M. Fevzi Ozkaynak

Anti-GD2 Antibody with GM-CSF, Interleukin-2, and Isotretinoin for Neuroblastoma

BACKGROUND Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma. METHODS Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis. RESULTS A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% at 2 years, P=0.02 without adjustment for interim analyses). CONCLUSIONS Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.)

Phase I Study of Chimeric Human/Murine Anti–Ganglioside GD2 Monoclonal Antibody (ch14.18) With Granulocyte-Macrophage Colony-Stimulating Factor in Children With Neuroblastoma Immediately After Hematopoietic Stem-Cell Transplantation: A Children’s Cancer Group Study

PURPOSE Ganglioside G(D2) is strongly expressed on the surface of human neuroblastoma cells. It has been shown that the chimeric human/murine anti-G(D2) monoclonal antibody (ch14.18) can induce lysis of neuroblastoma cells by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. The purposes of the study were (1) to determine the maximum-tolerated dose (MTD) of ch14.18 in combination with standard dose granulocyte-macrophage colony-stimulating factor (GM-CSF) for patients with neuroblastoma who recently completed hematopoietic stem-cell transplantation (HSCT), and (2) to determine the toxicities of ch14.18 with GM-CSF in this setting. PATIENTS AND METHODS Patients became eligible when the total absolute phagocyte count (APC) was greater than 1, 000/microL after HSCT. ch14.18 was infused intravenously over 5 hours daily for 4 consecutive days. Patients received GM-CSF 250 microg/m(2)/d starting at least 3 days before ch14.18 and continued for 3 days after the completion of ch14.18. The ch14.18 dose levels were 20, 30, 40, and 50 mg/m(2)/d. In the absence of progressive disease, patients were allowed to receive up to six 4-day courses of ch14.18 therapy with GM-CSF. Nineteen patients with neuroblastoma were treated. RESULTS A total of 79 courses were administered. No toxic deaths occurred. The main toxicities were severe neuropathic pain, fever, nausea/vomiting, urticaria, hypotension, mild to moderate capillary leak syndrome, and neurotoxicity. Three dose-limiting toxicities were observed among six patients at 50 mg/m(2)/d: intractable neuropathic pain, grade 3 recurrent urticaria, and grade 4 vomiting. Human antichimeric antibody developed in 28% of patients. CONCLUSION ch14.18 can be administered with GM-CSF after HSCT in patients with neuroblastoma with manageable toxicities. The MTD is 40 mg/m(2)/d for 4 days when given in this schedule with GM-CSF.

Phase I Study of ch14.18 With Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-2 in Children With Neuroblastoma After Autologous Bone Marrow Transplantation or Stem-Cell Rescue: A Report From the Children's Oncology Group

PURPOSE Recurrence of high-risk neuroblastoma is common despite multimodality therapy. ch14.18, a chimeric human/murine anti-G(D2) antibody, lyses neuroblastoma cells. This study determined the maximum tolerable dose (MTD) and toxicity of ch14.18 given in combination with interleukin-2 (IL-2) after high-dose chemotherapy (HDC)/stem-cell rescue (SCR). Biologic correlates including ch14.18 levels, soluble IL-2 receptor levels, and human antichimeric antibody (HACA) activity were evaluated. PATIENTS AND METHODS Patients were given ch14.18 for 4 days at 28-day intervals. Patients received IL-2 during the second and fourth courses of ch14.18 and granulocyte-macrophage colony-stimulating factor (GM-CSF) during the first, third, and fifth courses. The MTD was determined based on toxicities occurring with the second course. After the determination of the MTD, additional patients were treated to confirm the MTD and to clarify appropriate supportive care. RESULTS Twenty-five patients were enrolled. The MTD of ch14.18 was determined to be 25 mg/m(2)/d for 4 days given concurrently with 4.5 x 10(6) U/m(2)/d of IL-2 for 4 days. IL-2 was also given at a dose of 3 x 10(6) U/m(2)/d for 4 days starting 1 week before ch14.18. Two patients experienced dose-limiting toxicity due to ch14.18 and IL-2. Common toxicities included pain, fever, nausea, emesis, diarrhea, urticaria, mild elevation of hepatic transaminases, capillary leak syndrome, and hypotension. No death attributable to toxicity of therapy occurred. No additional toxicity was seen when cis-retinoic acid (cis-RA) was given between courses of ch14.18. No patient treated at the MTD developed HACA. CONCLUSION ch14.18 in combination with IL-2 was tolerable in the early post-HDC/SCR period. cis-RA can be administered safely between courses of ch14.18 and cytokines.

Clinical and laboratory features of 178 children with recurrent epistaxis.

Purpose To determine the clinical and laboratory features of 178 children referred for the evaluation of recurrent epistaxis to an outpatient hematology clinic in a university medical center. Patients and Methods Medical records of 3681 outpatient pediatric hematology referrals were retrospectively review, and 178 children with recurrent epistaxis from 1985 to 1999 were identified. Historic (other bleeding symptoms: gingival bleeding, easy bruising, menorrhagia, and gross blood in the urine or stool; duration and severity of the epistaxis episodes; and family history of bleeding) and laboratory (complete blood count and coagulation tests) data were analyzed. Results There were 103 boys and 75 girls with a median age of 84 months (range 15–219 months). Sixty-seven percent (n = 119) did not have a coagulopathy diagnosed and 33% (n = 59) did. The diagnoses included von Willebrand disease in 33, platelet aggregation disorders in 10, thrombocytopenia in seven, mild factor VIII deficiency in three, Bernard–Soulier syndrome in two, factor VII deficiency in one, factor IX deficiency in one, and factor XI deficiency in one, and coagulation inhibitor in one. Of the historic data, only a family history of bleeding was predictive of diagnosing a coagulopathy (P = 0.023). The duration and severity of the epistaxis and the presence of other bleeding symptoms had no predictive value. Children with a coagulopathy diagnosed had a longer median partial thromboplastin time (PTT) (33.1 vs. 30.5 seconds;P = 0.012). Conclusions One-third of children presenting with recurrent epistaxis have a diagnosable coagulopathy. A positive family history and a prolonged PTT are useful predictive data.

Infections Due to Nontuberculous Mycobacteria in Children with Leukemia

We reviewed the spectrum of infections due to nontuberculous mycobacteria (NTM) in children with leukemia. Three children acquired such infections. One patient developed pneumonia after the cessation of chemotherapy when Mycobacterium xenopi was identified in his lung biopsy specimen. He required 2 years of treatment with antituberculous agents and clarithromycin. Cultures of central and peripheral blood specimens from two patients yielded Mycobacterium fortuitum and Mycobacterium chelonae, respectively. Broviac catheters were likely the source of infection. Removal of the catheters and antibiotic treatment resulted in cure. Central venous catheters in leukemic children are potential sources of infection. For febrile neutropenic children with leukemia who do not respond to antibiotic therapy, cultures positive for diphtheroids or negative routine bacterial and fungal cultures should raise a suspicion for infections due to NTM. Systemic infections may require up to 2 years of therapy. Removal of the infected catheters during persistent or recurrent infections in necessary for control of the infection.

Randomized comparison of antibiotics with and without granulocyte colony-stimulating factor in children with chemotherapy-induced febrile neutropenia: a report from the Children's Oncology Group.

To determine if granulocyte colony‐stimulating factor (G‐CSF) with empirical antibiotics accelerates febrile neutropenia resolution compared with antibiotics without it.

Randomized double-blind comparison of single high-dose ondansetron and multiple standard-dose ondansetron in chemotherapy-naive pediatric oncology patients.

This prospective, double-blind, randomized study compares the antiemetic efficacy of an equivalent dose of ondansetron administered as a single high dose or as multiple standard doses in pediatric oncology patients. Thirty-one chemotherapy-naive patients were randomized at diagnosis to receive either single high-dose ondansetron (0.6 mg/kg, maximum dose 32 mg) or multiple standard-dose ondansetron (0.15 mg/kg, maximum dose 8 mg, every 4 hr for four doses). Antiemetic efficacy was assessed by an emesis scale described as follows: 1, no nausea or emesis; 2, nauseous but able to eat; 3, nauseous and unable to eat; and 4, emesis. Sixteen patients received high-dose and 15 received standard-dose ondansetron. Patients receiving moderately or severely emetogenic chemotherapy were evenly distributed between the two treatment groups. Eighty-one percent of patients receiving high-dose and 80% receiving standard-dose ondansetron rated 1 or 2 on the emesis scale (p = 0.93). No patient experienced any clinical or laboratory toxicity. Our study suggests that single high-dose ondansetron is as efficacious as the multiple standard-dose regimen and is well tolerated. Its use will facilitate the administration of ondansetron in pediatric patients receiving chemotherapy.

Urinary Tract Infections in Pediatric Oncology Patients with Fever and Neutropenia

The relevancy of the urinary tract as a source of infection during febrile neutropenia is not known. The authors sought to determine the frequency of urinary tract infections (UTIs) in pediatric cancer patients with febrile neutropenia. Urine was collected from a mid-stream void before the administration of antibiotics. Demographic, clinical, and laboratory data were collected. The frequency of UTI and usefulness of urinalysis and localizing signs in predicting UTI in pediatric cancer patients with fever and neutropenia were determined. Forty-five patients had 58 febrile neutropenic episodes eligible for study participation. No patient presented with localizing signs. The urinalysis was negative in 53 episodes and positive in 5 episodes. Four patients had 5 UTIs. The frequency of UTI was 8.6% (5 of 58 febrile neutropenia episodes). Four patients had bacteremia, none of whom had a UTI. The sensitivity, specificity, and negative predictive value of urinalysis was 40%, 94%, and 94%, respectively, and for localizing signs was undefined, 100%, and 91%, respectively. UTI is as common as bacteremia in the current pediatric cancer patients with fever and neutropenia. Urinalysis and urine culture should be obtained routinely as part of the diagnostic evaluation of patients with fever and neutropenia.

Detection of central nervous system leukemia in children with acute lymphoblastic leukemia by real-time polymerase chain reaction.

Accurate detection of central nervous system (CNS) involvement in children with newly diagnosed acute lymphoblastic leukemia (ALL) could have profound prognostic and therapeutic implications. We examined various cerebrospinal fluid (CSF) preservation methods to yield adequate DNA stability for polymerase chain reaction (PCR) analysis and developed a quantitative real-time PCR assay to detect occult CNS leukemia. Sixty CSF specimens were maintained in several storage conditions for varying amounts of time, and we found that preserving CSF in 1:1 serum-free RPMI tissue culture medium offers the best stability of DNA for PCR analysis. Sixty CSF samples (30 at diagnosis and 30 at the end of induction therapy) from 30 children with ALL were tested for CNS leukemic involvement by real-time PCR using patient-specific antigen receptor gene rearrangement primers. Six of thirty patient diagnosis samples were PCR-positive at levels ranging from 0.5 to 66% leukemic blasts in the CSF. Four of these patients had no clinical or cytomorphological evidence of CNS leukemia involvement at that time. All 30 CSF samples drawn at the end of induction therapy were PCR-negative. The data indicate that real-time PCR analysis of CSF is an excellent tool to assess occult CNS leukemia involvement in patients with ALL and can possibly be used to refine CNS status classification.

The Usefulness of Preoperative Screening for Bleeding Disorders

P ediatricians often perform preoperative evaluations on their patients. In addition to a detailed history and physical examination, prothrombin time (PT) and activated partial thromboplastin (aPTT) are often performed to identify patients at increased risk for perioperative bleeding. However, there has been controversy about the need for such testing and its value in decreasing the risk of perioperative bleeding. Studies in the otolaryngology literature have shown that there is no significant increase in the risk of post-tonsillectomy bleeding in patients with abnormal coagulation studies compared to those with normal studies.1-3 However, some studies have shown that an abnormal preoperative coagulation profile may identify those patients at increased risk for perioperative bleeding.4-6 While most of these studies have used perioperative bleeding as the endpoint to assess the usefulness of preoperative screening, only a few have performed detailed coagulopathy evaluations to define the bleeding disorder.4,7 To determine if preoperative screening is useful in identifying a bleeding disorder, we retrospectively reviewed the coagulopathy evaluations of 131 children referred for a prolonged preoperative aPTT.