Supportive care in pediatric acute myeloid leukemia:Expert-based recommendations of the NOPHO-DB-SHIP consortium.

INTRODUCTION: Pediatric acute myeloid leukemia (AML) is the second most common type of pediatric leukemia. Patients with AML are at high risk for several complications such as infections, typhlitis, and acute and long-term cardiotoxicity. Despite this knowledge, there are no definite supportive care guidelines as to what the best approach is to manage or prevent these complications. AREA COVERED: The NOPHO-DB-SHIP (Nordic-Dutch-Belgian-Spain-Hong-Kong-Israel-Portugal) consortium, in preparation for a new trial in pediatric AML patients, had dedicated meetings for supportive care. In this review, the authors discuss the available data and outline recommendations for the management of children and adolescents with AML with an emphasis on hyperleukocytosis, tumor lysis syndrome, coagulation abnormalities and bleeding, infection, typhlitis, malnutrition, cardiotoxicity, and fertility preservation. EXPERT OPINION: Improved supportive care has significantly contributed to increased cure rates. Recommendations on supportive care are an essential part of treatment for this highly susceptible population and will further improve their outcome.

Incidence of inhibitor development in PUPs with severe Haemophilia A in the CEE region between 2005 and 2015.

INTRODUCTION: This study analyses real-world data on 144 previously untreated patients (PUPs) with severe Haemophilia A, from seven countries in Central and Eastern Europe (CEE: Bulgaria, Croatia, Czech Republic, Hungary, Latvia, Serbia, and Slovenia), over a period of 11 years. It analyses the risk factors associated with development of inhibitors to factor VIII concentrates. METHODS: Cox proportional hazard models were used to estimate the hazard risk of factors possibly influencing the development of inhibitors. Patients were followed for up to 100 exposure days (EDs). RESULTS: Cumulative inhibitor incidence at the time of 100 EDs was 18.7%, slightly lower than the 25-35% incidence reported in most studies. Of PUPs who developed inhibitors, a majority (56%) developed them within the first 20 EDs and 88% by the 50th ED. FVIII class (recombinant or plasma-derived) did not influence the inhibitors' incidence rate (p = 0.64). We found a significant protective effect of prophylaxis compared to on-demand treatment (p = 0.003). PUPs who had an intensive peak treatment during the first 50 EDs were at significantly higher risk for inhibitor development (HR (95% CI) 5.3 (2.3-12.5), p < 0.001). CONCLUSION: Inhibitors are and will continue to be the most significant complication of haemophilia treatment with factor concentrates. This is particularly true for haemophilia A. In our cohort, we were able to show that the treatment regimen used during first 50EDs influenced significantly the inhibitor risk, but the class of the factor concentrate did not play an important role. Real world data will remain one of the important resources for improving our knowledge of haemophilia.

X-Linked Lymphoproliferative Disease in Latvia: A Report of Two Clinically Distinct Cases.

X-linked lymphoproliferative disease (XLP) is a rare primary immunodeficiency. Affected individuals usually present with the Epstein-Barr virus infection and have no apparent disease prior to presentation. The most common clinical manifestations are fulminant infectious mononucleosis, dysgammaglobulinaemia, and lymphoma (usually of B-cell origin). XLP is caused by mutations in the SH2D1A gene which encodes the intracellular adaptor molecule SAP (signalling lymphocyte activation molecule- (SLAM-) associated protein). SAP is predominantly expressed in T cells and NK cells and functions to regulate signal transduction pathways downstream of the SLAM family of surface receptors to control CD4+ T cell (and by extension B-cell), CD8+ T cell and NK cell function, and development of NKT cells. Thus, SAP mutations cause dysregulation of the immune system, with defects in both cellular and humoral immunity. Here we report two clinical cases of three patients who presented with different manifestations of XLP, namely, fulminant infectious mononucleosis, Burkitt lymphoma and hypogammaglobulinaemia.

Complex and monosomal karyotype are distinct cytogenetic entities with an adverse prognostic impact in paediatric acute myeloid leukaemia. A NOPHO-DBH-AML study.

Data on occurrence, genetic characteristics and prognostic impact of complex and monosomal karyotype (CK/MK) in children with acute myeloid leukaemia (AML) are scarce. We studied CK and MK in a large unselected cohort of childhood AML patients diagnosed and treated according to Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML protocols 1993-2015. In total, 800 patients with de novo AML were included. CK was found in 122 (15%) and MK in 41 (5%) patients. CK and MK patients were young (median age 2·1 and 3·3 years, respectively) and frequently had FAB M7 morphology (24% and 22%, respectively). Refractory disease was more common in MK patients (15% vs. 4%) and stem cell transplantation in first complete remission was more frequent (32% vs. 19%) compared with non-CK/non-MK patients. CK showed no association with refractory disease but was an independent predictor of an inferior event-free survival (EFS; hazard ratio [HR] 1·43, P = 0·03) and overall survival (OS; HR 1·48, P = 0·01). MK was associated with a poor EFS (HR 1·57, P = 0·03) but did not show an inferior OS compared to non-MK patients (HR 1·14, P = 0·62). In a large paediatric cohort, we characterized AML with non-recurrent abnormal karyotype and unravelled the adverse impact of CK and MK on prognosis.

Influence of IL15 gene variations on the clinical features, treatment response and risk of developing childhood acute lymphoblastic leukemia in Latvian population.

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Modern treatment protocols allow achievement of long-term event-free survival rates in up to 85% of cases, although the treatment response varies among different patient groups. It is hypothesized that treatment response is influenced by the IL15 gene variations, although research results are conflicting. To analyze IL15 gene variations influence treatment response, clinical course and the risk of developing ALL we performed a case-control and family-based study. The study included 81 patients with childhood ALL. DNA samples of both or one biological parent were available for 62 of ALL patients and 130 age and gender adjusted healthy samples were used as a control group. Analyzed IL15 gene variations: rs10519612, rs10519613 and rs17007695 were genotyped using PCR-RFLP assay. Our results shows that IL15 gene variations haplotypes are associated with the risk of developing childhood ALL (p < 0.05), although there is no such association for the variations separately. The variations rs10519612 and rs1059613 in a recessive pattern of inheritance were associated with hyperdiploidy (p = 0.048). Analyzed genetic variations had no impact on other clinical features and treatment response (assessed by the minimal residual disease) in our study.

Association of ARID5B Genetic Variants with Risk of Childhood B Cell Precursor Acute Lymphoblastic Leukaemia in Latvia

Background: Acute lymphoblastic leukaemia (ALL) is the most common malignancy in childhood. Despite numerous investigations very little is still known about its aetiology. However, in one genome wide association study conducted to identify the possible genetic risk factors, two allelic variations rs10821936 and rs10994982 in the 3rd intron of the ARID5B gene were identified as possible ALL risk alleles. Association between ARID5B gene variants and ALL risk was also been confirmed for different ethnic groups. Materials and Methods: Eight genetic variants in the gene ARID5B were genotyped - rs10994982, rs7908445, rs7923074, rs10821936, rs10821937, rs7896246, rs10821938 and rs7089424 in 77 ALL patients in remission and in 122 age and gender matched controls; parental samples were also genotyped in 50 cases. Results: Six out of the eight (rs7908445, rs7923074, rs10821936, rs10821937, rs7896246 and rs7089424) analysed allelic variations were identified in the case-control analysis as statistically significant risk alleles for ALL development. In the family study and using hybrid analysis, all allelic variations were significantly associated with ALL. During the study, risk haplotype was identified rs10994982/rs7908445/rs7923074/ rs10821936/ rs10821937/rs7896246/rs10821938/rs7089424 ­ ATACCAAG ­ with a frequency in cases of 0.17 and in the control group at 0.29 (chi square = 6.69, p value = 0.009). In the family association study the same haplotype showed statistical significance (chi squared = 10.3, p value = 0.001). Conclusions: Results of the study replicate and extend previously published findings for ARID5B localized allelic variants, but do not explain the mechanism of action related to the pathogenesis of ALL.

Analysis of possible genetic risk factors contributing to development of childhood acute lymphoblastic leukaemia in the Latvian population.

INTRODUCTION: Childhood acute lymphoblastic leukaemia (ALL) is a complex disease caused by a combination of genetic susceptibility and environmental exposure. Previous genome-wide association studies have reported several single nucleotide polymorphisms (SNPs) associated with the incidence of ALL. Several variations in genes encoding enzymes involved in carcinogenesis are suggested as being associated with an increased risk of ALL development. MATERIAL AND METHODS: We enrolled 77 paediatric ALL patients and 122 healthy controls, and in addition parental DNA was also available for 45 probands. SNPs rs10821936 (ARID5B), rs4132601 (IKZF1), rs2239633 (CEBPE), rs3731217 (CDKN2A) and rs1800566 (NQO1) and the presence of GSTT1 and GSTM1 null variants were detected. For statistical analysis the hybrid method of two designs 'Haplin' was used as well as linkage disequilibrium for family-based association studies. RESULTS: We identified the SNP rs10821936 in the ARID5B gene as being statistically significantly associated with childhood ALL, especially if the C allele is in a homozygous state, relative risk (RR) 4.65, 95% CI: 2.03-10.6, p = 0.0006. Statistically significant differences were not found in other SNPs. We found risk combinations including all five variations, the strongest association being found in a combination where all five genetic variants are in a homozygous state, CCTTTTTTCC, p = 0.032. CONCLUSIONS: The identified SNP rs10821936 could serve as a potential risk marker for childhood ALL development. Further studies in an independent population are needed for verification.

Lack of association between polymorphisms in genes MTHFR and MDR1 with risk of childhood acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is a complex disease caused by interactions between hazardous exogenous or/and endogenous agents and many mild effect inherited susceptibility mutations. Some of them are known, but their functional roles still requireinvestigation. Age is a recognized risk factor; children with disease onset after the age of ten have worse prognosis, presumably also triggered by inherited factors. MATERIALS AND METHODS: The MDR1 gene polymorphisms rs1045642, rs2032582 and MTHFR gene polymorphisms rs1801131 and rs1801133 were genotyped in 68 ALL patients in remission and 102 age and gender matched controls; parental DNA samples were also available for 42 probands. RESULTS: No case control association was found between analyzed polymorphisms and a risk of childhood ALL development. Linkage disequilibrium was not observed in a family-based association study either. Only marginal association was observed between genetic marker rs2032582A and later disease onset (p=0.04). CONCLUSIONS: Our data suggest that late age of ALL onset could be triggered by mild effect common alleles.

Natural clearance of hepatitis C virus in hemophilia patients.

OBJECTIVE: The objective of this study was to investigate the prevalence of HCV (hepatitis C virus) infection in hemophilia patients in Latvia and to analyze association between natural clearance of HCV and human leukocyte antigen (HLA) class II genes. MATERIAL AND METHODS: From 61 hemophilic patients participating in this study, 38 were adults and 23 were pediatric patients younger than 18 years. To analyze association between HLA class II alleles and natural clearance of HCV, the gene frequency was compared in hemophilia patients group and the control group of 60 healthy subjects, all men. Serum HCV RNA was qualitatively determined and HLA class II alleles were identified by polymerase chain reaction (PCR) method. RESULTS: HCV infection is common among hemophilia patients in Latvia. Antibodies to HCV were found in 45 of 61 (74%) hemophilia patients. In 41% of hemophilia patients (18 of 44), HCV infection resolved spontaneously. Children cleared HCV more frequently than adults (7 of 11 comparing to 11 of 33, respectively; OR=3.50; P<0.05). The frequency difference was found to be statistically significant when comparing HLA alleles distribution in the sample of hemophilia patients who naturally cleared HCV (n=18) and in the control group (n=60) (corresponding frequency of HLA-DRB1*07 allele - 4 (11.11%) and 9 (1.67%); OR=7.38; P<0.05). CONCLUSIONS: Natural clearance of HCV infection is frequently found in hemophilia patients in Latvia. Children are more likely to clear virus naturally than adults. There is an association between natural clearance of HCV and HLA allele DRB1*07 in hemophilia patients.