Long-term results in children with AML: NOPHO-AML Study Group--report of three consecutive trials.

In all, 447 children with acute myeloid leukaemia (AML) have been treated on three consecutive NOPHO studies from July 1984 to December 2001. NOPHO-AML 84 was of moderate intensity with an induction of three courses of cytarabine, 6-thioguanine and doxorubicin followed by four consolidation courses with high-dose cytarabine. The 5-year event-free survival (EFS), disease free survival (DFS) and overall survival (OS) were 29, 37 and 38%. NOPHO-AML 88 was of high intensity with the addition of etoposide and mitoxantrone in selected courses during induction and consolidation. The interval between the induction courses should be as short as possible, that is, time intensity was introduced. The 5-year EFS, DFS and OS were 41, 48 and 46%. In NOPHO-AML 93, the treatment was stratified according to response to first induction course. The protocol utilised the same induction blocks as NOPHO-AML 88, but after the first block, children with a hypoplastic, nonleukaemic bone marrow were allowed to recover before the second block. Consolidation was identical with NOPHO-AML 88. The 5-year EFS, DFS and OS in NOPHO-AML 93 were 48, 52 and 65%. The new NOPHO-AML protocol has been based on experiences from previous protocols with stratification of patients with regard to in vivo response and specific cytogenetic aberrations.

Intensive chemotherapy in childhood myelodysplastic syndrome. A comparison with results in acute myeloid leukemia.

Myelodysplastic syndrome (MDS) in children is often considered as a variant of acute myeloid leukemia (AML) and frequently treated as such. However, there are very few reported data on the outcome following AML treatment. We analyzed 20 consecutive cases of de novo MDS treated in Denmark according to the NOPHO AML protocols. The results were compared with those obtained in 31 children with de novo AML treated with the same protocols, and with the outcome in 10 children with MDS who received allogeneic bone marrow transplantation (BMT) without prior AML therapy. Distinction between MDS and AML was made morphologically according to the FAB criteria. All children were followed for at least 37 months. The proportion of complete remission in MDS and AML was 35 percent vs 74 percent. (P = 0.005), resistant disease 25 percent vs 10 percent (P = 0.14), death in cytopenia 40 percent vs 16 percent (P= 0.06), and 3-year survival 15 percent vs 35 percent. (P = 0.11), respectively. Duration of treatment-related cytopenia was similar in MDS and AML, except for a longer period of leukopenia in MDS following the second course of induction. Seven of 10 MDS children receiving BMT without prior chemotherapy are long-term survivors. Our data suggest that conventional AML regimens are associated with a low rate of complete remission, a high risk of death in cytopenia, and a limited curative potential in childhood MDS. Allogeneic BMT was in contrast associated with a high survival rate. BMT may, at least in some patients, be performed successfully without prior induction chemotherapy. The different response to therapy in MDS and AML may reflect fundamental biological differences between the two conditions.

Incidence of childhood cancer in Denmark 1943-1984.

A population-based study was carried out on 5790 tumours in children (aged 0-14 years) diagnosed in the period 1943-1984 in Denmark. Cases were identified from the files of the high-quality National Cancer Registry in which codes for tumours were based solely on topography until the end of 1977. To achieve a uniform data set following the outlines of the International Classification of Diseases for Oncology (ICD-O) coding system used by the Cancer Registry today, all cases of childhood cancer diagnosed prior to 1978 were re-evaluated, and an ICD-O code was applied. Tumours were aggregated into diagnostic groups suitable for analysis and presentation using an internationally agreed scheme, which was designed by the Manchester Children's Tumour Registry and modified recently by the International Agency for Research on Cancer. The average incidence rates for all histological types of childhood cancer combined were 137 per million boys and 111 per million girls, which are close to those reported from the USA but higher than most of the overall figures reported from Europe. The proportions of specific tumours were similar to those observed in other industrialized countries. The well known excess of cancer cases among boys compared to girls was due mainly to the occurrence of 90% more lymphomas, 30% more leukaemias and 15% more tumours of the central nervous system (CNS) among boys. Although significant increases were seen in the subgroups of CNS neoplasms and neuroblastomas (both sexes) and of lymphomas (boys only), no overall increase in childhood cancer was observed during the 42-year period of registration. While the increase in the incidence of CNS tumours was explained at least partly by better cancer surveillance, no interpretation can be offered for the increases seen for neuroblastomas and lymphomas. Our descriptive data suggest that environmental exposures do not play any significant role in the aetiology of the majority of childhood cancers.

[Acute lymphoblastic leukemia in children. A retrospective study: 1970-1991]. / Akut lymfoblastaer leukaemi hos børn. En retrospektiv opgørelse: 1970-1991.

From January 1970 through December 1991, 94 girls and 130 boys with a median age of 4.8 years were diagnosed with non-B cell acute lymphoblastic leukaemia (ALL) at the University Hospital, Rigshospitalet. Intensive risk-group adapted therapy based on age and white-cell count (WBC) at diagnosis, the presence of a mediastinal mass, central nervous system (CNS) or testicular leukaemia, T-cell disease, and certain cytogenetic translocations have been used since July 1981. Ninety-seven percent of all patients achieved complete remission (all patients diagnosed since July 1986). Ninety patients relapsed, all within five years from diagnosis: 59 in bone-marrow (BM), 20 in CNS (no BM-involvement), nine in testes (all isolated), one in the eye, and one in a lymph node. The five-year event-free survival increased from 0.20 to 0.72 from the first to the last five-year period (p < 0.0001). Age and WBC at diagnosis were of prognostic significance during the period 1970-1981, but not during the last 10-year period, when risk-adapted therapy was applied. Following a relapse, patients with an isolated testicular focus had the best five-year survival as compared to patients with CNS- and/or BM-involvement (1.00 vs 0.19; p = 0.003). Patients relapsing following cessation of therapy had a better prognosis than did patients relapsing on therapy (five-year survival 0.58 vs 0.17; p = 0.002). Identification of new risk factors, more individualized therapy and monitoring of minimal residual disease is expected to have increasing influence on the management of children with ALL.

Ct in the surveillance and current control of children with extracranial malignant tumours.

The clinical value of computerized body tomography (CT) was analysed in 221 consecutive examinations performed in the evaluation and surveillance of 74 children with various types of extracranial solid malignant tumours. CT was performed as part of a routine diagnostic reassessment in 104 cases and was clinically indicated in 117. CT detected subclinical relapse in five cases in the first category of scans and was diagnostic of local recurrence, progression or complications in 20 of the clinically indicated examinations. CT has been non-contributory or incorrect in 12 cases, and informative about the therapeutic response or confirmative of remission in the remaining scans. In order to utilize the limited capacity of the scanner in the best way possible, CT should primarily be performed in patients, where clinical findings indicate need for further investigations. Its use as an adjunct in the periodic diagnostic reassessment should be restricted to high risk patients or selected cases, otherwise difficult to investigate.

The clinical value of CT whole-body scanning in pediatric tumour investigation.

The results of 100 consecutive CT whole-body scans in children with suspicion of a tumour and possible malignancy have been analysed. The final diagnoses were these: a tumour in 40 patients; non-tumoural lesions such as cysts, abscesses or malformations in 22; various medical conditions in 30 cases; and no abnormality in eight. The suspicion of malignancy was confirmed in 36 patients. CT proved to be an accurate method in the diagnosing and differentiation between solid or predominantly solid tumours and various non-tumoural lesions. The clinical value of CT was assessed by comparing the information from CT with those obtained by routine clinical and other radiological means. CT was positive informative in 57% of the patients and correctly excluding a tumour in 28%. CT was either non contributory or misleading in 15%. Finally, the quality of the scans were evaluated and the specific problems related to pediatric CT are discussed.

Varicella zoster infections in children with acute lymphoblastic leukemia.

During the period July 1986 through December 1991, 67 children were treated for non-B-cell acute lymphoblastic leukemia at The Juliane Marie Centre, GGK, The University Hospital Rigshospitalet, Copenhagen. Twenty-five children were susceptible to varicella zoster (VZ) virus at diagnosis. For these patients the cumulated risk of VZ exposure was 90% after 32 months. Five patients developed varicella (two of whom had pneumonitis) during the period of antileukemic treatment. Two of these had received prophylactic treatment with acyclovir. The 2 year cumulated risk of having chickenpox or herpes zoster in children with previous VZ infection was 24% and 34%, respectively. VZ vaccination ought to be considered for this group of children in order to diminish transmission and morbidity.

CT in the staging of children with malignant tumours.

The application of CT whole-body scanning as an adjunct in the staging investigations was evaluated in 56 children with various types of extra-cranial solid malignant tumours. CT proved to be superior to conventional films in the detection of pulmonary or pleural dissemination. The abdominal lymph nodes were difficult to evaluate by CT, and abnormal nodes could only be diagnosed when they were unequivocally enlarged. The role of CT in the detection of liver metastases could not be established in this study due to the rare occurrence of liver involvement. CT seemed to be a valuable method in the prediction of the operability of the primary tumour, but seemed to have an inability to show local invasiveness of the tumour. CT is an important supplement to conventional, noninvasive methods in the staging of these patients because CT is able to detect otherwise undetectable dissemination and this results in an improved therapeutic approach in individual cases.

Immunological reclassification of 22 children with a former diagnosis of non-T, non-B ALL.

Stored peripheral blood or bone marrow mononuclear cells from 22 pediatric patients with verified acute lymphoblastic leukemia (ALL) previously classified as non-T, non-B ALL were re-investigated by flow cytometric analysis by means of a panel of B cell-specific and -associated monoclonal antibodies (moabs) using a new analytical method described by Platz et al, the so-called Delta Channel Value method. All 22 patients were immunologically re-characterized as pre-B ALL. The reproducibility between the first (acute) and subsequent re-analysis was almost complete. 20 of the tumor cell populations could be assigned to the B cell differentiation scheme recently proposed by Nadler et al. This scheme operates with four stages of pre-B cell differentiation and each stage is defined by the expression of one to four of the following markers: HLA-DR, CD19, CD10 and CD20. Two additional markers, CD24 and CD22, were investigated in our study and allowed further subdivision of the four subgroups proposed by Nadler et al. The composition of a panel of moabs for routine classification of pre-B ALL is proposed.

Changes in T1 relaxation processes in the bone marrow following treatment in children with acute lymphoblastic leukemia. A magnetic resonance imaging study.

Magnetic resonance imaging (MRI) and T1 relaxation time measurements of the vertebral bone marrow were performed in 11 children with acute lymphoblastic leukemia (ALL) at diagnosis. Nine of the children were re-examined after chemotherapeutic treatment. The results were compared with histological data from bone marrow biopsies obtained in close association to the MR examinations. Ten age matched children were examined as a control group. A 1.5 Tesla whole body scanner was used for the measurements. The pretreatment T1 relaxation times of the bone marrow were significantly prolonged, compared to the age matched controls. After chemotherapy the T1 relaxation times of the children with ALL decreased significantly towards or into the normal range. A significant correlation was found between the T1 relaxation time and the content of malignant blast cells in the bone marrow.

Ulcerated haemangioma successfully treated with interferon alfa-2b and topical granulocyte-macrophage colony-stimulating factor.

OBJECTIVE: We tested whether healing and regression could be promoted by granulocyte-macrophage colony-stimulating factor and interferon in a 6-month-old girl with an ulcerated haemangioma resistant to systemic steroid therapy. METHODS: Interferon alfa-2b (Introna, Schering-Plough) was given subcutaneously once daily at a dose of 3 million units/m2 for 5.5 months and rhGM-CSF (Molgramostim, Leucomax; Sandoz/Schering-Plough) 3.33 units was applied on the wound surfaces once and concomitantly with the initiation of interferon therapy. RESULTS: The ulcer healed completely within 1 month and the haemangioma almost totally regressed within 6 months. CONCLUSION: Local application of rhGM-CSF appears to be effective in promoting ulcer healing in an ulcerated haemangioma otherwise responding to interferon treatment.

A population-based study of 272 children with acute myeloid leukaemia treated on two consecutive protocols with different intensity: best outcome in girls, infants, and children with Down's syndrome. Nordic Society of Paediatric Haematology and Oncology (NOPHO).

From July 1984 the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) have registered all children with acute myeloid leukaemia (AML) and treated them on two consecutive protocols of different intensity (NOPHO-84 and NOPHO-88). We probably have information on every child with this diagnosis in our region. We found an annual incidence of AML of 0.7 new cases per 100,000 children < 16 years of age. We observed a distinct peak of incidence in the first 2 years of life. Children with Down's syndrome accounted for 13% of all cases. Eighty of 105 cases treated on NOPHO-84 achieved remission (78%). In NOPHO-88, 100/118 patients entered remission (85%). The overall event-free survival (p-EFS) for the two studies was 0.32 for NOPHO-84 and 0.42 for NOPHO-88. The majority of relapses occurred within 2 years of diagnosis. When looking for prognostic factors the strongest significant adverse factor found was male sex. Children with Down's syndrome (n = 35) had a very favourable outcome if they received therapy according to protocol, and infants (n = 26) had a superior outcome compared to children 1-2 years or > 10 years of age at diagnosis.

Four pairs of siblings with acute leukemia during 1966-1985 in the Nordic countries: indication of an elevated familial risk?

Four pairs of siblings with acute leukemia in the Nordic countries during 1966-1985 are reported. The national data indicate that the risk of leukemia is 5.9 times greater in siblings of children with leukemia.