Nicoletta Masera

Adrenal axis function after high-dose steroid therapy for childhood acute lymphoblastic leukemia

Background A 4‐week course of high‐dose glucocorticoids may cause prolonged adrenal suppression even after a 9‐day tapering phase. In this study, adrenal function and signs and symptoms of adrenal insufficiency were prospectively assessed in children with acute lymphoblastic leukemia (ALL) after induction treatment including high‐dose prednisone (PDN) or dexamethasone (DXM). Procedures Sixty‐four children with ALL, treated according to the AIEOP ALL 2000 Study protocol, underwent low dose ACTH (LD‐ACTH) stimulation 24 hr after the last tapered steroid dose. In those with impaired cortisol response, additional LD ACTH tests were performed every 1–2 weeks until cortisol levels normalized. Signs and symptoms of adrenal insufficiency were recorded during the observation period. Results All patients had normal basal cortisol values at diagnosis. Twenty‐four hours after last glucocorticoid dose, morning cortisol was reduced in 40/64 (62.5%) patients. LD‐ACTH testing showed adrenal suppression in 52/64 (81.5%) patients. At the following ACTH test 7–14 days later, morning cortisol values were reduced in 8/52 (15.4%) patients and response to the test was impaired in 12/52 (23%). Adrenal function completely recovered in all patients within 10 weeks. No difference was found between patients treated with PDN or DXM. Almost 35% of children with impaired cortisol values at the first test developed signs or symptoms of adrenal insufficiency. One child developed a severe adrenal crisis during adrenal suppression. Conclusions High‐dose glucocorticoid therapy in ALL children may cause prolonged adrenal suppression and related clinical symptoms. Laboratory monitoring of cortisol levels and steroid coverage during stress episodes may be indicated. Pediatr Blood Cancer 2008;50:537–541.

Optimal response to thalidomide in a patient with thalassaemia major resistant to conventional therapy.

Beta-thalassaemia major is a hereditary anaemia resulting from defects in β-globin production. The coexistence of hereditary persistence of foetal haemoglobin (HbF) during adult life in patients with β-thalassaemia reduces the severity of the disease; these patients have a mild disorder, sometimes not even requiring chronic transfusions. The clinical benefit of increased HbF, first inferred in 19761, is due to a decrease in the imbalance between β and non-β-chains and the consequent reduction of haemolysis. Many drugs have been studied as inducers of HbF for patients with β-thalassaemia and sickle cell disease. Hydroxyurea is currently used in moderate to severe forms of sickle cell disease2,3 and in some cases of thalassaemia intermedia4,5. Other inducers of HbF synthesis, such as butyrate6, 5-azacytidine7 and, more recently, decitabine, have also been shown to induce HbF in patients with sickle cell disease8. However, these HbF inducers have shown only a modest effect in the majority of β-thalassaemia patients as well as some degree of toxicity. As a result, they have not been used routinely in clinical practice. Thalidomide, a drug known for its immunomodulating and anti-angiogenic properties, has recently been demonstrated to induce γ-globin gene expression and to increase the proliferation of erythroid cells9,10. Only one patient affected by β-thalassaemia major treated successfully with thalidomide has been described so far11. n nWe report here the case of a young girl with β-thalassaemia (β+/β°) in a very severe clinical condition who could not be given any further transfusions because of the occurrence of severe post-transfusion reactions and who showed an outstanding response to thalidomide.

Distinctive characteristics of diabetes mellitus after hematopoietic cell transplantation during childhood

Abstract:u2002 We report on six patients who developed diabetes mellitus after hematopoietic cell transplantation (HCT). The prevalence in our cohort of long‐term survivors after HCT performed below 18u2003yr of age was 3%. The median age at onset of diabetes was 22.4u2003yr (range 11.3–34.4). The median period between HCT and diabetes was 10.1u2003yr (range 5.6–22.1). Five out of the six patients received total irradiation therapy and five had other endocrinological abnormalities. The onset of diabetes in all patients was insidious and none had diabetic ketoacidosis. Body mass indexes at diabetes onset were within normal levels. The clinical and laboratory features that characterized our patients with diabetes after HCT make it difficult to classify them as having type‐1 or type‐2 diabetes. The relatively high prevalence of diabetes and its insidious onset in this group of patients, advocate clinicians to evaluate carefully even slight variations in fasting blood glucose, usually included in the routine biochemistry follow‐up. These data also suggest that HbA1c and oral glucose‐tolerance test should be added to the follow‐up program of late complications if fasting blood glucose levels are slightly increased.

Agranulocytosis due to deferiprone: a case report with cytomorphological and functional bone marrow examination.

Deferiprone is an effective oral iron chelator which plays a particularly important role in the removal of cardiac iron burden in thalassaemic patients with transfusional iron overload1–5. Agranulocytosis, of uncertain pathogenesis, is its most important and severe side effect, reported in less than 2% of cases. Only a few such cases have so far been described in detail6–11: of these, the most recently reported was a case of fatal secondary agranulocytosis occurring in a child affected by Blackfan-Diamond anaemia11. n nIn this report we describe a case of agranulocytosis due to deferiprone in a child with β-thalassaemia treated at our Centre.

Organizing national responses for rare blood disorders: the Italian experience with sickle cell disease in childhood

BackgroundSickle cell disease (SCD) is the most frequent hemoglobinopathy worldwide but remains a rare blood disorder in most western countries. Recommendations for standard of care have been produced in the United States, the United Kingdom and France, where this disease is relatively frequent because of earlier immigration from Africa. These recommendations have changed the clinical course of SCD but can be difficult to apply in other contexts. The Italian Association of Pediatric Hematology Oncology (AIEOP) decided to develop a common national response to the rising number of SCD patients in Italy with the following objectives: 1) to create a national working group focused on pediatric SCD, and 2) to develop tailored guidelines for the management of SCD that could be accessed and practiced by those involved in the care of children with SCD in Italy.MethodsGuidelines, adapted to the Italian social context and health system, were developed by 22 pediatric hematologists representing 54 AIEOP centers across Italy. The group met five times for a total of 128xa0hours in 22xa0months; documents and opinions were circulated via web.ResultsRecommendations regarding the prevention and treatment of the most relevant complications of SCD in childhood adapted to the Italian context and health system were produced.For each topic, a pathway of diagnosis and care is detailed, and a selection of health management issues crucial to Italy or different from other countries is described (i.e., use of alternatives for infection prophylaxis because of the lack of oral penicillin in Italy).ConclusionsCreating a network of physicians involved in the day-to-day care of children with SCD is feasible in a country where it remains rare. Providing hematologists, primary and secondary care physicians, and caregivers across the country with web-based guidelines for the management of SCD tailored to the Italian context is the first step in building a sustainable response to a rare but emerging childhood blood disorder and in implementing the World Health Organization’s suggestion “to design (and) implement … comprehensive national integrated programs for the prevention and management of SCD.

An attempt to induce transient immunosuppression pre-erythrocytapheresis in a girl with sickle cell disease, a history of severe delayed hemolytic transfusion reactions and need for hip prosthesis

Abstract We report on a case of delayed hemolytic transfusion reaction (DHTR) occurred 7 days after an erythrocytapheresis or eritroexchange procedure (EEX) treated with rituximab and glucocorticoids in a 15-years old patient with sickle cell disease. EEX was performed despite a previous diagnosis of alloimmunization, in order to reduce hemoglobin S rate before a major surgery for avascular necrosis of the femoral head. A first dose of rituximab was administered before EEX. However, rituximab couldn’t prevent DHTR that occurred with acute hemolysis, hemoglobinuria and hyperbilirubinemia. A further dose of rituximab and three boli of methylprednisolone were given after the onset of the reaction. It is likely that the combined use of rituximab and steroids managed to gradually improve both patient’s general conditions and hemoglobin levels. Nor early or late side effects were registered in a 33-months follow-up period. This report suggests the potential effectiveness and safety of rituximab in combination with steroids in managing and mitigating the symptoms of delayed post-transfusional hemolytic reactions in alloimmunized patients affected by sickle cell disease with absolute need for erythrocytapheresis.

Lessons learned from the H1N1 pandemic: the need to improve systematic vaccination in Sickle Cell Disease children. A multi center survey in Italy.

During the recent H1N1 pandemic, children with Sickle Cell Disease (SCD) experienced more hospitalizations and more complications than the general pediatric population. We performed a retrospective multicenter survey at 9 Pediatric Haematology-Oncology Units across Italy. H1N1 admission rate was 5.2%, with all admissions occurring before vaccine availability. Length Of Stay (LOS) was 6.06 days (7.85 for Acute Chest Syndrome), longer than in other countries. Vaccination coverage was not homogeneous, ranging from 0 to 99%; several family-related and health-system related barriers in accessing vaccinations were identified that should be ameliorated to improve coverage in this high risk group of children.

Hydroxyurea prescription, availability and use for children with sickle cell disease in Italy: Results of a National Multicenter survey

The number of patients with sickle cell disease (SCD) has increased in Italy in the past decade due to immigration. In spite of the established efficacy of hydroxyurea (HU) in childhood, population‐based data regarding its prescription and effectiveness come mainly from studies performed in adults or outside Europe.

Diagnosis & management of newly diagnosed childhood autoimmune haemolytic anaemia. Recommendations from the red cell study group of the paediatric haemato-oncology Italian association

Autoimmune haemolytic anaemia is an uncommon disorder to which paediatric haematology centres take a variety of diagnostic and therapeutic approaches. The Red Cell Working Group of the Italian Association of Paediatric Onco-haematology (Associazione Italiana di Ematologia ed Oncologia Pediatrica, AIEOP) developed this document in order to collate expert opinions on the management of newly diagnosed childhood autoimmune haemolytic anaemia.The diagnostic process includes the direct and indirect antiglobulin tests; recommendations are given regarding further diagnostic tests, specifically in the cases that the direct and indirect antiglobulin tests are negative. Clear-cut definitions of clinical response are stated. Specific recommendations for treatment include: dosage of steroid therapy and tapering modality for warm autoimmune haemolytic anaemia; the choice of rituximab as first-line therapy for the rare primary transfusion-dependent cold autoimmune haemolytic anaemia; the indications for supportive therapy; the need for switching to second-line therapy. Each statement is provided with a score expressing the level of appropriateness and the agreement among participants.

Real-life experience with hydroxyurea in sickle cell disease: A multicenter study in a cohort of patients with heterogeneous descent

We conducted the first nation-wide cohort study of sickle cell disease (SCD) in Italy, a Southern European country exposed to intense recent flux migration from endemic areas for SCD. We evaluate the impact of hydroxyurea on a total of 652 pediatric and adult patients from 33 Reference Centers for SCD (mean age 24.5±15years, 51.4% males). Hydroxyurea median treatment duration was 7years (range: <1year to 29years) at a mean therapeutic dose of 18±4.7mg/kg/day. Hydroxyurea was associated with a significant increase in mean total and fetal hemoglobin and a significant decrease in mean hemoglobin S, white blood and platelet counts, and lactate dehydrogenase levels. Hydroxyurea was associated with a significant reduction in the incidence of acute chest syndrome (-29.3%, p<0.001), vaso-occlusive crisis (-34.1%, p<0.001), hospitalization (-53.2%, p<0.001), and bone necrosis (-6.9%, p<0.001). New silent cerebral infarction (SCI) occurred during treatment (+42.4%, p<0.001) but not stroke (+0.5%, p=0.572). These observations were generally consistent upon stratification for age, descent (Caucasian or African), genotype (βS/βS, βS/β0 or βS/β+) and duration of treatment (< or ≥10years). There were no new safety concerns observed compared to those commonly reported in the literature. Our study, conducted on a large population of patients with different descent and compound state supports the benefits of hydroxyurea therapy as a treatment option. Registered at clinical trials.gov (NCT02709681).