Outpatient treatment of fever and neutropenia for low risk pediatric cancer patients.

BACKGROUND: Fever and neutropenia (F&N) is a common complication of cancer chemotherapy. It is conveniently managed by hospitalization and empiric administration of parenteral antibiotics. This study attempted to determine whether pediatric cancer patients with F&N identified as low risk for morbidity and mortality by clinical criteria at the time of presentation could be treated safely as outpatients. METHODS: Seventy-three episodes of F&N in 41 patients were studied prospectively over 2 years. Eligibility criteria included age > or =2 years, reliable caretakers, and residence within 1 hour of the hospital. Exclusion criteria included hemodynamic instability, dehydration, severe mucositis, pneumonia, leukemia/lymphoma induction therapy, bone marrow transplantation, or other serious comorbidity. Patients were evaluated, received a single dose of intravenous ceftazidime, and were observed for 3-16 hours. They were randomized to receive either oral ciprofloxacin or intravenous ceftazidime as outpatients. Patients were seen daily until they had been afebrile for at least 48 hours and had a rising absolute phagocyte count of >500 cells/microL. RESULTS: Sixty-three of 73 episodes (86%) were successfully managed on an outpatient basis. For 31 of 33 episodes in the ceftazidime arm, the patients remained outpatients, compared with 32 of 40 in the ciprofloxacin arm; this difference was not statistically significant. On average, patients remained febrile for 2.7 days and were treated for 4.7 days. Seventy-seven percent of episodes required no modification of initial antibiotic therapy. Of the 10 patients who were hospitalized, 4 had prolonged fever and 3 had emesis. Protracted neutropenia was associated with the need for hospitalization. There were no deaths, intensive care unit transfers, or serious complications. CONCLUSIONS: Carefully selected low risk children with fever and neutropenia can be treated safely as outpatients. Close daily medical scrutiny is required.

Economic and resource utilization analysis of outpatient management of fever and neutropenia in low-risk pediatric patients with cancer.

PURPOSE: To measure resource allocation in outpatient management of fever and neutropenia in low-risk pediatric patients with cancer and its impact on their families. PATIENTS AND METHODS: A prospective clinical trial was conducted. Eligible patients received a single dose of intravenous (IV) antibiotics and were observed for several hours in clinic. Patients were randomly assigned to continue either IV or oral antibiotics and were seen daily as outpatients. Charges were calculated based on the number of resources used and Medicare/Medicaid reimbursement schedules. A questionnaire was used to measure the impact of outpatient treatment on the family. RESULTS: Seventy-three episodes of fever and neutropenia were studied. The median duration of treatment was 4 days. Eighty-six percent of the episodes were managed without hospitalization. The median calculated charge was $1840. The median calculated charge for patients receiving oral antibiotics was $1544 and was significantly less than the $2039 median charge for outpatients treated with IV antibiotics. The estimated charge for comparable inpatient treatment was $4503. Nearly all families preferred outpatient care, and few reported a loss of work hours or increased child care expenses. CONCLUSIONS: Outpatient treatment of low-risk episodes of fever and neutropenia is substantially less costly than inpatient care and is preferred by most families.

Neuropsychologic effects of chemotherapy on children with cancer: a longitudinal study.

PURPOSE: A prospective study was conducted to assess the effects of chemotherapy for cancer on children's long-term neuropsychologic status. PATIENTS AND METHODS: Ninety-nine children who received no cranial radiation therapy (CRT) completed four annual neuropsychologic assessments. Fifty-one patients received intrathecal (IT) chemotherapy (ITC); 48 received no CNS treatment. These two groups were compared using repeated-measures analysis of variance on IQ, memory, language, freedom from distractibility, academic achievement, executive functions, and fine-motor, perceptual-motor, and tactile-spatial skills. In addition, 51 of the sample of 99 patients had been examined 5 to 11 years after diagnosis. Their data were analyzed to evaluate the longer-term effects of chemotherapy. The predictability of demographic and medical variables on neuropsychologic outcome at 3-year and long-term follow-up study were assessed using multiple regression techniques. RESULTS: Overall, the effects of chemotherapy in the absence of CRT appear to be slight. Patients who received ITC and intravenous (IV) methotrexate declined slightly on perceptual-motor skills, but were still well within the normal range. Both groups, regardless of treatment, declined on academic achievement tests, although not to a statistically significant degree. Age effects were found on performance IQ (PIQ) and perceptual-motor skills. Socioeconomic status (SES) correlated with a large number of variables. Sex effects were not significant. CONCLUSION: The present results are largely consistent with previous findings for nonirradiated groups. Treatment effects from ITC are slightly more apparent 5 to 11 years after diagnosis than at 3-year follow-up evaluation but this does not constitute a clinically meaningful difference. More noticeable are academic declines among all groups, regardless of treatment.

Ethnicity and cure rates of Texas children with acute lymphoid leukemia.

BACKGROUND: Ethnic differences in the survival of children treated for acute lymphoid leukemia (ALL) have been described in several locations. Children of African, Polynesian, Native American, and Mexican ancestry had a less favorable outcome than children of European ancestry when treated in a similar manner by the same physicians and nurses. METHODS: We reviewed the medical records of the 94 European-American (E-A) and 84 Mexican-American (M-A) Texas children registered and treated in national collaborative ALL therapy trials at the M. D. Anderson Cancer Center in Houston between 1974 and 1985 and followed through June 1994. Information was collected regarding age, sex, presenting clinical features, risk for relapse grouping, protocol assignment, event free survival, and the financial status of their families. Cure was defined as initial continuous complete remission for more than seven years and cessation of therapy for more than four years. Presenting characteristics of E-A and M-A children were compared, and then related to cure rates by univariate and multivariate analyses. Event free survival rates of E-A and M-A children were determined together and by sex. RESULTS: Comparing presenting features, financial status as identified by pay code was significantly less for M-A children. Other features were not significantly different. By univariate analysis, an age of 2 to 6 years, female sex, initial white blood cell count below 10,000/microL, low risk grouping, registration on the most recent protocol, and full pay status were significantly associated with higher cure rates. By multivariate analysis, male gender, high risk group, and registration on earlier protocols were found to be significantly associated with a low cure rate. Event free survival and cure rate were lower for M-A children, but the differences were not statistically significant. CONCLUSIONS: Further study of larger numbers of patients, including contemporary immunophenotypic and genotypic characterization of ALL, is needed for better definition of possible ethnic differences. Ethnicity and financial status should be included in the analysis of clinical trials of ALL therapy.

Prevention of graft-versus-host disease with anti-CD5 ricin A chain immunotoxin after CD3-depleted HLA-nonidentical marrow transplantation in pediatric leukemia patients.

To determine if partial T cell depletion and intensive post-transplant immunosuppression is effective for the prevention of graft-versus-host disease (GVHD) in pediatric recipients of HLA-non-identical marrow transplants, 10 children with leukemia received high-dose thiotepa, cyclophosphamide and total body irradiation followed by transplantation of CD3-depleted marrow from matched unrelated or one-antigen mismatched related adult donors. To maximize the number of stem cells infused, a large volume (1-1.51) of marrow was harvested from the donors. After immunopurging, the marrow infused contained a median of 3.7 x 10(6) CD34+ cells/kg, 1.4 x 10(6) CD3+ cells/kg, and 1.6 x 10(6) CD5+ cells/kg as assessed by flow cytometry. Cyclosporine, methylprednisolone and anti-CD4 ricin A chain immunotoxin (XZ-CD5) were used for prevention of GVHD post-transplant. All patients achieved an ANC > 0.5 x 10(9)/l. No patient developed capillary leak syndrome or renal failure from XZ-CD5. Five developed grade 2-4 acute GVHD, and all responded to treatment with steroids. Five of nine evaluable patients developed chronic GVHD. Two patients relapsed, but the most common cause of death was infection with or without chronic GVHD. Four patients survive 10+ to 27+ months post-transplant. XZ-CD5 is well-tolerated in T cell-depleted marrow transplant recipients. However, partial T cell depletion and intensive post-transplant immunosuppression did not prevent moderate acute GVHD or chronic GVHD. This may have been due to the high number of T cells infused with the marrow.

Response to alpha-interferon in children with Philadelphia chromosome-positive chronic myelocytic leukemia.

The therapeutic efficacy and toxicity of alpha-interferon (alpha-IFN) (Roferon, Hoffmann-La Roche, Inc., Nutley, NJ) were determined in 15 children (age range, 6 to 20 years) with Philadelphia chromosome-positive chronic myelocytic leukemia (Ph+ CML). All patients had received cytoreductive therapy with either hydroxyurea (n = 13) or busulfan (n = 1) or both (n = 1) for 6 weeks to 46 months (median, 7 months) before beginning alpha-IFN therapy at a dose of 5 x 10(6) U/m2/d intramuscularly. This dose was escalated to 10 x 10(6) U/m2/d if leukemia was inadequately controlled. Ten children had a hematologic response, with nine showing a reduction in the percentage of Ph+ marrow cells, including four who had no detectable Ph+ cells in marrow samples collected 48 to 204 weeks after the initiation of therapy. Two of 15 patients remain free of Ph+ cells. Therapy was discontinued before week 104 in ten patients because of the following: (1) early hematologic responses without a decrease in Ph+ cells (three patients); (2) early resistant disease (one patient); (3) blast crisis (one patient); (4) progressive disease (two patients); (5) seizure attributed to high-dose alpha-IFN (one patient); or (6) an inadequate trial of alpha-IFN caused by aseptic necrosis or poor compliance (two patients). The most common side effects were mild and have included fever, malaise, headache, myalgias, and pain at the injection site. Adverse events causing interruption of therapy were seizures, aseptic necrosis, and myelofibrosis. alpha-IFN stabilizes the chronic phase of Ph+ CML in some children, is adequately tolerated when administered at a dose of 2.5 to 5 x 10(6) U/m2/d intramuscularly, and results in a significant decrease in the proportion of Ph+ metaphases in some patients. alpha-IFN in combination with an effective cytoreductive agent or agents appears worthy of further clinical testing in this disease.

Remission induction and continuation therapy in children with their first relapse of acute lymphoid leukemia. A Pediatric Oncology Group study.

Between January 1979 and April 1983, 113 children undergoing their first relapse of acute lymphoid leukemia (ALL) at any site were registered in Pediatric Oncology Group study 7834; 98 were eligible and evaluable. In addition to radiotherapy administered to sites of local relapse, induction consisted of vincristine, doxorubicin, and prednisone (VAP) chemotherapy. Continuation therapy consisted of triple-drug intrathecal therapy and regimens of 6-thioguanine and cytarabine alternating with vincristine, prednisone, cyclophosphamide, and cytarabine. Randomization in continuation was between VAP pulses or no pulse, regardless of the site of relapse. This report provides long-term follow-up of these patients. Thirty-two of 39 children with bone marrow involvement achieved a complete response (CR). Only one of these is alive in an unmaintained remission, a child who did not have an initial CR. Thirty-four of 36 evaluable children with central nervous system involvement as the site of relapse achieved CR. Of these ten are alive; eight are in continuing CR. Nineteen of 20 boys with testicular relapse achieved CR. Of these, 14 are still alive and not receiving therapy, although only one half received treatment in compliance with the protocol described. These results illustrate the possibility of cure of patients who have relapsed with ALL when it is (1) confined to a meningeal or gonadal site and (2) treated vigorously with radiotherapy and a new regimen of systemic chemotherapy. The results reconfirm the need to prevent an initial relapse at any site.

Season-of-birth and acute leukemia of infancy.

Because of its short and clearly delineated latency period, acute leukemia of infancy is particularly suited to etiologic analysis. From 1950 to mid-1985, 31 infants with acute leukemia (less than 1 year of age) were registered at the University of Texas, M.D. Anderson Cancer Center at Houston. The medical records of these infants were reviewed for demographic and birth information. Of the 31 infants, 14 (45%) were Hispanic. The sex ratio was 3:1 male/female) for white infants and 5:9 for Hispanic infants. Of the white infants, half had acute lymphocytic leukemia, compared with all but one of the Hispanic infants. There was a significant excess of winter births among the infants diagnosed with acute leukemia (P less than 0.05). The significant association between season-of-birth and the occurrence of leukemia cases is suggestive of periodicity of an environmental etiologic agent, perhaps acting in concert with endogenous rhythmicities in susceptibility to that agent. This finding is deserving of further study.

Long-term results in the treatment of acute nonlymphocytic leukemia: a Pediatric Oncology Group Study.

Complete remission (CR), 5-year remission duration (RD), and overall 5-year survival rates are 74%, 28% and 25%, respectively, for previously untreated children with acute nonlymphocytic leukemia diagnosed between 1977 and 1981, following induction therapy with vincristine, doxorubicin and prednisone (VAP), consolidation therapy with 6-thioguanine, cytosine arabinoside (TA) and cyclophosphamide/vincristine/cytosine arabinoside/prednisone (COAP), and maintenance therapy of alternating TA and COAP with or without VAP pulses. Approximately 20% are free of their disease for more than 5 years. High white blood cell counts (WBC) at diagnosis and M3 and M6 morphology were associated with lower CR rates, while M5 morphology was associated with higher CR rates. Patients with M1 morphology had shorter remission duration as compared to those with M4 or M5 morphology. Low WBC and age between 2 and 10 years at diagnosis were associated with longer remission durations and survival. Patients with M4 morphology also survived longer. The observed CR rates are comparable to other studies initiated at the same time as this study but survival is less than those reported more recently. Low WBC at diagnosis and M4/M5 morphology may identify relatively favorable prognostic groups.

A lineage switch in acute monocytic leukemia. A case report.

A case of congenital monocytic leukemia that underwent a lineage switch to acute lymphocytic leukemia (ALL) is described. The original leukemia had typical monocytic features, as evidenced by morphology (FAB M5), cytochemistry (nonspecific esterase) and immunophenotype (My4 positive). Cytogenetic study showed a pseudodiploid clone t(9;11)(p22;q21) that could be interpreted as a variant of the t(9;11)(p22;q23) reported in patients with the M5 type of leukemia. After successful remission induction with single-agent chemotherapy (VM-26) and subsequent sustained remission for 12 months with alternating VM-26 and VP-16-213, lineage switch to ALL (FAB L1) occurred. The presence of both lymphoid and myeloid markers on leukemic cells at lineage switch suggested the biphenotypic character of the patient's ALL. Our observation indicates that a lineage switch can occur from monocytic leukemia to ALL, although most of the cases previously reported have been in the reverse direction. This case emphasizes again the need to carry out careful and comprehensive marker studies to gain insight into the possible prognostic significance and the application of appropriate therapy.

Lineage heterogeneity in acute leukemia with the t(4;11) abnormality: implications for acute mixed lineage leukemia.

Acute leukemia associated with the t(4;11)(q21;q23) abnormality demonstrates marked lineage heterogeneity, including cases with features of acute mixed lineage leukemia. We report 7 patients with acute leukemia with the t(4;11) abnormality in which we have defined the range of lineage commitment associated with this disease utilizing a variety of cell characterization techniques. Each case could be classified either as acute lymphoblastic leukemia (ALL) (5 cases) or acute myelogenous leukemia (AML) (2 cases) based on standard light microscopic criteria supplemented by ultrastructural determination of myeloperoxidase. Evidence for acute mixed lineage leukemia was found in one of the AML patients in which coexpression of CD14 and CD19 surface antigens was demonstrated. Overall, the findings further confirm the lineage heterogeneity previously reported in association with t(4;11) acute leukemia. The implications of the findings as to the pathogenesis of t(4;11) acute leukemia are discussed.

Severe hypertensive reactions to teniposide (VM-26) in infants with congenital leukemia.

Two cases of infants with congenital leukemia who had severe, refractory hypertensive reactions to teniposide (VM-26) are described. Patients on a 5 mg/kg twice weekly schedule of teniposide had hypertensive reactions in which their systolic blood pressure was greater than 200 mm Hg after the second dose of teniposide. Hypertension combined with myelosuppression resulted in the patient's death in one case. Although the exact mechanism of this unusual toxicity of teniposide remains unknown, it might be an age-specific problem, considering the very young age of our patients. Meticulous monitoring of vital signs, including blood pressure, is mandatory in leukemic infants receiving teniposide.

Therapeutic modalities for central nervous system involvement by granulocytic sarcoma (chloroma) in children with acute nonlymphocytic leukemia.

Four cases of central nervous system involvement by granulocytic sarcoma (three intracranial and one paraspinal) in children with acute nonlymphocytic leukemia (FAB M1 or M2 subtype) are presented, and therapeutic modalities are discussed. All tumors were noted at initial presentation with diagnosis being made on clinical and radiological findings without biopsy. All patients had karyotypic abnormalities: three had translocation of chromosomes 8 and 21, and one had an unspecified hypodiploid clone. The three patients who developed intracranial tumors responded well to triple agent (cytosine arabinoside, hydrocortisone, and methotrexate) intrathecal chemotherapy and systemic chemotherapy, with or without local irradiation, as evidenced by rapid disappearance of the tumors. Two children are disease-free after 17 and 57 months. One patient with paraspinal tumor failed to achieve a systemic remission but had no evidence of granulocytic sarcoma at autopsy. Thus, the prognosis of CNS granulocytic sarcoma is not uniformly gloomy if treated aggressively by combined modalities. The value of surgical intervention in terms of primary management, however, is limited.

Spontaneous cure of end-stage acute nonlymphocytic leukemia complicated with chloroma (granulocytic sarcoma).

Spontaneous regression of end-stage acute nonlymphocytic leukemia (ANLL) complicated with chloroma (granulocytic sarcoma) was observed in a child after the patient had been sent home for terminal care. The patient was initially found to have the 8;21 translocation and has survived without any evidence of disease 101 months after the initial diagnosis and 80 months after the discontinuation of all therapy. Spontaneous regression of a wide variety of tumors has been reported, but this observed case has no features in common with those cases. Special implications of this case are discussed.

Acute lymphoblastic leukemia followed by acute granulocytic leukemia in a pediatric patient.

A 14-year-old white male patient had acute lymphoblastic leukemia characterized by a periodic acid-Schiff (PAS)-positive reaction, negative T and B cell markers, and negative nonspecific esterase and peroxidase reactions. Ten months after the initial diagnosis, the bone marrow appearance was compatible with acute granulocytic leukemia, with the presence of Auer rods, and with peroxidase-positive, nonspecific esterase-negative, and negative PAS reactions. Karyotyping and banding were not performed. The concurrence of both diseases in this patient is unique in pediatric oncology.

Acinar cell carcinoma of the pancreas in a 9-year-old child: case report with electron microscopic observations.

A case of acinar cell carcinoma of the pancreas in a 9-year-old boy is presented, in which the diagnosis was established by electron microscopy. Treatment was by combination chemotherapy and the survival time was two years.

Early detection of chemotherapy-related pancreatic enlargement in children using abdominal sonography: a preliminary report.

At least two chemotherapeutic agents, prednisone and L-asparaginase, have been demonstrated to produce pancreatic injury. Early diagnosis of pancreatitis is frequently not possible, as symptoms are vague, physical findings may be minimal, and laboratory studies are frequently inconclusive until the injury is severe. Abdominal echography, as a monitor of pancreatic size, has proven to be helpful in the diagnosis of subclinical and early pancreatic injury of 14 of 19 selected children receiving prednisone and/or L-asparaginase therapy for acute leukemia or non-Hodgkin's lymphoma at the M.D. Anderson Hospital and Tumor Institute. Employment of this new diagnostic method permits prompt withdrawal of the causative agent(s), thus preventing further insult.