Demetrios Petropoulos

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

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.

Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplants is the complex result of BK virus infection, preparative regimen intensity and donor type

Background Hemorrhagic cystitis is a common cause of morbidity after allogeneic stem cell transplantation, frequently associated with BK virus infection. We hypothesized that patients with positive BK viruria before unrelated or mismatched related donor allogeneic hematopoietic stem cell transplantation have a higher incidence of hemorrhagic cystitis. Design and Methods To test this hypothesis, we prospectively studied 209 patients (median age 49 years, range 19–71) with hematologic malignancies who received bone marrow (n=78), peripheral blood (n=108) or umbilical cord blood (n=23) allogeneic hematopoietic stem cell transplantation after myeloablative (n=110) or reduced intensity conditioning (n=99). Donors were unrelated (n=201) or haploidentical related (n=8). Results Twenty-five patients developed hemorrhagic cystitis. Pre-transplant BK viruria detected by quantitative PCR was positive in 96 patients. The one-year cumulative incidence of hemorrhagic cystitis was 16% in the PCR-positive group versus 9% in the PCR-negative group (P=0.1). The use of umbilical cord blood or a haploidentical donor was the only significant predictor of the incidence of hemorrhagic cystitis on univariate analysis. There was also a trend for a higher incidence after myeloablative conditioning. Multivariate analysis showed that patients who had a positive PCR pre-transplant and received haploidentical or cord blood grafts with myeloablative conditioning had a significantly higher risk of developing hemorrhagic cystitis (58%) than all other recipients (7%, P<0.001). Conclusions Hemorrhagic cystitis is the result of a complex interaction of donor type, preparative regimen intensity, and BK viruria.

Individualizing high-dose oral busulfan: Prospective dose adjustment in a pediatric population undergoing allogeneic stem cell transplantation for advanced hematologic malignancies

We investigated whether adjusting the oral busulfan (BU) dosage on the basis of early pharmacokinetic data to achieve a targeted drug exposure could reduce transplant-related complications in children with advanced hematologic malignancies. Twenty-five children received a preparative regimen consisting of thiotepa (250 mg/m2 i.v. daily for 3 days), BU (40 mg/m2 per dose p.o. every 6 h for 12 doses), and cyclophosphamide (60 mg/kg i.v. daily for 2 days) and then underwent allogeneic stem cell transplantation. Busulfan clearance and area under concentration time-curve (AUC) were determined after the first dose using a one-compartment pharmacokinetic (PK) model with first-order absorption. The initial PK analysis was successfully completed after the first BU dose in 21 patients (84%). A final AUC of 1000–1500 μm × min/dose was targeted and subsequent doses were modified as necessary to achieve this value. Fourteen of the 25 patients (56%) required dose adjustment. Follow-up PK analysis was completed in 21 patients and 16 of these achieved the targeted BU exposure for the course of therapy. Interpatient variability in BU clearance was high (up to five-fold). The most frequent regimen-related toxicities were cutaneous and gastrointestinal (stomatitis and diarrhea). Only one patient developed hepatic veno-occlusive disease. Our study demonstrates the feasibility of adjusting the oral BU dose in individual pediatric patients. Although toxicity associated with BU seemed to be reduced, this conclusion is tempered by the fact that the overall regimen-related toxicity (RRT) remains substantial and reflected the effects of all agents used in the preparative regimen. Bone Marrow Transplantation (2000) 26, 463–470.

Infections in 100 cord blood transplantations: Spectrum of early and late posttransplant infections in adult and pediatric patients 1996-2005

Cord blood-derived stem cells are successfully used in the treatment of cancer and congenital disorders in children. This alternative source of stem cells is also explored for adult cancer patients with limited donor options. However, delayed engraftment, prolonged neutropenia, secondary graft loss, and graft-versus-host disease (GVHD) in recipients of cord blood transplantation (CBT) make opportunistic infections a serious concern. We evaluated the spectrum of infections in adults and children undergoing CBT at our National Cancer Institute-designated comprehensive cancer center. The infection incidence rate ratio (total infection episodes/days at risk [survival after CBT] × 100) was 2.4 times higher in 35 adult patients than in 62 children, especially in adults with neutropenia (3 × higher) and GVHD (1.9 × higher). Ninety-two percent of fungal infection episodes occurred within 100 days after transplantation; half of these infections occurred in the first 30 days after CBT. Most bacterial infections (80%) were also diagnosed in the first 100 days, whereas late (>100 d) post-CBT cytomegalovirus and varicella zoster virus infections occurred only in children with chronic GVHD. Multivariate analysis showed that resolution of lymphocytopenia (≥1000 cells/μL) (hazard ratio [HR] 0.71; p < 0.0001) and successful engraftment (HR 0.20; p < 0.0001) were associated with a low risk of serious infection. Children (HR 0.36; p < 0.0002) with sustained engraftment (HR 0.39; p < 0.004) and those with cancer in remission (HR 0.47; p < 0.007) were less likely to die from infection. More effective measures for surveillance and prevention of late cytomegalovirus and varicella zoster virus infections in children with CBT and chronic GVHD are needed. Abbreviations: BCG = bacilli Calmette-Guèrin, CBT = cord blood transplantation, CMV = cytomegalovirus, GVHD = graft-versus-host disease, HHV = human herpesvirus, HLA = human lymphocyte antigen, HR = hazard ratio, VZV = varicella zoster virus.

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

Dapsone for Pneumocystis carinii prophylaxis in children undergoing bone marrow transplantation

1840. The median calculated charge for patients receiving oral antibiotics was

Tacrolimus for prevention of graft-versus-host disease after mismatched unrelated donor cord blood transplantation

1544 and was significantly less than the

High-dose sequential chemotherapy and autologous stem cell reinfusion in advanced pediatric solid tumors.

2039 median charge for outpatients treated with IV antibiotics. The estimated charge for comparable inpatient treatment was

Results of a 2-arm, phase 2 clinical trial using post-transplantation cyclophosphamide for the prevention of graft-versus-host disease in haploidentical donor and mismatched unrelated donor hematopoietic stem cell transplantation

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.

Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies

Children who undergo bone marrow transplantation (BMT) are at risk for Pneumocystis carinii pneu- monia (PCP). Prophylaxis using trimethoprim/sulfa- methoxazole (TMP/SMX) is highly effective but the incidence of adverse drug reactions is significant. We retrospectively reviewed 33 pediatric BMT (25 allogeneic and eight autologous) in whom dapsone was used for PCP prophylaxis because patients were unable to receive TMP/SMX. Dapsone was administered at 50 mg/m2 p.o. once a week from engraftment to 180 days post-autologous BMT, and to 1 year or throughout the duration of immunosuppressive treatment post-allogeneic BMT. With a total of 7268 patient days of dapsone prophylaxis and a median follow-up of 353 days post-BMT, no proven PCP was diagnosed. Sixteen cases of chest radiograph abnormalities were noted in this patient population but none was attributed to PCP. Dapsone was well tolerated by all children with no serious adverse effects; however, one patient developed Toxoplasma gondii encephalitis during dapsone prophylaxis. Dapsone warrants further evaluation as an alternative for PCP prophylaxis in pediatric BMT patients intolerant of TMP/SMX. Additional prophylaxis should be considered for patients at high risk for T. gondii encephalitis.