Pharmacogenomics of childhood acute lymphoblastic leukemia (ALL)

s3 Childhood ALL is a model for drug-responsive cancer: it is successfully cured with medications in 85%–90% of patients, but relapse remains unacceptably high for some subgroups, and therapy is complicated by the occurrence of adverse effects. Human germ-line genomic variability is common, with ∼1 in every 300 nucleotides (at least 10 million polymorphisms among humans) differing among individuals. Identifying the important genomic variants for purposes of optimizing anticancer therapy is the current challenge in cancer pharmacogenomics. Our research has been focused on elucidating the germ-line and acquired genomic variations that influence the effectiveness of and toxicity to chemotherapy regimens, with the long-term goal of individualizing therapy based on genetics to maximize cure and minimize toxicity. We and our many collaborators are pursuing candidate gene and whole genome approaches to this end, studying children enrolled on front-line ALL protocols at St. Jude and through the Children's Oncology Group. Based on these studies, candidate gene genotyping has been already incorporated into the treatment of childhood ALL and integrated with electronic medical records at St. Jude to optimize use of a few medications. This includes genetic testing for TPMT to adjust thiopurine doses and CYP2D6 to optimize use of codeine for vincristine neuropathy. Additional genotyping is conducted on a research basis and has identified SLCO1B1 as important for methotrexate disposition, IL15 as related to antileukemic drug response, ITPA as important for thiopurine toxicity, and a genomic basis to race-related differences in relapse risk. Gene expression analyses of ALL cells show expression signatures associated with resistance to chemotherapy and relapse. The principles and techniques of pharmacogenomics also have implications for adult malignancies. Because prognostic factors (including genomic variations) depend upon the details of therapy, collection of blood (for germ-line DNA) should be part of every cancer clinical trial to advance genomic research.

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Nutritional status and physical activity of childhood leukemia survivors

Paediatrica Indonesiana ◽

10.14238/pi54.2.2014.67-72 ◽

2014 ◽

Vol 54 (2) ◽

pp. 67

Author(s):

Conny Tanjung ◽

Johannes Bondan Lukito ◽

Prima Dyarti Meylani

Keyword(s):

Physical Activity ◽

Nutritional Status ◽

Childhood Leukemia ◽

Lymphoblastic Leukemia ◽

Induction Phase ◽

Childhood All ◽

Increased Risk ◽

Long Term Survivors ◽

First Time

Background Acute lymphoblastic leukemia (ALL), the mostcommon malignancy of childhood, has an overall cure rate ofapproximately 80%. Long-term survivors of childhood ALL areat increased risk for obesity and physical inactivity that may leadto the development of diabetes, dyslipidemia, metabolic syndrome,as well as cardiovascular dis eases, and related mortality in theyears following treatment.Objective To evaluate the physical activity and the propensityfor developing obesity longer term in ALL survivors.Methods This retrospective cohort study included all ALLsurvivors from Pantai Indah Kapuk (PIK) Hospital. We assessedtheir physical activity and nutritional status at the first time ofALL diagnosis an d at the time of interview.Results Subjects were 15 ALL survivors aged 7 to 24 years. Themedian fo llow up time was 6.4 years (range 3 to 10 years). Only2 out of 15 survivors were overweight and n one were obese.All survivors led a sedentary lifestyle. Most female subjectshad increased BMI, though most were not overweight/obese.Steroid therapy in the induction phase did not increase the riskof developing obesity in ALL survivors.Conclusion Lon g-term survivors of childh ood ALL do not meetphysical activity recommendations according to the CDC (Centersfor Disease Control). Howevei; steroid therapy do not seem tolead to overweight/obesity in ALL survivors.

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Long-term decline in intelligence among adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiation

Blood ◽

10.1182/blood-2013-03-487744 ◽

2013 ◽

Vol 122 (4) ◽

pp. 550-553 ◽

Cited By ~ 32

Author(s):

Kevin R. Krull ◽

Nan Zhang ◽

Aimee Santucci ◽

Deo Kumar Srivastava ◽

Matthew J. Krasin ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Radiation Dose ◽

Lymphoblastic Leukemia ◽

Adult Survivors ◽

Attention Problems ◽

Verbal Intelligence ◽

Childhood All ◽

Cranial Radiation ◽

Key Points

Key Points Adult survivors of childhood ALL treated with cranial radiation demonstrate a decline in verbal intelligence during an interval of 28 years. This decline was associated with current attention problems, but not gender, radiation dose, or age at radiation exposure.

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Cranial Irradiation Does Not Result in Pituitary-Gonadal Axis Dysfunction in Very Long-Term Male Survivors of Childhood Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v114.22.989.989 ◽

2009 ◽

Vol 114 (22) ◽

pp. 989-989

Author(s):

Niels J. van Casteren ◽

Rob Pieters ◽

Gert Dohle ◽

Manita van Baalen ◽

Sebastian Neggers ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Cranial Irradiation ◽

Gonadal Function ◽

Free T4 ◽

Childhood All ◽

Male Survivors ◽

Igf I

Abstract Abstract 989 Poster Board I-11 Introduction: One of the risks of childhood cancer treatment is fertility impairment later in life. In the past a large proportion of children with acute lymphoblastic leukemia (ALL) has received cranial irradiation as part of their treatment. The aim of this study was to evaluate whether cranial irradiation negatively affects pituitary regulated gonadal function in male survivors of childhood ALL. Patients and Methods: We examined gonadal function, including Inhibin B, LH, FSH, testosterone, and pituitary axis function by measuring TSH, Free-T4 and IGF-I levels in 89 long-term male survivors of childhood ALL after a median follow-up time of 19 year (range 7-34 years). Results: Twenty-nine out of 89 male ALL survivors received cranial irradiation. Inhibin, FSH, LH, Testosterone, testicular volume as well as TSH and Free-T4 levels were not different in the cranial irradiated group as compared to the non-irradiated group (table 1). In contrast, IGF-I levels were significantly lower in the cranial irradiated group. Survivors treated with total body irradiation or testicular irradiation had significantly decreased gonadal function based on hormone levels. Conclusions: These data show that, in contrast to the negative influence on the growth hormone axis, cranial radiotherapy as part of ALL treatment does not have a deleterious long-term effect on the hypothalamic–pituitary-gonadal axis or pituitary-thyroid axis. Disclosures: No relevant conflicts of interest to declare.

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Implication of Genetic Variations of Ikzf1, ARIDB5, and CEBPE Genes In the Risk of Childhood Acute Lymphoblastic Leukemia In Korea

Blood ◽

10.1182/blood.v116.21.3235.3235 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3235-3235

Author(s):

Dong Kyun Han ◽

Hee Nam Kim ◽

Min Ho Shin ◽

Minenori Eguchi-Ishimae ◽

Mariko Eguchi ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Genetic Variations ◽

Childhood Acute Lymphoblastic Leukemia ◽

Asian Countries ◽

Childhood All ◽

Genomic Variations ◽

Genotype Frequencies ◽

The Impact

Abstract Abstract 3235 Background: Recent western studies have showed the implication of the germline genomic variations in IKZF1 gene at 7p12.2, ARIDB5 gene at 10q21.2, and CEBPE gene at 14q11.2 on the risk of childhood acute lymphoblastic leukemia (ALL); the most significant association was observed in the single nucleotide polymorphism (SNP) rs4132601 which located at 3' region of the IKZF1. IKZF1 plays important role in lymphocyte differentiation, proliferation and function, ARIDB5 in embryogenesis and growth regulation, and CEBPE in regulation of myelopoiesis. Genomic variants in these genes are therefore considered to be involved in transcriptional regulation and differentiation of B cell progenitors. However, there have been no reports on the role of germline variations in leukemogenesis of childhood ALL in Asian countries. The aim of this study is to show the impact of these genetic variants on childhood ALL in Korea. Patients and Methods: To examine the association between genetic variations (IKZF1 rs4132601, ARIDB5 rs7089424, and CEBPE rs2239633) and the risk of childhood ALL, we here analyzed 228 children with ALL and 508 healthy individuals in Korea. Results: In ARIDB5 rs7089424, TG and GG genotypes were significantly associated with a risk for ALL (odds ratio [OR], 1.63; 95% confidential interval [CI], 1.07–2.48; P=0.02 for TG genotype, OR, 2.69; 95% CI, 1.42–5.07; P=0.002 for GG genotype). The allele incidence of ARIDB5 rs7089424 was also significantly associated with a risk for ALL (OR, 1.66; 95% CI, 1.24–2.22; P=0.0006). CEBPE rs2239633 TT genotype showed a significant association with a decreased risk for ALL (OR, 0.54; 95% CI, 0.33–0.90; P=0.02 for TT genotype). The allele incidence of CEBPE rs2239633 was also associated with a decreased risk for ALL (OR, 0.77; 95% CI, 0.61–0.97; P=0.02). There was no significant association between IKZF1 rs4132601 polymorphism and a risk for ALL in this study. Conclusion: These results suggest that genomic variations of ARIDB5 and CEBPE may play an important role in the risk for childhood ALL in Korea, compared with findings from western countries showing a significant relation between IKZF1 and childhood ALL. Several factors should be considered to explain a discrepancy between our results and the previous studies, which include different genotype frequencies in polymorphisms and varied susceptibility to ALL in different ethnic groups. Further studies incorporating larger number of cases and analyzing other SNPs or other Asian countries are warranted in childhood ALL. Disclosures: No relevant conflicts of interest to declare.

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Neurological morbidity in survivors of childhood acute lymphoblastic leukemia (ALL)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.9529 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 9529-9529

Author(s):

B. Morris ◽

R. Khan ◽

D. Ledet ◽

C. Howell ◽

C. Pui ◽

...

Keyword(s):

Back Pain ◽

Lymphoblastic Leukemia ◽

Sensory Neuropathy ◽

Neurological Symptoms ◽

Term Survival ◽

Childhood All ◽

Number Of Patients ◽

Neurological Morbidity ◽

Symptoms And Signs

9529 Background: The majority of children diagnosed with ALL over the past two decades have achieved long-term survival. This remarkable success is attributed in part to intensive central nervous system (CNS)-directed therapy that effectively prevents CNS relapse. Because treatment-related neurological morbidity is recognized but poorly characterized, the objective of this cross-sectional study was to estimate the prevalence of neurological symptoms and signs in long-term survivors of childhood ALL. Methods: After obtaining IRB approval, all long-term ALL survivors (≥ 5 years since diagnosis) aged 6–28 years who remained active patients at our institution were identified. All participants completed a questionnaire consisting of independent (and when possible validated) instruments designed to identify various neurological symptoms, as well as, a comprehensive and standardized neurologic examination by a board-certified neurologist. Results: Of the 433 potentially eligible subjects, 162 (37.4%) were enrolled. Participant demographic information and previous treatment exposure were similar to those not enrolled in the study. The rates of endorsed neurological symptoms were: neuropathy (40.1%), dizziness (33%), back pain (22.8%), fatigue (19.1%), falls (15.4%), headache (14.8%), seizures (10.5%), urinary incontinence (8.6%), and stroke (1.2%). Neurological examination confirmed an underlying sensory neuropathy in 44 patients (27.3%). Otherwise, signs of chronic cranial nerve dysfunction (1.9%) and motor weakness (5.6%) were rare. Conclusions: Symptoms and signs of a chronic sensory neuropathy, presumably from previous vincristine exposure, were evident in many patients. Complaints of fatigue, dizziness, and chronic back pain were also relatively common. The number of patients who routinely fall is of concern. Whether these falls are associated with symptoms/signs of neuropathy, weakness, and/or dizziness will require further analysis. Although headache was a common complaint, its prevalence may not differ significantly from a normal age-matched population. No significant financial relationships to disclose.

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Distinct gene expression profiles determine molecular treatment response in childhood acute lymphoblastic leukemia

Blood ◽

10.1182/blood-2004-04-1552 ◽

2005 ◽

Vol 105 (2) ◽

pp. 821-826 ◽

Cited By ~ 107

Author(s):

Gunnar Cario ◽

Martin Stanulla ◽

Bernard M. Fine ◽

Oliver Teuffel ◽

Nils v. Neuhoff ◽

...

Keyword(s):

Gene Expression ◽

Acute Lymphoblastic Leukemia ◽

Treatment Response ◽

Expression Profiles ◽

Lymphoblastic Leukemia ◽

Treatment Resistance ◽

Childhood Acute Lymphoblastic Leukemia ◽

Childhood All ◽

Resistance To Chemotherapy ◽

Intrinsic Feature

AbstractTreatment resistance, as indicated by the presence of high levels of minimal residual disease (MRD) after induction therapy and induction consolidation, is associated with a poor prognosis in childhood acute lymphoblastic leukemia (ALL). We hypothesized that treatment resistance is an intrinsic feature of ALL cells reflected in the gene expression pattern and that resistance to chemotherapy can be predicted before treatment. To test these hypotheses, gene expression signatures of ALL samples with high MRD load were compared with those of samples without measurable MRD during treatment. We identified 54 genes that clearly distinguished resistant from sensitive ALL samples. Genes with low expression in resistant samples were predominantly associated with cell-cycle progression and apoptosis, suggesting that impaired cell proliferation and apoptosis are involved in treatment resistance. Prediction analysis using randomly selected samples as a training set and the remaining samples as a test set revealed an accuracy of 84%. We conclude that resistance to chemotherapy seems at least in part to be an intrinsic feature of ALL cells. Because treatment response could be predicted with high accuracy, gene expression profiling could become a clinically relevant tool for treatment stratification in the early course of childhood ALL.

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Results of CoALL 07-03 study childhood ALL based on combined risk assessment by in vivo and in vitro pharmacosensitivity

Blood Advances ◽

10.1182/bloodadvances.2019000576 ◽

2019 ◽

Vol 3 (22) ◽

pp. 3688-3699 ◽

Cited By ~ 3

Author(s):

Franziska Schramm ◽

Udo zur Stadt ◽

Martin Zimmermann ◽

Norbert Jorch ◽

Arnulf Pekrun ◽

...

Keyword(s):

Drug Testing ◽

Drug Response ◽

Lymphoblastic Leukemia ◽

Term Outcome ◽

Childhood All ◽

Long Term Outcome ◽

Key Points

Key Points Report of the long-term outcome of children with acute lymphoblastic leukemia upon risk-adapted therapy accrued in trial CoALL 07-03. Lack of correlation between in vitro and in vivo drug response as well as a lower predictive value of in vitro drug testing.

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Chronic health conditions (CHC) and late mortality in survivors of acute lymphoblastic leukemia (ALL) in the Childhood Cancer Survivor Study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.10016 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 10016-10016

Author(s):

Stephanie Dixon ◽

Yan Chen ◽

Yutaka Yasui ◽

Ching-Hon Pui ◽

Stephen Hunger ◽

...

Keyword(s):

Cumulative Incidence ◽

Lower Risk ◽

Lymphoblastic Leukemia ◽

Malignant Neoplasm ◽

Benign Meningioma ◽

Childhood All ◽

Late Mortality ◽

The Us ◽

The Impact

10016 Background: The impact of evolving risk-stratified therapy on long-term morbidity and mortality in survivors of childhood ALL remains largely unknown. Methods: All-cause and health-related late mortality (HRM; captures death from late-effects occurring > 5 yrs from diagnosis), subsequent (malignant) neoplasm [S(M)N], CTCAE graded CHC and neurocognitive outcomes were assessed in 5-yr survivors of ALL diagnosed < 21 yrs of age from 1970-99. Therapy combinations defined 6 groups: 1970s-like ( 70s), standard and high risk 1980s- and 1990s-like ( 80sSR, 80sHR, 90sSR, 90sHR), relapse/transplant ( R/BMT). Cumulative incidence and standardized mortality ratios (SMR) were calculated. Piecewise exponential and log-binomial models estimated rate ratios (RR) with 95% confidence intervals (CI). Results: Among 6148 survivors (median age 31.5 yrs), 15-yr cumulative incidence of all-cause mortality was 5.8% (CI 5.3-6.2) and HRM was 1.5% (1.2-1.7). Compared to 70s, HRM was lower for 90sSR and 90sHR (RR 0.1, CI 0.0-0.3; 0.2, 0.1-0.7), similar to that in the US population (SMR; CI: 90sSR 1.1; 0.6-1.9, 90sHR 1.9; 0.8-3.7). 20-yr cumulative incidence of SN was 3.5% (CI 3.1-3.9). Compared to 70s, 90sSR had lower risk of benign meningioma (RR 0.1, CI 0.0-0.3) and SMN (0.3, 0.1-0.6) with no absolute excess risk compared to the US population. 90sSR was associated with a lower risk of CHCs (Table). Conclusions: More recent risk-stratified therapy has succeeded in reducing risk of late mortality and CHCs among long-term survivors of ALL. [Table: see text]

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Predictors of Vertebral Deformity in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia: The PETALE Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa806 ◽

2020 ◽

Author(s):

Melissa Fiscaletti ◽

Mariia Samoilenko ◽

Josée Dubois ◽

Marie-Claude Miron ◽

Geneviève Lefebvre ◽

...

Keyword(s):

Back Pain ◽

Acute Lymphoblastic Leukemia ◽

Vertebral Deformity ◽

Lymphoblastic Leukemia ◽

Childhood Acute Lymphoblastic Leukemia ◽

Childhood All ◽

Vertebral Deformities ◽

Male Sex ◽

Long Term Survivors

Abstract Background The prevalence of vertebral deformities in long-term survivors of childhood acute lymphoblastic leukemia (ALL) is unknown. Our objectives were to identify the prevalence of vertebral deformities and their risk factors among long-term childhood ALL survivors. Methods/Results We recruited 245 (49% male) long-term childhood ALL survivors from the Preventing Late Adverse Effects of Leukemia Cohort (French-Canadian ALL survivors treated between the years 1987 and 2010 with the Dana Farber Cancer Institute clinical trials protocols, who did not experience disease relapse and/or receive hematopoietic stem cell transplant). Median age at recruitment was 21.7 years (range, 8.5-41) and median time since diagnosis was 15.1 years (range, 5.4-28.2). All participants underwent spine radiograph and dual-energy X-ray absorptiometry scans. The prevalence of vertebral deformity was 23% with 88% classified as grade 1 according to the Genant method. The majority of vertebral deformities were clinically silent. Regression analysis confirmed male sex (risk ratio [RR] = 1.94; 95% confidence interval [CI], 1.16-3.24; P = 0.011), higher glucocorticoid cumulative dose (RR = 1.05; 95% CI, 1.00-1.10; P = 0.032), and back pain (RR = 2.44; 95% CI, 1.56-3.84; P < 0.001) as predictors of prevalent vertebral deformity. Sex differences in vertebral deformity predictors emerged. Conclusions We report a significant prevalence of vertebral deformities in this young cohort. Male sex, cumulative glucocorticoid dose, and back pain were identified as predictors of prevalent vertebral deformity. Back pain emerging as a strong predictor of vertebral deformity underscores the importance of ongoing bone health surveillance in survivors with persistent vertebral deformities treated with these earlier protocols.

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Long Term Survival Using Intensive Multiagent Chemotherapy for Relapses of Pediatric Acute Lymphoblastic Leukemia (ALL).

Blood ◽

10.1182/blood.v104.11.1953.1953 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1953-1953 ◽

Cited By ~ 1

Author(s):

Susan R. Rheingold ◽

Nancy J. Bunin ◽

Richard Aplenc ◽

Ann M. Leahey ◽

Beverly J. Lange

Keyword(s):

High Risk ◽

Lymphoblastic Leukemia ◽

High Dose ◽

Term Survival ◽

Childhood All ◽

Long Term Survival ◽

Chemotherapy Protocol ◽

Multiagent Chemotherapy ◽

Standard Risk

Abstract Relapses of childhood ALL that occur on therapy are associated with a dismal survival. To improve the prognosis for these patients, we developed an intensive multiagent chemotherapy protocol consisting of an induction with idarubicin, vincristine (VCR), dexamethasone (DEX), and peg-asparaginase (PEG). Consolidation included high-dose cytarabine (ARA-C), etoposide (VP-16), and PEG followed by VCR and methotrexate (MTX). After an interim maintenance (IM), induction and consolidation were repeated followed by maintenance therapy lasting two years. Maintenance and IM consisted of alternating two week cycles of VP-16, ARA-C, and PEG, with MTX ,VCR, DEX, and PEG. Between 1992 and 2002, 53 pts (32M, 21F) received treatment according to this protocol, 21 of whom were treated as part of the original study (Leahey AM et al., Med Ped Onco34(5):313–8, 2000). Median time to relapse was 37 months from diagnosis (range 12–86 mos). Twenty-one pts were on therapy at relapse and 25 pts were <36 months from diagnosis. Relapses included isolated bone marrow (BM) (32 pts), BM and central nervous system (CNS) (9 pts), BM and testicular (3 pts), and extramedullary (EM) (9 pts). By present day criteria 26 pts were standard risk (SR), 23 were high risk (HR), and 4 were infants. Two patients died in induction, and 2 never achieved a second remission. All others achieved remission by the end of induction (92%). Five-year event-free survival (EFS) and overall survival (OS) are both 56% +/−7% (CI 41%–68%), at a mean of 47 months from relapse (range 0–141 mos). Patients with a first complete remission (CR1) duration <36 months have an EFS of 40% +/−10% (CI 21%–58%); >36 months CR1 is associated with an EFS of 70% +/−9% (CI 50%–84%). Of the events in all pts who initiated therapy,13 were from refractory/recurrent ALL (25%), and 10 pts died of toxicity (19%). Four pts died from chemotherapy induced toxicity (8%), and 6 died from transplant (BMT) related toxicities (11%). Fourteen pts in second remission proceeded to BMT at a mean of 5 months from relapse (range 4.5–8 mos), and 7 of these pts remain in CR2. Of the 39 pts who continued on chemotherapy, 6 pts (35%) with CR1<36 months remain in CR2 and 16 patients (57%) with CR1>36 months remain in CR2 or 3. The 19 pts who were treated on modern standard risk (SR) protocols (CCG-1881 to present) were more salvagable than their 20 high risk (HR) counterparts (CCG-1882 to present). Five year EFS for SR and HR pts is 67% +/−8% (CI 48%–80%) and 38% +/−12% (CI 16%–59%) respectively. Intensive rotating therapy with reinduction and reconsolidation improves EFS. Children with early EM relapses of ALL, CR1 > 36 months, and SR patients all have very good long term survival. Novel therapies need to be integrated into intensive relapse protocols for children with early BM relapse and children treated upfront on HR protocols. Figure Figure Figure Figure

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