scholarly journals Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia

Blood ◽  
1995 ◽  
Vol 85 (7) ◽  
pp. 1897-1902 ◽  
Author(s):  
HL McLeod ◽  
MV Relling ◽  
Q Liu ◽  
CH Pui ◽  
WE Evans
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Tpmt Activity ◽  
Severe Toxicity ◽  
Recessive Trait ◽  
Thiopurine Methyltransferase ◽  
Biochemical Basis ◽  
Intrapatient Variability ◽  
Relationship Of ◽  
Risk Of Treatment

The activity of thiopurine methyltransferase (TPMT) exhibits genetic polymorphism, with approximately 1 in 300 individuals inheriting TPMT deficiency as an autosomal recessive trait, and about 11% having intermediate activity (ie, heterozygotes). Patients with TPMT deficiency accumulate excessive concentrations of 6-thioguanine nucleotides (TGNs) and develop severe toxicity when treated with standard dosages of mercaptopurine. High TPMT activity has been associated with lower concentrations of TGNs, yielding a higher risk of treatment failure in children with acute lymphoblastic leukemia (ALL). As the biochemical basis of these pharmacodynamic relationships has not been fully elucidated, we investigated the variability and relationship of TPMT activity in erythrocytes and lymphoblasts from children with ALL. A 58-fold range of erythrocyte TPMT activity was found among 119 patients receiving ALL chemotherapy (0.6 to 34.9 U/mL packed erythrocytes), but relatively low intrapatient variability (coefficient of variation, 13.5%) was observed over 1 year. A 27-fold range in TPMT activity was observed in leukemic blasts obtained from 42 patients at initial diagnosis (3.3 to 88.9 U/1 x 10(9) cells). TPMT activity in leukemic blasts at diagnosis was significantly correlated with TPMT in erythrocytes before therapy (rs = .75, P < .0001, N = 13). These data document extensive interpatient variability of TPMT activity in ALL blasts and establish its linkage to polymorphic TPMT activity in erythrocytes, providing a new mechanism by which erythrocytes serve as prognostic markers of mercaptopurine metabolism and TPMT activity in children with ALL.

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.

Loffler's Endomyocardial Fibrosis, Eosinophilia, and Acute Lymphoblastic Leukemia

PEDIATRICS ◽  
1977 ◽  
Vol 59 (6) ◽  
pp. 950-951
Author(s):  
Fabio Pereira ◽  
Hernan Moreno ◽  
William Crist ◽  
Rufino Ermocilla
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Normal Karyotype ◽  
Endomyocardial Fibrosis ◽  
Constant Feature ◽  
Cytogenetic Evidence ◽  
The Subject ◽  
Relationship Of ◽  
The Relationship ◽  
Peripheral Blood Eosinophilia

Eosinophilia is a constant feature of Loffler's endomyocardial fibrosis.1,2 Three cases of this syndrome have been described in which acute lymphoblastic leukemia was concurrently present.3,4 Cytogenetic evidence in one of these cases suggested that the eosinophilia was "reactive" because the eosinophils had a normal karyotype while the lymphoblasts showed chromosomal aneuploidy.4 The subject of eosinophilia and eosinophilic syndromes has been extensively reviewed by others.5-8 The purpose of this report is to describe a boy with long-standing eosinophilia who presented with intractable heart failure, striking peripheral blood eosinophilia, and 38% lymphoblasts in the bone marrow. Current thoughts concerning the relationship of endomyocardial fibrosis, acute lymphoblastic leukemia, and eosinophilia are summarized.

Cost-effectiveness of pharmacogenomics in clinical practice: a case study of thiopurine methyltransferase genotyping in acute lymphoblastic leukemia in Europe

2006 ◽  
Vol 7 (5) ◽  
pp. 783-792 ◽  
Author(s):  
M Elske van den Akker-van Marle ◽  
David Gurwitz ◽  
Symone B Detmar ◽  
Christine M Enzing ◽  
Michael M Hopkins ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Cost Effectiveness ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Thiopurine Methyltransferase

scholarly journals Heterogeneity of presenting features and their relation to treatment outcome in 120 children with T-cell acute lymphoblastic leukemia

Blood ◽  
1990 ◽  
Vol 75 (1) ◽  
pp. 174-179 ◽  
Author(s):  
CH Pui ◽  
FG Behm ◽  
B Singh ◽  
MJ Schell ◽  
DL Williams ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Mediastinal Mass ◽  
Lymphoblastic Leukemia ◽  
Patients Âgés ◽  
Increased Risk ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Leukocyte Counts ◽  
Risk Of Treatment

Abstract Presenting features of 120 consecutive children with T-cell acute lymphoblastic leukemia (ALL), representing 15% of all patients diagnosed as having ALL during the study period, were analyzed to determine relationships with treatment outcome. Patients' ages ranged from 1.7 to 18.8 years (median, 10.3 years) and their leukocyte counts from 1.7 to 1,070 x 10(9)/L (median, 100 x 10(9)/L). Central nervous system (CNS) leukemia was present in 12.5% of the cases, a mediastinal mass in 61%, and L2 lymphoblast morphology in 32%. A relatively high proportion of cases, 26%, had normal karyotypes at presentation. Of the cases tested, membrane CD1 expression was found in 38% of cases, CD3 in 33%, CD4 in 50%, CD5 in 94%, CD8 in 55%, and CD10 in 35%. Four presenting features were found to confer an increased risk of treatment failure: age greater than or equal to 15 years, L2 lymphoblast morphology, abnormal karyotype, and membrane CD3 expression. This study illustrates the heterogeneity of presentations of childhood T-cell ALL and suggests that the relative importance of risk factors in ALL differs according to immunophenotype and treatment strategy.

The Relationship Between Thiopurine Methyltransferase Activity and Genotype in Blasts From Patients With Acute Leukemia

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2856-2862 ◽  
Author(s):  
Sally A. Coulthard ◽  
Christopher Howell ◽  
Jill Robson ◽  
Andrew G. Hall
Keyword(s):  
Genetic Basis ◽  
Lymphoblastic Leukemia ◽  
Cell Activity ◽  
Leukemic Cell ◽  
Tpmt Activity ◽  
Thiopurine Methyltransferase ◽  
Polymerase Chain ◽  
American Society ◽  
The Relationship ◽  
Reduced Activity

Abstract The level of expression of the enzyme thiopurine methyltransferase (TPMT) is an important determinant of the metabolism of thiopurines used in the treatment of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Studies in red blood cells (RBC) have shown that TPMT expression displays genetic polymorphism with 11% of individuals having intermediate and one in 300 undetectable levels. The genetic basis for this polymorphism has now been elucidated and polymerase chain reaction (PCR)-based assays described for the most common mutations accounting for reduced activity. In previous studies, genotype has been correlated with red blood cell activity. In this report, we describe the relationship between genotype and TPMT activity measured directly in the target of drug action, the leukemic cell. We have demonstrated that the TPMT activity in lymphoblasts from 38 children and adults found by PCR to be homozygotes (*1/*1) was significantly higher than that in the five heterozygotes (*1/*3) detected (median, 0.25 v 0.08, P &lt; .002, Mann-Whitney U). Similar results were obtained when results from children were analyzed separately. However, comparison of activity in blasts from AML and ALL showed a higher level in the former (0.35 v 0.22 nU/mg,P &lt; .002, n = 17, 35), suggesting that factors other than genotype may also influence expression. © 1998 by The American Society of Hematology.

Outcome of the Rotterdam-84 CNS-ALL Chemotherapy Protocol without Radiotherapy for Isolated Central Nervous System Relapsed Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1955-1955
Author(s):  
Auke Beishuizen ◽  
Femke K. Aarsen ◽  
Jeanette E.W.M. van Dongen ◽  
Isabelle C. Streng ◽  
Rob Pieters ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Total Duration ◽  
Treatment Protocol ◽  
Severe Toxicity ◽  
Visual Spatial ◽  
Cns Relapse

Abstract Introduction Current protocols use radiotherapy (craniospinal irradiation) as the treatment of choice to cure isolated central nervous system (CNS) acute lymphoblastic leukemia (ALL) relapses. The severe toxicity of this treatment encouraged us to develop a new CNS-ALL protocol without radiotherapy. Patients and methods From Jan 1987 till Aug 2004, 13 children were diagnosed in our centre with an isolated CNS relapse after initial treatment according to standard DCOG-ALL protocols. Treatment of CNS relapse consisted of induction by weekly intrathecal Methotrexate (MTX). At remission, an Ommaya reservoir was implanted and CNS-directed intraventricular sandwich therapy, consisting of MTX day 1; ARA-C day 2 and MTX day 3 (dosage according to age) was given every four weeks for one year. At the same time systemic treatment, based on the ALL-6 protocol (JCO1996;14:911–8), was started in which at week 23, 44 and 65 intensification courses of 6 weeks duration with Teniposide, HD-ARA-C and HD-MTX were inserted. The total duration of treatment is 95 weeks. Six of 13 patients could be assessed for behavior, intelligence, memory, visual-spatial and visual-motor skills before and after treatment using the CBCL and WISC-RN tests among others. Results All 13 patients, 3 girls and 10 boys aged 2.3 till 14.8 years (9 precursor B-ALL and 4 T-ALL), had an early isolated CNS relapse after a median first remission duration of 16 months (range 2–30 months). Nine of them were high risk according to BFM relapse criteria (male, age < 6 years, T-ALL phenotype, relapse < 18 months from diagnosis). At present, eight patients are alive in 2nd complete remission (CR) with a median follow up of 82 months (range 7–189 months). Five patients relapsed, all high risk, of which three died. One died after a secondary AML, one after a bone marrow (BM) relapse in 2nd CR due to fungal sepsis and one after a combined BM and CNS relapse due to streptococcal meningitis/encephalitis during neutropenia. The fourth patient had a second CNS relapse after 42 months in second remission. He is still in 3rd CR for 86 months after an autologous BM infusion. The fifth patient had recently an isolated BM relapse after 11 months in 2nd CR and started systemic reinduction therapy. The 5 years EFS of this study is 57% ± 15% and the 5 years OS 73% ± 14%. Before start of chemotherapy no significant differences in psychological testing were found in comparison with the normal population. After stop chemotherapy significant lower scores were obtained on the domains of perceptual organization and behavior similar to those found in other patients treated for cancer. Furthermore, our treatment protocol has no significant effect on neurocognitive functioning in comparison with craniospinal radiotherapy. Conclusion Sandwich intraventricular therapy together with systemic anti-leukemia therapy without radiotherapy seems to be an effective treatment with minimal neurocognitive disfunctioning for isolated CNS-ALL relapse. Further investigations in a larger group of patients are essential with special emphasis on comparing late effects of this therapy with radiotherapy.

Effect of azole antifungal therapy on vincristine toxicity in childhood acute lymphoblastic leukemia

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10049-10049
Author(s):  
D. M. Te Loo ◽  
R. M. van Schie ◽  
P. M. Hoogerbrugge
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Side Effects ◽  
De Novo ◽  
Case Reports ◽  
Lymphoblastic Leukemia ◽  
Toxic Encephalopathy ◽  
Rank Test ◽  
Severe Toxicity ◽  
Peripheral Neurotoxicity ◽  
Cns Toxicity

10049 Background: Vincristine is one of the corner stitches in the treatment of children with acute lymphoblastic leukemia (ALL). Constipation and other peripheral and central neurotoxicities are the most common side effects. Drugs interfering with the metabolism of vincristine might potentiate these side effects. A group of drugs that interact with the metabolism of vincristine are azoles. Several case reports suggest that co-administration of azoles and vincristine lead to increased toxicity. A comparative study exploring toxicity in patients receiving vincristine with and without azoles, is lacking. For this reason, we retrospectively analyzed neurotoxicity induced by vincristine with (n = 20) and without (n = 20) co-administration of azoles in the same patient group. Methods: In total, twenty pediatric patients with de novo ALL were included in this study. Vincristine toxicity was graded retrospectively according to the National Cancer Institute toxicity scale without information considering comedication. Statistical analysis was performed using the Wilcoxon Signed Rank test and McNemar test. Results: Patients receiving vincristine in combination with prophylactic azole treatment experienced significantly more complaints of constipation and peripheral neurotoxicity (P = 0.001 and P< 0.001, respectively). Three patients (15%) treated with azole therapy developed severe toxicity and needed treatment at the pediatric intensive care unit. Vincristine induced CNS toxicity (convulsions, toxic encephalopathy and SIADH) was seen in 6 patients (30%). All these patients were treated with vincristine in combination with an azole. CNS toxicity was not observed in patients receiving vincristine alone (P = 0 .014). Because of severe toxicities, vincristine treatment was significantly reduced (50% of normal dose) in several patients. Conclusions: This study shows that vincristine toxicity is significantly increased when combined with azole treatment and even can be life threatening. Therefore we advise to avoid the combination of azole and vincristine treatment in patients with ALL. No significant financial relationships to disclose.

Intensification of Mercaptopurine/Methotrexate Maintenance Chemotherapy May Increase the Risk of Relapse for Some Children With Acute Lymphoblastic Leukemia

2003 ◽  
Vol 21 (7) ◽  
pp. 1332-1339 ◽  
Author(s):  
Kjeld Schmiegelow ◽  
Olle Björk ◽  
Anders Glomstein ◽  
Göran Gustafsson ◽  
Niels Keiding ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Maintenance Therapy ◽  
Cox Regression ◽  
Lymphoblastic Leukemia ◽  
Tpmt Activity ◽  
Control Group ◽  
Cox Regression Analysis ◽  
Cell Counts ◽  
Increased Risk ◽  
Risk Of Relapse

Purpose: Thioguanine nucleotides (TGNs) mediate the cytotoxicity of mercaptopurine (MP). Methylated MP metabolites (formed by thiopurine methyltransferase [TPMT]) and methotrexate (MTX) polyglutamates can inhibit de novo purine synthesis. We explored whether dose adjustment of MP and MTX by erythrocyte (E) levels of TGN and MTX (including polyglutamates) could improve outcome in childhood acute lymphoblastic leukemia (ALL). Patients and Methods: A total of 538 children with ALL were randomly assigned to have their oral MP/MTX maintenance therapy adjusted by white cell counts (WBC), E-TGN, and E-MTX (pharmacology group), or by WBC only (control group). Results: After a median follow-up of 7.8 years, 79 patients had relapsed. Cox regression analysis showed an increased risk of relapse for boys (P = .00003), high WBC at diagnosis (P = .03), pharmacology arm (6.6 times increased relapse hazard for girls), high TPMT activity (P = .002), and high average neutrophil counts during maintenance therapy (P = .0009), with a significant interaction between sex and randomization group (P = .0007). For girls, the relapse risk was 5% in the control group and 19% in the pharmacology group (P = .001) because of an increased relapse hazard during the first year after cessation of therapy. TPMT activity was the most significant predictor of relapses among girls in the pharmacology arm (P < .0001). Overall, the TPMT activity was higher for patients who relapsed after cessation of therapy compared with those who stayed in remission (girls 19.5 v 17.4 U/mL, P = .03; boys 19.3 v 18.0 U/mL, P = .04). Conclusion: Adding pharmacologically guided treatment intensification to dose adjustments by blood counts may not be warranted for girls, whereas new approaches to optimize maintenance therapy are needed for boys.

scholarly journals Genetic Heterogeneity and Evolution in Lymphoid Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. SCI-34-SCI-34
Author(s):  
Charles G. Mullighan
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Research Funding ◽  
Drug Exposure ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Genomic Analysis ◽  
Disease Recurrence ◽  
Relationship Of ◽  
The Relationship ◽  
Limiting Dilution

Abstract Patterns of mutation and clonal evolution in relapsed acute lymphoblastic leukemia Relapsed acute lymphoblastic leukemia remains a major cause of childhood cancer death, and this remains true despite the advent of new targeted and immunotherapeutic approaches. Recent years have witnessed the use of broad and deep serial genomic profiling approaches to dissect the relationship of genetic variegation to clonal evolution and relapse. Studies of over 90 children treated on St Jude Total Therapy protocols, incorporating genome, exome and transcriptome sequencing, coupled with limiting dilution xenografting to formally elucidate clonal structure have provided multiple key insights. In the majority of cases, the relapse-fated clone is a minor clone at diagnosis, that harbors resistance-enriched (and thus relapse-promoting) mutations at diagnosis, and/or acquires additional mutations the confer resistance after initial therapy. Approximately one third of cases relapse from a major clone, or show polyclonal evolution, and such cases typically have a shorter time to disease recurrence and relapse. A subset of cases exhibit complete discordance for somatic non-silent mutations, DNA copy number alterations and antigen receptor rearrangements between diagnosis and relapse, suggesting relapse represents a second leukemia; however such cases typically preserve the founding chromosomal rearrangement and a subset of non-coding mutations, indicating that relapse arises from an ancestral clone that has undergone divergent evolution early in leukemogenesis. Conversely, a subset of cases relapse with myeloid or lineage ambiguous leukemia but preserve genomic alterations indicating a common clonal origin but lineage plasticity: thus, careful genomic analysis is required to interpret the nature of disease recurrence/relapse. Approximately 15% of cases exhibit hypermutation, particularly in aneuploid leukemia and second or later relapse, associated with distinct mutational signatures and kinetics of hypermutation, thus identifying this process as a driver of treatment failure in a subset of ALL cases. Integrated analysis has identified over 80 recurrent targets of alteration at relapse that show variable patterns of enrichment in rising and falling clones. Importantly, several targets (e.g. NT5C2) are never identified at diagnosis despite deep sequencing approaches, suggesting adverse effects on leukemic fitness, and/or an absolute requirement of prior drug exposure to initiate mutagenesis. Integration of limiting dilution xenografting, coupled with genomic analysis of xenografts and drug exposure has not only formally confirmed and extended inferential clonal structures, but shown that in a subset of cases resistance is present at initial diagnosis, rather than being acquired after drug exposure. Finally, several groups have shown that the relationship of relapse-enriched mutations and relapse by be drug agnostic (e.g. IKZF1) or drug specific (e.g. NT5C2 and thiopurine resistance, and CREBBP and glucocorticoid resistance). As such mutations may now be detected at levels suitable for tracking of minimal residual disease, these insights offer the opportunity to identify the relapse-fated clone early in disease evolution, and modulate therapy accordingly to circumvent relapse. Disclosures Mullighan: Pfizer: Honoraria, Research Funding, Speakers Bureau; Cancer Prevention and Research Institute of Texas: Consultancy; Loxo Oncology: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Speakers Bureau.

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