Possible benefit of consolidation therapy with high-dose cytarabine on overall survival of adults with non-promyelocytic acute myeloid leukemia

In adults with non-promyelocytic acute myeloid leukemia (AML), high-dose cytarabine consolidation therapy has been shown to influence survival in selected patients, although the appropriate doses and schemes have not been defined. We evaluated survival after calculating the actual dose of cytarabine that patients received for consolidation therapy and divided them into 3 groups according to dose. We conducted a single-center, retrospective study involving 311 non-promyelocytic AML patients with a median age of 36 years (16-79 years) who received curative treatment between 1978 and 2007. The 131 patients who received cytarabine consolidation were assigned to study groups by their cytarabine dose protocol. Group 1 (n=69) received <1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles. The remaining patients received high-dose cytarabine (≥1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles). The actual dose received during the entire consolidation period in these patients was calculated, allowing us to divide these patients into 2 additional groups. Group 2 (n=27) received an intermediate-high-dose (<27 g/m2), and group 3 (n=35) received a very-high-dose (≥27 g/m2). Among the 311 patients receiving curative treatment, the 5-year survival rate was 20.2% (63 patients). The cytarabine consolidation dose was an independent determinant of survival in multivariate analysis; age, karyotype, induction protocol, French-American-British classification, and de novo leukemia were not. Comparisons showed that the risk of death was higher in the intermediate-high-dose group 2 (hazard ratio [HR]=4.51; 95% confidence interval [CI]: 1.81-11.21) and the low-dose group 1 (HR=4.43; 95% CI: 1.97-9.96) than in the very-high-dose group 3, with no significant difference between those two groups. Our findings indicated that very-high-dose cytarabine during consolidation in adults with non-promyelocytic AML may improve survival

Cytogenetic studies of Brazilian pediatric myelodysplastic syndrome cases: challenges and difficulties in a large and emerging country

Myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematopoietic stem cell diseases affecting children. Cytogenetics plays an important role in the diagnosis of these diseases. We report here the experience of the Cytogenetic Subcommittee of the Brazilian Cooperative Group on Pediatric Myelodysplastic Syndromes (BCG-MDS-PED). We analyzed 168 cytogenetic studies performed in 23 different cytogenetic centers; 84 of these studies were performed in patients with confirmed MDS (primary MDS, secondary MDS, JMML, and acute myeloid leukemia/MDS+Down syndrome). Clonal abnormalities were found in 36.9% of the MDS cases and cytogenetic studies were important for the detection of constitutional diseases and for differential diagnosis with other myeloid neoplasms. These data show the importance of the Cooperative Group for continuing education in order to avoid a late or wrong diagnosis

Evaluation of chromosomal abnormalities by cIg-FISH and association with proliferative and apoptotic indexes in multiple myeloma

Eighty-six newly diagnosed multiple myeloma (MM) patients from a public hospital of São Paulo (Brazil) were evaluated by cIg-FISH for the presence of del(13)(q14), t(4;14)(p16.3;q32) and del(17)(p13). These abnormalities were observed in 46.5, 9.3, and 7.0% of the patients, respectively. In order to identify the possible role of del(13)(q14) in the physiopathology of MM, we investigated the association between this abnormality and the proliferative and apoptotic indexes of plasma cells. When cases demonstrating t(4;14)(p16.3;q32) and del(17)(p13) were excluded from the analysis, we observed a trend towards a positive correlation between the proportion of cells carrying del(13)(q14) and plasma cell proliferation, determined by Ki-67 expression (r = 0.23, P = 0.06). On the other hand, no correlation between the proportion of cells carrying del(13)(q14) and apoptosis, determined by annexin-V staining, was detected (r = 0.05, P = 0.69). In general, patients carrying del(13)(q14) did not have lower survival than patients without del(13)(q14) (P = 0.15), but patients with more than 80% of cells carrying del(13)(q14) showed a lower overall survival (P = 0.033). These results suggest that, when del(13)(q14) is observed in a high proportion of malignant cells, it may have a role in determining MM prognosis. Another finding was a statistically significant lower overall survival of patients with t(4;14)(p16.3;q32) (P = 0.026). In the present study, almost half the patients with t(4;14)(p16.3;q32) died just after diagnosis, before starting treatment. This fact suggests that, in São Paulo, there may be even more patients with this chromosomal abnormality, but they probably die before being diagnosed due to unfavorable socioeconomic conditions. This could explain the low prevalence of this chromosomal abnormality observed in the present study

Mdr-1 And Gst Polymorphisms Are Involved In Myelodysplasia Progression

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterized by abnormal hematopoietic differentiation and maturation, which progress toward acute leukemia in approximately 30% of the cases. Drug metabolism polymorphisms in Cytochrome P450 2B6 (CYP2B6), Glutathione S-transferase (GST) and Dehydrogenase Quinone 1 (NQO1) enzymes and P-glycoprotein (MDR-1) could modify enzyme activity. Thus, the aim of this study was to identify the influence of CYP2B6 G15631T, GSTT1, GSTM1, NQO1 C609T and MDR-1 C3435T polymorphisms on MDS progression. We analyzed 78 MDS patients using the PCR-RFLP and multiplex method. The frequency of GST deletions and MDR-1 CC genotype was lower in progression-free patients compared to patients with progression; GST: 17% vs. 35% (P=0.018); MDR-1 gene: 19% vs. 48% (P=0.012). We also verified the influence of GST deletions and MDR-1 C3435T on patient overall survival and found no significant difference (RR=0.75; P=0.599 and RR=0.79; P=0.594 respectively). We concluded that GSTM1 deletion may contribute toward MDS progression probably due to toxic metabolite accumulation which generates cell toxicity and DNA damage. Moreover, MDR-1 C3435T may have a protective effect against MDS progression because the expected lower expression of P-glycoprotein would lead to a higher degree of cell death. To the best of our knowledge, this is the first study showing the relationship of these polymorphisms with MDS progression. © 2013 Elsevier Ltd.378970973Vardiman, J.W., Harris, N.L., Brunning, R.D., The World Health Organization (WHO) classification of the myeloid neoplasms (2002) Blood, 100, pp. 2292-2302Nolte, F., Hofmann, W.K., Myelodysplastic syndromes: molecular pathogenesis and genomic changes (2008) Ann Hematol, 87, pp. 777-795Weinshilboum, R., Inheritance and drug response (2003) N Engl J Med, 348, pp. 529-537Barragan, E., Collado, M., Cervera, J., Martin, G., Bolufer, P., Roman, J., The GST deletions and NQO1*2 polymorphism confers interindividual variability of response to treatment in patients with acute myeloid leukemia (2007) Leuk Res, 31, pp. 947-953Yuan, Z.H., Liu, Q., Zhang, Y., Liu, H.X., Zhao, J., Zhu, P., CYP2B6 gene single nucleotide polymorphisms and leukemia susceptibility (2011) Ann Hematol, 90, pp. 293-299Berkoz, M., Yalin, S., Association of CYP2B6 G15631T polymorphism with acute leukemia susceptibility (2009) Leuk Res, 33, pp. 919-923Traver, R.D., Horikoshi, T., Danenberg, K.D., Stadlbauer, T.H., Danenberg, P.V., Ross, D., NAD(P)H:quinone oxidoreductase gene expression in human colon carcinoma cells: characterization of a mutation which modulates DT-diaphorase activity and mitomycin sensitivity (1992) Cancer Res, 52, pp. 797-802Lanciotti, M., Dufour, C., Corral, L., Di Michele, P., Pigullo, S., De Rossi, G., Genetic polymorphism of NAD(P)H:quinone oxidoreductase is associated with an increased risk of infant acute lymphoblastic leukemia without MLL gene rearrangements (2005) Leukemia, 19, pp. 214-216Rao, D.N., Anuradha, C., Vishnupriya, S., Sailaja, K., Surekha, D., Raghunadharao, D., Association of an MDR1 gene (C3435T) polymorphism with acute leukemia in India (2010) Asian Pac J Cancer Prev, 11, pp. 1063-1066Penna, G., Allegra, A., Alonci, A., Aguennouz, M., Garufi, A., Cannavo, A., MDR-1 polymorphisms (G2677T and C3435T) in B-chronic lymphocytic leukemia: an impact on susceptibility and prognosis (2010) Med OncolRollinson, S., Roddam, P., Kane, E., Roman, E., Cartwright, R., Jack, A., Polymorphic variation within the glutathione S-transferase genes and risk of adult acute leukaemia (2000) Carcinogenesis, 21, pp. 43-47Krajinovic, M., Labuda, D., Richer, C., Karimi, S., Sinnett, D., Susceptibility to childhood acute lymphoblastic leukemia: influence of CYP1A1, CYP2D6, GSTM1, and GSTT1 genetic polymorphisms (1999) Blood, 93, pp. 1496-1501Smith, M.T., Wang, Y., Kane, E., Rollinson, S., Wiemels, J.L., Roman, E., Low NAD(P)H:quinone oxidoreductase 1 activity is associated with increased risk of acute leukemia in adults (2001) Blood, 97, pp. 1422-1426Jamroziak, K., Mlynarski, W., Balcerczak, E., Mistygacz, M., Trelinska, J., Mirowski, M., Functional C3435T polymorphism of MDR1 gene: an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia (2004) Eur J Haematol, 72, pp. 314-321Arruda, V.R., Lima, C.S., Grignoli, C.R., de Melo, M.B., Lorand-Metze, I., Alberto, F.L., Increased risk for acute myeloid leukaemia in individuals with glutathione S-transferase mu 1 (GSTM1) and theta 1 (GSTT1) gene defects (2001) Eur J Haematol, 66, pp. 383-388Wang, B., Jin, F., Xie, Y., Tang, Y., Kan, R., Zheng, C., Association analysis of NAD(P)H:quinone oxidoreductase gene 609C/T polymorphism with Alzheimer's disease (2006) Neurosci Lett, 409, pp. 179-181Rodrigues, F.F., Santos, R.E., Melo, M.B., Silva, M.A., Oliveira, A.L., Rozenowicz, R.L., Correlation of polymorphism C3435T of the MDR-1 gene and the response of primary chemotherapy in women with locally advanced breast cancer (2008) Genet Mol Res, 7, pp. 177-183Kim, R.B., Leake, B.F., Choo, E.F., Dresser, G.K., Kubba, S.V., Schwarz, U.I., Identification of functionally variant MDR1 alleles among European Americans and African Americans (2001) Clin Pharmacol Ther, 70, pp. 189-199Johnstone, R.W., Ruefli, A.A., Smyth, M.J., (2000) Trends Biochem Sci, 25, pp. 1-6. , Multiple physiological functions for multidrug transporter P-glycoprotein?Steven, J.P., (1992) Applied multivariate statistics for the social sciences, , Lawrence Erlbaum Associates, New Jerse

Pre-analytical parameters associated with unsuccessful karyotyping in myeloid neoplasm: a study of 421 samples

Cytogenetics is essential in myeloid neoplasms (MN) and pre-analytical variables are important for karyotyping. We assessed the relationship between pre-analytical variables (time from collection to sample processing, material type, sample cellularity, and diagnosis) and failures of karyotyping. Bone marrow (BM, n=352) and peripheral blood (PB, n=69) samples were analyzed from acute myeloid leukemia (n=113), myelodysplastic syndromes (n=73), myelodysplastic syndromes/myeloproliferative neoplasms (n=17), myeloproliferative neoplasms (n=137), and other with conclusive diagnosis (n=6), and reactive disorders/no conclusive diagnosis (n=75). The rate of unsuccessful karyotyping was 18.5% and was associated with the use of PB and a low number of nucleated cells (≤7×103/µL) in the sample. High and low cellularity in BM and high and low cellularity in PB samples showed no metaphases in 3.9, 39.7, 41.9, and 84.6% of cases, respectively. Collecting a good BM sample is the key for the success of karyotyping in MN and avoids the use of expensive molecular techniques