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The association between celiac disease (CD) and immune thrombocytopenia (ITP) is still uncertain. The aim of this study was to characterize the coexistence of these two diseases in Italian children.This is a retrospective multicenter study investigating the occurrence of CD in 28 children with ITP diagnosed from January 1, 2000, to December 31, 2019.The first diagnosis was ITP in 57.1% and CD in 32.1% of patients. In 3 patients (10.7%), the two diagnoses were simultaneous. All the potential and silent cases of CD in our cohort were diagnosed in the groups of “ITP first” and “simultaneous diagnosis”. In all children ITP was mild, and in 2 out of 8 not recovered from ITP at the time of CD diagnosis a normalization of platelet counts (100,000/μL) occurred 3 and 5 months after starting a gluten-free diet, respectively.We think that screening for CD should be considered in children with ITP regardless of the presence of gastrointestinal symptoms. Furthermore, some patients may recover from ITP after starting a gluten-free diet.İmmün trombositopeni (İTP) ve çölyak hastalığı (ÇH) arasındaki ilişki hala belirsizliğini korumaktadır. Bu çalışmanın amacı İtalyan çocuklarında bu iki hastalık arasındaki ilişkiyi ortaya koymaktır.Bu çalışma, 1 Ocak 2000’den 31 Aralık 2019’a kadar İTP tanısına ek olarak ÇH tanısı alan 28 çocuğun araştırıldığı geriye dönük çok merkezli bir çalışmadır.Hastaların %57,1’inde ilk tanı İTP ve %32,1’inde ÇH idi. Üç hastada (%10,7) iki tanı aynı anda konulmuştu. Kohortumuzdaki tüm potansiyel ve sessiz ÇH olguları “önce İTP” ve “eşzamanlı tanı” gruplarında teşhis edildi. Tüm çocuklarda İTP hafifti ve ÇH tanısı sırasında trombositopenisi devam eden 8 çocuktan 2’sinde, glutensiz diyete başladıktan sonra sırasıyla 3 ve 5 ayda trombosit sayılarında normalleşme (100.000/μL) görüldü.Bu çalışma İTP’li çocuklarda gastrointestinal semptomların varlığına bakılmaksızın ÇH taramasının yapılması gerektiğini düşündürmektedir. Bazı hastalarda trombosit sayılarının glutensiz bir diyete başladıktan sonra düzelebileceği akılda bulundurulmalıdır.

Acute promyelocytic leukaemia (APL) is a rare subtype ofchildhood acute myeloid leukaemia (AML), accounting for5–12% of all AML cases. Treatment with all-trans-retinoicacid (ATRA) and anthracyclines yields complete remission(CR) rates >90% and 10-year event-free survival (EFS) ratesaround 80%.1–3The recent front-line arsenic trioxide(ATO)-based regimens have further improved the APL out-come by reducing toxicity and preventing relapse.4–6Relapsed APL patients are a rare and heterogeneous group,whose prognosis depends on front-line treatment and timeelapsing between diagnosis and recurrence. Currently, ATOis the treatment of choice for relapsed APL. Due to the rarityof relapsed childhood APL, 17–27% in ATRA- andchemotherapy-1,3,7–9and 4% in ATO-containing regimens,10it will be difficult, in the future, to design future prospectivecomparative trials for these patients. In an attempt to designtherapeutic guidelines, recommendations on management ofrelapsed/refractory paediatric APL have been publishedrecently

Transfusion-dependent patients typically develop iron-induced cardiomyopathy, liver disease, and endocrine complications. We aimed to estimate the incidence of endocrine disorders in transfusiondependent thalassemia (TDT) patients during long-term iron-chelation therapy with deferasirox (DFX). We developed a multi-center follow-up study of 426 TDT patients treated with once-daily DFX for a median duration of 8 years, up to 18.5 years. At baseline, 118, 121, and 187 patients had 0, 1, or ≥2 endocrine diseases respectively. 104 additional endocrine diseases were developed during the follow-up. The overall risk of developing a new endocrine complication within 5 years was 9.7% (95% Confidence Interval [CI]: 6.3–13.1). Multiple Cox regression analysis identified three key predictors: age showed a positive log-linear effect (adjusted hazard ratio [HR] for 50% increase 1.2, 95% CI: 1.1–1.3, P=0.005), the serum concentration of thyrotropin showed a positive linear effect (adjusted HR for 1 mIU/L increase 1.3, 95% CI: 1.1–1.4, P

Background: The aim of the present study was to assess management strategies for immune thrombocytopenia (ITP) among Italian paediatric haematologists, and to compare these with those of recent international guidelines. Predictors of early remission or disease chronicity were also evaluated. Materials and methods: During a period of 1 year, 205 children (age: 1 month-18 years) with newly diagnosed ITP were prospectively enrolled by 16 centres belonging to the Italian Association of Paediatric Haematology and Oncology (AIEOP). We collected the subjects demographic data, history, clinical symptoms, platelet count and treatment at presentation and at subsequent visits. Results: Of the 205 patients, 47 (23%) were initially managed with a wait-and-see approach. Compared to these patients, children administered platelet-enhancing therapies were significantly younger (median age: 4.75 vs 7.96 years; p

Primary autoimmune neutropenia (pAN) is typified by onset in early infancy and a mild/moderate phenotype that resolves within 3 years of diagnosis. In contrast, secondary AN is classically an adult disease associated with malignancy, autoimmunity, immunodeficiency, viral infection, or drugs. This study describes a cohort of 79 children from the Italian Registry who, although resembling pAN, did not fully match the criteria for pAN because neutropenia either appeared after age 5 years (LO-Np) or lasted longer than 3 years (LL-Np). These 2 categories compared with classical pAN showed a far inferior rate of resolution (P < .001), lower severity of neutropenia (P = .03), leukopenia (P < .001), lymphopenia (P < .001) with low B+ (P = .001), increased need of granulocyte colony-stimulating factor (P = .04), and increased frequency of autoimmunity over the disease course (P < .001). A paired comparison between LO-Np and LL-Np suggested that LO-Np had a lower rate of resolution (P < .001) and lower white blood cell (P < .001) and lymphocyte (P < .001) values, higher occurrence of apthae (P = .008), and a stronger association with autoimmune diseases/markers (P = .001) than LL-Np, thus suggesting a more pronounced autoimmune signature for LO-Np. A next-generation sequencing panel applied in a small subgroup of LO-Np and LL-Np patients identified variants related to immune dysregulations. Overall, these findings indicate that there are important differences among pAN LL-Np and LO-Np. Forms rising after 3 years of age, with low tendency to resolution, require tight monitoring and extensive immune investigations aimed to early identify underlying immunologic disease.

Pediatric healthcare activity related to the Vatican City State is carried out at secondary and tertiary levels in the two main pediatric territorial and extra-territorial medical centers, which are administered by the Vatican: the Bambino Gesu Pediatric Hospital and the Mother and Child pediatric Department of the Casa Sollievo della Sofferenza Medical Center. Both centers are recognized by the Italian State and internationally with the formal legal status of Scientific Institutes for Clinical Research. The relations established between the Holy See, in the person of the Secretary of State, the Board of Directors, the President of the Board, and the Board of Auditors regulate the management of the two medical centers. The child healthcare and research activity of the two Vatican State administered medical centers is described in this article.

Background: The thrombopoietin receptor agonist eltrombopag has been shown to be safe and effective for children with chronic immune thrombocytopenia (ITP). The aim of the present study was to characterize eltrombopag use in current clinical practice.Material and Methods: This is a retrospective multicenter study conducted in 17 centers affiliated to the Italian Association of Pediatric Hematology and Oncology (AIEOP). The primary objective of the study was to determine the prevalence of eltrombopag use in Italian children affected by chronic ITP, after EMA authorization for pediatric age. The secondary objective was to assess efficacy in the first 6 months and safety during the whole period of eltrombopag treatment in current clinical practice. A total of 386 children with chronic ITP were retrospectively enrolled and eligible for analysis. Among these patients, 71 received eltrombopag.Results: The prevalence of eltrombopag use was 19% (95% CI 0.15–0.23). Thirty-one patients (44%) were male and 40 patients (56%) were female. The median age at the first dose of eltrombopag was 12 years (3–17 years). The median duration of eltrombopag treatment was 11 months (1–32 months) and the median starting dose was 50 mg/day (12, 5–75 mg/day). Thirty-two patients (45%) required one or more concomitant ITP medications during the first 6 months of treatment with eltrombopag. Thirty-nine patients (55%) never required concomitant medications. Median platelet counts and proportion of patients achieving the target platelet count of at least 30 × 109/L and 100 × 109/L significantly increased during the first 6 months of treatment (p < 0.0001). Additionally, eltrombopag has been proved effective in the absence of concomitant therapies. The most common Adverse Events were headache (7%) and thrombocytosis (6%).Conclusion: Our study highlighted the crucial role of eltrombopag as second line treatment in children with chronic ITP.

Background: To date, no data on the adherence to specific guidelines for children with chronic myeloid leukemia (CML) in chronic phase (CP) have been reported. Methods: Since 2001, guidelines for treatment with imatinib mesylate (IM) and monitoring in patients younger than 18 years with CP-CML have been shared with 9 pediatric referral centers (P centers) and 4 reference centers for adults and children/adolescents (AP centers) in Italy. In this study, the adherence to these guidelines was analyzed. Results: Thirty-four patients with a median age of 11.4 years and 23 patients with a median age of 11.0 years were managed at 9 P and at 4 AP centers, respectively. Evaluations of bone marrow (BM) and/or peripheral blood (PB) were available for more than 90% of evaluable patients. Cytogenetics and molecular monitoring of PB were more consistently performed in AP centers, whereas molecular analysis of BM was carried out more frequently in P centers. Before 2009, some patients who responded to IM underwent a transplantation, contrary to the guidelines’ recommendations. Conclusions: Our experience shows that having specific guidelines is an important tool for an optimal management of childhood CP-CML, together with exchange of knowledge and proactive discussions within the network.

Introduction Asplenic patients are at high risk of potentially fatal invasive infections, such as sepsis, meningitis, and pneumonia. It has been shown that infection from influenza viruses can precede or increase the risk of bacterial infection and of serious complications of the underlying disease. International and national guidelines recommend annual influenza vaccination in asplenic subjects. Following the Covid-19 pandemic, the major government and medical-scientific institutions in the US and in Europe have been planning how to contain infection during the 2020-2021 influenza season. Extending influenza vaccination is the safest and most effective way to reduce the circulation of influenza virus and to promote the correct diagnosis and management of suspected cases of SARS-CoV-2. Influenza vaccination also reduces complications associated with the underlying disease and visits to Emergency Units. Our study aims to evaluate influenza vaccination in a large population of asplenic patients and explore the main causes for non-vaccination to identify critical areas for improvement in the vaccination programme in these at-risk patients for the 2020-2021 influenza season. Methods The Italian Network of Asplenia (INA) is made up of 88 doctors working in 50 clinical centers in 27 cities and 16 of the 20 regions of Italy. It aims to build a large, prospective cohort of asplenic patients throughout Italy through which to study the interaction between asplenia and its associated underlying conditions, collecting precise, accurate data also in cases of rarer diseases. The study also aims to improve the quality of healthcare for this at-risk population. The number of patients enrolled in the Network who had had at least one dose of influenza vaccine at the time of diagnosis of asplenia was retrieved from the INA database. All participating centers were asked to answer a questionnaire to report the main obstacles for influenza vaccination. Results At 1st August 2020, 1,670 patients had been enrolled in the INA (783 females; 887 males). All underlying causes of asplenia are shown in Table 1. Only 466 (28%) patients had had at least one influenza vaccination, while 1,204 (72%) had never been vaccinated since diagnosis of asplenia. Thirty-five (70%) of the 50 centers answered the questionnaire. Main causes of non-vaccination were physicians' ambivalence concerning vaccination and patients' inadequate awareness or logistical problems. Conclusions These data show very low seasonal influenza vaccination cover even though asplenic patients are considered at-risk of complications associated with infection from influenza viruses. Since the 2020-2021 influenza season could see influenza viruses in circulation with SARS-CoV-2, influenza vaccination must be expanded as widely as possible, in particular to subjects of all ages at high risk. These results reveal important areas of concern in the management of asplenic patients and the need to improve the quality of information to physicians and patients alike. The INA co-ordinating center will launch a campaign to provide information and organize ad hoc meetings to widen influenza vaccination coverage in asplenic patients and reduce the pressure on the national health service during the next influenza season. Disclosures Forni: Novartis: Membership on an entity's Board of Directors or advisory committees. Colombatti:Addmedica: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Giona:Sanofi Genzyme: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Novartis: Research Funding. Ferrero:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Servier: Speakers Bureau. Perrotta:Novartis: Consultancy, Research Funding, Speakers Bureau. Casale:Novartis: Membership on an entity's Board of Directors or advisory committees.

Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating illness, characterize-ed by a monophasic course frequently associated with infections or previous immunization. Regarding pathogenesis, encephalomyelitis is associated with some immunological mechanisms. Post-infection or post-vaccination inflammatory reactions in the perivenular region in the central nervous system (CNS) may be explained by a molecular mimicry mechanism. An antecedent infection was identified in 72–77% of paediatric patients. We present a case of a 5 year-old girl in follow up for autoimmune thrombocytopenia (AT) and autoimmune haemolytic anaemia (AHA) in steroid treatment, with history of left hemiparesis, language delay, from as a consequence of perinatal suffering, who has developed ADEM. This patient presented with progressive weakness of limbs, neck pain associated with fever from one day. It was acute in onset and gradually progressive. She became quickly hypotonic and hyporesponsive and had reduced level of consciousness. Within 12 hours of admission, the patient developed sphincter incontinence and dysphagia. After exclusion of papilloedema, lumbar puncture has been performed. An urgent MRI was performed, which showed multiple subcortical lesions of varying size showing hyperintensities in TR at the bridge and in T2 at the medulla . Cerebrospinal fluid (CSF) study showed cell count of 40 cells/mm3 , protein 58 mg/dL, glucose 54 mg/dL. No oligoclonal bands were present in CSF. Blood and CSF cultures were negative like other infectiological analyzes. Also CSF-PCR for the presence of bacteria and virus was negative. Her autoimmune profile with antinuclear antibody was also negative. The clinical features and the MRI findings were suggestive of ADEM. Partial quadriplegia, and reduction of reflexes, as seen in the myelitic form of ADEM, were present. She had developed ADEM while on the maintenance dose of prednisolone. After diagnosis, intravenous methylprednisolone was given at 30 mg/kg daily for 5 days. After 48 hours there was a significant improvement in the patient‘s clinical condition. A regimen of oral steroid was advised after intravenous therapy . The patient responded well to steroid therapy. No residual lesion was found on follow-up. AT and AHA are relatively uncommone. There are studies postulating the possibility of a combination of several autoimmune diseases. Very few cases have been found with this rare association in the literature. Follow-up of these patients is essential for detecting the development of other autoimmune disease in such cases.

Porphyrias are a group of inherited metabolic disorders of heme biosynthesis leading to excessive accumulation and excretion of porphyrins.The variable clinical manifestations may determine a delay in the diagnosis, followed by a possible negative clinical outcome. We describe a case of a 14-year-old girl with Shwachman-Diamond syndrome (SDS) and epilepsy admitted with severe cyclic abdominal pain not responsive to antalgic therapy, localized in the epigastric area, irradiating to the whole abdomen and the back, associated to aspecific symptoms (diarrhea, fever,vomiting). During hospitalization, the girl was asymptomatic. We excluded infectious, autoimmune, endocrinological causes, a relapse of SDS and performed a screening for porphyria that resulted negative. After each attack, she referred presenting urinary retention followed by hyperchromic urines, anxiety and paresthesias. Past clinical data showed hyponatremia, tachycardia and hypertension. Eventually, increased values of ALA (8.21 mg/l) and PBG (3.96 mg/l) were found; exposure of fresh urines to sunlight caused a change of their color. Finally, genetic analysis was negative. These findings allowed the diagnosis of porphyria, therefore we prescribed a normocalorichyperglucidic diet andpreventive glucose solutions in stressing situations, with regression of symptoms. Acute porphyrias present with life-threatening crisis secondary to the injury of central, peripheral and autonomic nervous system. They can be triggered by drugs, alcohol, infections, reduced caloric intake, endogenous hormone cycles and stressing situations. The characteristic manifestations are severe cyclic abdominal pain, neurological or psychiatric symptoms and/or hyponatremia. Diagnostic is the assessment of plasmatic PBG/ALA, always increased during an attack, normal during remission. Treatment is human haemin although, in mild attacks, a diet with high carbohydrates and/or preventive glucose infusions is effective; a negative genetic evaluation should never exclude the diagnosis. It is important considering acute porphyria in the differential diagnosis of severe cyclic abdominal pain, particularly in subjects affected by different and/or rare clinical disorders.

Introduction Advances in paediatric oncology led to the increase in long-term survival, revealing the burden of therapy-related long-term side effects. We evaluated overall and cause-specific mortality in a large cohort of Italian childhood cancer survivors (CCSs) and adolescent cancer survivors identified through the off-therapy registry. Materials and methods CCSs alive 5 years after cancer diagnosis occurring between 1960 and 1999 were eligible; the last follow-up was between 2011 and 2014. Outcomes were reported as standardised mortality ratios (SMRs) and absolute excess risks (AERs). Results Among 12,214 CCSs, 1113 (9.1%) deaths occurred. Survival at 35 years since diagnosis was 87% (95% confidence interval [CI]: 86–88) and at 45 years was 81% (95% CI: 77–84). CCSs had an 11-fold increased risk of death (SMR 95% CI: 10.7–12), corresponding to an AER of 48 (95% CI: 45–51). Mortality decreased by 60% for survivors treated most recently (1990–1999). The most frequent causes of death were recurrence of the original cancer (56%), a subsequent neoplasm (19%) and cardiovascular diseases (5.8%). Among those who survived at least 15 years after diagnosis, a secondary malignancy was the leading cause of death. Conclusions This study confirms the impact of recent advances in anticancer therapy in reducing mortality, mainly attributable to recurrence but also to other causes. However, overall mortality continues to be higher than in the general population. A long-term follow-up is needed to prevent late mortality due to secondary neoplasms and non-neoplastic causes in CCSs.

Autoimmune hemolytic anemia (AIHA) is an uncommon disease of childhood caused by the premature destruction of erythrocytes by autoantibodies. In this rare disease both diagnostic criteria and therapeutic approaches are not well standardized. The Red Cell Working Group of the Pediatric Italian Hematogy and Oncology Association (AIEOP) developed specific recommendations to help Physicians for AIHA management. The document is available on the AIEOP website since November 1st 2013. The Italian Pediatric AIHA Group began an observational, retrospective and prospective study in order to monitor the management of children with AIHA diagnosed from 2010 to 2018, and to assess whether the availability of AIEOP recommendations had an impact on the clinical management of such patients in AIEOP Centers. We collected a national cohort of 159 children with AIHA from 21 AIEOP Centers; 48 patients were diagnosed before November 2013 and 111 patients after that date. Gender was 56% males and 44% females; median age at diagnosis was 47 months, with 11.9% under 12 months of age; 8.2% of children were born prematurely and 3.9% showed congenital malformations. 23.2 % of patients had a familiar history of immunological, hematological or oncological diseases. The median hemoglobin level at diagnosis was 6.1 gr/dL. Table 1 reports the distribution of our cases, according to the different type of autoantibodies. The comparison between the retrospective and prospective study did not reveal significative differences in clinical and biological presentation. The cold IgM forms were mainly post infective (38.4%) or primary forms (53.8%), only one patient had a secondary form due to a primitive immunodeficiency. These patients did not develop other diseases during follow up (median follow up: 28,6 months). The preliminary results of treatment and follow up of the 146 patients with warm antibody AIHA revealed the following: The treatment with conventional dose of steroids (median dose 2 mg/Kg, range 0.7- 3.5 mg/Kg) was started in 94.4% of patients, in 53% of cases on the same day of diagnosis. A high number of children used additional treatment: red blood cell transfusions (51.4%), high dose Prednisolone (59.7%), high dose i.v. Immunoglobulin (49.7%) and Plasma Exchange (1.4%). 9.5% of patients, with poor responsive disease, needed alternative drugs during the first four weeks of therapy. Response criteria were so defined: a complete response was defined as the achievement of an Hb concentration greater than or equal to the lower normal limit for age with no signs of haemolysis, i.e. normal reticulocyte count and bilirubine concentration. A partial response was defined as an increase of Hb >2 g/dL without the Hb concentration reaching a normal value for the patient age and no response as an increase of Hb< 2 g/dL and/or dependence on transfusion. A complete response was reached by 62.5%, 79.3%, 85.1% at 3, 4, 6 weeks respectively. 14.9% of patients had either a partial response or a resistant disease at 6 weeks. IgG/IgG+C3d positivity was a negative prognostic factor, as compared to positivity to C3d only, with the need of a second line treatment (prevalently Mabthera or Mycophenolate Mofetil) in 31.7% vs 0, respectively (p 0.009). Currently 6.1% of the patients were lost to follow up, 1.3% died, 55,8% are in Complete Response without events and 21.9% of the patients are still on treatment . At the last follow up, in the whole "cohort" of warm AIHA, 58% have a Primary form, 15.7% an isolated post infective form and 27.7% a Secondary form (56% Evans Syndrome). The management of the patients diagnosed after November 2013 was mostly in agreement with our recommendations, whose comprehensive therapeutic algorithm is reported in table 2, with prolonged steroid tapering in order to extend the treatment for at least 6 months. The most important difference between the retrospective and prospective study was the duration of first line treatment: 6 months or more, for steroid dependence, in 71.6% of patients in the prospective study versus 52.3% of the retrospective (p 0.031) and, more importantly, the percentage of relapsed patients: 8.3% in the prospective study versus 29.8% of the retrospective (p 0.001), these data need a longer follow up (median follow up: 24 months in the prospective study versus 63 in the retrospective) Disclosures Colombatti: Global Blood Therapeutics: Consultancy; Novartis: Consultancy; AddMedica: Consultancy.

Burkitt’s lymphoma (BL) is an aggressive B-cell non-Hodgkin lymphoma that is found predominantly in children, with the highest incidence occurring in Africa. The sporadic form occurs in non-endemic areas and typically involves the ileo-caecum and the bowel, whereas orbital and paranasal sinus involvement is rare. Here, we present an unusual case of sporadic BL in a Caucasian male child with rapidly progressive painful proptosis of the right eye. Magnetic resonance imaging showed an oval-shaped, extraconal mass in the supero-lateral part of the right orbit that deformed and dislocated the eyeball antero-inferiorly. The patient underwent anterior orbitotomy, and a biopsy of the excised tissue revealed a starry-sky appearance characteristic of BL. Postoperative aggressive chemotherapy was initiated with a good response after one week.

Autoimmune neutropenia of infancy (AIN) is characterized by low risk of severe infection, tendency to spontaneously resolve and typically onset at ≤4-5 years of age; it is due to auto-antibodies whose detection is often difficult. In case of negativity of 4 antineutrophils autoantibody tests, after having excluded ethnic, postinfection, drug induced, or congenital neutropenia, according to the Italian guidelines the patients will be defined as affected by "idiopathic neutropenia" (IN). We describe the characteristics of 85 IN patients enrolled in the Italian neutropenia registry: they were compared with 336 children affected by AIN. The 2 groups were clinically very similar and the main differences were detection age (later in IN), length of disease (longer in IN) and, among recovered patients, age of spontaneous recovery: the median age at resolution was 2.13 years in AINs and 3.03 years in INs (P = .00002). At bivariate analysis among AIN patients earlier detection age (P = .00013), male sex (P = .000748), absence of leucopenia (P = .0045), and absence of monocytosis (P = .0419) were significantly associated with earlier recovery; in the IN group only detection age (P = .013) and absence of monocytosis (P = .0333) were significant. At multivariate analysis detection age and absence of monocytosis were independently significant (P = 6.7e-05 and 4.4e-03, respectively) in the AIN group, whereas in the IN group only detection age stayed significant (P = .013).

Hereditary hypochromic microcytic anemia associated with loss‐of‐function DMT1 gene mutations and absence of liver iron overload Maddalena Casale;Adriana Borriello;Saverio Scianguetta;Domenico Roberti;Martina Caiazza;Debora Bencivenga;Immacolata Tartaglione;Saverio Ladogana;Matteo Maruzzi;Fulvio Della Ragione;Silverio Perrotta; American Journal of Hematology

Imatinib mesylate (IM) has demonstrated to be highly effective in children with chronic myeloid leukemia (CML). The main issues remain the long-term side effects in pre-pubertal children and the poor compliance in adolescents. The aims of this study were: a) to evaluate the feasibility and efficacy of IM given intermittently to molecular responder (MR) CML children in chronic phase (CP), b) to reduce the long-term side effects of MR patients (pts) who started IM in pre-pubertal age, c) to improve compliance of poorly compliant adolescents in major MR (MMR). Among CP-CML pts aged Fifteen of 58 CP-CML pts diagnosed between March 2001 and June 2015 received IM given intermittently for a median of 40 months(range: 14-86). Before starting int-IM, 5 pts had been in persistent MR4.5-MR5 for a median of 39 months (Group I), 4 pts had been in MR for a median of 28.5 months and had been suffering from long-term side effects (Group II), and 6 pts had been in MMR and were poorly compliant to treatment (Group III). Features and outcome of the 15 pts are shown in Table 1. Group I: 3/5 pts in MR4.5-MR5 discontinued int-IM after 16, 34 and 36 months and remain in continuous MR after 89, 90 and 107 months; 2 pts are still receiving int-IM for 14 and 36 months, respectively. Group II: 2/4 pts achieved a deeper MR (1 from MR4 to MR4.5 and 1 from MR4.5 to MR5) while on int-IM. However, 3 pts lost the response after 24 (cytogenetic relapse), 40 and 77 (molecular) months from the beginning of int-IM; all of them were successfully treated with IM given continuously. One pt is still receiving int-IM. Group III: 2/6 pts achieved a deeper MR (1 from MR3 to MR4.5 and 1 from MR3 to MR4) while on int-IM. However, 5/6 patients lost their response after a median time of 69 months (57-74). Four of them were treated with IM given continuously and 1 received dasatinib; all obtained a response. One, who achieved a deeper MR (MR3 to MR4), is still on int-IM after 86 months. Overall, 4/15 (26.7%) pts improved their molecular response while on int-IM and 3/15 pts (20%) successfully discontinued treatment. On the other hand, 8/15 pts (53.3%) failed int-IM after a median of 63 months (range 24-77) from the beginning (6 pts lost MMR and 2 pts had a cytogenetic relapse). No pt underwent a stem cell transplantation. Long-term side effects (bone metabolism, growth rate and pubertal development) progressively improved during IM given intermittently. At the last follow-up, 6 pts (4 MR5, 1 MR4.5, 1 MR3) are still receiving int-IM, 5 (3 MR4, 2 MR2) are receiving continuous IM, 3 (MR4.5-MR5) are treatment-free and 1 (MR3) is being treated with dasatinib. All patients are alive at a median time from diagnosis of 151 months (range 52-266). Our experience suggests that an intermittent schedule of IM given 3 weeks a month could be an effective strategy before stopping IM in CP-CML children in persistent deep MR. Moreover, this approach is capable of improving the molecular response in poor compliant pts and is useful to reduce IM-related long-term side effects. The relatively high number of relapses in group III (5/6, 83%) is indicative of its poor efficacy in pts not compliant to IM given continuously. Based on these data, a prospective cooperative study has been planned. Disclosures Malaspina: Sapienza University, Rome: Other: Resident in Hematology. Rizzo:Sapienza University, Rome: Other: Resident in Hematology. Locatelli:bluebird bio: Consultancy; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Foà:CELGENE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; CELTRION: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau.

Background Pulmonary embolism (PE) is a potentially lethal condition. Although it’s usually manifested with severe symptoms causing right ventricular dysfunction or haemodynamic instability, in case of partial arterial obstruction it can be asymptomatic. Cancer patients are at high risk of thromboembolic complications. The use of contrast-enhanced computerised tomography for cancer staging has documented a high incidence of asymptomatic PE. Case presentation We present a case of unsuspected PE in paediatric oncology patient. A 10-year-old boy presented with cervical and axillary lymph node swellings. No response to antibiotic therapy. Infectivological tests (mononucleosis, tuberculosis, toxoplasmosis…) were negative. Staging imaging revealed a positron emission tomography/computed tomography (PET-CT) avid anterior mediastinal lymph node. There weren’t liver, spleen and lung injury. Excisional biopsy of the lymph node was consistent with an anaplastic large cell lymphoma ALK+, t(2;5). After positioning of central venous catheter (CVC), the patient began treatment with chemotherapy with reduction of the lymphadenopathy. Subsequently, repositioning of CVC due to malfunction and displacement. After three months, he performed restaging; CT showed bilateral thromboembolism of the pulmonary arteries with partial obstruction. Echocardiogram showed a blood pressure’s increase in pulmonary artery (PAP 38 mmHg) but the child didn’t present respiratory and cardiac symptoms. Echo-color-doppler didn’t report venous thrombosis of the legs. Laboratory tests showed high platelet count. d-dimer levels and activated partial thromboplastin time value were increased. Inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) were normal. The patient discontinued chemotherapy and started standard anticoagulant treatment. Two weeks later, CT and ultrasound controls displayed substantial reduction of the obstruction of the pulmonary arteries and decrease of PAP. Conclusions Thromboembolic complications are frequent in children with lymphoma. Often, routine thoracic MDCT examinations of paediatric oncology patients reveal cases of unsuspected PE. It is necessary to identify children at an increased risk for the development of PE to define an appropriate management. However, recent studies have showed that the lack of diagnosis and treatment do not have a negative influence on patient outcome.

Meningioangiomatosis(MA) is a rare malformative or hamartomatous lesion involved in meninges and cortex. Although it was originally described in association with NF-2, recent studies have revealed that it occurs more frequently in sporadic form. The pathogenesis remains unclear. MA has distinct histological and biological features to meningioma(M) but their association(MA-M) isn’t unfrequent. Case report a 12-years-old male was referred to our paediatric division for a history of headhache associated to malformative lesions shown at a first radiological investigation (CT and MRI) done in other hospital when he was 6 years old. At that time, neurosurgeons recommended follow up program. The lesions haven’t change over the years, as shown at the follow-ups, however the persistence of headhache induced the family to request a second opinion. Our physical examination showed mental retardation. He had no family history or stigmata of NF2 and no seizure’s history, electroencephalography didn’t show anomalies. A head CT scan showed the presence of a right hyperdense single mass with gyriform signal pattern and clumped intralesional calcifications. MRI showed an intracranial mass measuring 2x3 × 2.5 cm located in the right posterior frontal cortex. The lesion was hyperintense on T2-weighted imaging and weakly hypointense on T1W1, with ring-like enhancement. MRI confirmed gyriform signal pattern associated to focal areas of cortical fronto-parietal dysplasia. The diagnosis of MA was made. Our patient didn’t present seizure and the lesions appeared stable compared with the previous MRI so, in compliance with the neurosurgeon’s advice, we established a long-term follow up program in association with symptomatic therapy for headhache. MA occurs mainly in children and younger adults with male predisposition, suffering from intractable seizure and less frequently headhache. Atypical symptoms included vomiting, diabetes insipidus, facial weakness, muscle atrophy and pain. MA is a single lesion usually stable or slowly growing. Imaging diagnoses for MA is difficult. The most common finding on CT is a round, single, hypodense mass with varying degrees of calcification. On MRI, the lesions seem confined to the cortex. On T1WI, MA shows a low or iso-intense signal, on T2WI lesions are more frequently hyperintense, but sometimes they can be hypointense. A gyriform signal pattern is common on either CT or MRI, typical of sporadic MA and it’s helpful to distinguish pure MA from MA-M.

// Gloria Milani 1 , Paola Rebora 2 , Benedetta Accordi 1 , Luisa Galla 1 , Silvia Bresolin 1 , Gianni Cazzaniga 3 , Barbara Buldini 1 , Rossella Mura 4 , Saverio Ladogana 5 , Eugenia Giraldi 6 , Valentino Conter 7 , Geertruy Te Kronnie 1 , Maria Grazia Valsecchi 2 and Giuseppe Basso 1 1 Laboratory of Oncohematology, Department of Women’s and Children’s Health, University of Padova, Italy 2 Center of Biostatistics for Clinical Epidemiology, Department of Health Sciences, University of Milano-Bicocca, Monza, Italy 3 Centro Ricerca Tettamanti, University of Milano-Bicocca, Ospedale San Gerardo, Monza, Italy 4 Oncoematologia Pediatrica e Patologia della Coagulazione, Ospedale Regionale per le Microcitemie, Cagliari, Italy 5 Oncoematologia Pediatrica, Ospedale “Casa Solievo della Sofferenza”, San Giovanni Rotondo, Italy 6 U.O. Pediatria, Ospedale Papa Giovanni XXIII, Bergamo, Italy 7 Pediatric Department, University of Milano-Bicocca, Ospedale San Gerardo, Monza, Italy Correspondence: Geertruy te Kronnie, email: // Keywords : Low PKCα expression, Childhood T-cell Acute Lymphoblastic Leukemia, T-ALL prognostic marker Received : April 8, 2014 Accepted : June 5, 2014 Published : June 6, 2014 Abstract Pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) outcome has improved in the last decades, yet one patient in every four still relapses. Except treatment response and immunophenotype, few markers are reliably prognostic in pediatric T-ALL patients. Aiming to improve T-ALL risk stratification, we investigated a new candidate biomarker with potential prognostic relevance. A phosphoproteomic screening of 98 pediatric T-ALL samples at diagnosis had been performed using the high-throughput Reverse Phase Protein Arrays technique, which led to the identification of PKCαS657 as an activated protein with a broad variation among T-ALL samples. To evaluate PKCα potential as a prognostic biomarker, PKCα expression was analyzed using RQ-PCR in a cohort of 173 patients, representative of ALL2000-ALLR2006 AIEOP study. A threshold of PKCα expression with the highest discrimination for incidence of relapse was identified. Patients with PKCα down-regulation, compared to patients with PKCα levels above the threshold, presented a markedly increased cumulative incidence of relapse (43.8% vs. 10.9%, P

Background: Immune Thrombocytopenia (ITP) is one of the most common conditions encoutered by the pediatric hematologist. Current first-line therapy includes: observation without drug therapy, corticosteroids and intravenous immune globulin. A minority of patients are refractory to first-line approaches. Second-line treatment options are: immunosuppressive agents and thrombopoietin receptor agonists (TPO-RA). Eltrombopag and Romiplostin are TPO-RA licensed for clinical use. Eltrombopag is, actually, the only TPO-RA approved in Italy (since two years ago) for children, over one year old, with a chronic and/or refractory ITP. Real life data of Eltrombopag are limited. Methods: We performed an Italian multicenter retrospective survey to study the clinical on-label use of TPO-RA, focus on Eltrombopag, in pediatric ITP. Our aims were, primarily, to bring out the prevalence of the use in clinical practice and secondarily to collect data on efficacy and toxicity. Results: We enrolled 69 pediatric ITP subjects from 15 Italian treatment centers (TC). 4 patients received Romiplostin as TPO-RA and were excluded by the analysis. 36/65 patients weer female (55%). Median age at ITP diagnosis: 6 years + 6 months (min 1 y + 2 m; max 16 y + 7 m). Median age at first Eltrombopag assumption: 11 years + 5 months (min 2 y + 0 m; max 17 y + 8 m). Accounting in 344 the total number of chronic ITP subjects treated by TC in the same observation period (July 2016-June 2018), we observed an Eltrombopag clinical use prevalence of 0.19 (95% CI 0.15 to 0.26). We underlined a "no response" to Eltrombopag (platelet count persistently less than 30000 per microliter) in 16/65 (25%); a "partial response" (platelet count between 30000 and 100000 per microliter) in 14/65 (21%) and a "complete response" (platelet count persistently up than 100000 per microliter) in 35/65 (54%). The overall response (partial or complete) was described in 49/65 (75%) children. During the follow up was seen in 16/49 (33%) subjects with initial response a platelet rise that waned to no response. There was no evidence of significant adverse events (clinicians are obliged, to monthly surveillance, by Italian drug agency for hypertransaminasemia and peripheral smear cell abnormalities). Conclusions: Our results demonstrate that Eltrombopag is a therapeutic option quite considered by Italian clinicians. Moreover, according with the percentages of clinical trials, Eltrombopag is safe and effective to rise platelet count. Further studies need to emphasize how factors favor a complete response and to know the incidence of long-term adverse effects. A prospective study designed and driven by Italian Association of Pediatric Hematology Oncology (AIEOP) Coagulation Disorders Working Group is, already, in progress. Disclosures No relevant conflicts of interest to declare.

Before 2000, allogeneic hematopoietic stem cell transplantation (HSCT) was the only potentially curative treatment for children with chronic myeloid leukemia (CML) in chronic phase (CP). The availability of imatinib (IM) and thereafter of second-generation (2G) tyrosine kinase inhibitors (TKIs) has extended therapeutic options for childhood CML. Experience with IM in managing children and adolescents with CP-CML resistant or intolerant to interferon treatment treated prompted us to outline guidelines with the aim of offering a uniform management approach for this category of patients (pts). IM was scheduled in newly diagnosed pts with CML in CP, including those with an HLA identical sibling (HLA+). Cytogenetics on bone marrow (BM) and molecular analysis on peripheral blood (PB) and on BM were suggested at planned time-points. These guidelines have been shared with both pediatric referral centers (P Centers) and reference center for adults and children (AP Centers) in Italy. The guidelines, summarized in Figure 1, have been updated over the years (yrs), with the contribution of colleagues managing adult CML. Fifty-seven CP-CML pts with a median age of 11.4 yrs, diagnosed between March 2001 and June 2015, were managed at 9 P centers (34 pts) and at 4 AP Centers (23 pts). All pts, including 16 with an HLA+, started IM that was discontinued early in 2 pts due to toxicity. HSCT from an HLA+ donor was performed in 2 pts in CP. A bone marrow aspirate at 3, 6, 9, 12, 18, 24 months was carried out in 85.5%, 98%, 83.5%, 100%, 95% and 94% of pts, respectively. Rates of molecular assessments on BM at 3, 6, 9, 12, 18 and 24 months were 73%, 78%, 92%, 84%, 86% and 100% of pts, respectively, significantly higher at 6 and 9 months in pts followed at P centers compared to those followed at AP centers. Cytogenetic evaluation rates at the same time points were 69%, 80%, 81%, 82% 73% and 75%, respectively, significantly higher in pts followed at AP centers compared to those followed at P centers. Rates of molecular assessments on PB at 3, 6, 9, 12, 18 and 24 months were 50%, 54%, 57%, 60%, 64% and 69% of pts, respectively, higher in pts followed at AP centers compared to those followed at P centers. Four pts (1 with HLA+) resistant to IM were rescued with 2G TKI and 3 of them then underwent a HSCT. Fifty pts (92.5%), including 13 HLA+ pts, achieved a cytogenetic or molecular (MR). Seven of the 50 responders (14%) underwent a HSCT from an HLA+ (6 pts) or from a matched unrelated donor (MUD), all in P centers before 2009. Seven HLA+ pts continued IM: in 3 it was given intermittently and thereafter discontinued in 1. Among the 36 responders without a HLA-identical sibling (HLA-), 10 pts (persistent MR, 2 pts; late side effects, 5 pts; poor compliance, 3pts) started intermittent IM, that was discontinued in 3 of them with deep MR. Overall, 18/36 (50%) pts failed IM: 2 had late toxicity and 16 (44%) developed disease recurrence (5 on intermittent IM and 1 pt after IM discontinuation). BCR-ABL1 mutation analysis was carried out in 11 pts: BCR-ABL1E255K combined with BCR-ABL1F359Vmutations were found in 1 pt and BCR-ABL135INS in 5 pts. Eleven pts were rescued with 2G TKIs (Dasatinib, 5 pts; Nilotinib, 6 pts), 5 pts restarted continuous IM and 2pts underwent a HSCT from a MUD. All 57 pts are alive at a median follow-up of 72 months (range, 12-184): 15 pts (26%) after a HSCT (HLA+, 9 pts; MUD, 6), 4 pts (7%) are treatment-free (1 pt after nilotinib), 27 pts (47.5%) are still receiving IM (continuous, 22 pts; intermittent, 5 pts), 10 pts (17.5%) are on treatment with 2G TKIs (dasatinib, 5 pts; nilotinib, 5 pts) and 1 pt with BCR-ABL1E255K and BCR-ABL1F359Vmutations is on third-line treatment with ponatinib. Our experience shows that pediatric guidelines are an important management tool for children and adolescents with CP-CML. Over the years, exchange of experience for monitoring and treatment of pediatric CP-CML with colleagues managing adult pts has contributed to update management strategies for this particular category of pts. Furthermore, exchange of knowledge and debate concerning some clinical situations within our network has allowed to have a progressively uniform approach for children and adolescents followed in these 13 Italian centers. Taking into account the rarity of the condition, shared pediatric guidelines and exchanges of experience and knowledge with adult hematologists will further contribute to an optimal management of childhood CML. Disclosures Biondi: BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Cellgene: Other: Advisory Board. Saglio:Ariad: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy. Foà:BMS: Consultancy; Ariad: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy; Gilead: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

Infection is a significant cause of death in patients with aplastic anaemia (AA). However, few studies have examined the characteristics of infections in patients with AA, especially in children. The aim of this retrospective study was to evaluate the incidence and types of infections in a large cohort of paediatric patients with AA referred to eight AIEOP (Italian Association of Paediatric Oncology and Haematology) centres in Italy. The study included 78 patients, 45 boys and 33 girls, median age 9.29 yrs (1st–3rd quartile 3.59– 13.09) diagnosed with AA. During the study period, 111 infectious episodes were observed in 42 (54%) patients. Fifty-one (46%) episodes were fever of unknown origin and 60 (54%) were documented infections (DI). In this group, microbiologically documented infection (MDI) with bacteremia accounted for 23 (38%) episodes, MDI without bacteremia for 7 (12%), clinically documented infection for 25 (42%) and invasive fungal diseases for 5 (8%). The rate (episodes ⁄ 1000 d at risk) was similar in severe aplastic anemia and very severe aplastic anemia both before and after day 120. During the first 120 d from diagnosis, the cumulative risk of a DI was 21% (95% CI 12–29) with the last episode at day 117, but the 50% of episodes were observed in the first 24 d. After day 120, the cumulative risk of DI was again 21% (95% CI 12–29), with the last episode at day 445 of follow-up, with 50% of episodes observed in the first 120 d of observation (240 d from the diagnosis of AA). We found a statistically significant association between the grade of aplasia at diagnosis and the incidence of IEs (P = 0.0002). No association was found between gender, age at diagnosis, response at day +120 and at day +180, use of G-CSF and occurrence of IEs. The actuarial overall survival at 5 yrs was 90% ± 3.6. The mortality rate attributable to infection complication was 9%. This is a large paediatric cohort study reporting the epidemiology of infectious complications in children with AA and that allow us to compare the epidemiological data in this diseases with that of the most recent studies in neutropenic children with cancer. Our findings confirm that infections represent the main cause of death in patients with AA and they are important for the design of management strategies of febrile neutropenia in these patients.

Acquired aplastic anemia (AA) is a rare heterogeneous disease characterized by pancytopenia and hypoplastic bone marrow. The incidence is 2-3/million inhabitants/year, in Europe, but higher in East Asia. Survival in severe aplastic anemia (SAA) has markedly improved in the past 2 decades because of advances in hematopoietic stem cell transplantation, immunosuppressive and biologic drugs, and supportive care. In SAA hematopoietic stem cell transplant (HSCT) from a matched sibling donor (MSD) is the treatment of choice. If a MSD is not available, the options include immunosuppressive therapy (IST) or unrelated donor HSCT. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of pediatric patients with AA. A preliminary, evidence-based document issued by a group of pediatric hematologists was discussed, modified and approved during a series of "Consensus Conferences" according to procedures previously validated by the AIEOP Board. The guidelines highlight the importance of referring pediatric patients with AA to pediatric centers with long experience in diagnosis, differential diagnosis, management, supportive care and follow-up of AA.

Imatinib mesylate (IM) is used for the management of childhood chronic myeloid leukaemia (CML). The most effective dosage of IM and its long-term efficacy in children are not well defined. The purpose of this multicentre study is to report on the long-term results of high-dose IM (340 mg/m2 /d) in CML patients in chronic phase (CP-CML) aged

Summary Sporadic essential thrombocythaemia (ET) is rare in paediatrics, and the diagnostic and clinical approach to paediatric cases cannot be simply copied from experience with adults. Here, we assessed 89 children with a clinical diagnosis of ET and found that 23 patients (25·8%) had a clonal disease. The JAK2 V617F mutation was identified in 14 children, 1 child had the MPL W515L mutation, and 6 had CALR mutations. The monoclonal X-chromosome inactivation pattern was seen in six patients (two with JAK2 V617F and two with CALR mutations). The other 66 patients (74·2%) had persistent thrombocytosis with no clonality. There were no clinical or haematological differences between the clonal and non-clonal patients. The relative proportion of ET-specific mutations in the clonal children was much the same as in adults. The higher prevalence of non-clonal cases suggests that some patients may not have myeloproliferative neoplasms, with significant implications for their treatment.

The outcome of children with acute lymphoblastic leukaemia (ALL) and early relapse remains unsatisfactory. In January 1995, the AIEOP (Associazione Italiana di Oncologia ed Ematologia Pediatrica) group opened a trial for children with ALL in first isolated or combined bone marrow relapse defined at high risk according to the length of first remission and the immunophenotype. The treatment plan included the combination of a single high-dose idarubicin and high-dose cytarabine as induction therapy followed by an intensive consolidation and stem cell transplant (SCT). In total, 100 children from 16 Italian centres were enrolled; 80 out of the 99 evaluable patients (81%) achieved second complete remission; eight (8%) died during induction and 11 (11%) failed to respond. A total of 42 out of the 80 responders (52.5%) received a SCT: 19 from an identical sibling, 11 from a matched unrelated donor and 12 from umbilical cord blood cells. The estimated 4-year overall survival and event-free survival were 25% and 21% respectively. Disease-free survival at 4 years was 25.8% for the 80 responders. At 4 years, 39 out of 100 children remain alive, with 27 of them free of leukaemia. This induction therapy has shown antileukaemic efficacy with acceptable toxicity; moreover, all responders proved eligible for intensive consolidation.

Imatinib (IM) is an established first-line treatment for children with chronic myeloid leukemia (CML). However, the most effective dosage of IM and overall management of newly-diagnosed childhood CML in chronic phase (CP) are not well defined. This study was designed to evaluate (a) the response to IM at a dosage equivalent in terms of drug exposure to the 600 mg daily utilized in adults and (b) the long-term outcome in newly-diagnosed children and adolescents with CML. Patients aged Between December 2002 and February 2014, 41 CML patients in CP (females: 13, males: 28; age 24 months. IM was started in all patients, including 16 with an HLA-matched sibling. The dosage of IM was modulated according to the occurrence of >2 WHO side-effects or response, mainly during the first 6 months of treatment. Forty patients are evaluable for treatment results. Median administered dosage of IM was 309 mg/m2/day, higher in males than in females (326 mg/m2vs 245 mg/m2, p .015) and in those younger than 10 years (314 mg/m2vs 262 mg/m2). Twenty-four patients (60%) experienced isolated or combined side effects: hematologic toxicity (medullary hypoplasia [n=1], neutropenia [n=7] and/or thrombocytopenia [n=6], anemia [n=1]) and/or extra-hematologic toxicity (arthralgia/myalgia [n=8], nausea [n=1], vomiting [n=1], diarrhea [n=1], abdominal pain [n=2], hepatitis [n=1], skin rash [n=2]. Persistent >3 WHO adverse events led to IM discontinuation in 6 patients (15%). At 3 months of IM treatment, hematologic response and PCyR rates were 91% and 54%, respectively; BCR-ABL1 transcript levels 7years successfully discontinued IM and 2 patients resumed continuous IM because of an increased BCR-ABL transcript. IM was interrupted in 8/33 (24%) responder patients, 4 of them in BCR-ABL1 IS In our experience, IM at a daily dose of 340 mg/m2 is effective in newly-diagnosed CML children with responses rates higher than those reported in children treated with IM at lower dosage. Considering the long-term follow-up, high-dose IM allowed to safely discontinue treatment in some patients with a deep MR; furthermore, it did not worsen the outcome both in patients submitted to a SCT and in those with disease progression or side-effects. Disclosures Saglio: BMS: Consultancy, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other.

Low levels of factor X (F.X) were detected in a 4-year-old boy who experienced acute lymphoblastic leukemia and bleeding manifestations. Laboratory data suggested the presence of a dysfunctional F.X molecule. Two novel F.X gene mutations were identified in the proband that was double heterozygous for both: a microdeletion (delC556) in exon VI resulting in a frameshift leading to a termination codon at position 226. This deletion was found in six family members with reduced F.X antigen and activity levels. A second mutation characterised by a G 1344 →C transversion in exon VIII was detected in the proband resulting in a Lys 408 →Asn substitution. This latter mutation was present in several asymptomatic family members from the paternal and the maternal side. The proband's sister was homozygous for the Lys 408 →Asn substitution and exhibited low F.X activity with a normal antigen level. The naturally occurring F.X Lys 408 →Asn (F.X K408N ) variant was isolated from plasma of either homozygous or double heterozygous individuals. NH 2 -terminal sequencing of the heavy chain of F.X K408N failed to show any sequence abnormality in patients who were also carriers of the delC556, suggesting that this latter lesion accounted for the lack of F.X synthesis. Purified F.X Lys 408 →Asn had an identical behaviour to normal F.X as judged by SDS–PAGE and immunoblotting. Clotting assay using purified F.X K408N and F.X-deficient plasma resulted in a laboratory phenotype similar to that observed in a homozygous subject for F.X Lys 408 →Asn substitution. This is the first characterisation of a naturally occurring F.X variant with a mutation at the COOH-terminal end of the molecule.

We describe a single center experience of 41 consecutive patients with poor prognosis acute myeloid leukemia (AML) who received a single course of FLAG regimen consisting of Fludarabine 30 mg/m2/day plus Cytarabine 2 gr/m2/day (days 1-5) and G-CSF 5 mg/Kg/day (from day 0 to polymorphonuclear recovery) as salvage therapy. Eleven patients were primarily refractory to previous chemotherapy, 10 patients were in first relapse, 2 patients in second relapse and 7 patients in relapse after transplants. Eleven cases were defined as secondary AML (diagnosis of AML made after a preexisting diagnosis of myelodysplastic syndrome). The median age was 52.6 years (range 16-72); 29 patients were males and 12 females. Overall, 23 (56%) patients reached complete remission (CR), 3 patients died of infection (2) or hemorrhage (1) during induction, and 15 (36%) patients had resistant disease. The highest CR rates (80%) were obtained in relapsed cases; de novo and secondary AML registered 60% and 45% of CR rates, respectively. Patients achieving CR received a second FLAG course as consolidation and were submitted to an individualized program post-remission therapy, depending on the age and performance status. Hematological and non hematological toxicities were acceptable. In conclusion, our data confirm that FLAG is a an high effective treatment for poor prognosis AML and in young patients allows intensive post remissional therapy including allogeneic BMT.

Imatinib (IM) is an established first-line treatment for children with chronic myeloid leukemia (CML). However, the most effective dosage and duration of IM treatment are not well defined. This study was designed to evaluate the response to high-dose IM and long-term outcome in pediatric CML patients, previously untreated or resistant to IFN. Patients aged From March 2001 to February 2013, 45 CML patients in CP (18 females, 27 males; median age: 119/12 years) were recorded from 9 Italian pediatric centers. Eight patients had previously received IFN. IM was started in all patients, including 16 with an HLA-matched sibling. The dosage was modulated according to hematologic toxicity and/or appearance of WHO >2 side- effects, mostly during the first 6 months of treatment (median administered dose: 309 mg/m2/day). Hematologic toxicity (medullary hypoplasia[n=1], neutropenia [n=11] and/or thrombocytopenia [n=6], anemia [n=1]) was observed in14/44 evaluable patients (32%); 13 patients (29.5%) experienced isolated or combined side effects: arthralgia/myalgia (n=10), nausea (n=1), vomiting (n=1), diarrhea (n=1), hepatitis (n=1), edema (n=1). After 3 months of IM treatment, 7/25 of tested patients (28%) obtained complete cytogenetic response (CCyR). Overall, 34/36 evaluable patients (94%) obtained a CCyR at a median time of 6 months. A molecular response (12 months received IM at the same daily dosage for 3 weeks a month (intermittent therapy). IM given without interruption was resumed in 3 of these 9 patients because of an increased BCR-ABL transcript. The growth rate showed a delay in height, which recovered over time, in 6 children who received IM prior to puberty. Overall, IM was stopped in 22/44 evaluable patients (50%) because of various reasons: stem cell transplant (SCT) in 8 patients (3 in CP, 1 in CCyR, 3 in MMR, 1 in CMR); hematologic (n=2) or extra-hematologic toxicity (n=2) (WHO grading >3) during the first 6 months in 4; recurrent disease in 6 (3 increased BCR-ABL transcript, 2 cytogenetic relapse,1 blast crisis [BC]); no response in 1; CMR ( 88 months in 2 and pancreatitis in 1 patient in CMR for 75 months. Twelve patients underwent a SCT after a median time of 8 months: 8 from an identical siblings (5 responders to IM [1 CMR, 3 MMR, 1 CCyR]), 3 MUD (2 in CCyR and 1 in MMR) and 1 cord blood in CCyR after chemotherapy for CB. Three patients, transplanted from an identical sibling, had disease recurrence after 24 (molecular relapse), 36 (cytogenetic relapse) and 83 (BC) months, respectively. At the last follow-up, all patients are alive (CMR= 25; MMR=14; CCyR=3; minor CyR=2; too early=1) at a median of 52 months (range: 3-146). Of 42 patients evaluable for treatment, 23 are receiving IM at a dosage of 340 mg/m2 (4 intermittent IM); 11 are in CMR without any treatment (8 after SCT; 3 at 32, 33 and 50 months after IM discontinuation); 4 are in treatment with dasatinib, 3 with nilotinib and 1 with IFN. In our experience, higher dose IM is an effective treatment for childhood CP CML, associated with sustained responses. Moreover, IM can be safely discontinued in pediatric CML patients with a deep CMR lasting more than 7 years. For patients candidates to a SCT, IM provides a safe bridging option to transplant, at no increased risk. Since patients may lose their response, a close and regular monitoring should be performed, mostly for those who stop IM, as SCT and new TK inhibitors may be successfully employed in patients failing IM. Disclosures: Saglio: Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Reports in adults have shown that a BCR-ABL1 IS In order to confirm the relevance of this cut-off in the pediatric population treated with high-dose IM, we investigated the impact a cohort of children and adolescents with CML in chronic phase (CP) followed at 11 Italian Centers. Forty-four of 53 CP-CML patients treated with IM at a dose of 340 mg/m2/day who had available BCR-ABL1 levels at 3 months and had been followed for at least 12 months were included in this analysis. Cytogenetics were planned on bone marrow (BM) cells before and during IM therapy as well as molecular analysis on peripheral blood (PB) monthly and on BM every 3 months. Complete cytogenetic response (CCyR) was defined as the absence of Ph+ metaphases. Peripheral blood BCR-ABL1 levels were measured by quantitative RT-PCR assay expressed as International Scale (IS). Major molecular response (MMR) was defined as ≤0.1% BCR-ABL1 IS, while molecular response (MR) was considered as ≤0.01% BCR-ABL1 IS. Complete molecular response (CMR) was used to indicate levels of disease ≤0.0032% BCR-ABL1 IS or undetectable. BCR-ABL1 transcript levels Forty-four CP-CML patients - females: 17, males: 27; median age at diagnosis: 11.2 years (range: 3.1-15,8); median follow-up: 73.5 months (range:15-151.3) who had received IM at a median dose of 300 mg/m2/day (range: 140-380) were evaluable for molecular response. At 3 months of IM treatment, BCR-ABL1 transcript levels In conclusion, the high-doses of IM used in our study allowed to achieve better short and long term results in childhood CP-CML than those reported with lower doses of IM (Millot et al, 2014). Using such doses, the prognostic impact of a BCR-ABL1 IS Disclosures Saglio: BMS: Consultancy, Other: Fees for occasional speeches; Novartis: Consultancy, Other: Fees for occasional speeches; Pfizer: Consultancy, Other: Fees for occasional speeches ; ARIAD: Consultancy, Other: Fees for occasional speeches.