Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients.

Alpha-mannosidosis is a rare lysosomal storage disease. Hematopoietic SCT (HSCT) is usually recommended as a therapeutic option though reports are anecdotal to date. This retrospective multi institutional analysis describes 17 patients that were diagnosed at a median of 2.5 (1.1-23) years and underwent HSCT at a median of 3.6 (1.3-23.1) years. In all, 15 patients are alive (88%) after a median follow-up of 5.5 (2.1-12.6) years. Two patients died within the first 5 months after HSCT. Of the survivors, two developed severe acute GvHD (>=grade II) and six developed chronic GvHD. Three patients required re-transplantation because of graft failure. All 15 showed stable engraftment. The extent of the patients' developmental delay before HSCT varied over a wide range. After HSCT, patients made developmental progress, although normal development was not achieved. Hearing ability improved in some, but not in all patients. We conclude that HSCT is a feasible therapeutic option that may promote mental development in alpha-mannosidosis.

Costs of on-demand and prophylactic treatment for severe haemophilia in Norway and Sweden.

The expected annual cost (in the year 2000 prices) for a 30-year-old patient with average individual and treatment characteristics for on-demand EUR 51,832 (95% CI: 44,324-59,341) and for prophylaxis EUR 146,118 (95% CI: 129,965-162,271), was obtained from panel-data analysis of an 11-year retrospective panel of 156 patients with severe haemophilia in Norway and Sweden. Costs included haemophilia-related treatment costs within the health-care sector (factor concentrate, doctors' visits, diagnostic procedures, hospitalisation, invasive procedures, etc.) and cost for haemophilia-related resource use in other sectors (lost production, use of special equipment, adaptation of workplace and domicile, etc). Although costs of lost production, reconstructive surgery and hospitalisation were higher for on-demand, they did not balance out the higher costs of factor-concentrate consumption in prophylaxis. The cut-off risk of premature death, where on-demand and prophylaxis would have been equally costly, was 3.7 percentage units higher for on-demand than for prophylaxis. Such a great risk difference has not been reported elsewhere to our knowledge. Estimated cost-elasticities indicated that annual costs of prophylaxis would increase by approximately the same proportion as a potential increase in the price of factor concentrate and decrease less than proportionately with a reduction in prescribed dose kg(-1). For on-demand, the annual costs would increase by approximately the same proportion as an increase in the prescribed dose kg(-1).

Outcome of children with high-risk acute lymphoblastic leukemia (HR-ALL): Nordic results on an intensive regimen with restricted central nervous system irradiation.

BACKGROUND: Improvement in outcome of childhood high-risk (HR) ALL was sought with a very intensive Nordic protocol leaving most patients without CNS-RT. METHODS: A total of 426 consecutive children entered the NOPHO-92 HR-ALL program. HR criteria included WBC > or =50 x 10(9)/L, CNS or testicular involvement, T-cell, lymphomatous features, t(9;22), t(4;11), or slow response. Of these, 152 children had very high risk (VHR) with special definitions. CNS consolidation was based on high-dose MTX (8 g/m2) and ARA-C (12 g/m2) alternating. VHR patients also received cranial RT. RESULTS: The 9-year EFS was 61 +/- 3%, OS 74 +/- 2%, and EFS for T-ALL 62 +/- 4%. Cumulative incidence of isolated CNS relapse was 4.7 +/- 1%, and CNS relapse in total 9.9 +/- 2%. Poor prognostic factors were WBC > or =200 x 10(9)/L and a very slow response. CONCLUSIONS: HR-ALL was successfully treated on the NOPHO-92 regimen, with a relatively low CNS relapse rate for non-irradiated children. WBC > or =200 x 10(9)/L and very slow response emerged as strong poor prognostic factors.

On-demand vs. prophylactic treatment for severe haemophilia in Norway and Sweden: differences in treatment characteristics and outcome.

Using an 11-year panel of 156 Norwegian and Swedish patients with severe haemophilia, and including retrospective case-book data from birth, we compared the differences in the haemophilia-related resource use between on-demand and prophylactic treatment. Patients treated on-demand had more surgery (arthrodeses, prostheses implantations and synovectomies) and more days lost from work. Median annual factor-concentrate consumption among adults (18+) was 211,000 IU [interquartile range (IQR) 154,000-268,000] or 3,024 IU kg-1 year(-1) for patients on prophylactic treatment and 55,000 IU (IQR 28,000-91,000) for on-demand patients (780 IU kg(-1) year(-1)). This was partly explained by the fact that the median dose per kg body weight was twice as great 28, (IQR 24-32) for prophylaxis compared with 14 (IQR 12-16) for on-demand. Prescribed dose per kg body weight was found to be an important factor explaining the variation in total annual factor-concentrate consumption per patient for both types of treatment. Other variables included in the panel-data regression analysis were the number of weeks on secondary prophylaxis for on-demand patients and age, body weight and type of haemophilia for children (0-17 years) on prophylaxis. Differences were consistently substantial and will affect both costs and benefits of the two treatment strategies.

No disadvantage in outcome of using matched unrelated donors as compared with matched sibling donors for bone marrow transplantation in children with acute lymphoblastic leukemia in second remission.

PURPOSE: We evaluated the outcome of children with acute lymphoblastic leukemia (ALL) in second remission (2CR), comparing bone marrow transplantation (BMT) using either matched sibling donors or unrelated donors (URDs). PATIENTS AND METHODS: A total of 65 patients, aged 2 months to 20 years at BMT, with ALL in 2CR underwent allogeneic BMT at seven Nordic centers during 1990 to 1997. Of the first relapses, 85% were in bone marrow; 46% occurred on therapy, and 54%, off therapy. The preparative regimens were cyclophosphamide plus total-body irradiation +/- antithymocyte/antilymphocyte globulin, busulfan plus cyclophosphamide +/- antithymocyte/antilymphocyte globulin, or cytarabine plus total-body irradiation. Of the allografts, 37 were from HLA-matched siblings and 28 were from URDs. RESULTS: In the sibling versus URD graft recipient groups, the posttransplantation 5-year event-free survival was 39% versus 54% (P =.4), the estimated posttransplantation relapse rate was 76% versus 40% (P = not significant [NS]), and the toxic death rate was 19% versus 11% (P = NS). The incidence of significant (grade 2 to 4) acute graft-versus-host disease (GVHD) was 38% versus 64% (P <.05) and was 14% versus 32% (P <.10) for severe (grade 3 to 4) acute GVHD; the incidence of chronic GVHD was 26% versus 57% (P <.05) and was 13% versus 22% (P = NS) for extensive chronic GVHD in the sibling and URD groups. CONCLUSION: BMT with matched URD allografts offers at least equal survival for children with ALL in 2CR, as compared with allografts from matched sibling donors. URD allografts were not associated with a higher toxic mortality rate, although both acute and chronic GVHD were more frequent with URD. Indications for using matched URD allografts in ALL 2CR can be considered the same as for using matched sibling donors.

[Long-term survival following surgery and radiotherapy of brain tumors in childhood]. / Langtidsoverlevelse etter kirurgi og strålebehandling av hjernesvulster i barnealder.

BACKGROUND: Brain tumours are seen in about one third of children with neoplastic disease. Treatment usually includes surgery and/or radiotherapy. Radiotherapy may have serious late effects, especially in children under the age of three; but is necessary for survival in children with medulloblastomas or high-grade gliomas. MATERIALS AND METHODS: We report ten and 20 years survival rates in 115 children with primary brain tumours (58 medulloblastoma, 14 high-grade gliomas, and 43 low-grade gliomas) operated at the National Hospital and given radiotherapy at the Norwegian Radium Hospital during the years 1970-1995. RESULTS: No patients with medulloblastomas or high-grade gliomas relapsed after ten years. Overall ten and 20 years survival in children treated with radiotherapy to tumour doses > 50 Gy for medulloblastoma was 51.5% and for high-grade gliomas 20%. Median survival for patients with low-grade gliomas was not reached at 20 years, but these patients were still at risk for late deaths. INTERPRETATION: Long-term survival in children with high-grade gliomas or medulloblastoma equals cure, while late relapses may occur in low-grade gliomas.

Improving outcome through two decades in childhood ALL in the Nordic countries: the impact of high-dose methotrexate in the reduction of CNS irradiation. Nordic Society of Pediatric Haematology and Oncology (NOPHO).

In this population-based material from the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden), 2860 children below 15 years of age were diagnosed with acute lymphoblastic leukemia (ALL) from July 1981 to June 1998. The annual incidence was 3.9/100,000 children and was stable throughout the study period. The development from regional or national protocols to common Nordic treatment protocols for all risk groups was completed in 1992 through a successive intensification with multidrug chemotherapy, including pulses of methotrexate in high doses and avoidance of cranial irradiation in most children. The overall event-free survival (EFS) at 5 years has increased from 56.5 +/- 1.7% in the early 1980s to 77.6 +/- 1.4% during the 1990s. The main improvements were seen in children with non-high risk leukemia. In high-risk patients, progress has been moderate, especially in children with high WBC (> or =100 x 10(9)/l) at diagnosis. During the last time period (January 1992-June 1998), only 10% of the patients have received cranial irradiation in first remission, while 90% of the patients have received pulses of high dose methotrexate (5-8 g/m2) isolated or combined with high-dose cytosine arabinoside (total dose 12 g/m2) plus multiple intrathecal injections of methotrexate as CNS-targeted treatment, not translating into increased cumulative incidence of CNS relapse.

Allogeneic bone marrow transplantation in second remission of childhood acute lymphoblastic leukemia: a population-based case control study from the Nordic countries.

This study compares allogeneic BMT with conventional chemotherapy for childhood ALL in second remission. Seventy-five children were transplanted between July 1981 and December 1995. For each patient two control patients matching the following criteria were selected from the Nordic database of ALL: (1) time of diagnosis, (2) T vs. non-T ALL, (3) site of relapse, (4) initial risk group, (5) sex and (6) relapse < or > or =6 months after cessation of therapy. The minimal time of follow-up was 24 months. Mortality rate in CR2, leukemic relapse rate and the proportion in continued second remission were 16/75 (21%), 22/75 (29%) and 37/75 (50%), respectively. P2.-EFS for the BMT group was significantly better than that for the control group (0.40 vs. 0.23, P = 0.02). Children transplanted for bone marrow relapses in particular had a higher P2.-EFS (0.35 vs. 0.15 for the control group, P<0.01). Also, children grafted for early BM relapses had a higher P2.-EFS (0.32 vs. 0.11 for the control group P = 0.01). The outcome was similar when children were transplanted after early or late relapse. Also, there was no difference in outcome between the BMT and the chemotherapy group for children with late relapses. We conclude that allogeneic BMT with an HLA-identical sibling donor or other family donor should be performed in children relapsing in bone marrow during therapy or within 6 months of discontinuing therapy.

[Adults treated as children for acute lymphocytic leukemia--methotrexate, late effects and quality of life]. / Voksne behandlet for akutt lymfatisk leukemi som barn--metotreksat, seneffekter og livskvalitet.

From 1975 to 1980, 153 Norwegian children were diagnosed with acute lymphocytic leukaemia. In 1995, all 98 survivors were studied and compared to matched family controls. 132 children were treated with the national protocol. Of these, 93 (70.5%) were survivors at the time of the study. The remaining five survivors were treated with different treatment schemes. The national protocol included methotrexate infusions combined with intrathecal methotrexate as prophylactics against neuroleukaemia, instead of the irradiation. Neither doxorubicin nor cyclophosphamide were included. In this study, a questionnaire was used that covered demographic data, quality of life, and medical information the response rates were 96% (94 persons) for survivors and 92% (90 persons) for family controls. Information was also obtained for the remaining four survivors. No significant differences were found between survivors and controls with regard to quality of life and demographics, with one exception, Somatisation on the GHQ-28. Hospital records of all patients were checked for possible late effects. One case of serious sequela (hemiparesis during therapy) was found, probably related to methotrexate therapy. Seven other serious, possible sequelae were recorded, but probably not related to methotrexate. There were no cases of secondary malignant neoplasm.

Long-term survival and quality of life in patients treated with a national all protocol 15-20 years earlier: IDM/HDM and late effects?

In a follow-up matched control study the 93 (70.5%) survivors of 132 children treated with a national protocol for acute lymphoblastic leukemia (ALL) and 5 survivors of the other 21 cases of ALL in childhood diagnosed in the same period were evaluated. Thus it was also a population-based study. The national treatment protocol was used in the period 1975-1980. Methotrexate (MTX) infusions combined with intrathecal MTX were used as prophylaxis against neuroleukemia instead of irradiation. Neither doxorubicin (Adriamycin) nor cyclophosphamide was used in the protocol. A questionnaire covering demographic data, number of offspring, learning problems, level of athletic performance, education, and work status as well as medical information was used. Forms were received from 94 (96%) of the 98 adult surviving cases and corresponding controls in the family. Interviews were performed in the remaining four cases (4%). There were no statistical differences between the two groups with respect to physical and mental health and quality of life. Hospital records of all patients were also checked for possible late effects. There was no definite case of secondary malignant neoplasm; however, there was one case of prolactinoma and only one case of serious sequelae (hemiparesis during therapy), probably due to intrathecal and intravenous MTX.

Impact of morning versus evening schedule for oral methotrexate and 6-mercaptopurine on relapse risk for children with acute lymphoblastic leukemia. Nordic Society for Pediatric Hematology and Oncology (NOPHO).

PURPOSE: To study the risk of non-B-cell acute lymphoblastic leukemia (ALL) relapse in relation to the routines of administration of oral methotrexate (MTX) and 6-mercaptopurine (6MP) and to the erythrocyte (E) levels of the intracellular cytotoxic metabolites, that is, MTX polyglutamates and 6-thioguanine nucleotides (E-MTX and E-6TGN). PATIENTS AND METHODS: E-MTX and E-6TGN levels were measured at least three times (medians, eight and nine) in 294 children with non-B-cell ALL during oral MTX and 6MP therapy. For each patient, we registered (a) the individual circadian schedule of drug administration and (b) the coadministration of food, and (c) calculated a mean (m) of all E-MTX and E-6TGN measurements and (d) the product of mE-MTX and mE-6TGN (mE-MTX*6TGN), due to their synergistic action. RESULTS: A total of 42 patients were on a morning schedule, 219 were on an evening schedule, and 33 had miscellaneous routines. A total of 149 patients took the drugs with meals, 106 took the drugs between meals, and 39 had varying routines. With a median follow-up of 78 months, ALL has recurred in 66 patients. The patients on an evening schedule had a superior outcome [probability of event-free survival (pEFS) = 0.82 +/- 0.03 vs. 0.57 +/- 0.08; p = 0.0002], whereas the coadministration of food did not significantly influence outcome. Patients with a mE-MTX*6TGN < 813 [product of median mE-MTX (4.7 nmol/mmol Hb) and mE-6TGN (173 nmol/mmol Hb)] had an inferior outcome (pEFS = 0.70 +/- 0.04 vs. 0.85 +/- 0.03; p = 0.003), even if only patients on an evening schedule were analyzed. Thus, 109 patients on the MTX/6MP evening schedule with an mE-MTX*6TGN < or = 813 (nmol/mmol Hb)2 had a pEFS of 0.89 +/- 0.03 and a probability of continuous hematopoietic remission of 0.91 +/- 0.03. CONCLUSIONS: An evening schedule should be recommended for oral MTX/6MP maintenance therapy. The value of individual dose adjustments by E-MTX and E-6TGN remains to be determined in prospective randomized trials.

[Investigation and treatment of immune thrombocytopenic purpura in children in Norway]. / Utredning og behandling av immuntrombocytopenisk purpura hos barn i Norge.

The treatment of immune thrombocytopenic purpura (ITP) in children has been debated for a long time. Some years ago the Norwegian paediatric haematology and oncology group proposed guidelines for investigation and therapy. In order to assess the present management of ITP in Norway, we sent a questionnaire to all paediatric departments. Answers from 22 departments could be analyzed. The estimated number of new ITP cases was 54, giving an incidence of 6.7 per 100,000 children. Most of the departments treat only a few patients (one to three patients a year). Investigation and treatment of ITP follows roughly the Norwegian guidelines. Disagreement exists about the indication for start of drug treatment (the lowest accepted platelet count differed from < 5 to 30 x 10(9)/l) and about choice of drug (1/2 prefer steroids, 2/3 immunoglobulins). There seems to be great interest for this topic among the Norwegian pediatricians. A prospective registration of all ITP cases in Norway has now been started.

Allogeneic bone marrow transplantation in first remission for children with very high-risk acute lymphoblastic leukemia: a retrospective case-control study in the Nordic countries. Nordic Society for Pediatric Hematology and Oncology (NOPHO).

Among children with high-risk (HR) ALL there are subgroups with very-high-risk (VHR) features and poor prognosis despite developments in conventional chemotherapy for childhood ALL. We evaluated the outcome of VHR-ALL in children receiving allogeneic BMT (allo-BMT) in first remission (1CR) in a retrospective case-control study. In the population-based ALL material of the five Nordic countries, 22 children with VHR-ALL have undergone allo-BMT in 1CR between 1981-1991. We compared the outcome in these 22 children with 44 closely matched control patients who received conventional chemotherapy on HR-ALL protocols, as well as with a group of 405 children representing the remaining HR-ALL patients in the Nordic ALL database. The disease-free survival at 10 years was 73% in children receiving allo-BMT in 1CR, 50% in the matched controls (P = 0.02), and 59% in the remaining HR-ALL patients. The good prognosis of the allo-BMT group was due to a low relapse rate of 9%, as opposed to 41% in the group of matched controls. The superiority of allo-BMT as therapy in 1CR was mainly apparent in those with a very high WBC of > or = 100 x 10(9)/I at diagnosis; in the allo-BMT group 9/10 survived, as opposed to 8/20 of the matched controls (P = 0.03). We conclude that allo-BMT in 1CR should be seriously considered for children with a matched sibling donor and a VHR-ALL with WBC of > or = 100 and other established VHR criteria.

Risk of relapse in childhood acute lymphoblastic leukemia is related to RBC methotrexate and mercaptopurine metabolites during maintenance chemotherapy. Nordic Society for Pediatric Hematology and Oncology.

PURPOSE: During maintenance chemotherapy for childhood acute lymphoblastic leukemia (ALL), the cytotoxic metabolites of methotrexate (MTX polyglutamates) and mercaptopurine (6MP) (thioguanine nucleotides [6TGN]) accumulate intracellularly, including in erythrocytes (E-MTX and E-6TGN) with large interindividual variations. In the present Nordic Society for Pediatric Hematology and Oncology (NOPHO) study, the relation of E-MTX and E-6TGN to relapse risk was explored. PATIENTS AND METHODS: Two hundred ninety-seven patients with non-B-cell ALL, aged 1 to 14 years, on oral MTX and 6MP had E-MTX and E-6TGN levels measured three to 35 (median, eight) and three to 75 (median, nine) times, respectively. For each patient, a mean of all E-MTX (mE-MTX) and E-6TGN (mE-6TGN) measurements was calculated, as well as the product of mE-MTX and mE-6TGN (mE-MTX-6TGN), since MTX and 6MP may have synergistic action. RESULTS: For patients in remission, the median mE-MTX and mE-6TGN values were 4.7 nmol/mmol hemoglobin (Hgb) (range, 0.4 to 10.3) and 173 nmol/mmol Hgb (range, 58 to 846). With a median follow-up duration of 66 months for patients in remission, 64 patients relapsed. Cox regression analysis identified mE-MTX-6TGN and sex to be the most significant parameters to predict relapse (global P = .001). Factors that predicted a better prognosis were high mE-MTX 6TGN and female sex. Patients who had a mE-MTX-6TGN less than the product of the median mE-MTX and median mE-6TGN (813 [nmol/mmol Hgb]2) had a significantly poorer event-free survival (EFS) than did patients with higher values (5-year probability of EFS [pEFS5y], 0.70 v 0.86; P = .001). CONCLUSION: The pharmacokinetics of MTX and 6MP may have significant influence on the risk of relapse. The value of dose adjustments by E-MTX and E-6TGN remains to be determined.

Disseminated fungal disease resistant to fluconazole treatment in a child with leukemia.

During a chemotherapy induced leukopenic period fluconazole (3 mg/kg/day i.v.) was administered as empiric antifungal treatment in a 5-year-old girl with leukemia and a presumed catheter infection due to Staphylococcus epidermidis. Despite intensive treatment with antibiotics and fluconazole the patient died. In one blood culture Candida krusei was isolated post mortem, and at autopsy Aspergillus fumigatus was found in multiple organs. Both fungi showed high MIC values to fluconazole. We feel that this drug should not be used when the possibility of a systemic infection with an unidentified fungus exists.

[Autologous bone marrow transplantation in children--experience with neuroblastoma]. / Autolog beinmargstransplantasjon hos barn--erfaringer ved neuroblastom.

Autologous bone marrow transplantation permits the use of greatly intensified cytoreductive therapy for cancer. Since 1983 seven children with disseminated neuroblastoma (stage IV) were treated by this method. Five were treated in first, and one in second complete remission; one child was in partial remission. Tumor cell purging of the marrow inoculum was performed in five cases. All children had engraftment and were discharged from hospital free of disease. Relapse was observed in three children within two years. Four children remain healthy at follow-up 5-77 months after autotransplantation. We describe and discuss indications, methods, side effects and results.

Feulgen DNA values in Wilms' tumour in relation to prognosis.

Single-cell DNA measurements were performed on Feulgen-stained nuclei in 4 mu tumour sections from 30 patients with Wilms' tumour, all treated with initial nephrectomy. Fifteen patients died from their tumours within 2 years of nephrectomy. The remaining 15 had survived for at least 10 years without evidence of recurrence. Based on the histograms, the tumours were classified as being euploid (E type) or aneuploid (A type). Twenty tumours were euploid and 10 aneuploid. The euploid tumours predominated in the group of survivors. The group of 10 aneuploid tumours contained 7 tumour deaths. The tendency for aneuploid tumours to be associated with early tumour death, however, was not statistically significant.

The significance of HIV antigen and HIV antibodies specific against envelope and core proteins in serum of HIV-infected hemophiliacs.

Serial serum samples from the 21 HIV-infected Norwegian hemophiliacs have been assayed for the presence of HIV antigen and antibodies to HIV specific for the core protein p24 and the envelope protein gp41. HIV antigen was detected in 4 patients, of whom 3 have developed AIDS to date. HIV antigen appeared in serum 10 to 24 months before the diagnosis in these patients. Antibodies to gp41 was a constant finding. Antibodies to p24 disappeared from the serum in 1 patient who developed AIDS and from 3 persons free of symptoms related to the HIV infection. The detection of HIV antigen in HIV antibody-positive hemophiliacs appears to be of considerable prognostic significance.

HIV infection in Norwegian haemophiliacs: the prevalence of antibodies against HIV in haemophiliacs treated with lyophilized cryoprecipitate from volunteer donors.

334 of 389 (86%) registered Norwegians with coagulation factor defects were screened for antibodies to the human immunodeficiency virus (HIV) in 1985/1986. 21 persons were confirmed anti-HIV positive. They were all persons with clinically severe haemophilia A and represent 18.4% of 114 tested persons with severe haemophilia A. 3 patients have developed AIDS, 3 have persistent generalized lymphadenopathy. At least 8 of the 21 seropositive persons (38%) have been infected through lyophilized cryoprecipitates prepared from volunteer plasma donated in national blood banks. None of 10 heterosexual partners have antibodies to HIV. We conclude that the policy of using small-pooled lyophilized cryoprecipitates instead of commercial concentrates has reduced HIV-infection among Norwegian haemophiliacs. Today, the prevalence of HIV antibodies in the haemophilia population in Norway is among the lowest in Western Europe.