Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial.
TL;DR: In this paper, the authors assessed whether treatment intensity could be adjusted for children and young adults according to MRD risk stratification and found no significant difference in EFS between the groups given one delayed intensification (94·4% at 5 years, 95% CI 91·1-97·7) and that given two delayed intensifications (95·5, 92·8-98·2; unadjusted odds ratio 1·00, 95 percent CI 0·43-2·31; twosided p=0·99).
Abstract: Summary Background Minimal residual disease (MRD) is the most sensitive and specific predictor of relapse risk in children with acute lymphoblastic leukaemia (ALL) during remission. We assessed whether treatment intensity could be adjusted for children and young adults according to MRD risk stratification. Methods Between Oct 1, 2003 and June 30, 2011, consecutive children and young adults (aged 1–24 years) with ALL from the UK and Ireland were recruited. Eligible patients were categorised into clinical standard, intermediate, and high risk groups on the basis of a combination of National Cancer Institute (NCI) criteria, cytogenetics, and early response to induction therapy, which was assessed by bone marrow blast counts taken at days 8 (NCI high-risk patients) and 15 (NCI standard-risk patients) after induction began. Clinical standard-risk and intermediate-risk patients were assessed for MRD. Those classified as MRD low risk (undetectable MRD at the end of induction [day 29] or detectable MRD [less than 0·01%] at day 29 that became undetectable by week 11) were randomly assigned to receive one or two delayed intensification courses. Patients had received induction, consolidation, and interim maintenance therapy before they began delayed intensification. Delayed intensification consisted of pegylated asparaginase on day 4; vincristine, dexamethasone (alternate weeks), and doxorubicin for 3 weeks; and 4 weeks of cyclophosphamide and cytarabine. Computer randomisation was done with stratification by MRD result and balancing for sex, age, and white blood cell count at diagnosis by method of minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcome was event-free survival (EFS), which was defined as time to relapse, secondary tumour, or death. Our aim was to rule out a 7% reduction in EFS in the group given one delayed intensification course relative to that given two delayed intensification courses. Analyses were by intention to treat. This trial is registered, number ISRCTN07355119. Findings Of 3207 patients registered in the trial overall, 521 MRD low-risk patients were randomly assigned to receive one (n=260) or two (n=261) delayed intensification courses. Median follow-up of these patients was 57 months (IQR 42–72). We recorded no significant difference in EFS between the group given one delayed intensification (94·4% at 5 years, 95% CI 91·1–97·7) and that given two delayed intensifications (95·5%, 92·8–98·2; unadjusted odds ratio 1·00, 95% CI 0·43–2·31; two-sided p=0·99). The difference in 5-year EFS between the two groups was 1·1% (95% CI −5·6 to 2·5). 11 patients (actuarial relapse at 5 years 5·6%, 95% CI 2·3–8·9) given one delayed intensification and six (2·4%, 0·2–4·6) given two delayed intensifications relapsed (p=0·23). Three patients (1·2%, 0–2·6) given two delayed intensifications died of treatment-related causes compared with none in the group given one delayed intensification (p=0·08). We recorded no significant difference between groups for serious adverse events and grade 3 or 4 toxic effects; however, the second delayed intensification course was associated with one ( Interpretation Treatment reduction is feasible for children and young adults with ALL who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD by the end of induction therapy. Funding Medical Research Council and Leukaemia and Lymphoma Research.
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TL;DR: The most common cancer in childhood is now curable in 90% of patients and the subsets of acute lymphoblastic leukemia that are most resistant to current therapy are being targeted.
Abstract: The most common cancer in childhood is now curable in 90% of patients. Current efforts are focused on devising molecular-based therapy for the subsets of acute lymphoblastic leukemia that are most resistant to current therapy.
1,339 citations
TL;DR: Monitoring of minimal residual disease (MRD) has become routine clinical practice in frontline treatment of virtually all childhood acute lymphoblastic leukemia and in many adult ALL patients, and the efficacy of innovative drugs are currently being evaluated with MRD diagnostics within clinical trials.
380 citations
Mie University1, St. Jude Children's Research Hospital2, Tokyo Medical and Dental University3, University of Pittsburgh4, Copenhagen University Hospital5, Bosch6, University Health System7, University of Tokyo8, Children's Hospital Los Angeles9, University of Copenhagen10, National University of Singapore11
TL;DR: Results indicate that a comprehensive pharmacogenetic model integrating NUDT15 variants may inform personalized thiopurine therapy, and patients with defective N UDT15 alleles showed excessive levels of thiopURine active metabolites and toxicity.
Abstract: Jun Yang and colleagues perform targeted sequencing of NUDT15 and identify loss-of-function variants associated with thiopurine intolerance. Functionally, they show that NUDT15 inactivates thiopurine metabolites, providing a mechanism to explain the association between NUDT15 loss-of-function variants and thiopurine toxicity.
358 citations
TL;DR: The value of having achieved MRD negativity is substantial in both pediatric and adult patients with ALL and warrants consideration as an early measure of disease response for evaluating new therapies, improving the efficiency of clinical trials, accelerating drug development, and for regulatory approval.
Abstract: Importance Minimal residual disease (MRD) refers to the presence of disease in cases deemed to be in complete remission by conventional pathologic analysis. Assessing the association of MRD status following induction therapy in patients with acute lymphoblastic leukemia (ALL) with relapse and mortality may improve the efficiency of clinical trials and accelerate drug development. Objective To quantify the relationships between event-free survival (EFS) and overall survival (OS) with MRD status in pediatric and adult ALL using publications of clinical trials and other databases. Data Sources Clinical studies in ALL identified via searches of PubMed, MEDLINE, and clinicaltrials.gov. Study Selection Our search and study screening process adhered to the PRISMA Guidelines. Studies that addressed EFS or OS by MRD status in patients with ALL were included; reviews, abstracts, and studies with fewer than 30 patients or insufficient MRD description were excluded. Data Extraction and Synthesis Study sample size, patient age, follow-up time, timing of MRD assessment (postinduction or consolidation), MRD detection method, phenotype/genotype (B cell, T cell, Philadelphia chromosome), and EFS and OS. Searches of PubMed and MEDLINE identified 566 articles. A parallel search on clinicaltrials.gov found 67 closed trials and 62 open trials as of 2014. Merging results of 2 independent searches and applying exclusions gave 39 publications in 3 arms of patient populations (adult, pediatric, and mixed). We performed separate meta-analyses for each of these 3 subpopulations. Results The 39 publications comprised 13 637 patients: 16 adult studies (2076 patients), 20 pediatric (11 249 patients), and 3 mixed (312 patients). The EFS hazard ratio (HR) for achieving MRD negativity is 0.23 (95% Bayesian credible interval [BCI] 0.18-0.28) for pediatric patients and 0.28 (95% BCI, 0.24-0.33) for adults. The respective HRs in OS are 0.28 (95% BCI, 0.19-0.41) and 0.28 (95% BCI, 0.20-0.39). The effect was similar across all subgroups and covariates. Conclusions and Relevance The value of having achieved MRD negativity is substantial in both pediatric and adult patients with ALL. These results are consistent across therapies, methods of and times of MRD assessment, cutoff levels, and disease subtypes. Minimal residual disease status warrants consideration as an early measure of disease response for evaluating new therapies, improving the efficiency of clinical trials, accelerating drug development, and for regulatory approval. A caveat is that an accelerated approval of a particular new drug using an intermediate end point, such as MRD, would require confirmation using traditional efficacy end points.
342 citations
TL;DR: Deep whole-exome sequencing is used to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse and it is shown that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosed to relapse is not associated with mutation burden.
Abstract: There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.
285 citations
References
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15 Jun 2006
TL;DR: Practical Statistics for Medical Research is a problem-based text for medical researchers, medical students, and others in the medical arena who need to use statistics but have no specialized mathematics background.
Abstract: Most medical researchers, whether clinical or non-clinical, receive some background in statistics as undergraduates. However, it is most often brief, a long time ago, and largely forgotten by the time it is needed. Furthermore, many introductory texts fall short of adequately explaining the underlying concepts of statistics, and often are divorced from the reality of conducting and assessing medical research.
Practical Statistics for Medical Research is a problem-based text for medical researchers, medical students, and others in the medical arena who need to use statistics but have no specialized mathematics background.
The author draws on twenty years of experience as a consulting medical statistician to provide clear explanations to key statistical concepts, with a firm emphasis on practical aspects of designing and analyzing medical research. The text gives special attention to the presentation and interpretation of results and the many real problems that arise in medical research
17,322 citations
11,536 citations
TL;DR: With effective risk-adjusted chemotherapy, prophylactic cranial irradiation can be safely omitted from the treatment of childhood ALL.
Abstract: Background Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse. Methods We conducted a clinical trial to test whether prophylactic cranial irradiation could be omitted from treatment in all children with newly diagnosed ALL. A total of 498 patients who could be evaluated were enrolled. Treatment intensity was based on presenting features and the level of minimal residual disease after remission-induction treatment. The duration of continuous complete remission in the 71 patients who previously would have received prophylactic cranial irradiation was compared with that of 56 historical controls who received it. Results The 5-year event-free and overall survival probabilities for all 498 patients were 85.6% (95% confidence interval [CI], 79.9 to 91.3) and 93.5% (95% CI, 89.8 to 97.2), respectively. The 5-year cumulative risk of isolated CNS relapse was 2.7% (95% CI, 1.1 to 4.3), and t...
1,004 citations
TL;DR: Monitoring patients with childhood ALL at consecutive time points gives clinically relevant insight into the effectiveness of treatment, and combined information on MRD from the first 3 months of treatment distinguishes patients with good prognoses from those with poor prognose, and this helps in decisions whether and how to modify treatment.
907 citations
TL;DR: Residual leukemia after induction of a remission is a powerful prognostic factor in childhood ALL and detection of residual disease by PCR should be used to identify patients at risk for relapse and should be taken into account in considering alternative treatment.
Abstract: Background and Methods The implications of the detection of residual disease after treatment of acute lymphoblastic leukemia (ALL) are unclear. We conducted a prospective study at 11 centers to determine the predictive value of the presence or absence of detectable residual disease at several points in time during the first six months after complete remission of childhood ALL had been induced. Junctional sequences of T-cell–receptor or immunoglobulin gene rearrangements were used as clonal markers of leukemic cells. Residual disease was quantitated with a competitive polymerase-chain-reaction (PCR) assay. Of 246 patients enrolled at diagnosis and treated with a uniform chemotherapy protocol, 178 were monitored for residual disease with one clone-specific probe (in 74 percent) or more than one probe (in 26 percent). The median follow-up period was 38 months. Results The presence or absence and level of residual leukemia were significantly correlated with the risk of early relapse at each of the times studi...
764 citations