Systematic review and meta‐analysis of randomized trials of central nervous system directed therapy for childhood acute lymphoblastic leukemia

Richards, Sue; Pui, Ching‐Hon; Gayon, Paul

doi:10.1002/pbc.24228

Cited by 86 publications

(69 citation statements)

References 60 publications

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“…on June 7, 2019. by guest www.bloodjournal.org From whereas adding it for those treated with intrathecal methotrexate yields little benefit. 94 The case for eliminating prophylactic cranial irradiation can be summarized as follows. First, even among patients treated before 2000 with less effective chemotherapy regimens than those in contemporary use, the substitution of intravenous and intrathecal methotrexate therapy could yield EFS comparable with that of cranial irradiation with additional intrathecal treatment.…”

Section: Pharmacogenomics-guided Continuation (Maintenance) Treatmentmentioning

confidence: 99%

“…First, even among patients treated before 2000 with less effective chemotherapy regimens than those in contemporary use, the substitution of intravenous and intrathecal methotrexate therapy could yield EFS comparable with that of cranial irradiation with additional intrathecal treatment. 94 Second, the remission retrieval rate is high for patients with isolated CNS relapse who did not receive prior prophylactic cranial irradiation. In this regard, all 11 patients with an isolated CNS relapse in our Total Therapy XV study 7 remain in subsequent remission after retrieval therapy for 4 to 11 years and, in all likelihood, are cured of their leukemia.…”

Section: Pharmacogenomics-guided Continuation (Maintenance) Treatmentmentioning

confidence: 99%

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Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?

Pui

Mullighan

Evans

et al. 2012

Blood

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Improved supportive care, more precise risk stratification, and personalized chemotherapy based on the characteristics of leukemic cells and hosts (eg, pharmacokinetics and pharmacogenetics) have pushed the cure rate of childhood acute lymphoblastic leukemia to near 90%. Further increase in cure rate can be expected from the discovery of additional recurrent molecular lesions, coupled with the development of novel targeted treatment through high-throughput genomics and innovative drug-screening systems. We discuss specific areas of research that promise to further refine current treatment and to improve the cure rate and quality of life of the patients. (Blood. 2012;120(6):1165-1174) IntroductionOptimal use of existing antileukemic agents and improved supportive care in contemporary clinical trials have improved the 5-year survival rate of childhood acute lymphoblastic leukemia (ALL) above 85% in developed countries (Table 1). [1][2][3][4][5][6][7][8] Further advances in survival and quality of life will require a better understanding of ALL pathobiology, the mechanisms of drug resistance, and drug disposition in the host, together with the development of innovative therapeutics. To this end, the advent of high-resolution genomewide analyses of gene expression, DNA copy number alterations, and epigenetic changes, and more recently, next-generation wholegenome and transcriptome sequencing have provided new insights into leukemogenesis, drug resistance, and host pharmacogenomics, identified novel subtypes of leukemia, and suggested potential targets for therapy. 9,10 Paralleling these advances has been the development of novel monoclonal antibodies, small molecule inhibitors, chemotherapeutics, and cell-based treatment strategies. 9 Here we discuss some of the current challenges and future directions in pediatric ALL research. Emerging leukemia subtypesTraditionally, ALL has been classified into precursor T (or T-cell), precursor B, and B-cell (Burkitt) phenotypes, which are then further subdivided according to recurrent karyotypic abnormalities, including aneuploidy and translocations. 9,11 Detailed profiling of submicroscopic alterations and mutational analyses have allowed refinement of these classification schema, identification of genetic alterations that coexist and cooperate with chromosomal alterations in leukemogenesis, and discovery of new ALL subtypes that lack alterations on cytogenetic analysis. Like acute myeloid leukemia, 12 many ALL subtypes are characterized by genetic alterations that perturb multiple key cellular pathways, including hematopoietic development, signaling or proliferation, and epigenetic regulation. Recent studies have identified a novel high-risk immature T-cell subtype, termed "early T-cell precursor" ALL, which is characterized by immunologic markers and a gene expression profile reminiscent of double-negative 1 thymocytes that retain the ability to differentiate into both T-cell and myeloid, but not B-cell, lineages. 13 Whole genome sequencing showed that the mutational spectru...

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Section: Pharmacogenomics-guided Continuation (Maintenance) Treatmentmentioning

confidence: 99%

Section: Pharmacogenomics-guided Continuation (Maintenance) Treatmentmentioning

confidence: 99%

Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?

Pui

Mullighan

Evans

et al. 2012

Blood

Self Cite

451

339

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show abstract

“…12 With total therapy program XV, Pui et al obtained a 85.6% 5-year event-free survival rate. 13 In this study CNS prophylaxis was radiation-free and consisted of triple intrathecal therapy (ITT), which proved superior to standard intrathecal methotrexate in a randomized clinical trial, 14 along with systemic CNS-active therapy.…”

Section: Introductionmentioning

confidence: 99%

Randomized trial of radiation-free central nervous system prophylaxis comparing intrathecal triple therapy with liposomal cytarabine in acute lymphoblastic leukemia

et al. 2015

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“…Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and requires aggressive CNS-directed chemotherapy to achieve cure rates of over 85 % [1]. Acute neurologic complications are not uncommon and include seizures, encephalopathy, neuropathy, and stroke-like episodes [2].…”

Section: Introductionmentioning

confidence: 99%

Neurologic morbidity and quality of life in survivors of childhood acute lymphoblastic leukemia: a prospective cross-sectional study

et al. 2014

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Purpose Childhood acute lymphoblastic leukemia (ALL) is treated with potentially neurotoxic drugs and neurologic complications in long-term survivors are inadequately studied. This study investigated neurologic morbidity and its effect on quality of life in long-term survivors of childhood ALL. Methods Prospective, single institution, cross-sectional, institutional review board-approved study of long-term ALL survivors. Participants were recruited from institutional clinics. Participants answered an investigator-administered questionnaire followed by evaluation by a neurologist. Quality of life (QOL) was also assessed. Results Of the 162 participants recruited over a 3-year period, 83.3 % reported at least one neurologic symptom of interest, 16.7 % had single symptom, 11.1 % had two symptoms, and 55.6 % had three or more symptoms. Symptoms were mild and disability was low in the majority of participants with neurologic symptoms. Median age at ALL diagnosis was 3.9 years (0.4–18.6), median age at study enrollment was 15.7 years (6.9–28.9), and median time from completion of ALL therapy was 7.4 years (1.9–20.3). On multivariable analyses, female sex correlated with presence of dizziness, urinary incontinence, constipation, and neuropathy; use of≥10 doses of triple intrathecal chemotherapy correlated with uri-nary incontinence, back pain, and neuropathy; cranial radiation with ataxia; history of ALL relapse with fatigue; and CNS leukemia at diagnosis with seizures. Decline in mental QOL was associated with migraine and tension type headaches, while physical QOL was impaired by presence of dizziness and falls. Overall, good QOL and physical function was maintained by a majority of participants. Conclusions Neurologic symptoms were present in 83 % long-term ALL survivors. Symptoms related morbidity and QOL impairment is low in majority of survivors. Female sex, ≥10 doses of intrathecal chemotherapy, and history of ALL relapse predispose to impaired QOL. Implications for Cancer Survivors This study will educate survivors and their care providers regarding cancer or treatment-related neurologic symptoms and morbidity. This study will help them understand factors contributing to impaired QOL when present.

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Systematic review and meta‐analysis of randomized trials of central nervous system directed therapy for childhood acute lymphoblastic leukemia

Cited by 86 publications

References 60 publications

Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?

Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?

Randomized trial of radiation-free central nervous system prophylaxis comparing intrathecal triple therapy with liposomal cytarabine in acute lymphoblastic leukemia

Neurologic morbidity and quality of life in survivors of childhood acute lymphoblastic leukemia: a prospective cross-sectional study

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