No evidence of association of methylenetetrahydrofolate reductase polymorphism with occurrence of second neoplasms after treatment of childhood leukemia

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been associated not only with the risk for acute lymphoblastic leukemia (ALL) in adults and children, but also with increased methotrexate toxicity. The present study aimed to investigate whether MTHFR polymorphisms modify the risk for development of secondary malignancies in children treated for ALL with protocols that included high-dose methotrexate. MTHFR genotypes were determined in DNA samples isolated from archived bone marrow smears of 15 patients with a second malignancy and a matched control group of 30 patients who did not developed a second malignancy after the treatment for ALL. The frequencies of MTHFR C677T and A1298C genotypes in all patients were: C677T: CC 40%, CT 46.7% and TT 13.3% and A1298C: AA 46.7%, AC 44.4% and CC 8.9%. The relative risk for second malignancy was not significantly increased in ALL patients having at least one polymorphic C667T [odds ratio (OR) 1.51; 95% confidence interval (CI) 0.43 - 5.31] or one polymorphic A1298C allele (OR 1; 95% CI 0.29 - 3.46). Our study suggests that MTHFR polymorphisms are not associated with increased risk of second cancer in children treated with high-dose methotrexate.     

Clinical Impacts of Copy Number Variations in B-cell Differentiation and Cell Cycle Control Genes in Pediatric B-cell Acute Lymphoblastic Leukemia: a Single Centre Experience

BackgroundIKZF1 gene deletions have been identified as a poor prognostic factor in pediatric B-cell acute lymphoblastic leukemia (B-ALL), especially in the presence of co-occurring deletions (IKZF1^plus profile). This study aimed to determine the frequency of IKZF1 deletions and deletions in other B-cell differentiation and cell cycle control genes, and their prognostic impact in Slovenian pediatric B-ALL patients.Patients and methodsWe studied a cohort of 99 patients diagnosed with B-ALL from January 2012 to December 2020 and treated according to the ALL IC-BFM 2009 protocol. Eighty-eight bone marrow or peripheral blood samples were analysed for copy number variations (CNVs) using the SALSA MLPA P335 ALL-IKZF1 probemix.ResultsAt least one CNV was detected in more than 65% of analysed samples. The most frequently altered genes were PAX5 and CDKN2A/B (30.7%, 26.1%, and 25.0%, respectively). Deletions in IKZF1 were present in 18.2% of analysed samples and were associated with an inferior 5-year event-free survival (EFS; 54.8% vs. 85.9%, p = 0.016). The IKZF1^plus profile was identified in 12.5% of the analysed samples, and these patients had an inferior 5-year EFS than those with deletions in IKZF1 only and those without deletions (50.8% vs. 75.0% vs. 85.9%, respectively, p = 0.049). Overall survival (OS) was also worse in patients with the IKZF1^plus profile than those with deletions in IKZF1 only and those without deletions (5-year OS 76.2% vs. 100% vs. 93.0%, respectively). However, the difference between the groups was not statistically significant.ConclusionsOur results are in concordance with the results obtained in larger cooperative clinical trials. Copy number variations analysis using the SALSA MLPA kit is a reliable tool for initial diagnostic approach in children with B-ALL, even in smaller institutions in low- and middle-income countries.Key words: B-acute lymphoblastic leukemia, IKZF1 deletions, IKZF1 ^plus , MLPA, pediatric, copy number variations (CNVs)     

Development of treatment and clinical results in childhood acute myeloid leukemia in Slovenia in the period from 1991 to 2010

Background

A review of treatment and survival of children with acute myeloid leukemia (AML) in Slovenia from 1991 to 2010.

Methods

We collected demographic data, information on the time, and course of treatment of patients with AML, which were classified in three risk groups and treated according to standard arm of BFM AML protocols 83, 93, 98, and 04. We assessed the rate of remission, event-free survival and overall survival, the incidence of relapse, the secondary neoplasms, secondary AML, the proportion of patients treated with hematopoietic stem cell transplantation (HSCT) and causes of death. The 2- and 5-year overall survival (5yOS) was estimated according to age group, risk group, the presence of remission, and the time of the treatment.

Results

There were 50 patients, 18 males (36?%) and 32 females (64?%) included in this study. Secondary AML was presented in four patients. Patients treated with HSCT were 18 (36?%), 9 of them in first remission. The 2-year overall survival (2yOS) was 63.7?±?6.8?% and 5-year survival was 55.0?±?7.2?%. Differences in survival between age groups (0–5 years, 6–10 years and more than 10 years) was not significant. All patients in standard risk group lived for more than 2 years, in high-risk group 2yOS was 56.7?±?7.7?% (p?=?0.05). Patients who were in remission before second treatment block had 2yOS 77.8?±?7.4?% and 5yOS 63.8?±?8.8?%, compared to the patients who were not in remission (2yOSand 5yOS 37.5?±?12.1?%, p?=?0.001). The 2yOS in patients treated with HSCT in first remission was 62?%. There were 17 patients (34?%) who had relapse of the disease, 23 (64?%) patients died, 14 (61?%) due to progression of the disease.

Conclusions

The results of treatment of AML in our center are comparable with other European centers. Survival was better in the standard risk group and in patients who were in remission before second treatment block. We observed a trend of improvement in survival in the time observed.     

Malignant blue nevus with lymph node metastases in five-year-old girl

We report an unusual case of a malignant blue nevus in a five-year-old girl, which turned out to be malignant only after the development of lymph node metastases three years after the excision of the primary tumor on the patient's cheek. A functional bilateral neck dissection was performed and the patient is alive with no evidence of disease 8 years after the excision of the primary skin lesion.     

Individualized long‐term enzyme therapy for Gaucher disease type 1 in Slovenia

Background: Gaucher disease type 1 (GD1) was the first lysosomal storage disorder for which an effective enzyme replacement therapy was developed. We describe the management of eight GD1 patients in Slovenia who were diagnosed between the ages of 2 and 15 years. Methods: Patients were individually assessed to establish initial enzyme doses and monitored frequently to determine the effects of long‐term enzyme dose regimens. Outcomes up to 10 years after long‐term treatment are described by changes in the Zimran severity score index, chitotriosidase and acid phosphatase levels, and after 2001, bone parameters (DEXA bone mineral density scores and the MRI bone marrow burden score). Results: Following the initiation of enzyme therapy with individualized dose regimens (range 25–56 U/kg/14 days) and followed by a gradual reduction of doses (range 12–35 U/kg/14 days) during long‐term maintenance, disease status improved in all patients as measured by the Zimran severity score index (from a mean of 11.25 [median 11.5] before therapy to a mean of 4.12 [median 3.5] at last report). Anemia and leucopenia resolved in all patients, chitotriosidase and acid phosphatase levels decreased in all patients (and by over 75% in six patients) within 1 year of treatment. Bone marrow burden scores improved in all monitored patients and DXA scores improved in six of seven monitored patients. Conclusions: We conclude that enzyme therapy with relatively low, individualized dose regimens is well‐tolerated and effective in children and young adults with GD1 disease, who are regularly monitored for changes in disease status.