Treatment of pediatric acute lymphoblastic leukemia Cooper, Stacy L; Brown, Patrick A
Pediatric clinics of North America/The Pediatric clinics of North America,
02/2015, Letnik:
62, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Acute lymphoblastic leukemia (ALL) is the most common pediatric oncologic diagnosis, and advances in its treatment have led to progressive improvements in survival. The 4 main components of therapy ...are remission induction, consolidation, maintenance, and central nervous system-directed therapy, and usually last 2 to 3 years. Treatment intensity based on risk-based stratification is the cornerstone of treatment. Patients with features of more favorable disease are spared the more toxic effects of chemotherapy, whereas more aggressive regimens are reserved for those with higher-risk disease. Prognosis of relapsed pediatric ALL depends primarily on duration of remission and site of relapse.
In this study, we compared ex-situ catalytic pyrolysis (CP) and in-situ CP of hybrid poplar in a micro-reactor system. When both pyrolysis and catalysis were performed at 700 °C, the carbon yield of ...olefins was greater for ex-situ CP than for in-situ CP (17.4% vs. 5.4%). On the other hand, in-situ CP produced more aromatic hydrocarbons than ex-situ CP (26.1% vs. 18.9%). The remarkably high yield of olefins from ex-situ CP indicates the potential of exploiting the process to preferentially produce olefins as a primary product from biomass, with aromatics being the secondary products. The carbon yield of carbonaceous residues from ex-situ CP was 18.6% compared to 31.3% for in-situ CP. Substantial carbon was deposited as char during ex-situ CP, which could be easily recovered as by-product, simplifying catalyst regeneration. The effects of catalyst loading, pyrolysis temperature and catalysis temperature on product distributions for ex-situ CP were also investigated. Our results showed that catalyst temperature strongly affected product distribution. While high catalyst temperature enhanced both olefin and aromatic production, yield of olefin increased to a greater extent than did aromatics. Neither pyrolysis temperature nor catalyst loadings had significant effect on product distribution for ex-situ CP.
Tisagenlecleucel is a CD19-specific chimeric antigen receptor T-cell therapy, US Food and Drug Administration-approved for children, adolescents, and young adults (CAYA) with relapsed and/or ...refractory (RR) B-cell acute lymphoblastic leukemia (B-ALL). The US Food and Drug Administration registration for tisagenlecleucel was based on a complete response (CR) rate of 81%, 12-month overall survival (OS) of 76%, and event-free survival (EFS) of 50%. We report clinical outcomes and analyze covariates of outcomes after commercial tisagenlecleucel.
We conducted a retrospective, multi-institutional study of CAYA with RR B-ALL across 15 US institutions, who underwent leukapheresis shipment to Novartis for commercial tisagenlecleucel. A total of 200 patients were included in an intent-to-treat response analysis, and 185 infused patients were analyzed for survival and toxicity.
Intent-to-treat analysis demonstrates a 79% morphologic CR rate (95% CI, 72 to 84). The infused cohort had an 85% CR (95% CI, 79 to 89) and 12-month OS of 72% and EFS of 50%, with 335 days of median follow-up. Notably, 48% of patients had low-disease burden (< 5% bone marrow lymphoblasts, no CNS3, or other extramedullary disease), or undetectable disease, pretisagenlecleucel. Univariate and multivariate analyses associate high-disease burden (HB, ≥ 5% bone marrow lymphoblasts, CNS3, or non-CNS extramedullary) with inferior outcomes, with a 12-month OS of 58% and EFS of 31% compared with low-disease burden (OS; 85%, EFS; 70%) and undetectable disease (OS; 95%, EFS; 72%;
< .0001 for OS and EFS). Grade ≥ 3 cytokine release syndrome and neurotoxicity rates were 21% and 7% overall and 35% and 9% in patients with HB, respectively.
Commercial tisagenlecleucel in CAYA RR B-ALL demonstrates efficacy and tolerability. This first analysis of commercial tisagenlecleucel stratified by disease burden identifies HB preinfusion to associate with inferior OS and EFS and increased toxicity.
Lengthy, multidrug, toxic, and low-efficacy regimens limit management of pulmonary nontuberculous mycobacterial disease.
In this phase II study, we investigated the efficacy and safety of liposomal ...amikacin for inhalation (LAI) in treatment-refractory pulmonary nontuberculous mycobacterial (Mycobacterium avium complex MAC or Mycobacterium abscessus) disease.
During the double-blind phase, patients were randomly assigned to LAI (590 mg) or placebo once daily added to their multidrug regimen for 84 days. Both groups could receive open-label LAI for 84 additional days. The primary endpoint was change from baseline to Day 84 on a semiquantitative mycobacterial growth scale. Other endpoints included sputum conversion, 6-minute-walk distance, and adverse events.
The modified intention-to-treat population included 89 (LAI = 44; placebo = 45) patients. The average age of the sample was 59 years; 88% were female; 92% were white; and 80 and 59 patients completed study drug dosing during the double-blind and open-label phases, respectively. The primary endpoint was not achieved (P = 0.072); however, a greater proportion of the LAI group demonstrated at least one negative sputum culture (14 32% of 44 vs. 4 9% of 45; P = 0.006) and improvement in 6-minute-walk test (+20.6 m vs. -25.0 m; P = 0.017) at Day 84. A treatment effect was seen predominantly in patients without cystic fibrosis with MAC and was sustained 1 year after LAI. Most adverse events were respiratory, and in some patients it led to drug discontinuation.
Although the primary endpoint was not reached, LAI added to a multidrug regimen produced improvements in sputum conversion and 6-minute-walk distance versus placebo with limited systemic toxicity in patients with refractory MAC lung disease. Further research in this area is needed. Clinical trial registered with www.clinicaltrials.gov (NCT01315236).
The natural history of relapsing remitting multiple sclerosis (RRMS) is variable and prediction of individual prognosis challenging. The inability to reliably predict prognosis at diagnosis has ...important implications for informed decision making especially in relation to disease modifying therapies. We conducted a systematic review in order to collate, describe and assess the methodological quality of published prediction models in RRMS. We searched Medline, Embase and Web of Science. Two reviewers independently screened abstracts and full text for eligibility and assessed risk of bias. Studies reporting development or validation of prediction models for RRMS in adults were included. Data collection was guided by the checklist for critical appraisal and data extraction for systematic reviews (CHARMS) and applicability and methodological quality assessment by the prediction model risk of bias assessment tool (PROBAST). 30 studies were included in the review. Applicability was assessed as high risk of concern in 27 studies. Risk of bias was assessed as high for all studies. The single most frequently included predictor was baseline EDSS (n = 11). T2 Lesion volume or number and brain atrophy were each retained in seven studies. Five studies included external validation and none included impact analysis. Although a number of prediction models for RRMS have been reported, most are at high risk of bias and lack external validation and impact analysis, restricting their application to routine clinical practice.
IMPORTANCE: Standard chemotherapy for first relapse of B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents, and young adults is associated with high rates of severe toxicities, ...subsequent relapse, and death, especially for patients with early relapse (high risk) or late relapse with residual disease after reinduction chemotherapy (intermediate risk). Blinatumomab, a bispecific CD3 to CD19 T cell–engaging antibody construct, is efficacious in relapsed/refractory B-ALL and has a favorable toxicity profile. OBJECTIVE: To determine whether substituting blinatumomab for intensive chemotherapy in consolidation therapy would improve survival in children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL. DESIGN, SETTING, AND PARTICIPANTS: This trial was a randomized phase 3 clinical trial conducted by the Children’s Oncology Group at 155 hospitals in the US, Canada, Australia, and New Zealand with enrollment from December 2014 to September 2019 and follow-up until September 30, 2020. Eligible patients included those aged 1 to 30 years with B-ALL first relapse, excluding those with Down syndrome, Philadelphia chromosome–positive ALL, prior hematopoietic stem cell transplant, or prior blinatumomab treatment (n = 669). INTERVENTIONS: All patients received a 4-week reinduction chemotherapy course, followed by randomized assignment to receive 2 cycles of blinatumomab (n = 105) or 2 cycles of multiagent chemotherapy (n = 103), each followed by transplant. MAIN OUTCOME AND MEASURES: The primary end point was disease-free survival and the secondary end point was overall survival, both from the time of randomization. The threshold for statistical significance was set at a 1-sided P <.025. RESULTS: Among 208 randomized patients (median age, 9 years; 97 47% females), 118 (57%) completed the randomized therapy. Randomization was terminated at the recommendation of the data and safety monitoring committee without meeting stopping rules for efficacy or futility; at that point, 80 of 131 planned events occurred. With 2.9 years of median follow-up, 2-year disease-free survival was 54.4% for the blinatumomab group vs 39.0% for the chemotherapy group (hazard ratio for disease progression or mortality, 0.70 95% CI, 0.47-1.03); 1-sided P = .03). Two-year overall survival was 71.3% for the blinatumomab group vs 58.4% for the chemotherapy group (hazard ratio for mortality, 0.62 95% CI, 0.39-0.98; 1-sided P = .02). Rates of notable serious adverse events included infection (15%), febrile neutropenia (5%), sepsis (2%), and mucositis (1%) for the blinatumomab group and infection (65%), febrile neutropenia (58%), sepsis (27%), and mucositis (28%) for the chemotherapy group. CONCLUSIONS AND RELEVANCE: Among children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL, postreinduction treatment with blinatumomab compared with chemotherapy, followed by transplant, did not result in a statistically significant difference in disease-free survival. However, study interpretation is limited by early termination with possible underpowering for the primary end point. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02101853
Summary
While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with chemotherapy improves ...relapse ALL response rates. This phase 2 Children's Oncology Group study tested the hypothesis that adding the proteasome inhibitor bortezomib to chemotherapy increases complete response rates (CR2). Evaluable patients (n = 135, 103 B‐ALL, 22 T‐ALL, 10 T‐lymphoblastic lymphoma) were treated with reinduction chemotherapy plus bortezomib. Overall CR2 rates were 68 ± 5% for precursor B‐ALL patients (<21 years of age), 63 ± 7% for very early relapse (<18 months from diagnosis) and 72 ± 6% for early relapse (18–36 months from diagnosis). Relapsed T‐ALL patients had an encouraging CR2 rate of 68 ± 10%. End of induction minimal residual disease (MRD) significantly predicted survival. MRD negative (MRDneg; MRD <0·01%) rates increased from 29% (post‐cycle 1) to 64% following cycle 3. Very early relapse, end‐of‐induction MRDneg precursor B‐ALL patients had 70 ± 14% 3‐year event‐free (EFS) and overall survival (OS) rates, vs. 3‐year EFS/OS of 0–3% (P = 0·0001) for MRDpos (MRD ≥0·01) patients. Early relapse patients had similar outcomes (MRDneg 3‐year EFS/OS 58–65% vs. MRDpos 10–19%, EFS P = 0·0014). These data suggest that adding bortezomib to chemotherapy in certain ALL subgroups, such as T‐cell ALL, is worthy of further investigation. This study is registered at http://www.clinical.trials.gov as NCT00873093.
IMPORTANCE: Extended-spectrum β-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by ...these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective “carbapenem-sparing” option to treat extended-spectrum β-lactamase producers. OBJECTIVES: To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae. DESIGN, SETTING, AND PARTICIPANTS: Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study. INTERVENTIONS: Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician. MAIN OUTCOMES AND MEASURES: The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used. RESULTS: Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% 1-sided 97.5% CI, −∞ to 14.5%; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group. CONCLUSIONS AND RELEVANCE: Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting. TRIAL REGISTRATION: anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122
This paper examines the values of the CHE principles of Connectivity, Humanness and Empathy as a guiding framework for maximizing the ethical and methodological advantages of semi-structured ...interview research practices. The authors draw from two separate educational studies and apply the CHE principles to analyse and evaluate the effectiveness of decision-making in facilitating sustainable relationships with the participants in each study. Findings highlight that dialogical relations with participants were evident in both studies, and identify significant junctures where decision-making and actions influenced effective rapport-building and respectful and reciprocal relationships with participants in the research. The CHE principles emerge as providing a robust framework for educational researchers to employ when auditing their decision-making prior to and during their engagement in qualitative interviews.
Socialization is a process whereby people learn the norms and values of society. African American caregivers often engage in socialization processes that teach girls about Black womanhood, and female ...sexual and reproductive health. African American women experience high rates of adverse sexual and reproductive health outcomes that may be explained in part by socialization processes. The present study investigated the childhood socialization experiences of young Black women, and perceptions of the influence of these experiences on women’s adult sexual and reproductive health attitudes and behaviors. In-depth interviews were conducted with 25 Black women enrolled at a large public university. We identified several themes in their socialization experiences: Endorsement of traditional feminine gender norms/roles; Preparation for prejudice; Promotion of ambition and independence; Promotion of racial pride; Guidance on sexual and reproductive health; Limited engagement in sexual socialization. We also identified themes related to the perceived influence of these experiences, such as the adoption or rejection of caregivers’ socialization messages by participants. These findings, as illustrated in quotes from participants, elucidate sociocultural processes in Black women’s sexual and reproductive health, and provide guidance for how families, educators, and healthcare providers engage with Black women and girls about sexual and reproductive health.
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