Rasburicase: a new approach for preventing and/or treating tumor lysis syndrome.

Tumor lysis syndrome (TLS) is an oncologic emergency requiring prompt attention to the management of potentially life-threatening metabolic derangements. Hyperuricaemia is one of the prominent features of TLS which, if not adequately prevented or treated, may lead to renal failure, requiring dialysis. Conventional management of hyperuricaemia involved the use of aggressive hydration, urinary alkalinization and allopurinol. Despite these measures, as many as 14.1% of high-risk patients may still develop renal failure. With the advent of newer agents such as rasburicase, the paradigm of TLS management has shifted towards risk stratification and the use of rasburicase in conjunction with hydration in patients at high risk for TLS. The advantage of rasburicase over allopurinol is its rapid onset of action, lack of need for urine alkalinization, which may worsen hyperphosphataemia and a satisfactory safety profile. Overall, rasburicase offers a safe and more effective alternative to allopurinol in patients at highest risk for TLS. Some of the unanswered questions requiring further investigation with regard to rasburicase use include the optimal number of doses needed, optimal dose based on uric acid levels and tumor burden, dosing in obese patients and maximum dose.

Phase I/II dose escalation study of recombinant human interleukin-11 following ifosfamide, carboplatin and etoposide in children, adolescents and young adults with solid tumours or lymphoma: a clinical, haematological and biological study.

Thrombocytopenia remains the major dose-limiting toxicity of myelosuppressive chemotherapy in children with solid tumours. Recombinant human interleukin-11 (rhIL-11) has been approved by the Food and Drug Administration as treatment for adults with solid tumours and lymphomas with severe chemotherapy-induced thrombocytopenia. We conducted a phase I/II trial of rhIL-11 following ifosfamide, carboplatin and etoposide (ICE) chemotherapy in children with solid tumours or lymphomas. Patients received ifosfamide 1800 mg/m(2)/d for 5 d, carboplatin 400 mg/m(2)/d for 2 d and etoposide 100 mg/m(2)/d for 5 d with rhIL-11 subcutaneous (s.c.) at 25-125 microg/kg/d on days 6-33. Forty-seven patients with median age 10.5 years (range, 0.7-26 years) were studied. Median days to absolute neutrophil count >/=0.5 x 10(9)/l, platelet count >/=50 x 10(9)/l and platelet transfusions were 23, 18, 18, 16.5 and 18.5, 21, 20, 18 and 3, 3, 4, and 2 d at doses 25, 50, 75 and 100 Schulteg/kg respectively. There was a dose-dependent increase in C(max) (7.6-25.5 ng/ml), AUC(0-rho) (57-209 ng.h/ml) and T(1/2) (4-8.2 h) respectively. There was a 4% incidence of anti-IL-11 antibody formation. Clinically important adverse events to rhIL-11 were papilloedema and periosteal bone formation. In summary, rhIL-11 was well tolerated at doses of

Veno-occlusive disease in pediatric patients receiving actinomycin D and vincristine only for the treatment of rhabdomyosarcoma.

OBJECTIVES: Veno-occlusive disease (VOD) following standard chemotherapy has been reported in patients receiving vincristine actinomycin D, and cyclophosphamide for the treatment of Wilms tumor and more rarely rhabdomyosarcoma. The dose and schedule of administration of actinomycin D in patients with Wilms tumor and the increased dose of cyclophosphamide administered to patients with rhabdomyosarcoma have been considered the likely etiology for VOD. METHODS: The authors report four cases of VOD in patients with rhabdomyosarcoma treated with vincristine and actinomycin D only. No risk factors for the development of VOD were identified. VOD was diagnosed clinically by the presence of at least two of three findings as defined by McDonald et al. VOD occurred after two to four doses of actinomycin D and approximately 7 to 14 days after the dose. All patients recovered with no evidence of permanent hepatic damage. CONCLUSIONS: VOD can occur in patients with "low-stage" rhabdomyosarcoma treated with vincristine and actinomycin D alone. Although chemotherapy-related VOD is a potentially severe disease, the outcome is good and resumption of chemotherapy is well tolerated.

A pilot study of tacrolimus and mycophenolate mofetil graft-versus-host disease prophylaxis in childhood and adolescent allogeneic stem cell transplant recipients.

Tacrolimus (FK506)/mycophenolate mofetil (MMF) has been demonstrated to be an effective salvage therapy for steroid-resistant chronic graft-versus-host disease (GVHD), but its effectiveness as prophylaxis for acute GVHD (aGVHD) is unknown. We investigated the safety and efficacy of FK506/MMF in preventing aGVHD and sparing the use of methotrexate and methylprednisolone in childhood and adolescent allogeneic stem cell transplant (AlloSCT) recipients. Thirty-four childhood and adolescent patients (median age, 7 years; range, 0.5-21 years; 24 males and 10 females) undergoing 37 AlloSCTs for malignant (n = 22) and nonmalignant (n = 12) disorders received FK506 (0.03 mg/kg/d by continuous intravenous infusion) and MMF (15 mg/kg per dose orally or intravenously twice daily). Stem cell sources included 22 umbilical cord blood donors (21 unrelated and 1 related), 6 related bone marrow donors, and 9 related peripheral blood donors. Malignant diagnoses included 7 acute lymphoblastic leukemias, 3 acute myeloid leukemias, 1 acute promyelocytic leukemia, 2 non-Hodgkin lymphomas, 4 Hodgkin diseases, 3 chronic myeloid leukemias, and 2 neuroblastomas; nonmalignant diagnoses included 2 beta-thalassemias, 1 sickle cell disease, 4 aplastic anemias, 1 Wiskott-Aldrich syndrome, 1 Hurler syndrome, 2 hemophagocytic lymphohistiocytoses, and 1 myelodysplastic syndrome. The probability of developing grade > or =II aGVHD was 45.4% +/- 9.7% (7 related bone marrow/related peripheral blood; 5 umbilical cord blood), and for chronic GVHD it was 38.1% +/- 19.7%. FK506/MMF was well tolerated. Three patients had grade III to IV neurotoxicity (disorientation and leukoencephalopathy); 4 patients developed grade III to IV nephrotoxicity (all received concomitant nephrotoxins). Patients who achieved target mycophenolic acid levels (1.0-3.5 microg/mL) before day +30 had a significantly reduced incidence of developing grade >/=II aGVHD (16.7% +/- 15.2% versus 100%; P <.02). These results suggest that FK506/MMF is well tolerated and may be a safe and effective methotrexate- and methylprednisolone-sparing alternative GVHD prophylaxis regimen after AlloSCT. Further pharmacokinetic and pharmacodynamic studies are ongoing in pediatric and adolescent AlloSCT recipients to define optimal MMF dosing.

Prophylactic use of myelopoietic growth factors in children after myelosuppressive and myeloablative therapy.

Judicious use of myelopoietic colony-stimulating factors is not well defined and is the source of ongoing controversy in the pediatric patient population. Prophylactic colony-stimulating factors may provide little clinically relevant benefits in children with hematologic malignancies or solid tumors after myelosuppressive chemotherapy. Although several studies demonstrated that recombinant human granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor accelerate neutrophil engraftment after myeloablative therapy and stem cell transplantation, their use did not alter morbidity or mortality after stem cell transplantation and has been associated with delayed platelet engraftment. Large prospective randomized multicenter studies are necessary to demonstrate an improvement in infectious complications, duration of hospitalization, overall survival, and cost-benefit ratio with the prophylactic use of myelopoietic growth factors after myelosuppressive or myeloablative chemotherapy in children and adolescents. Additional pediatric studies comparing the safety, efficacy, and cost effectiveness of granulocyte colony-stimulating factor versus granulocyte macrophage colony-stimulating factor are needed.

Periostitis secondary to interleukin-11 (Oprelvekin, Neumega). Treatment for thrombocytopenia in pediatric patients.

Interleukin-11 (Oprelvekin, Neumega) is a newly introduced thrombopoietic growth factor that stimulates production, differentiation, and maturation of megakaryocytes and platelets. Reversible periostitis has been reported as the side effect of the drug in primates and in the phase I/II trials. We report our experience with 5 cases of periostitis, occurring in thrombocytopenic children with three non-malignant and two malignant conditions, out of 24 pediatric patients treated with IL-11 at 75 micro g/kg per day for a median of 17 days. The findings were noted in the clavicle or the proximal humerus. Two patients also had forearm and lower-extremity long-bone involvement. All patients had normal bones before IL-11 was given, changes occurred in both non-malignant and malignant diseases, and periostitis disappeared after use of the drug was discontinued. The distribution and appearance of the changes are similar to prostaglandin E1 and hypervitaminosis A. The changes are reversible after termination of treatment and are most noted in younger patients. The exact mechanism is not clear. The detection of periostitis makes it essential for the radiologists to inquire as to what medications patients are receiving. The pediatric doses (75 g/kg/d) are above those recommended for adult patients (50 g/kg/d) and this may account for the pediatric bone changes of periostitis.

A case of severe thrombocytopenia and antiepileptic hypersensitivity syndrome.

Thrombocytopenia is a known complication of antiepileptic drug therapy. We present a case of a 3-year-old child who developed fever, rash, and severe thrombocytopenia within 10 days of initiating therapy with carbamazepine for new onset epilepsy. The patient's thrombocytopenia resolved following discontinuation of carbamazepine and introduction of valproic acid, however, his seizure disorder became poorly controlled. Phenobarbital was added to valproic acid therapy, which resulted in reoccurrence of fever, rash, and thrombocytopenia consistent with antiepileptic hypersensitivity syndrome. Discontinuation of phenobarbital, valproic acid and introduction of zonisamide resulted in resolution of his symptoms. The potential etiologies of thrombocytopenia in this case include carbamazepine-induced antiepileptic hypersensitivity syndrome, phenobarbital-induced antiepileptic hypersensitivity syndrome as a result of cross-reactivity with carbamazepine, and/or dose-dependent thrombocytopenia caused by valproic acid therapy. The pathogenesis and cases of aromatic anticonvulsant-induced immune-mediated thrombocytopenia are discussed. Alternative therapies for antiepileptic hypersensitivity syndrome with thrombocytopenia include gabapentin, levetiracetam, tiagabine, topiramate, and zonisamide.

A randomized clinical trial of nebulized magnesium sulfate in addition to albuterol in the treatment of acute mild-to-moderate asthma exacerbations in adults.

STUDY OBJECTIVE: We sought to compare the efficacy and safety of nebulized magnesium sulfate (MgSO(4)) plus albuterol with that of albuterol alone in adult patients with mild-to-moderate acute asthma exacerbations. METHODS: Patients were randomized to receive nebulized MgSO(4) (384 mg in 6 mL of sterile water) or an equal volume of placebo (normal saline solution) in a double-blind fashion after each dose of nebulized albuterol administered (2.5 mg/3 mL) every 20 minutes for the first hour of the study. Spirometry was performed at baseline and every 20 minutes for 2 hours. Monitoring for safety included vital signs, pulse oximetry, and serum magnesium levels. Improvement in percent predicted forced expiratory volume in 1 second was chosen as a primary efficacy end point. RESULTS: Among 74 patients enrolled, 37 were randomized to each of 2 study groups. There were no statistically or clinically significant differences between the 2 study groups in percent predicted forced expiratory volume in 1 second at any point during the trial or overall. There were no significant differences in vital signs, pulse oximetry, or serum magnesium levels at any point during the study. CONCLUSION: The combination of nebulized MgSO(4) and albuterol provides no benefit in addition to that provided by therapy with albuterol in adult patients with mild-to-moderate asthma exacerbations. The efficacy of nebulized MgSO(4) in patients with severe asthma exacerbations remains unknown.

Thalidomide use in pediatric patients.

OBJECTIVE: To provide a detailed overview of thalidomide use in pediatric patients. DATA SOURCES: English-language articles were identified through a MEDLINE search (1966-February 2001); key terms included thalidomide, child, graft-versus-host disease, cancer, HIV, Crohn's disease, Behçet's disease, and lupus erythematosus. References cited in those articles were also evaluated. DATA SYNTHESIS: Thalidomide appears to be effective in patients with chronic, not acute, graft-versus-host disease (GVHD) and in healing aphthous ulcers in patients with HIV infection. Limited case reports suggest efficacy of thalidomide in the treatment of cutaneous manifestations of Behçet's disease, Crohn's disease, and lupus in children; however, the recurrence of disease is almost universal on drug discontinuation. CONCLUSIONS: Thalidomide should be used as a last resort when all other therapies fail, preferably in male or prepubescent female patients.

Antiepileptic hypersensitivity syndrome: clinicians beware and be aware.

Antiepileptic hypersensitivity syndrome is a serious idiosyncratic, non-dose-related adverse reaction reported to occur with phenytoin, phenobarbital, carbamazepine, primidone, and lamotrigine. The reaction usually develops 1 to 12 weeks after initiation of therapy with one of the above agents and is recognized by the classic triad of fever, rash, and internal organ involvement. Immediate discontinuation of the suspected anticonvulsant is essential for good outcome. Patients usually are managed supportively with hydration, antihistamines, H(2)-receptor blockers, and topical corticosteroids. In severe cases, the use of systemic corticosteroids may be necessary. The use of intravenous immune globulin should be limited to severe cases where Kawasaki disease or idiopathic thrombocytopenic purpura cannot be ruled out. Education of health care professionals and patients is imperative to improving outcomes and prevention of this reaction in the future.