Laurel J. Steinherz

Transfusion-Associated Acute Chagas Disease Acquired in the United States

Excerpt Although a significant problem in Latin America (1), the transmission ofTrypanosoma cruziinfection by transfusion has not been unequivocally documented in the United States. We report a cas...

Improved disease-free survival of children with acute lymphoblastic leukemia at high risk for early relapse with the New York regimen--a new intensive therapy protocol: a report from the Childrens Cancer Study Group.

An intensive multimodal therapy was developed for the treatment of a subpopulation of children with acute lymphoblastic leukemia (ALL) who had a predicted event-free survival of less than 40% on previously reported therapeutic regimens (at high risk for early relapse). Induction with multiagent chemotherapy and radiotherapy to bulky disease-bearing areas (peripheral lymph nodes and mediastinum) was followed by consolidation, CNS prophylaxis, and cyclical remission maintenance therapy. Ninety-six (96%) of 100 previously untreated patients, 1 to 17 years of age, attained a complete remission. Seven patients received other maintenance therapy or a bone marrow transplant in remission. Sixty-six of the remaining 89 (74%) are in continuous complete remission at 22+ to 72+ months (median, 44+ months). Marrow relapse occurred in 15 (17%), CNS relapse in 5 (6%), and testicular relapse in one. Sixty-six of the 93 evaluable patients (71%) (including the induction failures) are event-free survivors. Two patients died of infection during the induction phase. No patient died during consolidation or maintenance without recurrent disease. The patients spent a median of 19, 0, and 0 days hospitalized during induction, consolidation, and maintenance, respectively. The most common complications were bacteremia and mucositis during induction and mucositis and fever during periods of neutropenia in consolidation. Maintenance was well tolerated. We conclude that the treatment protocol is intensive, but the inherent toxicities are manageable with adequate supportive care. The life table--projected event-free survival of 69% +/- 5% 48 months from diagnosis is encouraging.

Long-term follow-up of short intensive multiagent chemotherapy without high-dose methotrexate (‘Orange’) in children with advanced non-lymphoblastic non-Hodgkin's lymphoma: a Children's Cancer Group Report

Despite prolonged therapy (18 months), children with advanced non-lymphoblastic, non-Hodgkins lymphoma (NHL) treated on previous Childrens Cancer Group (CCG) trials achieved less than a 60% 5-year event-free survival (EFS). In this study we piloted a shorter but more intensive protocol (‘Orange’) to determine the feasibility, safety, and efficacy of this alternative treatment approach. Thirty-nine children received a CHOP-based induction, etoposide/ifosfamide consolidation, DECAL (dexamethasone, etoposide, cisplatin, cytosine arabinoside (Ara-C) and L-asparaginase) intensification, and either one or two similar but less intense maintenance courses. Patients were stratified to standard-risk (5 months) vs high-risk (7 months) treatment. High risk was defined as either bone marrow disease, CNS disease, mediastinal mass ⩾ one-third thoracic diameter at T5 and/or LDH ⩾2 times institutional upper limits of normal. All other patients were considered to be standard risk. Results were compared with the previous CCG NHL study (CCG-503). Sixteen and 23 patients were considered standard- vs high-risk, respectively. The 5-year EFS and overall survival (OS) were 77 ± 7% and 80 ± 7%, respectively. The 5-year EFS and OS were significantly better in the standard- vshigh-risk subgroups (100% vs 61 ± 11%) (P < 0.003) and (100% vs 65 ± 11%) (P < 0.01), respectively. Lactate dehydrogenase (LDH) ⩾2 × normal (NL) was associated with significantly poorer outcomes (LDH ⩾2 × NL vs <2 × NL) (5-year EFS: 55 ± 12% vs 100%) (P < 0.0004). This CCG hybrid regimen, ‘Orange’, of short and more intensive therapy resulted in a significant improvement in outcomes compared with the previous CCG trial of more prolonged but less intense therapy. This regimen that deletes high-dose methotrexate, if confirmed in a larger trial, could be considered as an alternative treatment approach in children without high tumor burdens (LDH <2 × NL) and Murphy stage III disease.

Human Granulocyte Colony-Stimulating Factor in Children With High-Risk Acute Lymphoblastic Leukemia: A Children’s Cancer Group Study

PURPOSE To investigate the effect of granulocyte colony-stimulating factor (G-CSF) on hematopoietic toxicities, supportive care requirements, time to complete intensive therapy, and event-free survival (EFS) and overall survival (OS) in children with high-risk acute lymphoblastic leukemia (HR-ALL). PATIENTS AND METHODS A total of 287 children with HR-ALL were randomly assigned to intensive chemotherapy regimens (New York I [NY I] or NY II) as part of the Childrens Cancer Group (CCG)-1901 protocol. The induction phases consisted of five drugs (vincristine, prednisone, l-asparaginase, daunorubicin, and cyclophosphamide). Initial consolidation comprised six-agent chemotherapy combined with 18 Gy of total-brain irradiation. Patients were randomly assigned to receive G-CSF (5 microg/kg/day) during either induction or initial consolidation. A crossover study analysis was done on the 259 patients who completed both phases of therapy. RESULTS The mean time to neutrophil recovery (>/= 0.5 x 109/L) was reduced with G-CSF (16.7 v 19.1 days, P =.0003); however, patients who received G-CSF did not have significantly reduced episodes of febrile neutropenia (149 v 164, P =.41), positive blood cultures (57 v 61, P =.66), or serious infections (75 v 79, P =.62). Hospitalization (14.0 v 13.9 days, P =.87) and induction therapy completion times (NY I, 30.3 v 31.3 days, P =.11; NY II, 33.4 v 32.3 days, P =.40) were not significantly altered. There were no differences in 6-year EFS (P =.24) or OS (P =.54) between patients receiving or not receiving G-CSF on CCG-1901, NY I and NY II. CONCLUSION Children with high-risk ALL do not appear to benefit from prophylactic G-CSF.

A prospective randomized double-blind trial of bolus urokinase in the treatment of established Hickman catheter sepsis in children

BACKGROUND The incidence of Hickman catheter sepsis is 10% to 40%, with resultant catheter loss in one third of infections. Urokinase causes dissolution of colonized intracatheter fibrin thrombi and may improve salvage. STUDY AIMS To evaluate the efficacy of 12-hour-interval slow-push urokinase infusion in addition to standard antibiotic therapy in the treatment of catheter sepsis in a pediatric oncology population. METHODS A two-arm randomized double-blind trial was undertaken, with catheter salvage rate as the end point. Patients with Hickman catheter sepsis were randomized after culture data confirmed the diagnosis. The study drug was administered by a slow intravenous push and given at 12-hour intervals for a total of four doses. The catheters were aspirated after 1 hour. RESULTS AND CONCLUSIONS The trial was stopped after 41 patients were entered into the study; 18 patients received a placebo, and 23 received the urokinase. In the placebo group, six catheters were lost; in the urokinase group, eight were lost. The rate of bacterial clearance was equivalent for both. After administration of the study drug, each group had three episodes of fever and chills; two of these resulted in hypotension (one in each group). The authors conclude that slow-push urokinase infusion during established Hickman catheter sepsis does not result in improved catheter salvage or bacterial clearance. Slow intravenous push infusions in this setting may provoke hemodynamic instability even after initiation of antibiotics.

Comparison of idarubicin to daunomycin in a randomized multidrug treatment of childhood acute lymphoblastic leukemia at first bone marrow relapse: A report from the Children's Cancer Group

The outcome of children with acute lymphoblastic leukemia (ALL) and bone marrow relapse has been unsatisfactory largely because of failure to prevent subsequent leukemia relapses. Ninety-six patients were enrolled and received vincristine, prednisone, L-asparaginase, and an anthracycline as reinduction therapy. Ninety-two patients were randomized to receive either daunomycin (DNR) or idarubicin (IDR). After achievement of second complete remission (CR2), maintenance chemotherapy included the same anthracycline, IDR or DNR, high-dose cytarabine, and escalating-dose methotrexate. Compared to DNR (45 mg/m2/week x 3), IDR (12.5 mg/m2/week x 3) was associated with prolonged myelosuppression and more frequent serious infections. Halfway through the study, the dose of IDR was reduced to 10 mg/m2. Overall, second remission was achieved in 71% of patients. Reinduction rate was similar for IDR and DNR. Reasons for induction failure differed; none of 15, 1 of 5, and 5 of 7 reinduction failures were due to infection for DNR, IDR (10 mg/m2), and IDR (12.5 mg/m2), respectively. Two-year event-free survival (EFS) was better among patients who received IDR (12.5 mg/m2) (27 +/- 18%) compared to DNR (10 +/- 8%, P = 0.05) and IDR (10 mg/m2) (6 +/- 12%, P = 0.02). However, after 3 years of follow-up, late events in the high-dose IDR group result in a similar EFS to the lower-dose IDR and DNR groups. In conclusion, IDR is an effective agent in childhood ALL. When used weekly at 12.5 mg/m2 during induction, the EFS outcome during the first 2 years of treatment appears better than lower-dose IDR or DNR (45 mg/m2), although this difference was not sustained at longer periods of follow-up. Increased hematopoietic toxicity seen at this dose might be reduced through the use of supportive measures, such as hematopoietins and intestinal decontamination.

Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma: A Report From the Children's Oncology Group.

Although chemotherapy has improved outcome of osteosarcoma, 30–40% of patients succumb to this disease. Survivors experience substantial morbidity and mortality from anthracycline‐induced cardiotoxicity. We hypothesized that the cardioprotectant dexrazoxane would (i) support escalation of the cumulative doxorubicin dose (600 mg/m2) and (ii) not interfere with the cytotoxicity of chemotherapy measured by necrosis grading in comparison to historical control data.

Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma

Although chemotherapy has improved outcome of osteosarcoma, 30–40% of patients succumb to this disease. Survivors experience substantial morbidity and mortality from anthracycline‐induced cardiotoxicity. We hypothesized that the cardioprotectant dexrazoxane would (i) support escalation of the cumulative doxorubicin dose (600 mg/m2) and (ii) not interfere with the cytotoxicity of chemotherapy measured by necrosis grading in comparison to historical control data.

Pythium insidiosum Pleuropericarditis Complicating Pneumonia in a Child with Leukemia

We describe a 12-year-old boy with acute myeloid leukemia who developed pleuropericarditis while he was neutropenic and was receiving intravenously administered antibiotic and antifungal therapy for pneumonia. A KOH preparation of the purulent material from an extensive diagnostic and therapeutic pleuropericardial drainage procedure revealed multiple irregularly septate hyphae, and cultures yielded the organism Pythium insidiosum. After completing a 12-month course of intravenously administered liposomal amphotericin B (AmBisome; Fujisawa Healthcare) and itraconazole, the patient remained alive, in clinical remission, and symptom free.

Cardiac tamponade in the pediatric oncology population: Treatment by percutaneous catheter drainage

PURPOSE The treatment of pericardial effusion resulting in cardiac tamponade has undergone an evolution in recent years, with the use of less invasive drainage methods in selected cases. To determine optimal therapy for pediatric oncology patients with pericardial effusion and tamponade, the authors reviewed their institutional experience with percutaneous catheter drainage. METHODS Patient records and operative reports were reviewed, and nine patients were identified who met clinical and echocardiographic criteria of cardiac tamponade and were treated with percutaneous pericardial catheter drainage. RESULTS The median age at time of diagnosis was 14 years (range, 5 months to 19 years), and the male:female ratio was 7:3. Underlying malignancies included acute myeloblastic leukemia in three, acute lymphoblastic leukemia in one, and Hodgkins disease, B-cell lymphoma, medulloblastoma, desmoplastic small round cell tumor, and rhabdomyosarcoma in one each. EIght patients (89%) were receiving granulocyte colony-stimulating factor (GCSF) during the period when tamponade developed. All patients had a large or moderate-to-large pericardial effusion and right ventricular collapse with hemodynamic compromise on echocardiography, and two patients (22%) also had pericardial thickening. In nine patients, percutaneous catheter drainage was performed intraoperatively and under fluoroscopic or echocardiographic guidance. A median of 300 mL (range, 82 to 500 mL) of fluid was removed from the pericardial sac during the initial drainage, and cytology was positive in one (6%). Complete echocardiographic resolution was observed in eight patients (89%); a small posterior component persisted in one patient but was not significant hemodynamically. The catheters remained in place for a median of 5 days (range, 1 to 35 days) while repeat aspirations were performed. Tamponade resolved in all patients, and one died of overwhelming systemic sepsis. The survival period was 10 to 22 months, and tamponade or the drainage procedure did not contribute to death. Four patients remain alive after 4 month to 7 years of follow-up. CONCLUSION Cardiac tamponade was effectively treated in all patients and did not recur with percutaneous catheter drainage alone. THere was no evidence of pericardial loculation or infection despite pancytopenia being prevalent with underlying illness and chemotherapy. Percutaneous catheter drainage is an effective treatment for pediatric oncology patients with pericardial tamponade. Because of its simplicity in comparison to move invasive techniques, initial treatment with percutaneous drainage should be considered in this patient population.