Asparaginase is an important component for treatment of childhood acute lymphoblastic leukemia (ALL). The basis for interindividual differences in asparaginase sensitivity remains unclear. To comprehensively identify genetic variants important in the cytotoxicity of asparaginase, we used a genome-wide association approach using the HapMap lymphoblastoid cell lines (87 CEU trio members) and 54 primary ALL leukemic blast samples at diagnosis. Asparaginase sensitivity was assessed as the drug concentration necessary to inhibit 50% of growth (inhibitory concentration (IC) 50). In CEU lines, we tested 2 390 203 single-nucleotide polymorphism (SNP) genotypes at the individual SNP (P0.001) and gene level (P0.05), and identified 329 SNPs representing 94 genes that were associated with asparaginase IC 50. The aspartate metabolism pathway was the most overrepresented among 199 pathways evaluated (P8.1 × 10 3), with primary involvement of adenylosuccinate lyase and aspartyl-tRNA synthetase genes. We validated that SNPs in the aspartate metabolism pathway were also associated with asparaginase sensitivity in primary ALL leukemic blast samples (P5.5 × 10 5). Our genome-wide interrogation of CEU cell lines and primary ALL blasts revealed that inherited genomic interindividual variation in a plausible candidate pathway can contribute to asparaginase sensitivity. © 2011 Macmillan Publishers Limited All rights reserved.

Chen    Wenjian Yang    Fan    Stocco Gabriele    Kristine radomski Crews    Jun Yang    Paugh Steven W.    裴正康     William Evans    Mary Relling   

Leukemia

2011

Purpose: We review recent advances in the biologic understanding and treatment of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), identify therapeutically challenging subgroups, and suggest future directions of research. Methods: A review of English literature on childhood acute leukemias from the past 5 years was performed. Results: Contemporary treatments have resulted in 5-year event-free survival rates of approximately 80% for childhood ALL and almost 60% for pediatric AML. The advent of high-resolution genome-wide analyses has provided new insights into leukemogenesis and identified many novel subtypes of leukemia. Virtually all ALL and the vast majority of AML cases can be classified according to specific genetic abnormalities. Cooperative mutations involved in cell differentiation, cell cycle regulation, tumor suppression, drug responsiveness, and apoptosis have also been identified in many cases. The development of new formulations of existing drugs, molecularly targeted therapy, and immunotherapies promises to further advance the cure rates and improve quality of life of patients. Conclusion: The application of new high-throughput sequencing techniques to define the complete DNA sequence of leukemia and host normal cells and the development of new agents targeted to leukemogenic pathways promise to further improve outcome in the coming decade. © 2011 by American Society of Clinical Oncology.

裴正康     William Carroll    Meshinchi Soheil    Arceci Robert J.   

Journal of Clinical Oncology

2011

We analyzed the long-term outcome of 1011 patients treated in five successive clinical trials (Total Therapy Studies 11, 12, 13A, 13B, and 14) between 1984 and 1999. The event-free survival improved significantly (P0.003) from the first two trials conducted in the 1980s to the three more recent trials conducted in the 1990s. Approximately 75% of patients treated in the 1980s and 80% in the 1990s were cured. Early intensive triple intrathecal therapy, together with more effective systemic therapy, including consolidation and reinduction treatment (Studies 13A and 13B) as well as dexamethasone (Study 13B), resulted in a very low rate of isolated central nervous system (CNS) relapse rate (2%), despite the reduced use of cranial irradiation. Factors consistently associated with treatment outcome were age, leukocyte count, immunophenotype, DNA index, and minimal residual disease level after remission induction treatment. Owing to concerns about therapy-related secondary myeloid leukemia and brain tumors, in our current trials we reserve the use of etoposide for patients with refractory or relapsed leukemia undergoing hematopoietic stem cell transplantation, and cranial irradiation for those with CNS relapse. The next main challenge is to further increase cure rates while improving quality of life for all patients. © 2010 Macmillan Publishers Limited All rights reserved.

裴正康     Deqing Pei    John torrey Sandlund    Raul corrêa Ribeiro    Jeffrey Rubnitz    Susana catalina Raimondi    Onciu Mihaela    Dario Campana    Larry Kun    Sima Jeha    Cheng Cheng    Scott Howard    Metzger Monika L.    Bhojwani    James Downing    William Evans    Mary Relling   

Leukemia

2010

Acute lymphoblastic leukemia (ALL), a clonal expansion of hematopoietic blasts, is a highly heterogeneous disease comprising many entities for which distinct treatment strategies are pursued. Although ALL is a success story in pediatric oncology, results in adults lag behind those in children. An expansion of new drugs, more reliable immunologic and molecular techniques for the assessment of minimal residual disease, and efforts at more precise risk stratification are generating new aspects of adult ALL therapy. For this review, the authors summarized pertinent and recent literature on ALL biology and therapy, and they discuss current strategies and potential implications of novel approaches to the management of adult ALL. © 2010 American Cancer Society.

Stefan Faderl    Susan O'Brien    裴正康     Wendy Stock    Wetzler Meir    Dieter Hoelzer    Hagop Kantarjian   

Cancer

2010

Minimal residual disease (MRD) at the end of remission-induction therapy predicts relapse in acute lymphoblastic leukemia (ALL). We examined the clinical significance of levels below the usual threshold value for MRD positivity (0.01%) in 455 children with B-lineage ALL, using polymerase chain reaction amplification of antigen-receptor genes capable of detecting at least 1 leukemic cell per 100 000 normal mononucleated cells (0.001%). Of the 455 clinical samples studied on day 46 of therapy, 139 (30.5%) had MRD 0.001% or more with 63 of these (45.3%) showing levels of 0.001% to less than 0.01%, whereas 316 (69.5%) had levels that were either less than 0.001% or undetectable. MRD measurements of 0.001% to less than 0.01% were not significantly related to presenting characteristics but were associated with a poorer leukemia cell clearance on day 19 of remission induction therapy. Patients with this low level of MRD had a 12.7% (± 5.1%; SE) cumulative risk of relapse at 5 years, compared with 5.0% (± 1.5%) for those with lower or undetectable MRD (P < .047). Thus, low levels of MRD (0.001%-< 0.01%) at the end of remission induction therapy have prognostic significance in childhood ALL, suggesting that patients with this finding should be monitored closely for adverse events. © 2010 by The American Society of Hematology.

Stow Patricia    Key Laura    Chen Xiaohua    Qiulu Pan    Geoffrey Neale    Elaine Coustan-Smith    Charles Mullighan    Zhou Yinmei    裴正康     Dario Campana   

Blood

2010

The genetic variations that result in allergy to asparaginase are as yet undetermined. We interrogated more than 500,000 single-nucleotide polymorphisms (SNPs) in 485 children with acute lymphoblastic leukemia (ALL), 322 in a discovery cohort, and 163 in a validation cohort. In the top 100 SNPs associated with allergy in the discovery cohort, chromosome 5 was overrepresented as compared with other chromosomes (P = 0.00032), hosting 10 SNPs annotated to genes. Among these 10 SNPs, one SNP (rs4958381), in GRIA1 on chromosome 5q33, was replicated in the validation cohort (P = 1.8 × 10, 2.9 × 10, and 3.5 × 10 in the discovery, validation, and combined cohorts, respectively). Four additional SNPs annotated to GRIA1 were also significantly associated with allergy (P 0.05) in both cohorts. Chromosome 5q33 has previously been associated with asthma and atopy. These data contribute to the growing body of evidence that there is an inherited component to predisposition to drug allergy. © 2010 American Society for Clinical Pharmacology and Therapeutics.

Chen    Deqing Pei    Wenjian Yang    Cheng Cheng    Sima Jeha    Nancy jean Cox    William Evans    裴正康     Mary Relling   

Clinical Pharmacology and Therapeutics

2010

Cheng Qing    Cheng Cheng    Kristine radomski Crews    Raul corrêa Ribeiro    裴正康     Mary Relling    William Evans   

American Journal of Human Genetics

2010

BACKGROUND: To extend investigation beyond global cognitive measures prevalent in the literature, this study examined attention and working memory (WM) abilities of survivors of childhood acute lymphoblastic leukemia (ALL), the separate contributions of attention and WM to intelligence quotient (IQ), and their association with neuroimaging changes. METHODS: Ninety-seven children with ALL received risk-directed therapy based on presenting clinical and biological factors. During consolidation therapy, low-risk patients received half the dose of intravenous methotrexate that standard-risk/high-risk patients received, and fewer doses of triple intrathecal therapy. Patients were classified according to end of consolidation magnetic resonance imaging scans (normal or leukoencephalopathy), and continuous measures of white matter structure were computed. As part of the protocol study, children completed cognitive assessment 2 years later (completion of therapy), using Digit Span Forward (DSF) for attention and Digit Span Backward (DSB) for WM. RESULTS: For the total sample and the standard-/high-risk group, Total Digit Span (TDS), DSF, and DSB were impaired relative to norms (P <.05). In the low-risk group, only DSB was impaired (P <.0001). Across groups, a higher percentage of patients performed below the average range (scale score <7) on DSB (66%) compared with the DSF (14%) or TDS (18%). Regression analysis indicated that DSB predicted estimated IQ (P <.05), after accounting for DSF. Leukoencephalopathy was predictive of lower TDS (P <.05). CONCLUSIONS: WM appears to be especially sensitive to treatment-related changes in ALL survivors, detecting difficulties potentially missed by global intelligence measures. These findings may facilitate the identification of vulnerable neural pathways and the development of targeted cognitive interventions. © 2010 American Cancer Society.

Ashford Jason    Schoffstall Corrie    Reddick Wilburn E.    Leone Christina    Laningham Fred H.    Glass John O.    Deqing Pei    Cheng Cheng    裴正康     Conklin Heather M.   

Cancer

2010

Background: We sought to improve outcome in patients with childhood acute myeloid leukaemia (AML) by applying risk-directed therapy that was based on genetic abnormalities of the leukaemic cells and measurements of minimal residual disease (MRD) done by flow cytometry during treatment. Methods: From Oct 13, 2002, to June 19, 2008, 232 patients with de-novo AML (n=206), therapy-related or myelodysplasia-related AML (n=12), or mixed-lineage leukaemia (n=14) were enrolled at eight centres. 230 patients were assigned by block, non-blinded randomisation, stratified by cytogenetic or morphological subtype, to high-dose (18 g/m, n=113) or low-dose (2 g/m, n=117) cytarabine given with daunorubicin and etoposide (ADE; induction 1). The primary aim of the study was to compare the incidence of MRD positivity of the high-dose group and the low-dose group at day 22 of induction 1. Induction 2 consisted of ADE with or without gemtuzumab ozogamicin (GO anti-CD33 monoclonal antibody); consolidation therapy included three additional courses of chemotherapy or haematopoietic stem-cell transplantation (HSCT). Levels of MRD were used to allocate GO and to determine the timing of induction 2. Both MRD and genetic abnormalities at diagnosis were used to determine the final risk classification. Low-risk patients (n=68) received five courses of chemotherapy, whereas high-risk patients (n=79), and standard-risk patients (n=69) with matched sibling donors, were eligible for HSCT (done for 48 high-risk and eight standard-risk patients). All 230 randomised patients were analysed for the primary endpoint. Other analyses were limited to the 216 patients with AML, excluding those with mixed-lineage leukaemia. This trial is closed to accrual and is registered with ClinicalTrials.gov, number NCT00136084. Findings: Complete remission was achieved in 80% (173 of 216 patients) after induction 1 and 94% (203 of 216) after induction 2. Induction failures included two deaths from toxic effects and ten cases of resistant leukaemia. The introduction of high-dose versus low-dose cytarabine did not significantly lower the rate of MRD-positivity after induction 1 (34% vs 42%, p=0·17). The 6-month cumulative incidence of grade 3 or higher infection was 79·3% (SE 4·0) for patients in the high-dose group and 75·5% (4·2) for the low-dose group. 3-year event-free survival and overall survival were 63·0% (SE 4·1) and 71·1% (3·8), respectively. 80% (155 of 193) of patients achieved MRD of less than 0·1% after induction 2, and the cumulative incidence of relapse for this group was 17% (SE 3). MRD of 1% or higher after induction 1 was the only significant independent adverse prognostic factor for both event-free (hazard ratio 2·41, 95% CI 1·36-4·26; p=0·003) and overall survival (2·11, 1·09-4·11; p=0·028). Interpretation: Our findings suggest that the use of targeted chemotherapy and HSCT, in the context of a comprehensive risk-stratification strategy based on genetic features and MRD findings, can improve outcome in patients with childhood AML. Funding: National Institutes of Health and American Lebanese Syrian Associated Charities (ALSAC). © 2010 Elsevier Ltd.

Jeffrey Rubnitz    Inaba Hiroto    Gary Dahl    Raul corrêa Ribeiro    Bowman W. Paul    Jeffrey Taub    Stanley Pounds    Razzouk Bassem I.    Norman Lacayo    Cao Xueyuan    Meshinchi Soheil    Degar Barbara A.    Airewele Gladstone E.    Susana catalina Raimondi    Onciu Mihaela    Elaine Coustan-Smith    James Downing    Wing hang Leung    裴正康     Dario Campana   

The Lancet Oncology

2010

BACKGROUND: Allopurinol and urate oxidase are both effective in preventing or treating hyperuricemia during remission induction therapy for lymphoid malignancies, but to the authors' knowledge, their effects on concomitant anticancer drug therapy have not been compared. METHODS: The authors compared plasma methotrexate pharmacokinetics in pediatric patients with newly diagnosed acute lymphoblastic leukemia who received concomitant allopurinol (n = 20) versus those treated with nonrecombinant or recombinant urate oxidase (n = 96) during high-dose methotrexate administration before conventional remission induction therapy. RESULTS: The minimum plasma concentration of uric acid was significantly (P < .0001) lower after urate oxidase treatment than the concentration after allopurinol treatment. Methotrexate clearance was significantly higher (median, 117.1 mL/minute/m vs 91.1 mL/minute/ m ; P = .019) in patients who received urate oxidase. A higher proportion of patients in the allopurinol group had elevated methotrexate plasma concentrations (36% vs 7%; P = .003) and experienced mucositis (45% vs 16%; P = .003) after methotrexate treatment compared with the urate oxidase group. CONCLUSIONS: The lower rate of methotrexate clearance in patients who received allopurinol likely reflected a less potent hypouricemic effect of allopurinol, leading to precipitation of uric acid in renal tubules. Hence, during remission induction therapy for lymphoid malignancies, the authors concluded that renally excreted drugs should be monitored closely, especially in patients who are receiving allopurinol. © 2010 American Cancer Society.

Kristine radomski Crews    Zhou Yinmei    Pauley Jennifer L.    Scott Howard    Sima Jeha    Mary Relling    裴正康    

Cancer

2010