[Prognostic value of early treatment response in children with acute lymphoblastic leukemia: a single institution experience in Shanghai, China].

OBJECTIVE: Early response to therapy is one of the most important prognostic factors in childhood acute lymphoblastic leukemia (ALL). This study aimed to assess the prognostic value of morphological assessment of bone marrow blasts during remission induction and determination of minimal residual disease (MRD) after remission induction. METHODS: From January 1998 to May 2003, 193 children with newly diagnosed ALL were enrolled on the ALL-XH-99 protocol. Blast cell count in the bone marrow was examined on day 19 of remission induction and by the completion of remission induction. MRD was measured with the flow cytometry. Event-free survival (EFS) was estimated by Kaplan-Meier analysis and the distributions of EFS were compared using the log-rank test. A Cox proportional hazards model was used to identify independent prognostic factors. RESULTS: The 4-year EFS was significantly worse in patients with > or = 5% lymphoblasts in the bone marrow on day 19 as compared to those with <5% lymphoblasts on that date (42.59%+/- 14.28% vs 74.24%+/- 6.67%; p< 0.01). The 4-year EFS was significantly worse in patients with any amount of lymphoblasts in the bone marrow on the remission date as compared to that of other patients with no morphologically identifiable blasts (63.47%+/-9.23% vs 76.41%+/- 6.09%; p<0.05). The patients with MRD <0.01 had significantly better outcome than those with a level > or = 0.01% (15-month EFS:94.44%+/-5.40% vs 23.81%+/- 20.26%; p<0.01). CONCLUSIONS: Early treatment response as assessed by morphological examination or minimal residual leukemia determination by flow cytometry has important prognostic significance, and can be performed in a resource-poor patient population.

[Prognostic value of early treatment response in children with acute myeloid leukemia].

OBJECTIVE: To assess the prognostic value of early treatment response in children with acute myeloid leukemia (AML). METHODS: Sixty-one children with AML, 37 male and 24 female, aged 96 months (6 - 154 months), underwent treatment according to the protocol AML-XH-99 with a total treatment course of 15 months and were followed up for 12 months (1 - 74 months). Bone marrow smear was made 48 hours after the end of the first course of induction treatment. Then the children were divided into 2 groups according to the number of bone marrow blast cells: group with the number of blast cells > or = 0.15 and group with the number of blast cells < 0.15. Second bone marrow smear was made when complete remission was achieved after the end of the treatment course. Then the children were divided into 2 groups according to the number of bone marrow blast cells: group with the number of blast cells of 0.00 and group with the number of blast cells between 0.00 and 0.05. The probability of event-free survival (EFS) was estimated by Kaplan-Meier analysis. Log-rank test was used to compare the 5-year EFS (pEFS) of different groups. The differences in the biological features were compared by Chi-square analysis or Fisher exact test. RESULTS: The pEFS of the group with the number of blast cells > or = 0.15 was 18% +/- 15%, significantly shorter than that of the group with the number of blast cells < 0.15 (49% +/- 11%, P = 0.079). The 3 patients without morphologically identifiable blast all survived 5 years after complete remission had been achieved, and the pEFS of the 39 patients with the number of blast cells between 0.00 and 0.05 was 53% +/- 10%. The pEFS of the patients among which complete remission was achieved after the first course of treatment (n = 39) was 54% +/- 10%, significantly higher than that of the patients without complete remission after the first course of treatment (10% +/- 9%, P = 0.0002). Multiple factor analysis showed that achievement of complete remission after the first course of treatment and existence of central nervous system leukemia were both independent prognostic factors with the hazard ratios of 4.007 and 7.050 respectively and the 95% confidential intervals of 1.019 to 6.163 and 0.018 to 0.547 respectively (P = 0.045 and P = 0.008). The number of blasts 48 hours after the end of the first course of induction treatment was highly correlated with the rate of complete remission after the first treatment course (P = 0.000 028 8). CONCLUSION: With important prognostic significance, early treatment response, such as the number of blasts 48 hours after the end of the first course of induction treatment can predict whether complete remission can be achieved.

[Prognostic value of minimal residual disease in childhood B-cell acute lymphoblastic leukemia].

OBJECTIVE: To assess the prognostic value of minimal residual disease (MRD) in childhood B-cell acute lymphoblastic leukemia (ALL) after induction chemotherapy. METHODS: From September 2001 to October 2004, 102 patients with newly diagnosed B-ALL were enrolled in protocol ALL-XH-99. MRD after induction therapy, before high-dose methotrexate and early intensification as well as at 1 year and 2 year maintenance therapy was detected by multiparameter-flow-cytometry (MP-FCM). RESULTS: (1) The probability of 39-month event-free survival (EFS) for patients with a level of MRD < 10(-4), was significantly higher than for those with a higher MRD [(83.00 +/- 9.90)% vs 0.00%, P < 0.01]. (2) Univariate analysis indicated that the MRD level at achieving complete remission (CR) had no relationship with the biologic features at presentation (gender, age, white blood cells and cytogenetic abnormalities), but did with Philadelphia chromosome, the time reaching CR, ALL-XH-99 risk group and lymphoblasts in bone marrow on day 19 after induction therapy (P < 0.05). (3) Multivariate analysis suggested that MRD level after the first induction course was an independent prognostic factor (hazard ratio, 5.381; 95% CI 0.004 to 0.624; P < 0.05). CONCLUSION: The MRD level at achieving CR is one of important prognostic factor in the treatment of childhood B-cell ALL, and might be used to assess the early treatment response.

[Prognostic value of both detection of lymphoblasts in the period of early treatment and minimal residual disease in childhood acute lymphoblastic leukemia].

OBJECTIVE: To assess the prognostic value of both morphological persistent disease on day 19, on complete remission (CR) and minimal residual disease (MRD) in the bone marrow (BM) after multiagent remission induction therapy. METHODS: From January 1998 to May 2003, 193 patients with newly diagnosed ALL were enrolled on protocol of ALL-XH-99. BM blast counts on day 19 and on CR after induction therapy were examined. BM MRD at the end of induction therapy was detected by MP-FCM. RESULTS: (1) The probability of 5-year event-free survival (pEFS) was significantly worse for patients with > or = 0.050 BM lymphoblasts on day 19 than that with < 0.050 BM lymphoblasts [(42.59 +/- 14.28)% vs (74.24 +/- 6.67)%, P < 0.001]. (2) The 5-year pEFS was significantly worse for patients with a low percentage of lymphoblasts (< 0.050) in BM on CR as compared to those with no morphological persistent lymphoblasts [(63.47 +/- 9.23)% vs (76.41 +/- 6.09)%, P < 0.05]. (3) No significant difference was found in BM lymphoblasts between patients with MRD (> or = 10(-4) of nucleated bone marrow cells) and those without MRD (< 10(-4)) at the end of induction therapy (P > 0.05). The 22-month pEFS was significantly worse for patients with MRD as compared with those without MRD on CR [(23.81 +/- 20.26)% vs (94.44 +/- 5.40)%, P = 0.001]. CONCLUSIONS: BM lymphoblast > or = 0.050 on day 19 after induction therapy is an independent prognostic factor for childhood ALL; low percentage of lymphoblasts and minimal residual disease in BM on remission also do it. Patients with > or = 0.050 lymphoblast in BM on day 19 or with MRD > or = 10(-4) at the end of induction therapy should receive altered and more intensive chemotherapy.

[Analysis on GST-Pi genetic polymorphism in children with acute leukemia].

OBJECTIVES: To study the frequency distribution patterns of the genetic polymorphisms for glutathione S-transferase Pi (GST-Pi) in children with acute leukemia, and explore the possible relationship of GST-Pi gene mutation to the vulnerability of children with leukemia and the chemotherapeutic response. METHOD: Direct DNA sequencing was applied to detect the genotype polymorphism in 85 healthy children as the control group and 120 children with acute leukemia. The distribution difference of the genotypes between them was analyzed. RESULTS: Gene mutation rate of GST-Pi exon5 was 47.5% in children with acute leukemia, significantly higher than that of 31.8% in the control group (OR = 1.944, 95% CI 1.088-3.473), and this polymorphism distribution pattern was similar to that reported abroad. The mutation rate was much higher in ALL group than in others groups and was not significantly between the AML children and the control group. The overall mutation rate of B-lineage ALL (60.3%) was markedly higher than that of T-ALL (47.1%), but the homozygous mutation rate of the latter group (17.6%) was much higher than that of the former group (3.4%) (P < 0.05). The average survival time of the children with wild type exon5 was 24 months, longer than that of the mutation group (17.6 months), however with no statistical difference (P > 0.05). The genotype of exon5 had no effect on the survival time of AML children. No Ala(114)Val variant genotype of GST-Pi exon6 reported in literatures was found in this study, but two new mutant genotypes were discovered. A/G hybridity at 99 loci of exon6 was found in one healthy child and such hybrid genotype did not result in amino acid alteration. G-->T/G bases hybridity at 103 loci of exon6 occurred in two children with leukemia, leading to GAC of Asp (aspartic acid) replaced by TAC of Try (tyrosine) at 147 loci of the protein peptide chain, producing Asp(147) Try hybrid mutation with a genotypic frequency of 1.7%. CONCLUSION: The gene mutation of GST-Pi exon5 is one of the potential vulnerable factors in leukemogenesis of the Chinese children and the genetic polymorphism of exon6 in Chinese is greatly different from that in other races. The role of the newly discovered variant genotype Asp(147) Try in leukemogenesis remains to be further studied.