Outcome of relapsed/refractory acute promyelocytic leukaemia in children, adolescents and young adult patients — a 25‐year Italian experience

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Risk factors for endocrine complications in transfusion-dependent thalassemia patients on chelation therapy with deferasirox: a risk assessment study from a multicentre nation-wide cohort

Transfusion-dependent patients typically develop iron-induced cardiomyopathy, liver disease, and endocrine complications. We aimed to estimate the incidence of endocrine disorders in transfusion-dependent thalassemia (TDT) patients during long-term iron-chelation therapy with deferasirox (DFX).We developed a multicentre 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%CI=6.3-13.1). Multiple Cox regression analysis identified 3 key predictors: age showed a positive log-linear effect (adjusted HR for 50% increase=1.2, 95%CI=1.1-1.3, P=0.005), the serum concentration of thyrotropin (TSH) showed a positive linear effect (adjusted HR for 1 mIU/L increase=1.3, 95%CI=1.1-1.4, P

Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34+ cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34+ cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34+ cells infused and younger age at GT affected positively the plateau of CD3+ transduced cells, lymphocytes and CD4+ CD45RA+ naive T cells, whereas the cell dose positively influenced the final plateau of CD15+ transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT034786

Hemophagocytic inflammatory syndrome in ADA-SCID: report of two cases and literature review

Hemophagocytic inflammatory syndrome (HIS) is a rare form of secondary hemophagocytic lymphohistiocytosis caused by an impaired equilibrium between natural killer and cytotoxic T-cell activity, evolving in hypercytokinemia and multiorgan failure. In the context of inborn errors of immunity, HIS occurrence has been reported in severe combined immunodeficiency (SCID) patients, including two cases of adenosine deaminase deficient-SCID (ADA-SCID). Here we describe two additional pediatric cases of ADA-SCID patients who developed HIS. In the first case, HIS was triggered by infectious complications while the patient was on enzyme replacement therapy; the patient was treated with high-dose corticosteroids and intravenous immunoglobulins with HIS remission. However, the patient required HLA-identical sibling donor hematopoietic stem cell transplantation (HSCT) for a definitive cure of ADA-SCID, without HIS relapse up to 13 years after HSCT. The second patient presented HIS 2 years after hematopoietic stem cell gene therapy (GT), secondarily to Varicella-Zoster vaccination and despite CD4+ and CD8+ lymphocytes’ reconstitution in line with other ADA SCID patients treated with GT. The child responded to trilinear immunosuppressive therapy (corticosteroids, Cyclosporine A, Anakinra). We observed the persistence of gene-corrected cells up to 5 years post-GT, without HIS relapse. These new cases of children with HIS, together with those reported in the literature, support the hypothesis that a major dysregulation in the immune system can occur in ADA-SCID patients. Our cases show that early identification of the disease is imperative and that a variable degree of immunosuppression could be an effective treatment while allogeneic HSCT is required only in cases of refractoriness. A deeper knowledge of immunologic patterns contributing to HIS pathogenesis in ADA-SCID patients is desirable, to identify new targeted treatments and ensure patients’ long-term recovery

A case report of desmoplastic infantile astrocytoma/ganglioglioma in an infant: the gentle giant

Brain tumours are the most frequent solid tumours and the first cause of cancer-related death in childhood. Their diagnosis has been increasing due to the improvement of diagnostic tools. Low-grade gliomas and embryonal tumours are the most frequent (50% and 20%, respectively). A 10-month-old male presented with hyporeactivity, drowsiness, right arm hypomobility and inappetence. Hospitalised, his Fundus Oculi which showed papilla with regular margins, lightly congested and raised. EEG revealed slow track and specific activity in the back left temporal region. Gadolinium-MRI of the brain revealed a cystic tumour of 7 × 9×12 cm, with intense and heterogeneous enhancement that involved the left cerebral hemisphere. The mass compressed the left and third ventricle and the brainstem was shifted beyond the median line. The right ventricle was expanded and there was sweating of cerebrospinal fluid for the Monro’s foramen obstruction. The patient underwent complete exeresis of tumour. Histology confirmed diagnosis of Desmoplastic Infantile Astrocytoma/Ganglioglioma (DIA/DIG), grade I WHO. Immunophenotype: astrocytic (GFAP, Vimentin), neuronal (synaptophysin). MIB-1: 5%. After hospitalisation, the patient started rehabilitation with a gradual recovery of motor functions. Actually at 30 months of follow up the patient is free of disease and healthy. DIA/DIG is a rare paediatric brain tumour (1.25% of brain tumours), characterised by divergent glioneuronal differentiation and intense desmoplasia. Superficial in location and affecting mainly the frontotemporal region, it presents as a large, cystic, often dura-attached mass in patients younger than 2 years of age. On MRI, they are large hypodense cystic masses with a solid isodense or slightly hyperdense superficial portion. The histologic diagnosis is characterised by the presence of astrocytic, neuronal, and primitive neuroectodermal markers. The treatment of choice is radical surgical excision, which does not require additional treatment. Post-operative clinical and MRI controls should be used when only partial tumour removal can be performed; indeed, long-term stability or complete disappearance of the tumour residual may follow even an incomplete surgical tumour removal. Chemotherapy is used in partial exeresis and progressive disease; radiotherapy is a last resource. DIA/DIG diagnosis is crucial as they share some neuroradiological and histological findings of malignant brain tumours

Autoimmune lymphoproliferative syndrome (ALPS) in a child: a new disorder to ‘climb’

Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder of the immune system caused by a mutation in the Fas apoptotic pathway. It can present with a wide range of clinical manifestations, including noninfectious nonmalignant lymphoadenopathy, splenomegaly and autoimmune pathology (frequently autoimmune citopenias). Revised diagnostic criteria allowed an improvement in its management. A 3-year-old boy was hospitalised for severe isolated thrombocytopenia (PLT 8000/mcl) and hemorragic syndrome. On physical examination, he had inguinal limphoadenopathy. His blood exams showed positivity for autoimmunity and normal lymphocyte population. Bone marrow aspirate revealed an immune throbocytopenia, so he started treatment with Immunoglobulins (Ig), with a good response. We performed an exeresis of his inguinal lymph node, increasing in dimensions, and found reactive follicular hyperplasia with dermatopathic aspects in absence of neoplasy. After one month, thrombocytopenia associated with neutropenia (N 800/mcl), positivity of direct and indirect Coombs test, anti-neutrophils antibodies negatives and splenomegaly on sonography. He assumed steroids for 2 weeks, with a good response. After 4 months, he presented again with thrombocytopenia, associated with emolitic autoimmune anaemia (Hb 5,2 g/dl) so he began therapy with Ig and steroids, with initial good response. Two months after stop therapy, new episode of thrombocytopenia, hemorragic syndrome and an increase of his splenomegaly. Therefore, we performed FAS-induced apoptosis test (negative) and researched double negative lymphocites that were positive (CD3+TCRαβ+CD4-CD8-:3,5%; CD19+CD27+:4,8%; CD3+CD25+/CD3+HLADR+ ratio:0,1%). He started therapy with mycophenolate mofetil and with Ig on demand. As we obteined a poor response, we shifted it to syrolimus, with progressive reduction of splenomegaly and increase of PLT. ALPS is a rare pathology that should be investigated in children with autoimmune citopenias and nonmalignant limphoproliferation. Its various clinical manifestations complicate diagnosis and treatment. First line treatment includes prednisone and Ig; for unresponsive patients mycophenolate mofetil and syrolimus are effective, the latter in children with refractory multilineage autoimmune cytopenias. Research over the past decades have increased our knowledge on its pathophysiology resulting in an improvement of its management. Its diagnosis is indeed crucial as ALPS may progress to lymphoma

A case of rare meningioangiomatosis associated with cortical dysplasia

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

Un esordio insidioso di epatite autoimmune

Bambina di 9 anni veniva ricoverata presso la Pediatria di altro Ospedale per tosse persistente. Anamnesi personale e familiare muta. All’esame obiettivo importante splenomegalia ed epatomegalia. Gli esami ematici evidenziavano pancitopenia (GB 3830/mcl, Hb 9,5 g/dl, PLT 81000/mcl), coagulazione alterata (PT INR 1,62), transaminasi aumentate (GPT/GOT 372/1274 UI/l), indici di flogosi e Rx torace negativi. Nel sospetto di malattia ematologia, veniva trasferita presso l’Oncoematologia pediatrica del nostro Ospedale. Veniva eseguita un’ecografia addominale con ecocolordoppler con riscontro di epatomegalia con ecostruttura disomogenea e splenomegalia (dl 19 cm) con asse splenoportale di calibro aumentato, epatopeto come da ipertensione portale. Aspirato midollare, ceruloplasmina, alfa1antitripsina, esami infettivologici per virus epatotropi negativi; mentre riscontro di ipergammaglobulinemia, iperIgG, segni di deficit di sintesi epatica con modesta coagulopatia ed iperbilirubinemia diretta, positivita di ASMA, ANA ed ANCA. Un esame obiettivo mirato mostrava cute subitterica, eritema palmare e spider nevi al volto ed agli arti superiori. Nel sospetto di epatite autoimmune (EA), la piccola veniva trasferita nella nostra UOC di Pediatria e sottoposta a biopsia epatica con esame istologico compatibile col sospetto diagnostico. A completamento si eseguivano Colangio-RM, ileo-colonscopia ed EGDS che escludevano, rispettivamente, alterazioni a carico dei dotti biliari, MICI e segni endoscopici di ipertensione portale. Si avviava terapia con prednisone, vitamina K ed acido ursodesossicolico. L’iniziale follow-up ha documentato una rapida e brillante risposta alla terapia. L’EA e una patologia infiammatoria progressiva del fegato ad eziologia sconosciuta, caratterizzata da incremento di transaminasi, gammaglobuline ed autoanticorpi e, istologicamente, da epatite da interfaccia. In base al tipo di autoanticorpi si distinguono due tipi di EA: tipo 1 (ANA e/o SMA); tipo 2 (LKM1 e/o LC1). Devono essere escluse altre cause di epatopatia con quadro sovrapponibile (epatiti virali, malattia di Wilson, NAFLD, deficit di alfa1antitripsina, epatiti da farmaci)1,2. Nel 40% dei casi l’esordio puo essere insidioso con astenia, malessere, prurito, artralgie, addominalgia ed ittero incostante. Inoltre, puo essere caratterizzato dal riscontro accidentale di aumento delle transaminasi in assenza di sintomi specifici, in corso di indagini per altra patologia. In una minoranza di casi l’EA si puo presentare con splenomegalia e pancitopenia, che possono orientare per malignita oncoematologiche2. L’EA risponde bene alla terapia immunosoppressiva se iniziata tempestivamente. Una rapida e completa remissione indotta con appropriata terapia migliora la prognosi, controllando l’evoluzione della fibrosi. Pertanto, e fondamentale considerare l’EA anche nei quadri piu sfumati dal momento che una diagnosi ritardata comporta un trattamento tardivo con maggiore probabilita di evoluzione verso il trapianto di fegato