Background High-dose methotrexate (HDMTX) for cancer treatment can be complicated by delayed methotrexate elimination (DME) and associated acute kidney injury (AKI). This study evaluated glucarpidase for the treatment of DME and HDMTX-AKI in pediatric hemato-oncology patients. Methods This multicenter, retrospective study reviewed the medical records of pediatric patients (1–18 years) with ALL or NHL, who were given glucarpidase as rescue therapy for DME or HDMTX-AKI at 13 Italian AIEOP centers between January 1, 2015, and June 30, 2023. Patients also received uniform supportive therapy, per study protocols and guidelines, to prevent and treat AKI. Results Data were available for 42/44 patients given glucarpidase, following i.v. HDMTX as monotherapy (non-high risk ALL [non-HR ALL], n=24), or within combined intensive chemotherapy blocks (HR-ALL, n=13; NHL, n=5). Median time to glucarpidase infusion was 53hours (range 32–72). Most patients required glucarpidase during the first cycle of HDMTX. Glucarpidase led to a rapid decrease in plasma MTX levels (median 72.53%; range 12.62%–94.57%). Median time for complete elimination of MTX and its metabolites was 216hours (range 120–672). Recovery of renal function (return of serum creatinine to ≤1.5 times baseline value) took a median 18 days (range 4–72). Of the 22/42 patients (52%) re-challenged with HDMTX (at 40–100% of recommended dose), none experienced DME and all completed per-protocol number of HDMTX cycles. Conclusions Our experience shows that glucarpidase is effective and well tolerated for the treatment of DME and HDMTX-AKI in pediatric patients with hemato-oncologic diseases.

High-dose methotrexate (HD-MTX) infusions are commonly used to consolidate remission in children with acute lymphoblastic leukemia (ALL). We investigate the potential role of candidate polymorphisms in SLCO1B1 (rs4149056 and rs2306283), ABCB1 (rs1045642), ABCC2 (rs717620), ABCC3 (rs9895420), and ABCC4 (rs7317112) drug transporters genes on HD-MTX pharmacokinetics and patients' outcome (meant both as relapse and drug-related toxicities) in an Italian cohort of 204 ALL pediatric patients treated according to the AIEOP-BFM ALL 2009 protocol. TaqMan SNP genotyping assays determined patient's genotypes. Measurements of HD-MTX plasma concentration were available for 814 HD-MTX courses in 204 patients; MTX clearance was estimated by a two-compartmental linear pharmacokinetic model with first-order elimination and a Bayesian approach, via ADAPT. Independent contributions of age and ABCC4 SNP rs7317112 (A>G, intronic) on MTX clearance were detected in a multivariate analysis (p = 1.57 × 10-8 and p = 2.06 × 10-5, respectively), suggesting a delayed elimination of the drug in older patients and an accelerated one in carriers of the variant GG genotype. After multiple corrections, the association between ABCC2 SNP rs717620 (-24 C>T) and severe hematological toxicity was found (p < 0.005). Moreover, SLCO1B1 SNP rs4149056 (c.521T>C, p.V174A) affected patients' outcomes: carriers of the variant C allele presented a reduced risk of relapse compared to wild-type TT (hazard risk: 0.27, 95% confidence interval [CI]: 0.08-0.90, p = 0.037). Taken together, these data highlighted the importance of variants in drug transporters genes on HD-MTX disposition in the AIEOP-BFM ALL 2009 protocol consolidation phase, and their putative role as predictive markers of outcome.

INTRODUCTION:Experiences related to pediatric oncology diagnosis cause great imbalances within the family structure. Assessing the frailties and needs of families and children with cancer from a psychosocial perspective is an important step in providing appropriate pediatric psychology care. METHODS:The aim of this study was to develop an Italian translation of the last version of the Psychosocial Assessment Tool questionnaire (PAT 3.1) and to pilot-test it among pediatric oncological families. The guidelines for cross-cultural adaptation of health-related quality of life measures were followed. Specifically, two independent forward translations were produced, followed by a reconciliation step by a multidisciplinary expert committee and back-translation. Revision of the original text and all translations were performed by the expert committee leading to a final version, which was pilot-tested by cognitive debriefing on five families. Subsequently, the final Italian PAT 3.1 version was approved. RESULTS:The Italian version of the PAT 3.1 generated in the present study is a useful instrument to examine the psychosocial risk of the families with a child with cancer. CONCLUSIONS:This instrument will be a valuable tool for future clinical trials and it will help clinicians to target specific pediatric psychology support intervention. The questionnaire will be further validated through a multicenter Italian study on psychosocial screening of pediatric oncology and pediatric general diseases.

Introduction T-cell acute lymphoblastic leukemia (T-ALL) has been historically associated with inferior outcome compared to B-cell precursor ALL with slower treatment response and lack of recurrent prognostic cytogenetic alterations. With the introduction of next-generation sequencing analyses, a deeper characterization of childhood ALL has been achieved. However, if for B-ALL the identification of fusion-class genes has clinical implication, the frequency and relevance of gene fusions in T-ALL still remain poor. Here we describe the incidence of gene-class fusions in the pediatric cohort of T-ALL patients treated according to the AIEOP-BFM ALL 2017 protocol and explore the association with presenting patient characteristics and early treatment response. Methods From Dec 1st 2021 to Mar 31st 2024, in AIEOP Italian centers 132 consecutive patients with T-ALL have been enrolled in the trial AIEOP-BFM ALL 2017 Study. According to material availability, Whole transcriptome RNA-seq was performed at disease onset in 128 (97%) patients (Universal RNA-seq kit, Tecan with paired-end sequencing on Nextseq2000). The analysis was performed with 4 independent pipelines with the purpose to detect fusion genes (Dragen RNA, Star, Fusion Catcher, Arriba) and results were evaluable in 123 (96%) patients (5 cases were excluded due to poor library quality). Results Among 123 evaluable patients, at least one fusion gene was identified in 51 (41.5%) patients and validated through real-time PCR. Most common gene-class fusions were STIL::TAL1 (n=10, 8.1%), KMT2A-rearranged (KMT2Ar, n=9, 7.3%), ABL-class (n=8, 6.5%) and MLLT10-class (n=8, 6.5%). Other fusions were identified in 16 (13.0%) patients, with ETV6-class in 4 patients (3.3%) and CDK6-class in 2 patients (1.6%), in addition to single non recurrent fusion/cases. All gene-class fusions were mutually exclusive. Patient characteristics at diagnosis were evaluated in association with the presence of gene-class fusions. ABL-class and MLLT10-class fusions were more common in females and patients with MLLT10-class fusion tended to be older (age ≥ 10 years). Patients with STIL::TAL1 fusion were more likely to have hyperleukocytosis (white blood cell counts ≥ 100 × 109/L) and central nervous system disease (CNS3). We investigated whether the presence of gene-class fusion was associated with treatment response in term of prednisone poor response (PPR), high level of bone marrow disease (≥10% of blasts) measured by flow-cytometry (FCM-MRD) at induction day 15, end of induction (EOI) PCR-MRD, end of consolidation (EOC) PCR-MRD and final risk group classification. Patients carrying a KMT2Ar were characterized by higher proportion of PPR, FCM-MRD with ≥10% of blasts and higher EOI MRD levels: of note, approximately half (44.4%) of them had EOI MRD ≥5x10-3. The presence of MLLT10-class fusion was associated with high EOI MRD, with 50% of patients having levels ≥5x10-3, as well as for STIL::TAL1 patients (40% of patients with ≥5x10-3). No association was found at EOC between PCR-MRD levels and gene-class fusions. Interestingly, all patients carrying KMT2Ar except one were classified as HR while a lower proportion of HR patients was found among patients with ABL-class fusion. Indeed, the presence of ABL-class fusion was not associated with any unfavorable early treatment responses. Conclusion Our study showed a high incidence of gene-class fusions in children and adolescents with newly diagnosed T-ALL. We found that KMT2Ar, STIL::TAL1 and MLLT10-class fusions are associated with high risk features in a prospective cohort of uniformly treated patients with pediatric T-ALL. On the contrary, patients carrying ABL-class fusions did not show adverse characteristics of early treatment response. Despite a longer follow-up is required, prognostic relevant gene-class fusions might integrate current risk stratification and identify patients who might qualify for early interventional studies or targeted therapies.

Abstract Background Infant leukemia is a rare form of acute leukemia diagnosed prior to 1 year of age with an extremely poor prognosis, due to its poor response to current therapies. It comprises about 4% of childhood acute lymphoblastic leukemia (ALL). Isolated initial cutaneous involvement in ALL is very uncommon, and even more in infant ALL. Case Presentation Here we present a case of 2-month-old infant, presenting only nodular skin infiltrates on the scalp with the diagnosis of infant acute lymphoblastic leukemia (ALL), characterized by the immunophenotype of the most immature B-cell precursors (pro-B ALL) and chromosomal translocation t (9;11), associated with the rearrangement of KMTLA2 and AF9 genes, that is a negative prognostic factor. She underwent hematopoietic stem cell transplantation (HSCT) and she is still in remission Conclusions This represents a peculiar case because isolated initial cutaneous involvement in ALL is rare. In fact, most reports of ALL leukemia cutis in literature are single cases. The novel treatment strategies, obtained from recent discoveries regarding the peculiar biology of these leukemias, are increasingly being incorporated into clinical trials and have the potential to improve the prognosis.

IntroductionIn Europe, despite recent advances in clinical development, most of the drugs currently used to treat childhood cancers are adult medicines, prescribed outside of the authorized indication. In this context, a monocentric retrospective cohort analysis was conducted, evaluating pediatric, adolescent, and young adult patients affected by onco-hematologic disease, treated with targeted therapies used off-label or as compassionate use. MethodsThe analysis was conducted on 45 patients aged less than or equal to 30 years with cancer, having received at least one targeted therapy prescribed as off-label or compassionate use at a large Italian pediatric center between January 1, 2016 and June 30, 2021. Data collected included information on the patient and tumor, data on off-label/compassionate treatment, and data on safety and efficacy. ResultsTotal 25 out of 45 patients treated with off-label or compassionate targeted therapies were affected by onco-hematological diseases. Overall, 22 out of the 52 agents (42%) were prescribed in patients with relapsed neoplasm and 39% (20/52) in patients with refractory diseases. Complete response was observed in more than half (27/52) of treatments. At least one adverse reaction occurred in 76% (n = 22) of agents administered to patients with onco-hematological tumor and in 43% (n = 10) of agents prescribed to patients with solid tumor. ConclusionThis work aims to provide a snapshot of off-label and compassionate use prescriptions in a large Italian pediatric cancer center. This study confirms that targeted agents for unauthorized indications are often prescribed in pediatric patients with cancer, especially after disease relapse and that these treatments are mostly tolerable and effective.

Background: In adult oncology, the practice of tracking symptoms and toxicities using patient-reported outcomes (PROs) has increased and correlates with increased survival. In contrast, symptom monitoring using PROs is not common in pediatric oncology. Only in the last couple of years attention has also been paid to the patient’s perception in pediatrics and listening to the voice of children and to making them participate in the treatment. Methods: A comprehensive literature search was conducted in MEDLINE/PubMed and PsycINFO to identify relevant articles published through December 2022. Results: From 58 non-duplicate articles, 33 met our eligibility criteria. Of these, 17 were used in clinical trials. Conclusions: The dissemination and use of these tools will therefore have surprising repercussions on the control of pain and physical symptoms of small patients as well as on physical and psychological aspects. The administration and use of the PROs ensures optimal use of the drugs currently present in clinical trials by researcher and nurse and aims at a safer and more controlled approval of new drugs.

BackgroundInfant leukemia is a rare form of acute leukemia diagnosed prior to the age of 1 and is characterized by an extremely poor prognosis due to its dismal response to current therapeutic approaches. It comprises about 4% of all childhood cases of acute lymphoblastic leukemia (ALL). Isolated initial cutaneous involvement in ALL is uncommon, and even more so in infant ALL.Case presentationHere, we present the case of a 2-month-old healthy-appearing infant, initially presenting with a single scalp nodule and subsequently diagnosed with an infant ALL. The leukemia was characterized by the most immature B-lineage immunophenotype [pro-B ALL/B-I, according to the European Group for the Immunological Characterization of Leukaemias (EGIL) classification] and chromosomal translocation t(9;11)(p22;q23), resulting in fusion gene KMTLA2::MLLT3, which is considered a negative prognostic factor. The patient underwent hematopoietic stem cell transplantation and is still in remission.ConclusionsThis case is peculiar because of the rare occurrence of isolated initial cutaneous involvement in ALL. Despite the healthy appearance of the patient, every suspicious symptom suggestive of malignancies should be further investigated to anticipate the diagnosis and start treatment early.

10017 Background: Bosutinib is a tyrosine kinase inhibitor (TKI), approved for adults with Philadelphia Chromosome (Ph+) CML; at the standard initial dose of 400 mg/day in ND patients, and 500 mg/day in resistant/intolerant (R/I) patients, administered orally once daily (QD) with food. Compared to the TKIs already approved in pediatrics, bosutinib has a different tolerability profile, and preclinical data suggest that longitudinal growth is potentially less impaired. Study NCT04258943 is an international, open-label, phase I/II trial, sponsored by the Erasmus Medical Center and the Children's Oncology Group, and funded by Pfizer Inc. The phase II arm enrolled ND patients, as well as R/I ones. The latter are not included in this analysis. Methods: ND patients aged 1-18 years with chronic phase CML, without evidence for organ toxicities, were enrolled. Main exclusion criteria included known T315I or V299L BCR-ABL1 mutations, and use of proton pump inhibitors and CYP3A inducers/inhibitors. The primary objectives of the phase II part of the study were to assess the safety and pharmacokinetics (PK) of bosutinib at the recommended phase II dose, which is body surface area adjusted, and consists of 300 mg/m 2 QD for ND patients (max 500 mg/day), as determined in the phase I part of the study. Based on regulatory authorities requirements, at least 35 patients have to be enrolled in phase II, with a total of 50-60 patients in phase I and II combined. This allows for pooled AE rates to be estimated with a maximum standard error of 0.071 and 0.065, respectively. Results: On 20/12/2022, 25 ND patients were screened, and 24 were enrolled: 15 males, median age 13 years (range: 5-17). The median follow up was 14 (range: 0.9-31) months. The most common non-hematological adverse events (AEs) were diarrhea (n = 16, Grade (Gr) ≤ 2 = 13), abdominal pain (n = 10, Gr ≤ 2 = 10), and nausea/vomiting (n = 8/8, Gr ≤ 2 = 7/8). Most common hematological AEs included platelet count decrease (n = 11, Gr ≤ 2 = 5), and anemia (n = 10, Gr ≤ 2 = 4). At 6 and 12 months, the cumulative incidence of Major Cytogenetic Response (MCyR) was 85% (95%CI 49%-96%) and 92.5% (95%CI 39%-99%), while for Complete CyR it was 77% (47%-91%) and 88.3% (95%CI 55%-98%), and for Major Molecular Response it was 23% (95%CI 7%-46%) and 30% (95%CI 10%-54%), respectively. Three patients permanently discontinued bosutinib due to intolerance, four due to unsatisfactory response per investigator’s judgment, 17 were still on treatment at time of dataset lock. Conclusions: Bosutinib was well tolerated, despite common grade 1-2 gastrointestinal AEs. The preliminary efficacy seems comparable to published data from other second generation TKIs in children and to ND adult patients treated with bosutinib. Clinical trial information: NCT04258943 .

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.

BackgroundInfant leukemia is a rare form of acute leukemia diagnosed prior to the age of 1 and is characterized by an extremely poor prognosis due to its dismal response to current therapeutic approaches. It comprises about 4% of all childhood cases of acute lymphoblastic leukemia (ALL). Isolated initial cutaneous involvement in ALL is uncommon, and even more so in infant ALL.Case presentationHere, we present the case of a 2-month-old healthy-appearing infant, initially presenting with a single scalp nodule and subsequently diagnosed with an infant ALL. The leukemia was characterized by the most immature B-lineage immunophenotype [pro-B ALL/B-I, according to the European Group for the Immunological Characterization of Leukaemias (EGIL) classification] and chromosomal translocation t(9;11)(p22;q23), resulting in fusion gene KMTLA2::MLLT3, which is considered a negative prognostic factor. The patient underwent hematopoietic stem cell transplantation and is still in remission.ConclusionsThis case is peculiar because of the rare occurrence of isolated initial cutaneous involvement in ALL. Despite the healthy appearance of the patient, every suspicious symptom suggestive of malignancies should be further investigated to anticipate the diagnosis and start treatment early.

10020 Background: Phase I/II trials play a key role for children with relapsed/refractory tumors. Life expectancy beyond 8-12 weeks is a common eligibility criterion. However, there are no objective means to determine life expectancy for trial candidates. A better understanding of the risk factors associated with early mortality on trial could maximize the efficiency of such trials, whilst ensuring the ethical aspects of recruitment. Methods: Patients with relapsed/refractory solid tumors or lymphomas aged < 18 years and participating in interventional clinical trials with a dose-finding part between 2000-2018 in 14 ITCC centers (across 5 European countries) were eligible. The mortality at 30 and 90 days (30-DM and 90-DM, respectively) from Cycle1-Day1 (C1D1) and its association with clinical, laboratory and efficacy data were assessed. Validated prognostic scores (RMH, MDACC) were correlated with early mortality rates. Results: Overall, 527 cases were included in the study; 19 subjects had participated in > 1 trial, leaving a total of 507 subjects enrolled in their first phase I/II trial. Median age at C1D1 was 11.6 years (range, 0.5-17.9); male:female ratio 1.2:1; central nervous system (CNS) tumors (40%) Vs extra-CNS tumors (60%); 75% cases were treated in trials with at least one targeted therapy. The 30-DM (24/507) and 90-DM (116/507) were 4.7% (95%CI 3.1-7.0) and 23.0% (95%CI 19.3-26.8), respectively. At baseline the clinical variables which correlated with higher 90-DM in the univariate analysis were: performance status (Lansky or Karnofsky) ≤80%, no school/work attendance, requirement of opioids, ≥3 metastatic sites, Hb < 100 g/dL and Total Bilirubin, LDH or AST above normal levels (up to the maximum permitted according to protocol eligibility criteria). Higher RMH and MDACC scores also correlated with higher 90-DM. Conclusions: To our knowledge this is the largest case series of children and adolescents participating in pediatric phase I/II trials to date, in which most of the patients were treated with targeted or immuno-oncology agents. The reported 30-DM and 90-DM will serve as a reference benchmark for future trials. Performance status ≤80%, no school/work attendance, requirement of opioids and ≥3 metastatic sites correlated with higher 90-DM. Adult prognostic scores (RMH, MDACC) showed good correlation with 90-DM in the pediatric population. Prognostic factors of early mortality should be given appropriate relevance at the time of study design, informing families and recruiting patients to these studies.

Infant leukemia is a rare form of acute leukemia diagnosed prior to the age of 1 and is characterized by an extremely poor prognosis due to its dismal response to current therapeutic approaches. It comprises about 4% of all childhood cases of acute lymphoblastic leukemia (ALL). Isolated initial cutaneous involvement in ALL is uncommon, and even more so in infant ALL.Here, we present the case of a 2-month-old healthy-appearing infant, initially presenting with a single scalp nodule and subsequently diagnosed with an infant ALL. The leukemia was characterized by the most immature B-lineage immunophenotype [pro-B ALL/B-I, according to the European Group for the Immunological Characterization of Leukaemias (EGIL) classification] and chromosomal translocation t(9;11)(p22;q23), resulting in fusion gene KMTLA2::MLLT3, which is considered a negative prognostic factor. The patient underwent hematopoietic stem cell transplantation and is still in remission.This case is peculiar because of the rare occurrence of isolated initial cutaneous involvement in ALL. Despite the healthy appearance of the patient, every suspicious symptom suggestive of malignancies should be further investigated to anticipate the diagnosis and start treatment early.

Background: Bosutinib is a second-generation Tyrosine Kinase Inhibitor (TKI), approved for adults with Chronic Myeloid Leukemia (CML), and tested for the first time in children in this phase I/II trial, sponsored by Erasmus Medical Center and the Children’s Oncology Group, and funded by Pfizer Inc. The phase I arm established the recommended phase 2 dose (RP2D) in resistant/intolerant (R/I) pediatric patients at 400 mg/m2 QD (max 600 mg/day), based on safety and target exposure as defined in adults. Extrapolation from safety and PK data in R/I children and target exposure from adults established the RP2D for newly diagnosed (ND) patients at 300 mg/m2 QD (max 500 mg/day). Aims: We present updated safety and efficacy results of bosutinib in R/I pediatric patients with CML treated at the RP2D in the phase I and II portion of the study, as well as efficacy data in ND patients. Methods: R/I and ND patients (as per ELN2013 criteria), aged 1-18 years with chronic phase CML, without evidence for organ toxicities, were enrolled. Main exclusion criteria included known T315I or V299L BCR-ABL1 mutations, use of proton pump inhibitors and CYP3A inducers/inhibitors. Due to the rarity of CML in children, the sample size was not based on formal calculations: a total of 60 patients needed to be enrolled in this phase I/II combined study per regulatory authorities’ requirements. Results: Thirteen R/I patients received the RP2D of which 11 were in phase I. Median age was 15 (range: 6-17) years, sex M:F ratio 8:5. Twelve patients were resistant and 1 intolerant to prior therapy with 5 patients having received ≥2 previous TKIs. Seven were reported in Complete Cytogenetic Response (CCyR) at baseline including 2 with Major Molecular Response (MMR). Ten patients received the capped dose of 600 mg/day. Median follow-up was 11 (range 1-25) months. At the RP2D, one patient experienced a DLT in phase I (transaminase and bilirubin increase and rash). Gastrointestinal (GI) and skin toxicities were the most common; namely 12/13 (92%) with diarrhea, of which 2 (17%) were grade 3/4, and 8/13 (62%) with skin rash, of which 1 (13%) was grade 3/4. At time of dataset lock (February 14, 2023), 11/13 (84.6%) R/I patients achieved/maintained CCyR, and 7/13 (53.8%) MMR, as best response. One patient who achieved CCyR on treatment lost the response after 12 months, while all patients which entered the study with either CCyR or MMR maintained the response. Of the 5 patients not in CCyR at baseline, 4 (80%, 95%CI: 28-99%) achieved CCyR and 1 had no response data available (on treatment for <1 month). Of the 10 patients not in MMR at baseline, 5 (50%, 95%CI: 19-81%) achieved MMR on study (2 had no response data available, on treatment for <3 months). Median time to response was 3 months for CCyR and 8 months for MMR. Two patients permanently discontinued the drug due to toxicities (one rash, one persistent GI toxicity and fatigue), three due to insufficient response. In phase II, 24 ND patients were enrolled: sex M:F ratio 15:9, median age 13 (range: 5-17) years. The median follow-up was 14 (range: 0.9-31) months. Cumulative incidence of CCyR was 77% (47%-91%) and 88.3% (95%CI 55%-98%) at 6 and 12 months respectively, and for MMR it was 23% (95%CI 7%-46%) and 30% (95%CI 10%-54%). Three patients permanently discontinued bosutinib due to intolerance four due to unsatisfactory response with 17 still on treatment at time of dataset lock. Summary/Conclusion: Bosutinib at the RP2D was well-tolerated and its preliminary efficacy in R/I and ND pediatric patients seems comparable to that recorded in adult patients treated with the same drug and in line with other second generation TKIs. Keywords: Pediatric, Chronic myeloid leukemia, Clinical trial

Five-year event-free survival in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) currently exceeds 80–85%. However, 15–20% of patients still experience a relapsed/refractory disease. From 1 January 2015 to 31 December 2020, thirty-nine patients, 0–21 years old with r/r BCP-ALL were treated with blinatumomab with the aim of inducing remission (n = 13) or reducing MRD levels (n = 26) in the frame of different multiagent chemotherapy schedules, in seven AIEOP centers. Patients were treated in compassionate and/or off-label settings and were not enrolled in any controlled clinical trials. Treatment was well tolerated; 22 (56.4%) patients reported adverse events (AE) on a total of 46 events registered, of which 27 (58.7%) were ≤2 grade according to CTCAE. Neurological AEs were 18 (39.1%); only two patients required transient blinatumomab discontinuation. Complete remission (CR) rate was 46% for the 13 patients treated with ≥5% blasts and 81% PCR/FC MRD negativity in the 26 patients with blasts < 5%. Median relapse-free survival was 33.4 months (95% CI; 7.5–59.3); median overall survival was not reached over a mean follow-up of 16 months. In our study, as in other real-life experiences, blinatumomab proved to be effective and well-tolerated, able to induce a high rate of CR and MRD negativity.

To the Editors: In Italy, the B.1.1.529 (Omicron) variant of concern (VOC) of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now dominant1 and sotrovimab is thought to retain activity against it.2,3 To the best of our knowledge, there are few data on its use in children less than 12 years old and weighing less than 40 kg.4 European Medicine Agency (EMA) and Italian Medicine Agency (AIFA) both authorized sotrovimab for treating COVID-19 in adults and adolescents (from 12 years of age and weighing at least 40 kilograms) who do not require supplemental oxygen and who are at increased risk of the disease becoming severe. We describe a series of 5 children less than 12 years old, treated with sotrovimab in the Department of Pediatric and Public Health Sciences, Infectious Diseases Unit, Regina Margherita Children’s Hospital, Turin. All 5 patients were admitted for reasons other than COVID-19 and tested positive for SARS-CoV-2 infection. They were hospitalized to ensure clinical observation because they all fulfilled the criteria for high risk of progression to severe COVID-19 (Table 1) and they all met AIFA’s indications for treatment with sotrovimab, with the exception of age and weight.5 None of them had received vaccination for SARS-CoV-2 (4 out 5 were less than 5 years old). As required by the hospital’s policy, off-label monoclonal antibodies (mAb) use for age and weight was prescribed after Hospital Drug Committee approval and once we obtained the informed parental consent. TABLE 1. - Demographic and COVID-19 Related Symptoms in Our Pediatric Patients Subjects Age Weight Sex Ethnicity Comorbidity First positive test for SARS-CoV-2 COVID-19 related symptoms Sotrovimab infusion Patient 1 2 months 5.5 kg F Caucasian ALL at onset 27 January 2022 Fatigue 29 January 2022 Patient 2 1 year 12.5 kg M African Mucopolysaccharidosis type I, sleep apnea syndrome with nocturnal NIV, AHSCT complicated with reactivation of CMV and EBV infection, immunosuppressive treatment with anti–B lymphocyte monoclonal antibodies (rituximab) 2 January 2022 Rhinitis, sore throat 8 January 2022 Patient 3 1 year 10 kg F African Embryonal rhabdomyosarcoma and neutropenia (ongoing chemotherapeutic agents) 27 January 2022 Fever 29 January 2022 Patient 4 2 years 14 kg M Caucasian ALL (ongoing chemotherapeutic agents) 27 January 2022 Fever 29 January 2022 Patient 5 8 years 18 kg M Hispanic Chronic pulmonary graft versus host disease after AHSCT in ALL 1 January 2022 Headache, rhinitis 8 January 2022 AHSCT indicates allogeneic hematopoietic stem cell transplant; ALL, acute lymphoblastic leukemia; CMV, cytomegalovirus; EBV, epstein barr virus; F, female; M, male; NIV, noninvasive ventilation. Since pediatric clinical trials on SARS-CoV-2 treatment with sotrovimab are lacking in children, there are no formal guidelines and recommendations about the dosage in patients younger than 12 years of age and weighing less than 40 kg. Considering that the recommended dose in adults and adolescents (weighing at least 40 kg) is a single 500 mg intravenous administration,3 we established a dose based on anthropometric values of 12.5 mg/kg for our patients. There were no significant adverse events and reactions that required the cessation of infusion. None of the treated patients required either intensive care admission or oxygen supplementation, except for 1, who presented pulmonary worsening the day after Sotrovimab infusion and recovered with a short course of steroids. Among the first 2 patients treated, none was readmitted for reasons related to COVID-19 or Multisystem Inflammatory Syndrome in children (MIS-C) within 30 days of follow-up. Of the other 3, 1 was discharged the day after sotrovimab infusion and another 5 days later; the last is still hospitalized for reasons other than COVID-19. These 3 children did not develop COVID-19 related symptoms at the 7-day follow-up. In conclusion, the administration of sotrovimab in the initial phase of SARS-CoV-2 infection might be considered also in young children with risk factors for severe COVID-19. Although our data are limited, this report provides preliminary information on the use, weight-based dosage and tolerability of sotrovimab in young children at high risk for unfavourable and complicated COVID-19 evolution.

A 12-year-old male being treated for a high-risk relapsed T-acute lymphoblastic leukemia presented progressive weakness and numbness of both legs after having received a chemotherapy regimen that included bortezomib. Diagnosis of acute Guillain-Barré syndrome-like inflammatory demyelinating polyneuropathy was made following clinical examination, cerebrospinal fluid analysis, electrodiagnostic studies, magnetic resonance imaging, and serum immunoglobulin antibodies to anti-ganglioside. Intravenous immunoglobulin treatment was started, resulting in complete clinical recovery. Although in rare cases, Guillain-Barré syndrome after bortezomib therapy has been reported; this paper suggests that GBS may occur when bortezomib is administered and high‑dose intravenous immunoglobulin lead to a resolution of the symptoms.

An exercise program (EP) during cancer treatment seems to be a valid strategy against physiological and quality-of-life impairments, but scientific evidence of benefits among pediatric patients is still limited. This review summarizes the literature focused on randomized controlled trials of EP offered to patients during leukemia and lymphoma treatment. Studies published up to June 2017 were selected from multiple databases and assessed by three independent reviewers for methodological validity. The review identified eight studies, but several types of bias have to be avoided to provide evidence-based recommendations accessible to patients, families, and professionals.

Purpose: This study intends to translate and make any necessary cultural adaptations of the Pediatric PRO-CTCAE version for Italian oncological patients aged 7-18 years and their caregivers. Methods: The questionnaire has been forward/backward translated into Italian and subjected to detailed verification by fluent Italian speakers, children and their parents, for use in clinical trials in Italian populations. The Italian version includes 130 questions that assess 62 symptoms. To verify the patients' comprehension some interviews were completed with 24 oncological children and adolescents in different age groups and 24 parents (M-age = 41.2). Caregivers were interviewed independently. Results: A final Italian version of the Pediatric PRO-CTCAE was produced. Across the age range, most patients and caregivers were able to understand and answer the questions. The 7-9 years old had greater challenges completing two terms which were retested in a second round of interviews. There were no comprehension differences on the basis of trials enrollment phase. Conclusions: The translation and adaptation of the Pediatric PRO-CTCAE confirms that this instrument is also suitable for assessing symptom toxicities among Italian cancer patients. Its rapid integration into care pathways is necessary to guarantee an early response to patient symptoms and to facilitate drug tolerability assessment.