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C H Pui

Publications and source records attributed to C H Pui.

At least 55 records · Page 3Linked to original sources
PubMed2000

Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia.

BACKGROUND: Children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) have a poor prognosis, and there is no consensus on the optimal treatment for this variant of ALL. METHODS: We reviewed the medical records of patients with Ph-positive ALL who were treated with intensive chemotherapy, with or without bone marrow transplantation, by 10 study groups or large single institutions from 1986 to 1996. Data on 326 children and young adults, who ranged in age from 0.4 to 19.9 years (median, 8.1), were analyzed to determine the rate of complete remission and the probability of event-free, disease-free and overall survival according to standard prognostic factors and type of treatment. RESULTS: The 267 patients who achieved a complete remission after induction chemotherapy (82 percent) were stratified into three subgroups according to the age and leukocyte count at the time of diagnosis: those with the best prognosis (a leukocyte count of less than 50,000 per cubic millimeter and an age of less than 10 years; 95 patients); those with an intermediate prognosis (intermediate-risk features; 92 patients); and those with the worst prognosis (a leukocyte count of more than 100,000 per cubic millimeter; 80 patients). The estimates of disease-free survival at five years (+/-SE) were 49+/-5 percent) for patients with the best prognosis), 30+/-5 percent (for those with an intermediate prognosis), and 20+/-5 percent (for those with the worst prognosis) (P<0.001 for the overall comparison). We also found that transplantation of bone marrow from an HLA-matched related donor offered significantly greater benefit than intensive chemotherapy alone in terms of protecting patients from relapse or other adverse events (relative risk, 0.3; 95 percent confidence interval, 0.2 to 0.5; P<0.001). This finding was consistent in all three groups. CONCLUSIONS: Unlike the usual type of all, Ph-positive ALL is associated with a poor prognosis. Nevertheless, in some patients with favorable prognosis features, the disease can be be controlled by intensive chemotherapy. Transplantation of bone marrow from an HLA-matched related donor is superior to other types of transplantation and to intensive chemotherapy alone in prolonging initial complete remissions.

Adolescent↗
PubMed2000

Glutathione S-transferase genotypes in children who develop treatment-related acute myeloid malignancies.

Epipodophyllotoxin-associated secondary myeloid leukemia is a devastating complication of acute lymphoblastic leukemia (ALL) therapy. The risk factors for treatment-related myeloid leukemia remain incompletely defined. Genetic deficiencies in glutathione S-transferase (GST) activities have been linked to higher frequencies of a number of human malignancies. Our objective was to determine whether the null genotype for GSTM1, GSTT1, or both, was more frequent in children with ALL who developed treatment-related myeloid malignancies as compared to those who did not. A PCR technique was used to assay for the null genotype for GSTM1 and GSTT1 in 302 children with ALL, 57 of whom also subsequently developed treatment-related acute myeloid leukemia or myelodysplastic syndrome. Among children with ALL who did not develop treatment-related myeloid malignancies, the frequencies of GSTM1 and GSTT1 wild-type, GSTM1 null-GSTT1 wild-type, GSTM1 wild-type-GSTT1 null, and GSTM1 and GSTT1 null genotypes were 40%, 42%, 9% and 9%, respectively. The corresponding frequencies for patients who developed acute myeloid malignancies were 42%, 32%, 11% and 16%, respectively (P = 0.26). A statistically significant increase in the frequency of the GST null genotype was observed in male patients who developed myeloid malignancies as compared to male ALL control patients (P = 0.036), but was not observed in female patients (P = 0.51). Moreover, a logistic regression analysis of possible predictors for myeloid malignancies, controlling for gender and race, did not reveal an association of GSTM1 or GSTT1 null genotypes (P = 0.62 and 0.11, respectively) with treatment-related malignancies. Our data suggest that GSTM1 and GSTT1 null genotypes may not predispose to epipodophyllotoxin-associated myeloid malignancies.

Antineoplastic Agents, Phytogenic↗
PubMed2000

Individualized methotrexate dosing in children with relapsed acute lymphoblastic leukemia.

Although high-dose methotrexate has been extensively studied in children with newly diagnosed acute lymphoblastic leukemia (ALL), there are fewer data in children with relapsed ALL, many of whom have been heavily pretreated and have subclinical kidney dysfunction. We characterized the pharmacokinetics of adaptively controlled methotrexate given as a 24-h infusion during consolidation therapy in 24 children with relapsed ALL. To achieve the target steady-state concentration of 65 microM, dosage adjustments were required in 14 patients, with doses ranging from 2854 to 6700 mg/m2 per course. The mean steady-state plasma concentration (Cpss) of 68.0 microM was different (P = 0.025) than the predicted Cpss (mean = 87.4 microM; range 35.7-184 microM) had no adjustment in dose been made. The coefficient of variation in Cpss was reduced from 41% to 18% by individualizing doses. Predisposing factors that correlated with decreased methotrexate clearance were female sex (P = 0.03), age greater than 6 years (P = 0.01), and prior history of heavy amphotericin B treatment (>30 mg/kg) (P = 0.03), but no factor predicted low clearance as well as the measured initial methotrexate clearance during the infusion (P < 0.0001). There was no life-threatening toxicity with the regimen. We conclude that dosage individualization decreases interpatient variability and avoids potentially toxic methotrexate exposures in heavily pretreated ALL patients.

Adolescent↗
PubMed2000

Prognostic factors in infants with acute myeloid leukemia.

Little is known about the factors that affect treatment outcome in very young children with acute myeloid leukemia (AML). We therefore analyzed the prognostic impact of various presenting clinical and laboratory features by discrete age group in 299 children with AML treated in four consecutive clinical trials between 1980 and 1997. Differences in presenting features, as well as treatment outcome, were compared between children aged 12 months or less (n = 28) or 13 to 24 months (n = 28) and those more than 24 months of age (n = 243). Children in the two youngest groups (24 months of age or less) had similar presenting features and treatment outcome. Collectively, these 56 children were significantly more likely than the 243 older patients to have M4 or M5 leukemia (70% vs 30%), CNS leukemia (33% vs 22%), the t(9;11) (p22;q23) (18% vs 6%) or other 11q23 translocations (23% vs 3%), and less likely to have Auer rods (2% vs 54%) or the t(8;21) (q22;q22) (0% vs 17%). Among patients aged 24 months or less, two factors independently predicted a favorable prognosis: FAB M4 or M5 leukemia (relative risk of relapse, 0.4; 95% confidence interval, 0.2-0.9) and the t(9;11) (relative risk, 0.3; 95% confidence interval, 0.1-1.0). Leukocyte count and 11q23 translocations other than the t(9;11) lacked prognostic significance. Among older patients, a leukocyte count <50 x 10(9)/l and the presence of the t(9;11) conferred a favorable prognosis.

Acute Disease↗
PubMed2000

New definition of remission in childhood acute lymphoblastic leukemia.

The extent of clearance of leukemic cells from the blood or bone marrow during the early phase of therapy is an independent prognostic factor in acute lymphoblastic leukemia (ALL). Several methods are available to measure the minimal residual disease (MRD) remaining after initial intensive chemotherapy. The most promising are flow cytometric detection of aberrant immunophenotypes and polymerase chain reaction analysis of clonal antigen-receptor gene rearrangements. When applied together, these techniques enable one to monitor MRD in virtually all cases of ALL. Patients who achieve an 'immunologic' or 'molecular' remission (ie leukemic involvement of <0.01% of nucleated bone marrow cells at the end of remission induction therapy) are predicted to have a better clinical outcome than patients whose remission is defined solely by morphologic criteria. In studies to date, patients with MRD at a level of 10(-2) or more at the end of induction have fared almost as poorly as those with > or =5% blast cells in the bone marrow (ie induction failures). Sequential monitoring of MRD can improve the clinical utility of risk assessment still further. Additional studies are needed to determine the critical levels of MRD at various times of treatment and whether therapeutic intervention based on MRD findings can improve clinical outcome.

Child↗
PubMed2000

Late effects in survivors of infant leukemia.

Little is known about the incidence of and risk factor for late effects of infant leukemia. We evaluated 19 children with acute lymphoblastic leukemia and 15 with acute myeloid leukemia who were diagnosed at age 12 months or younger and have survived for more than 5 years after the diagnosis (median length of follow-up, 13 years; range, 5.7-29 years). Ten patients received chemotherapy alone (group A), 17 received chemotherapy and CNS-directed radiation therapy (CRT) (group B), and seven received chemotherapy, CRT and bone marrow transplantation (group C). The most frequently observed late sequelae included problems in growth (66% of survivors), learning (50%), hypothyroidism (15%), and pubertal development (12%). Cataract, cardiac and hearing abnormalities occurred in 6% of patients. Only eight patients (24%) survive without late effects. In comparison to patients in group A, patients in groups B and C had a higher incidence of having at least one late complication (P = 0.009), a greater decrease in height Z score at 5 years after diagnosis (P = 0.023), and a higher incidence of academic difficulties (P = 0.004). The estimated odds of academic difficulties increased by 18% (P = 0.032) for each month younger in age at the time of CRT. These results indicate that late sequelae are common in longterm survivors of infant leukemia and are often related to CRT and the patient's age at the time of CRT.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Long-term results of Total Therapy studies 11, 12 and 13A for childhood acute lymphoblastic leukemia at St Jude Children's Research Hospital.

We present the long-term results of three consecutive clinical trials (Total Therapy studies 11, 12 and 13A) conducted for children with newly diagnosed acute lymphoblastic leukemia (ALL) between 1984 and 1994. In study 11 (1984-1988), the overall event-free survival rates (+/-1 s.e.) were 71.8 +/- 2.4% and 69.3 +/- 2.4%, and the cumulative risks of isolated central nervous system (CNS) relapse 5.6 +/- 1.2% and 5.9 +/- 1.3%, at 5 and 10 years, respectively. In study 12 (1988-1991), event-free survival rates were 67.6 +/- 3.4% and 61.5+/- 9.0%, and isolated CNS relapse rates were 10.4 +/- 2.3% and 10.4 +/- 2.3%, respectively. Early intensive intrathecal therapy in study 13A (1991-1994) has yielded a very low 5-year isolated CNS relapse rate of 1.2 +/- 0.9%, boosting the 5-year event-free survival rate to 76.9 +/- 3.3%. Factors consistently associated with an adverse prognosis included male sex, infant or adolescent age group, leukocyte count >100 x 10(9)/l, nonhyperdiploidy karyotype and poor early response to treatment. Risk classification based on age and leukocyte count had prognostic significance in B-lineage but not T-lineage ALL. Early therapeutic interventions or modifications for patients with specific genetic abnormalities or persistent minimal residual leukemia may further improve long-term results.

Central Nervous System Neoplasms↗
PubMed2000

Acute lymphoblastic leukemia in children.

As the overall long-term event-free survival rate in children with acute lymphoblastic leukemia approaches 80%, emphasis is being placed on risk-directed therapy so that patients are neither overtreated nor undertreated. It has become apparent that a risk assignment system based on primary genetic abnormalities is inadequate by itself. For example, leukemias with the MLL-AF4 or BCR-ABL fusion gene are, in fact, heterogeneous diseases. Many require allogeneic hematopoietic stem-cell transplantation; some, if the patient is of favorable age and has a low presenting leukocyte count, can be cured with chemotherapy alone. Measurement of early responses to therapy and extent of minimal residual disease can greatly improve the accuracy of risk assessment. Consideration of the variable effects of therapy on the prognostic significance of specific genetic abnormalities is also important. Therefore, TEL-AML1 fusion confers a favorable prognosis in some protocols of chemotherapy but not in others. Studies to identify genetic polymorphisms with pharmacokinetic and pharmacodynamic significance promise to guide further refinement of treatment strategies. This will allow maximization of anticancer effects without induction of unacceptable toxicity in individual patients.

Antineoplastic Agents↗
PubMed2000

CNS involvement in children with newly diagnosed non-Hodgkin's lymphoma.

PURPOSE: To determine the frequency of CNS involvement at diagnosis of non-Hodgkin's lymphoma (NHL), to characterize its pattern of presentation, and to determine its prognostic significance. PATIENTS AND METHODS: We reviewed the records of 445 children (1975 through 1995) diagnosed with NHL (small noncleaved cell NHL/B-cell acute lymphoblastic leukemia [SNCC NHL/B-ALL], 201 patients; lymphoblastic, 113; large cell, 119; other, 12). Tumor burden was estimated by serum lactate dehydrogenase (LDH) measurement and reclassification of disease stage irrespective of CNS involvement (modified stage). RESULTS: Thirty-six of 445 children with newly diagnosed NHL had CNS involvement (lymphoma cells in the CSF [n = 23], cranial nerve palsy [n = 9], both features [n = 4]), representing 13%, 7%, and 1% of small noncleaved cell lymphoma, lymphoblastic lymphoma, and large-cell cases, respectively. By univariate analysis, CNS disease at diagnosis did not significantly impact event-free survival (P =. 095), whereas stage and LDH did; however, children with CNS disease at diagnosis were at 2.0 times greater risk of death than those without CNS disease at diagnosis. In a multivariate analysis, CNS disease was not significantly associated with either overall or event-free survival, whereas both serum LDH and stage influenced both overall and event-free survival. Among cases of SNCC NHL/B-ALL, CNS disease was significantly associated with event-free and overall survival (univariate analysis); however, in multivariate analysis, only LDH had independent prognostic significance. Elevated serum LDH or higher modified stage were associated with a trend toward poorer overall survival among children with CNS disease. CONCLUSION: A greater tumor burden at diagnosis adversely influences the treatment outcome of children with NHL and CNS disease at diagnosis, suggesting a need for ongoing improvement in both systemic and CNS-directed therapy.

Adolescent↗
PubMed2000

Hypersensitivity or development of antibodies to asparaginase does not impact treatment outcome of childhood acute lymphoblastic leukemia.

PURPOSE: Development of antibodies and hypersensitivity to asparaginase are common and may attenuate asparaginase effect. Our aim was to determine the relationship between antiasparaginase antibodies or hypersensitivity reactions and event-free survival (EFS). PATIENTS AND METHODS: One hundred fifty-four children with acute lymphoblastic leukemia received Escherichia coli asparaginase 10,000 IU/m(2) intramuscularly three times weekly for nine doses during multiagent induction and reinduction phases and for seven monthly doses during continuation treatment. Erwinia asparaginase was used in case of clinical hypersensitivity to E coli but not for subclinical development of antibodies. Plasma antiasparaginase antibody concentrations were measured on day 29 of induction in 152 patients. RESULTS: Antibodies were detectable in 54 patients (35.5%), of whom 30 (55.6%) exhibited hypersensitivity to asparaginase. Of the 98 patients who had no detectable antibodies, 18 (18.4%) had allergic reactions. Patients with antibodies were more likely to have a reaction than those without antibodies (P <.001). Among the 50 patients who experienced allergic reactions (including two for whom antibodies were not measured), 36 (72.0%) were subsequently given Erwinia asparaginase; seven (19.4%) reacted to this preparation. EFS did not differ among patients who did and did not have antibodies (P =.54), with 4-year EFS (+/- 1 SE) of 83% +/- 6% and 76% +/- 5%, respectively. Similarly, EFS did not differ among patients who did and did not develop allergic reactions (P =.68), with 4-year estimates of 82% +/- 6% and 78% +/- 5%, respectively. CONCLUSION: In this setting, in which most patients with allergy were switched to another preparation, there was no adverse prognostic impact of clinical or subclinical allergy to asparaginase.

Adolescent↗
PubMed1999

Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus.

BACKGROUND: Patients with acute lymphoblastic leukemia are often treated with 6-mercaptopurine, and those with homozygous deficiency in thiopurine S-methyltransferase (TPMT) enzyme activity have an extreme sensitivity to this drug as a result of the accumulation of higher cellular concentrations of thioguanine nucleotides. We studied the metabolism, dose requirements, and tolerance of 6-mercaptopurine among patients with different TPMT phenotypes. METHODS: We compared, by use of statistical modeling, 6-mercaptopurine pharmacology and tolerance in 180 patients who achieved remission on St. Jude Children's Research Hospital Protocol Total XII composed of weekly methotrexate (40 mg/m(2)) and daily oral 6-mercaptopurine (75 mg/m(2)) given for 2.5 years, interrupted every 6 weeks during the first year for treatment with either high-dose methotrexate or teniposide plus cytarabine. Statistical tests were two-sided. RESULTS: Erythrocyte concentrations of thioguanine nucleotides (pmol/8 x 10(8) erythrocytes) were inversely related to TPMT enzyme activity (P<.01), with averages (+/- standard deviations) of 417 (+/-179), 963 (+/-752), and 3565 (+/-1282) in TPMT homozygous wild-type (n = 161), heterozygous (n = 17), and homozygous-deficient (n = 2) patients, respectively. There was complete concordance between TPMT genotype and phenotype in a subset of 28 patients for whom TPMT genotype was determined. There were no sex differences in thioguanine nucleotide concentrations (P =.24), TPMT enzyme activity (P =.22), or average weekly prescribed dose of 6-mercaptopurine (P=.49). The cumulative incidence of 6-mercaptopurine dose reductions due to toxicity was highest among patients homozygous for mutant TPMT (100%), intermediate among heterozygous patients (35%), and lowest among wild-type patients (7%) (P<.001), with average (+/- standard deviation) final weekly 6-mercaptopurine doses of 72 (+/-60), 449 (+/-160), and 528 (+/-90) mg/m(2), respectively. Lowering doses of 6-mercaptopurine in TPMT heterozygotes and in deficient patients allowed administration of full protocol doses of other chemotherapy while maintaining high thioguanine nucleotide concentrations. CONCLUSION: We conclude that genetic polymorphism in TPMT is an important determinant of mercaptopurine toxicity, even among patients who are heterozygous for this trait.

Antimetabolites, Antineoplastic↗
PubMed1999

High incidence of secondary brain tumours after radiotherapy and antimetabolites.

BACKGROUND: Brain tumours rarely occur in survivors of childhood acute lymphoblastic leukaemia after cranial radiotherapy. An unusually high frequency of brain tumours seen among children enrolled in one of our leukaemia treatment protocols, Total Therapy Study XII, prompted us to identify the potential causes of this complication. METHODS: We assessed clinical, biological, and pharmacokinetic features in all 52 children who received prophylactic cranial radiotherapy. We compared the cumulative incidence of brain tumours between subgroups, and with that of 421 children who received radiotherapy in previous studies. FINDINGS: The incidence of brain tumours among irradiated children (six of 52, 12.8% [SE 5.0]) was high compared with patients in the same study who did not receive radiotherapy (none of 101; p=0.0008) and with other protocols that included cranial radiotherapy (p<0.0001). Of the six children, four had erythrocyte concentrations of thioguanine nucleotide metabolites higher than the 70th percentile for the entire cohort, and three had a genetic defect in thiopurine catabolism. The 8-year cumulative incidence of brain tumour among children with defective versus wild-type thiopurine methyltransferase phenotype was 42.9% (SE 20.6) versus 8.3% (4.7; p=0.0077). This protocol differed from previous protocols, in that more intensive systemic antimetabolite therapy was given before and during radiotherapy. INTERPRETATION: These data support the elimination of prophylactic radiotherapy for acute lymphoblastic leukaemia except in patients at high risk of central-nervous-system relapse. Underlying genetic characteristics and treatment variables may be associated with an increased risk of radiation-associated brain tumours.

Adolescent↗
PubMed1999

Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia.

6-Mercaptopurine (6MP) and methotrexate are the backbone of continuation therapy for childhood acute lymphoblastic leukemia (ALL). In studies of oral 6MP and methotrexate, indices of chronic systemic exposure to active metabolites of these agents, namely, red blood cell (RBC) concentrations of methotrexate polyglutamates (MTXPGs) and thioguanine nucleotides (TGNs) have positively correlated with event-free survival (EFS). Our objective was to evaluate whether MTXPGs, TGNs, and the dose intensity of administered methotrexate and 6MP were prognostic in the setting of a treatment protocol in which all treatment was coordinated through a single center, and the weekly doses of methotrexate were given parenterally. On protocol Total XII, 182 children achieved remission and received weekly methotrexate 40 mg/m2 parenterally and daily oral 6MP, interrupted every 6 weeks during the first year by pulse chemotherapy. A total of 709 TGN, 418 MTX-PG, and 267 thiopurine methyltransferase (TPMT) measurements, along with complete dose intensity information (dose received divided by protocol dose per week) for 19,046 weeks of 6MP and methotrexate, were analyzed. In univariate analyses, only higher dose intensity of 6MP and of weekly methotrexate were significant predictors of overall EFS (P =.006 and. 039, respectively). The occurrence of neutropenia was associated with worse outcome (P =.040). In a multivariate analysis, only higher dose intensity of 6MP (P =.020) was a significant predictor of EFS, with lower TPMT activity (P =.096) tending to associate with better outcome. 6MP dose intensity was also associated (P =.007) with EFS among patients with homozygous wild-type TPMT phenotype. Lower 6MP dose intensity was primarily due to missed weeks of therapy and not to reductions in daily dose. We conclude that increased dose-intensity of oral 6MP is an important determinant of EFS in ALL, particularly among those children with a homozygous wild-type TPMT phenotype. However, increasing intensity of therapy such that neutropenia precludes chemotherapy administration may be counterproductive.

Administration, Oral↗
PubMed1999

Reduced folate carrier expression in acute lymphoblastic leukemia: a mechanism for ploidy but not lineage differences in methotrexate accumulation.

Methotrexate (MTX) is one of the most active and widely used agents for the treatment of acute lymphoblastic leukemia (ALL). To elucidate the mechanism for higher accumulation of MTX polyglutamates (MTX-PG) in hyperdiploid ALL and lower accumulation in T-lineage ALL, expression of the reduced folate carrier (RFC) was assessed by reverse transcription-polymerase chain reaction in ALL blasts isolated from newly diagnosed patients. RFC expression exhibited a 60-fold range among 29 children, with significantly higher expression in hyperdiploid B-lineage ALL (median, 11.3) compared with nonhyperdiploid ALL (median, 2.1; P <.0006), but no significant difference between nonhyperdiploid B-lineage and T-lineage ALL. Furthermore, mRNA levels of RFC (mapped by FISH to chromosome 21) were significantly related to chromosome 21 copy number (P =.0013), with the highest expression in hyperdiploid ALL blasts with 4 copies of chromosome 21. To assess the functional significance of gene copy number, MTX-PG accumulation was compared in ALL blasts isolated from 121 patients treated with either low-dose MTX (LDMTX; n = 60) or high-dose MTX (HDMTX; n = 61). After LDMTX, MTX-PG accumulation was highest in hyperdiploid B-lineage ALL with 4 copies of chromosome 21 (P =.011), but MTX-PG accumulation was not significantly related to chromosome 21 copy number after HDMTX (P =.24). These data show higher RFC expression as a mechanism for greater MTX accumulation in hyperdiploid B-lineage ALL and indicate that lineage differences in MTX-PG accumulation are not due to lower RFC expression in T-lineage ALL.

Carrier Proteins↗
PubMed1999

Hyperdiploid acute lymphoblastic leukemia with 51 to 65 chromosomes: a distinct biological entity with a marked propensity to undergo apoptosis.

To determine the cellular basis for the excellent clinical outcome of hyperdiploid acute lymphoblastic leukemia (ALL), defined by a modal chromosome number of 51 to 65, we assessed the growth potential of leukemic cells from 129 children with newly diagnosed ALL. Flow cytometric analysis was used to compare leukemic cell recoveries at the beginning and at the end of 7-day cultures on allogeneic bone marrow-derived stromal layers. The median percentage of cell recovery after culture was 91% (range, <1% to 550%). Among the 25 hyperdiploid cases, only two had cell recoveries above the median value, compared with 63 of 104 cases with different ploidies (P <.001); 21 had recoveries within the first quartile, in contrast to only 12 of the 104 other cases. Cell recoveries in the 16 cases with duplications of chromosomes 4 and 10, a feature previously associated with a superior outcome, were all within the first quartile. Flow cytometric studies indicated that rapid induction of apoptosis was the underlying cause of low cell recoveries in cases with hyperdiploidy. The demise of hyperdiploid cells on stroma was not due to failure to adhere with stromal elements (as shown by electron microscopy) or to deficiencies of interleukin-1 (IL-1), IL-2, IL-3, IL-4, IL-6, IL-7, IL-11, stem-cell factor, interferon- (IFN-), tumor necrosis factor- (TNF-), or to combinations of these cytokines. Inactivation of IL-4, IFN- and TNF-, which if secreted by stromal layers could be toxic to ALL cells, failed to improve the survival of hyperdiploid blasts. We conclude that leukemic cells bearing 51 to 65 chromosomes have a marked propensity to undergo apoptosis. The stringent survival requirements of these cells, together with their potentially higher sensitivity to antileukemic drugs, may well account for the high cure rates achieved in patients with this form of ALL.

Adolescent↗
PubMed1999

Genetic abnormalities and drug resistance in acute lymphoblastic leukemia.

Recent advances in cytogenetics and molecular genetics have made it possible to identify an array of genomic abnormalities with prognostic and therapeutic significance. Hyperdiploidy > 50 chromosomes and ETV6-CBFA2 fusions have been used to identify low-risk cases, and BCR-ABL and MLL-AF4 to define high-risk leukemias. Despite their clinical utility, the risk classification system based on these findings lack absolute precision and should be complemented with other variables, the most important of which is the early blast cell response to remission induction therapy. Studies of tumor suppressor genes and proto-oncogenes in the BCL2 family genes may unravel the mechanisms of leukemia cell progression and the development of drug resistance, leading to innovative therapies. As the cure rates for childhood acute lymphoblastic leukemia (ALL) approach 80%, precise methods of risk assessment are needed to permit better selection of treatment that is neither excessive nor inadequate for individual patients. Because one or more genetic abnormalities underlie every case of leukemia, a risk assignment system based on primary genetic abnormalities has great intuitive appeal. Even though over 90% of childhood ALL cases can be readily classified according to numerical or gross structural chromosomal abnormalities, molecular analyses are essential to identify therapeutically relevant, submicroscopic genetic lesions not visible by karyotyping. This review focuses mainly on recent advances in genetic studies that have contributed to therapeutic advances or that hold promise for the future.

Burkitt Lymphoma↗