Family cancer history and risk of childhood acute leukemia (France)

OBJECTIVE: A case-control study was carried out to investigate the role of a family history of solid tumor or hematologic neoplasm in the etiology of childhood acute leukemia. METHODS: Family cancer history in first- and second-degree relatives was compared in 279 incident cases (242 cases of acute lymphocytic leukemia and 37 of acute myeloid leukemia) and 285 controls. Recruitment was stratified by age, gender, hospital, area of residence, and ethnic origin. Odds ratios (OR) were estimated using an unconditional regression model taking into account the stratification variables, socioeconomic status, and familial structure. RESULTS: A significant association between childhood acute leukemia and a family history of hematologic neoplasm (OR = 2.7, confidence interval (CI) = 1.1-6.9) was found. This association was particularly clear-cut when the cases were restricted to acute myeloid leukemia (OR = 13.3, CI = 2.5-70.9). Childhood acute leukemia was associated with a family history of solid tumor (OR = 1.5, CI = 1.0-2.2), and elevated odds ratios were observed for family history of gastrointestinal cancer and melanoma. Those results are most unlikely to be explained by socioeconomic status and familial structure, which were very similar for the cases and controls. Differential misclassification is also unlikely for the first-degree relatives, even though it is difficult to rule it out for the second-degree relatives' history. CONCLUSION: The present study supports the hypothesis that a family history of cancer may be a risk factor for childhood acute leukemia.     

Genomics of racial and ethnic disparities in childhood acute lymphoblastic leukemia

Although the cure rates of childhood acute lymphoblastic leukemia (ALL) have improved dramatically in the past 40 years, not all children have benefited equally from this impressive progress. Racial and ethnic disparities in the incidence and treatment outcome of childhood ALL persist, with Hispanic children having an elevated risk of developing ALL and one of the lowest survival rates after ALL therapy. A critical barrier to progress is the lack of an understanding of the causes of ALL disparities, particularly racial and ethnic differences in ALL biology. In this review, the authors summarize the current knowledge on population variation in childhood ALL incidence and treatment outcome, discuss the contributing genetic and nongenetic variables, and highlight possible therapeutic interventions to mitigate disparities in ALL. Cancer 2014;120:955–962 . © 2013 American Cancer Society.     

Fetal growth and childhood acute lymphoblastic leukemia: Findings from the childhood leukemia international consortium

Positive associations have been reported between the measures of accelerated fetal growth and risk of childhood acute lymphoblastic leukemia (ALL). We investigated this association by pooling individual‐level data from 12 case–control studies participating in the Childhood Leukemia International Consortium. Two measures of fetal growth—weight‐for‐gestational‐age and proportion of optimal birth weight (POBW)—were analysed. Study‐specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, and combined in fixed effects meta‐analyses. Pooled analyses of all data were also undertaken using multivariable logistic regression. Subgroup analyses were undertaken when possible. Data on weight for gestational age were available for 7,348 cases and 12,489 controls from all 12 studies and POBW data were available for 1,680 cases and 3,139 controls from three studies. The summary ORs from the meta‐analyses were 1.24 (95% CI: 1.13, 1.36) for children who were large for gestational age relative to appropriate for gestational age, and 1.16 (95% CI: 1.09, 1.24) for a one‐standard deviation increase in POBW. The pooled analyses produced similar results. The summary and pooled ORs for small‐for‐gestational‐age children were 0.83 (95% CI: 0.75, 0.92) and 0.86 (95% CI: 0.77, 0.95), respectively. Results were consistent across subgroups defined by sex, ethnicity and immunophenotype, and when the analysis was restricted to children who did not have high birth weight. The evidence that accelerated fetal growth is associated with a modest increased risk of childhood ALL is strong and consistent with known biological mechanisms involving insulin‐like growth factors. © 2013 UICC     

Early life exposure to infections and risk of childhood acute lymphoblastic leukemia

Evidence from a growing number of studies indicates that exposure to common infections early in life may be protective against childhood acute lymphoblastic leukemia (ALL). We examined the relationship between three measures of early life exposure to infections-daycare attendance, birth order and common childhood infections in infancy-with the risk of ALL in non-Hispanic white and Hispanic children, two ethnicities that show sociodemographic differences. The analysis included 669 ALL cases (284 non-Hispanic whites and 385 Hispanics) and 977 controls (458 non-Hispanic whites and 519 Hispanics) ages 1-14 years enrolled in the Northern California Childhood Leukemia Study (NCCLS). When the three measures were evaluated separately, daycare attendance by the age of 6 months (odds ratio [OR] for each thousand child-hours of exposure = 0.90, 95% confidence interval [CI]: 0.82-1.00) and birth order (OR for having an older sibling = 0.68, 95% CI: 0.50-0.92) were associated with a reduced risk of ALL among non-Hispanic white children but not Hispanic children, whereas ear infection before age 6 months was protective in both ethnic groups. When the three measures were assessed simultaneously, the influence of daycare attendance (OR = 0.83, 95% CI: 0.73-0.94) and having an older sibling (OR = 0.59, 95% CI: 0.43-0.83) became stronger for non-Hispanic white children. In Hispanic children, a strong reduction in risk associated with ear infections persisted (OR = 0.45, 95% CI: 0.25-0.79). Evidence of a protective role for infection-related exposures early in life is supported by findings in both the non-Hispanic white and Hispanic populations within the NCCLS.     

Testicular relapse in acute childhood leukemia

The successful induction and maintenance of hematologic remission in childhood acute leukemia has led to the recognition of extramedullary leukemia as a major clinical problem [1–6]. The central nervous system is the most common site of extramedullary relapse [1,7–12], A more recently recognized form of extramedullary relapse is the testis [13–22]. This paper will review a series of patients with childhood acute leukemia who suffered testicular relapse. Modes of therapy for testicular relapse and research conducted into the etiology of testicular relapse will be discussed.     

Association of childhood acute lymphoblastic leukaemia with cancers in family members

Children whose twins have had leukaemia have a higher risk of contracting acute lymphoblastic leukaemia (ALL), confirming a prenatal origin of the disease. This association was not true when considering other types of affected first-degree relatives. Children whose fathers were diagnosed with testicular cancer have a higher risk of ALL.     

Trends in childhood acute lymphoblastic leukemia in Western Australia, 1960-2006

Increases in the incidence of childhood acute lymphoblastic leukemia (ALL) have been reported in some countries, while other reports from similar geographical regions have indicated stable rates. The reasons for the discrepancies have been debated in the literature, with the focus on whether the observed increases are "real" or an artifact resulting from improvements in diagnosis, case ascertainment and population coverage over time. We used population-based data from Western Australia to investigate trends in the incidence of childhood ALL between 1960 and 2006. Age-standardized incidence rates (ASRs) and rate ratios (indicating annual percent change) were estimated using Poisson regression. Between 1960 and 2006, the ASR was 3.7 per 100,000 person-years, with an annual percent increase of 0.40% (95% CI: -0.20, 1.00). Between 1982 and 2006, the ASR was 3.8, with an annual percent increase of 0.80% (95% CI = -0.70 to 2.30). This increased to 1.42% (95% CI: -0.30, 3.0) when a sensitivity analysis was undertaken to assess the effect of excluding the final 2 years of data. Annual increases of 3.7% (95% CI: -0.50, 8.00) among children aged 5-14 years, and of 3.10% (95% CI: 0.50, 5.70) in girls, were observed for this latter period. These results were supported by national Australian incidence data available for 1982-2003. There may have been a small increase in the incidence of ALL since 1982 among girls and older children, but an overall increase appears unlikely. No impact of folate supplementation or fortification is apparent.     

The prenatal origin of childhood acute lymphoblastic leukemia

Until recently, the etiology of childhood acute lymphoblastic leukemia (ALL) has remained relatively elusive. Several studies have established a time frame for the development of ALL which could lead to the identification of specific exposures linked to leukemogenesis from the generation of the initial leukemic clone until clinical diagnosis. Utilizing newborn screening ('Guthrie') cards, leukemic clones have been detected retrospectively in dried blood spots using two different PCR-based approaches: (i) the amplification of patient/leukemia-specific breakpoint fusion sequences of rearranged oncogenes; and (ii) the amplification of clonal immunoglobulin heavy chain gene (IgH) or T cell receptor (TcR) gene rearrangements. These studies support the hypothesis that a large proportion of childhood ALL cases arise in utero. In several studies, a long latency period from the generation in utero of the initial ALL clone to clinical diagnosis, indicates that additional genetic events are required for the full development of the leukemia phenotype, potentially from postnatal exposures (e.g. infections). The identification of leukemia-associated translocations in umbilical cord blood samples of healthy newborns, suggest that in the future children may be identified prospectively who have an increased risk of developing leukemia.     

Prognostic factors and outcome of recurrence in childhood acute myeloid leukemia

BACKGROUND: Outcome after recurrence of childhood acute myeloid leukemia (AML) is poor. We performed this study to identify prognostic factors for recurrence and for survival after recurrence of AML. METHODS: The clinical characteristics, biological features, treatment modalities, and outcomes of children with de novo AML who were enrolled on 3 consecutive clinical protocols from 1987 to 2002 at St. Jude Children's Research Hospital were studied. Regression modeling was used to identify prognostic factors for recurrence and for survival after recurrence. RESULTS: The outcome after recurrence was poor, with a 5-year survival estimate of only 23.3% +/- 5.7%. Multivariable analysis indicated that male sex (P = .005), autologous stem cell transplant before recurrence (P = .097), each additional month from diagnosis to recurrence (P = .041), and stem cell transplant after recurrence (P < .001) were associated with a better survival after recurrence, whereas M5 or M7 morphology (P = .001) were significantly predictive of a lower survival estimate after recurrence. CONCLUSIONS: Survival after recurrence was poor in children with AML. Novel therapies are urgently needed to prevent or to treat recurring AML.     

Prophylaxis and treatment of neoplastic meningeosis in childhood acute lymphoblastic leukemia

The introduction of cranial radiotherapy (CRT) has provided efficient control of overt or subclinical meningeosis in acute leukemia. Especially due to the long-term toxicity of CRT, reduction or elimination of radiotherapy appeared mandatory after cure rates of more than 70% had been achieved in acute lymphoblastic leukemia (ALL). Several large clinical trials of the Berlin-Frankfurt-Münster (BFM) Study Group with more than 3500 patients since 1981 have demonstrated that intensive systemic and intrathecal chemotherapy without or with limited CRT can efficiently prevent central nervous system (CNS) relapses in a large percentage of patients. However, only in low-risk patients prophylactic radiotherapy can be completely and safely replaced by conventional doses of methotrexate. In addition, reduction of chemotherapy in low-risk ALL increased the rate of relapses with CNS involvement. Thus, only a combination of multidrug induction, high-dose methotrexate (HD-MTX) consolidation, and reintensification allowed safe elimination of CRT in low-risk ALL. This approach combined with CRT with 12Gy and 18 Gy in medium and high risk ALL, respectively, reduced the incidence of relapses with CNS involvement to less than 5% (trial ALL-BFM 86). Patients with inadequate response to therapy, or with T-cell ALL, or with overt CNS disease are at particularly high risk for relapse with CNS involvement, and require more systemic and intrathecal chemotherapy combined with cranial irradiation. In B-cell ALL, short intensive chemotherapy pulses including HD-MTX could completely replace radiotherapy. In AML, post-consolidation CRT appears to be advantageous with regard to control of extramedullary as well as systemic relapses.     

TP53 alterations in relapsed childhood acute lymphoblastic leukemia

TP53 alterations are frequent relapse‐acquired mutations in childhood acute lymphoblastic leukemia (ALL). The present study evaluated the clinical significance of relapsed childhood ALL in Taiwan. Diagnostic and/or relapsed bone marrow or peripheral blood was obtained from 111 children with relapsed ALL who were initially treated by using Taiwan Pediatric Oncology Group (TPOG) ALL protocols from January 1997 to May 2018. Mutations were detected by PCR and sequencing, as well as by multiplex ligation‐dependent probe amplification to detect copy number alterations. Copy number and/or sequence alterations of TP53 were detected in 29% (28 of 98) and in 46% (6 of 13) of patients with relapsed B‐cell and T‐cell ALL, respectively. This incidence was much higher than that in several similar studies conducted in Caucasian populations. Seventy percent of all TP53 alterations were gained at relapse in 67 matched samples by back‐tracking matched diagnostic samples. TP53 alterations were associated with lower 5‐year event‐free survival (EFS) and overall survival (OS) rates (P = .013 and P = .0002, respectively). Multivariate analysis confirmed the prognostic significance of TP53 alterations. Forty‐five patients received hematopoietic stem‐cell transplantations post‐relapse. Patients with TP53 alterations (14/45) had inferior 5‐year EFS and OS than patients without TP53 alterations after transplantation (P = .002 and P = .001, respectively). The significance of these TP53 alterations for patients who received transplantations was confirmed by multivariate analysis. In conclusion, TP53 alterations were enriched and useful as prognostic markers in relapsed childhood ALL.     

In vitro cellular drug resistance adds prognostic information to other known risk-factors in childhood acute lymphoblastic leukemia

Leukemic cells from 230 children with newly diagnosed B-cell precursor ALL were tested for in vitro drug resistance to a panel of anti-cancer drugs. Minimal residual disease (MRD) was measured by RQ-PCR. During follow-up, 24 relapses occurred in the 159 children with MRD <0.1% day 29. The risk of any relapse was correlated to vincristine and doxorubicin resistance, with a relative risk of 3.7 (95% CI 1.3-10.5; p = 0.016) for patients resistant to both drugs. There was a significant correlation also for the subgroup with extra-medullary relapses. Our findings indicate that analysis of drug resistance can add prognostic information to other known risk-factors including MRD.