Improving Drug Safety in Pediatric and Young Adult Patients with Hemato-Oncological Diseases: A Prospective Study of Active Pharmacovigilance.

The acquisition of relevant pediatric clinical safety data is essential to ensure tolerable drug therapies. Comparing the real number of Adverse Drug Reaction (ADR) reports in clinical practice with the literature, the idea of ADR underreporting emerges. An active pharmacovigilance observational prospective study was conducted to assess the safety of oncology pharmacological prescriptions in patients aged 0-24 years at Institute for Maternal and Child Health IRCCS Burlo Garofolo in Trieste and IRCCS CRO National Cancer Institute in Aviano (Italy) between January 2021 and October 2023. Prescriptions and ADRs were evaluated by a multidisciplinary team. A total of 1218 prescriptions for 38 patients were analyzed, and 190 ADRs of grade 3-5 were collected. As compared to historical data, we registered a significant increase (p < 0.001) in the number of ADRs. The risk of ADR was 3.4 times higher in the case of off-label prescriptions compared to on-label ones (OR 3.4; [1.47; 7.89]; p-value = 0.004). The risks of error and near-miss were reported for 6.3% and 18.2% of total prescriptions, respectively. Of the total of 133 interactions, 47 (35.3%) resulted in ADRs. This study shows the importance of pro-active pharmacovigilance to efficiently highlight ADRs, and the fundamental role of multidisciplinary teams (oncologist, pharmacist, pharmacologist, pediatrician, nurse) in improving patients' safety during therapy.

Impact of Mercaptopurine Metabolites on Disease Outcome in the AIEOP-BFM ALL 2009 Protocol for Acute Lymphoblastic Leukemia.

In the maintenance phase of Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP)- Berlin-Frankfurt-Muenster (BFM) acute lymphoblastic leukemia (ALL) 2009 protocol, mercaptopurine (MP) is given at the planned dose of 50 mg/m2 /day; however, dose adjustments are routinely performed to target patients' white blood cells to the optimal range of 2,000-3,000 cells/µL. Pediatric patients with ALL (n = 290, age: median (1st-3rd quartile): 4.8 (3.0-8.1) years; boys: 56.9%) were enrolled mainly in 4 medium-large Italian pediatric hospitals; 14.1% of patients relapsed after a median (1st-3rd quartile) follow-up time of 4.43 (3.82-5.46) years from maintenance beginning. MP metabolites (thionucleotide (TGN) and methyl-derivatives (MMPN)) were measured in the erythrocytes of 387 blood samples of 200 patients by high performance liquid chromatography with ultraviolet detection. Single-nucleotide polymorphisms (SNPs; (rs1800462, rs1800460, and rs1142345 in TPMT gene, rs116855232 in NUDT15, rs1127354, rs7270101, rs6051702 in ITPA, and rs2413739 in PACSIN2) were characterized by Taqman SNP genotyping assays. Cox proportional hazard models did not show an impact of TGN levels and variability on relapse. In contrast, after multivariate analysis, relapse hazard ratio (HR) increased in children with ALL of the intermediate risk arm compared with those in standard risk arm (3.44, 95% confidence interval (CI), 1.31-9.05, P = 0.012), and in carriers of the PACSIN2 rs2413739 T allele compared with those with the CC genotype (heterozygotes CT: HR, 2.32, 95% CI, 0.90-5.97, P = 0.081; and homozygous TT: HR, 4.14, 95% CI, 1.54-11.11, P = 0.005). Future studies are needed to confirm the lack of impact of TGN levels and variability on relapse in the AIEOP-BFM ALL trials, and to clarify the mechanism of PACSIN2 rs2413739 on outcome.

Case report: Venetoclax therapy in a boy with acute myeloid leukemia in Shwachman Diamond syndrome.

Shwachman-Diamond syndrome (SDS) is a rare bone marrow failure syndrome characterized by exocrine pancreatic insufficiency, bone abnormalities, progressive cytopenia, and predispositions to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). AML, in these patients, is associated with a poor prognosis and with an increased risk of organ toxicity and infectious complications from chemotherapy and hematopoietic stem cell transplantation (HSCT), thus leading to high rates of treatment-related morbidity and mortality. The BCL-2 inhibitor venetoclax has revolutionized the treatment of AML in elderly adults, especially for treatment-naive elderly patients who are ineligible for intensive chemotherapy. There is limited evidence on the use of venetoclax in pediatric patients with SDS-related MDS or AML. Here, we report a case of a 14-year-old boy with SDS with AML arising from MDS. The patient was treated with two cycles of conventional chemotherapy with fludarabine and cytarabine with an initial good response but immediate relapse and substantial toxicity. Treatment with venetoclax and azacitidine was started, with a substantial reduction of leukemic burden (good response on peripheral leukemic infiltration and partial response in the bone marrow after one course). However, it was followed by multiple infectious complications and worsening of the general condition not allowing treatment to be continued, and the patient eventually died from multiorgan failure. With the limitations of observation of a single patient, our experience suggests that venetoclax/azacitidine combination therapy may represent a therapeutic possibility for patients with SDS and AML, even though it may be associated with significant toxicity.

Whole Lung Irradiation after High-Dose Busulfan/Melphalan in Ewing Sarcoma with Lung Metastases: An Italian Sarcoma Group and Associazione Italiana Ematologia Oncologia Pediatrica Joint Study.

PURPOSE: To analyze toxicity and outcome predictors in Ewing sarcoma patients with lung metastases treated with busulfan and melphalan (BU-MEL) followed by whole-lung irradiation (WLI). METHODS: This retrospective study included 68 lung metastatic Ewing Sarcoma patients who underwent WLI after BU-MEL with autologous stem cell transplantation, as part of two prospective and consecutive treatment protocols. WLI 12 Gy for <14 years old and 15 Gy for ≥14 years old patients were applied at least eight weeks after BU-MEL. Toxicity, overall survival (OS), event-free survival (EFS) and pulmonary relapse-free survival (PRFS) were estimated and analyzed. RESULTS: After WLI, grade 1-2 and grade 3 clinical toxicity was reported in 16.2% and 5.9% patients, respectively. The five-year OS, EFS and PRFS with 95% confidence interval (CI) were 69.8% (57.1-79.3), 61.2% (48.4-71.7) and 70.5% (56.3-80.8), respectively. Patients with good histological necrosis of the primary tumor after neoadjuvant chemotherapy showed a significant decreased risk of pulmonary relapse or death compared to patients with poor histological necrosis. CONCLUSIONS: WLI at recommended doses and time interval after BU-MEL is feasible and might contribute to the disease control in Ewing sarcoma with lung metastases and responsive disease. Further studies are needed to explore the treatment stratification based on the histological response of the primary tumor.

Case Report: Use of Anakinra in Multisystem Inflammatory Syndrome During COVID-19 Pandemic.

During COVID-19 outbreak, a large number of children with severe inflammatory disease has been reported. This condition, named Pediatric Multi-inflammatory Syndrome temporally associated with COVID-19 (PIMS-TS) or Multisystem Inflammatory Syndrome associated with Coronavirus Disease 2019 (MIS-C), shares some clinical features with Kawasaki disease and is frequently complicated by myocarditis or shock. It has been suggested that MIS-C belongs to the group of cytokine storm syndromes triggered by SARS-CoV-2 infection. So far, intravenous immunoglobulin (IVIG) and systemic glucocorticoids are the most common therapeutic approaches reported in this group of patients. However, the use of anakinra in patients with severe forms of COVID-19 is showing promising results. Here we reported two patients with multisystem inflammatory syndrome complicated with shock. Both the patients presented a poor response to IVIG and systemic glucocorticoids and received anakinra. Treatment with IL-1 receptor antagonist showed a rapid improvement of clinical conditions and biochemical analysis in both patients and demonstrated a good safety profile. Thus, we look forward for future controlled clinical trials with the aim to demonstrate the effectiveness of anakinra in patients with MIS-C and established precise criteria for its use.

The Challenge of Next Generation Sequencing in a Boy With Severe Mononucleosis and EBV-related Lymphoma.

A severe course of infectious mononucleosis should always lead up to the suspicion of a primary immunodeficiency. We describe the case of a boy with severe mononucleosis accompanied by the development of hemophagocytic lymphohistiocytosis and lymphoma. By whole exome sequencing, we identified a mutation of uncertain significance in CTPS2, a gene closely related to CTPS1, which is involved in a primary immune deficiency with susceptibility to herpesviruses. We discuss the challenge of a correct interpretation of data from whole exome sequencing, questioning whether the CTPS2 variant found in our patient is just an incidental finding or a mutation with variable penetrance.

A survey on hematology-oncology pediatric AIEOP centres: The challenge of posterior reversible encephalopathy syndrome.

OBJECTIVES: Posterior reversible encephalopathy syndrome (PRES) is one of the most common neurological complications in hematology-oncology pediatric patients. Despite an increasingly recognized occurrence, no clear consensus exists regarding how best to manage the syndrome, because most cases of PRES have reported in single-case reports or small series. Aim of this paper is to identify incidence, clinical features, management, and outcome of PRES in a large series of hematology-oncology pediatric patients. METHODS: The cases of PRES occurred in twelve centers of the Italian Association of Pediatric Hematology and Oncology were reported. RESULTS: One hundred and twenty-four cases of PRES in 112 pediatric patients were recorded with an incidence of 2.1% and 4.7%, respectively, in acute lymphoblastic leukemia in first complete remission and hematopoietic stem cell transplantation (HSCT). The majority of cases occurred after a cycle of chemotherapy rather than after stem cell transplant. PRES after chemotherapy significantly differs from that after HSCT for diagnosis, time of presentation, risk factors, management, and outcome. CONCLUSIONS: This study demonstrates that PRES is a common neurological complication and occurring preferentially in course of induction treatment of some hematologic malignancies, as ALL and after HSCT. It also highlights great clinical differences in the management and outcome in patients with PRES occurring after chemotherapy or after HSCT.

First description of Merkel Cell polyomavirus DNA detection in a patient with Stevens-Johnson syndrome.

Merkel Cell polyomavirus (MCPyV), a ubiquitous DNA tumor virus, has been found to be associated with Merkel cell carcinoma and chronic lymphocytic leukaemia while other associations are still being explored. MCPyV sequences have also been detected in normal tissues of tumor patients and in the blood of healthy donors. This report documents a new MCPyV association with the Stevens-Johnson syndrome, a rare immune-modulated mucocutaneous process particularly associated with specific drugs and infective agents. A high MCPyV viral load was detected simultaneously in fluid from skin lesions (2.0 × 10(4) copies/ml) and in matched blood (7.4 × 10(5) copies/ml) from a young adult patient after bone marrow transplant for a relapsed T-cell acute lymphatic leukaemia. MCPyV clearance concurred with the complete resolution of skin lesions after 5 days of cidofovir treatment. DNA sequencing classified the amplicons as the European/Italian MKL-1 strain. Given its ubiquitous nature, MCPyV could account for part of Stevens-Johnson syndrome idiopathic cases.

A singular case of congenital self-healing histiocytosis with skin, liver and atypical eye involvement.

PURPOSE: To describe a rare case of congenital self-healing Langerhans cell histiocytosis (CSHLCH) presenting with atypical eye involvement. DESIGN: Case report. METHODS: A female newborn presented with purpuric lesions over the trunk, limbs, and face. Liver ultrasonography revealed hypoechogenic lesions with blurred borders. Biomicroscopy showed right posterior synechiae with fibrinoid deposits on the lens. At 7 months she presented with right acute glaucoma. RESULTS: Biomicroscopy showed the presence of inflammatory pseudo-membrane covering the anterior surface of the lens, iris, and iridocorneal angle. Ab externo trabeculotomy was performed; access to the anterior chamber with capsulorrhexis forceps permitted a peeling of the pseudo-membrane with normalization of the intraocular pressure. Histologic examination of the membrane revealed an inflammatory tissue with CD1a and S-100 positive histiocytic cells. CONCLUSIONS: This is the first case of CSHLCH describing acute glaucoma secondary to a pseudo-inflammatory membrane with typical histiocytic cells, occluding the iridocorneal angle.

Marriage and parenthood among childhood cancer survivors: a report from the Italian AIEOP Off-Therapy Registry.

BACKGROUND: The aim of this study was to describe the patterns of marriage and parenthood in a cohort of childhood cancer survivors included in the Off-Therapy Registry maintained by the Italian Association of Pediatric Hematology and Oncology. DESIGN AND METHODS: We analyzed a cohort of 6,044 patients diagnosed with cancer between 1960 and 1998, while aged 0 to 14 years and who were 18 years old or older by December 2003. They were followed up through the regional vital statistics registers until death or the end of follow up (October 30, 2006), whichever occurred first, and their marital status and date of birth of their children were recorded. The cumulative probabilities of being married and having a first child were computed by gender and compared by tumor type within the cohort. Marriage and fertility rates (the latter defined as the number of live births per woman-year) were compared with those of the Italian population of the same age, gender, area of residence and calendar period by means of the observed to expected (O/E) ratios. RESULTS: During the follow-up period, 4,633 (77%) subjects had not married. The marriage O/E ratios were 0.56 (95% CI: 0.51-0.61) and 0.70 (95% CI: 0.65-0.76) among men and women, respectively. Overall, 263 men had 367 liveborn children, and 473 women had 697 liveborn children. The female fertility O/E ratio was 0.57 (95% CI: 0.53-0.62) overall, and 1.08 (95% CI: 0.99-1.17) when analyses were restricted to married/cohabiting women CONCLUSIONS: Childhood cancer survivors are less likely to marry and to have children than the general population, confirming the life-long impact of their previous disease on their social behavior and choices. The inclusion of counseling in the strategies of management and long-term surveillance of childhood cancer patients could be beneficial to survivors as they approach adulthood.

[Time trend in cancer incidence among 0-24 year-old residents of the Province of Trieste, Italy, 1972-2003]. / Andamento nel tempo dell'incidenza dei tumori maligni nei residenti nella Provincia di Trieste sotto i 25 anni d'età, 1972-2003.

OBJECTIVE: to report and analyse time trends in cancer incidence among children (0-14 years of age), adolescents (15-19 years) and young adults (20-24 years) living in the Italian province of Trieste (2003 population, 242,000), between 1972 and 2003. DESIGN: population-based study of descriptive epidemiology. SETTING AND PARTICIPANTS: the new cases of cancer diagnosed to the residents of the province of Trieste below 25 years of age were extracted from the database of the Trieste Cancer Registry (period 1972-1994) and from the database of the Friuli-Venezia Giulia Cancer Registry (period 1995-2003), according to the International Classification of Childhood Cancer (3rd edition). MAIN OUTCOME MEASURES: age-specific and age-standardized (Italian 1981 census population as standard) incidence rates, by diagnostic group, sex and period of diagnosis. Time trend in incidence was analysed by using a Poisson regression model adjusted for calendar year, sex and 5 year age-group, and was expressed as annual percent change (APC) in rates. RESULTS: in the period 1972-2003, the new cases of cancer were 168 in the age-group 0-14 years, 79 in the age-group 15-19 years and 111 in the age-group 20-24 years, while the person-years at risk were respectively: 1,050,027; 431,673; 496,450. The APC in the incidence of all cancers combined was 2.3% (IC 95% 0.6%-3.9%) in children, 4.4% (IC 95% 1.8%-7.1%) in adolescents and 5.1% (IC 95% 2.8%-7.5%) in young adults. Hodgkin lymphomas (APC =12.7%; IC 95% 2.6%-23.7%; 7 cases) in the age-group 0-14 years, skin melanomas and carcinomas (APC =8.2%; IC 95% 4.5%-12.0%; 49 cases) and central nervous system tumours (APC = 6.4%; IC 95% 1.5%-11.5%; 25 cases) in the age-group 15-24 years were the malignancies characterised by the highest increase in incidence. CONCLUSION: the increase in incidence rates observed in this study can be only partly explained by the small number of ascertained cases, by an improvement in diagnostic techniques and by more efficient registration. However, few environmental and hereditary factors are consistently associated with cancers affecting young people. Therefore, it is imperative to continue to carry out descriptive and analytical studies with primary prevention as the ultimate aim.

Uselessness of anti-actin antibody in celiac disease screening.

BACKGROUND: Serum anti-actin IgA antibodies (AAA) were identified in patients with celiac disease (CD), and a close correlation emerged between the presence of AAA and mucosa damage, but test for AAA found in celiacs have a wide range of sensitivity and specificity values. AIM: To compare 1) the sensitivity and specificity of untreated, calcium-chelated and heated sera from 102 celiacs, 52 sick patients and 103 healthy controls in the determination of AAA, and 2) the reliability of AAA with anti-transglutaminase antibodies (anti-tTG) in diagnosing celiac disease and in predicting intestinal damage. The intestinal derived AAA was isolated by using the phage-display library technique. RESULTS: Treated sera was significantly more sensitive than untreated (p=0.0001), and showed a significant correlation between AAA and the three degrees (3a, 3b, 3c) of intestinal damage (p=0.01). Sensitivity and specificity values of anti-tTG assay were higher than the AAA assay, and anti-tTG serum-concentration was only significantly correlated with more severe (3b and 3c) intestinal damage degrees. AAA isolated by phage display showed similar results of serum AAA in immunofluorescence assay. CONCLUSIONS: Notwithstanding correlation between AAA and celiac disease, AAA assay, also after treatments, has little to offer in screening for CD compared to the well-established anti-transglutaminase assay.