Anne Mäkipernaa

Factor VIII Products and Inhibitor Development in Severe Hemophilia A

BACKGROUND For previously untreated children with severe hemophilia A, it is unclear whether the type of factor VIII product administered and switching among products are associated with the development of clinically relevant inhibitory antibodies (inhibitor development). METHODS We evaluated 574 consecutive patients with severe hemophilia A (factor VIII activity, <0.01 IU per milliliter) who were born between 2000 and 2010 and collected data on all clotting-factor administration for up to 75 exposure days. The primary outcome was inhibitor development, which was defined as at least two positive inhibitor tests with decreased in vivo recovery of factor VIII levels. RESULTS Inhibitory antibodies developed in 177 of the 574 children (cumulative incidence, 32.4%); 116 patients had a high-titer inhibitory antibody, defined as a peak titer of at least 5 Bethesda units per milliliter (cumulative incidence, 22.4%). Plasma-derived products conferred a risk of inhibitor development that was similar to the risk with recombinant products (adjusted hazard ratio as compared with recombinant products, 0.96; 95% confidence interval [CI], 0.62 to 1.49). As compared with third-generation full-length recombinant products (derived from the full-length complementary DNA sequence of human factor VIII), second-generation full-length products were associated with an increased risk of inhibitor development (adjusted hazard ratio, 1.60; 95% CI, 1.08 to 2.37). The content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. CONCLUSIONS Recombinant and plasma-derived factor VIII products conferred similar risks of inhibitor development, and the content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. Second-generation full-length recombinant products were associated with an increased risk, as compared with third-generation products. (Funded by Bayer Healthcare and Baxter BioScience.).

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.

Recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of febrile neutropenia: a double blind placebo-controlled study in children.

In a double blind study of 58 episodes of fever and profound neutropenia, children with cancer received either recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) or placebo, combined with identical antimicrobial therapy, i.e. imipenem, on admission. The criteria for discontinuation of therapy were identical. A difference was demonstrated both in the number of hospital days, totaling 252 days in the rhGM-CSF group and 354 in the placebo group, days receiving antibiotics (220 vs. 322), and in the resolution of neutropenia (4.5 days vs. 6.0 days; P < 0.05). The number of episodes requiring antimicrobial therapy for longer than 10 days was 5 of 28 (12%) in the rhGM-CSF group as opposed to 15 of 30 (50%) in the placebo group (P = 0.01). rhGM-CSF was well-tolerated. We conclude that rhGM-CSF was efficacious in accelerating myeloid recovery and reducing the length of hospitalization in febrile neutropenia.

Acute thrombocytopenic purpura following measles, mumps and rubella vaccination. A report on 23 patients

An acute thrombocytopenic purpura developed shortly after measles‐mumps‐rubella vaccination in 23 of approximately 700 000 children immunized over a period of seven years. The mean interval from inoculation to the onset of purpura was 19 days. Bone marrow aspirates obtained from 13 patients showed increased or normal amounts of megakaryocytes. Platelet survival time was markedly shortened in the two patients studied. Fifteen patients recovered (the platelet count exceeded 100 x 109/1) in one month, five in two months and two in six months. Increase in platelet‐associated immunoglobulin was detected in 10 of 15 patients. Circulating antiplatelet autoantibodies (AAb) against glycoprotein IIb/IIIa were detected in 5 of 15 patients. The findings are compatible with an autoimmune mechanism triggered by immune response to measles‐mumps‐rubella vaccination. As evaluated by the clinical course and the presence of AAb, post‐vaccination thrombocytopenic purpura appears to be indistinguishable from childhood acute idiopathic thrombocytopenic purpura.

Obesity and metabolic changes are common in young childhood brain tumor survivors

A population based cross‐sectional study was used to examine the prevalence of metabolic syndrome and its components in childhood brain tumor survivors.

Long‐term Quality of Life and Psychosocial Coping after Treatment of Solid Tumours in Childhood A Population‐Based Study of 94 Patients 11–28 Years after Their Diagnosis

ABSTRACT. In order to assess the long‐term quality of life after childhood cancer, we examined and interviewed 94 survivors of childhood solid tumours (excluding brain tumours) diagnosed in our hospital between 1960 and 1976. Their follow‐up times ranged from 10.7 to 27.7 years, and their ages at the time of this study from 11.3 to 41.5 years. The subjects had a higher educational level than the Finnish general population. Fewer of the females and as many of the males were married as in the general population. Eight healthy men had been rejected for military service because of the history of cancer. An unsatisfied desire to know more about their own medical history was evident. According to our findings, some subjects after childhood solid tumour are at risk of developing emotional and social problems. However, the great majority of the survivors were well balanced psychologically, living a normal social life and showing adequate capacity to cope.

Cerebral sinus venous thromboses in children with acute lymphoblastic leukaemia - a multicentre study from the Nordic Society of Paediatric Haematology and Oncology.

We present a prospective multicentre cohort of 20 children with acute lymphoblastic leukaemia (ALL) and cerebral sinus venous thrombosis (CSVT). The study covers a period of 5 years and comprises 1038 children treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL 2008 protocol. The cumulative incidence of CSVT was 2%. Sixteen of the thromboses were related to asparaginase and 16 to steroids. Most CSVTs occurred in the consolidation phase. Nearly all were treated with low molecular weight heparin without bleeding complications. Mortality related to CSVT directly or indirectly was 10%, emphasizing the importance of this complication.

Granulocyte-macrophage colony-stimulating factor support in therapy of high-risk acute lymphoblastic leukemia in children

BACKGROUND Our purpose was to increase the dose intensity of chemotherapy and reduce the days with neutropenic fever in childhood high-risk (HR) acute lymphoblastic leukemia (ALL) by systematic use of granulocyte-macrophage colony-stimulating factor (GM-CSF). PROCEDURE All children with HR-ALL in Finland during 1990-1996 were included. Two open-label study groups were formed: 1) 34 children diagnosed between January, 1992, and December, 1996, received seven or nine courses (depending on cranial RT or no cranial RT) of GM-CSF at 5 microg/kg s.c. daily until an absolute neutrophil count (ANC) of 1,000 x 10(6)/liter at scheduled places in the protocol and 2) 80 control children, those diagnosed between January, 1990, and December, 1991, plus all with significant coexpression of myeloid markers, did not receive GM-CSF. RESULTS Dose intensity increased in patients who received regular GM-CSF support. The intensive phase of therapy, including induction, consolidation courses, and delayed intensification, was 33 days shorter (P < 0.001) in children with seven courses and 26 days shorter (P < 0.01) in those with nine courses of GM-CSF compared to controls. The number of infections during the whole ALL therapy was reduced by use of GM-CSF in children aged >5 years (P < 0.001), but not in those aged <5 years. The mean total duration of intravenous antibiotics per child was 39 days in the GM-CSF group and 48 days in the control group (P < 0. 001). Systematic use of GM-CSF was cost-effective. CONCLUSIONS Systematic use of GM-CSF improved dose intensity by shortening the intensive treatment period by about 4 weeks. Use of GM-CSF reduced the days for inpatient antibiotics by about 1 week per child, which translates into reduced costs.

Granulocyte-colony-stimulating factor after allogeneic and autologous bone marrow transplantation in children.

We evaluated the use of granulocyte CSF (G-CSF) after both allogeneic BMT (allo-BMT) and autologous BMT (ABMT) in children. After allo-BMT, G-CSF was used in 15 children who were compared with 20 historical controls. The ABMT patients were two sequential groups: the G-CSF group of 13 children and 11 historical controls. The patients were conditioned with different high-dose chemotherapy regimens with or without total body irradiation. G-CSF was administered at 5 micrograms/kg/day s.c. and was continued until an absolute neutrophil count (ANC) of 1,000 x 10(6)/l was reached. Following allo-BMT, G-CSF accelerated myeloid engraftment with a difference of 5 days at the ANC level of 500 x 10(6)/l (P<0.02) and 9 days at 1,000 x 10(6)/l (P<0.001). In the ABMT patients, G-CSF also accelerated myeloid engraftment. The difference between the G-CSF group and the control group was 6 days at ANC 200 (P<0.05), 11 days at ANC 500 (P<0.02) and 17 days at ANC 1,000 (P<0.005). In the ABMT patients, benefit by G-CSF was also observed in a smaller number of days with fever and days on antibiotics. We conclude that G-CSG significantly accelerated myeloid engraftment, after both allogeneic and autologous BMT in children, and also decreased the duration of febrile illness in the ABMT patients.

High-dose thiotepa with autologous bone marrow rescue in recurrent malignant oligodendroglioma: a case report.

High-dose thiotepa with autologous bone marrow rescue is a new and promising treatment modality in several kinds of solid tumors. We used this regimen in a pediatric patient who had the third recurrence of his malignant oligodendroglioma of brain that developed during ‘8 in 1’ chemotherapy. We achieved complete response after a total dose of 1125 mg/m2 of intravenous thiotepa. Good penetration into the CNS renders thiotepa potentially useful for chemosensitive brain tumors, and one course of high-dose thiotepa can be administered with acceptable toxicity by utilizing autologous bone marrow rescue.