Serum iron level in acute lymphoblastic leukaemia.

Serum iron level (SIL) was studied by atomicabs orption spectrophotometry in 57 children with acute lymphoblastic leukaemia. SIL depended on the activity of the disease. Mean SIL was highest in untreated children. Normalization of myelograms during treatment was accompanied by a decrease of SIL. A significant decrease was observed in organ localizations and in infections during remission of the leukaemia. SIL may be helpful as an auxiliary test in the management of leukaemic children.     

Management of leukaemic infiltration of the testis.

Of 95 boys treated for acute lymphoblastic leukaemia 25 have developed leukaemic infiltration of the testes. In 15 children relapse was apparently confined to the testes, and since treatment 7 of these boys remain in remission. The median duration of remission after testicular relapse was 72 weeks, considerably longer than that reported after other forms of leukaemic relapse.     

Serum Immunoglobulin Levels in Children with Acute Lymphoblastic Leukaemia and Their Mothers and Sibs

Serum immunoglobulins G, A, and M were estimated in 29 children with acute lymphoblastic leukaemia and their first-degree relatives. 6 newborn sibs had high IgM levels in cord blood. IgG and IgM were raised in the mothers'' sera and there was a significant decrease in the serum IgG of sibs aged 2 to 10 years. The findings suggest the presence of some antigenic stimulus, possibly a virus, in the intrauterine life of affected sibships. It is postulated that the immunoglobulin abnormalities may be related pathogenetically to the leukaemic process.     

Prognostic factors in acute lymphoid leukaemia of childhood. II. Cell surface markers

Monoclonal sera have been used to determine the surface phaenotype of leukaemic cells during the last three years. Bone-marrow specimens of 57 children with recently diagnosed acute lymphoid leukaemia were examined; four cases were classified as T-cell leukaemia, 2 cases as B-cell leukaemia, in 37 cases cALLa was positive and fourteen children were classified as O-cell type, based on the absence of markers. Analysis of symptom-free survival revealed a very poor prognosis in B-cell leukaemia; there was no significant difference between the remaining groups. Within the cALLa positive cases L1 exhibited a markedly more favourable prognosis than L2.     

Myelodysplastic syndromes in children: Observations on five cases

Five paediatric patients with a myelodysplastic syndrome (MDS) (age range 4-12 years) are described. The frequency of MDS in our institution in the last 13 years is 1.12% of all leukaemic syndromes. Diagnosis and classification were made according to the recent proposals of the FAB Co-operative Group: four refractory anaemia with excess of blasts in transformation (RAEB-T) and one refractory anaemia with excess of blasts (RAEB). The haematqlogical picture at onset is presented with morphological, cytochemical, immunological and cytogenetic data. Two patients had trisomy 8 and one had monosomy 7. In three patients an evolution towards acute myeloid leukaemia was observed. Multiple drug treatment used in the chronic phase and/or during transformation in acute leukaemia did not produce complete remission. Low-dose Ara-C was employed in one case in the chronic phase without improvement. Four patients died 3-17 months after diagnosis. One is alive with persistent leukaemia 8 months after diagnosis.     

Transient myeloproliferation and acute myeloid leukemia in infants with Down's syndrome

Transient neonatal myeloproliferative disorders (TMD's) indistinguishable from acute leukaemia by clinical and morphological criteria have been described in neonates with Down's syndrome. To analyse its clinical significance, 10 infants under 1 year of age presenting with Down's syndrome and the morphological picture of acute myelogenous leukaemia were reviewed. 3 of these children had true AML leading to death after 2, 8 and 11 months. In the other 7 children the diagnosis TMD was suggested as spontaneous or in one case interferon-induced remission occurred within 4 to 25 weeks after diagnosis. The interferon-treated patient died of SIDS at the age of 11 months. Another one of the TMD children developed fatal erythroleukaemia at the age of 2 years. Regarding initial clinical and haematological parameters, TMD was indistinguishable from true congenital leukaemie. In all patients classification according to the FAB criteria was difficult, as mainly undifferentiated or poorly differentiated myeloid blasts were seen, sometimes with erythro- or megakaryocytic features. Because of the difficulties in the differential diagnosis of TMD and true AML it is recommended to delay specific cytostatic therapy in neonates with Down's syndrome, until definite progression of the leukaemic process is observed or cytogenetic analyses suggesting true AML are available.     

Immune response in families of children with acute lymphoblastic leukaemia

The immune status of 33 mothers, 17 fathers, and 14 sibs of children with acute lymphoblastic leukaemia was studied with the following tests: peripheral blood lymphocyte counts, lymphocyte transformation with phytohaemagglutinin, serum immunoglobulin levels, isohaemagglutinin titres, and levels of antibody to herpes simplex and Epstein-Barr viruses. No significant abnormality was shown by these tests, with the exception of a lymphocytosis detected in parents at an early stage of their child''s disease. The significance of these findings is discussed in the light of the concept that viral infection relates to the aetiology of childhood leukaemia. It is concluded that there is no defect of immunity in these families.     

MANIFEST INTESTINAL INVOLVEMENT DURING BONE-MARROW REMISSION IN A CASE OF ACUTE LYMPHOBLASTIC LEUKAEMIA

ABSTRACT: Aronson, A. S., Garwicz, S., Landbcrg, T., Nelson, O. and Brun, A. (Departments of Paediatrics, Radiotherapy, Paediatric Surgery, Pathology, University Hospital, Lund, Sweden). Manifest intestinal involvement during bone-marrow remission in a case of acute lymphoblastic leukaemia. Acta Paediatr Scand, 64:369, 1975.–Massive leukaemic involvement of the intestine appeared in a 9-year-old girl with acute lymphoblastic leukaemia. The unusual feature in this case was that the gut involvement occurred during complete haematolog-ical remission. Surgical and subsequent radiological treatment completely eradicated the engagement and at autopsy 9 months later there were no signs of the intestinal involvement.     

Clinical significance of glucocorticoid receptors in acute leukaemia. Preliminary observations in Hungary and review of the literature

Glucocorticoid receptor (GR) levels were quantitated in leukaemic blast cells separated from peripheral blood of 15 children with acute lymphocytic leukaemia (ALL) and of 6 children with acute non-lymphocytic leukaemia (ANLL). Using a whole-cell assay, it was found that specific (3H)-dexamethasone binding exhibited a wide range in both types of acute leukaemia: GR levels scattered between 0-22,346/cell and 0-8772/cell in ALL and ANLL patients, respectively. In this paper we discuss our observations together with current knowledge on GR levels in leukaemic blast cells and their relationship to glucocorticoid sensitivity and disease outcome.     

Bone marrow chromosomes in acute lymphoblastic leukaemia: A long-term study

The bone marrow chromosomes of 25 children with acute lymphoblastic leukaemia (ALL) were examined at diagnosis before treatment, during remission, and in 12 cases, also during relapse. Follow-up was for at least six years. At diagnosis, 17 patients had a major population of chromosomally abnormal cells and of these 11 had identifiable clones. The commonest abnormality was hyperdiploidy. Eight patients had predominantly normal cells, but four of these had a minor abnormal clone. In remission, some samples were completely normal but, when pooled, remission samples had a minor population of chromosomally aberrant cells which were rarely clonal. The incidence of structural abnormalities was the same in patients who ultimately relapsed and those who remained in first remission at the end of the study, but the presence of hyperdiploid cells and/or clones in remission was more frequently associated with subsequent relapse. Relapse patterns were of two kinds: in three patients there was a return of the chromosomal abnormalities seen at diagnosis; in six others, chromosomal features in relapse were distinct from those at diagnosis. It is suggested that relapse associated with distinct chromosomal features may represent malignant transformation of a previously unaffected cell line. While chromosomal abnormalities seen prior to treatment can be related to the leukaemic event alone, abnormalities seen in remission and in relapse may result partly from drug and X-ray treatment. The relative importance of treatment and other factors to chromosomal change in ALL is discussed.     

Bone marrow chromosomes in acute lymphoblastic leukaemia: a long-term study.

The bone marrow chromosomes of 25 children with acute lymphoblastic leukaemia (ALL) were examined at diagnosis before treatment, during remission, and in 12 cases, also during relapse. Follow-up was for at least six years. At diagnosis, 17 patients had a major population of chromosomally abnormal cells and of these 11 had identifiable clones. The commonest abnormality was hyperdiploidy. Eight patients had predominantly normal cells, but four of these had a minor abnormal clone. In remission, some samples were completely normal but, when pooled, remission samples had a minor population of chromosomally aberrant cells which were rarely clonal. The incidence of structural abnormalities was the same in patients who ultimately relapsed and those who remained in first remission at the end of the study, but the presence of hyperdiploid cells and/or clones in remission was more frequently associated with subsequent relapse. Relapse patterns were of two kinds: in three patients there was a return of the chromosomal abnormalities seen at diagnosis; in six others, chromosomal features in relapse were distinct from those at diagnosis. It is suggested that relapse associated with distinct chromosomal features may represent malignant transformation of a previously unaffected cell line. While chromosomal abnormalities seen prior to treatment can be related to the leukaemic event alone, abnormalities seen in remission and in relapse may result partly from drug and X-ray treatment. The relative importance of treatment and other factors to chromosomal change in ALL is discussed.     

Cell membrane fluidity in blast cells of children with acute leukaemia

Plasma membrane fluidity has been investigated by determining steady-state fluorescence polarization (FP) of the apolar stain 1,6-diphenyl-1,3,5,-hexatriene in intact blast cells, separated from peripheral blood and bone marrow of children with various types of acute leukaemia. FP-values of blast cells taken before antileukaemic therapy were compared with FP-values of peripheral blood and bone marrow mononuclear cells separated from patients in complete remission as well as from control patients and from healthy volunteers. Moreover, fluorescence polarization measurements were also performed using blast cells of leukaemic patients on short-term single-drug prednisolone pretreatment. The results have shown that untreated blast cells have significantly lower FP-values than normal mononuclear cells of peripheral blood or bone marrow. No compartment difference has been observed within blast cells, while normal mononuclear cells from peripheral blood have significantly higher FP-values than bone marrow cells. FP-values of cells separated in remission or during prednisolone treatment do not differ from control values.     

Long-term control of central nervous system leukaemia.

Seventy-four children with acute lymphoblastic leukaemia had one or more episodes of central nervous system (CNS) leukaemia. 5 children had CNS involvement at diagnosis; 4 survived for less than one year. In 35 children who had not had a previous bone marrow relapse on treatment and who received combination chemotherapy, the median duration of haematological remission from the time of first CNS relapse was almost 3 years. 5 children received full dose (2400 rads) craniospinal irradiation after their first CNS relapse; 4 have remained in CNS and haematological remission for 2 1/2 years or more. 18 children who had a CNS relapse after irradiation received 4-weekly intrathecal methotrexate; in 8 children this was given via an intraventricular reservoir. The median duration of CNS remission in children receiving intrathecal methotrexate was 2 years. Systemic and intrathecal treatment was stopped in 7 children after 2 1/2 years in continuous remission and in 2 children after 2 years. 4 of these 9 children remain in remission at intervals from 41 to 69 weeks off treatment but one is severely retarded. These results show that CNS disease is compatible with prolonged survival, but illustrate the difficulties of eradicating established CNS leukaemia.     

Neurological complications of childhood leukaemia.

We have reviewed the neurological complications not directly attributable to leukaemic infiltration in a group of 438 children with leukaemia or lymphoma. 61 children had one or more complications due chiefly to bleeding, infection, or drug toxicity. Early death from intracranial haemorrhage occurred in 1% of children with lymphoblastic leukaemia and 7% of children with myeloblastic leukaemia. Measles and chicken pox were the most serious infective complications; one child remains severely retarded after presumed measles encephalitis, one child with chicken pox died, and a second remains disabled. 2 additional cases of measles encephalitis and one of progressive multifocal leucoencephalopathy are described. Drugs which caused neurotoxicity included vincristine, cytosine arabinoside, L-asparaginase, and phenothiazines, but most problems were caused by methotrexate. Methotrexate toxicity was more prevalent and more serious in children who had had previous central nervous system leukaemia. We conclude that viral infections and methotrexate pose the greatest neurological hazards to children with leukaemia.     

Bone marrow immunoglobulin-secreting cells are not reduced in children with leukaemia as compared to children with solid tumours

Children with leukaemia exhibit multiple immunological disturbances, including low circulating levels of immunoglobulins, caused by both the disease and chemotherapy. We investigated the number of isotype-specific immunoglobulin-secreting cells (ISCs) in the bone marrow at the time of diagnosis in 32 children and during therapy in 12 children with leukaemia. We compared these to the number of ISCs in 17 untreated children with solid tumours and related the ISCs to serum immunoglobulin levels, lymphocyte subsets, response to mitogenic stimulation and serum cytokine levels. Bone marrow specimens were analysed for isotype-specific (immunoglobulins G, A and M) ISCs using the ELISPOT method. At the time of diagnosis, for all isotypes, the total number of ISCs per millilitre of bone marrow in children with leukaemia was no different from that in children with solid tumours. Chemotherapy significantly decreased the number of ISCs. The quantitative relationship between the different isotypes was unaffected by both tumour type and therapy. It can be concluded that in childhood leukaemia, tumour replacement of bone marrow cells does not cause a decreased number of ISCs and can therefore not account for the low serum immunoglobulin levels observed at time of diagnosis. Chemotherapy reduces the number of ISCs without changing the isotype distribution.     

Marrow transplantation in treatment of children with aplastic anaemia or acute leukaemia.

Seventy-six patients, aged 2 to 17 years, were treated with bone marrow transplantation for severe aplastic anaemia or acute leukaemia refractory to conventional therapy. 16 of the 22 patients (73%) who received marrow transplantations for aplastic anaemia are surviving, 12 of these for over one year. In acute leukaemia, using preparation with cyclophosphamide and total body irradiation, 8 of 33 patients (24%) receiving allogeneic and 5 of 8 (63%) receiving syngeneic transplantations are continuing in remission from 3 months to beyond 2 years. The longest continuing remission off therapy is now over 4 1/2 years after preparation with total body irradiation. The major causes of failure remain graft-versus-host disease, infection, graft rejection (aplastic anaemia), and leukaemic relapse.     

PERSISTENCE OF IN VITRO LYMPHOCYTE RESPONSE TO TUBERCULIN IN SKIN TEST NEGATIVE CHILDREN IMMUNIZED WITH BCG IN INFANCY

Abstract. PPD stimulated lymphocyte reactivity was tested in 119 children aged 11 to 12 years. The lymphocyte responses was evaluated by measuring the extent of tritiated thymidine incorporation by cultured cells. In a group of sixty-four tuberculin negative children who had been BCG vaccinated in the neonatal period, lymphocyte response was significantly greater than in a group of non-vaccinated tuberculin negative children matched for sex. The highest reactivity appeared in another group of children vaccinated in infancy and tuberculin positive. Lymphocytes from BCG vaccinated children retain some sensitivity to tuberculin even years after the BCG vaccination and even at the time when the skin reactivity disappeared.     

Nephrotic syndrome of childhood and disorder of T cell function

In thirty-two patients with nephrotic syndrome (NS) phytohemagglutinin (PHA)-induced lymphocyte proliferation was studied at various stages of the disease. We demonstrated that lymphocyte transformation during acute exacerbation is markedly decreased, especially if cells are cultured in patient serum. During treatment with steroids PHA-stimulation improves. During full remission all patients showed their maximal lymphocyte stimulation. On the basis of these results and reports from the literature we postulate that patients with the NS have a T cell clone which inhibits the transformation capacity of the remaining lymphocytes through production of a heat stable serum factor. The same or a second factor produced by these lymphocytes could at the same time exert a toxic effect on the glomerular basement membrane.This investigation was supported by grants of the Deutsche Forschungsgemeinschaft (SFB 107, Mainz)     

SERIAL DETERMINATIONS OF SERUM FERRITIN IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA Evaluation of its Usefulness as a Prognostic Index

Abstract. Thirty children with acute lymphoblastic leukemia were monitored with serial serum ferritin determinations for up to 17 months. In children with acute lymphoblastic leukemia before initiation of therapy, or in relapse, the mean serum ferritin concentration was 636 μg/l. In children who went into primary remission, the mean serum ferritin concentration fell from 265 μg/l prior to start of treatment, to 161 μg/l after 3 months of treatment. Five patients relapsed. Their serum ferritin levels prior to the relapses ranged from 7 to 135 μg/l. At the time of relapse a further increase in serum ferritin was found in only 2 of the children. Thus, whereas high serum ferritin levels may signal disease activity in acute lymphoblastic leukemia, a normal serum ferritin level does not exclude disease activity or impending relapse.     

Changes in coagulation and fibrinolysis in childhood acute lymphoblastic leukaemia re-induction therapy using three different asparaginase preparations

Recently we reported the influence of two different Escherichia coli asparaginase (ASP) preparations on fibrinolytic proteins in childhood acute lymphoblastic leukaemia (ALL) demonstrating a significant association between ASP activity and haemostatic alterations. The present study was designed for prospective evaluation of coagulation and fibrinolytic parameters in leukaemic children receiving different ASP preparations during the course of re-induction. Forty leukaemic children receiving ASP (Medac: n = 13; Bayer: n = 10; Erwinia: n = 17) at 3-day intervals during re-induction were enrolled in this study. Blood samples for coagulation studies were obtained before each ASP administration together with serum samples for pharmacokinetic monitoring. Compared with Medac ASP 10,000 IU/m², patients receiving Bayer ASP or Erwinia ASP showed significantly higher fibrinogen values. Antithrombin and plasminogen showed normal values in children after Erwinia ASP. α2-antiplasmin and D-Dimer were no different in the groups studied. Neither side-effects, nor sustained asparagine depletion was observed in the majority of children treated with Erwinia ASP. Conclusion Data of this study show a down-regulation of coagulation proteins in children treated with Medac ASP, less pronounced in patients after Bayer or Erwinia ASP. Since children treated with Erwinia ASP showed no adequate asparagine depletion during the course of ASP therapy, a dose adjustment should be discussed to guarantee asparagine depletion, the specific metabolic therapy for ALL. Received: 13 January 1997 / Accepted: 5 May 1997