Pharmacokinetics and Pharmacodynamics of Oral Methotrexate and Mercaptopurine in Children With Lower Risk Acute Lymphoblastic Leukemia: A Joint Children's Cancer Group and Pediatric Oncology Branch Study

We prospectively assessed the pharmacokinetics of methotrexate,mercaptopurine, and erythrocyte thioguanine nucleotide levels in ahomogenous population of children with lower risk acute lymphoblastic leukemia and correlated pharmacokinetic parameters with disease outcome. The maintenance therapy regimen included daily oralmercaptopurine (75 mg/m²) and weekly oral methotrexate (20 mg/m²). One hundred ninety-one methotrexate doses and 190 mercaptopurine doses were monitored in 89 patients. Plasma drugconcentrations of both agents were highly variable. The area under theplasma concentration-time curve (AUC) of methotrexate ranged from 0.63 to 12 µmolh/L, and the AUC of mercaptopurine ranged from 0.11 to8 µmolh/L. Drug dose, patient age, and duration of therapy didnot account for the variability. Methotrexate AUC was significantly higher in girls than boys (P = .007). There was considerableintrapatient variability for both agents. Erythrocyte thioguaninenucleotide levels were also highly variable (range, 0 to 10 pmol/g Hgb)and did not correlate with mercaptopurine dose or AUC. A Cox regression analysis showed that mercaptopurine AUC was a marginally significant (P = .043) predictor of outcome, but a direct comparison ofmercaptopurine AUC in the remission and relapsed patient groups failedto show a significant difference. Methotrexate and mercaptopurineplasma concentrations and erythrocyte thioguanine nucleotide levelswere highly variable, but measurement of these pharmacokineticparameters at the start of maintenance will not distinguish patientswho are more likely to relapse.     

Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia in the Elderly: Prognostic Factors and Treatment Outcome

Data on all patients diagnosed with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) aged 55 or older, seen in our institution over a 17-year period, were studied to determine the incidence and range of clinical and biological subtypes, and the outcome of different therapeutic approaches. Twenty-five Ph+ ALL cases (median age: 64 years) were diagnosed between 1986 and 2003 (28% of all B-lineage elderly ALL seen during this period). Karyotypic analysis was performed successfully in 22 cases, while 3 were only diagnosed by molecular biology analysis. All patients had B-cell lineage ALL. Co-expression of myeloid markers was observed in 20% of tested cases. One patient died before chemotherapy could be given. All other patients received "curative" treatment according to different protocols used during the period of study. Overall the complete remission (CR) rate was 76% (95% confidence interval, CI: 55-91%). Fifteen patients achieved CR after one course of chemotherapy and 4 patients after salvage therapy. Median disease-free survival (DFS) of the entire cohort was 5.6 months (95% CI: 4.5-8.4 months) and median overall survival was 10.1 months (95% CI: 7.9-13 months). In multivariate analysis, age≥70 years was of poor prognostic value for achieving CR ( p =0.05) and hyperleukocytosis at diagnosis was of poor prognostic value for overall survival ( p =0.001). Overall survival duration was not significantly influenced by achieving CR. Ph+ ALL patients did not show a significant difference in terms of outcome as compared with Philadelphia-negative ALL patients. The very poor overall outcome in elderly patients with Ph+ ALL may be significantly improved by the introduction of imatinib mesylate into current treatment regimens.     

CD7^＋急性髓细胞性白血病临床及实验室特征分析

CD7抗原是T细胞性急性淋巴细胞性白血病(acute lymphoblastic leukemia,T-ALL)最敏感的检测指标之一,但其特异性不强,在10%~20%的急性髓细胞性白血病(acute myeloid leukemia,AML)中也有表达[1~2],且AML中CD7+常与多药耐药相关,提示疾病恶性度高、预后差[3~5]。本文报道本院新近收治的1例CD7+AML并复习已知文献,对CD7抗原在AML中的表达及其临床意义进行总结。临床资料患者男性,51岁。2005年11月21日因“低热、乏力、面色苍白1月余”入院。既往史及体格检查均无特殊。入院后查肝功能、肾功能、电解质、尿常规、粪常规及出凝血功能…     

A Case of T-Cell Acute Lymphoblastic Leukemia after Treatment of Acute Promyelocytic Leukemia

We diagnosed T-cell acute lymphoblastic leukemia (T-ALL) with multiple cytogenetic abnormalities in a 17-year-old girl a year after she had received a diagnosis of acute promyelocytic leukemia (APML). After the diagnosis of APML in June 2001, the patient was treated with idarubicin and all-trans-retinoic acid. In September 1999, her younger sister also received a diagnosis of APML and to date has remained well. T-ALL after remission of APML is very rare, and only 1 such case has been reported. Possible causes include therapy-related reasons, genetic susceptibility to leukemia, and environmental exposure.     

Immunophenotypes and Outcome of Philadelphia Chromosome-Positive and -Negative Thai Adult Acute Lymphoblastic Leukemia

Little evidence exists in Asian countries regarding the incidence, immunologic characteristics, and clinical outcomes of adult patients with Philadelphia chromosome-positive (Ph+) and -negative (Ph-) acute lymphoblastic leukemia (ALL). In this study, we prospectively studied 324 Thai adult acute leukemia patients, 79 (24%) of whom were identified as having ALL. Immunophenotyping was performed by 5-parameter flow cytometry, and karyotyping was conducted by standard banding methods. The Ph chromosome was detected in 18.5% of cases. The mean age of Ph+ ALL patients was 29 years (50% male), and that of Ph- ALL patients was 33 years (62% female). The Ph+ ALL patients had significantly higher white blood cell (WBC) counts (mean, 93 x 10(9)/L), with 67% having WBC counts higher than 50 x 10(9)/L. In contrast, most Ph- ALL patients had WBC counts lower than 50 x 10(9)/L (mean, 36 x 10(9)/L; P < .05). CD10 and CD34 were more highly expressed in the Ph+ ALL patients (mean expression, 83% and 87%, respectively) than in the Ph- ALL patients (45% and 57%; P < .005). The aberrant expression of myeloid antigens, including CD33 and CD13, was also significantly observed in the Ph+ ALL patients. The median survival time of Ph+ ALL patients was 8 months, compared with 22 months for the Ph- ALL patients. In conclusion, immunophenotyping results showed that Ph+ ALL in Thai adults arises from B-cells at an earlier stage of development. Extreme leukocytosis, a younger age, male sex, high expression levels of CD10 and CD34, aberrant myeloid antigens, and poorer rates of survival appeared to be associated with the Ph chromosome in Thai adult ALL cases. The incidence of the Ph chromosome among Thai adult ALL patients was not different from that found in Western countries.     

Minimal Residual Disease Status Before Allogeneic Bone Marrow Transplantation Is an Important Determinant of Successful Outcome for Children and Adolescents With Acute Lymphoblastic Leukemia

The efficacy of allografting in acute lymphoblastic leukemia (ALL)is heavily influenced by remission status at the time of transplant.Using polymerase chain reaction (PCR)-based minimal residual disease(MRD) analysis, we have investigated retrospectively the impact ofsubmicroscopic leukemia on outcome in 64 patients receiving allogeneicbone marrow transplantation (BMT) for childhood ALL. Remission BMspecimens were taken 6 to 81 days (median, 23) before transplant. Allpatients received similar conditioning therapy; 50 received grafts fromunrelated donors and 14 from related donors. Nineteen patients weretransplanted in first complete remission (CR1) and 45 in second orsubsequent CR. MRD was analyzed by PCR of Ig or T-cell receptor  or rearrangements, electrophoresis, and allele-specific oligoprobing.Samples were rated high-level positive (clonal band evident afterelectrophoresis; sensitivity 10² to 10³),low-level positive (MRD detected only after oligoprobing; sensitivity 10³ to 10⁵), or negative. Excluding 8 patients transplanted in CR2 for isolated extramedullary relapse (allMRD), MRD was detected at high level in 12 patients, lowlevel in 11, and was undetectable in 33. Two-year event-free survivalfor these groups was 0%, 36%, and 73%, respectively (P < .001). Follow-up in patients remaining in continuing remission is 20 to96 months (median, 35). These results suggest that MRD analysis couldbe used routinely in this setting. This would allow identification ofpatients with resistant leukemia (who may benefit from innovative BMTprotocols) and of those with more responsive disease (who may becandidates for randomized trials of BMT versus modern intensive relapsechemotherapy).     

Distinctive Multidrug Sensitivity and Outcome of Acute Erythroblastic and Megakaryoblastic Leukemia in Children With Down Syndrome

We assessed the in vitro chemosensitivity of acute erythroblastic and megakaryoblastic leukemia cells from children with Down syndrome (DS) compared to non-DS children. We conducted in vitro tests using the MTT assay of bone marrow samples from 12 children with DS and 16 children without DS. Patients were newly diagnosed based on the morphology and expression of platelet-specific antigens. Induction failure occurred more frequently in the non-DS group (n = 4) than in the DS group (n = 0, P = .053). Children with DS had a superior event-free survival (EFS) probability of 0.750 at 4 years, compared to an EFS probability of 0.375 for non-DS children (P = .049). Blast cells from DS patients were significantly more sensitive to daunorubicin, melphalan, mitoxantrone, 4-hydroperoxy-cyclophosphamide, vincristine, etoposide, bleomycin, and pirarubicin than those from non-DS patients. Four of the 16 non-DS patients were found to have acquired an extra chromosome 21 in their leukemia cells: blasts from these patients also tended to have greater chemosensitivity than those from patients without an extra chromosome 21. Blast cells from DS patients are markedly sensitive to various drugs. These results suggest that the fragility of blast cells derived from DS patients may be related to an increased susceptibility to apoptosis.     

MTHFR Gene Polymorphisms and the Risk of Acute Lymphoblastic Leukemia in Adults and Children: A Case Control Study in India

Genetic polymorphisms in the methylene tetrahydrofolate reductase (MTHFR) gene have been associated with the development of acute leukemias and various malignancies. The role of MTHFR polymorphism in the development of pediatric acute lymphoblastic leukemia (ALL) has been extensively studied among north Indians in various settings, yet its association with acute leukemias remains unresolved. To evaluate the relationship between functional MTHFR polymorphisms, C677T and A1298C and possible effect on risk of ALL in adults and children in North Indian population by comparing them with healthy controls. DNA was isolated from peripheral blood of 184 ALL patients (33 adults, 151 children) and 155 controls and analyzed by a PCR-restriction fragment length polymorphism assay. The frequency of MTHFR 677CT and 1298 AC genotypes were significantly lower among adult ALL cases when compared to the controls. We found a 1.74-fold reduced risk of ALL in individuals with 1298AC polymorphic variant and a 9.17-fold decreased risk of adult ALL. However, no statistically significant difference was evident between the above polymorphisms and susceptibility to ALL in children. Polymorphisms in the MTHFR gene possibly modulate risk of ALL in north Indian adults but not in children, although larger studies are needed.