C H Pui

St. Jude Children's Research Hospital, Memphis, Tennessee, United States

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Publications (340)3991.23 Total impact

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    ABSTRACT: Purpose: We sought to determine whether cranial radiotherapy (CRT) is necessary to prevent relapse in any subgroup of children with acute lymphoblastic leukemia (ALL). Patients and methods: We obtained aggregate data on relapse and survival outcomes for 16,623 patients age 1 to 18 years old with newly diagnosed ALL treated between 1996 and 2007 by 10 cooperative study groups from around the world. The proportion of patients eligible for prophylactic CRT varied from 0% to 33% by trial and was not related to the proportion eligible for allogeneic stem-cell transplantation in first complete remission. Using a random effects model, with CRT as a dichotomous covariate, we performed a single-arm meta-analysis to compare event-free survival and cumulative incidence of isolated or any CNS relapse and isolated bone marrow relapse in high-risk subgroups of patients who either did or did not receive CRT. Results: Although there was significant heterogeneity in all outcome end points according to trial, CRT was associated with a reduced risk of relapse only in the small subgroup of patients with overt CNS disease at diagnosis, who had a significantly lower risk of isolated CNS relapse (4% with CRT v 17% without CRT; P = .02) and a trend toward lower risk of any CNS relapse (7% with CRT v 17% without CRT; P = .09). However, this group had a relatively high rate of events regardless of whether or not they received CRT (32% [95% CI, 26% to 39%] v 34% [95% CI, 19% to 54%]; P = .8). Conclusion: CRT does not have an impact on the risk of relapse in children with ALL treated on contemporary protocols.
    No preview · Article · Jan 2016 · Journal of Clinical Oncology
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    Full-text · Dataset · Oct 2014
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    ABSTRACT: Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults. Methods: We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL. Results: Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib. Conclusions: Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.).
    Full-text · Article · Sep 2014 · New England Journal of Medicine
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    ABSTRACT: We sought to improve lumbar spine bone mineral density (LS-BMD) in long-term survivors of childhood acute lymphoblastic leukemia (ALL) using calcium and cholecalciferol supplementation. This double-blind, placebo-controlled trial randomized 275 participants (median age, 17 [9-36.1] years) with age- and gender-specific LS-BMD Z-scores <0 to receive nutritional counseling with supplementation of 1,000 mg/day calcium and 800 International Unit cholecalciferol or placebo for 2 years. The primary outcome was change in LS-BMD assessed by quantitative computerized tomography (QCT) at 24 months. Linear regression models were employed to identify the baseline risk factors for low LS-BMD and to compare LS-BMD outcomes. Pre-randomization LS-BMD below the mean was associated with male gender (P = 0.0024), White race (P = 0.0003), lower body mass index (P < 0.0001), and cumulative glucocorticoid doses of ≥5,000 mg (P = 0.0012). One hundred eighty-eight (68%) participants completed the study; 77% adhered to the intervention. Mean LS-BMD change did not differ between survivors randomized to supplements (0.33 ± 0.57) or placebo (0.28 ± 0.56). Participants aged 9-13 years and those 22-35 years had the greatest mean increases in LS-BMD (0.50 ± 0.66 and 0.37 ± 0.23, respectively). Vitamin D insufficiency (serum 25[OH]D <30 ng/ml) found in 296 (75%), was not associated with LS-BMD outcomes (P = 0.78). Cholecalciferol and calcium supplementation provides no added benefit to nutritional counseling for improving LS-BMD among adolescent and young adult survivors of ALL (93% of whom had LS-BMD Z-scores above the mean at study entry). Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Full-text · Article · May 2014 · Pediatric Blood & Cancer
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    ABSTRACT: With improved contemporary therapy, we re-assess long-term outcome in patients completing treatment for childhood acute lymphoblastic leukemia to determine when cure can be declared with a high degree of confidence. In 6 successive clinical trials between 1984 and 2007, 1291(84.5%) patients completed all therapy in continuous complete remission. The post-therapy cumulative risk of relapse or development of a second neoplasm and the event-free survival rate and overall survival were analyzed according to the presenting features and the three treatment periods defined by relative outcome. Over the three treatment periods, there has been progressive increase in the rate of event-free survival (65.2% vs 74.8% vs 85.1% [P<0.001]) and overall survival (76.5% vs 81.1% vs 91.7% [P<0.001]) at 10 years. The most important predictor of outcome after completion of therapy was the type of treatment. In the most recent treatment period, which omitted the use of prophylactic cranial irradiation, the post-treatment cumulative risk of relapse was 6.4%, death in remission 1.5%, and development of a second neoplasm 2.3% at 10 years, with all relapses except one occurring within 4 years off therapy. None of the 106 patients with the t(9;22)/BCR-ABL1, t(1;19)/TCF3-PBX1 or t(4;11)/MLL-AFF1 had relapsed after 2 years from completion of therapy. These findings demonstrate that with contemporary effective therapy that excludes cranial irradiation, approximately 6% of children with acute lymphoblastic leukemia may relapse after completion of treatment, and those who remain in remission at 4 years post-treatment may be considered cured (i.e., less than 1% chance of relapse).Leukemia accepted article preview online, 30 April 2014; doi:10.1038/leu.2014.142.
    Full-text · Article · Apr 2014 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    ABSTRACT: Asparaginase is an essential component of pediatric acute lymphoblastic leukemia (ALL) therapy. However, asparaginase-induced hypersensitivity reactions can compromise its efficacy either by directly influencing the pharmacokinetics of asparaginase or by leading to a discontinuation of asparaginase treatment. Here, we report successful challenges using native Escherichia coli asparaginase after previous hypersensitivity reactions to both PEGylated E. coli asparaginase and Erwinia asparaginase. The two patients included in this case report were diagnosed with B-precursor ALL at St. Jude Children's Research Hospital and were treated with a common regimen. Both patients developed hypersensitivity reactions to PEGylated E. coli asparaginase and Erwinia asparaginase early in treatment, and they were challenged with native E. coli asparaginase. Serum samples were collected for estimating the pharmacokinetic parameters of each patient during native E. coli asparaginase therapy. Challenges with native E. coli asparaginase were successful, and asparaginase serum concentrations above therapeutic levels were attained in both patients. These two cases suggest that some patients can be given native E. coli asparaginase after hypersensitivity reactions to PEGylated asparaginase and achieve therapeutic concentrations of the drug in serum.
    No preview · Article · Apr 2014 · Cancer Chemotherapy and Pharmacology
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    ABSTRACT: Reliable prognostic factors have not been established for advanced-stage pediatric lymphoblastic lymphoma (LL). We analyzed treatment outcomes and potential risk factors in children and adolescents with advanced-stage LL treated over a 40-year period. From 1962 through 2002, 146 patients (99 boys and 47 girls) with stage III (n = 111) or stage IV (n = 35) LL were treated at St Jude Children's Research Hospital. The five treatment eras were 1962-1975 (no protocol), 1975-1979 (NHL-75), 1979-1984 (Total 10 High), 1985-1992 (Pediatric Oncology Group protocol), and 1992-2002 (NHL13). Age at diagnosis was <10 years in 65 patients and ≥10 years in 81. Outcomes improved markedly over successive treatment eras. NHL13 produced the highest 5-year event-free survival (EFS) estimate (82.9% ± 6.1% [SE]) compared with only 20.0% ± 8.0% during the earliest era. Treatment era (P < 0.0001) and age at diagnosis (<10 years versus ≥10 years, P = 0.0153) were independent prognostic factors, whereas disease stage, lactate dehydrogenase level, and presence of a pleural effusion were not. Treatment era and age were the most important prognostic factors for children with advanced-stage LL. We suggest that a better assessment of early treatment response may help to identify patients with drug-resistant disease who require more intensive therapy.
    Preview · Article · Jun 2013 · Annals of Oncology
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    Full-text · Article · Mar 2013 · JNCI Journal of the National Cancer Institute
  • D. Campana · C.-H. Pui

    No preview · Article · Jan 2013
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    ABSTRACT: With the use of risk-directed therapy for childhood acute lymphoblastic leukemia (ALL), outcome has improved dramatically in the past 40 years. However, a substantial portion of patients, many of whom have no known risk factors, experience relapse. Taking a genome-wide approach, in the present study, we evaluated the relationships between genotypes at 444 044 single nucleotide polymorphisms (SNPs) with the risk of relapse in 2535 children with newly diagnosed ALL after adjusting for genetic ancestry and treatment regimen. We identified 134 SNPs that were reproducibly associated with ALL relapse. Of 134 relapse SNPs, 133 remained prognostic after adjusting for all known relapse risk factors, including minimal residual disease, and 111 were significant even among patients who were negative for minimal residual disease after remission induction therapy. The C allele at rs7142143 in the PYGL gene was associated with 3.6-fold higher risk of relapse than the T allele (P = 6.7 × 10 -9). Fourteen of the 134 relapse SNPs, including variants in PDE4B and ABCB1, were also associated with antileukemic drug pharmacokinetics and/or pharmacodynamics. In the present study, we systematically identified host genetic variations related to treatment outcome of childhood ALL, most of which were prognostic independent of known risk factors for relapse, and some of which also influenced outcome by affecting host disposition of antileukemic drugs.
    Full-text · Article · Nov 2012 · Blood

  • No preview · Article · Sep 2012
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    H M Conklin · K R Krull · W E Reddick · D Pei · C Cheng · C H Pui
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    ABSTRACT: Background Treatment of acute lymphoblastic leukemia (ALL) has included the use of prophylactic cranial irradiation in up to 20% of children with high-risk disease despite known cognitive risks of this treatment modality. Methods Patients enrolled on the St Jude ALL Total Therapy Study XV, which omitted prophylactic cranial irradiation in all patients, were assessed 120 weeks after completion of consolidation therapy (n = 243) using a comprehensive cognitive battery. χ2 analysis was used to compare the percentage of below-average performers among the entire ALL patient group to the expected rate based on the normative sample. Univariate logistic regression was used to estimate the effect of intensity of chemotherapy (treatment arm), age at diagnosis, and sex on the probability of below-average performance. All statistical tests were two-sided. ResultsOverall, the ALL group had a statistically significantly higher risk for below-average performance on a measure of sustained attention (67.31% more than 1 SD below the normative mean for omission errors, P <. 001) but not on measures of intellectual functioning, academic skills, or memory. Patients given higher intensity chemotherapy were at greater risk for below-average performance compared with those given lower intensity therapy on measures of processing speed (27.14% vs 6.25%, P =. 009) and academic abilities (Math Reasoning: 18.60% vs 3.90%, P =. 008; Word Reading: 20.00% vs 2.60%, P =. 007; Spelling: 27.91% vs 3.90%, P =. 001) and had higher parent-reported hyperactivity (23.00% vs 9.84%, P =. 018) and learning problems (35.00% vs 16.39%, P =. 005). Neither age at diagnosis nor sex was associated with risk for below-average cognitive performance. Conclusions Omitting cranial irradiation may help preserve global cognitive abilities, but treatment with chemotherapy alone is not without risks. Caregiver education and development of interventions should address both early attention deficits and cognitive late effects.
    Full-text · Article · Aug 2012 · Journal of the National Cancer Institute
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    ABSTRACT: Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
    Full-text · Article · Aug 2012 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    Full-text · Article · Jun 2012 · Cancer Research

  • No preview · Article · Feb 2010 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
  • M. Onciu · C.-H. Pui
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    ABSTRACT: Precise diagnosis and classification are essential to the successful treatment and biologic study of the childhood leukemias. In broadest terms, the leukemias are classified as acute versus chronic and as lymphoid versus myeloid. The terms acute and chronic originally referred to the relative durations of survival of patients with these diseases when effective therapy was not available. With improvements in treatment, they have taken on new meanings. Acute currently refers to leukemia characterized by rapid tumor cell proliferation and a predominance of blast cells, while chronic leukemia encompasses a variety of myeloproliferative and lympho-proliferative disorders in which the predominant tumor cells show variable degrees of differentiation beyond the blast stage. The vast majority of childhood leukemia cases are acute, unlike those in adults. The most common subtype, acute lymphoblastic (also termed lymphocytic or lymphoid) leukemia (ALL) accounts for 75 to 80% of all childhood cases, while acute myeloid (also termed myelocytic, myelogenous, or non-lymphoblastic) leukemia (AML) makes up approximately 20%. By contrast, chronic myeloid leukemia (CML) represents only approximately 2% of childhood leukemias and chronic lymphocytic leukemia (CLL) is reported only rarely in children. Finally, myelodysplastic syndrome (MDS) designates a heterogeneous group of clonal diseases related to a subset of AML. It is characterized by peripheral blood cytopenias, normocellular or hypercellular but non-productive bone marrow (inefficient hematopoiesis), and dysmorphic maturation of hematopoietic precursors. It may evolve into frank AML or result in death through cytopenic complications.
    No preview · Article · Jan 2010
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    ABSTRACT: 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 (P=0.003) 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.
    Full-text · Article · Dec 2009 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    ABSTRACT: An international childhood acute lymphoblastic leukemia (ALL)working group was formed during the 27th annual meeting of the International Society of Pediatric Oncology in 1995. Since then, 10 workshops have been held to address many issues that help advance treatment outcome of childhood ALL but require international collaboration (Table 1). The group was fondly named after 'Ponte di Legno,' a place in Lombardy, Italy, because the first major workshop was held there. In celebration of the 10th anniversary of the first major meeting, the group returned to Ponte di Legno on 6 and 7 May 2009 for its 11th meeting (Figure 1). During the meeting, Professor Giuseppe Masera was honored for his vision and contributions to further develop the International-BFM study group and to co-found the Ponte di Legno working group. The meeting began with greetings by Professor Andrea Biondi. This report summarizes the data presented and the discussion in the meeting.
    Full-text · Article · Nov 2009 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    ABSTRACT: Asparaginase (ASP) is used routinely in frontline clinical trials for the treatment of childhood acute lymphoblastic leukemia (ALL). The goals of this study were to assess the pharmacokinetics and pharmacodynamics of ASP and to mathematically model the dynamics between ASP and asparagine (ASN) in relapsed ALL. Forty children were randomized to receive either native or polyethylene glycolated (PEG) Escherichia coli ASP during reinduction therapy. Serial plasma ASP and ASN, cerebrospinal fluid (CSF) ASN, and serum anti-ASP antibody samples were collected. The ASP clearance was higher (P = 0.001) for native vs. PEG ASP. Patients with antibodies to PEG ASP had faster PEG ASP clearance (P = 0.004) than did antibody-negative patients. Patients who were positive for antibodies had higher CSF ASN concentrations than did those who were negative (P = 0.04). The modeling suggests that by modifying dosages, comparable ASN depletion is achievable with both preparations. At relapse, there were significant pharmacokinetic and pharmacodynamic differences attributable to ASP preparation and antibody status.
    Full-text · Article · Oct 2009 · Clinical Pharmacology &#38 Therapeutics
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    ABSTRACT: CONTEXT: Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80%, considerable unexplained interindividual variability exists in treatment response. OBJECTIVES: To assess the contribution of inherited genetic variation to therapy response and to identify germline single-nucleotide polymorphisms (SNPs) associated with risk of minimal residual disease (MRD) after remission induction chemotherapy. DESIGN, SETTING, AND PATIENTS: Genome-wide interrogation of 476,796 germline SNPs to identify genotypes that were associated with MRD in 2 independent cohorts of children with newly diagnosed ALL: 318 patients in St Jude Total Therapy protocols XIIIB and XV and 169 patients in Children's Oncology Group trial P9906. Patients were enrolled between 1994 and 2006 and last follow-up was in 2006. MAIN OUTCOME MEASURES: Minimal residual disease at the end of induction therapy, measured by flow cytometry. RESULTS: There were 102 SNPs associated with MRD in both cohorts (median odds ratio, 2.18; P < or = .0125), including 5 SNPs in the interleukin 15 (IL15) gene. Of these 102 SNPs, 21 were also associated with hematologic relapse (P < .05). Of 102 SNPs, 21 were also associated with antileukemic drug disposition, generally linking MRD eradication with greater drug exposure. In total, 63 of 102 SNPs were associated with early response, relapse, or drug disposition. CONCLUSION: Host genetic variations are associated with treatment response for childhood ALL, with polymorphisms related to leukemia cell biology and host drug disposition associated with lower risk of residual disease
    No preview · Article · Jan 2009

Publication Stats

20k Citations
3,991.23 Total Impact Points

Institutions

  • 1981-2014
    • St. Jude Children's Research Hospital
      • • Department of Oncology
      • • Department of Biostatistics
      • • Department of Pharmaceutical Sciences
      • • Department of Pathology
      • • Division of Leukemia/Lymphoma
      Memphis, Tennessee, United States
  • 1990-2006
    • University of Tennessee
      • • Department of Pediatrics
      • • College of Medicine
      • • Division of Hematology and Oncology
      Knoxville, Tennessee, United States
    • California State University, Sacramento
      Sacramento, California, United States
  • 2000
    • University of Verona
      Verona, Veneto, Italy
  • 1997
    • University of Pavia
      Ticinum, Lombardy, Italy
  • 1996
    • National Cancer Institute (USA)
      베서스다, Maryland, United States
  • 1993
    • New York Medical College
      • Department of Pediatrics
      New York, New York, United States