Polymorphisms of SLC19A1 80 G>A, MTHFR 677 C>T, and Tandem TS Repeats Influence Pharmacokinetics, Acute Liver Toxicity, and Vomiting in Children With Acute Lymphoblastic Leukemia Treated With High Doses of Methotrexate.

Introduction: High dose methotrexate (HD-Mtx) is highly effective and significantly improves overall acute lymphoblastic leukemia (ALL) patients survival. The pharmacodynamics of Mtx depends on the polymorphism of genes encoding proteins engaged in the folate metabolism pathway. The aim of the current study is to determine the relationship between variants of folate metabolism-related genes and the frequency of acute toxicities of HD-Mtx. Material and Methods: A group of 133 patients aged 1.5-18.1 years (median: 6.3) was treated in accordance with the ALL-IC-2002 and ALL-IC-2009 protocols. The following polymorphisms were determined: 80 G>A SLC19A1 (solute carrier family 19 member 1; rs1051266) with direct DNA sequencing, as well as 677 C>T MTHFR (methylenetetrahydrofolate reductase; rs1801133) and the tandem repeats of the TS (thymidylate synthase) with PCR technique. HD-Mtx organ toxicities were evaluated based on the laboratory tests results and the National Cancer Institute criteria. Results: In patients with genotypes AA for SLC19A1 and CC or CT for MTHFR Mtx steady state concentrations (Css) and AUCinf were distinctly higher. In patients with genotype 3R/3R for TS initial elimination rate constant was significantly higher (P = 0.003). Patients receiving Mtx at the dose of 5 g/m2 had lower clearance (4.35 vs. 8.92 L/h/m2) as compared to the ones receiving 2 g/m2 that indicates non-linear Mtx elimination at the higher dose. Liver impairment was the most frequently observed toxicity. The homozygous genotype was associated with a significantly higher incidence of hepatic toxicity for both the SLC19A1 (P = 0.037) and TS (P = 0.002). Logistic regression analysis indicated an increased risk of vomiting for the 2R/3R genotype of the TS gene (OR 3.20, 95% CI 1.33-7.68, P = 0.009) and for vomiting and hepatic toxicity for the 3R/3R genotype (vomiting: OR 3.39, 95% CI 1.12-10.23, P = 0.031; liver toxicity: OR 2.28, 95% CI 1.05-4.95, P = 0.038). None of the acute toxicities differed between the analyzed dosing groups. Conclusions: Determination of polymorphisms of SLC19A1, MTHFR, and TS genes might allow for a better prior selection of patients with higher risk of elevated Mtx levels. Our study is the first one to report the increased risk of hepatotoxicity and vomiting in patients with TS polymorphisms.

[Recommendation for using granulocyte and granulocyte-macrophage growth factor during anti-cancer therapy in children]. / Rekomendacje stosowania granulocytarnych i granulocytarno-makrofagowych czynników wzrostu w przebiegu leczenia przeciwnowotworowego u dzieci.

Neutropenia is the most often side effect during antineoplastic treatment. In this article current recommendations for clinical applications of granulocyte and granulocyto-macrophage hematopoietic factors and possibility of protection of neutropenia, and its serious complications in pediatric oncology are presented.

[Acute lymphoblastic leukemia in children with initial leucocytosis above 50,000/mm3: summary of treatment results of Polish Pediatric Leukemia/Lymphoma Study Group]. / Ostra bialaczka limfoblastyczna u dzieci ze wstepna leukocytoza powyzej 50,000/mm3: podsumowanie wyników leczenia Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczek i Chloniaków.

Initial leucocytosis, presence of t(9;22) and t(4;11) translocations and poor response to therapy with steroids or induction chemotherapy are still included to poor risk factors group. From 1981 to 1986, children with acute lymphoblastic leukemia (ALL) and initial WBC above 50,000/mm3, achieved significantly worse treatment results than children with lower WBC: over 6-year disease-free survival were respectively 33% and 60%. In attempt to improve treatment results in children with hyperleucocytosis, modified American protocols called: New York (1987), New York I (1997), and New York II (1999) were introduced consecutively in the centers of Polish Pediatric Leukemia/ Lymphoma Study Group. Actually treatment results obtained with those protocols in three groups of patients: group I: 214 children (1987-1996), group II: 58 children (1997-1999), and group III: 77 children (1999-2001) are presented. The observation was completed in March 31, 2004. In evaluated groups the first complete remissions (CR) were achieved in 91%, 95%, and 96% of patients, respectively. Relapses occurred in 72 patients of group I (37%), in 12 patients of group II (21%), and in 13 patients of group III (18%). The 5-year overall survivals were: 62%, 79%, and 78% (p=0.05) respectively; 5 year event-free survivals (EFS) were: 52%, 74%, and 69% (p=0.01) respectively. A significant improvement in treatment results in second compared with first group was achieved. Treatment results obtained with New York II are comparable with results obtained with New York I. The analysis of treatment results achieved shows the improvement of the prognosis in children with ALL and initial WBC above 50 000/mm3 in comparison with patients treated before 1987. There is strong necessity of unification of risk group qualification criteria in childhood ALL in term of comparable estimation treatment results achieved in different centers all over the world.

[Minimal residual disease in childhood acute leukemias]. / Minimalna choroba resztkowa w ostrych bialaczkach u dzieci.

Monitoring of residual leukemic cells, so called minimal residual disease (MRD) in acute leukemias is of great importance in clinical practice. Especially evaluation of early response to treatment has a important prognostic value, and modifies the therapy schedule in a nowadays used treatment protocols. Methods used for monitoring of MRD consist of molecular techniques, which detect chromosomal aberrations or immunoglobulins and lymphocyte T receptor genes rearrangements, as well as method of flow cytometry, which detect immunophenotype typical for the leucemic clone. The paper shows advantages and disadvantages each of those methods. The best approach to monitoring MRD in ALL during and after the treatment seems to be combination of molecular and immunological techniques.

[Significance of L-asparaginase activity and biochemical parameters evaluation in children with acute lymphoblastic leukemia]. / Znaczenie oceny aktywnosci L-asparaginazy oraz badan biochemicznych w monitorowaniu leczenia dzieci z ostra bialaczka limfoblastyczna.

L-asparaginase is one of the most important agent used in multidrug chemotherapy regimens in the treatment of malignancies which derive from lymphoid system (acute lymhoblastic leukemias and non-hodgkin lymphoma). L-asparaginase leads to enzymatic cleavage of L-asparagine (amino acid essential for lymphoblasts' growth) to ammonia and L-aspartic acid, what results in depletion of L-asparagine in a serum and cerebrospinal fluid, and finally leads to destruction of lymphoblasts, which lack ability of endogenic L-asparagine production. In the course of L-asparaginase therapy severe side effects could be observed such as: coagulation disturbances, acute pancreatitis, anaphilactic shock and other types of allergic reaction, as well as liver and CNS failure. Monitoring of L-asparaginase activity in serum is recomended in order to optimalize therapy with L-asparaginase and reducing risk of severe side effects. Continuous assessment of L-asparaginase activity during therapy gives also opportunity to detect asymptomatic inactivation of L-ASPA - so called "silent inactivation", which is cused by production of antibodies against xenogenic protein, especcialy in IgG class. This process leads to shortening of half-life of L-ASPA. The paper shows presently available monitoring methods during therapy with L-ASPA, with all their pros and cons.

[Perspectives in the use of imatinib in the treatment of childhood cancers]. / Perspektywy zastosowania imatinibu w leczeniu nowotworów dzieciecych.

Introduction of novel diagnostic methods and multimodal therapy has resulted in about 70% probability of cure of childhood neoplasms. However, treatment results of some neoplastic diseases in children, including chronic myelogenous leukemia (CML) still remain unsatisfactory. The only chance of cure remains allogeneic hematopoietic stem cell transplantation, however availability of transplantation is still low as a limited number of donors is available. In neoplastic diseases in which treatment results remain poor, intensification of treatment components (chemotherapy, radiotherapy) did not succeed in improving the treatment results. In recent years no improvement was made in gene therapy. With introduction of new drugs that selectively inhibit mechanisms of maturation and proliferation of cancer cells, new hope has arisen. In our paper we present the mechanism of action of imatinib, the tyrosine kinase inhibitor which was employed in the treatment of CML and gastrointestinal stromal tumors. Currently, there are several ongoing studies assessing the efficacy of this novel drug in the therapy of brain tumors, neuroblastoma, lung and prostate cancer.

[Advances in the treatment of children with high risk acute lymphoblastic leukemia (ALL) treated with modified "NEW YORK" protocols between 1987 and 2002]. / Postepy w leczeniu dzieci z ostra bialaczka limfoblastyczna (ALL) wysokiego ryzyka wg modyfikowanych programów "NOWY JORK" w latach 1987-2002.

From 1981 to 1986, in children with ALL and initial WBC > or = 50,000/mm3, over 6-year disease-free survival was significantly lower (33%) than in children with WBC < 50,000/mm3 (60%). In attempt to improve this unsatisfactory results, three modified American protocols named: "New York", "New York I", and "New York II", "New York I", and "New York II" were introduced consecutively in the centers of Polish Pediatric Leukemia Lymphoma Study Group (respectively, in 1987, 1997, and 1999). The treatment results achieved in three consecutive therapeutic groups of children with ALL and initial WBC > or = 50,000/mm3: group I--213 children (1987-1996), group II--58 children (1997-1999), and group III--52 children (1999-2001) are presented. The observation was completed in December 31, 2002. In three evaluated groups the first complete remissions (CRs) were achieved in 90.6%. 94.8%. and 94.2% of patients, respectively. Relapses occurred in 71 patients of group I (37%), in 9 patients of group II (16%), and in 6 patients of group III (12%). The complications of treatment caused death in 7 children of group I, in 1 child of group II, and in 2 children of group III. Eighty-one (38%), 11 (18.9%), and 9 (17.3%) patients, respectively, died due to progression of disease. The event-free survival (EFS) in three evaluated groups did not depend on age of children and WBC. The rates of 2-, 5-, and 10-year event-free survival (EFS) in group I were: 69.9%, 55.3%, and 53.6%, respectively and the rates of 2- and 5-year EFS in group II were: 80.7% and 72.7%, respectively. The rate of 2-year EFS in group III was 71.6%. The analysis of achieved treatment results in three evaluated groups shows the gradual improvement of the prognosis in children with ALL and initial WBC > or = 50,000/mm3 treated with the use of modified protocols "New York" and "New York I" in comparison with patients treated before 1987. Longer observation is needed for evaluation of efficacy and complications of "New York II" protocol.