Thiopurine methyltransferase genetics is not a major risk factor for secondary malignant neoplasms after treatment of childhood acute lymphoblastic leukemia on Berlin-Frankfurt-Münster protocols

Blood ◽  
2009 ◽  
Vol 114 (7) ◽  
pp. 1314-1318 ◽  
Author(s):  
Martin Stanulla ◽  
Elke Schaeffeler ◽  
Anja Möricke ◽  
Sally A. Coulthard ◽  
Gunnar Cario ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Malignant Neoplasm ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Tpmt Activity ◽  
Malignant Neoplasms ◽  
Thiopurine Methyltransferase ◽  
Childhood All ◽  
Increased Risk ◽  
Secondary Malignant Neoplasm

AbstractThiopurine methyltransferase (TPMT)is involved in the metabolism of thiopurines such as 6-mercaptopurine and 6-thioguanine. TPMT activity is significantly altered by genetics, and heterozygous and even more homozygous variant people reveal substiantially decreased TPMT activity. Treatment for childhood acute lymphoblastic leukemia (ALL) regularly includes the use of thiopurine drugs. Importantly, childhood ALL patients with low TPMT activity have been considered to be at increased risk of developing therapy-associated acute myeloid leukemia and brain tumors. In the present study, we genotyped 105 of 129 patients who developed a secondary malignant neoplasm after ALL treatment on 7 consecutive German Berlin-Frankfurt-Münster trials for all functionally relevant TPMT variants. Frequencies of TPMT variants were similarly distributed in secondary malignant neoplasm patients and the overall ALL patient population of 814 patients. Thus, TPMT does not play a major role in the etiology of secondary malignant neoplasm after treatment for childhood ALL, according to Berlin-Frankfurt-Münster strategies.

Thiopurine methyltransferase Genotype Is Not a Risk Factor for Secondary Malignant Neoplasias after Treatment for Childhood Acute Lymphoblastic Leukemia on Berlin-Frankfurt-Muenster Protocols.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 150-150 ◽  
Author(s):  
Martin Stanulla ◽  
Elke Schaeffeler ◽  
Anja Moericke ◽  
Gunnar Cario ◽  
Michel Eichelbaum ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Brain Tumors ◽  
Patient Population ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Tpmt Activity ◽  
Malignant Neoplasms ◽  
Acute Leukemias ◽  
Childhood All ◽  
Increased Risk

Abstract The thiopurines mercaptopurine and thioguanine are important components of contemporary polychemotherapeutic treatment protocols for acute leukemias. Thiopurines are prodrugs that undergo intestinal and hepatic metabolism. Activation occurs via a multistep pathway to form thioguanine nucleotides, which are thought to be the major cytotoxic compound through triggering cell cycle arrest and apoptosis. This process is in competition with direct inactivation of thiopurines or their metabolites by thiopurine S-methyltransferase (TPMT). TPMT is a cytosolic enzyme that is ubiquitously expressed in the human body and catalyzes the S-methylation of thiopurines. The TPMT locus is subject to genetic polymorphism, with heterozygous individuals (5 to 11% of Caucasians) having intermediate TPMT activity, and homozygous individuals (0.3 to 0.5% of Caucasians) having low TPMT activity. At least 20 variant TPMT alleles (*2 to *18) have been described so far that confer decreased enzyme activities compared to the TPMT*1 wild-type allele. TPMT genotype is highly concordant with TPMT phenotype. With regard to long-term adverse effects, patients who have diminished TPMT activity were shown to be at increased risk of developing chemotherapy-induced acute myeloid leukemia and radiation-induced second brain tumors tumors after exposure towards mercaptopurine during therapy for childhood acute lymphoblastic leukemia (ALL). To investigate if such an association is generalizable to other entities of secondary malignant neoplasms (SMN) and different treatment approaches for ALL, we collected specimens of 72 patients who developed a SMN after ALL treatment on Berlin-Frankfurt-Muenster (BFM) protocols, analyzed their TPMT genotype and compared genotype frequencies to these in the general ALL patient population. The 72 patient cohort consisted of 49 hematological SMN (half of them received cranial irradiation), 12 brain tumors, and 11 other solid SMN. Neither in the entire patient group nor in subgroup analyses, differences in allele frequencies of TPMT variants conferring diminished enzyme activity were detectable when comparing SMN patients to the overall ALL patient population. Thus, low TPMT activity does not seem to play a major role in the etiology of SMN after treatment for childhood ALL according to BFM treatment strategies. Factors potentially helpful for the explanation of the previously described relationsship of TPMT activity with SMN will be presented.

scholarly journals Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study

Blood ◽  
2009 ◽  
Vol 113 (24) ◽  
pp. 6077-6084 ◽  
Author(s):  
Kjeld Schmiegelow ◽  
Ibrahim Al-Modhwahi ◽  
Mette Klarskov Andersen ◽  
Mikael Behrendtz ◽  
Erik Forestier ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Maintenance Therapy ◽  
Lymphoblastic Leukemia ◽  
Cumulative Risk ◽  
Malignant Neoplasm ◽  
Tpmt Activity ◽  
Second Malignant Neoplasm ◽  
Childhood All ◽  
Monosomy 7 ◽  
Increased Risk

Abstract Among 1614 children with acute lymphoblastic leukemia (ALL) treated with the Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL-92 protocol, 20 patients developed a second malignant neoplasm (SMN) with a cumulative risk of 1.6% at 12 years from the diagnosis of ALL. Nine of the 16 acute myeloid leukemias or myelodysplastic syndromes had monosomy 7 (n = 7) or 7q deletions (n = 2). In Cox multivariate analysis, longer duration of oral 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy (P = .02; longest for standard-risk patients) and presence of high hyperdiploidy (P = .07) were related to increased risk of SMN. Thiopurine methyltransferase (TPMT) methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. Of 524 patients who had erythrocyte TPMT activity measured, the median TPMT activity in 9 patients developing an SMN was significantly lower than in the 515 that did not develop an SMN (median, 12.1 vs 18.1 IU/mL; P = .02). Among 427 TPMT wild-type patients for whom the 6MP dose was registered, those who developed SMN received higher average 6MP doses than the remaining patients (69.7 vs 60.4 mg/m2; P = .03). This study indicates that the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMNs in childhood ALL.

scholarly journals HLA-DP genetic variation, proxies for early life immune modulation and childhood acute lymphoblastic leukemia risk

Blood ◽  
2012 ◽  
Vol 120 (15) ◽  
pp. 3039-3047 ◽  
Author(s):  
Kevin Y. Urayama ◽  
Anand P. Chokkalingam ◽  
Catherine Metayer ◽  
Xiaomei Ma ◽  
Steve Selvin ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Acute Lymphoblastic Leukemia ◽  
Immune Modulation ◽  
Lymphoblastic Leukemia ◽  
Human Leukocyte ◽  
Potential Interaction ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Childhood All ◽  
Increased Risk ◽  
Ear Infections

Abstract The human leukocyte antigen (HLA) genes are candidate genetic susceptibility loci for childhood acute lymphoblastic leukemia (ALL). We examined the effect of HLA-DP genetic variation on risk and evaluated its potential interaction with 4 proxies for early immune modulation, including measures of infectious exposures in infancy (presence of older siblings, daycare attendance, ear infections) and breastfeeding. A total of 585 ALL cases and 848 controls were genotyped at the HLA-DPA1 and DPB1 loci. Because of potential heterogeneity in effect by race/ethnicity, we included only non-Hispanic white (47%) and Hispanic (53%) children and considered these 2 groups separately in the analysis. Logistic regression analyses showed an increased risk of ALL associated with HLA-DPB1*01:01 (odds ratio [OR] = 1.43, 95% CI, 1.01-2.04) with no heterogeneity by Hispanic ethnicity (P = .969). Analyses of DPB1 supertypes showed a marked childhood ALL association with DP1, particularly for high-hyperdiploid ALL (OR = 1.83; 95% CI, 1.20-2.78). Evidence of interaction was found between DP1 and older sibling (P = .036), and between DP1 and breastfeeding (P = .094), with both showing statistically significant DP1 associations within the lower exposure categories only. These findings support an immune mechanism in the etiology of childhood ALL involving the HLA-DPB1 gene in the context of an insufficiently modulated immune system.

Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983

Blood ◽  
2002 ◽  
Vol 99 (12) ◽  
pp. 4257-4264 ◽  
Author(s):  
Smita Bhatia ◽  
Harland N. Sather ◽  
Olga B. Pabustan ◽  
Michael E. Trigg ◽  
Paul S. Gaynon ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Brain Tumors ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Malignant Neoplasms ◽  
Childhood All ◽  
Second Neoplasms ◽  
Increased Risk ◽  
The Impact

Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). With improvement in survival, it is important to assess the impact of contemporary risk-based therapies on second neoplasms in ALL survivors. A cohort of 8831 children diagnosed with ALL and enrolled on Children's Cancer Group therapeutic protocols between 1983 and 1995 were observed to determine the incidence of second neoplasms and associated risk factors. The median age at diagnosis of ALL was 4.7 years. The cohort had accrued 54 883 person-years of follow-up. Sixty-three patients developed second neoplasms, including solid, nonhematopoietic tumors (n = 39: brain tumors n = 19, other solid tumors n = 20), myeloid leukemia or myelodysplasia (n = 16), and lymphoma (n = 8). The cumulative incidence of any second neoplasm was 1.18% at 10 years (95% confidence interval, 0.8%-1.5%), representing a 7.2-fold increased risk compared with the general population. The risk was increased significantly for acute myeloid leukemia (standardized incidence ratio [SIR] 52.3), non-Hodgkin lymphoma (SIR 8.3), parotid gland tumors (SIR 33.4), thyroid cancer (SIR 13.3), brain tumors (SIR 10.1), and soft tissue sarcoma (SIR 9.1). Multivariate analysis revealed female sex (relative risk [RR] 1.8), radiation to the craniospinal axis (RR 1.6), and relapse of primary disease (RR 3.5) to be independently associated with increased risk of all second neoplasms. Risk of second neoplasms increased with radiation dose (1800 cGy RR 1.5; 2400 cGy RR 3.9). Actuarial survival at 10 years from diagnosis of second neoplasms was 39%. Follow-up of this large cohort that was treated with contemporary risk-based therapy showed that the incidence of second neoplasms remains low after diagnosis of childhood ALL.

scholarly journals Serum endocan and endothelial dysfunction in childhood acute lymphoblastic leukemia survivors: a tertiary center experience

2021 ◽  
Vol 12 ◽  
pp. 204062232110159
Author(s):  
Laila M. Sherief ◽  
Elhamy R. Abd El-khalek ◽  
Ibrahim A. Libda ◽  
Osama A. Gaber ◽  
Naglaa M. Kamal ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Endothelial Dysfunction ◽  
Serum Ferritin ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Blood Cholesterol ◽  
Control Group ◽  
Childhood All ◽  
Increased Risk ◽  
Tertiary Center

Background: An increased risk of cardiovascular complications is reported in survivors of childhood acute lymphoblastic leukemia (ALL). Early identification of impaired vascular health may allow for early interventions to improve outcomes. Aim: The study was conducted to assess the endothelial dysfunction in ALL survivors using a new marker, serum endocan, and measurement of the mean common carotid arteries intima media thickness (cIMT). Methods: A case-control study was conducted on 100 childhood ALL survivors (aged 6–18 years), with 80 healthy age and sex-matched children as a control group. Lipid profile, hepatitis markers, and serum ferritin where measured, in addition to the measurement of serum endocan. and cIMT by B-mode high-resolution ultrasonography for all study participants. Results: Triglycerides, total cholesterol, post prandial glucose, and serum ferritin were significantly higher in ALL survivors than controls ( p < 0.05). Dyslipidemia was detected in 6% of ALL survivors. ALL survivors showed statistically higher serum endocan levels (470.41 ± 556.1 ng/l, versus, 225.94 ± 185.2 ng/l, respectively) and increased cIMT levels compared with the control group (0.650 ± 0.129 mm versus 0.320 ± 0.095 mm, respectively) p < 0.05. Serum endocan was positively correlated with cIMT and blood cholesterol. Conclusions: The survivors of childhood ALL demonstrated an elevated level of serum endocan and increased cIMT. These can be used as predictors of endothelial dysfunction, and, as a consequence, the risk of developing premature atherosclerosis.

scholarly journals Genetic Mediators of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia

2013 ◽  
Vol 31 (17) ◽  
pp. 2182-2188 ◽  
Author(s):  
Kevin R. Krull ◽  
Deepa Bhojwani ◽  
Heather M. Conklin ◽  
Deqing Pei ◽  
Cheng Cheng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Lymphoblastic Leukemia ◽  
Linear Models ◽  
Lymphoblastic Leukemia ◽  
Response Speed ◽  
Attention Problems ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Childhood All ◽  
Increased Risk ◽  
Neurocognitive Outcomes

Purpose Survivors of childhood acute lymphoblastic leukemia (ALL) are at increased risk for neurocognitive problems, with significant interindividual variability in outcome. This study examined genetic polymorphisms associated with variability in neurocognitive outcome. Patients and Methods Neurocognitive outcomes were evaluated at the end of therapy in 243 survivors treated on an institutional protocol featuring risk-adapted chemotherapy without prophylactic cranial irradiation. Polymorphisms in genes related to pharmacokinetics or pharmacodynamics of antileukemic agents, drug metabolism, oxidative stress, and attention problems in noncancer populations were examined as predictors of outcome, using multiple general linear models and controlling for age at diagnosis, sex, race, and treatment intensity. Results Compared with national norms, the cohort demonstrated significantly higher rates of problems on direct assessment of sustained attention (P = .01) and on parent ratings of attention problems (P = .02). Children with the A2756G polymorphism in methionine synthase (MS) were more likely to demonstrate deficits in attentiveness (P = .03) and response speed (P = .02), whereas those with various polymorphisms in glutathione S-transferase demonstrated increased performance variability (P = .01) and reduced attentiveness (P = .003). Polymorphisms in monoamine oxidase (T1460CA) were associated with increased attention variability (P = .03). Parent-reported attention problems were more common in children with the Cys112Arg polymorphism in apoliopoprotein E4 (P = .01). Conclusion These results are consistent with our previous report of association between attention problems and MS in an independent cohort of long-term survivors of childhood ALL treated with chemotherapy only. The results also raise the possibility of an impact from genetic predispositions related to oxidative stress and CNS integrity.

Second malignancies in patients treated for childhood acute lymphoblastic leukemia.

1998 ◽  
Vol 16 (8) ◽  
pp. 2848-2853 ◽  
Author(s):  
V M Kimball Dalton ◽  
R D Gelber ◽  
F Li ◽  
M J Donnelly ◽  
N J Tarbell ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Confidence Interval ◽  
Radiation Field ◽  
Lymphoblastic Leukemia ◽  
Epithelioid Sarcoma ◽  
Late Complications ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Malignant Neoplasms ◽  
Childhood All ◽  
Induction Failure

PURPOSE Second malignant neoplasms (SMN) are devastating late complications of childhood acute lymphoblastic leukemia (ALL) and its treatment. We evaluated the incidence and type of SMN diagnosed before leukemic relapse in a large series of patients with ALL. PATIENTS AND METHODS We reviewed the outcome of all patients treated for childhood ALL between 1972 and 1995 on Dana-Farber Cancer Institute (DFCI) and DFCI ALL Consortium protocols. The follow-up time from diagnosis of ALL to induction failure, relapse, remission death, or SMN, whichever occurred first, ranged from 0 to 24.0 years (median, 7.6 years; mean, 6.7 years). RESULTS Thirteen SMNs were diagnosed among 1,597 patients. Eight tumors occurred in a radiation field (five in the CNS and three in the head and neck), two occurred outside of a radiation field (one adenocarcinoma of the sigmoid colon and one epithelioid sarcoma of the chest wall), and three were hematopoietic malignancies. The median time to occurrence was 6.7 years (range, 1.0 to 17.2 years) and the cumulative incidence of second malignancy before another first event was 2.7% (95% confidence interval, 0.7 to 4.7). The risk of a first event, which included induction failure, relapse, or remission death, was 31.0% (95% confidence interval, 28.5 to 33.5). CONCLUSION We found a more than 10-fold risk of other first events when compared with SMN. Thus, we conclude that SMN before first relapse is a relatively uncommon occurrence among survivors of childhood ALL. Future therapeutic regimens must focus on reducing leukemia relapse and enhancing quality of life, as well as preventing SMNs.

scholarly journals Study of Some Biochemical Parameters in Iraqi Children with Acute Lymphoblastic Leukemia

2015 ◽  
Vol 12 (2) ◽  
pp. 371-378
Author(s):  
Baghdad Science Journal
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Biochemical Parameters ◽  
Serum Proteins ◽  
Lymphoblastic Leukemia ◽  
White Blood Cells ◽  
Total Serum ◽  
Childhood All ◽  
Marrow Cavity ◽  
Increased Risk

Leukemia or cancer of the blood is the most common childhood cancer, Acute lymphoblastic leukemia (ALL), is the most common form of leukemia that occurs in children. It is characterized by the presence of too many immature white blood cells in the child’s blood and bone marrow, Acute lymphoblastic leukemia can occur in adults too, treatment is different for children. Children with ALL develop symptoms related to infiltration of blasts in the bone marrow, lymphoid system, and extramedullary sites, such as the central nervous system (CNS). Common constitutional indications consist of fatigue (50%), pallor (25%), fever (60%), and weight loss (26%). Infiltration of blast cells in the marrow cavity and periosteum often lead to bone pain (23%) and disturbance of normal hematopoiesis. Thrombocytopenia with platelet counts less than 100,000 are seen in approximately 75% of patients. About 40% of patients with childhood ALL present with hemoglobin levels less than 7 g/dL. Although leukocyte counts greater than 50,000/mm3 occur in 20% of cases, neutropenia defined as an absolute neutrophil count less than 500 is common at presentation and is associated with an increased risk of infection. The aim of this study was to investigate the differentiations in some biochemical parameters (Hb, PCV, total serum proteins Aspartate amino transferase(AST), Alanin amino transferase (ALT), and Malondialdehyde (MDA) in blood which can be conceder as a marker of ALL. Samples were collected from 50 patients (between 1-16 years old) diagnosed with ALL after one month treatment with induction therapy, compared with 30 control samples taken from healthy persons at the same age . The ALT and MDA showed a significant increase p < 0.001 and p

scholarly journals Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia

2014 ◽  
Vol 32 (9) ◽  
pp. 949-959 ◽  
Author(s):  
Deepa Bhojwani ◽  
Noah D. Sabin ◽  
Deqing Pei ◽  
Jun J. Yang ◽  
Raja B. Khan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Multivariable Analysis ◽  
Brain Magnetic Resonance Imaging ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Intrathecal Therapy ◽  
High Dose ◽  
Asymptomatic Patients ◽  
A Genome ◽  
Increased Risk

Purpose Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. Patients and Methods Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. Results Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. Conclusion MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.

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