Severe complications of nivolumab monotherapy in an adolescent with malignant melanoma.

This study presents a case of a 17-year-old female patient who had previously undergone surgical resection of melanoma in the right periscapular area. She was administered adjuvant treatment with the PD-1 inhibitor nivolumab as monotherapy. The mechanism of action of this drug is based on increased stimulation of the immune system. The patient developed a series of complications including capillary leak syndrome and hypothyroidism after the fifth cycle of therapy, as a result of dysregulation of immunity. Nivolumab treatment had to be discontinued and glucocorticosteroids were administered as a salvage therapy. After several months, two relapses developed in the subcutaneous tissue - first in the left and then in the right iliac region, confirmed as distant metastases of malignant melanoma, treated with resections of the lesions and intensity-modulated radiation therapy. Follow-up imaging studies and clinical examinations showed no metastases or pathologically enlarged lymph nodes.

Real pandemic world results of pharmacokinetic-tailored personalized prophylaxis of bleeds in Polish children and adolescents with severe hemophilia A.

Introduction: In 2020, the new nationwide protocol of prophylaxis in Polish plasma-derived FVIII (pdFVIII) previously treated patients (PTPs) with severe hemophilia A (sHA) was introduced, resulting in the necessity of switching from pdFVIII to recombinant FVIII (octocog-alpha; rFVIII). The study aimed to: (1) assess the safety of switching from pdFVIII to rFVIII, (2) assess the safety and efficacy of pharmacokinetically based (PK-based) personalized prophylaxis in severe hemophilia A. Patients and methods: 151 children and adolescents receiving prophylaxis with a standard dose (40 U/kg 3 x weekly) of pdFVIII were included in this study. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) were analyzed for all patients before enrollment. Using myPKFiT application, pharmacokinetic (PK) analysis followed by the selection of the optimal model of prophylaxis was performed in all patients. Two possible models of prophylaxis (standard-dose rFVIII versus PK-based rFVIII) were discussed, with parents leaving the choice to their decision. Parents reported all episodes of bleeds. Screening for inhibitor was performed every 3 months. ABR and AJBR were prospectively analyzed again after a minimum follow-up time of 26 weeks. Results: 141/151 (93.4%) patients completed the study. 34 patients decided to continue standard prophylaxis with rFVIII (Group I), whereas 107 were switched to PK-based prophylaxis (Group II). The risk of inhibitor development could be assessed in 137/151 (90.7%) patients. Only 2/137 (1.47%) patients (both on PK-based prophylaxis) developed low-titer inhibitor with its spontaneous elimination. The retrospective analysis of bleeds during the last 12 months of standard pdFVIII prophylaxis revealed that patients who decided to continue standard prophylaxis had historically lower ABR and AJBR than those who started PK-based personalized prophylaxis. After a minimum of 26 weeks, ABR and AJBR improved significantly in both groups. There was no significant difference in ABR and AJBR between Group I and Group II during the follow-up period. However, the rate of reduction of ABR and AJBR was higher in patients on PK-based personalized prophylaxis. Conclusion: (1) Switching from pdFVIII to rFVIII (octocog-alpha) in PTPs with sHA is safe, (2) PK-based personalized prophylaxis may decrease ABR and AJBR in children and adolescents with sHA.

Successful Treatment of Large B-Cell Lymphoma in a Child with Compound Heterozygous Mutation in the ATM Gene.

Ataxia-telangiectasia (AT) is a multisystemic neurodegenerative inborn error of immunity (IEI) characterized by DNA repair defect, chromosomal instability, and hypersensitivity to ionizing radiation. Impaired DNA double-strand break repair determines a high risk of developing hematological malignancies, especially lymphoproliferative diseases. Poor response to treatment, excessive chemotherapy toxicities, and the need for avoiding exposure to ionizing radiation make the successful clinical management of patients with AT challenging for oncologists. We describe the favorable outcome of the LBCL with IRF4 rearrangement at stage III in a 7-year-old female patient diagnosed with AT. The patient was treated according to the B-HR arm of the INTER-B-NHL-COP 2010 protocol, including the administration of rituximab, cyclophosphamide, methotrexate, prednisone, etc. She presented excessive treatment toxicities despite individually reduced doses of methotrexate and cyclophosphamide. However, in the MRI there was no significant reduction in pathologic lymph nodes after three immunochemotherapy courses. Therefore, a lymph node biopsy was taken. Its subsequent histopathological examination revealed tuberculosis-like changes, though tuberculosis suspicion was excluded. After two following immunochemotherapy courses, PET-CT confirmed complete remission. From March 2022 onwards, the patient has remained in remission under the care of the outpatient children's oncology clinic.

MicroRNA gene methylation landscape in pediatric B-cell precursor acute lymphoblastic leukemia.

BACKGROUND: Aberrant DNA methylation is an important mechanism by which the normal patterns of microRNA expression are disrupted in human cancers including B-cell precursor acute lymphoblastic leukemia (BCP ALL), the most common pediatric malignancy. OBJECTIVES: To characterize the methylation profile landscape of microRNA genes in BCP ALL patients. MATERIAL AND METHODS: We employed Infinium® MethylationEPIC BeadChip Arrays to measure the methylation of microRNA genes from bone marrow samples of children with BCP ALL (n = 38) and controls without neoplasms (n = 4). RESULTS: This analysis revealed differential methylation of the microRNA genes in the pediatric BCP ALL when compared to the control. A subcluster amongst BCP ALL patients with TCF3-PBX1 genetic subtype was also observed. No other differences were observed in association with age, gender or risk group. Several interesting leukemia-related phenotypes are enriched by the genes with hyperand hypomethylated sites located in promoters as well as gene bodies. The top 3 miRNA genes, promoters of which were the most statistically significantly hypermethylated in BCP ALL were MIR1273G, MIR1304 and MIR663, and the top 3 hypomethylated were MIR4442, MIR155 and MIR3909. CONCLUSIONS: In this study, a different microRNA genes methylation landscape was shown in pediatric BCP ALL compared to children without neoplasms. A visible subcluster among BCP ALL samples consisted of individuals with TCF3-PBX1 genetic subtype. No other differences were observed in association with age, gender or risk group. Several interesting leukemia-connected phenotypes were found, associated with genes with hyperand hypomethylated sites located on promoters as well as gene bodies.

Body Mass Index (BMI) and Infectious/Febrile Episodes in Children with Intermediate Risk Acute Lymphoblastic Leukemia (IR ALL).

The incidence of treatment related mortality in children with acute lymphoblastic leukemia (ALL) is reported to be between 2% and 4% with infections being the leading cause. AIM: To establish a relationship between body mass index at diagnosis (BMI 0), after protocol I therapy completion (BMI I) and the incidence rate ratio (IRR) of infectious/febrile episodes in children with ALL intermediate risk. METHODS: Thirty one consecutive patients (2-18 years old, with a male to female ratio of 19/12) with newly diagnosed ALL that were treated uniformly according to ALL IC 2009 protocol were included in this analysis. RESULTS: A BMI decrease of at least 5% during protocol I therapy and BMI 1 under 15th percentile score corresponds significantly with higher IRR (with P-values 0.04 and 0.006 respectively) during the whole intensive therapy. CONCLUSION: Some relationships between BMI reduction and higher IRR in ALL patients were found, but their significance is limited by the size of the group analyzed.

Immunologic effects of intermediate-dose IL-2 i.v. after autologous hematopoietic cell transplantation in pediatric solid tumors.

Adoptive immunotherapy with interleukin-2 (IL-2) may control minimal residual disease (MRD) and prevent relapse after autologous hematopoietic cell transplantation (AHCT). The objective of this study was to determine the immunologic effects of intermediate doses of intravenous (i.v.) IL-2 after AHCT in children with poor-prognosis solid tumors. Eleven patients received a median five cycles consisting of escalating doses of IL-2 i.v. for 5 days after a median time interval of 94 days post-AHCT. The phenotype of lymphocyte subsets was investigated before and after each cycle, and parallel determination of natural killer (NK) cell activity was performed. Immunotherapy induced a significant increase in total lymphocyte count (TLC), T, NK, and, to some extent, B cells. Among NK cells, CD56+ bright cells expanded more than CD56+ dim cells. High expansion of CD56+ cells with CD94 inhibitory receptor was observed, whereas no difference was recorded in the number of CD3+ CD56+ and CD8+ CD57+ cells. NK activity stabilized after the first cycle of IL-2 and remained elevated during the study period. Cycles of IL-2 immunotherapy induced repeated significant expansion of T cells and NK cells, mostly of the immature CD56+ bright phenotype. Despite enhanced NK activity, relapses occurred frequently, which might have been due to increased CD94 activation and a poor response from the cytotoxic NK T cells and CD8+ CD57+ T cells.

Immune reconstitution after haematopoietic cell transplantation in children: immunophenotype analysis with regard to factors affecting the speed of recovery.

Immune reconstitution was studied prospectively in 66 children who underwent 77 haematopoietic cell transplantations (HCT): 46 autologous HCTs in 39 patients and 31 allogeneic HCTs in 27 patients. We studied the dynamic analysis of immune recovery with regard to potential factors affecting its speed, including age, type of HCT, diagnosis, graft-versus-host disease (GvHD) and cytomegalovirus (CMV) infection reactivation. Absolute counts of different lymphocyte subsets and immunoglobulin serum levels were determined in peripheral blood of patients on d -7 and +16, and then at various intervals up to 24 months post transplant. Common patterns of immune recovery after both allogeneic and autologous HCT were identified: (i) CD4+CD45RO+ peripheral T-cell expansion on d +16; (ii) inverted CD4+:CD8+ ratio from d +30 onwards; (iii) rapid natural killer (NK) cell (CD16+/-CD56+) count normalization. We observed prolonged T-cell lymphopenia (CD3+, CD3+CD4+, CD4+CD45RA+) until 24 months after autologous HCT, whereas in the allogeneic setting CD3+CD4+ cells, including naive CD45RA+ cells, returned to normal values at 9 months post transplant. Age > 10 years and coexistence of GvHD and CMV reactivation were associated with a substantial delay in T- (CD4+, including CD45RA+) and B-cell recovery after allogeneic HCT. Multidrug GvHD prophylaxis resulted in impaired T- (CD4+, CD4+CD45RA+) and B-cell reconstitution only in the early phase after allogeneic HCT (up to 4 months). Our results demonstrated that T-cell recovery was severely impaired in children after autologous HCT. It should be emphasized that specific approaches to enhance immune reconstitution are necessary to control minimal residual disease and avoid the risk of infectious complications in the autologous setting. Thymic involution after allogeneic HCT seems to be associated with age and coexistence of GvHD and CMV reactivation.