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Biomedical subjects

S Durrant

Publications and source records attributed to S Durrant.

At least 19 recordsLinked to original sources
PubMed2006

Combination antithymocyte globulin and soluble TNFalpha inhibitor (etanercept) +/- mycophenolate mofetil for treatment of steroid refractory acute graft-versus-host disease.

Antitumor necrosis factor-alpha antibodies are increasingly being used for the treatment of steroid-refractory acute graft-versus-host disease (GVHD) complicating allogeneic stem cell transplantation. We retrospectively reviewed the outcomes of 16 patients with refractory acute predominantly visceral GVHD treated with combination antithymocyte globulin (ATG), tacrolimus and etanercept +/- mycophenolate mofetil (MMF) at our institution. Overall response rate (CR+PR) was 81%, with median survival post commencing salvage immunosuppression 224 days (range 20-1216 days). In total, eight patients (50%) died, including from progressive GVHD in two cases (13%), infection in five (31%) and relapse of underlying malignancy in one (6%). In comparison to our previous experience of ATG+tacrolimus as treatment for refractory visceral GVHD, both response rate and overall survival were improved with addition of etanercept, with no apparent increase in infectious complications. As such, use of etanercept in combination with ATG +/- MMF for treatment of steroid refractory acute GVHD appears to be associated with high response rates, significant survival and no unexpected toxicity. Further study of this immunosuppression combination in a larger cohort of patients in this setting is indicated.

Acute Disease↗
PubMed2006

Myeloablative allogeneic stem cell transplantation for advanced stage multiple myeloma: very long-term follow up of a single center experience.

We aimed to review the long-term outcome of myeloablative allogeneic stem cell transplantation (SCT) performed for multiple myeloma (MM) at our institution. Records of all patients who received standard myeloablative allogeneic SCT for MM were retrospectively reviewed. Overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) were calculated using the Kaplan-Meier method. In total 37 transplants had been performed. Median follow up post-SCT was 108 months (range: 33-148). The majority of patients suffered advanced stage disease and/or had received multiple prior therapies prior to SCT. Transplant-related mortality (TRM) at 100 days was 32%. Grades 2-4 acute graft-vs.-host disease (GVHD) occurred in 18 patients (49%), and extensive stage chronic GVHD in seven (28%) of 25 patients surviving greater than day 100. Median OS, PFS, and EFS were 28 months, 66 months and 13 months, respectively, with 5 year OS, PFS, and EFS 40%, 54% and 24%. Our results suggest that allogeneic SCT, even when performed in advanced stage, heavily pretreated MM, still results in long-term EFS in a significant minority of patients. Efforts should continue on alternative allogeneic SCT approaches to reduce the high early TRM rate associated with myeloablative conditioning.

Adult↗
PubMed2004

Oral versus intravenous ganciclovir for the prophylaxis of cytomegalovirus disease after allogeneic bone marrow transplantation.

BACKGROUND: Prophylactic low dose i.v. ganciclovir in patients at risk after allogeneic bone marrow transplantation (BMT) is highly effective in the prevention of cytomegalovirus (CMV) disease and infection. AIM: In this study, we sought to assess the tolerability of oral ganciclovir in patients after allogeneic BMT. METHODS: CMV seropositive patients or those with CMV seropositive donors were randomised to be treated with i.v. ganciclovir 5 mg/kg three times weekly or oral ganciclovir 3 g daily from engraftment to day 84. The period of accrual was from May 1997 to October 1998. Patients were monitored for CMV infection by weekly serology. Thirty-one patients received oral ganciclovir and 27 patients received i.v. ganciclovir, the treatment groups being balanced for clinical characteristics and prognostic factors. RESULTS: Renal dysfunction, transfusion requirements and significant nausea and vomiting were not different. There were no documented cases of CMV disease during the study period although three patients developed CMV polymerase chain reaction positivity at various times. One patient treated with i.v. ganciclovir developed non-fatal gastrointestinal CMV disease after the study period on day 108. Eight patients in the oral group failed to complete planned therapy, whereas two patients failed to complete the i.v. course. CONCLUSION: We conclude that oral ganciclovir is a reasonable, well-tolerated alternative to i.v. ganciclovir for the prophylaxis of CMV disease after allogeneic BMT.

Administration, Oral↗
PubMed2003

Successful mobilization of peripheral blood stem cells after addition of ancestim (stem cell factor) in patients who had failed a prior mobilization with filgrastim (granulocyte colony-stimulating factor) alone or with chemotherapy plus filgrastim.

This study assessed the ability of recombinant human stem cell factor (rHuSCF) to mobilize stem cells in 44 patients who had failed a prior mobilization (CD34(+) yield 0.5-1.9 x 10(6)/kg BW) with filgrastim-alone or chemotherapy-plus-filgrastim. The same mobilization regimen was used with the addition of rHuSCF. In the filgrastim-alone group (n=13), rHuSCF 20 microg/kg was started 3 days before filgrastim and continued for the duration of filgrastim. In the chemotherapy-plus-filgrastim group (n=31), rHuSCF 20 microg/kg/day plus filgrastim 5-10 microg/kg/day were administered concurrently. Leukaphereses were continued to a maximum of four procedures or a target of >or=3 x 10(6) CD34(+) cells/kg. In both groups, CD34(+) yield (x 10(6)/kg BW) of the study mobilization was higher than that of the prior mobilization (median: 2.42 vs 0.84 P=0.002 and 1.64 vs 0.99 P=<0.001, respectively). In all 54 and 45% of patients in the filgrastim-alone group and chemotherapy-plus-filgrastim group, respectively, reached the threshold yield of 2 x 10(6)/kg. The probability of a successful mobilization was the same in those with a CD34+ yield of 0.5-0.75 x 10(6)/kg BW in the prior mobilization as in those with 0.76-1.99 x 10(6)/kg BW. Downmodulation of c-kit expression and a lower percentage of Thy-1 positivity in the mobilized CD34(+) cells were noted in the successful mobilizers compared with those in the poor mobilizers. This study shows that rhuSCF is effective in approximately half the patients who had failed a prior mobilization and allows them to proceed to transplant. It also points to the likely role of the SCF/c-kit ligand pair in mobilization.

Adult↗
PubMed2003

Impact of stem cell donation modality on normal donor quality of life: a prospective randomized study.

As part of a previously reported trial comparing granulocyte-colony stimulating factor (G-CSF) stimulated bone marrow and peripheral blood stem cells (PBSCs) in allogeneic stem cell transplantation, we included a questionnaire to compare donor morbidity and long-term complications between the two donation procedures. Bone marrow donation was associated with significantly more donors experiencing localized pain at the donation site compared to PBSC collection. However, this was not associated with any increased delay in returning to normal activity. Although a minority of bone marrow donors suffered chronic pain at the donation site, no serious long-term side effects relating to G-CSF stimulated stem cell donation were identified.

Adolescent↗
PubMed2003

Imatinib produces significantly superior molecular responses compared to interferon alfa plus cytarabine in patients with newly diagnosed chronic myeloid leukemia in chronic phase.

We analyzed molecular responses in 55 newly diagnosed chronic-phase chronic myeloid leukemia (CML) patients enrolled in a phase 3 study (the IRIS trial) comparing imatinib to interferon-alfa plus cytarabine (IFN+AraC). BCR-ABL/BCR% levels were measured by real-time quantitative RT-PCR and were significantly lower for the imatinib-treated patients at all time points up to 18 months, P<0.0001. The median levels for imatinib-treated patients continued to decrease and had not reached a plateau by 24 months. A total of 24 IFN+AraC-treated patients crossed over to imatinib. Once imatinib commenced, the median BCR-ABL/BCR% levels in these patients were not significantly different to those on first-line imatinib for the equivalent number of months. The incidence of progression in imatinib-treated patients, defined by hematologic, cytogenetic or quantitative PCR criteria, was significantly higher in the patients who failed to achieve a 1 log reduction by 3 months or a 2 log reduction by 6 months, P=0.002. A total of 49 patients were screened for BCR-ABL kinase domain mutations. Mutations were detected in two imatinib-treated patients who crossed over from IFN+AraC and both lost their imatinib response. In conclusion, first-line imatinib-treated patients had profound reductions in BCR-ABL/BCR%, which significantly exceeded those of IFN+AraC-treated patients and early measurements were predictive of subsequent response.

Antimetabolites, Antineoplastic↗
PubMed2002

Human peripheral blood Valpha24+ Vbeta11+ NKT cells expand following administration of alpha-galactosylceramide-pulsed dendritic cells.

BACKGROUND AND OBJECTIVES: We have undertaken the first clinical trial involving the administration of alpha-GalactosylCeramine (alpha-GalCer)-pulsed dendritic cells (DCs) to human subjects, to determine safety, optimal dose, optimal administration route and immunological effects. MATERIALS AND METHODS: Subjects (n = 4) with metastatic malignancy received two infusions of alpha-GalCer-pulsed DCs intravenously, and two infusions intradermally. The percentages of Valpha24 Vbeta11 NKT cells in peripheral blood (PB) were determined by three-colour flow cytometry and the PB NKT cell numbers were calculated using the total number of PB lymphocytes/ml determined by automated full-blood counts. RESULTS: No serious treatment related adverse events were observed during the study period. Administration of alpha-GalCer-pulsed DCs in vivo can significantly (P < 0.03) increase PB Valpha24+ Vbeta11+ NKT cell numbers above pretreatment baseline levels after the transient fall in the NKT numbers within 48 h. CONCLUSIONS: Administration of alpha-GalCer-pulsed DCs is well tolerated, modulates PB Valpha24+ Vbeta11+ NKT cells and may have a role in the therapy of malignancies sensitive to activities of Valpha24+ Vbeta11+ NKT cells, or for autoimmune diseases.

Blood Cells↗
PubMed2002

153Sm EDTMP for bone marrow ablation prior to stem cell transplantation for haematological malignancies.

This study examined the safety of adding 153Sm lexidronam to standard conditioning regimens in patients undergoing stem cell transplantation for marrow based haematological malignancies in whom total-body irradiation as part of conditioning was desirable but not feasible. Ten such patients were enrolled, seven with multiple myeloma. An escalating regimen of 19-45 GBq of 153Sm lexidronam was added 12-14 days prior to the standard transplantation regimen. Evaluation parameters included time to engraftment, status at day +100 by International Bone Marrow Transplant Registry (IBMTR) criteria and toxicity during this period. Absorbed marrow radiation doses were estimated using the MIRDOSE 3 program. No adverse events were attributable to 153Sm lexidronam. Of the seven patients with multiple myeloma, four achieved complete response, two partial response, and another had stable monoclonal band at 3 months post-transplant. One patient with Refractory Anaemic with Excess Blasts in transformation (RAEBt) died of a presumed fungal infection, whilst another with acute myeloid leukaemia relapsed, dying at day +153. A patient with low-grade lymphoma showed no evidence of residual disease at day +100. The total marrow absorbed dose was estimated to be 0.7+/-0.2 mGy x MBq(-1). Regional uptake was markedly non-uniform with poor uptake in the appendicular skeleton. Dose-limiting toxicity was not attained. At the activities used 153Sm lexidronam was not associated with additional toxicity in this population. Adequate absorbed radiation dose to appendicular marrow is unlikely to be deliverable by this approach alone.

Adult↗
PubMed2002

Survival following mechanical ventilation of recipients of bone marrow transplants and peripheral blood stem cell transplants.

Survival of bone marrow transplant recipients requiring mechanical ventilation is poor but improving. This study reports a retrospective audit of all haematopoietic stem cell transplant (HSCT) recipients requiring mechanical ventilation at an Australian institution over a period spanning 11 years from 1988 to 1998. Recipients of autologous transplants are significantly less likely to require mechanical ventilation than recipients of allogeneic transplants. Of 50 patients requiring mechanical ventilation, 28% survived to discharge from the intensive care unit, 20% to 30 days post-ventilation, 18% to discharge from hospital and 12% to six months post-ventilation. Risk factors for mortality in the HSCT recipient requiring mechanical ventilation include renal, hepatic and cardiovascular insufficiency and greater severity of illness. Mechanical ventilation of HSCT recipients should not be regarded as futile therapy.

Adolescent↗
PubMed2001

Granulocyte-colony-stimulating factor (G-CSF)-primed allogeneic bone marrow: significantly less graft-versus-host disease and comparable engraftment to G-CSF-mobilized peripheral blood stem cells.

Prospective studies have shown rapid engraftment using granulocyte-colony-stimulating factor-mobilized peripheral blood stem cells (G-PBSCs) for allogeneic transplantation, though the risks for graft-versus-host disease (GVHD) may be increased. It was hypothesized that the use of G-CSF to prime bone marrow (G-BM) would allow rapid engraftment without increased risk for GVHD compared with G-PBSC. Patients were randomized to receive G-BM or G-PBSCs for allogeneic stem cell transplantation. The study was designed (beta <.8) to detect a difference in the incidence of chronic GVHD of 33% (alpha <.05). The plan was to recruit 100 patients and to conduct an interim analysis when the 6-month follow-up point was reached for the first 50 patients. Fifty-seven consecutive patients were recruited (G-BM, n = 28; G-PBSC, n = 29). Patients in the G-PBSC group received 3-fold more CD34(+) and 9-fold more CD3(+) cells. Median times to neutrophil (G-BM, 16 days; G-PBSC, 14 days; P <.1) and platelet engraftment (G-BM, 14 days; G-PBSC, 12 days; P <.1) were similar. The use of G-PBSC was associated with steroid refractory acute GVHD (G-BM, 0%; G-PBSC, 32%; P <.001), chronic GVHD (G-BM, 22%; G-PBSC, 80%; P <.02), and prolonged requirement for immunosuppressive therapy (G-BM, 173 days; G-PBSC, 680 days; P <.009). Survival was similar for the 2 groups. Compared with G-PBSC, the use of G-BM resulted in comparable engraftment, reduced severity of acute GVHD, and less subsequent chronic GVHD.

Acute Disease↗
PubMed2001

In vitro anti-tumour activity of alpha-galactosylceramide-stimulated human invariant Valpha24+NKT cells against melanoma.

alpha-galactosylceramide (KRN 7000, alpha-GalCer) has shown potent in vivo anti-tumour activity in mice, including against melanoma and the highly specific effect of inducing proliferation and activation of human Valpha24+NKT-cells. We hypothesized that human Valpha24+NKT-cells activated by alpha-GalCer might exhibit anti-tumour activity against human melanoma. To investigate this, Valpha24+NKT-cells were generated from the peripheral blood of patients with melanoma after stimulation with alpha-GalCer pulsed monocyte-derived dendritic cells (Mo-DCs). Valpha24+NKT-cells did not exhibit cytolytic activity against the primary autologous or allogeneic melanoma cell lines tested. However, proliferation of the melanoma cell lines was markedly suppressed by co-culture with activated Valpha24+NKT-cells (mean +/- SD inhibition of proliferation 63.9 +/- 1.3%). Culture supernatants of activated Valpha24+NKT-cell cultures stimulated with alpha-GalCer pulsed Mo-DCs exhibited similar antiproliferative activities against melanoma cells, indicating that the majority of the inhibitory effects were due to soluble mediators rather than direct cell-to-cell interactions. This effect was predominantly due to release of IFN-gamma, and to a lesser extent IL-12. Other cytokines, including IL-4 and IL-10, were released but these cytokines had less antiproliferative effects. These in vitro results show that Valpha24+NKT-cells stimulated by alpha-GalCer-pulsed Mo-DCs have anti-tumour activities against human melanoma through antiproliferative effects exerted by soluble mediators rather than cytolytic effects as observed against some other tumours. Induction of local cytokine release by activated Valpha24+NKT-cells may contribute to clinical anti-tumour effects of alpha-GalCer.

Adjuvants, Immunologic↗
PubMed2001

Allogeneic haemopoietic cell transplants in Australia, 1996--a multi-centre retrospective comparison of the use of peripheral blood stem cells with bone marrow.

A retrospective comparison was carried out on adult patients receiving HLA-identical allogeneic haemopoietic stem cell transplants from siblings in Australia in 1996, comparing bone marrow with G-CSF-mobilised peripheral blood stem cells. A total of 131 transplant recipients from nine centres were included in this study, of whom 79 received bone marrow, 44 blood stem cells and eight both. All but three of the 131 patients had cyclosporin and methotrexate as graft-versus-host disease prophylaxis. The minimum follow-up time for surviving patients is 27 months. Comparisons were carried out between the BM and PBSC groups. There were no significant differences between groups in age, sex, diagnosis, donor characteristics or pretransplant conditioning. Median time to neutrophil recovery of 0.5 x 10(9)/l was 14 days for PBSC recipients, compared to 19 days for marrow recipients (P < 0.0005). median time to platelet recovery of 20 x 10(9)/l was 17 days for PBSC recipients, compared to 28 days for marrow recipients (P < 0.0005). there were no significantly increased risks of either acute or chronic GVHD in the PBSC recipients. there were no significant differences between the groups in the incidence of major transplant-related complications, disease-free survival or overall survival.

Adolescent↗
PubMed2001

Effects of glycosylated recombinant human granulocyte colony-stimulating factor after high-dose cytarabine-based induction chemotherapy for adult acute myeloid leukaemia.

The Australian Leukaemia Study Group (ALSG) investigated whether G-CSF would accelerate haemopoietic recovery after induction treatment for acute myeloid leukaemia (AML) intensified with high-dose cytarabine, and therefore improve response rates and survival. Patients were randomised to receive lenograstim (glycosylated recombinant human G-CSF) 5 microg per kg body weight subcutaneously daily from day 8 after starting chemotherapy, or no cytokine, following chemotherapy with cytarabine 3 g/m2 every 12 h on days 1, 3, 5, and 7, together with idarubicin 9 or 12 mg/m2 on days 1, 2, and 3, plus etoposide 75 mg/m2 on days 1 to 7 inclusive. Patients had untreated AML, and were aged 16 to 60 years. Overall, 54 evaluable patients were randomised to receive lenograstim and 58 to no cytokine. Patients in the lenograstim arm had a significantly shorter duration of neutropenia <0.5 x 10(9)/l compared to patients in the no cytokine arm (median 18 vs 22 days; P = 0.0005), and also shorter duration of total leucopenia <1.0 x 10(9)/l (17 vs 19 days; P = 0.0002), as well as a reduction in duration of treatment with therapeutic intravenous antibiotics (20 vs 24 days; P= 0.015) and a trend to reduced number of days with fever >38.0 degrees C (9 vs 12 days; P = 0.18). There were no differences between the two groups in platelet recovery, red cell or platelet transfusions, or non-haematological toxicities. For patients achieving CR after their first induction course, a reduction in the time to the start of the next course of therapy was observed in the lenograstim arm, from a median of 40.5 days to a median of 36 days (P = 0.082). The overall complete response rates to chemotherapy were similar, 81% in the lenograstim arm vs 75% for the no cytokine arm (P = 0.5), and there was no significant difference in the survival durations. We conclude that the granulopoietic stimulating effect of G-CSF is observed after induction therapy for AML intensified by high-dose cytarabine, resulting in an improvement in a number of clinically important parameters with no major adverse effects.

Acute Disease↗