Prolonged use of nimotuzumab in children with central nervous system tumors: safety and feasibility.

Primary brain tumors constitute the most frequent solid tumor of childhood. High expression of the epidermal growth factor receptor (EGFR) protein has been associated with tumor progression and enhanced tumorigenicity in adult and children gliomas. Nimotuzumab is a humanized antibody that targets the EGFR and has proven efficacy in adult and children gliomas. To provide a new therapeutic option for patients with active, poor prognosis central nervous system (CNS) tumors and to evaluate the feasibility and safety of long-term nimotuzumab therapy in children with diverse CNS tumors, an expanded access program was launched at the Juan Manuel Marquez hospital. Patients were required to be 18 or younger and have one CNS tumor: low-grade glioma (LGG) or high-grade glioma (HGG), brainstem glioma (BSG), ependymoma or primitive neuroectodermal tumor (PNET), and a Lansky or Karnofsky performance status ≥40. Treatment consisted of weekly nimotuzumab administered at 150 mg/m(2) for 12 weeks, continuing every 14 days in the absence of severe condition worsening or unacceptable toxicity. Nimotuzumab was administered alone or in combination with radiotherapy, chemotherapy, or both, depending on the tumor type, stage, and previous treatment. Eighty-eight patients, 39 with BSG, 25 with HGG, 9 with progressive LGG, 9 with anaplastic ependymomas, and 6 with other tumor types, including PNET, neuroblastoma, meduloblastoma, and thalamic tumors, were treated with the antibody. The mean number of nimotuzumab doses was 36, from 1 to 108. The most frequent adverse events were mild to moderate skin rash, mucositis, vomiting, seizures, hypothermia, hyperthermia, and paleness. One patient had a grade 3 mucositis, while the other had a grade 3 bleeding on surgery. Sixteen children stopped treatment after at least 2 years with stable disease, partial or complete response. All children were able to maintain the best response achieved on treatment after a 3-year interruption. In summary, this study shows the feasibility of very prolonged administration of nimotuzumab together with the lack of rebound effect after treatment cessation.

Treatment of children with high grade glioma with nimotuzumab: a 5-year institutional experience.

Brain tumors are a major cause of cancer-related mortality in children. Overexpression of epidermal growth factor receptor (EGFR) is detected in pediatric brain tumors and receptor density appears to increase with tumor grading. Nimotuzumab is an IgG1 antibody that targets EGFR. Twenty-three children with high-grade glioma (HGG) were enrolled in an expanded access program in which nimotuzumab was administered alone or with radio-chemotherapy. The mean number of doses was 39. Nimotuzumab was well-tolerated and treatment with the antibody yielded a survival benefit: median survival time was 32.66 mo and the 2-y survival rate was 54.2%. This study demonstrated the feasibility of prolonged administration of nimotuzumab and showed preliminary evidence of clinical benefit in HGG patients with poor prognosis.

Concomitant Mycobacterium avium infection and Hodgkin's disease in a lymph node from an HIV-negative child.

We report a case of an immunocompetent child with simultaneously an infection with Mycobacterium avium and Hodgkin's disease in a cervical lymph node. A positive PCR result for M. avium on a biopsy of the lymph node directed the definitive diagnosis for both etiologies and avoided a possible dissemination of this infection after chemotherapy was started.

Efficacy and safety of iorEPOCIM for chemotherapy- or radiotherapy-induced anemia in pediatric cancer patients.

INTRODUCTION: Recombinant human erythropoietin (RHuEPO) is an erythropoiesis stimulating agent (ESA) used to treat anemia in patients with total or relative erythropoietin deficit. In cancer patients, it is administered to optimize hemoglobin (Hb) levels, correct anemia and reduce the need for transfusions. Cuba produces a RHuEPO, registered in 1998 as iorEPOCIM, that is widely used in the national public health system, mainly to treat patients with anemia due to chronic kidney disease (CKD). OBJECTIVE: Evaluate the efficacy and safety of iorEPOCIM in pediatric cancer patients with anemia following chemotherapy or radiotherapy. The working hypothesis posed an Hb increase>or=15 g/l in 70% of patients receiving iorEPOCIM for 8 weeks. METHODS: A Phase IV, multicenter, open clinical trial was conducted. Participants were 157 patients aged 1-19 years with anemia and cyto-histological diagnosis of cancer in any location. Patients received either 600 U/kg iorEPOCIM intravenously, once weekly, or 150 U/kg iorEPOCIM subcutaneously, 3 times a week, for 8 weeks. All patients had blood tests every week to determine hemoglobin and hematocrit, and reticulocyte and platelet counts. Mean number of transfusions required by patients during the treatment period was compared to the mean number of transfusions received in the preceding 8 weeks. Adverse events (AE) were recorded at the 4th and 8th weeks and classified by intensity and causality. RESULTS: Hb levels rose>or=15 g/l in 68.8% of patients, and transfusion requirements decreased 17%. The most frequent adverse events were fever (19.3%), vomiting (10.2%) and flu-like syndrome (9.6%). Intensity of AE was predominantly mild. Only 7 AE were classified as very probably related to the product and none of those was severe. CONCLUSIONS: iorEPOCIM proved to be safe and effective at the doses and frequencies used in this patient population. As a result, this medication was recommended for use in all pediatric oncology and hematology services in the country.

Clinical experience with nimotuzumab in cuban pediatric patients with brain tumors, 2005 to 2007.

Introduction Nimotuzumab, developed in Cuba, is a humanized monoclonal antibody that targets the epidermal growth factor receptor (EGFR). It has been evaluated in malignant brain tumors in adults and children, and shown to be therapeutically safe and effective in terms of increased survival and improved quality of life. Objective Describe nimotuzumab's safety profile and clinical benefits in terms of disease control and survival in pediatric patients with progressive or recurrent primary brain tumors who were included in an expanded access program. Methods An open, prospective clinical study was designed. Between December 2005 and December 2007, 22 patients were included, all of whom had an histological and/or radiological diagnosis of progressive or recurrent primary brain tumor, classified as high-grade malignant glioblastoma (n=6), diffuse brain stem glioma (n=6), ependymoblastoma (n=5), low-grade glioma (n=4), or thalamic tumor (n=1); life expectancy of at least 4 weeks; and a Karnofsky or Lansky Performance Status score of ≥50. Nimotuzumab was administered on a 100 mg weekly intravenous infusion schedule for 6 to 8 weeks, followed by a bi-weekly maintenance phase, as long as there was no deterioration in the patient's functional capacity. Therapeutic protocols were followed for administration as monotherapy or in combination with chemotherapy and/or radiotherapy. All patients received clinical and imaging follow-up. Results Nimotuzumab was well tolerated in all therapeutic modalities, even with prolonged exposure. A minority of patients reported slight or moderate adverse events, such as vomiting, mucositis and chills, as classified by the Common Terminology Criteria for Adverse Events (CTCAE). The disease was controlled in 64% (14/22) of patients; 6-month and 1-year survival rates were 82% and 64%, respectively; average survival was 20.3 months and median survival, 19 months. Recovery of neurological functions and improvement in general status were notable in patients who attained control of the disease. Conclusions As used in this study, nimotuzumab demonstrated a broad safety profile, making it acceptable for chronic use, and implied clinical benefits in terms of increased survival and improved functional status in these patients, compared to findings described in the literature. These results indicate further studies of this product are warranted.

Protocol-based treatment for children with cancer in low income countries in Latin America: a report on the recent meetings of the Monza International School of Pediatric Hematology/Oncology (MISPHO)--part II.

Pediatric cancer programs in low-income countries (LIC) can improve outcomes. However, treatment must be tailored to the patient's living conditions and the availability of supportive care. In some cases, a more intense regimen will decrease survival since the increase in death from toxicity may exceed any decrease in relapse. Attempts to practice evidence-based pediatric oncology are thwarted by the lack of evidence derived from local experience in LIC to determine optimal therapy. This report summarizes treatment regimens used by pediatric oncologists from 15 countries of the Caribbean, Central and South America who participate in the Monza International School of Pediatric Hematology/Oncology (MISPHO). Patients with hepatoblastoma, Wilms tumor, and histiocytosis treated on unmodified published protocols had outcomes comparable to those in high-income countries (HIC). Those with rhabdomyosarcoma, osteosarcoma, Hodgkin lymphoma, and acute myeloid leukemia treated with unmodified regimens had event-free survival estimates 10%-20% lower than those reported in HIC due to higher rates of toxic death, abandonment of therapy, and relapse. Treatment of retinoblastoma is complicated by advanced stages and extraocular disease at diagnosis; improved outcomes depend on education of pediatricians and the public to recognize early signs of this disease. Use of unmodified protocols for Burkitt lymphoma and acute lymphoblastic leukemia have been associated with unacceptable toxicity in LIC, so MISPHO centers have modified published regimens by giving lower doses of methotrexate and reducing use of anthracyclines. Despite the use of all-trans-retinoic acid during induction for acute promyelocytic leukemia, the incidence of fatal hemorrhage remains unacceptably high.