Pharmacokinetics of prednisolone in children with acute lymphoblastic leukaemia

Summary The pharmacokinetics of soluble oral prednisolone were studied during induction therapy in six children with acute lymphoblastic leukaemia. There was a three- to four-fold variation in the pharmacokinetics of total and free prednisolone. For total prednisolone, the mean elimination half-life was relatively short (1.37 h) and the total clearance, relatively high (15.1 ml min^-1 kg^-1). The mean free fraction was high (0.37).     

Decreased natural killer cell activity in children with untreated acute leukemia

Natural killer cell activity was evaluated in children with acute lymphocytic and acute myelogenous leukemia. Peripheral blood mononuclear cells isolated at the time of diagnosis and before initiation of therapy were mixed with 51Cr-labeled K562 or MOLT-4 target cells at a ratio of 100:1. In 13 consecutive cases of acute lymphocytic leukemia, the mean percentage of lysis of K562 cells (15.0%) was significantly below that of adult (49.8%) and age-related controls (35.9%). A similar pattern was observed against MOLT-4 targets (acute lymphocytic leukemia, 11.3%; adults, 39.8%; and pediatric controls, 28.4%). The mean activity in 8 cases of acute myelogenous leukemia was also markedly reduced (6.8% versus K562 and 6.0% versus MOLT-4). Linear regression analyses of white blood cell, lymphocyte, and leukemia blast counts failed to demonstrate any correlation between peripheral cell counts and natural killer cell activity. Thus, it would not appear that the observed decrease in lysis was due merely to dilution of effectors with blasts. The lytic activity of cells isolated from patient blood was significantly lower than that from cells isolated from an equal volume of blood from a normal adult. These results suggest that the decreased natural killer cell activity is not explained by simple dilution. Instead, they indicate an absolute decrease in lytic potential. Additional experiments have precluded suppressor cell involvement and competitive inhibition of blasts with target cells as possible causes for depressed lysis.     

Bone mineral density in children with acute lymphoblastic leukaemia

Bone mineral density (BMD) may be negatively affected by the disease or its treatment in patients with acute lymphoblastic leukaemia (ALL). Therefore, we evaluated lumbar spine and total body BMD and bone metabolism in children with ALL at diagnosis, during treatment with chemotherapy and 1 year after completion of treatment. 32 children (21 boys and 11 girls) participated in the study. 14 children started the study at diagnosis and 18 during or after the treatment period. Lumbar spine and total body BMD were measured with dual energy X-ray absorptiometry, and expressed as standard deviation scores (SDS). Blood samples were obtained to assess bone metabolism. 3 of 14 children had low lumbar spine BMD (< -2 S.D.) at diagnosis. All children had normal total body BMD. Markers of bone turnover were depressed. Total body BMD SDS decreased significantly during the first year of treatment (P < 0.001). Lumbar spine BMD SDS did not change significantly. Parameters of bone turnover increased to normal during the treatment period. Parathyroid hormone had increased significantly after 1 year (P < 0.05). Mineral homeostasis was disturbed in some patients during treatment. 4 of 9 patients had low total body BMD and 1 patient low lumbar spine BMD one year after completion of treatment. All patients had normal biochemical results at that time. In conclusion, lumbar spine BMD and bone turnover were decreased in some patients at diagnosis. Total body BMD decreased significantly during treatment and was low in 4 of the 9 patients 1 year after completion of the treatment.     

Childhood acute lymphoblastic leukemia with natural killer activity. Clinical and cellular features of three cases

Leukemic cells from 3 of 28 children with acute lymphoblastic leukemia (ALL) had natural killer (NK) activity against K562 and Molt-3, but not against Raji as determined by the 4-hour 51Cr release assay at a 40:1 effector:target ratio; the highest percent lysis against K562 in each patient ranged from 55.9% to 147.4% of the normal lymphocyte value and that against Molt-3 from 28.0% to 127.9%. Their leukemic cells were nonphagocytic, nonadherent, and negative for nonspecific esterase. Leukemic cells from two of them displayed similar morphologic and immunologic features. The cells had a round nucleus, and were E-receptors (E)+, Leu-5+, IgG-Fc+, Ia+, OKM1+ or OKM1-, T-cell antigens-, B markers-, and monocyte antigen-, indicating their NK cell origin. The other patient's cells were characterized by the irregularly shaped nucleus, and were E+, Leu-5+, IgG-Fc+, T+, OKT6+, Leu-2a+, and OKM1+. The presence of E which are identical to E of T-cells and a high density of T-cell antigens including OKT6 on the cells suggested their T-cell nature. Of the three patients, two without thymic enlargement had leukemic cells of NK cell origin, and the other one with the symptom leukemic cells of the T-cell lineage, the clinical feature probably reflecting the cell lineage of their leukemic cells.     

The risk of traumatic lumbar punctures in children with acute lymphoblastic leukaemia

BackgroundTraumatic lumbar punctures with blasts (TLP+) in children with acute lymphoblastic leukaemia (ALL) obscure central nervous system status and are associated with a poorer event-free survival (EFS).MethodsWe conducted a retrospective cohort study of all lumbar punctures (LPs) for children with ALL diagnosed at our institution from 2005 to 2009. We utilised random-effects and fixed-effects repeated-measures logistic regression analyses to identify risk factors for TLPs. Fixed-effects models use each patient as his or her own control. We used survival analysis to describe outcomes after a TLP+.Results264 children underwent 5267 evaluable lumbar punctures (LPs), of which 944 (17.9%) were traumatic. In the multivariable random-effects model, variables significantly associated with TLPs were age <1 year (odds ratio (OR) 3.46, 95% confidence interval (CI) 2.06–5.81) or age ⩾10 years (OR 2.00, CI 1.66–2.40); body mass index percentile ⩾95 (OR 1.44, CI 1.19–1.75); platelet count <100 × 10³/μL (OR 1.49, CI 1.08–20.7); fewer days since previous LP (OR 5.13, CI 2.34–11.25 for ⩾16 days versus 0–3 days); and a preceding TLP (OR 1.43, CI 1.19–1.73). In the fixed-effects model, image-guidance reduced the odds of TLP (OR 0.55, CI 0.32–0.95). The 5-year EFS (±SE) for children with TLP+ (77 ± 8%) was significantly lower than for children with CNS1 status (93 ± 2%; p = 0.002).ConclusionsThe frequency of TLP remains high. Consistent with previous studies, a TLP+ at diagnosis was associated with a poorer EFS. These risk factors can allow identifying interventions to reduce TLPs and directing interventions to those at highest risk.     

Direct association of socio-economic status with T-cell acute lymphoblastic leukaemia in children

Lymphoblasts from 186 consecutive untreated children <18 years were analysed by flow cytometry in Brazil. Socio-economic status was defined by family income; undernourishment by height and weight for age standardised z scores below -1.28. The observed frequencies were precursor-B (pre-B) CD10 positive acute lymphoblastic leukaemia (ALL) (CD10+) 65%, pre-B CD10 negative (CD10-) 13%, and T-ALL 18%. The typical incidence peak at age 2-5 years was observed among the CD10 positive cases. Nutritional variables were not associated with immunophenotypes. Low monthly per capita income was associated with T-immunophenotype (P=0.024). In conclusion, a direct association between unfavourable socio-economic status and the T-phenotype indicates a potential role of socio-economic factors on the genesis of ALL in children, thus confirming indirect data of the international literature.     

Pharmacokinetics of oral and intramuscular methotrexate in children with acute lymphoblastic leukaemia

Summary Repeated methotrexate absorption studies were performed under standard conditions in 127 children receiving either oral or intramuscular methotrexate for acute lymphoblastic leukaemia. There was marked variability in peak concentration, area under the serum concentration curve and clearance both between patients and in repeated studies on the same patient. Although the intramuscular route produced higher serum concentrations and AUC than the oral route, variability within and between patients was considerable and was most marked at higher concentrations. Neither age or sex could account for variation in methotrexate absorption or clearance.Intramuscular methotrexate, although producing higher serum concentrations and AUC, does not reduce the variability observed with oral administration. Prediction of subsequent methotrexate concentrations from the knowledge of one absorption profile is not possible.     

Presence of clone-specific markers at birth in children with acute lymphoblastic leukaemia

Recent studies have suggested that development of childhood acute lymphoblastic leukaemia may often be initiated in utero. To provide further evidence of an prenatal origin of childhood leukaemia, we conducted a molecular biological investigation of nine children with B-precursor acute lymphoblastic leukaemia carrying the chromosomal translocation t(12;21), the most common subtype of all childhood acute lymphoblastic leukaemia. Specifically, for each child we identified the non-constitutive chromosomal sequences made up by the t(12;21) fusion gene. From these, leukaemia clone-specific DNA primers were constructed and applied in nested polymerase chain reaction analyses of DNA extracted from the patients' Guthrie cards obtained at birth. Leukaemia clone-specific fusion gene regions were demonstrated in Guthrie card DNA of three patients, age 2 years 11 months, 3 years 4 months, and 5 years 8 months at leukaemia diagnosis. Our findings are consistent with previous observations, and thus provide further evidence that the development of t(12;21) B-precursor acute lymphoblastic leukaemia may be initiated in utero. Review of the current literature moreover indicates that age at leukaemia may be inversely correlated with the burden of cells with leukaemia clonal markers, i.e. leukaemia predisposed cells at birth, and that certain types of childhood acute lymphoblastic leukaemia develop as a multiple step process involving both pre- and postnatal genetic events.     

Unpredictable serum levels after oral methotrexate in children with acute lymphoblastic leukaemia

Summary Serum methotrexate levels were measured for 5 h after oral intake in 11 children with acute lymphoblastic leukaemia. The curves obtained with the child's regular dose of methotrexate varied widely, and were independent of the doses used. Peak levels were found in samples taken up to 3 h after ingestion, and ranged from 300 to 1250 ng/ml. In the doses used, methotrexate toxicity was present in one of the eleven children, and was associated with a delayed peak and a high 5-h methotrexate level. Individual drug metabolism could be an important factor in the response to treatment, and needs to be evaluated in the assessment of protocols.     

Factors affecting survival in White and Asian children with acute lymphoblastic leukaemia

Some studies suggest that Asian children with leukaemia have a worse outcome than Whites. Survival of Asians with ALL treated at the Birmingham Children's Hospital from 1975 to 1994 was the same as that of Whites, despite their greater deprivation and poorer nutrition. For one 5-year period (1980-1984) Asians had significantly poorer survival, even after adjustment for prognostic factors. Poor treatment compliance during that period may have contributed to this difference.     

Feasibility of a school reintegration programme for children with acute lymphoblastic leukaemia

Despite children with acute lymphoblastic leukaemia missing a significant amount of school, little empirical literature guides the optimal content, setting and timing of a school reintegration programme. We examined the feasibility of a 4-month school reintegration intervention by: (1) developing collaboration with a community-based advocacy organisation; (2) developing intervention modules and observable end points; and (3) determining how the study achieved recruitment expectations. Eight families with children aged 6–12 years diagnosed with acute lymphoblastic leukaemia and parents were enrolled in the study. An experienced advocate implemented a series of eight modules over a 4-month period (twice per month) with the families. Participants completed pre–post measures. Successful collaboration with the advocacy organisation and the development of an intervention module series were achieved. Recruitment aims proved more difficult: enrolment was extended when recruitment for the original 1- to 6-month post-diagnosis window proved difficult. The advocate was able to complete between three and seven of the modules (mean = 5.2, standard deviation = 1.5). Families preferred clinic-based intervention. Challenges faced and lessons learned include: (1) advocacy organisations may be useful resources for school reintegration interventions; (2) school reintegration interventions must be flexibly applied; and (3) measurement end points constructed to gauge programme effectiveness.     

Interleukin-2 induction of lymphokine-activated killer activity in the peripheral blood of an acute lymphoblastic leukaemia patient--case study.

In this case study an acute lymphoblastic leukaemia (ALL) patient relapsing after autotransplant had remission reinduced with chemotherapy and consolidated after initial response by a course of therapy with recombinant interleukin-2 (rIL-2) given subcutaneously. Immunological parameters measured during therapy demonstrated an increase in the numbers of T cells and in lymphokine-activated killer (LAK) cell activity against autologous leukaemic blasts and LAK-sensitive cell lines. The therapy was well tolerated and administered on an out-patient basis. The patient has remained in haematological remission for over twelve months. Sustained remissions have not been observed previously in relapsed transplant patients using chemotherapy alone. The data suggests that rIL-2 deserves further evaluation in ALL patients who are immunologically intact with residual disease after primary or secondary chemotherapy.     

Role of Toll-like receptors in natural killer cell function in acute lymphoblastic leukemia

Natural killer (NK) cells are specialized lymphocytes primarily involved in the response to infection and tumors. NK cells are characterized by the presence of specific surface molecules, as well as a wide repertoire of receptors that impart microenvironment-dependent effector functions. Among these receptors, Toll-like receptors (TLRs) can be activated to condition the NK response to either a cytotoxic or immunoregulatory phenotype. However, cellular function is frequently impaired during disorders such as cancer. In the last decade, it has become increasingly evident that the stimulation of NK cells is a requirement for their increased cytotoxic activity. TLR activation has been suggested as an alternative route for reestablishing the antitumor activity of NK cells. The present review summarizes the characteristics of NK cells, their receptors, the expression and function of NK cell TLRs, and their functional status in cancer, primarily acute lymphoblastic leukemia.     

Hypothyroidism in induction chemotherapy of children with acute lymphoblastic leukaemia: A single-centre study

Hypothyroidism as a long-term complication in cancer survivors has been an issue, but few studies have focused on changes in thyroid hormone levels during chemotherapy for leukaemia. This retrospective study was conducted to assess the characteristics of children with acute lymphoblastic leukaemia (ALL) and hypothyroidism during induction chemotherapy and to investigate the prognostic value of hypothyroidism in ALL. Patients with a detailed thyroid hormone profile at ALL diagnosis were enrolled. Hypothyroidism was defined as low serum levels of free tetraiodothyronine (FT4) and/or free triiodothyronine (FT3). The Kaplan-Meier method was used to create survival curves, and multivariate Cox regression analysis was used to screen prognostic factors associated with progression-free survival (PFS) and overall survival (OS). There were 276 children eligible for the study, and 184 patients (66.67%) were diagnosed with hypothyroidism, including 90 cases (48.91%) with functional central hypothyroidism and 82 cases (44.57%) with low T3 syndrome. Hypothyroidism was correlated with the dosages of L-Asparaginase (L-Asp) (P = .004) and glucocorticoids (P = .010), central nervous system (CNS) status (P = .012), number of severe infections (grade 3, 4 or 5) (P = .026) and serum albumin level (P = .032). Hypothyroidism was an independent prognostic factor for PFS in ALL children (P = .024, 95% CI: 1.1-4.1). We conclude that hypothyroidism is commonly present in ALL children during induction remission, which is related to chemotherapy drugs and severe infections. Hypothyroidism was a predictor of poor prognosis in childhood ALL.     

Glucocorticoid use in acute lymphoblastic leukaemia

Glucocorticoids (prednisone and dexamethasone) play an essential part in the treatment of acute lymphoblastic leukaemia (ALL), but their optimum doses and bioequivalence have not been established. Results of preclinical studies have shown that dexamethasone has a longer half-life and better CNS penetration than does prednisone. In prospective randomised trials, dexamethasone improved control of CNS leukaemia. At a prednisone-to-dexamethasone dose ratio of less than seven, dexamethasone (6-18 mg/m(2) per day) resulted in a better event-free survival than did prednisone (40-120 mg/m(2) per day), and high-dose dexamethasone (10-18 mg/m(2) per day) improved the outcome of T-cell ALL and high-risk ALL. However, dexamethasone caused more adverse effects, including infection, bone fracture, osteonecrosis, mood and behaviour problems, and myopathy. At a dose ratio greater than seven, the two drugs showed no difference in efficacy. Therefore, the efficacy of prednisone and dexamethasone is dose dependent and needs to be carefully assessed against the toxic effects. Moreover, although dexamethasone generally showed increased activity in ALL cells in vitro, the dose ratio of the two drugs that exerted equivalent cytotoxic effects differed substantially in samples from individuals. The selection of the type and dose of glucocorticoid should be based on the risk of relapse, treatment phase, and the chemotherapeutic drugs used concomitantly.