National Cancer Institute®
Last Modified: June 1, 2002
UI - 11990710
AU - Waber DP
TI - More good news about neuropsychological late effects in long-term survivors of acute lymphoblastic leukemia.
SO - J Pediatr Hematol Oncol 2002 Feb;24(2):86-7
AD - Department of Psychiatry, The Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
UI - 11979454
AU - Albertsen BK; Schroder H; Jakobsen P; Avramis VI; Muller HJ; Schmiegelow
TI - K; Carlsen NT Antibody formation during intravenous and intramuscular therapy with Erwinia asparaginase.
SO - Med Pediatr Oncol 2002 May;38(5):310-6
AD - Department of Pharmacology, University of Aarhus, Aarhus, Denmark. firstname.lastname@example.org
BACKGROUND: Determination of the frequency of antibody formation during first and second exposure to Erwinia asparaginase after i.v. and i.m. administration. PROCEDURE: Thirty-nine children with newly diagnosed acute lymphoblastic leukemia (ALL) were included in this prospective study. Antibodies were determined (ELISA method) in plasma from these patients on specific days during and after therapy with 30,000 IU/m(2) i.v. or i.m. every day for ten days during the induction phase (first exposure). For 19 children, antibodies were measured in plasma during and after the re-induction phase (second exposure) following treatment with 30,000 IU/m(2) i.v. or i.m. twice a week for two weeks (Mondays and Thursdays). On the same days of therapy, enzyme activity (spectrophotometric method) and the concentration of asparagine (HPLC) was determined. RESULTS: During the first exposure, none of the patients developed anti-Erwinia asparaginase antibodies. During the second exposure, one patient (1 of 8 patients) treated intravenously developed antibodies, which were associated with disappearance of enzyme activity and reappearance of asparagine. Three of eleven patients developed antibodies of pharmacokinetic importance after i.m. therapy. None of the children had any clinical symptoms of hypersensitivity. CONCLUSIONS: The formation of antibodies and subsequently altered pharmacokinetics of Erwinia asparaginase seemed to be of importance only during a second period of asparaginase therapy. Copyright 2002 Wiley-Liss, Inc.
UI - 11984799
AU - Naumburg E; Bellocco R; Cnattingius S; Jonzon A; Ekbom A
TI - Perinatal exposure to infection and risk of childhood leukemia.
SO - Med Pediatr Oncol 2002 Jun;38(6):391-7
AD - Department of Women's and Children's Health, Section for Pediatrics, Uppsala University, Akademiska Barnsjukhuset, Uppsala, Sweden. email@example.com
BACKGROUND: A population-based case-control study was conducted to investigate the association between childhood leukemia and infectious exposures during pregnancy and early neonatal period. PROCEDURE: Children born and diagnosed with leukemia between 1973 and 1989 in Sweden (578 lymphatic, 74 myeloid) were selected as cases. One control was randomly selected for each case and individually matched by sex, month, and year of birth. Children with Down's syndrome were excluded. Exposure data were blindly abstracted from antenatal, obstetric, and other standardized medical records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by conditional logistic regression. RESULTS: A history of maternal infection was not significantly associated with childhood leukemia, OR = 1.25 (95% CI 0.95-1.65). Maternal lower genital tract infection significantly increased the risk of childhood leukemia, OR = 1.78 (95% CI 1.17-2.72), and especially for children over 4 years of age at diagnosis, OR = 2.01 (95% CI 1.12-3.80). Neonatal infection was not associated with the risk of leukemia. The results remained unaltered after adjustment for potential confounders, and separate analyses for myeloid and lymphoid leukemia. CONCLUSIONS: We could document an association between exposure to maternal lower genital tract infection in utero, and a subsequent risk for childhood leukemia, which indicate the importance of an early exposure. Copyright 2002 Wiley-Liss, Inc.
UI - 11902302
AU - Meshinchi S; Thomson B; Finn LS; Leisenring W; Green C; Radich JP; Loken
TI - M; Hawkins D Comparison of multidimensional flow cytometry with standard morphology for evaluation of early marrow response in pediatric acute lymphoblastic leukemia.
SO - J Pediatr Hematol Oncol 2001 Dec;23(9):585-90
AD - Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA. firstname.lastname@example.org
PURPOSE: We compared multidimensional flow cytometry (MDF) with morphology in evaluating early marrow response to induction chemotherapy in pediatric ALL. METHODS: Chemotherapy response was determined by standard morphology or by MDF assessed by residual leukemic cell percentage remaining in the marrow on days 7, 14, and 28 of induction. Bone marrow response was classified as M3 (>25% leukemic blasts) or M1/M2 (< or = 25% leukemic blasts). Multidimensional flow cytometry evaluation was compared with that of standard morphology. Available day-7 and day-14 marrow slides were also reevaluated by a single pathologist without patients' clinical information. RESULTS: Of 46 day-7 specimens, eight (17%) had discordant MDF and morphologic results (P < 0.001), including six classified as M3 by morphology but were M1/M2 by MDF, and two were classified as M3 by MDF but were M1/M2 by morphology. Of 24 day-14 bone marrow specimens, five (20.5%) were discordant (P < 0.001), including two classified as M3 by morphology but were M1/M2 by MDF, and three were classified as M3 by MDF but were M1/M2 by morphology. Reevaluation of the blinded day-7 and day-14 marrow slides yielded discordance between repeated pathology readings of 11% (P < 0.001) and 6% (P = 0.04), respectively. CONCLUSION: Our data show significant discordance between the morphologic and MDF evaluation of early marrow response. Early response to therapy is a significant prognostic indicator in pediatric acute lymphoblastic leukemia and is used to alter subsequent treatment; thus, precise assessment of response is important. A larger comparison of MDF with morphology for the evaluation of early response, including correlation with clinical outcome, is warranted.
UI - 11902549
AU - Pui CH; Campana D; Evans WE
TI - Childhood acute lymphoblastic leukaemia--current status and future perspectives.
SO - Lancet Oncol 2001 Oct;2(10):597-607
AD - Leukaemia/Lymphoma Division, Fahad Nassar Al-Rashid Chair of Leukaemia Research at St Jude Children's Research Hospital, Memphis, TN 38105, USA. email@example.com
The current cure rate of 80% in childhood acute lymphoblastic leukaemia attests to the effectiveness of risk-directed therapy developed through well-designed clinical trials. In the past decade there have been remarkable advances in the definition of the molecular abnormalities involved in leukaemogenesis and drug resistance. These advances have led to the development of promising new therapeutic strategies, including agents targeted to the molecular lesions that cause leukaemia. The importance of host pharmacogenetics has also been recognised. Thus, genetic polymorphisms of certain enzymes have been linked with host susceptibility to the development of de novo leukaemia or therapy-related second cancers. Furthermore, recognition of inherited differences in the metabolism of antileukaemic agents has provided rational selection criteria for optimal drug dosages and scheduling. Treatment response assessed by measurements of submicroscopic leukaemia (minimal residual disease) has emerged as a powerful and independent prognostic indicator for gauging the intensity of therapy. Ultimately, treatment based on biological features of leukaemic cells, host genetics, and the amount of residual disease should improve cure rates further.
UI - 11920210
AU - Pagano L; Pulsoni A; Tosti ME; Mele A; Mele L; Corvatta L; Miraglia E;
TI - Almici C; Manna A; Del Poeta G; Lanza F; Masini L; Recchia A; Equitani F; Leone G; Mandelli F; The Italian GIMEMA Group (Gruppo Italiano Malattie Ematologiche dell'Adulto) Acute leukemia following a previous malignancy: do acute lymphoid leukemia and acute myeloid leukemia have common risk factors?
SO - Hematol J 2000;1(5):329-32
AD - Department of Hematology, Catholic University, Largo Francesco Vito 1, I-00168 Rome, Italy. firstname.lastname@example.org
INTRODUCTION: Within the framework of the GIMEMA Study Group, the characteristics of acute lymphoid leukemia and acute myeloid leukemia occurring in patients who have suffered a previous malignancy were studied. Assessment was also made of the clinical course, laboratory features and overall outcome of these conditions. MATERIALS AND METHODS: A four-year, multi-center retrospective study was conducted to evaluate the effect of treatment for previous hematological malignancy on the development of secondary leukemia. The study collected in the GIMEMA Archive of Adult Acute Leukemia 3934 new cases of acute leukemia (2964 AML, 901 ALL, 60 acute biphenotypic leukemia). Among these cases, data were evaluated from patients with a personal history of a previous malignancy, and included inquiring into demographic data, history of neoplastic diseases in the 1st degree relatives, type and treatment of the previous malignancy, latency until the development of a secondary acute leukemia diagnosis, laboratory features, treatment and outcome at the onset of secondary acute leukemia. RESULTS: Approximately 200 (5.1%) patients presented a previous malignancy. Twenty-one were affected by ALL and 179 by AML. The proportion of patients with secondary AML was higher than that of patients with secondary ALL (179/2964 vs 21/901, O.R. 2.69-95% C.I. 1.66-4.39, P<0.001). The median latency, from the onset of the previous malignancy to the development of secondary ALL was 27 months and to the development of secondary AML was 52 months (P<0.05). Furthermore, of patients who previously received chemotherapy more developed a second AML (66/127 sAML vs 5/21 sALL; O.R. 3.46-95% C.I. 1.10-11.56, P<0.01). CONCLUSION: In most cases, chemotherapy treatment for a previous malignancy can play a role in the development of secondary AML. In almost all cases of secondary ALL, the role of previous drugs does not appear to be relevant. On the basis of our analysis, performed systematically for the first time on a large adult series of acute leukemia, we conclude that in these patients a biological predisposition to cancer may be suspected.
UI - 11986237
AU - Skibola CF; Smith MT; Hubbard A; Shane B; Roberts AC; Law GR; Rollinson
TI - S; Roman E; Cartwright RA; Morgan GJ Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia.
SO - Blood 2002 May 15;99(10):3786-91
AD - NFCR Center for Genomics and Nutrition, School of Public Health, and the Department of Nutritional Sciences, University of California, Berkeley, CA 94720-7360, USA.
We previously reported that 2 polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene at positions C677T and A1298C were associated with lower risk of adult acute lymphocytic leukemia (ALL). In the present study, we have examined whether polymorphisms in other folate-metabolizing genes play a role in ALL susceptibility. Polymorphisms in methionine synthase (MS A2756G), cytosolic serine hydroxymethyltransferase (SHMT1 C1420T), and a double (2R2R) or triple (3R3R) 28-bp tandem repeat in the promoter region of thymidylate synthase (TS) were studied and found to modulate ALL risk. In a univariate analysis, SHMT1 1420CT individuals exhibited a 2.1-fold decrease in ALL risk (odds ratio [OR] = 0.48; 95% confidence interval [CI], 0.25-0.91), whereas the 1420TT genotype conferred a 3.3-fold reduction in risk (OR = 0.31; 95% CI, 0.10-0.90). Similarly, TS 2R3R individuals exhibited a 2.8-fold reduction in ALL risk (OR = 0.36; 95% CI: 0.16-0.83), while the TS 3R3R genotype conferred an even greater level of protection (OR = 0.25; 95% CI, 0.08-0.78). However, no significant associations were evident for the MS 2756AG polymorphism (OR = 0.79; 95% CI, 0.38-1.7). In addition, potential interactions between the SHMT1 and TS or MS genes were observed. TS 3R3R individuals who were SHMT1 1420CT/TT had a 13.9-fold decreased ALL risk (OR = 0.072; 95% CI, 0.0067-0.77). Further, MS 2756AG individuals who were SHMT1 1420CT/TT had a 5.6-fold reduction in ALL risk (OR = 0.18; 95% CI, 0.05-0.63). This study suggests an important role for uracil misincorporation and resultant chromosomal damage in the pathogenesis of ALL, and that genetic interactions involving low penetrance polymorphisms in folate-metabolizing genes may increase ALL risk.
UI - 11949261
AU - Peshikova MV; Dolgushin II; Rusanova NN
TI - [Etiology and structure of infectious complications of cytostatic therapy in children with acute lymphoblastic leukemia and non-B-cell non-Hodgkin lymphomas]
SO - Zh Mikrobiol Epidemiol Immunobiol 2002 Jan-Feb;(1):70-1
AD - State Medical Academy, Chelyabinsk, Russia.
A retrospective analysis of medical histories with acute lymphoblast leucosis and non-B-cell non-Hodgkin lymphomas made it possible to reveal infectious complications of cytostatic therapy in 100% of children, namely: sepsis (0.3%), unidentified infection (12%), local infection (87.7%). Infectious complications of the cytopenic nature were localized mainly in the upper sections of the gastrointestinal tract and in upper respiratory tract. Bacterial infectious complications caused by opportunistic microorganisms with the prevalence of Gram positive flora, resistant to cephalosporins of generations I and II, occurred most frequently.
UI - 11986774
AU - Ma X; Buffler PA; Selvin S; Matthay KK; Wiencke JK; Wiemels JL; Reynolds
TI - P Daycare attendance and risk of childhood acute lymphoblastic leukaemia.
SO - Br J Cancer 2002 May 6;86(9):1419-24
AD - Division of Public Health Biology and Epidemiology, University of California-Berkeley, California, CA 94720-7360, USA.
The relationship between daycare/preschool ("daycare") attendance and the risk of acute lymphoblastic leukaemia was evaluated in the Northern California Childhood Leukaemia Study. Incident cases (age 1-14 years) were rapidly ascertained during 1995-1999. Population-based controls were randomly selected from the California birth registry, individually matched on date of birth, gender, race, Hispanicity, and residence, resulting in a total of 140 case-controls pairs. Fewer cases (n=92, 66%) attended daycare than controls (n=103, 74%). Children who had more total child-hours had a significantly reduced risk of ALL. The odds ratio associated with each thousand child-hours was 0.991 (95% confidence interval (CI): 0.984-0.999), which means that a child with 50 thousand child-hours (who may have, for example, attended a daycare with 15 other children, 25 h per week, for a total duration of 30.65 months) would have an odds ratio of (0.991)(50)=0.64 (95% CI: 0.45, 0.95), compared to children who never attended daycare. Besides, controls started daycare at a younger age, attended daycare for longer duration, remained in daycare for more hours, and were exposed to more children at each daycare. These findings support the hypothesis that delayed exposure to common infections plays an important role in the aetiology of childhood acute lymphoblastic leukaemia, and suggest that extensive contact with other children in a daycare setting is associated with a reduced risk of acute lymphoblastic leukaemia. Copyright 2002 Cancer Research UK
UI - 12015772
AU - Lehtinen SS; Huuskonen UE; Harila-Saari AH; Tolonen U; Vainionpaa LK;
TI - Lanning BM Motor nervous system impairment persists in long-term survivors of childhood acute lymphoblastic leukemia.
SO - Cancer 2002 May 1;94(9):2466-73
AD - Department of Pediatrics, Oulu University Central Hospital, Oulu, Finland. email@example.com
BACKGROUND: The objective of the current study was to determine whether therapy for childhood acute lymphoblastic leukemia (ALL) results in long-lasting neurologic signs or electrophysiologic injuries within the motor tracts. METHODS: Twenty-seven children who were treated for ALL were studied clinically 5 years after the cessation of therapy by means of motor-evoked potentials (MEPs) elicited by magnetic stimulation transcranially and peripherally. An equal number of healthy children matched with regard to age, gender, and height served as the control group. RESULTS: The MEP latencies to the hands and legs elicited by stimulation at the cortex were prolonged significantly in the children treated for ALL compared with the control group, with the differences being 2.2 milliseconds [ms] (P < 0.001) from the cortex to the thenar on the right side and 2.0 ms (P < 0.001) on the left, and 1.4 ms (P = 0.004) from the cortex to the leg on the right side and 1.3 ms (P = 0.004) on the left. Correspondingly, the MEP latency from the fifth lumbar vertebrae (LV) level to the leg also was prolonged, by 1.0 ms (P = 0.005) on the right side and 0.8 ms (P = 0.005) on the left side. The calculated latency between the cortex and the LV level was not found to be significantly longer in those patients treated for ALL compared with the healthy controls. Neurologic signs, in the form of depressed deep tendon reflexes, were observed in 8% of the patients, whereas approximately 33% of the patients were found to have fine or gross motor difficulties and dysdiadochokinesia. CONCLUSIONS: Neurologic signs still persisted 5 years after therapy for ALL. Approximately 33% of the patients had fine or gross motor difficulties and dysdiadochokinesia, and demyelinative injuries to the peripheral nerve tracts were found proximally but not within the central nervous system. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10503
UI - 11681411
AU - Dervieux T; Medard Y; Verpillat P; Guigonis V; Duval M; Lescoeur B;
TI - Suciu S; Vilmer E; Jacqz-Aigrain E Possible implication of thiopurine S-methyltransferase in occurrence of infectious episodes during maintenance therapy for childhood lymphoblastic leukemia with mercaptopurine.
SO - Leukemia 2001 Nov;15(11):1706-12
AD - Service de Pharmacologie Pediatrique et Pharmacogenetique, Hopital Robert Debre, Paris, France.
6-Mercaptopurine (6-MP) is metabolized by thiopurine S-methyltransferase (TPMT), an enzyme subject to genetic polymorphism. We investigated the relationships between the TPMT locus (TPMT activity and genotype) and the pharmacological response to 6-MP during maintenance therapy of 78 children with acute lymphoblastic leukemia (ALL). For each patient, 6-MP dosage, leukocyte counts and occurrence of infectious episodes were monitored on an 8 week basis. Higher 6-MP dosage was associated with higher TPMT activity (P = 0.03) and higher average leukocyte counts (P < 0.01). Eight patients (10%) carrying a TPMT mutant genotype (one homozygous and seven heterozygous) received lower 6-MP doses (average: 48 vs 65 mg/m2/day; P = 0.02) and had on average lower leukocyte counts (2834 vs 3398 cells/mm3; P = 0.003) than patients carrying the wild-type TPMT genotype. Higher occurrence of infectious episodes graded 2 or 3 was correlated with higher 6-MP dosage (P < 0.01) but no difference was observed between TPMT mutants and TPMT wild-type patients. Patients who received 6-MP dosage above the group median (62 mg/m2/day) or having a TPMT activity above the group median (21.5 nmol/h/ml) had a higher percentage of 8 week periods with infectious episodes requiring treatment (34% vs 17% and 33% vs 19%, respectively) than those with 6-MP dose or TPMT activity below the group median (P < 0.01). In the last 25 patients enrolled in the study, steady-state erythrocyte thioguanine nucleotide (TGN) concentrations were associated with lower leukocyte counts (P= 0.01) but not with a higher occurrence of infectious episodes. In contrast, higher steady-state erythrocyte methylmercaptopurine nucleotide (MeMPN) concentrations were associated with higher 6-MP dosage (P< 0.01) and higher occurrence of infectious episodes (P < 0.001). In conclusion, during maintenance therapy of ALL, children with higher TPMT activity receive a higher 6-MP dosage and may have infectious episodes caused by metabolism of 6-MP into methylmercaptopurine nucleotides.
UI - 11929791
AU - Taub JW; Konrad MA; Ge Y; Naber JM; Scott JS; Matherly LH; Ravindranath
TI - Y High frequency of leukemic clones in newborn screening blood samples of children with B-precursor acute lymphoblastic leukemia.
SO - Blood 2002 Apr 15;99(8):2992-6
AD - Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, Michigan 48201, USA. firstname.lastname@example.org
The detection of leukemia cells on newborn genetic screening cards ("Guthrie cards") of a small group of patients and several sets of identical twins developing acute lymphoblastic leukemia (ALL) with identical phenotypic and chromosomal markers has provided evidence that childhood ALL cases may arise in utero. We conducted a retrospective study of a randomly selected group of childhood B-precursor ALL patients to determine the frequency of the presence of "leukemic" clones prenatally in ALL cases by testing newborn screening cards. The 17 ALL patients analyzed had a median age of 46 months (range, 18 months to 13 years) and had median presenting white blood cell (WBC) counts of 10 950/microL (range, 2900-70 300/microL) at diagnosis. A clonal rearrangement of the immunoglobulin heavy chain (IgH) gene was identified in diagnostic lymphoblasts and sequenced and patient-specific primers were used to amplify DNA from blood samples on the patient's newborn screening cards. Twelve of the 17 (71%) analyzed newborn cards had detectable IgH rearrangements amplified by seminested polymerase chain reaction. DNA sequencing confirmed that the IgH rearrangements detected matched the IgH sequences identified from diagnostic leukemia cells, indicating the presence of a "leukemic" clone at birth. There were no differences in age or presenting WBC counts between the cases with or without positive newborn screening cards. All 6 patients with hyperdiploid ALL had detectable "leukemic" clones on their cards. The results of our study support the notion that a high proportion of childhood B-precursor ALL cases arise in utero, although postnatal events are also important factors in leukemogenesis.
UI - 11960906
AU - Kuerbitz SJ; Pahys J; Wilson A; Compitello N; Gray TA
TI - Hypermethylation of the imprinted NNAT locus occurs frequently in pediatric acute leukemia.
SO - Carcinogenesis 2002 Apr;23(4):559-64
AD - Department of Pediatrics and Department of Genetics, Case Western Reserve University and Ireland Cancer Center, Cleveland, OH 44109, USA.
Recent studies have demonstrated imprinting of the human neuronatin (NNAT) gene. NNAT maps to 20q11.2-q12, a region exhibiting loss of heterozygosity in acute myeloid leukemia and myelodysplastic/myeloproliferative disease. To investigate possible epigenetic dysregulation of genes in this region relevant to leukemogenesis, we analyzed methylation of the NNAT gene in normal tissues and in leukemias. We found a differential methylation pattern, typical of imprinted genes, at sites in the CpG island containing NNAT exon 1 in normal pituitary, peripheral blood cells and bone marrow-derived CD34-positive hematopoietic progenitor cells. Substantial or complete loss of the unmethylated NNAT allele was observed in leukemia cell lines and in 20 of 29 (69%) acute myeloid or lymphoid leukemia samples. While most highly expressed in brain, NNAT mRNA was also detected in normal hematopoietic progenitor cells and in leukemia cells exhibiting the normal methylation pattern, although not in hypermethylated leukemia cells. Demethylation by treatment of hypermethylated leukemia cells with 5-aza-2'-deoxycytidine resulted in reactivation of NNAT expression, concomitant with a reversion to the normal methylation pattern. The data demonstrate that hypermethylation of the NNAT locus is a frequent event in both myeloid and lymphoid acute leukemias of childhood. Aberrant hypermethylation of the NNAT locus suggests that the dysregulation of genes at 20q11.2-q12 in leukemia may be the result of epigenetic as well as genetic events.
UI - 12041882
AU - Krajinovic M; Labuda D; Sinnett D
TI - Childhood acute lymphoblastic leukemia: genetic determinants of susceptibility and disease outcome.
SO - Rev Environ Health 2001 Jul-Sep;16(4):263-79
AD - Hopital Sainte-Justine, Departement de Pediatrie, Universite de Montreal, Canada. email@example.com
The origin of acute lymphoblastic leukemia (ALL), the most common pediatric cancer, can be explained by a combination of genetic factors and environmental exposure. The environmental toxicants to which an individual is exposed are biotransformed and eliminated from the body after metabolic conversion mediated by Phase I and Phase II xenobiotic-metabolizing enzymes. Phase I enzymes catalyze hydroxylation, reduction and oxidation reactions of xenobiotics (carcinogens/drugs), often converting them into more active or toxic compounds. Phase II enzymes catalyze conjugation reactions (glucuronidation, acetylation, methylation), thereby converting the metabolites into non-reactive, water-soluble products that are eliminated from the organism. The genetic polymorphism underlying the variation in enzyme activity can modify susceptibility to diverse adult cancers, probably by influencing the activation and removal of toxicants or drugs. Here we present an overview of the role of genetic variants of certain Phase I and Phase II enzymes in the development of childhood ALL, a good model for such studies because of its short latency period. The genetic contribution to the development of ALL is examined by association studies that analyze the loci of Phase I enzymes (cytochrome P-450, myeloperoxidase) and Phase II enzymes (quinone-oxidoreductase, glutathione-S-transferase, N-acetyltransferase). The loci of the enzyme variants CYPlA1, CYP2E1, NQO1, GSTM1, GSTP1, NAT2 are associated with disease development, and evidence of gene-gene interactions has emerged as well. Despite the improvements in treatment, resistant cases of ALL remain a leading cause of cancer-related death in children. Although the underlying mechanism of drug resistance is not well understood, differences in the capacity of ALL patients to process drugs and environmental carcinogens could play a role by modifying the risk of recurrent malignancy, as well as the response to therapy. Therefore, polymorphic genes encoding carcinogen- and drug-metabolizing enzymes may not only increase the risk of ALL but also influence the risk of relapse in patients. We found that the prognosis of patients with CYPlA1 and NQO1 variants was worse than that of patients who lack these variants. We conclude that genotyping ALL patients for functional polymorphisms of candidate genes can become an important tool in predicting disease outcome.
UI - 11920234
AU - Mancini M; Nanni M; Sirleto P; De Cuia MR; Castoldi GL; Cilloni D;
TI - Cimino G; Mecucci C; Pane F; Annino L; Di Raimondo F; Santoro A; Specchia G; Tedeschi A; Todeschini G; Foa R; The GIMEMA study group Detection of BCR/ABL rearrangements in adult acute lymphoblastic leukemia using a highly sensitive interphase fluorescence in situ hybridization method (D-FISH).
SO - Hematol J 2001;2(1):54-60
AD - Department of Cellular Biotechnologies and Hematology, University 'La Sapienza', Rome, Italy. firstname.lastname@example.org
INTRODUCTION: One hundred-and-six adult cases of acute lymphoblastic leukemia were prospectively investigated using a highly sensitive interphase fluorescence in situ hybridization assay which utilizes DNA probes that detect a double BCR/ABL fusion signal (D-FISH) in cells carrying the t(9;22) to evaluate the reliability and specificity of this method for the detection of the Ph translocation. The results were compared with those obtained in the same cases by conventional cytogenetics and by reverse-transcription polymerase chain reaction. MATERIALS AND METHODS: The study was performed using DNA probes that span the common breakpoints of the t(9;22) translocation and that detect a double BCR/ABL fusion in cells carrying this karyotypic anomaly, one on the abnormal chromosome 9 and one on the Ph chromosome. RESULTS: Interphase D-FISH detected a high number of rearranged cases (22/106) compared to conventional cytogenetics (15/106) and RT-PCR (21/106). CONCLUSION: Interphase D-FISH emerges as a reliable, fast and relatively inexpensive tool for the detection of BCR/ABL rearrangements in adult ALL patients at diagnosis. It has a sensitivity clearly higher than conventional karyotyping and it may prove also superior to that of RT-PCR in cases with unusual BCR/ABL breakpoints. Our results suggest that D-FISH might be considered as the initial test for the diagnosis of Ph+ adult ALL.
UI - 11986937
AU - Chessells JM; Harrison CJ; Kempski H; Webb DK; Wheatley K; Hann IM;
TI - Stevens RF; Harrison G; Gibson BE; MRC Childhood Leukaemia working party Clinical features, cytogenetics and outcome in acute lymphoblastic and myeloid leukaemia of infancy: report from the MRC Childhood Leukaemia working party.
SO - Leukemia 2002 May;16(5):776-84
AD - Molecular Haematology Unit, Camelia Botnar Laboratories, Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
The clinical features, cytogenetics and response to treatment have been examined in 180 infants (aged <1 year) with acute leukaemia; 118 with acute lymphoblastic leukaemia (ALL) and 62 with acute myeloid leukaemia (AML). Comparison of clinical features showed no difference in age or sex distribution between infants with ALL and AML but infants with ALL tended to have higher leucocyte counts at presentation. Cytogenetic abnormalities involving 11q23 were found in 66% of ALL and 35% of AML cases, the commonest, t(4;11) being found only in ALL. The other recognised 11q23 translocations were found in both types of leukaemia. Few patients had the common cytogenetic abnormalities associated with ALL in older children and few with AML had good risk abnormalities. Four year event-free survival 60% cf 30% (P = 0.001) and survival 65% cf 41% (P = 0.007) were significantly better in AML than ALL. These results were due to a lower risk of relapse 27% cf 62% at four years. Superior event-free survival was also seen in the subgroup of patients with 11q23 abnormalities and AML (55% cf 23%). The reasons for superior response in AML are unknown but may be related to the intensity of treatment, lineage of the leukaemia or other as yet unidentified factors.
UI - 11986953
AU - O'Donnell PH; Guo WX; Reynolds CP; Maurer BJ
TI - N-(4-hydroxyphenyl)retinamide increases ceramide and is cytotoxic to acute lymphoblastic leukemia cell lines, but not to non-malignant lymphocytes.
SO - Leukemia 2002 May;16(5):902-10
AD - Division of Hematology-Oncology, Childrens Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA.
The retinoid, N-(4-hydroxyphenyl)retinamide (4-HPR), mediates p53-independent cytotoxicity and can increase reactive oxygen species and ceramide in solid tumor cell lines. We determined changes in ceramide and cytotoxicity upon treatment with 4-HPR (3-12 microM) in six human acute lymphoblastic leukemia (ALL) cell lines: T cell (MOLT-3, MOLT-4, CEM), pre-B-cell (NALM-6, SMS-SB), and null cell (NALL-1). Exposure to 4-HPR (12 microM) for 96 h caused 4.7 (MOLT-3), 3.5 (MOLT-4), 3.9 (CEM), 2.9 (NALM-6), 4.7 (SMS-SB), AND 4.5 (NALL-1) logs of cell kill. The average 4-HPR concentration that killed 99% of cells (LC(99)) for all six lines was 4.8 microM (range: 1.5-8.9 microM). Treatment with 4-HPR (9 microM) for 24 h resulted in an 8.9 +/- 1.0-fold (range: 4.9-15.7-fold) increase of ceramide. Ceramide increase was time- and dose-dependent and abrogated by inhibitors of de novo ceramide synthesis. Concurrent inhibition of ceramide glycosylation/acylation by d,l-threo-(1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol) (PPMP) further increased ceramide levels, and synergistically increased 4-HPR cytotoxicity in four of six ALL cell lines. 4-HPR was minimally cytotoxic to peripheral blood mononuclear cells and a lymphoblastoid cell line, and increased ceramide <2-fold. Thus, 4-HPR was cytotoxic and increased ceramide in ALL cell lines, but not in non-malignant lymphoid cell types.
UI - 11071631
AU - Gajjar A; Harrison PL; Sandlund JT; Rivera GK; Ribeiro RC; Rubnitz JE;
TI - Razzouk B; Relling MV; Evans WE; Boyett JM; Pui CH Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia.
SO - Blood 2000 Nov 15;96(10):3381-4
AD - Departments of Hematology-Oncology, Biostatistics and Epidemiology, Pharmaceutical Sciences, and Pathology, St Jude Children's Research Hospital, Memphis, TN, USA. email@example.com
The effect of traumatic lumbar puncture at the time of initial diagnostic workup on treatment outcome in children with newly diagnosed acute lymphoblastic leukemia (ALL) was investigated. The findings of the first 2 lumbar punctures performed on 546 patients with newly diagnosed ALL treated on 2 consecutive front-line studies (1984-1991) at St Jude Children's Research Hospital were retrospectively reviewed. Lumbar punctures were performed at the time of diagnosis and again for the instillation of first intrathecal chemotherapy. The event-free survival (EFS) experience for patients with 1 cerebrospinal fluid (CSF) sample contaminated with blast cells was worse than that for patients with no contaminated CSF samples (P =.026); that of patients with 2 consecutive contaminated CSF samples was particularly poor (5-year EFS = 46 +/- 9%). In a Cox multiple regression analysis, the strongest prognostic indicator was 2 consecutive contaminated CSF samples, with a hazard ratio of 2.39 (95% confidence interval, 1. 36-4.20). These data indicate that contamination of CSF with circulating leukemic blast cells during diagnostic lumbar puncture can adversely affect the treatment outcome of children with ALL and is an indication to intensify intrathecal therapy.
UI - 11732506
AU - Kebelmann-Betzing C; Seeger K; Wolf R; Henze G
TI - Traumatic lumbar puncture at diagnosis and outcome in childhood acute lymphoblastic leukemia.
SO - Blood 2001 Dec 1;98(12):3496-7
UI - 11964308
AU - Ogawa R; Streiff MB; Bugayenko A; Kato GJ
TI - Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21(WAF1/CIP1) proteins in human acute lymphoblastic leukemia cells.
SO - Blood 2002 May 1;99(9):3390-7
AD - Division of Hematology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Glucocorticoids are integral to successful treatment of childhood acute lymphoblastic leukemia (ALL) and other lymphoid malignancies. A large body of data indicates that in various model systems, elevation of cyclic adenosine monophosphate (cAMP) can potentiate glucocorticoid response, although this has not been well evaluated as a potential leukemia treatment. Although cAMP analogs have been studied, little data exist regarding the potential toxicity to leukemia cells of pharmacologic elevation of cAMP levels in leukemic blasts. Using MTT assays of cell proliferation on CEM ALL cells, we found that aminophylline and other nonspecific phosphodiesterase (PDE) inhibitors suppress cell growth. This effect is replicated by the PDE4-specific PDE inhibitor rolipram, but not by specific inhibitors of the PDE1 or PDE3 classes. We found that PDE inhibitors cause increased dexamethasone sensitivity and a synergistic effect with the adenylyl cyclase activator forskolin. We observed several important cellular characteristics associated with this treatment, including elevation of cAMP, induction of p53 and p21(WAF1/CIP1) proteins, G(1) and G(2)/M cell cycle arrest, and increased apoptosis. Sensitivity to forskolin and rolipram is shared by at least 2 pediatric ALL cell lines, CEM and Reh cells. Some cell lines derived from adult-type lymphoid malignancies also show sensitivity to this treatment. These findings suggest that PDE inhibitors have therapeutic potential in human ALL and characterize the molecular mechanisms that may be involved in this response.
UI - 11964322
AU - Branford S; Rudzki Z; Walsh S; Grigg A; Arthur C; Taylor K; Herrmann R;
TI - Lynch KP; Hughes TP High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance.
SO - Blood 2002 May 1;99(9):3472-5
AD - Institute of Medical and Veterinary Science, Adelaide, Australia. firstname.lastname@example.org
Point mutations were found in the adenosine triphosphate (ATP) binding region of BCR/ABL in 12 of 18 patients with chronic myeloid leukemia (CML) or Ph-positive acute lymphoblastic leukemia (Ph(+) ALL) and imatinib resistance (defined as loss of established hematologic response), but they were found in only 1 of 10 patients with CML with imatinib refractoriness (failure to achieve cytogenetic response). In 10 of 10 patients for whom samples were available, the mutation was not detected before the initiation of imatinib therapy. Three mutations (T315I, Y253H, and F317L present in 3, 1, and 1 patients, respectively) have a predicted role in abrogating imatinib binding to BCR/ABL, whereas 3 other mutations (E255K, G250E, and M351T, present in 4, 2, and 2 patients, respectively) do not. Thus we confirm a high frequency of mutations clustered within the ATP-binding region of BCR/ABL in resistant patients. Screening may allow intervention before relapse by identifying emerging mutations with defined impacts on imatinib binding. Certain mutations may respond to higher doses of imatinib, whereas other mutations may mandate switching to another therapeutic strategy.
UI - 12057546
AU - Meller S; Treleaven J
TI - Translocations at 11q23 in childhood ALL: age under 1 and poor prognosis.
SO - Lancet 2002 Jun 1;359(9321):1873-4
AD - Children's Department, Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
UI - 12057554
AU - Pui CH; Gaynon PS; Boyett JM; Chessells JM; Baruchel A; Kamps W;
TI - Silverman LB; Biondi A; Harms DO; Vilmer E; Schrappe M; Camitta B Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region.
SO - Lancet 2002 Jun 1;359(9321):1909-15
AD - St Jude Children's Research Hospital and the University of Tennessee, College of Medicine, Memphis, TN 38105, USA. email@example.com
BACKGROUND: The prognosis and optimum treatment of childhood acute lymphoblastic leukaemia (ALL) with abnormalities of chromosomal band 11q23 are controversial. We aimed to identify prognostic factors that might help in planning future therapy, and to assess the effectiveness of haemopoietic stem-cell transplantation in patients with the t(4;11) translocation, which is associated with a particularly poor outcome. METHODS: We reviewed data on 497 children and young adults who had ALL with various 11q23 abnormalities, including the translocations t(4;11), t(9;11), and t(11;19). All patients were treated with intensive chemotherapy, with or without haemopoietic stem-cell transplantation in first complete remission, by 11 study groups and single institutions from 1983 to 1995. FINDINGS: Age was the most important prognostic factor. In a Cox's proportional-hazard model stratified by 11q23 abnormalities, infants younger than 1 year fared significantly worse than patients 1 year of age or older (hazard ratio for event-free survival 1 84 [95% CI 1 38-2 47], p=0 0001). Among infants, any category of 11q23 abnormality conferred a dismal outcome, whereas in older patients, t(4;11) and t(9;11) were associated with a worse outcome than were other 11q23 changes. In the largest subgroup--256 patients with t(4;11)--any type of transplantation was associated with significantly worse disease-free survival (1 61 [1 10-2 35], p=0 014) and overall survival (1 76 [1 08-2 45], p=0 004) compared with chemotherapy only. Even transplantation with stem cells from HLA-matched related or HLA-matched unrelated donors tended to be associated with a worse outcome than chemotherapy alone. INTERPRETATION: The prognosis of acute lymphoblastic leukaemia with an 11q23 abnormality is particularly dismal in infants. Allogeneic transplantation with haemopoietic stem cells from an HLA-matched related donor does not seem to improve the clinical outcome in patients with t(4;11)-positive leukaemia.
UI - 11820585
AU - Akopyan H; Sirenko A; Sedneva I; Jakimovich M; Kluchivska O; Stojka R;
TI - Hnatejko O Cytogenetic assay in apoptosis investigations.
SO - Folia Histochem Cytobiol 2001;39 Suppl 2():158-60
AD - Institute of Hereditary Pathology, Academy of Medical Sciences and Institute of Cell Biology, National Academy of Science, Lviv, Ukraine.
The mitotic figure, named premature anaphase (PA) or C-anaphase, could be considered as a cytogenetic forerunner of following cell apoptosis in G1 phase. To confirm this hypothesis the comparative analysis was performed using cytogenetic, cytologic, flow cytometric and DNA fragmentation methods upon the cells with different proliferative ability and degree of differentiation. PA level was significantly increased in bone marrow and blood cells in vitro in cases of acute lymphoblastic leukemia and non-Hodgkin lymphoma, decreased until total disappearance in remission and not revealed in control. Particularly high PA level was registered in embryonal liver's haemopoetic stem cells ex vivo. Flow cytometry measurements showed appearance of additional sub-G1 peak of apoptotic DNA loss both in leukaemic and embryonal cells, whereas DNA-ladder phenomenon was revealed just only in embryonal samples in vivo. Significant positive correlation between the frequency of cells with apoptotic DNA loss and PA level on the chromosomal preparations was registered. Thus, premature anaphase phenomenon is considered as non-random event, associated with high risk of following cell death.
UI - 11787864
AU - Liu HC; Chen SH; Chang KH; Chiang LC; Liu CY; Chang HL; Tsai LL; Liang
TI - DC Overall and event-free survivals for acute lymphoblastic leukemia in children at a single institution in Taiwan.
SO - Pediatr Hematol Oncol 2002 Jan-Feb;19(1):19-29
AD - Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan.
The results of treatment for childhood acute lymphoblastic leukemia (ALL) have improved dramatically over the past three decades. The authors present the long-term outcome of patients (n = 151) with ALL enrolled in 4 consecutive clinical trials conducted from 1982 to 1993 at Mackay Memorial Hospital. During this period, the backbone of the treatment remained relatively unchanged, including a 3- to 4-drug remission induction, central nervous system (CNS)-directed therapy, and cyclic pulses of vincristine and dexamethasone during maintenance therapy. More intensive therapy, consisting of reintensification and addition of more drugs during maintenance, was reserved for high-risk and very-high-risk patients. The overall survival and event-free survival (+/- 1 SE) were 70 +/- 4.1% and 64 +/- 4.3 %, respectively, with follow-up ranging from 7.6 to 18.7years (median 12.2 year). The isolated CNS relapse rate was 4.3%. The dropout rate significantaly decreased from 35% in 1982-1984 to 0% in 1991-1993. Although the patient population is small, the overall results for childhood ALL at the authors' hospital are encouraging as compared to earlier reports in Taiwan.
UI - 12040438
AU - Hatta Y; Koeffler HP
TI - Role of tumor suppressor genes in the development of adult T cell leukemia/lymphoma (ATLL).
SO - Leukemia 2002 Jun;16(6):1069-85
AD - First Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.
Adult T cell leukemia/lymphoma (ATLL) is one of the peripheral T cell malignant neoplasms strongly associated with human T cell leukemia virus type-I (HTLV-I). Although the viral transactivating protein Tax has been proposed to play a critical role in leukemogeneis as shown by its transforming activity in various experimental systems, additional cellular events are required for the development of ATLL. One of the genetic events in ATLL is inactivation of tumor suppressor genes. Among many candidates for tumor suppressor genes, the main genetic events have been reported to center around the cyclin-dependent kinase inhibitors ((CDKIs) p15INK4A, p16INK4B, p18INK4C, p19INK4D, p21WAF1, p27KIP1, and p57KIP2), p53 and Rb genes; all of them play a major regulatory role during G1 to S transition in the cell cycle. Acute/lymphomatous ATLL has frequent alterations of p15 (20%) and p16 (28-67%), while chronic/smoldering ATLL has fewer abnormalities of p15 (0-13%) and p16 (5-26%). Most of these changes are deletion of the genes; fewer samples have mutations. ATLL patients with deleted p15 and/or p16 genes have significantly shorter survival than those individuals with both genes preserved. Although genetic alterations of p18, p19, p21, p27 have rarely been reported, inactivation of these genes may contribute to the development of ATLL because low expression levels of these genes seem to mark ATLL. The p53 gene is mutated in 10-50% of acute/lymphomatous ATLL. Functional impairment of the p53 protein, even if the gene has wild-type sequences, has been suggested in HTLV-I infected cells. Each of these genetic events are mainly found in acute/lymphomatous ATLL, suggesting that alterations of these genes may be associated with transformation to an aggressive phenotype. The Rb tumor suppressor gene is infrequently structurally altered, but one half of ATLL cases have lost expression of this key protein. Notably, alterations of one of the CDKIs, p53 and Rb genes appear to obviate the need for inactivation of other genes in the same pathway. A novel tumor suppressor gene on chromosome 6q may also have a critical role in the pathogenesis of ATLL. Taken together, tumor suppressor genes are frequently altered in acute/lymphomatous ATLL and their alteration is probably the driving force fueling the transition from chronic/smoldering to acute/lymphomatous ATLL.
UI - 12040444
AU - Penther D; Preudhomme C; Talmant P; Roumier C; Godon A; Mechinaud F;
TI - Milpied N; Bataille R; Avet-Loiseau H Amplification of AML1 gene is present in childhood acute lymphoblastic leukemia but not in adult, and is not associated with AML1 gene mutation.
SO - Leukemia 2002 Jun;16(6):1131-4
AD - Laboratory of Hematology, University Hospital, Nantes, France.
The AML1/CBFA2/RUNX1 gene is the target of many recurrent translocations seen in different leukemia subtypes. The t(12;21)(p13;q22) is the most frequent translocation observed in childhood B acute lymphoblastic leukemia (ALL), occurring in 20% to 25% of cases. In adult ALL this rearrangement is scarce. Another route of AML1deregulation could be point mutations in the runt domain. We now report on AML1amplification in two cases of childhood ALL, found in a series of 107 consecutive children with B-lineage ALL analyzed by fluorescence in situ hybridization (FISH). A parallel analysis of 42 adult B-ALL failed to detect any AML1 rearrangement by FISH. The two patients with AML1 amplification were further analyzed using molecular techniques. SSCP analysis did not detect any mutation. Furthermore, direct sequencing of the cDNA did not reveal any mutation. In conclusion, AML1amplification seems to be observed only in childhood ALL and is not associated with AML1 gen