Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome.

Relapse is the main reason for treatment failure in childhood acute lymphoblastic leukemia. Despite improvements in the up-front therapy, survival after relapse is still relatively poor, especially for high-risk relapses. The aims of this study were to assess outcomes following acute lymphoblastic leukemia relapse after common initial Nordic Society of Paediatric Haematology and Oncology protocol treatment; to validate currently used risk stratifications, and identify additional prognostic factors for overall survival. Altogether, 516 of 2735 patients (18.9%) relapsed between 1992 and 2011 and were included in the study. There were no statistically significant differences in outcome between the up-front protocols or between the relapse protocols used, but an improvement over time was observed. The 5-year overall survival for patients relapsing in the period 2002-2011 was 57.5±3.4%, but 44.7±3.2% (P<0.001) if relapse occurred in the period 1992-2001. Factors independently predicting mortality after relapse included short duration of first remission, bone marrow involvement, age ten years or over, unfavorable cytogenetics, and Down syndrome. T-cell immunophenotype was not an independent prognostic factor unless in combination with hyperleukocytosis at diagnosis. The outcome for early combined pre-B relapses was unexpectedly poor (5-year overall survival 38.0±10.6%), which supports the notion that these patients need further risk adjustment. Although survival outcomes have improved over time, the development of novel approaches is urgently needed to increase survival in relapsed childhood acute lymphoblastic leukemia.

The association of reduced folate carrier 80G>A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number.

The reduced folate carrier (RFC) is involved in the transport of methotrexate (MTX) across the cell membrane. The RFC gene (SLC19A1) is located on chromosome 21, and we hypothesized that the RFC80 G>A polymorphism would affect outcome and toxicity in childhood leukemia and that this could interact with chromosome 21 copy number in the leukemic clone. A total of 500 children with acute lymphoblastic leukemia treated according to the common Nordic treatment protocols were included, and we found that the RFC AA variant was associated with a 50% better chance of staying in remission compared with GG or GA variants (P = .046). Increased copy numbers of chromosome 21 appear to improve outcome also in children with GA or GG variant. In a subset of 182 children receiving 608 high-dose MTX courses, we observed higher degree of bone marrow toxicity in patients with the RFC AA variant compared with GA/GG variants (platelet 73 vs 99/105 x 10(9)/L, P = .004, hemoglobin 5.6 vs 5.9/6.0 mmol/L, P = .004) and a higher degree of liver toxicity in patients with RFC GG variant (alanine aminotransferase 167 vs 127/124 U/L, P = .05). In conclusion, the RFC 80G>A polymorphism interacts with chromosome 21 copy numbers and affects both efficacy and toxicity of MTX.

Symptoms and time to diagnosis in children with brain tumours.

INTRODUCTION: Clinical symptoms in brain tumours in children are variable at onset and diagnosis is often delayed. Symptoms were investigated with regard to brain tumour localisation, prediagnostic symptomatic intervals and malignancy. MATERIAL AND METHODS: Clinical data from children aged 0-17 years from Southern Denmark were analysed retrospectively and the results were correlated with data on prehospital symptoms obtained from interviews with parents and general practitioners. RESULTS: A total of 55 children diagnosed during a period of five years were indentified and 31 interviews were obtained. A total of 19 (41%) of the tumours were supratentorial hemispheric and midline and 27 (59%) were infratentorial. At supratentorial localisations, 42% experienced vomiting as their first symptom followed by seizures in 37% and headache in 31%. At infratentorial localisations, headache occurred in 62%, vomiting in 55% and ataxia in 48% of the cases. The prediagnostic symptomatic interval had a median duration of 30 days with vomiting (range 3-330 days), a median of 75 days with headache (5-730 days) and a median of 75 days with ataxia (1-730 days). CONCLUSION: Diagnosis is often late in relation to the presenting symptoms. An earlier diagnosis may be achieved if a brain tumour is considered as soon as any child presents with the relevant symptoms. FUNDING: Not relevant. TRIAL REGISTRATION: ISRCTN88306789.

Long-term cardiac follow-up of children treated with anthracycline doses of 300 mg/m2 or less for acute lymphoblastic leukemia.

BACKGROUND: The cardiotoxic effect of anthracyclines has been well described for moderate to high cumulative doses (>350 mg/m(2)). However, the question of whether sub-clinical signs of cardiomyopathy may develop and progress over time in children receiving doses of <350 mg/m(2) is controversial. The aim of the present study was to examine cardiac function with serial echocardiography from diagnosis to last follow-up, relapse, or death, and to investigate whether suspected risk factors (e.g., age at diagnosis, gender, cumulative dose, and length of follow-up) had a significant influence on cardiac function. PROCEDURE: An unselected cohort of 80 patients treated with multi-drug chemotherapy including anthracycline doses of 300 mg/m(2) or less for childhood acute lymphoblastic leukemia was followed with serial echocardiograms. The deviations of each echocardiogram from normal values for the same age and body-surface areas were calculated. The influences of risk factors were analyzed using univariate and multivariate regression. Lowess curves of time dependence were calculated. RESULTS: All echocardiographic parameters including ejection fraction (EF) deteriorated significantly over time. Male gender was significantly associated with systolic dilatation of the left ventricle and positively associated with left ventricular mass. Reduction of EF was significantly associated with age at diagnosis and male gender. CONCLUSIONS: Anthracycline doses of <300 mg/m(2) may contribute to a decline in cardiac function over time. Although the deterioration in cardiac parameters was not associated with clinical symptoms, life-long cardiac surveillance for these patients is important to establish the impact of low-dose anthracycline therapy on long-term cardiac health.

Myeloid neoplasm with prominent eosinophilia and PDGFRA rearrangement treated with imatinib mesylate.

The FIP1L1-PDGFRA fusion gene is the most frequent genetic aberration in myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1. Affected patients in adult populations are very sensitive to imatinib therapy. Pediatric cases are rare and so far only one case of FIP1L1-PDGFRA positive disease has been reported. We report a 2-year-old female with a myeloid neoplasm associated with eosinophilia and rearrangement of PDGFRA. Treatment with imatinib resulted in complete and durable clinical, hematological, and molecular remission within 3 months after starting treatment.

Treatment of the X-linked lymphoproliferative, Griscelli and Chédiak-Higashi syndromes by HLH directed therapy.

BACKGROUND: Griscelli syndrome type 2 (GS2), the X-linked lymphoproliferative (XLP) and the Chédiak-Higashi (CHS) syndromes are diseases that all may develop hemophagocytic syndromes. We wanted to investigate whether the treatment protocols for hemophagocytic lymphohistiocytosis (HLH) can also be used for these syndromes. PROCEDURE: In the HLH-94/HLH-2004 treatment study registries, we evaluated all patients with GS2 (n = 5), XLP (n = 2) or CHS (n = 2) treated between 1994 and 2004. RESULTS: All patients responded to the therapy, and all are alive but one (suffering from CHS), with a mean follow-up of 5.6 years. All GS2, one XLP and one CHS patient underwent hematopoietic stem cell transplant. Mean follow-up post transplant was 6.0 years. Six of the seven transplanted children achieved non-active disease status at the time for SCT. Neurological sequelae were reported in all, except for the XLP patients. CONCLUSIONS: Our results indicate that HLH treatment can be an effective first line treatment to induce remission in patients with GS2, XLP and CHS that have developed a hemophagocytic syndrome. We suggest that these patients should be included as a separate cohort in the international HLH study.

Anti-Erwinia asparaginase antibodies during treatment of childhood acute lymphoblastic leukemia and their relationship to outcome: a case-control study.

PURPOSE: A case-control study was performed to determine whether patients who had been treated with Erwinia asparaginase as part of their treatment for childhood acute lymphoblastic leukemia (ALL) and who showed relapsed of their disease more often developed anti-asparaginase antibodies than patients who remained in remission. METHODS: A group of 13 patients who showed relapsed of their disease (median follow-up 35 months) were randomly matched with control patients of the same risk group (two control patients to each case), who had received therapy of the same intensity during the same period (median follow-up 70 months). Anti- Erwinia asparaginase antibodies were measured (ELISA method) during maintenance therapy after asparaginase treatment (30,000 IU/m(2) daily for 10 days in all patients plus twice weekly for 2 weeks in intermediate-risk and high-risk ALL patients). RESULTS: The overall incidence of anti- Erwinia asparaginase antibodies was 8% (3 of 39 patients). There was no statistically significant difference in the incidence of antibody formation between patients who had suffered relapse (1 of 13) and those who had not (2 of 26). In two of the three patients who developed antibodies, the antibodies disappeared after some time, whereas one patient had measurable antibody levels for more than a year after asparaginase therapy. CONCLUSIONS: In this study, the development of anti-Erwinia asparaginase antibodies was rare and was unrelated to the risk of relapse.

[Trimethoprim-sulfamethoxazole as antibacterial prophylaxis during induction therapy of children with acute lymphatic leukemia]. / Trimethoprim-sulfamethoxazol som antibakteriel profylakse under induktionsbehandling af børn med akut lymfatisk leukaemi.

INTRODUCTION: Children with acute lymphoblastic leukaemia (ALL) are treated with intensive chemotherapy, which results in profound immunosuppression. Treatment with trimethoprim/sulphamethoxazole (TMP-SMX) is therefore used in some departments as prophylaxis against infections with both bacteria and Pneumocystis carinii. The use of TMP/SMX for prophylaxis during the induction therapy is not uniform in the four departments of paediatric oncology in Denmark. This gave us the opportunity to describe the effect of TMP/SMX on bacterial infections in children with ALL during the induction therapy. MATERIAL AND METHODS: Between 1 January 1992 and 31 December 1997, 210 children were diagnosed with ALL in Denmark. From a retrospective review of the medical charts, the number of children with fever (> 38 degrees C), the number of febrile days, days of antibiotic treatment, and the number of positive blood cultures were registered for each febrile episode. RESULTS: One hundred and fourteen children received TMP/SMX prophylaxis (10-30 mg/SMX/kg/day) and 76 did not. Children who received TMP/SMX prophylaxis had significantly fewer episodes of fever (66/114 (58%) vs. 60/76 (79%), p < 0.01) and significantly fewer children who received the prophylaxis had positive blood cultures before the start of antibiotic treatment compared with children who did not receive prophylaxis (23/114 (20%) vs 37/76 (49%), p < 0.001)). Nineteen different species were isolated from the blood stream before the start of antibiotic treatment. In the non-prophylaxis group there were a preponderance of isolates with Staph. aureus, Str. pneumoniae, E. coli, and P. aeruginosa. There was no difference in the mortality between the two groups (p = 0.44). There were no cases of P. carinii pneumonia in the period of induction therapy. DISCUSSION: TMP/SMX prophylaxis during induction therapy for childhood ALL seems to reduce the risk of bacteraemias and febrile illness.

[Improved survival in children with neuroblastoma]. / Forbedret overlevelse hos børn med neuroblastom.

INTRODUCTION: The aims of the present study were to analyze whether changes in incidence and mortality rates have taken place in Denmark during the period 1981-2005, and whether the distribution of known prognostic factors has changed during this period. MATERIAL AND METHODS: A total of 206 children below 15 years of age with neuroblastoma or ganglioneuroblastoma who were diagnosed in Denmark between 1981 and 2005. RESULTS: The incidence was 8.68 per million children below 15 years of age (world standard 9.6) and 43.5 per million children below 12 months of age and these incidences have remained unchanged since 1970. The mortality rate has decreased steadily during the study period. The prognostic factors age, stage and site of primary tumour did not change during the study period and were not different from those reported by others. 32% of the children were below 12 months of age at diagnosis. 53% of the children had metastatic disease. The overall 5-year survival increased over the study period from 38% in 1981-1985 to 69% in 2001-2005. A significant increase in the survival of children > 12 months of age with stage 4 disease was also observed. Relapse/disease progression more than three years from diagnosis occurred in only 2% of patients. The median time from relapse to death was three months. CONCLUSION: The survival of children with neuroblastoma in Denmark has increased significantly over the last 25 years.

Late cardiac effects of anthracycline containing therapy for childhood acute lymphoblastic leukemia.

BACKGROUND: At present about 80% of children with acute lymphoblastic leukemia (ALL) will be cured following treatment with multi-drug chemotherapy. A major concern for this growing number of survivors is the risk of late effects of treatment. The aim of this study was to determine whether signs of cardiomyopathy were present in patients treated in childhood with cumulative anthracycline doses of less than 300 mg/m(2). PROCEDURE: Evaluation of cardiac function in a cohort of 63 long-term survivors in first continuous remission following treatment of ALL with multi-drug chemotherapy including anthracyclines was performed using standard M-mode echocardiography and tissue doppler imaging (TDI). Associations between age at diagnosis, cumulative dose of anthracycline, sex, length of follow-up, and deviations from normal values in M-mode echocardiograms were evaluated using univariate and multivariate regression analysis. TDI data were compared to normal values using Wilcoxon matched-pairs signed-ranks test. RESULTS: By standard M-mode echocardiography the most significant findings were diastolic dilation of the left ventricle, thinner interventricular septum (IVS), decreased left ventricular mass (LVM) in females, follow-up dependent dilation of the left ventricle in systole and follow-up dependent decrease in ejection fraction (EF). TDI abnormalities included signs of early diastolic dysfunction and myocardial hypertrophy, and were also found in structures that appeared normal by M-mode echocardiography. CONCLUSIONS: This study adds to the growing evidence that even low to moderate doses of anthracyclines might lead to progressive cardiac dysfunction. It is important that children treated with anthracyclines receive life long follow-up for signs of cardiomyopathy.

Fusion of NUP98 and the SET binding protein 1 (SETBP1) gene in a paediatric acute T cell lymphoblastic leukaemia with t(11;18)(p15;q12).

Three NUP98 chimaeras have previously been reported in T cell acute lymphoblastic leukaemia (T-ALL): NUP98/ADD3, NUP98/CCDC28A, and NUP98/RAP1GDS1. We report a T-ALL with t(11;18)(p15;q12) resulting in a novel NUP98 fusion. Fluorescent in situ hybridisation showed NUP98 and SET binding protein 1(SETBP1) fusion signals; other analyses showed that exon 12 of NUP98 was fused in-frame with exon 5 of SETBP1. Nested polymerase chain reaction did not amplify the reciprocal SETBP1/NUP98, suggesting that NUP98/SETBP1 transcript is pathogenetically important. SETBP1 has previously not been implicated in leukaemias; however, it encodes a protein that specifically interacts with SET, fused to NUP214 in a case of acute undifferentiated leukaemia.

Flow cytometric DNA index, G-band karyotyping, and comparative genomic hybridization in detection of high hyperdiploidy in childhood acute lymphoblastic leukemia.

High hyperdiploid acute lymphoblastic leukemia in children is related to a good outcome. Because these patients may be stratified to a low-intensity treatment, we have investigated the sensitivity of flow cytometry (FCM), G-band karyotyping (GBK), and high-resolution comparative genomic hybridization (HR-CGH) in detecting high hyperdiploid leukemic clones. Twenty-six girls and 34 boys with acute lymphoblastic leukemia diagnosed in 1998 to 1999 were analyzed by FCM, GBK, and HR-CGH. The correlations between DNA indices obtained by FCM, GBK, and HR-CGH were significant (rs=0.61 to 0.77; P<0.001 for all comparisons). However, in 4 of 18 patients, high hyperdiploidy was overlooked by GBK or HR-CGH, and even when FCM was applied, 2 of 18 patients with high hyperdiploidy by GBK and/or HR-CGH were classified as nonhigh hyperdiploid. If high hyperdiploid subclones were included, FCM could detect all high hyperdiploid patients found by either GBK or HR-CGH, but would then in addition classify 15% to 20% of the remaining patients as high hyperdiploid. Thus, both GBK and HR-CGH overlook patients with high hyperdiploidy, and FCM only detects all high hyperdiploid patients if small high hyperdiploid clones are included. In addition, FCM detects patients with high hyperdiploid subclones, not detected by either GBK or HR-CGH, and the challenge remains to determine the prognosis of patients with such high hyperdiploid subclones.

Antibody formation during intravenous and intramuscular therapy with Erwinia asparaginase.

BACKGROUND: Determination of the frequency of antibody formation during first and second exposure to Erwinia asparaginase after i.v. and i.m. administration. PROCEDURE: Thirty-nine children with newly diagnosed acute lymphoblastic leukemia (ALL) were included in this prospective study. Antibodies were determined (ELISA method) in plasma from these patients on specific days during and after therapy with 30,000 IU/m(2) i.v. or i.m. every day for ten days during the induction phase (first exposure). For 19 children, antibodies were measured in plasma during and after the re-induction phase (second exposure) following treatment with 30,000 IU/m(2) i.v. or i.m. twice a week for two weeks (Mondays and Thursdays). On the same days of therapy, enzyme activity (spectrophotometric method) and the concentration of asparagine (HPLC) was determined. RESULTS: During the first exposure, none of the patients developed anti-Erwinia asparaginase antibodies. During the second exposure, one patient (1 of 8 patients) treated intravenously developed antibodies, which were associated with disappearance of enzyme activity and reappearance of asparagine. Three of eleven patients developed antibodies of pharmacokinetic importance after i.m. therapy. None of the children had any clinical symptoms of hypersensitivity. CONCLUSIONS: The formation of antibodies and subsequently altered pharmacokinetics of Erwinia asparaginase seemed to be of importance only during a second period of asparaginase therapy.

High-resolution comparative genomic hybridisation yields a high detection rate of chromosomal aberrations in childhood acute lymphoblastic leukaemia.

BACKGROUND: Cytogenetic aberrations are of prognostic significance in childhood acute lymphoblastic leukaemias and a high detection rate could improve the biological understanding and classification of these diseases. METHODS: Bone-marrow samples from 92 children with acute lymphoblastic leukaemia were studied by high-resolution comparative genomic hybridisation (HRCGH) using dynamic standard reference intervals that enhance both specificity and sensitivity in the detection of aberrations. RESULTS: In 80 patients (87%) HRCGH revealed a total of 405 aberrations, mostly whole chromosome gains (n = 265) and partial losses (n = 80). The 25 leukaemias with a gain of more than five whole chromosomes by HRCGH harboured only 7% of all losses. With G-band karyotyping 59 patients (64%) had aberrations. HRCGH revealed more aberrations per patient than did G-band karyotyping (median: 3 vs. 1, P = 0.005), revealed aberrations in 27 of the 34 patients for whom the G-band karyotyping failed or was found to be normal, and specifically revealed more 9p losses (21% vs. 5%, P < 0.005), 12p losses (12% vs. 2%, P < 0.05) and 17q gains (11% vs. 1%, P < 0.01). Compared to the present study, the frequency of patients with aberrant karyotypes was significantly lower in previous conventional CGH studies (64% vs. 87%, P < 0.0001), as was the rate of partial aberrations per patient (1.1% vs. 1.7, P < 0.001), particularly with fewer 6q losses, 9p losses and 17q gains detected. CONCLUSION: HRCGH is superior to conventional CGH as an adjunct to G-band karyotyping as it detects recurrent aberrations at a significantly higher rate than both these techniques.