Aberrant microRNA expression and its implications in the pathogenesis of leukemias

Background

MicroRNAs (miRNAs) are a class of non-coding, endogenous, small RNAs that negatively regulate gene expression by inducing degradation or translational inhibition of target mRNAs. Aberrant expression of miRNAs appears to be a common characteristic of hematological malignancies including leukemias.

Aim

Here we review the available data supporting a role of aberrant expression of miRNAs in the pathogenesis of leukemias including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL).

Conclusions

The expression signatures of miRNAs provide exciting opportunities in the diagnosis, prognosis, and therapy of leukemia. Since miRNAs can function as either oncogenes or tumor suppressor genes in leukemogenesis, the potential of using these small RNAs as therapeutic targets opens up new opportunities for leukemia therapy by either inhibiting or augmenting their activity.     

Leukämien im Kindesalter

Background

Leukemia is the most frequent malignant disease in childhood. Acute and chronic diseases of lymphatic or myeloid origin can be distinguished.

Results

Acute lymphoblastic leukemia (ALL) is the most frequent type of leukemia with more than 80?% of all leukemias, acute myeloid leukemia accounts for 15?% and chronic myeloid leukemia (CML) 2–3?%. Chronic lymphatic leukemias do not occur in childhood. Whereas various primary and secondary tumor genetic lesions could be determined as the basis of the disease in ALL and AML, CML has a monogenetic origin caused by the BCR-ABL1 fusion gene. With the contemporary multimodal chemotherapy strategies the prognosis of leukemia is excellent. In selected patients with an unfavorable prognosis allogeneic hematopoietic stem cell transplantation (HSCT) is indicated and CML can be specifically treated with tyrosine kinase inhibitors.

Perspectives

Many new therapeutic agents with targeted mechanisms of action are being investigated in clinical trials with respect to efficacy and safety in pediatric leukemia. In the future, it is hoped that unspecific chemotherapy can partly be replaced by targeted therapies with reduced side effects, with the aim of reducing the acute side effects and the substantial delayed toxicity.

     

Central nervous system involvement at presentation in the chronic phase of chronic myelogenous leukemia in childhood.

With the advent of more effective chemotherapy an increasing incidence of central nervous system involvement in acute lymphocyte (ALL) and myelocytic leukemias (AML) and chronic myelocytic leukemia (CML) in blast crisis has become evident. Meningeal involvement in the chronic phase of CML is rare. We report two children whose initial presentation of Ph1 CML was in the central nervous system as documented by cytocentrifugation. Aggressive combination chemotherapy and cranial irradiation has resulted in prolonged survival without blastic transformation or further meningeal disease. An approach to children with CML is suggested.     

Trends in survival after diagnosis with hematologic malignancy in adolescence or young adulthood in the United States, 1981‐2005

BACKGROUND:

There are few population‐based studies of long‐term survival of adolescents and young adults with hematologic malignancies; most pertain to patients diagnosed in the 1990s or earlier. Period analysis was used to obtain up‐to‐date information on survival expectations of adolescents and young adults diagnosed with hematologic malignancies through the early 21st century.

METHODS:

Period analysis was used to calculate 5‐ and 10‐year relative survival for adolescents and young adults diagnosed with Hodgkin lymphoma (HL), non‐Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), and chronic myelocytic leukemia (CML) for 5 5‐year periods from 1981‐1985 to 2001‐2005, using data from the Surveillance, Epidemiology, and End Results database.

RESULTS:

Survival strongly improved for each of the 5 hematologic malignancies. Increases in 10‐year relative survival between 1981‐1985 and 2001‐2005 were as follows: HL, from 80.4% to 93.4%; NHL, from 55.6% to 76.2%; ALL, from 30.5% to 52.1%; AML, from 15.2% to 45.1%; CML, from 0 to 74.5% (P < .001 in all cases). However, although survival improved steadily throughout the period examined for the lymphomas and CML, survival was stable during the late 1990s and early 21st century for the acute leukemias.

CONCLUSIONS:

Survival expectations for adolescents and young adults with hematologic malignancies have strongly improved since the 1980s. However, with the exception of HL, survival rates have not reached the levels observed for children diagnosed with these malignancies, and survival expectations for patients with acute leukemia have stabilized at relatively low levels. Cancer 2009. © 2009 American Cancer Society.     

Understanding disparities in leukemia: a national study

Purpose

Disparities in solid tumors have been well studied. However, disparities in hematologic malignancies have been relatively unexplored on population-based levels. The purpose of this study is to examine the relationship between race/ethnicity and acute leukemia mortality.

Methods

All patients with acute leukemia [acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML)] were identified in the Surveillance Epidemiology and End Results database, 1999–2008. Kaplan–Meier curves were generated to reflect survival probabilities by race/ethnicity. Multivariable Cox proportional hazard models estimated hazard of mortality by race with adjustment for individual (age, gender, year of diagnosis) and select genetic factors.

Results

A total of 39,002 patients with acute leukemia were included in the study. Overall, there was a mortality disparity in acute leukemia for blacks (HR 1.17, p?<?0.0001) and Hispanics (HR 1.13, p?<?0.0001) compared with non-Hispanic whites. In stratified analysis, disparities in ALL were greater than AML; blacks (HR[ALL]1.45, p?<?0.0001; HR[AML]1.12, p?<?0.0011); Hispanics (HR[ALL]1.46, p?<?0.0001; HR[AML]1.06, p?<?0.0001). Adjustment for individual patient and select genetic factors did not explain disparities.

Conclusions

Blacks and Hispanics suffer decreased survival in acute leukemia as compared to others. Further investigation is needed to understand the drivers of poor cancer outcomes in these populations.     

Leukemia following breast cancer: an international population-based study of 376,825 women

Purpose To quantify long-term temporal trends in the excess absolute risk (EAR) of secondary leukemia among breast cancer (BC) survivors, using multivariate analyses to evaluate the effects of subtype, age at BC diagnosis, attained age, and calendar year. Patients and methods We identified 376,825 1-year survivors of BC within 4 nationwide, population-based cancer registries in Sweden, Denmark, Finland, and Norway (1943–2001). Estimates of EAR (per 100,000 person-years) were modeled using Poisson regression methods and cumulative risks calculated using a competing risk model. Results A total of 687 non-chronic lymphocytic leukemias (EAR = 9.05; 95% confidence interval (CI) = 7.5–10.7) was reported. Significantly elevated risks were observed for the first time for chronic myeloid leukemia (CML) (EAR = 2.06; 95% CI = 1.3–2.9) and acute lymphoblastic leukemia (ALL) (EAR = 0.62; 95% CI = 0.2–1.1), in addition to acute myeloid leukemia (AML) (EAR = 5.00; 95% CI = 3.9–6.2). Excesses of CML, ALL, AML and all leukemias combined persisted over 25 years after BC diagnosis. For all leukemias, EAR decreased with increasing calendar year (P = 0.04) of BC diagnosis. Risk for all leukemia and AML by calendar year of BC diagnosis depended on age at diagnosis. For women diagnosed with BC after 1985, the 10-year cumulative risk of leukemia for those diagnosed before and after age 50 was small, 0.10% and 0.14%, respectively. Conclusions Although secondary leukemia is a rare event, BC survivors experience statistically significant excesses for at least 25 years after diagnosis, including CML and ALL. Decreasing leukemia risks in recent calendar years likely reflect changes in treatment.     

NQO1 rs1800566 (C609T), PON1 rs662 (Q192R), and PON1 rs854560 (L55M) polymorphisms segregate the risk of childhood acute leukemias according to age range distribution

Purpose

The risk of developing childhood leukemia has been associated with gene polymorphisms that decrease the activity of detoxifying metabolic enzymes and enzymes involved in systemic oxidative stress. We investigated the NQO1 and PON1 polymorphisms for associations with susceptibility to childhood leukemia.

Methods

Samples from 1,027 Brazilian children (519 acute lymphoblastic leukemia, ALL; 107 acute myeloid leukemia, AML; 401 controls) were analyzed. TaqMAN real-time assays were used to determine the NQO1 rs1800566 (C609T), PON1 rs662 (Q192R), and PON1 rs854560 (L55M) frequencies. Logistic regression was used to evaluate the association of polymorphisms with cases and controls, with age and somatic fusion genes (MLL-r and ETV6-RUNX1) as covariables.

Results

Children with at least one NQO1 variant allele were at lower risk for developing infant AML (odds ratio (OR) 0.26, 95?% confidence interval (CI) 0.10–0.68); no association was detected for ALL. PON1 rs854560 (L55M) was associated with an increased risk of developing childhood leukemia (LM?+?MM, OR 1.93, 95?% CI 1.32–2.81). The PON1 rs662 R192R genotype had a statistically significant decreased frequency in ALL (OR 0.64, 95?% CI 0.43–0.93). Infant ALL cases were more likely to harbor homozygous PON1 rs854560 alleles than controls (OR 1.72, 95?% CI 1.03–2.89); at least one M allele was associated with an increased risk of ALL in children older than 1?year (OR 1.99, 95?% CI 1.17–3.3).

Conclusions

The NQO1 rs1800566 (C609T), PON1 rs854560 (L55M), and PON1 rs662 (Q192R) polymorphisms modified risk depending on leukemia subtype (decreased in AML, increased and decreased in ALL, respectively), age strata, and variant genotype combinations.     

Birth weight and other risk factors for acute leukemia in the Jerusalem Perinatal Study cohort.

OBJECTIVES: To assess the effect of birth weight of children and their siblings and other perinatal/parental factors on the risk of acute leukemia. METHODS: We linked data from the Jerusalem Perinatal Study, a population-based research cohort (n = 88,829) of offspring born 1964 to 1976, with Israel's Cancer Registry. Risk factors for acute leukemia were assessed using univariate and multivariate proportional hazards models. RESULTS: Leukemias developed in 65 individuals [24 acute myeloid leukemias (AML) and 41 acute lymphoblastic leukemias (ALL)]. A positive linear relation was found between gender-adjusted birth weight and all leukemias [hazard ratio (HR) 1.85, 95% confidence interval (95% CI) 1.1-3.0] and AML (HR 2.9, 95% CI 1.3-6.4). The association between birth weight and AML was especially notable among infants (HR 8.14, 95% CI 1.8-38.9 for age 0 to 1 year) but was also observed among subjects ages >14 years at diagnosis. The relation was particularly strong among females (P = 0.001). Other risk factors for AML risk on univariate analysis were maternal origin, socioeconomic status, birth weight of sibling > 3,500 g, and family size. On multivariate analysis, only birth weight retained borderline significance (adjusted HR 2.38 per kg, 95% CI 1.0-5.7). Significant predictors for ALL in both univariate and multivariate analyses were male sex (adjusted HR 1.92, 95% CI 1.0-3.7) and birth weight categories > or = 3,000 g introduced into the model as nonlinear terms. CONCLUSION: Birth weight is associated with an increased risk of acute leukemia in infants, children, and young adults. Perinatal factors play a role in the development of childhood leukemias, but the patterns of association vary by leukemia type.     

Breast-feeding and risk of childhood acute leukemia.

BACKGROUND: Breast-feeding is well known to have a protective effect against infection in infants. Although the long-term effects of breast-feeding on childhood cancer have not been studied extensively, a protective effect against childhood Hodgkin's disease and lymphoma has been suggested previously from small investigations. In this study, we tested the hypothesis that breast-feeding decreases the risk of childhood acute leukemia. METHODS: A total of 1744 children with acute lymphoblastic leukemia (ALL) and 1879 matched control subjects, aged 1-14 years, and 456 children with acute myeloid leukemia (AML) and 539 matched control subjects, aged 1-17 years, were included in the analysis. Information regarding breast-feeding was obtained through telephone interviews with mothers. All leukemias combined, histologic type of leukemia (ALL versus AML), immunophenotype of ALL (early pre-B cell, pre-B cell, or T cell), and morphology of AML were assessed separately in the data analysis. RESULTS: Ever having breast-fed was found to be associated with a 21% reduction in risk of childhood acute leukemias (odds ratio [OR] for all types combined = 0.79; 95% confidence interval [CI] = 0.70-0.91). A reduction in risk was seen separately for AML (OR = 0.77; 95% CI = 0.57-1.03) and ALL (OR = 0.80; 95% CI = 0.69-0.93). The inverse associations were stronger with longer duration of breast-feeding for total ALL and AML; for M0, M1, and M2 morphologic subtypes of AML; and for early pre-B-cell ALL. CONCLUSION: In this study, breast-feeding was associated with a reduced risk of childhood acute leukemia. If confirmed in additional epidemiologic studies, our findings suggest that future epidemiologic and experimental efforts should be directed at investigating the anti-infective and/or immune-stimulatory or immune-modulating effects of breast-feeding on leukemogenesis in children.     

Incidence and predictors of treatment-related mortality in paediatric acute leukaemia in El Salvador

Survival rates among children with leukaemia in low-income countries are lower than those in high-income countries. This has been attributed in part to higher treatment-related mortality (TRM). We examined the demographics, treatment, and outcomes of paediatric patients in El Salvador with acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML) to determine the incidence, causes, and risk factors for TRM. Two trained data managers collected data prospectively; no patients were excluded. Biological, socioeconomic and nutritional predictors were examined. A total of 469 patients with ALL and 78 patients with AML were included. The 2-year cumulative incidence of TRM was significantly higher among children with AML (35.4±6.4%) than those with ALL (12.5±1.7%; P<0.0001). However, the proportion of deaths attributable to the toxicity of treatment did not differ significantly between AML (25/47, 53.2%) and ALL (55/107, 51.4%; P=0.98). Among children with ALL, low monthly income (P=0.04) and low parental education (P=0.02) significantly increased the risk of TRM. Among children with AML, biological, socioeconomic, and nutritional variables were not associated with TRM. In this low-income country, toxic death significantly contributes to mortality in both ALL and AML. A better understanding of the effect of socioeconomic status on TRM may suggest specific strategies for patients with ALL.     

Maternal fetal loss history and increased acute leukemia subtype risk in subsequent offspring: a systematic review and meta-analysis

Purpose

History of fetal loss including miscarriage and stillbirth has been inconsistently associated with childhood (0–14 years) leukemia in subsequent offspring. A quantitative synthesis of the inconclusive literature by leukemia subtype was therefore conducted.

Methods

Eligible studies (N?=?32) were identified through the screening of over 3500 publications. Random-effects meta-analyses were conducted on the association of miscarriage/stillbirth history with overall (AL; 18,868 cases/35,685 controls), acute lymphoblastic (ALL; 16,150 cases/38,655 controls), and myeloid (AML; 3042 cases/32,997 controls) leukemia. Sensitivity and subgroup analyses by age and ALL subtype, as well as meta-regression were undertaken.

Results

Fetal loss history was associated with increased AL risk [Odds Ratio (OR) 1.10, 95% Confidence Intervals (CI) 1.04–1.18]. The positive association was seen for ALL (OR 1.12, 95%CI 1.05–1.19) and for AML (OR 1.13, 95%CI 0.91–1.41); for the latter the OR increased in sensitivity analyses. Notably, stillbirth history was significantly linked to ALL risk (OR 1.33, 95%CI 1.02–1.74), but not AML. By contrast, the association of ALL and AML with previous miscarriage reached marginal significance. The association of miscarriage history was strongest in infant ALL (OR 2.34, 95%CI 1.19–4.60).

Conclusions

In this meta-analysis involving >50,000 children, we found noteworthy associations by indices of fetal loss, age at diagnosis, and leukemia type; namely, of stillbirth with ALL and miscarriage history with infant ALL. Elucidation of plausible underlying mechanisms may provide insight into leukemia pathogenesis and indicate monitoring interventions prior to and during pregnancy.

     

Trends in survival of leukemia among children,adolescents, and young adults: A population-based study in Osaka,Japan

This study focused on children as well as adolescents and young adults (AYAs) and aimed to examine trends in survival of leukemia over time using population-based cancer registry data from Osaka, Japan. The study subjects comprised 2254 children (0-14 years) and 2,905 AYAs (15-39 years) who were diagnosed with leukemia during 1975-2011. Leukemia was divided into four types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and other leukemias. We analyzed 5-year overall survival probability (5y-OS), using the Kaplan-Meier method and expressed time trends using the joinpoint regression model. For recently diagnosed (2006-2011) patients, a Cox proportional hazards model was applied to determine predictors of 5y-OS, using age group, gender, and treatment hospital as covariates. Over the 37-year period, 5y-OS greatly improved among both children and AYAs, for each leukemia type. Among AYAs, 5y-OS of ALL improved, especially after 2000 (65% in 2006-2011), when the pediatric regimen was introduced but was still lower than that among children (87% in 2006-2011, P < .001). Survival improvement was most remarkable in CML, and its 5y-OS was over 90% among both children and AYAs after the introduction of molecularly targeted therapy with tyrosine kinase inhibitors. Among patients with recently diagnosed AML, the risk of death was significantly higher for patients treated at nondesignated hospitals than those treated at designated cancer care hospitals. The changes in survival improvement coincided with the introduction of treatment regimens or molecularly targeted therapies. Patient centralization might be one option which would improve survival.     

Risk of subsequent malignancies in survivors of childhood leukemia

Purpose

The diagnosis of childhood leukemia now carries a much improved overall survival. With this knowledge comes concern for late effects of therapy, especially the risk of secondary malignancy.

Methods

Patients diagnosed with AML or ALL between the ages of 0 and 18 years who survived at least 5 years after diagnosis were included in analysis. Cumulative incidence of subsequent malignancy at 30 years was calculated. To compare incidence of subsequent malignancies with rates of the US population, standardized incidence ratios (SIRs) were calculated.

Results

Four thousand eight hundred six patients were included in the analysis. Median follow-up was 14.5 years (range 5.0–35.9 years). A total of 82 patients developed a second malignancy. The most common second tumor was brain (24 %) followed by thyroid (22 %). Cumulative incidences of secondary malignancy at 30 years for ALL patients and AML patients were 3.9 and 4.3 %, respectively (p?=?0.10). Patients were at an increased risk of malignancy compared to the US population (SIR?=?3.9, 95 % CI?=?3.2–4.8). The SIR for all malignancies for patients diagnosed between 1973 and 1979, 1980 and 1989, and 1990 and 1999 were 2.1 (95 % CI?=?1.3–3.4), 4.3 (95 % CI?=?3.1–5.9), and 4.4 (95 % CI?=?2.7–6.6), respectively.

Conclusions

Although incidence of secondary malignancy at 30 years in survivors of childhood leukemia is low, the rate exceeds the expected rate of malignancy for a cohort of this age by nearly 4:1. The development of a subsequent malignancy has significant impact on overall-survival and continued research is needed to assess the long-term risk of subsequent malignancy with modern therapy.

Implications for Cancer Survivors

Although survivors of childhood leukemia experience an increased rate of malignancy compared to their peers, the development of a subsequent malignancy is still a rare event. However, continued long-term follow-up is warranted.     

Trends in adult leukemia incidence and survival in Denmark, 1943–2003

The etiology of leukemia is largely unknown. Ecological data indicating trends in incidence and survival can provide information about changes in risk factors, can reflect underlying changes in diagnostic classification, and can measure therapeutic advances. From the records of the Danish Cancer Registry with registration starting from 1943, we calculated age-specific, period-specific, and age-standardized (world standard) incidence rates of chronic lymphoid leukemia (CLL), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML) for persons above the age of 18. Kaplan–Meier survival curves and median survival times were calculated. Between 1943 and 2003, there were 26,036 cases of leukemia reported. The age-specific incidence rates of CLL, CML, and AML were higher for older men and women, while the incidence rates of ALL by age were more homogeneous. The age-standardized incidence rates during the study period increased for CLL and AML, increased less strongly for ALL, and decreased for CML in both men and women, although the incidence rates for women were almost always lower. Patients with CLL had the longest survival time in all age groups. The median survival time increased for all leukemia subtypes throughout the period of study most pronounced for CLL since 1950 and CML since 1990.     

DNA ligases in human leukemia

Following partial purification on sucrose gradient and/or phosphocellulose chromatography, DNA ligase was tested in peripheral white blood and bone marrow cells of nearly 100 patients with various kinds of leukemias, mainly acute leukemias. Terminal deoxynucleotidyl transferase (TdT) was tested in parallel. DNA ligase of acute myeloblastic leukemia (AML) was extracted with the same sedimentation coefficient (5.5S) on sucrose gradient, and eluted with the same KCl molarity (0.3 M) than the one extracted from normal lymphocytes. Acute lymphoblastic leukemias (ALL) were characterized by no detectable DNA ligase activity--in most T or non T-non B-ALL, or a low activity in pre-B and B (Burkitt type) ALL, with levels similar to the one observed in chronic lymphocytic leukemia (CLL). An inverse relationship was observed between DNA-ligase and TdT in ALL, ligase being undetectable in cells positive for TdT and being present in some T or non T-non B, and in all pre-B and B-ALL negative for TdT. AML and chronic myelocytic leukemia (CML) were characterized by a markedly higher DNA-ligase activity. This activity was higher in the most differentiated subtypes--M2, M3 and M4 subtypes of FAB classification--and in CML. Moreover a high degree of correlation was observed in AML between the DNA ligase activity and the S phase fraction measured by 3 H-thymidine autoradiography or flow cytophotometry on the total cell sampling. Besides their clinical interest, these results are discussed in relation with the role of DNA-ligase in DNA replication and repair.     

p53 Protein Expression in Leukemias

p53 protein expression has been investigated by immunohistochemistry in 58 patients with leukemia. Seven of 24 cases with acute myeloid leukemia (AML), 3 of 15 cases with chronic lymphocytic leukemia (CLL), one of 11 cases with chronic myeloid leukemia (CML) and 4 of 8 cases with acute lymphoid leukemia (ALL) had p53 protein expression. Of patients having p53 expression, one case with AML had refractory anemia with excess blasts-transformation (RAEB/t), one case with CLL had Richter's syndrome and another one with CML was in accelerated phase. Finally, 26% of leukemia cases had p53 protein expression. It may be concluded that p53 protein abnormalities may have an important role in leukomogenesis and in the development of more malignant clones in chronic leukemias.     

Treatment-related mortality in children with acute lymphoblastic leukemia in Central America

BACKGROUND:

The objectives of this study were to describe the incidence, timing, and predictors of treatment‐related mortality (TRM) among children with acute lymphoblastic leukemia (ALL) in El Salvador, Guatemala, and Honduras.

METHODS:

Patients aged <20 years who were diagnosed with ALL between January 2000 and March 2008, who received treatment in any of the 3 countries, and who started induction chemotherapy were included in the study. Almost all patients were treated on the El Salvador‐Guatemala‐Honduras II protocol, which was based on the St. Jude Total XIII and XV protocols. Biologic, socioeconomic, and nutritional variables were examined as predictors of TRM.

RESULTS:

Of 1670 patients, TRM occurred as a first event in 156 children (9.3%); TRM occurred during remission induction therapy in 92 of 156 children (59%), between remission induction and maintenance therapy in 27 of 156 children (17%), and during maintenance therapy in 37 of 156 children (24%). Although the TRM rate decreased in patients who were diagnosed after July 1, 2004 (11.2% vs 7.9%; P = .02), the rate of induction death did not change (5.2% vs 5.8%; P = .58). Independent predictors of induction death included higher risk ALL (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.03‐3.27; P = .04), lower initial platelet counts (OR per 10 × 10⁹/L, 0.94; 95% CI, 0.89‐0.98; P = .005), and longer travel time to the clinic (OR, 1.06 per hour; 95% CI, 1.01‐1.14; P = .03).

CONCLUSIONS:

In Central America, TRM remains an important cause of treatment failure in children with ALL. A large proportion of TRM occurs in maintenance, although this proportion has decreased over time. Supportive care interventions should especially target children who present with low platelet counts. Further study on transfusion ability and the location of induction deaths is required. Cancer 2011;. © 2011 American Cancer Society.     

Toxicity of high dose Ara-C in children and adolescents

The toxicity of high dose cytosine arabinoside (Ara-C) in 23 leukemic children aged 1.5 years to 16 years 11 months was evaluated. The group included 11 children with acute lymphoblastic leukemia (ALL), nine with acute nonlymphoblastic leukemia (ANLL), two with chronic myelocytic leukemia (CML) in blastic crisis, and one with Burkitt's lymphoma. Toxicity consisted of bone marrow suppression in all patients, with a mean nadir time of 11 days for platelets and granulocytes. All patients experienced nausea and vomiting; 12 of 23 had drug induced fever; seven of 23 conjunctivitis; five of 23 mucositis; four of 23 diarrhea, and one of 23 elevated transaminase with hyperbilirubinemia. Adverse reactions were mild and reversible in all patients. No serious neurologic toxicity was seen. The toxicity observed in four patients with prior cranial irradiation was not any different from nonirradiated patients. The only life-threatening effect was neutropenia, the consequences of which were generally well controlled with antibiotic therapy. While this agent was effective in induction of remission in AML patients resistant to standard doses of Ara-C, it had no significant effect in a very small number of patients with relapsed ALL and CML in blast crisis. Side effects of high dose Ara-C though relatively substantial are manageable enough to warrant wider scale efficacy trials of this agent in childhood leukemias and solid tumors.     

High levels of 5′-nucleotidase activity in blastic chronic myelogenous leukemia with common all-antigen

The activity of 5′-nucleotidase (5′-N) on the surface of leukemia cells was determined in 44 patients with blast crisis of chronic myelogenous leukemia (CML) and in 52 patients with acute myeloblastic (AML) or acute lymphoblastic (ALL) leukemia. The phenotype of blast cells was classified according to immunological surface markers, including the common ALL-antigen (cALLA). High 5′-N activities were found in the presence of cALLA, whereas low to undetectable levels were characteristic for cALLA-negative leukemias, the difference being highly significant (p 0.0001). While there was a certain overlap of 5′-N levels between cALLA-positive ALL and cALLA-negative AML, no overlap of 5′-N was observed between cALLA-positive lymphoid and cALLA-negative myeloid blast crisis of CML. Thus, 5′-N affords an additional easily-testable biochemical marker that may have its diagnostic and prognostic value especially in the case of blastic chronic myelogenous leukemia.     

Maternal prenatal intake of one-carbon metabolism nutrients and risk of childhood leukemia

Purpose

Folate, vitamins B12 and B6, riboflavin, and methionine are critical nutrients for the one-carbon metabolism cycle involved in DNA synthesis and epigenetic processes. We examined the association between maternal intake of these nutrients before pregnancy and risk of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in a matched case–control study.

Methods

Maternal dietary intake and vitamin supplement use in the year before pregnancy was assessed by food frequency questionnaire for 681 ALL cases, 103 AML cases, and 1076 controls. Principal component analysis was used to construct a variable representing combined nutrient intake, and conditional logistic regression estimated the odds ratio (OR) and 95% confidence interval (CI) for the association of ALL and AML with the principal component and each nutrient.

Results

Higher maternal intake of one-carbon metabolism nutrients from food and supplements combined was associated with reduced risk of ALL (OR for one-unit change in the principal component = 0.91, CI 0.84–0.99) and possibly AML (OR for the principal component = 0.83, CI 0.66–1.04). When analyzed separately, intake of supplements high in these nutrients was associated with a reduced risk of ALL in children of Hispanic women only.

Conclusions

In conclusion, these data suggest that higher maternal intake of one-carbon metabolism nutrients may reduce risk of childhood leukemia.