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Biomedical subjects

A A Fauser

Publications and source records attributed to A A Fauser.

At least 55 records · Page 3Linked to original sources
PubMed2000

Retroviral transduction of T lymphocytes for suicide gene therapy in allogeneic stem cell transplantation.

Transplantation of suicide gene modified allogeneic T lymphocytes is an approach to prevent T cell mediated GVHD while preserving the 'graft-versus-leukemia' (GVL) effect of an allograft. A prerequisite for such a therapy is the efficient transduction of T cells with suitable vectors. Since existing techniques allow only insufficient transduction of T cells, the development of more efficient gene transfer protocols into these cells is of great importance. We present here a protocol for the highly efficient transduction of human primary T cells at high densities (1 x 10(6) cells/ml) by retroviral infection. The presented protocol allowed us to obtain transduction rates of more than 70% of CD3+ cells after two cycles of infection. It is based on the use of FBS-free media for both the production of retrovirus-containing supernatant, as well as the cultivation of the primary T cells. Since the protocol presented here works just as efficiently under large scale conditions, it may easily be adapted to clinical needs and 'good manufacturing practice' (GMP) standards.

Fibronectins↗
PubMed2000

Clinical scale production of an improved retroviral vector expressing the human multidrug resistance 1 gene (MDR1).

Retroviral vectors are currently the most important and best characterized tools for ex vivo genetic modification of hematopoietic progenitor/stem cells. As a prerequisite for clinical applications, large volumes of high-titer vector supernatants have to be generated in compliance with 'GMP' guidelines. This goal can be reached using a carefully selected producer cell clone and a conventional large-scale cell culture system. The retroviral vector SF1m provides efficient expression of the human multidrug resistance 1 (MDR1) gene in hematopoietic progenitor/stem cells in vitro and in NOD/SCID mouse repopulating human cells in vivo. Currently, a clinical phase I/II study is in preparation to test whether intensified consolidation chemotherapy is enabled by autologous transplantation of peripheral blood progenitor/stem cells that have been genetically modified with SF1m. Using multi-tray cell factories >19 l of serum-free vector containing supernatant were generated from cells of a previously established SF1m-producer clone, based on the PG13 packaging cell line. Testing of the final samples revealed sufficient quality (>1.5 x 10(6) infectious particles/ml) for clinical scale transduction of CD34+ cells. Results from the production runs and the applied biosafety concept are described.

Animals↗
PubMed2000

Review of comparative studies between conventional and liposomal amphotericin B (Ambisome) in neutropenic patients with fever of unknown origin and patients with systemic mycosis.

Fungal infections are an important cause of morbidity and mortality in immunocompromised patients. Treatment with amphotericin B is the main therapeutic approach. However, this treatment is limited by the substantial toxicity. We present the data of the first randomized prospective comparative trial in adults (134 patients with fever of unknown origin) with conventional amphotericin B and a liposomal formulation of amphotericin B (AmBisome, published in 1997 by Prentice et al. (Br. J. Haematol. 98, 711-718) and the data of adults with documented fungal infections (59 patients), treated in this trial. Patients received either conventional amphotericin B 1 mg kg-1 per day, liposomal amphotericin B 1 mg kg-1 per day or liposomal amphotericin B 3 mg kg-1 per day. Patients were entered if they had fever of unknown origin (FUO), defined as temperature of 38 degrees C or more, not responding to 96 h of systemic broad-spectrum antibiotic treatment, and neutropenia (< 0.5 x 10(9) l-1). Efficacy of treatment was assessed, with success defined as resolution of fever for three consecutive days (< 38 degrees C) in the group of patients with FUO and the freedom of clinical signs and/or the elimination of fungus in the group of patients with documented fungal infections. The safety of treatment and renal and hepatic toxicity of liposomal and conventional amphotericin B were compared. No statistically significant difference was found in the treatment efficacy in the three study arms. However, there is a tendency of better treatment results in the two groups of patients, who received liposomal amphotericin B. Thirty-five per cent of patients with documented fungal infections and 46% of patients with FUO responded to amphotericin B. In the patients group, that received 1 mg kg-1 liposomal amphotericin B it was 63 and 49%, in the group of patients that received 3 mg kg-1 liposomal amphotericin B it was 47 and 64%. Evidence of toxicity due to amphotericin B was seen in 50 patients (83%), toxicity due to liposomal amphotericin B, 1 mg kg-1, was seen in 35 patients (50%), and due to liposomal amphotericin B 3 mg kg-1 in 34 patients (54%). This was a statistically significant difference (P = 0.001). It was concluded that liposomal amphotericin B was safer than conventional amphotericin B, but both formulations are equivalent in treatment efficacy. The prophylactic use of amphotericin B in these immunocompromised patients is discussed.

Adult↗
PubMed1999

Interferon-alpha before allogeneic bone marrow transplantation in chronic myelogenous leukemia does not affect outcome adversely, provided it is discontinued at least 90 days before the procedure.

The influence of interferon-alpha (IFN) pretreatment on the outcome after allogeneic bone marrow transplantation (BMT) in chronic myelogenous leukemia (CML) is controversial. One goal of the German randomized CML Studies I and II, which compare IFN +/- chemotherapy versus chemotherapy alone, was the analysis of whether treatment with IFN as compared to chemotherapy had an influence on the outcome after BMT. One hundred ninety-seven (23%) of 856 Ph/bcr-abl-positive CML patients were transplanted. One hundred fifty-two patients transplanted in first chronic phase were analyzed: 86 had received IFN, 46 hydroxyurea, and 20 busulfan. Forty-eight patients (32%) had received transplants from unrelated donors. Median observation time after BMT was 4.7 (0.7 to 13.5) years. IFN and chemotherapy cohorts were compared with regard to transplantation risks, duration of treatments, interval from discontinuation of pretransplant treatment to BMT, conditioning therapy, graft-versus-host disease prophylaxis and risk profiles at diagnosis and transplantation, and IFN cohorts also with regard to performance and resistance to IFN. Outcome of patients receiving related or unrelated transplants pretreated with IFN, hydroxyurea, or busulfan was not significantly different. Five-year survival after transplantation was 58% for all patients (57% for IFN, 60% for hydroxyurea and busulfan patients). The outcome within the IFN group was not different by duration of prior IFN therapy more or less than 5 months, 1 year, or 2 years. In contrast, a different impact was observed in IFN-pretreated patients depending on the time of discontinuation of IFN before transplantation. Five-year survival was 46% for the 50 patients who received IFN within the last 90 days before BMT and 71% for the 36 patients who did not (P =.0057). Total IFN dosage had no impact on survival after BMT. We conclude that outcome after BMT is not compromised by pretreatment with IFN if it is discontinued at least 3 months before transplantation. Clear candidates for early transplantation should not be pretreated with IFN.

Adolescent↗
PubMed1999

Peripheral blood stem cell transplantation from unrelated donors: a comparison with marrow transplantation.

Peripheral blood stem cell (PBSC) transplants from HLA-A, -B, and -DR compatible unrelated donors (n = 45) were compared with bone marrow (BM; BM group, n = 45). Eighteen patients received CD34-selected PBSC (CD34 group). The PBSCs contained more mononuclear cells, CD34(+), CD3(+), and CD56(+) cells compared with marrow (P <.001). Engraftment was achieved in all 45 patients in the BM group, in 43 of 45 (95%) in the PBSC group, and in 14 of 18 (78%) in the CD34 group (P <.01). In multivariate analysis, a short time to absolute neutrophil count (ANC) equal to 0.5 x 10(9)/L was associated with the PBSC/CD34 groups (P <.001) and granulocyte colony-stimulating factor (G-CSF) treatment (P =.017). A short time to platelets equal to 50 x 10(9)/L was associated with PBSC (P =. 003) and no methotrexate (P =.015). Grades II-IV acute graft-versus-host disease (GVHD) was 20% in the BM controls, 30% in the PBSC group, and 18% in the CD34 group (not significant [NS]). The probability of chronic GVHD was 85% in the BM group, 59% in the PBSC group, and 0% in the CD34 group (P <.01). One-year transplant-related mortality was 21% and 27% and survival was 53% and 54% in the BM and PBSC groups, respectively (NS). The 2-year relapse-free survival was 41% and 46% in the two groups, respectively.

Adult↗
PubMed1999

Guidelines for anti-emetic therapy: acute emesis.

Anti-emetic therapy has become integral to the management of patients with cancer. Goals related to complete emesis control include providing treatment that reduces hospitalisation and time in the ambulatory setting, care that is convenient for the patient and therapy that enhances patients' quality of life. A panel of clinical, health economic and basic scientists with expertise in various oncology disciplines reviewed published literature to develop evidence-based consensus guidelines for the prevention and treatment of chemotherapy-induced emesis. Currently, serotonin receptor antagonists and corticosteroids are the two categories of anti-emetics that are most effective, have the fewest side-effects and are convenient to use. These agents are recommended in combination for highly emetogenic chemotherapy regimens and as single agents or in combination for moderately to highly emetogenic chemotherapy. When possible, these agents may be given orally in single doses; current evidence does not support dose escalation for either category of anti-emetics. In special situations, such as the use of high-dose chemotherapy combination regimens, the most emetogenic component of the regimen should dictate the choice of anti-emetic. Appropriate anti-emetic use described in these guidelines represents both good medical practice and a sensible economic approach to care.

Acute Disease↗
PubMed1999

A second unrelated bone marrow transplant: successful quantitative monitoring of mixed chimerism using a highly discriminative PCR-STR system.

A second bone marrow transplant (BMT) might be considered as an option in patients with leukaemia with graft failure after BMT. We report the successful treatment of a patient with graft failure by a second stem cell transplant from another unrelated donor. We evaluated the usefulness of an unrelated donor as the source of the second BMT in this clinical setting. In addition to this, a penta PCR-STR system was tested and shown to be sensitive for monitoring of marrow engraftment. The conditioning regimen for the first transplantation consisted of busulfan and cyclophosphamide while anti-thymocyte globulin and CY were used for the second BMT. The patient successfully engrafted at day +11 after second BMT.

Adult↗
PubMed1999

An open, randomized, multicentre study comparing the use of low-dose ceftazidime or cefotaxime, both in combination with netilmicin, in febrile neutropenic patients. German Multicentre Study Group.

To reduce drug acquisition costs, the clinical and bacteriological efficacy of low-dose ceftazidime i.v. (1 g tid) was compared with cefotaxime i.v. (2 g tid). Both regimens were combined with netilmicin i.v. (2 mg/kg bodyweight tid), in an open, randomized, multicentre trial in febrile neutropenic patients. The addition of antibiotics for gram-positive coverage was part of the protocol; alteration in the antibiotics for gram-negative cover or premature discontinuation of the study antibiotics were judged as failure. One hundred and eighty six patients were randomized by nine German centres, the patients matched for age, underlying diseases and duration of neutropenia (median duration 14 days) in both treatment arms. Infections were documented microbiologically in 29% of the patients, clinically in 16% and suspected (fever of unknown origin) in 102/186 patients (55%). The 82 pathogens isolated were predominantly gram-positive bacteria. In an intent-to-treat analysis, the overall response rate without modification at the final evaluation was 58% in the ceftazidime group and 34% in the cefotaxime group (P < 0.01). The success rates with modification were 84% and 64%, respectively. The failure rate in a highly immunosuppressed subgroup of the patients (bone marrow transplant recipients) was higher for cefotaxime (53%) than for the ceftazidime arm (14%) (P < 0.001). Response rates were significantly higher in the ceftazidime group for patients with microbiologically documented and possible infections. No major bacterial superinfections occurred in the low-dose treatment arm. The tolerability was good for both regimens. Low-dose ceftazidime combined with netilmicin proved to be superior to recommended doses of cefotaxime/netilmicin in febrile neutropenic patients.

Adolescent↗
PubMed1998

High efficiency gene transfer to human hematopoietic SCID-repopulating cells under serum-free conditions.

Stable gene transfer to human pluripotent hematopoietic stem cells (PHSCs) is an attractive strategy for the curative treatment of many genetic hematologic disorders. In clinical trials, the levels of gene transfer to this cell population have generally been low, reflecting deficiencies in both the vector systems and transduction conditions. In this study, we have used a pseudotyped murine retroviral vector to transduce human CD34(+) cells purified from bone marrow (BM) and umbilical cord blood (CB) under optimized conditions. After transduction, 71% to 97% of the hematopoietic cells were found to express a low-affinity nerve growth factor receptor (LNGFR) marker gene. Six weeks after transplantation into immunodeficient NOD/LtSz-scid/scid (NOD/SCID) mice, LNGFR expression was detected in 6% to 57% of CD45(+) cells in eight of nine engrafted animals. Moreover, proviral DNA was detected in 8.3% to 45% of secondary colonies derived from BM cells of engrafted NOD/SCID mice. Our data show consistent transduction of SCID-repopulating cells (SRCs) and suggest that the efficiency of gene transfer to human hematopoietic repopulating cells can be improved using existing retroviral vector systems and carefully optimized transduction conditions.

Animals↗
PubMed1998

A second unrelated bone marrow transplant with an unrelated donor marrow: treatment of a patient with relapsed leukemia.

A second bone marrow transplant might be considered as an option in patients with leukemia relapsing after bone marrow transplantation. We report the successful treatment of a patient with relapsed ALL with a second BMT from the same unrelated donor. We evaluated the usefulness of an unrelated donor as the source of the second BMT in this clinical setting. The conditioning regimen for the first transplantation consisted of BU and CY while fractionated TBI and CY were used for the second BMT. Acute skin GVHD, grade III which developed after second BMT, was successfully treated with the use of a new immunosuppressive drug, mycophenolate mofetil. Hemorrhagic cystitis and a CMV infection developed as complications during the second BMT and were successfully treated. The patient was alive and well after the second BMT with limited chronic skin GVHD up to day +170.

Adult↗
PubMed1998

Mycophenolate mofetil for the treatment of acute and chronic GVHD in bone marrow transplant patients.

The efficacy and safety of mycophenolate mofetil (MMF) in combination with CsA and prednisolone for the treatment of acute and chronic GVHD (aGVHD and cGVHD, respectively) after BMT and PBSCT from HLA-mismatched and -matched donors was evaluated in an open single center trial. Twenty-four patients, 17-48 years of age, with acute (n = 17) and chronic GVHD (n = 7) were treated with 2 g MMF daily in addition to CsA and prednisolone. Overall grade improvement of aGVHD was found in 11 of 17 (65%) patients treated with MMF. MMF therapy in the treatment of cGVHD led to moderate improvement in three of six patients with limited cGVHD. The most common adverse hematologic events of MMF were leukopenia (n = 6), anemia (n = 4) and thrombocytopenia (n = 3). Hematological adverse events were not severe and did not require the discontinuation of MMF. In this preliminary study, we have shown that MMF can be used safely for the treatment of aGVHD. In addition, the MMF therapy resulted in significant dose reduction of prednisolone for the treatment of GVHD.

Acute Disease↗
PubMed1998

Total body irradiation and cyclophosphamide is a conditioning regimen for unrelated bone marrow transplantation in a patient with chronic myelogenous leukemia and renal failure on hemodialysis.

Five years after the diagnosis of Ph chromosome-positive chronic myeloid leukemia (CML) a 31-year-old patient developed malignant nephrosclerosis with renal failure. He then underwent an allogeneic unrelated BMT in first chronic phase CML. The preparative regimen consisted of fractionated total body irradiation (TBI) and cyclophosphamide (CY). We studied the pharmacokinetics of cyclophosphamide on hemodialysis and compared clinical parameters including time to engraftment and toxicity with parameters of a patient with normal renal function who also received an unrelated marrow as treatment for CML in first chronic phase. Our results suggest that TBI/CY is a suitable conditioning regimen for allogeneic transplantation in patients with hematological malignancy and renal failure on hemodialysis.

Adult↗
PubMed1998

Chronic eosinophilic leukemia: successful treatment with an unrelated bone marrow transplantation.

The optimal treatment of eosinophilic leukemia is still uncertain. We report the successful treatment of a 21-year-old patient with eosinophilic leukemia, without cytogenetic abnormalities, by bone marrow transplantation from an unrelated donor. The conditioning regimen for the transplantation consisted of fractionated total body irradiation and cyclophosphamide. Acute GVHD, grade I, post-transplantation was successfully treated. No other severe complications occured. The patient is alive in complete remission 21 months after unrelated bone marrow transplantation.

Adult↗
PubMed1997

Oral dolasetron mesilate (MDL 73,147EF) for the control of emesis during fractionated total-body irradiation and high-dose cyclophosphamide in patients undergoing allogeneic bone marrow transplantation.

The purpose of the present study was to evaluate the efficacy and safety of oral dolasetron mesilate in the prevention of nausea and vomiting that might otherwise be induced by total-body irradiation (TBI) and high-dose cyclophosphamide. In an open non-comparative study 20 patients who received TBI for 3 days and high-dose cyclophosphamide chemotherapy for 2 days as part of their preparation for bone marrow transplantation were given oral dolasetron mesilate at dosages ranging from 50 to 200 mg 1 h before each fraction of radiotherapy and cyclophosphamide administration. Initial rescue therapy consisted of intravenous dolasetron mesilate. If nausea and vomiting remained uncontrolled, standard antiemetics were to be used. Of the 20 patients, 13 had only two emetic episodes or fewer in the 3-day TBI period. On days 1 and 2 of cyclophosphamide administration, 11 and 6 patients had fewer than two emetic episodes. From day 1 to day 3, 15 patients experienced no nausea or only mild nausea, and on the days of chemotherapy 8 and 7 patients had mild nausea or none at all. Rescue with i.v. dolasetron mesilate was needed by 3 and 6 patients during the TBI and the chemotherapy periods respectively. In 2 patients additional antiemetics were used on days 2-3 and 4-5. Mild to moderate headache was reported in 6 patients. No unexpected abnormalities were observed in haematology, biochemistry or urinalysis, and vital signs were unaffected throughout the study period. The data suggest that oral dolasetron mesilate is effective and safe for the prevention of nausea and vomiting during TBI and cyclophosphamide chemotherapy prior to bone marrow transplantation. Future controlled studies should evaluate combination antiemetic therapy with dolasetron mesilate for this indication.

Administration, Oral↗
PubMed1996

Therapeutic equivalence of single oral doses of dolasetron mesilate and multiple doses of ondansetron for the prevention of emesis after moderately emetogenic chemotherapy. European Dolasetron Comparative Study Group.

This multicentre, randomised, double-blind study was designed to compare the anti-emetic efficacy and safety of single oral doses of dolasetron mesilate with that of the approved oral, multiple-dose regimen of ondansetron in 399 cancer patients receiving moderately emetogenic chemotherapy. Single oral doses of 25, 50, 100 or 200 mg of dolasetron mesilate were administered 1 h prior to the initiation of moderately emetogenic chemotherapy. Multiple doses of ondansetron (8 mg x 3 or 8 mg x 4) capsules, or matching placebo for patients randomised to dolasetron, were given 1.5 h before and 6.5, 14.5 and 22.5 h after the start of chemotherapy (total dose = 32 mg). Efficacy was evaluated for 24 h after the initiation of chemotherapy. The most frequently used moderately emetogenic chemotherapeutic agents included cyclophosphamide, doxorubicin and carboplatin (28.4, 23.1 and 20.6% of patients, respectively). A statistically significant (P < 0.001) linear dose-response relationship was observed over the entire dolasetron dosage range for all efficacy parameters. Complete response rates were 45.0, 49.4, 60.5 and 76.3% for 25, 50, 100 and 200 mg dolasetron mesilate, respectively, and 72.3% of ondansetron patients. A single oral 200 mg dolasetron mesilate dose was therapeutically equivalent to ondansetron for all efficacy parameters and patient satisfaction was high. Overall, there were no significant differences in the incidence of adverse events between any of the dolasetron mesilate doses, or between dolasetron and ondansetron. Headache was most frequently reported (approximately 15% for each drug). No clinically important changes in vital signs or clinical laboratory parameters were observed with either drug. In conclusion, a single oral 200 mg dolasetron mesilate dose was therapeutically equivalent to multiple-dose ondansetron in the prevention of emesis and nausea following moderately emetogenic chemotherapy.

Adult↗