Background: The level of minimal residual disease during remission induction is the most important prognostic indicator in patients with acute lymphoblastic leukaemia (ALL). We aimed to establish the clinical significance of minimal residual disease in a prospective trial that used sequential minimal residual disease measurements to guide treatment decisions. Methods: Between June 7, 2000, and Oct 24, 2007, 498 assessable patients with newly diagnosed ALL were enrolled in a clinical trial at St Jude Children's Research Hospital. We provisionally classified the risk of relapse as low, standard, or high according to patients' baseline clinical and laboratory features. Final risk assignment to establish treatment intensity was based mainly on minimal residual disease levels measured on days 19 and 46 of remission induction, and on week 7 of maintenance treatment. Additional measurements of minimal residual disease were made on weeks 17, 48, and 120 (end of treatment). The primary aim was to establish the association between event-free survival and patients' minimal residual disease levels during remission induction and sequentially post-remission. This trial was registered at ClinicalTrials.gov, number NCT00137111. Findings: Irrespective of the provisional risk classification, 10-year event-free survival was significantly worse for patients with 1% or greater minimal residual disease levels on day 19 compared with patients with lower minimal residual disease levels (69·2%, 95% CI 49·6-82·4, n=36 vs 95·5%, 91·7-97·5, n=244; p<0·001 for the provisional low-risk group and 65·1%, 50·7-76·2, n=56 vs 82·9%, 75·6-88·2, n=142; p=0·01 for the provisional standard-risk group). 12 patients with provisional low-risk ALL and 1% or higher minimal residual disease levels on day 19 but negative minimal residual disease (<0·01%) on day 46 were treated for standard-risk ALL and had a 10-year event-free survival of 88·9% (43·3-98·4). For the 280 provisional low-risk patients, a minimal residual disease level of less than 1% on day 19 predicted a better outcome, irrespective of the minimal residual disease level on day 46. Of provisional standard-risk patients with minimal residual disease of less than 1% on day 19, the 15 with persistent minimal residual disease on day 46 seemed to have an inferior 10-year event-free survival compared with the 126 with negative minimal residual disease (72·7%, 42·5-88·8 vs 84·0%, 76·3-89·4; p=0·06) after receiving the same post-remission treatment for standard-risk ALL. Of patients attaining negative minimal residual disease status after remission induction, minimal residual disease re-emerged in four of 382 studied on week 7, one of 448 at week 17, and one of 437 at week 48; all but one of these six patients died despite additional treatment. By contrast, relapse occurred in only two of the 11 patients who had decreasing minimal residual disease levels between the end of induction and week 7 of maintenance therapy and were treated with chemotherapy alone. Interpretation: Minimal residual disease levels during remission induction treatment have important prognostic and therapeutic implications even in the context of minimal residual disease-guided treatment. Sequential minimal residual disease monitoring after remission induction is warranted for patients with detectable minimal residual disease.

裴正康     Deqing Pei    Elaine Coustan-Smith    Sima Jeha    Cheng Cheng    Bowman W. Paul    John torrey Sandlund    Ribeiro Raul C.    Rubnitz Jeffrey E.    Inaba Hiroto    Bhojwani    Tanja andrea Gruber    Leung Wing H.    James Downing    Evans William E.    Mary Relling    Dario Campana   

The Lancet Oncology

2015

Purpose To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. Methods A review of English literature on childhood ALL focusing on collaborative studies was performed. The resulting article was reviewed and revised by the committee chairs of the major ALL study groups. Results With long-term survival rates for ALL approaching 90% and the advent of high-resolution genome-wide analyses, several international study groups or consortia were established to conduct collaborative research to further improve outcome. As a result, treatment strategies have been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia chromosome - positive, and Philadelphia chromosome - like ALL. Many recurrent genetic abnormalities that respond to tyrosine kinase inhibitors and multiple genetic determinants of drug resistance and toxicities have been identified to help develop targeted therapy. Several genetic polymorphisms have been recognized that show susceptibility to developing ALL and that help explain the racial/ethnic differences in the incidence of ALL. Conclusion The information gained from collaborative studies has helped decipher the heterogeneity of ALL to help improve personalized treatment, which will further advance the current high cure rate and the quality of life for children and adolescents with ALL.

裴正康     Jun Yang    Stephen Hunger    Pieters Rob    Martin Schrappe    Biondi Andrea    Vora Ajay    André Baruchel    Lewis Silverman    Kjeld Schmiegelow    Gabriele Escherich    Keizo Horibe    Benoit    Shai Izraeli    Yeoh Allen    Liang Der-Cherng    James Downing    Evans William E.    Mary Relling    Mullighan Charles G.   

Journal of Clinical Oncology

2015

Advances in the treatment of childhood cancers have resulted in part from the development of national and international collaborative initiatives that have defined biologic determinants and generated risk-adapted therapies that maximize cure while minimizing acute and long-term effects. Currently, more than 80% of children with cancer who are treated with modern multidisciplinary treatments in developed countries are cured; however, of the approximately 160,000 children and adolescents who are diagnosed with cancer every year worldwide, 80% live in low-and middle-income countries (LMICs), where access to quality care is limited and chances of cure are low. In addition, the disease burden is not fully known because of the lack of population-based cancer registries in low-resource countries. Regional and ethnic variations in the incidence of the different childhood cancers suggest unique interactions between genetic and environmental factors that could provide opportunities for etiologic research. Regional collaborative initiatives have been developed in Central and South America and the Caribbean, Africa, the Middle East, Asia, and Oceania. These initiatives integrate regional capacity building, education of health care providers, implementation of intensity-graduated treatments, and establishment of research programs that are adjusted to local capacity and local needs. Together, the existing consortia and regional networks operating in LMICs have the potential to reach out to almost 60% of all children with cancer worldwide. In summary, childhood cancer burden has been shifted toward LMICs and, for that reason, global initiatives directed at pediatric cancer care and control are needed. Regional networks aiming to build capacity while incorporating research on epidemiology, health services, and outcomes should be supported.

Carlos Rodríguez-Galindo    Friedrich Paola    Alcasabas Patricia    Antillon Frederico    Banavali Shripad    Castillo    Israëls Trijn    Sima Jeha    Harif Mhamed    Sullivan Michael J.    Quah Thuan-Chong    Patte Catherine    裴正康     Ronald duncan Barr    Gross Thomas G.   

Journal of Clinical Oncology

2015

Background: Few data define the dose-specific relation between alkylating agent exposure and semen variables in adult survivors of childhood cancer. We undertook this study to test the hypothesis that increased exposure to alkylating agents would be associated with decreased sperm concentration in a cohort of adult male survivors of childhood cancer who were not exposed to radiation therapy for their childhood cancer. Methods: We did semen analysis on 214 adult male survivors of childhood cancer (median age 7·7 years [range 0·01-20·3] at diagnosis, 29·0 years [18·4-56·1] at assessment, and a median of 21·0 years [10·5-41·6] since diagnosis) who had received alkylating agent chemotherapy but no radiation therapy. Alkylating agent exposure was estimated using the cyclophosphamide equivalent dose (CED). Odds ratios (ORs) and 95% CIs for oligospermia (sperm concentration >0 and <15 million per mL) and azoospermia were calculated with logistic regression modelling. Findings: Azoospermia was noted in 53 (25%) of 214 participants, oligospermia in 59 (28%), and normospermia (sperm concentration ≥15 million per mL) in 102 (48%) participants. 31 (89%) of 35 participants who received CED less than 4000 mg/m were normospermic. CED was negatively correlated with sperm concentration (correlation coefficient=-0·37, p<0·0001). Mean CED was 10 830 mg/m (SD 7274) in patients with azoospermia, 8480 mg/m (4264) in patients with oligospermia, and 6626 mg/m (3576) in patients with normospermia. In multivariable analysis, CED was significantly associated with an increased risk per 1000 mg/m CED for azoospermia (OR 1·22, 95% CI 1·11-1·34), and for oligospermia (1·14, 1·04-1·25), but age at diagnosis and age at assessment were not. Interpretation: Impaired spermatogenesis was unlikely when the CED was less than 4000 mg/m. Although sperm concentration decreases with increasing CED, there was substantial overlap of CED associated with normospermia, oligospermia, and azoospermia. These data can inform pretreatment patient counselling and use of fertility preservation services. Funding: US National Cancer Institute, American Lebanese Syrian Associated Charities.

Daniel Green    Liu    Kutteh William H.    Ke Raymond W.    Shelton Kyla    Sklar Charles    Chemaitilly Wassim    裴正康     James Klosky    Sheri Spunt    Metzger Monika L.    Deo kumar Srivastava    Kirsten kimberlie Ness    Leslie Robison    Melissa Hudson   

The Lancet Oncology

2014

Purpose: The prognosis for older adolescents and young adults with acute lymphoblastic leukemia (ALL) has been historically much worse than that for younger patients. We reviewed the outcome of older adolescents (age 15 to 18 years) treated in four consecutive Total Therapy studies to determine if recent improved treatment extended to this high-risk group. Patients and Methods: Between 1991 and 2007, 963 pediatric patients, including 89 older adolescents, were enrolled on Total Therapy studies XIIIA, XIIIB, XIV, and XV. In the first three studies, treatment selection was based on presenting clinical features and leukemic cell genetics. In study XV, the level of residual disease was used to guide treatment, which featured intensive methotrexate, glucocorticoid, vincristine, and asparaginase, as well as early triple intrathecal therapy for higher-risk ALL. Results: The 89 older adolescents were significantly more likely to have T-cell ALL, the t(4;11)(MLL-AF4), and detectable minimal residual disease during or at the end of remission induction; they were less likely to have the t(12;21)(ETV6-RUNX1) compared with younger patients. In the first three studies, the 44 older adolescents had significantly poorer event-free survival and overall survival than the 403 younger patients. This gap in prognosis was abolished in study XV: event-free survival rates at 5 years were 86.4% ± 5.2% (standard error) for the 45 older adolescents and 87.4% ± 1.7% for the 453 younger patients; overall survival rates were 87.9% ± 5.1% versus 94.1% ± 1.2%, respectively. Conclusion: Most older adolescents with ALL can be cured with risk-adjusted intensive chemotherapy without stem-cell transplantation. © 2010 by American Society of Clinical Oncology.

裴正康     Deqing Pei    Dario Campana    Bowman W. Paul    John torrey Sandlund    Sue Kaste    Raul corrêa Ribeiro    Jeffrey Rubnitz    Elaine Coustan-Smith    Sima Jeha    Cheng Cheng    Metzger Monika L.    Bhojwani    Inaba Hiroto    Susana catalina Raimondi    Onciu Mihaela    Scott Howard    Wing hang Leung    Downing James R.    Evans William E.    Mary Relling   

Journal of Clinical Oncology

2011

Osteonecrosis is a severe glucocorticoid-induced complication of acute lymphoblastic leukemia treatment. We prospectively screened children (n = 364) with magnetic resonance imaging of hips and knees, regardless of symptoms; the cumulative incidence of any (grade 1-4) versus symptomatic (grade 2-4) osteonecrosis was 71.8% versus 17.6%, respectively. We investigated whether age, race, sex, acute lymphoblastic leukemia treatment arm, body mass, serum lipids, albuminandcortisol levels, dexamethasone pharmacokinetics, and genome-wide germline genetic polymorphisms were associated with symptomatic osteonecrosis.Age more than 10 years (odds ratio, = 4.85; 95% confidence interval, 2.5-9.2; P = .00001) and more intensive treatment (odds ratio = 2.5; 95% confidence interval, 1.2-4.9; P = .011) were risk factors and included as covariates in all analyses. Lower albumin (P = .05) and elevated cholesterol (P = .02) associated with symptomatic osteonecrosis, and severe (grade 3 or 4) osteonecrosis was linked to poor dexamethasone clearance (P = .0005). Adjusting for clinical features, polymorphisms of ACP1 (eg, rs12714403, P = 1.9 × 10, odds ratio = 5.6; 95% confidence interval, 2.7-11.3), which regulates lipid levels and osteoblast differentiation, were associated with risk of osteonecrosis as well as with lower albumin and higher cholesterol. Overall, older age, lower albumin, higher lipid levels, and dexamethasone exposure were associated with osteonecrosis and may be linked by inherited genomic variation. © 2011 by The American Society of Hematology.

Kawedia Jitesh D.    Sue Kaste    Deqing Pei    Panetta John C.    Cai Xiangjun    Cheng Cheng    Geoffrey Neale    Scott Howard    Evans William E.    裴正康     Mary Relling   

Blood

2011

Although five-year survival rates for childhood acute lymphoblastic leukemia (ALL) are now over 80% in most industrialized countries, not all children have benefited equally from this progress. Ethnic differences in survival after childhood ALL have been reported in many clinical studies, with poorer survival observed among African Americans or those with Hispanic ethnicity when compared with European Americans or Asians. The causes of ethnic differences remain uncertain, although both genetic and non-genetic factors are likely important . Interrogating genome-wide germline SNP genotypes in an unselected large cohort of children with ALL, we observed that the component of genomic variation that co-segregated with Native American ancestry was associated with risk of relapse (P = 0.0029) even after adjusting for known prognostic factors (P = 0.017). Ancestry-related differences in relapse risk were abrogated by the addition of a single extra phase of chemotherapy, indicating that modifications to therapy can mitigate the ancestry-related risk of relapse. © 2011 Nature America, Inc. All rights reserved.

Yang Jun J.    Cheng Cheng    Meenakshi Devidas    Cao Xueyuan    Fan    Dario Campana    Wenjian Yang    Geoffrey Neale    Nancy jean Cox    Paul Scheet    Borowitz Michael J.    Naomi Winick    Paul langlie Martin    Cheryl Willman    Bowman W. Paul    Bruce matthew Camitta    Carroll Andrew    Gregory Reaman    William Carroll    Loh    Stephen Hunger    裴正康     William Evans    Mary Relling   

Nature Genetics

2011

Abnormal fat deposition in the epidural space or spinal epidural lipomatosis (SEL) due to corticosteroid treatment or obesity may cause obstruction to cerebrospinal fluid flow. Little is known about SEL in patients with hematologic malignancies who require frequent lumbar punctures and corticosteroid treatment that places them at risk. Records and radiologic images of patients with SEL and leukemia or non-Hodgkin lymphoma (NHL) treated at a single institution from 1999-2009 were reviewed. Risk factors were compared with 405 control patients with leukemia. Fourteen patients with leukemia or NHL were diagnosed with SEL. The majority of patients underwent diagnostic imaging after unsuccessful lumbar punctures within 1 month of their primary diagnosis. Prior to SEL diagnosis, all patients received systemic and/or intrathecal corticosteroids. SEL diagnosis led to modification of intrathecal administration in eight patients, including Ommaya reservoir placement in four patients. All patients completed protocol-specified chemotherapy without neurologic symptoms or surgical intervention. Risk factors for developing SEL include older age and high body mass index. Investigation for SEL in leukemia or lymphoma patients with difficult lumbar punctures is warranted. Placement of an Ommaya reservoir may facilitate safe CNS-directed therapy in severely affected patients. © 2011 Springer-Verlag.

Rachel Brennan    Helton Kathleen J.    Deqing Pei    Cheng Cheng    Inaba Hiroto    Metzger Monika L.    Scott Howard    Jeffrey Rubnitz    Raul corrêa Ribeiro    John torrey Sandlund    Sima Jeha    裴正康     Bhojwani   

Annals of Hematology

2011

Because survival with both chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT) approaches to high-risk pediatric acute lymphoblastic leukemia (ALL) generally improves through the years, regular comparisons of outcomes with either approach for a given indication are needed to decide when HSCT is indicated. Improvements in risk classification are allowing clinicians to identify patients at high risk for relapse early in their course of therapy. Whether patients defined as high risk by new methods will benefit from HSCT requires careful testing. Standardization and improvement of transplant approaches has led to equivalent survival outcomes with matched sibling and well-matched unrelated donors; however, survival using mismatched and haploidentical donors is generally worse. Trials comparing chemotherapy and HSCT must obtain sufficient data about therapy and stratify the analysis to assess the outcomes of best-chemotherapy with best-HSCT approaches. © 2011 American Society for Blood and Marrow Transplantation.

Michael Pulsipher    Peters Christina    裴正康    

Biology of Blood and Marrow Transplantation

2011

Asparaginases are a cornerstone of treatment protocols for acute lymphoblastic leukemia (ALL) and are used for remission induction and intensification treatment in all pediatric regimens and in the majority of adult treatment protocols. Extensive clinical data have shown that intensive asparaginase treatment improves clinical outcomes in childhood ALL. Three asparaginase preparations are available: the native asparaginase derived from Escherichia coli (E. coli asparaginase), a pegylated form of this enzyme (PEG-asparaginase), and a product isolated from Erwinia chrysanthemi, ie, Erwinia asparaginase. Clinical hypersensitivity reactions and silent inactivation due to antibodies against E. coli asparaginase, lead to inactivation of E. coli asparaginase in up to 60% of cases. Current treatment protocols include E. coli asparaginase or PEG-asparaginase for first-line treatment of ALL. Typically, patients exhibiting sensitivity to one formulation of asparaginase are switched to another to ensure they receive the most efficacious treatment regimen possible. Erwinia asparaginase is used as a second- or third-line treatment in European and US protocols. Despite the universal inclusion of asparaginase in such treatment protocols, debate on the optimal formulation and dosage of these agents continues. This article provides an overview of available evidence for optimal use of Erwinia asparaginase in the treatment of ALL. © 2010 American Cancer Society.

Rob Pieters    Stephen Hunger    Boos Joachim    Rizzari Carmelo    Lewis Silverman    André Baruchel    Goekbuget Nicola    Schrappe Martin    裴正康    

Cancer

2011