follow-up cohort. All had received hematopoietic stem cell transplantation (HSCT) and/or testicular radiation for childhood acute leukemia and were older than 18 years at last L.E.A. evaluation. Total testosterone deficiency was defined as a <12 nmol/l level or by substitutive therapy, partial deficiency as normal testosterone with elevated luteinizing hormone (>10 UI/l). After myeloablative total body irradiation (n = 178), 55.6% had total deficiency, 15.7% partial deficiency, and 28.7% were normal. A 4-6 Gy testicular boost and a younger age at HSCT increased significantly the risk. After a Busulfan-containing myeloablative conditioning regimen (n = 53), 28.3% had total deficiency, 15.1% partial deficiency, 56.6% were normal (62.5% vs. 0% in patients without or with additional testicular radiation). A 24-Gy testicular radiation without HSCT induced total or partial deficiency in 71.4% and 28.6%, respectively (n = 21). Total testosterone deficiency increased the risk of metabolic syndrome: 25% vs. 12.1% in men with partial testosterone deficiency and 8.8% when Leydig cell function was normal (p = 0.031).

Impact of the First Wave of COVID-19 on Pediatric Oncology and Hematology: A Report from the French Society of Pediatric Oncology.

Data regarding coronavirus disease 2019 (COVID-19) description are still limited in pediatric oncology. The French society of pediatric oncology (SFCE) initiated a study to better describe COVID-19 in patients followed in French pediatric oncology and hematology wards. All patients diagnosed with COVID-19 and followed in a SFCE center were enrolled. Data from medical records were analyzed for all patients enrolled up to the end of May 2020. Data were available for 37 patients. Thirty-one were children under 18 years of age. Nineteen patients were female. Seventeen patients had a solid tumor, 16 had a hematological malignancy and four recently underwent hematopoietic stem cell transplantation (HSCT) for non-oncological conditions. Twenty-eight patients presented symptoms, most often with fever, cough, rhinorrhea and asthenia. Ground-glass opacities were the most frequent radiological finding with abnormalities mostly bilateral and peripherally distributed. Twenty-four patients received chemotherapy a month prior to COVID-19 diagnosis. Most patients did not require hospitalization. Three patients required oxygen at the time of diagnosis. In total, five patients were admitted in an intensive care unit because of COVID-19 and one died from the disease. Children and young adults treated for a cancer and/or with a HSCT may be at risk for severe COVID-19 and should be closely monitored.

Results of successive EORTC-CLG 58 881 and 58 951 trials in paediatric T-cell acute lymphoblastic leukaemia (ALL).

Outcomes in childhood T-cell acute lymphoblastic leukaemia (T-ALL) are steadily improving due to intensive therapy. Between 1989 and 2008, 599 children with newly diagnosed T-ALL were enrolled in two successive European Organization for Research and Treatment of Cancer - Children's Leukaemia Group trials (58881 and 58951), both based on the Berlin-Frankfurt-Munster protocol and without cranial irradiation. In the latter trial induction chemotherapy was intensified. The most important randomizations were Medac Escherichia coli asparaginase versus Erwinia asparaginase in trial 58881, and dexamethasone (6 mg/m2 /day) versus prednisolone (60 mg/m2 /day) and prolonged versus conventional asparaginase duration in trial 58951. 8-year event-free survival (EFS) increased from 65·1% to 74·0% in trial 58951. Improvement was most profound for patients with white blood cell (WBC) counts <100 × 109 /l and "good responders" to prephase. Medac E. coli asparaginase was associated with longer EFS [hazard ratio (HR) 0·54, P = 0·0015] and overall survival (HR 0·51, P = 0·0018). Induction therapy with dexamethasone did not improve EFS compared to prednisolone. Remarkably, intensification of central nervous system (CNS)-directed therapy in trial 58951 resulted in fewer bone marrow relapses, while the incidence of CNS relapses remained low. In summary, we showed that adequate asparaginase therapy, intensified induction treatment and intensification of CNS-directed chemotherapy can result in an improvement of outcome in T-ALL patients with good prephase response and initial WBC counts <100 × 109 /l, representing approximately 50% of T-ALL patients.

Late effects after hematopoietic stem cell transplantation for ß-thalassemia major: the French national experience.

In this retrospective study, we evaluate long-term complications in nearly all ß-thalassemia-major patients who successfully received allogeneic hematopoietic stem cell transplantation in France. Ninety-nine patients were analyzed with a median age of 5.9 years at transplantation. The median duration of clinical follow up was 12 years. All conditioning regimens were myeloablative, most were based on busulfan combined with cyclophosphamide, and more than 90% of patients underwent a transplant from a matched sibling donor. After transplantation, 11% of patients developed thyroid dysfunction, 5% diabetes, and 2% heart failure. Hypogonadism was present in 56% of females and 14% of males. Female patients who went on to normal puberty after transplant were significantly younger at transplantation than those who experienced delayed puberty (median age 2.5 vs 8.7 years). Fertility was preserved in 9 of 27 females aged 20 years or older and 2 other patients became pregnant following oocyte donation. In addition to patient's age and higher serum ferritin levels at transplantation, time elapsed since transplant was significantly associated with decreased height growth in multivariate analysis. Weight growth increased after transplantation particularly in females, 36% of adults being overweight at last evaluation. A comprehensive long-term monitoring, especially of endocrine late effects, is required after hematopoietic stem cell transplantation for thalassemia.

Prevalence and characteristics of metabolic syndrome in adults from the French childhood leukemia survivors' cohort: a comparison with controls from the French population.

The prevalence of the metabolic syndrome among adults from the French LEA childhood acute leukemia survivors' cohort was prospectively evaluated considering the type of anti-leukemic treatment received, and compared with that of controls. The metabolic profile of these patients was compared with that of controls. A total of 3203 patients from a French volunteer cohort were age- and sex-matched 3:1 to 1025 leukemia survivors (in both cohorts, mean age: 24.4 years; females: 51%). Metabolic syndrome was defined according to the National Cholesterol Education Program's Adult Treatment Panel III criteria. Metabolic syndrome was found in 10.3% of patients (mean follow-up duration: 16.3±0.2 years) and 4.5% of controls, (OR=2.49; P<0.001). Patients transplanted with total body irradiation presented the highest risk (OR=6.26; P<0.001); the other treatment groups also showed a higher risk than controls, including patients treated with chemotherapy only. Odd Ratios were 1.68 (P=0.005) after chemotherapy only, 2.32 (P=0.002) after chemotherapy and cranial irradiation, and 2.18 (P=0.057) in patients transplanted without irradiation. Total body irradiation recipients with metabolic syndrome displayed a unique profile compared with controls: smaller waist circumference (91 vs 99.6 cm; P=0.01), and increased triglyceride levels (3.99 vs 1.5 mmol/L; P<0.001), fasting glucose levels (6.2 vs 5.6 mmol/L; P=0.049), and systolic blood pressure (137.9 vs 132.8 mmHg; P=0.005). By contrast, cranial irradiation recipients with metabolic syndrome had a larger waist circumference (109 vs 99.6 cm; P=0.007) than controls. Regardless of the anti-leukemic treatment, metabolic syndrome risk was higher among childhood leukemia survivors. Its presentation differed depending on the treatment type, thus suggesting a divergent pathophysiology. This study is registered at clinicaltrials.gov identifier: 01756599.

Appendicitis in a Neutropenic Patient: A Multicentric Retrospective Study.

To study the management of acute appendicitis in neutropenic patients, we retrospectively reviewed cases of acute appendicitis in neutropenic children treated for cancer. The patients' demographics, medical records, and outcomes were tracked. We compared nonoperative treatment versus emergency or delayed surgery. The cases of 30 patients with a mean age of 8.8 years in 12 French departments of Pediatric Hematology/Oncology between 1995 and 2013 were studied. Most patients (90%) were treated for hematological malignancies. Seven of the 30 children were successfully treated with exclusive medical treatment. Early surgery was performed in 6 patients, and the remaining 17 underwent combined management with a first-line antibiotic treatment and delayed appendectomy. Treatments were successful in all cases with transitory complications in only 3 patients. No death linked to infection was reported. Surgery was well tolerated even in the neutropenic period. Appendix perforation was a major risk factor of prolonged hospitalization. Histologic as well as bacteriologic and mycologic/parasitologic analyses were required in case of surgery. Analysis of diagnostic assessments showed the major importance of imaging (ultrasonography and tomography) on diagnosis confirmation. We could not come to a conclusion in the few numbers of reviewed cases because of a significant difference in management strategies, but we can conclude that early surgery after adequate supportive care is an acceptable modality of treatment and must be chosen in the face of life-threatening conditions.

Metabolic syndrome in long-term survivors of childhood acute leukemia treated without hematopoietic stem cell transplantation: an L.E.A. study.

Cardiovascular conditions are serious long-term complications of childhood acute leukemia. However, few studies have investigated the risk of metabolic syndrome, a known predictor of cardiovascular disease, in patients treated without hematopoietic stem cell transplantation. We describe the overall and age-specific prevalence, and the risk factors for metabolic syndrome and its components in the L.E.A. (Leucémie de l'Enfant et de l'Adolescent) French cohort of childhood acute leukemia survivors treated without hematopoietic stem cell transplantation. The study included 650 adult patients (mean age at evaluation: 24.2 years; mean follow-up after leukemia diagnosis: 16.0 years). The prevalence of metabolic syndrome was 6.9% (95% CI 5.1-9.2). The age-specific cumulative prevalence at 20, 25, 30 and 35 years of age was 1.3%, 6.1%, 10.8% and 22.4%, respectively. The prevalence of decreased high-density lipoprotein cholesterol, increased triglycerides, increased fasting glucose, increased blood pressure and increased abdominal circumference was 26.8%, 11.7%, 5.8%, 36.7% and 16.7%, respectively. Risk factors significantly associated with metabolic syndrome in the multivariate analysis were male sex (OR 2.64; 95% CI 1.32-5.29), age at last evaluation (OR 1.10; 95% CI 1.04-1.17) and body mass index at diagnosis (OR 1.15; 95% CI 1.01-1.32). The cumulative steroid dose was not a significant risk factor. Irradiated and non-irradiated patients exhibited different patterns of metabolic abnormalities, with more frequent abdominal obesity in irradiated patients and more frequent hypertension in non-irradiated patients. Survivors of childhood acute leukemia are at risk of metabolic syndrome, even when treated without hematopoietic stem cell transplantation or central nervous system irradiation. A preventive approach with regular screening for cardiovascular risk factors is recommended. clinicaltrials.gov identifier:01756599.

Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network.

Juvenile myelomonocytic leukemia (JMML) is a rare and severe myelodysplastic and myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations. Genetic profiling and whole-exome sequencing of a large JMML cohort (118 and 30 cases, respectively) uncovered additional genetic abnormalities in 56 cases (47%). Somatic events were rare (0.38 events/Mb/case) and restricted to sporadic (49/78; 63%) or neurofibromatosis type 1 (NF1)-associated (8/8; 100%) JMML cases. Multiple concomitant genetic hits targeting the RAS pathway were identified in 13 of 78 cases (17%), disproving the concept of mutually exclusive RAS pathway mutations and defining new pathways activated in JMML involving phosphoinositide 3-kinase (PI3K) and the mTORC2 complex through RAC2 mutation. Furthermore, this study highlights PRC2 loss (26/78; 33% of sporadic JMML cases) that switches the methylation/acetylation status of lysine 27 of histone H3 in JMML cases with altered RAS and PRC2 pathways. Finally, the association between JMML outcome and mutational profile suggests a dose-dependent effect for RAS pathway activation, distinguishing very aggressive JMML rapidly progressing to acute myeloid leukemia.

CD200/BTLA deletions in pediatric precursor B-cell acute lymphoblastic leukemia treated according to the EORTC-CLG 58951 protocol.

DNA copy number analysis has been instrumental for the identification of genetic alterations in B-cell precursor acute lymphoblastic leukemia. Notably, some of these genetic defects have been associated with poor treatment outcome and might be relevant for future risk stratification. In this study, we characterized recurrent deletions of CD200 and BTLA genes, mediated by recombination-activating genes, and used breakpoint-specific polymerase chain reaction assay to screen a cohort of 1154 cases of B-cell precursor acute lymphoblastic leukemia uniformly treated according to the EORTC-CLG 58951 protocol. CD200/BTLA deletions were identified in 56 of the patients (4.8%) and were associated with an inferior 8-year event free survival in this treatment protocol [70.2% ± 1.2% for patients with deletions versus 83.5% ± 6.4% for non-deleted cases (hazard ratio 2.02; 95% confidence interval 1.23-3.32; P=0.005)]. Genetically, CD200/BTLA deletions were strongly associated with ETV6-RUNX1-positive leukemias (P<0.0001), but were also identified in patients who did not have any genetic abnormality that is currently used for risk stratification. Within the latter population of patients, the presence of CD200/BTLA deletions was associated with inferior event-free survival and overall survival. Moreover, the multivariate Cox model indicated that these deletions had independent prognostic impact on event-free survival when adjusting for conventional risk criteria. All together, these findings further underscore the rationale for copy number profiling as an important tool for risk stratification in human B-cell precursor acute lymphoblastic leukemia. This trial was registered at www.ClinicalTrials.gov as #NCT00003728.