Intravenous busulfan in pretransplant chemotherapy: bioavailability and patient benefit.
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Administration, Oral↗
Biomedical subjects
John R Wingard
Publications and source records attributed to John R Wingard.
Cytomegalovirus in hematopoietic stem cell transplant recipients: Current status, known challenges, and future strategies.
Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after hematopoietic stem cell transplantation. Significant progress has been made in the prevention of CMV disease over the past decade, but prevention of late CMV disease continues to be a challenge in selected high-risk populations. The pretransplantation CMV serostatus of the donor and/or recipient remains an important risk factor for posttransplantation outcome despite the use of antiviral prophylaxis and preemptive therapy; CMV-seropositive recipients of T cell-depleted grafts in particular continue to have a survival disadvantage compared with seronegative recipients with seronegative donors. The risk of developing antiviral drug resistance remains low in most patients; however, in a setting of intense immunosuppression (eg, after transplantation from a haploidentical donor), the incidence may be as high as 8%. Primary CMV infection via blood transfusion can be reduced by the provision of seronegative or leukocyte-depleted blood products; however, a small risk of 1% to 2% of CMV disease remains. Surveillance and preemptive therapy are effective in preventing the sequelae of transfusion-related CMV infection. Indirect immunomodulatory effects of CMV are increasingly recognized in hematopoietic stem cell transplant recipients. Strategies currently being investigated include long-term suppression of CMV with valganciclovir for the prevention of late CMV infection and disease, adoptive transfer of CMV-specific T cells, and donor and recipient vaccination strategies.
Acyclovir↗
The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of multiple myeloma: an evidence-based review.
Evidence supporting the role of hematopoietic stem cell transplantation (SCT) in the therapy of multiple myeloma (MM) is presented and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published medical literature and for grading the quality of the evidence, the strength of the evidence, and the strength of the treatment recommendations. Treatment recommendations based on the evidence presented in the review were made unanimously by a panel of MM experts. Recommendations for SCT as an effective therapy for MM include the following: SCT is preferred to standard chemotherapy as de novo therapy; SCT is preferred as de novo rather than salvage therapy; autologous peripheral blood stem cell transplantation (PBSCT) is preferred to bone marrow transplantation (BMT); and melphalan is preferred to melphalan plus total body irradiation as the conditioning regimen for autologous SCT. Recommendations that SCT is not effective include the following: current purging techniques of bone marrow. Recommendations of equivalence include the following: PBSCT using CD34+ selected or unselected stem cells. No recommendation is made for indications or transplantation techniques that have not been adequately studied, including the following: SCT versus standard chemotherapy as salvage therapy, tandem autologous SCT, autologous or allogeneic SCT as a high-dose sequential regimen, allogeneic BMT versus PBSCT, a preferred allogeneic myeloablative or non-myeloablative conditioning regimen, and maintenance therapy post-autologous SCT with interferon alpha post-SCT. The priority area of needed future research is maintenance therapy posttransplantation with nothing versus interferon alpha versus other agents such as corticosteroids or thalidomide or its derivatives.
Antineoplastic Agents↗
A phase III, randomized, double-blind, placebo-controlled, multinational trial of iseganan for the prevention of oral mucositis in patients receiving stomatotoxic chemotherapy (PROMPT-CT trial).
Microfloral invasion and colonization of oral cavity mucosal tissues contribute to the pathophysiology of ulcerative oral mucositis (UOM). Iseganan is an analog of Protegrin-1, a naturally occurring peptide with broad-spectrum microbicidal activity. A randomized, double-blind, placebo-controlled study was conducted to evaluate iseganan in preventing UOM after stomatotoxic therapy. Patients received an oral rinse of iseganan 9 mg or placebo, swished/swallowed 6 times daily, starting with stomatotoxic therapy and continuing for 21-28 days. One hundred sixty three and 160 patients, respectively, were randomized to receive iseganan or placebo. One hundred and two patients (32%) were affected by a drug dispensing error, caused by a flawed computerized allocation system. Among all 323 patients, analyzed according to randomization assignment, 43% and 33% of iseganan and placebo patients, respectively, did not develop UOM (P = 0.067). On an 11-point scale, iseganan patients experienced less mouth pain (3.0 and 3.8 (P = 0.041), throat pain (3.8 and 4.6 (P = 0.048)), and difficulty swallowing (3.9 and 4.7 (P = 0.074)), compared to placebo patients. On the 5-point NCI CTC scale, iseganan patients experienced lower stomatitis scores (1.6 and 2.0 (P = 0.0131). Iseganan was well tolerated; no systemic absorption was detected. Iseganan is safe and may be effective in reducing UOM and its clinical sequelae.
Adolescent↗
Transplanted human cord blood cells give rise to hepatocytes in engrafted mice.
Recent studies suggest that rodent hepatocytes may be derived from hematopoietic stem cells. In the current study, the potential hematopoietic origin of hepatocytes was addressed using xenogeneic transplantation of human cord blood cells. CD34(+) or CD45(+) human cord blood cells were transplanted into "conditioned" newborn NOD/SCID/beta2-microglobulin(null) mice. At 4 to 5 months post-transplantation, livers of the recipient mice were cryosectioned and examined for evidence of human hepatocyte engraftment using RT-PCR to detect human albumin mRNA, immunohistochemistry to detect human hepatocytic proteins, and fluorescence in situ hybridization (FISH) to detect the presence of human centromeric DNA. Analysis of the bone marrow of transplanted mice revealed that 21.0-45.9% of the cells were human CD45(+) cells. FISH analysis of frozen sections of transplanted mouse liver revealed the presence of engrafted cells positive for human centromeric DNA. That engrafted human cells functioned as hepatocytes was indicated by the expression of human albumin mRNA, as judged by RT-PCR. FISH analysis with human and mouse centromeric DNA probes excluded spontaneous cell fusion as the cause for the generation of human hepatocytes. Human cord blood cells can give rise to hepatocytes in a xenogeneic transplantation model. This model will be useful to further characterize the cord blood progenitors of hepatocytes.
Animals↗
Typhlitis with concurrent appendicitis in a patient with chronic lymphocytic leukemia.
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Adult↗
Lipid formulations of amphotericins: are you a lumper or a splitter?
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Amphotericin B↗
Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis.
BACKGROUND: Voriconazole is a broad-spectrum triazole that is active against aspergillus species. We conducted a randomized trial to compare voriconazole with amphotericin B for primary therapy of invasive aspergillosis. METHODS: In this randomized, unblinded trial, patients received either intravenous voriconazole (two doses of 6 mg per kilogram of body weight on day 1, then 4 mg per kilogram twice daily for at least seven days) followed by 200 mg orally twice daily or intravenous amphotericin B deoxycholate (1 to 1.5 mg per kilogram per day). Other licensed antifungal treatments were allowed if the initial therapy failed or if the patient had an intolerance to the first drug used. A complete or partial response was considered to be a successful outcome. RESULTS: A total of 144 patients in the voriconazole group and 133 patients in the amphotericin B group with definite or probable aspergillosis received at least one dose of treatment. In most of the patients, the underlying condition was allogeneic hematopoietic-cell transplantation, acute leukemia, or other hematologic diseases. At week 12, there were successful outcomes in 52.8 percent of the patients in the voriconazole group (complete responses in 20.8 percent and partial responses in 31.9 percent) and 31.6 percent of those in the amphotericin B group (complete responses in 16.5 percent and partial responses in 15.0 percent; absolute difference, 21.2 percentage points; 95 percent confidence interval, 10.4 to 32.9). The survival rate at 12 weeks was 70.8 percent in the voriconazole group and 57.9 percent in the amphotericin B group (hazard ratio, 0.59; 95 percent confidence interval, 0.40 to 0.88). Voriconazole-treated patients had significantly fewer severe drug-related adverse events, but transient visual disturbances were common with voriconazole (occurring in 44.8 percent of patients). CONCLUSIONS: In patients with invasive aspergillosis, initial therapy with voriconazole led to better responses and improved survival and resulted in fewer severe side effects than the standard approach of initial therapy with amphotericin B.
Adolescent↗
A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis in immunocompromised patients.
We report a randomized, double-blind, multicenter trial in which amphotericin B colloidal dispersion (ABCD [Amphotec]; 6 mg/kg/day) was compared with amphotericin B (AmB; 1.0-1.5 mg/kg/day) for the treatment of invasive aspergillosis in 174 patients. For evaluable patients in the ABCD and AmB treatment groups, respective rates of therapeutic response (52% vs. 51%; P=1.0), mortality (36% vs. 45%; P=.4), and death due to fungal infection (32% vs. 26%; P=.7) were similar. Renal toxicity was lower (25% vs. 49%; P=.002) and the median time to onset of nephrotoxicity was longer (301 vs. 22 days; P<.001) in patients treated with ABCD. Rates of drug-related toxicity in patients receiving ABCD and AmB, respectively, were 53% versus 30% (chills), 27% versus 16% (fever), 1% versus 4% (hypoxia) and 22% versus 24% (toxicity requiring study drug discontinuation). ABCD appears to have equivalent efficacy and superior renal safety, compared with AmB, in the treatment of invasive aspergillosis. However, infusion-related chills and fever occurred more frequently in patients receiving ABCD than in those receiving AmB.
Adolescent↗
Antifungal chemoprophylaxis after blood and marrow transplantation.
Invasive fungal infections are common and deadly in recipients of blood and marrow transplants. Current diagnostic techniques do not allow accurate early diagnosis, especially of infection with mould pathogens, and delays in diagnosis are associated with treatment failure. This lack of early diagnosis has provided the impetus for the development of antifungal prophylaxis. Fluconazole prophylaxis is highly effective for the control of invasive yeast infections and associated with few breakthrough infections. The development of antimould prophylaxis in this patient population is a high priority.
Antifungal Agents↗
An assay for long-term engrafting human hematopoietic cells based on newborn NOD/SCID/beta2-microglobulin(null) mice.
OBJECTIVE: Of various types of xenograft assays, the use of NOD/SCID mice has been the most popular method for quantitating candidate human stem cells. Limitations of the assay include low levels of engraftment, except when large numbers of cells are injected, and the development of thymic lymphoma, which precluded observation of long-term engraftment. In order to establish an assay that allows long-term in vivo engraftment and higher engraftment levels by a reasonable number of human cells, we tested a model based on "conditioned newborn" NOD/SCID or NOD/SCID/beta2-microglobulin(null) (BMG(null)) mice. MATERIALS AND METHODS: Using human cord blood mononuclear cells, we tested various nonradiation conditioning regimens and cell injection routes. Conditioning with a combination of 5-fluorouracil (5FU) and anti-mouse c-kit blocking antibody (Ack-2) or a combination of busulfan (BU) and cyclophosphamide (CY) and the use of facial vein for the cell injection route yielded the highest levels of multilineage engraftment. RESULTS: At 4-5 months posttransplantation, the median of engraftment level in bone marrow with 5FU/Ack-2 and BU/CY regimens were 0.9% (range: 0.2-40.5%) and 2.1% (range: 0.3-2.4%) in NOD/SCID mice, and 11.3% (range: 0.7-38%) and 14.1% (range: 0.8-52%) in NOD/SCID/BMG(null) mice, respectively. Multilineage engraftment was demonstrated by flow cytometry and by the growth of multilineage colonies in methylcellulose culture. Secondary transplantation of the isolated human CD45(+) cells, also performed at 4-5 months posttransplantation, revealed engraftment at the levels of 1.5 +/- 0.42% at 2 months after secondary transplantation. CONCLUSION: Our assay may provide a quantitative method for analysis of human hematopoietic stem cells.
Animals↗
Racial and ethnic composition of volunteer cord blood donors: comparison with volunteer unrelated marrow donors.
BACKGROUND: Umbilical cord blood is an alternative peripheral blood progenitor cell source for patients who need transplantation. A presumed advantage of cord blood is the ability to increase minority recruitment. STUDY DESIGN AND METHODS: The racial composition of five member cord blood banks of the National Marrow Donor Program (NMDP) was compared, representing 9020 cord blood donors with NMDP marrow donors from comparable geographic areas, representing 417,676 donors. Cord blood and marrow donors self-reported racial designations on questionnaires. Donor statistics were compared with baseline racial data of deliveries from participating hospitals for cord blood donors and with geographic census data for marrow donors. RESULTS: The California, Florida, and Massachusetts cord blood banks recruited a lower percentage of minorities than the corresponding marrow donor centers. In New York and Colorado, minority recruitment was equivalent. In California, Florida, Massachusetts, and New York, the cord blood banks recruited a lower percentage of minorities than those delivering at the respective hospitals. The cord blood banks in California, Colorado, Florida, and Massachusetts recruited a lower percentage of minorities compared with delivery data than the corresponding marrow donor centers compared with census population (p < 0.001). In New York, the percentages were similar. CONCLUSION: The problem of insufficient minority recruitment of cord blood has not yet been solved. Better strategies are needed to recruit minority donors.
Adult↗
Conditioning therapy with intravenous busulfan and cyclophosphamide (IV BuCy2) for hematologic malignancies prior to allogeneic stem cell transplantation: a phase II study.
Busulfan (Bu) is commonly used as a component of conditioning regimens for hematopoietic stem cell transplantation. Precise delivery of the oral formulation is compromised by erratic gastrointestinal absorption. An IV Bu formulation was developed to provide dose assurance and complete bioavailability. In a phase I study, the plasma bioequivalence of IV Bu was established at approximately 80% of the oral dose. We now report the findings of the first phase II study, in which 61 adults with hematologic cancers were treated with a Bu-cyclophosphamide (BuCy) regimen consisting of IV Bu (0.8 mg/kg every 6 hours x 16) followed by Cy (60 mg/kg qd x 2) and transplantation of stem cells from an HLA-matched sibling donor. The median age of study participants was 37 years; 75% of patients had active disease; 48% were heavily pretreated, and 13% had undergone a prior transplantation. Median follow-up was 2.3 years; median time to engraftment (absolute neutrophil count, >0.5 x 10(9)/L) was 13 days; 100% of patients with cytogenetic and/or molecular markers had documented chimerism; and there were no engraftment failures. Two-year overall and disease-free survival were 67% and 42%, respectively. There were no unexpected toxic reactions. Fatal veno-occlusive disease occurred in 2 patients, 1 of whom had undergone a prior transplantation. Treatment-related mortality at 100 days was 9.8% (6/61). Bu pharmacokinetics after IV drug administration demonstrated high inter- and intrapatient consistency; 86% of patients maintained an area under the curve between 800 and 1500 microMol-min. In conclusion, the IV Bu in this regimen was very well tolerated and demonstrated excellent antitumor efficacy, most likely because of dose assurance with predictable pharmacokinetics.
Adult↗
A prospective randomized trial of prophylactic platelet transfusion and bleeding incidence in hematopoietic stem cell transplant recipients: 10,000/L versus 20,000/microL trigger.
An optimal platelet-count threshold for prophylactic platelet transfusion in hematopoietic stem cell transplant (HSCT) recipients has yet to be determined. Between July 1997 and December 1999, we performed the first prospective randomized clinical trial addressing this issue in 159 HSCT recipients who received a prophylactic platelet transfusion when the morning platelet count fell below a 10,000/microL (10K) or 20,000/microL (20K) threshold. Subsequent prophylactic transfusions were administered according to a predetermined algorithm. The number of prophylactic and therapeutic transfusions and the incidence of minor and major bleeding were compared between the 2 groups. The groups were matched according to patient and transplantation characteristics. There were no significant differences in bleeding incidence or severity. Fourteen percent of patients in the 10K arm compared to 17% in the 20K arm had major bleeding events. Only 3 central nervous system bleeds occurred, 2 in the 10K group and 1 in the 20K group. No deaths were attributed to bleeding. An average of 11.4 days of bleeding occurred in both groups. An average of 10.4 platelet transfusions per patient were administered in the 10K group compared to 10.2 in the 20K group (P = .94). More transfusions were given above the assigned transfusion threshold in the 10K group than in the 20K group (4.3/patient versus 1.9/patient, respectively, P = .05). Safety measures incorporated into our study may have precluded demonstration of significant differences in platelet use between the groups. In conclusion, a platelet transfusion trigger of 10K was found to be safe; however, a decrease in platelet use was not achieved because of safety measures incorporated into our study design.
Adolescent↗
Increased risk of lethal graft-versus-host disease-like syndrome after transplantation into NOD/SCID mice of human mobilized peripheral blood stem cells, as compared to bone marrow or cord blood.
We tested the ability of human cells from different hematopoietic tissues to generate graft versus host disease-like syndrome (GVHD) in sublethally irradiated non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. Tissue sources of human hematopoietic cells were: (1) bone marrow (BM), (2) nonmobilized peripheral blood (PB), (3) mobilized peripheral blood stem-progenitor cells (PBSC), and (4) cord blood (CB). To avoid interindividual donor variation, part of this study was done using BM, PB, and PBSC donated by a single healthy adult volunteer. A total of 179 NOD/SCID mice received graded human hematopoietic cell doses [5-500 x 10(6) mononuclear cells (MNC), containing 2-325 x 10(6) CD3(+) T cells, per mouse] from individual donors. Mice were observed for the development of GVHD and sacrificed 60 days after transplantation (earlier if ill). Mice were analyzed quantitatively by flow cytometry for human hematopoietic cell types and histologically, especially for human T lymphocytes infiltrating BM. No mouse transplanted with the tested doses of human CB or BM cells developed GVHD (experimentally defined as >10% human T lymphocytes infiltrating the mouse BM). For PB and PBSC, the frequencies of death, death with GVHD, and GVHD were directly related to the dose and source of human cells. Because PB cells contaminate harvested BM, the results from infused BM and PB were next combined for further analysis (BM/PB). The relative risks (hazard ratios estimated from the proportional hazards model) for death with GVHD, for each 10 human T cell dose increase, were 1.15 for BM/PB (p < 0.0001) and 1.47 for PBSC (p < 0.0001). In this in vivo xenogeneic model, the average T cell from human PBSC generated GVHD more potently than did the average T cell from human BM/PB, and the average CB T cell had a much lower GVHD potential. These results suggest that the potential for clinical GVHD from an HLA-disparate donor graft is likely to be quantitatively dependent both on the total number of T lymphocytes in the donor graft and the tissue source of the graft. Quantitative criteria for optimal T cell content of allogeneic donor hematopoietic grafts from different sources are discussed.
Animals↗
Prophylaxis, empirical therapy, or pre-emptive therapy of fungal infections in immunocompromised patients: which is better for whom?
Immunocompromised patients are at risk of developing fungal infections. Over time, the incidence of fungal infections and the spectrum of causative organisms have changed. In addition, treatment strategies in this high-risk population have also changed. Traditional approaches (using polyene-based therapy and older azoles), including empirical treatment strategies, have evolved to include prophylaxis in populations at the greatest risk. These strategies, although effective against Candida species, have not really impacted infections caused by Aspergillus spp. With the recent approval of antifungal agents with demonstrated activity against Aspergillus and other mould infections, there is hope for better outcomes in the treatment of established infections. Several agents, with activity against Aspergillus, have been shown to be effective in the empirical setting. The role of these new antifungal agents in the prophylactic setting remains unknown at present, but the potential for reducing Aspergillus infections is promising and requires ongoing study. The other area of significant research in fungal infections has been the search for accurate, non-invasive, rapid diagnostic tests. Over the past year, several publications have indicated that early diagnosis is possible in immunocompromised patients. These new diagnostics have paved the way for a new strategy, called pre-emptive therapy, enabling infected patients to be identified at an earlier stage of infection. This strategy will permit targeted antifungal therapy in those at greatest risk, and will avoid unnecessary, potentially toxic therapy in those not infected. Validations of the various techniques show promise and are reviewed in this paper.
Antifungal Agents↗
Stem cell transplantation: supportive care and long-term complications.
With increasing hematopoietic stem cell transplant (HSCT) activity and improvement in outcomes, there are many thousands of HSCT survivors currently being followed by non-transplant clinicians for their healthcare. Several types of late sequelae from HSCT have been noted, and awareness of these complications is important in minimizing late morbidity and mortality. Late effects can include toxicities from the treatment regimen, infections from immunodeficiency, endocrine disturbances, growth impairment, psychosocial adjustment disorders, second malignancies, and chronic graft-versus-host disease (GVHD). A variety of risk factors for these complications have been noted. The clinician should be alert to the potential for these health issues. Preventive and treatment strategies can minimize morbidity from these problems and optimize outcomes.
Follow-Up Studies↗
Clinical research: the best or worst of times?
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Adverse Drug Reaction Reporting Systems↗