A double-blind randomized placebo-controlled study of oral glutamine in the prevention of mucositis in children undergoing hematopoietic stem cell transplantation: a pediatric blood and marrow transplant consortium study.

Severe mucositis is a common cause of morbidity in hematopoietic stem cell transplant (HSCT) recipients. Glutamine has been shown to reduce mucositis in children receiving chemotherapy. Patients were randomized in a double-blind manner to receive glutamine or glycine at a dose of 2 g/m(2)/dose (maximum dose 4 g) twice daily until 28 days post transplant or discharge if sooner. Mucositis was graded by use of a modified Walsh scale. A total of 120 children were evaluable: 57 children received glutamine and 63 received glycine. The mean mucositis score was 3.0+/-0.3 vs 3.9+/-0.4 (P=0.07) in the glutamine and glycine groups, respectively. The glutamine group demonstrated a reduction in mean number of days of intravenous narcotics use (12.1+/-1.5 vs 19.3+/-2.8 in the glycine group, P=0.03) and total parenteral nutrition (17.3+/-1.7 vs 27.3+/-3.6 in glycine group, P=0.01). There was no statistically significant difference in toxicity between the two groups. Glutamine appears to be safe and beneficial in reducing the severity of mucositis. Strong consideration should be given to include oral glutamine supplementation as a routine part of supportive care of SCT patients.

Clinical parameters associated with low bacteremia risk in 1100 pediatric oncology patients with fever and neutropenia.

BACKGROUND: Traditionally, children with malignant disease who present with fever and neutropenia are hospitalized for parenteral antibiotics. More recently, outpatient strategies have been proposed for lower risk cohorts of such patients. The authors sought to identify clinical and laboratory parameters that are associated with a low risk of bacteremia in children with malignant disease who presented with febrile neutropenia. METHODS: A multicenter, retrospective cohort of children with malignant disease and fever with neutropenia was established in three pediatric oncology centers over a 5-year period. A total of 1171 episodes of febrile neutropenia (absolute neutrophil count [ANC] < 500 cells per mm(3)) were identified in children with malignant disease age > 1 year. The endpoints examined were 1) bacteremia and 2) intensive care unit admission or death related to bacteremia. The odds ratio was used to determine which of the following admission parameters and cut-off values were associated with the lowest risk for bacteremia: ANC, absolute phagocyte count (APC), absolute monocyte count (AMC), platelet count, and admission temperature. RESULTS: A total of 189 episodes of bacteremia were identified among the 1171 episodes of febrile neutropenia (14% bacteremia). Only 11 of 1171 episodes (0.9%) resulted in intensive care unit admission, and 3 of these patients died. All 11 patients had an AMC < 30 cells per mm(3). The lowest frequency of bacteremia (6.1%) occurred in the children with an admission AMC of > or = 155 cells per mm(3). None of the patients identified as low risk by AMC required an intensive care unit admission or died. No level of ANC, APC, temperature, or platelet count was associated with a statistically significant decrease in the risk for bacteremia in the patient population. CONCLUSIONS: Adverse outcomes due to bacteremia are infrequent in pediatric oncology patients who present with fever and neutropenia are treated with parental antibiotics. Patients with fever and neutropenia and an AMC value of > or = 155 cells per mm(3) have the lowest risk for bacteremia and may be potential candidates for outpatient management.

Secondary myelodysplasia with monosomy 7 arising after treatment for acute lymphoblastic leukemia in childhood.

Monosomy 7 is recognized as a characteristic, clonal abnormality associated with acquired myelodysplasia (MDS) or acute myeloid leukemia (AML). It can occur as a late complication of cytotoxic therapy and is usually associated with exposure to alkylating agents or radiation therapy. We report two patients with therapy-related myelodysplasia (t-MDS) associated with monosomy 7 occurring in children after completion of therapy for acute lymphoblastic leukemia (ALL). Both children were noted to have t-MDS with monosomy 7 at the time of cessation of chemotherapy. Neither child had received an alkylating agent or radiation therapy during treatment. One child had a unique dicentric marker chromosome that was shown by fluorescent in situ hybridization to be derived from chromosome 7. This report emphasizes the need to identify and minimize therapy-related side effects without compromising cure rates.

Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia.

A multicenter investigation of allogeneic bone marrow transplantation for children with sickle cell disease was conducted that included 27 European and North American transplant centers. Fifty-nine patients who ranged in age from 3.3 to 15.9 years (median, 10.1 years) received HLA-identical sibling marrow allografts between September 1991 and April 2000. Fifty-five patients survive, and 50 survive free from sickle cell disease, with a median follow-up of 42.2 months (range, 11.8 to 115 months) after transplantation. Of the 50 patients with successful allografts, 13 developed stable mixed donor-host hematopoietic chimerism. The level of donor chimerism, measured > or =6 months after transplantation in peripheral blood, varied between 90% and 99% in 8 patients. Five additional patients had a lower proportion of donor cells (range, 11% to 74%). Among these 5 patients, hemoglobin levels varied between 11.2 and 14.2 g/dL (median, 11.3 g/dL; mean, 12.0 g/dL). In patients who had donors with a normal hemoglobin genotype (Hb), the Hb S fractions were 0%, 0%, and 7%, corresponding to donor chimerism levels of 67%, 74%, and 11%, respectively. Among patients who had donors with sickle trait, the Hb S fractions were 36% and 37%, corresponding to donor chimerism levels of 25% and 60%, respectively. Thus, allograft recipients with stable mixed chimerism had Rb S levels similar to donor levels, and only 1 patient required a red blood cell transfusion beyond 90 days posttransplantation. None of the patients have experienced painful events or other clinical complications related to sickle cell disease after transplantation. These observations strongly suggest that patients with sickle cell disease who develop persistent mixed hematopoietic chimerism after transplantation experience a significant ameliorative effect.

Screening sinus CT scans in pediatric bone marrow transplant patients.

OBJECTIVE: To determine how sinus disease noted on pre-bone marrow transplant (BMT) screening sinus computed tomography (CT) scans relates to subsequent development of clinical and/or radiographic sinusitis and correlates with overall prognosis. METHODS: A retrospective review of medical records, CT scans, and BMT database statistics was performed on all pediatric BMT recipients from January 1992 through December 1997. Fifty-four pre-BMT CT scans were performed on 51 children, aged from 2 months to 17 years. Sinus disease was staged according to criteria established by Lund and Kennedy [V.J. Lund, D.W. Kennedy, Ann. Otol. Rhinol. Laryngol. S167 (1995) 17-21.]. RESULTS: The average age of BMT recipients was 6.8 years. Most common oncologic diagnoses included acute myelogenous leukemia (37%), acute lymphoblastic leukemia (17%), and stage IV neuroblastoma (13%). Screening sinus CT scans were routinely performed 1-3 months prior to BMT. On pre-BMT CT scans 48% of the patients had no evidence of sinus disease, 25.9% mild disease, 9.3% moderate disease, and 16.7% severe disease. Two-thirds (66.7%) of patients with severe sinus disease on pre-BMT CT scans experienced clinical sinusitis post-BMT. In contrast, sinus symptoms were much less common (21.4%) in those with mild disease on CT scan. Overall, 39.3% of patients with sinus abnormalities on pre-BMT CT scans had clinical sinusitis during their post-BMT course, compared to 23.1% of those with normal CT scans pre-BMT. In addition, those patients demonstrating sinus disease on their pre-BMT CT scan were more likely to have radiographic sinusitis post-BMT (25.0%) than those with no disease (7.7%). Seventy-eight percent of those with severe sinusitis had died by 2-year follow up, compared to 69.2% of patients with normal CT scans pre-BMT. CONCLUSIONS: Severity of radiographic sinus disease on pre-BMT CT scans was noted to correlate with clinical and radiographic sinusitis later in the post-BMT course, and was associated with a trend toward decreased survival. Pre-BMT CT scans may be useful in determining which children need early and more aggressive intervention for clinical sinusitis post-BMT.

Use of amphotericin B colloidal dispersion in children.

PURPOSE: To describe the experience with a new lipid-based amphotericin product (amphotericin B colloidal dispersion or ABCD) in children with fever and neutropenia who are at high risk for fungal infection. PATIENTS AND METHODS: Forty-nine children with febrile neutropenia were treated in a prospective, randomized trial comparing ABCD with amphotericin B. An additional 70 children with presumed or proven fungal infection were treated with 5 different open-label studies of ABCD. Patients were registered into these studies for reasons of: 1) failure to respond to amphotericin B; 2) development of nephrotoxicity or preexisting renal impairment; or 3) willingness to participate in a dose-escalation study. Extensive data detailing response and toxicity were collected from each patient. RESULTS: In the randomized trial, there was significantly less renal toxicity in the children receiving ABCD than in those receiving amphotericin B (12.0% vs. 52.4% [P = 0.003]). Other adverse symptoms were not significantly different. In the additional open-label studies, although 80% of patients receiving ABCD reported some adverse symptom, the majority of these were infusion related, and nephrotoxicity was reported in only 12% of these patients. CONCLUSIONS: ABCD was well-tolerated at doses up to 5 times greater then those usually tolerated with amphotericin B. Renal toxicity was markedly less than expected, and there were no other unexpected severe toxicities. Further randomized studies are needed to further define the role of this and other liposomal products in children.

Feasibility of oral ciprofloxacin for the outpatient management of febrile neutropenia in selected children with cancer.

BACKGROUND: Children with cancer who develop an episode of chemotherapy-induced febrile neutropenia usually are admitted to the hospital for intravenous empiric antibiotic therapy. In the current study, the authors examined the use of ciprofloxacin as outpatient management in selected patients with fever during an episode of neutropenia. METHODS: Febrile neutropenic patients with a diagnosis of cancer were eligible for outpatient management with oral ciprofloxacin if they appeared well and demonstrated the following characteristics: age 1-21 years, malignancy in remission, absolute phagocyte count > 100/mm(3), > 7 days since the initiation of the last course of chemotherapy, and reliable parents. Eligible children received a single dose of ceftazidime and were observed for 2-23 hours. Patients were discharged receiving oral ciprofloxacin (20/mg/kg/day divided in 2 doses) until the patient was afebrile for 24 hours, had sterile blood cultures, and had evidence of bone marrow recovery. Patients were admitted if they appeared toxic, had positive blood cultures, or were febrile for >/= 5 days. RESULTS: Forty-five evaluable episodes occurred in 32 children. Forty of the 45 patients (89%) were treated successfully in the outpatient setting. The 95% lower confidence bound on the proportion of successful outcomes was 70%. Five children required hospitalization: 2 due to noncompliance, 1 to receive intravenous acyclovir for herpes zoster, and 2 (4%) whose blood cultures were positive for Streptococcus viridans and S. pneumoniae. All had uncomplicated hospitalizations. CONCLUSIONS: The current study demonstrates that very carefully selected, low risk patients with febrile neutropenia may be treated successfully without hospitalization using oral ciprofloxacin. Additional research is required to refine further the optimal criteria for the selection of appropriate patients for outpatient management.

Carboplatin for the treatment of children with newly diagnosed optic chiasm gliomas: a phase II study.

Management of low grade optic glioma in children and adolescents remains controversial. Treatment with chemotherapy may delay or eliminate the need for radiation therapy. Children with newly diagnosed optic chiasm glioma were eligible for enrollment in this phase II trial and received intravenous carboplatin (CBDCA) (560 mg/m2) every four weeks. Patients were monitored closely for toxicity and tumor status. Twelve children were enrolled. Six patients had stable disease, four a partial response and two progressed on therapy. Overall progression free survival was 83 +/- 11%. The median duration of follow-up was 38.6 months (range 18-63 months). No deaths were noted in our series. Thrombocytopenia was the major toxicity, and two patients required platelet transfusions. One child developed an urticarial reaction requiring discontinuation of therapy. Another child developed unilateral high frequency hearing loss. No renal toxicity was encountered. We have demonstrated that carboplatin can eliminate or delay radiation therapy in children and adolescents with low grade optic glioma. CBDCA deserves further investigation in larger clinical trials as a treatment for children with optic chiasm glioma.

Acute renal failure due to obstruction in Burkitt lymphoma.

Acute renal failure in Burkitt lymphoma is commonly the result of tumor lysis syndrome. We present a 15-year-old boy who developed hypertension, seizures, and acute renal failure due to extrinsic compression of the bladder and ureters by a large retrovesical Burkitt lymphoma. The causes of acute renal failure in Burkitt lymphoma and the incidence of acute urinary obstruction in this disease are reviewed.

Recombinant interleukin-6 in the treatment of congenital thrombocytopenia associated with absent radii.

PURPOSE: The role interleukin-6 (IL-6) in the treatment of congenital thrombocytopenias is unknown. The purpose of this case report is to describe the efficacy of IL-6 in a child with thrombocytopenia with absent radii (TAR) syndrome. METHODS: A 23-month-old girl with TAR syndrome was treated with recombinant IL-6 (Sigosix; Serono Laboratories, Norwell, MA) at a dose of 7 micrograms/kg subcutaneously daily. Complete blood counts were monitored weekly. The child was closely monitored for any toxicity. RESULTS: After 3 weeks of therapy, the patient had an increase in platelet count from a baseline of 5,000 to 8,000/microliter to a maximal level of 33,000/microliter. She was platelet transfusion-independent during IL-6 therapy. Fevers and chills, the main toxicities encountered, were controlled with acetaminophen and ibuprofen. An increase in the IL-6 dose caused anemia with no further increase in platelet count. After discontinuation of the drug, her hemoglobin rose to baseline and the platelet count returned to pretreatment levels. CONCLUSIONS: We conclude that IL-6 may benefit some children with TAR syndrome. The role of IL-6 and other thrombopoietic agents in the treatment of TAR and other congenital thrombocytopenias deserves further clinical study.

Safety and cost-effectiveness of outpatient total body irradiation in pediatric patients undergoing stem cell transplantation.

PURPOSE: To determine the feasibility, safety, and cost of delivering total body irradiation (TBI) in an outpatient setting. PATIENTS AND METHODS: The records of 33 pediatric patients with hematopoietic malignancies undergoing TBI in preparation for bone marrow transplantation (BMT) at the Children's Medical Center of Dallas between February 1992 and June 1997 were retrospectively reviewed. Seventeen children received TBI in an outpatient setting, including 7 patients younger than 8 years of age. All patients had a good performance status (Karnofsky index > 90%) and lived or were housed within a 50-mile radius of the hospital. Patients received 1200 cGy or 1350 cGy in 8 or 9 fractions twice daily over 4 to 5 days and were admitted for high-dose chemotherapy after the last TBI fraction. Mean age was 9 years (range 13 months to 16 years). Close contact was maintained with the BMT staff during outpatient TBI. RESULTS: Eleven patients (65%) received oral ondansetron for nausea and vomiting, 6 received promethazine and ondansetron, and 3 required dexamethasone. Only 2 of the 17 children (12%) required admission during TBI for persistent vomiting and poor oral intake. Two other children (12%) required outpatient administration of intravenous fluids. The other 13 patients (76%) tolerated the outpatient TBI regimen well. Taking into account hospitalization and ambulance transport charges, outpatient TBI represented a savings of approximately $3250 per patient compared with inpatient TBI. CONCLUSIONS: Fractionated TBI delivered in an outpatient setting to selected children of all ages is a safe and cost-effective practice.

Early discharge of low-risk febrile neutropenic children and adolescents with cancer.

During the past decade, a relatively lower-risk patient population of febrile neutropenic children with cancer (over one-half of all these patients) has been identified. These patients can be safely discharged from the hospital before their absolute neutrophil count (ANC) exceeds 500/mm3. To evaluate the practice of early discharge of these patients, 580 consecutive episodes of chemotherapy-induced febrile neutropenia in 253 children and adolescents with cancer between June 1992 and May 1995 were reviewed. Three hundred thirty episodes ended in discharge before the patient's ANC was > 500/mm3. Patients were characterized as being at relatively lower risk if they had sterile blood cultures, were afebrile for > 24 hours, appeared well, and were thought to have evidence of marrow recovery. Of the 330 episodes, only 21 (6%) were associated with admission for recurrent fever during the subsequent 7 days. In retrospect, in only six of these 21 cases of readmission (or 2% of 330 episodes) was there evidence of bone marrow recovery, and none of the blood cultures were positive during the subsequent hospitalization. All patients who met low-risk criteria fared well during their second hospitalization. This early discharge strategy was safe and resulted in substantial cost savings.

BK papova virus pneumonia following hematopoietic stem cell transplantation.

BK papova virus infection is frequently seen after bone marrow transplantation as a causative agent of hemorrhagic cystitis. We report an 8-month-old child with osteopetrosis who died of a severe interstitial pneumonia after receiving an unrelated umbilical cord transplant. On autopsy, BK virus was detected in the lung tissue using immunofluorescence assay, cell culture and PCR. No other pathogens were recovered. BK virus infection should be considered as a cause of interstitial pneumonia in children undergoing transplantation.

Acute splenic complications in children with sickle cell-hemoglobin C disease.

OBJECTIVE: To determine the frequency and severity of acute splenic complications in children and adolescents with sickle cell (SC) hemoglobin C disease. METHODS: The medical records of 271 patients with SC disease seen at our center were reviewed to evaluate the incidence and severity of acute complications involving the spleen. RESULTS: Sixteen (6%) children had acute splenic complications. Thirteen (5%) had 16 episodes of acute splenic sequestration (ASSC), with the initial event occurring at a mean age of 8.9 years (range, 2 to 17 years). Splenomegaly had been noted before the initial event in 6 (46%) of the 13 cases, and 3 (23%) had a history of painful splenic infarction. Two young children (aged 4 and 6 years) had a hemoglobin value less than 2 gm/dl, one without history of splenic enlargement. Three (23%) children had a second episode of ASSC. Three additional patients had a history of acute painful splenic infarction, two of whom also had splenic hemorrhage. Eight (3%) of the 271 children required splenectomy (1 after the initial episode of ASSC, 3 after a second episode of ASSC, 2 as a result of pain accompanying chronic infarction and ASSC, and 2 because of splenic hemorrhage). No deaths resulted from ASSC. CONCLUSIONS: We conclude that (1) acute splenic complications in children and adolescents with SC disease are relatively uncommon, (2) most episodes of ASSC occur in preadolescents, (3) ASSC can be life threatening, even in younger children, and (4) prior splenomegaly is not a good predictor of ASSC. Thus it is vital that the parents of all children with SC disease be instructed to palpate their child's spleen regularly.

Safety of early hospital discharge of selected febrile children and adolescents with cancer with prolonged neutropenia.

PROBLEM: The safety of early hospital discharge (i.e., before the absolute neutrophil count [ANC] exceeds 500 cell/mm3) of febrile neutropenic children and adolescents with cancer who had experienced prolonged neutropenia (i.e., for more than 7 days) following admission has not been studied. METHOD OF STUDY: Three hundred and thirty nine consecutive admissions of children and adolescents with cancer for management of febrile neutropenia were reviewed. Early discharge criteria included absence of fever for 24 hours prior to discharge, sterile blood cultures for 24 hours, evidence of bone marrow recovery defined as a sustained increase in platelet count and ANC or absolute phagocyte count (APC), and control of local infection if present. Children hospitalized with febrile neutropenia who remained neutropenic for more than 7 days were analyzed to assess their outcomes following discharge it they had met criteria for early hospital discharge. RESULTS: Thirty-three patients in whom neutropenia had persisted for more than 7 days were discharged before attaining an ANC greater than 500/mm3 when they met the early discharge criteria. Only two children (6%) required readmission for recurrent fever, a rate which was not different from that of patients discharged after a more transient episode of neutropenia (2 of 33 vs. 3 of 121, P = 0.3). Both patients who were readmitted had a source of local infection which worsened despite oral antibiotics. Both patients appeared clinically well at the time of readmission and had sterile cultures during their second hospitalization with resolution of local infection. CONCLUSION: This study confirms that low-risk criteria used to select children with cancer for discharge before complete resolution of neutropenia can be safely applied to those patients whose neutropenia lasted more than 7 days following admission.

A pilot study of outpatient management of febrile neutropenic children with cancer at low risk of bacteremia.

Febrile neutropenic children with cancer were eligible for outpatient management with intravenous ceftriaxone therapy if they displayed selected low-risk criteria. Nineteen children were enrolled. All patients had sterile blood cultures, and only one of them was hospitalized because of persistent fever. This pilot study suggests that selected children with febrile neutropenia might be successfully managed without hospitalization.

Osteogenic sarcoma in a child with transfusion-dependent Diamond-Blackfan anemia.

PURPOSE: Diamond-Blackfan anemia or congenital pure red blood cell aplasia is one of the best defined congenital hematopoietic disorders. Although it has been suggested that affected patients are predisposed to developing acute leukemia, there have been no reports of sarcoma in patients with Diamond-Blackfan anemia. We describe a child who had Diamond-Blackfan anemia and who developed an osteogenic sarcoma. PATIENT AND METHODS: A case is presented of a 5-year-old girl who had transfusion-dependent Diamond-Blackfan anemia and hemochromatosis and who developed an osteogenic sarcoma of the tibia. RESULTS: The patient had an initial response with an ifosfamide-containing chemotherapy regimen but died of multiple pulmonary metastases. CONCLUSION: Our patient is the 10th reported case of malignancy in Diamond-Blackfan anemia but the first instance of sarcoma. Given the increased rate of leukemia in Diamond-Blackfan anemia patients, we speculate there may also exist an association between osteogenic sarcoma occurring at a particularly young age and this uncommon hematologic disorder.

Enteral nutritional support by gastrostomy tube in children with cancer.

We examined the use of gastrostomy tubes in malnourished children with cancer as part of our ongoing efforts to improve their supportive care. Patients were examined on the basis of percentage of weight loss and percentage of desirable body weight. Twenty-five patients underwent gastrostomy tube placement followed by aggressive enteral nutritional support. Gastrostomy tubes were placed at a mean of 3.5 months (range, 0.3 to 8 months) after diagnosis; mean weight loss had been 10.1% (range, to 21%) of desirable body weight. There were no immediate postoperative complications. Gastrostomy tube feedings were well tolerated by all patients. All children gained or maintained weight, and 60% of the severely malnourished children returned to a desirable body weight after an average of 4.9 months (range, 1 to 13 months). Weight gain averaged 12.9% (range, to 45.4%) of desirable body weight. The most common complications were 38 episodes of inflammation at the gastrostomy tube site during periods of severe neutropenia, which were treated successfully with topically or orally administered antibiotics, and 13 episodes of cellulitis, which required intravenously administered antibiotics. The infection rate was 1.58 episodes per 1000 days of use compared with a rate of 5.0 per 1000 days previously reported with total parenteral nutrition. The monthly costs of gastrostomy tube nutrition support were 9% of those associated with use of total parenteral nutrition. Gastrostomy tube use in children with cancer is a safe, effective, and cost-effective method of reversing malnutrition. Further investigation with larger numbers of patients is warranted.