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Biomedical subjects

K Bradstock

Publications and source records attributed to K Bradstock.

At least 19 recordsLinked to original sources
PubMed2006

Pamidronate reduces bone loss after allogeneic stem cell transplantation.

BACKGROUND: Rapid bone loss occurs from the proximal femur after allogeneic stem cell transplantation (alloSCT). OBJECTIVE: The objective of the study was to evaluate effects of high-dose pamidronate therapy on bone loss (BMD) after alloSCT. DESIGN: This was a randomized, multicenter, open-label, 12-month prospective study of iv pamidronate (90 mg/month) beginning before conditioning vs. no pamidronate. All 116 patients also received calcitriol (0.25 microg/d) and calcium (1000 mg/d), which were continued for another year. MAIN OUTCOME MEASURES: Primary objectives were to compare changes in BMD 12 months after alloSCT at the femoral neck, lumbar spine, and total hip between the treatment arms and assess influences of glucocorticoid and cyclosporin therapy on these changes. RESULTS: Pamidronate reduced bone loss at the spine, femoral neck, and total hip by 5.6, 7.7, and 4.9% (all P < or = 0.003), respectively, at 12 months. However, BMD of the femoral neck and total hip was still 2.8 and 3.5% lower than baseline, respectively (P < 0.05) with pamidronate. Only differences at the total hip remained significant between the two groups at 24 months. Benefits were restricted to patients receiving an average daily prednisolone dose greater than 10 mg and cyclosporin therapy for more than 5 months within the first 6 months of alloSCT. CONCLUSIONS: Pamidronate markedly reduced but did not completely prevent postallogeneic bone marrow transplantation bone loss. BMD benefits were greatest in patients on higher doses of immunosuppressive therapy, but most were lost 12 months after stopping pamidronate. Studies of more potent bisphosphonates or anabolic therapy with PTH after alloSCT are warranted with the aim of durable maintenance of bone mass.

Adolescent↗
PubMed2006

Autologous stem cell transplantation in adults with acute lymphoblastic leukemia in first complete remission: analysis of the LALA-85, -87 and -94 trials.

To evaluate the results of autologous stem cell transplantation (ASCT) in a large population of adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR), we performed an individual data-based overview of the last three trials from the LALA group. Overall, 349 patients with ALL prospectively randomized in the consecutive LALA-85, -87, and -94 trials to receive either ASCT or chemotherapy as post-CR treatment were analyzed. Eligibility criteria were 15-50-year-old patients without sibling donors in both LALA-85/87 trials and 15-55-year-old patients with high-risk ALL and no sibling donors in the LALA-94 trial. Intent-to-treat analysis, which compared 175 patients from the ASCT arm to 174 patients from the chemotherapy arm, showed that ASCT was associated with a lower cumulative incidence of relapse (66 vs 78% at 10 years; P=0.05), without significant gain in disease-free or overall survival. Despite a possible lack of statistical power, a nested case-control analysis performed in 85 patient pairs adjusted for time to transplant and prognostic covariates confirmed these intent-to-treat results in patients actually transplanted. Of interest, the reduced relapse risk after ASCT translated in better disease-free survival in the 300 rapid responders who reached CR after the first induction course.

Adult↗
PubMed2004

Interferon-alpha-2b and oral cytarabine ocfosfate for newly diagnosed chronic myeloid leukaemia.

BACKGROUND: Treatment with interferon and subcutaneous cytarabine produces superior cytogenetic responses in chronic myeloid leukaemia (CML) than treatment with interferon alone, but at the expense of greater toxicity. Cytarabine ocfosfate (YNK01) is an oral precursor of cytarabine that may overcome some of the inconvenience and toxicities associated with subcutaneous cytarabine administration. PATIENTS AND METHODS: We studied the efficacy and tolerability of combination therapy with interferon-alpha-2b and YNK01 in patients with newly diagnosed, untreated CML. Forty patients were treated with interferon-alpha-2b (5 MU/m2/day) plus monthly courses of YNK01 (600 mg/day for 10 days) for 1 year. RESULTS: The 6-month complete haematological response rate was 63% and the 1-year major cytogenetic response rate was 30%, with 10% of cytogenetic responses being complete. With a median follow-up of 57 months, the estimated 5-year overall survival was 86% (95% confidence interval 70% to 94%). Treatment tolerability was poor, with toxicity leading to discontinuation of one or both drugs in 60% of cases. The median daily dose of interferon alpha-2b was 7.75 MU and the median dose of YNK01 was 600 mg/day for each 10-day treatment cycle. CONCLUSIONS: Interferon-alpha-2b and YNK01 produce cytogenetic responses comparable to those achieved with interferon-alpha-2b and parenteral cytarabine, although toxicity was excessive. Alternate dosing strategies may enhance the tolerability of YNK01.

Administration, Oral↗
PubMed2003

Differences between graft product and donor side effects following bone marrow or stem cell donation.

We report graft product stem cell yields and donor safety results of a randomized multicenter study comparing allogeneic peripheral blood stem cell (PBSC) PBSC transplantation with BM transplantation. Matched HLA-identical sibling donors (n=329) were randomized to filgrastim-mobilized PBSC or bone marrow (BM) donation groups. Median yields per kg recipient weight of CD34(+) cells, T cells, and natural killer (NK) cells, respectively, were approximately two-fold, eight-fold, and greater than eight-fold in the PBSC group than in the BM group (CD34(+) cells, 5.8 x 10(6)/kg vs 2.7 x 10(6)/kg; T cells, 300.1 x 10(6)/kg vs 35.7 x 10(6)/kg; NK cells, 28.2 x 10(6)/kg vs 3.6 x 10(6)/kg; P<0.001 for each). In connection with the cell collection procedures, PBSC donors spent a shorter median time in hospital than BM donors (0 vs 2 days; median difference -2 days, 95% CI -2 to 2) and had fewer median days of restricted activity (2 vs 6 days; median difference -3 days, 95% CI -4 to 2). Overall, 65% of PBSC donors and 57% of BM donors reported at least one adverse event (AE), most of which were transient, mild-moderate in severity, and without clinical sequelae. PBSC donors experienced predominantly filgrastim-related AEs, while BM donors experienced predominantly harvest-related AEs.

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

Flow cytometric quantitation and characterization of the T-lymphocyte memory response to CMV in healthy donors.

BACKGROUND: Levels of circulating CMV Ag-specific lymphocytes determine CMV reactivation risk in immunocompromised individuals. METHODS: Frequencies of T cells producing cytokines after stimulation by CMV Ag were measured in hematopoietic stem-cell donors using flow cytometry. RESULTS: In seropositive individuals (n = 75) the mean number of CD8(+) (CD8(bright), CD8(dim)) and CD4(+) cells producing IFN-gamma was respectively 3.1% (12.6/microL) and 0.38% (3.2/microL), over 10-fold higher than in seronegative subjects (n = 22). CMV stimulation induced tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in both CD4(+) and CD8(+) cells (usually together), with a shift from memory- to effector-cell phenotype, while only a small proportion of CD4(+) cells produced IL-4. Although the normal range was wide, neither age, sex nor HLA type affected the frequency. DISCUSSION: These quantitative studies and the recognition of CD4(+) cells as potential effectors of CMV immunity are of relevance for immunotherapeutic approaches to prevent CMV disease after stem-cell transplantation.

Adoptive Transfer↗
PubMed2001

Routine fluorescence in situ hybridization with the MLL probe does not reliably detect two separate signals on one chromosome 11 in patients with trisomy 11.

Trisomy 11 is considered to be a rare cytogenetic abnormality in myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). Duplication of the MLL gene (localized to 11q23) has been found on one chromosome 11 in patients with trisomy 11, detected by DNA techniques. We investigated copy number of MLL in seven patients with trisomy 11 to see if duplication could be assessed by the detection of two separate signals on fluorescence in situ hybridization (FISH). If so, FISH could provide a quick easy screen of MLL status in routine referrals. The diagnostic bone marrow aspirate showed trisomy 11 in five adult patients with MDS/AML as part of a complex karyotype and in two children with acute lymphoblastic leukemia (ALL) as part of a hyperdiploid karyotype. Fluorescence in situ hybridization utilized the suspensions remaining after the cytogenetic harvest. Two FISH probes were used on the adult patients (MLL - Oncor and Vysis), and one (Vysis) for the two children with ALL. Analysis showed that the proximity of the two putative hybridization signals made it very difficult to unambiguously see two separate signals. The hybridisations (Oncor probe) were convincing of MLL duplication (namely two distinct signals) in only one patient, but this was not borne out with the other MLL probe (Vysis). We conclude that conventional FISH with MLL probe is not suited to act as a screen for MLL duplication in patients with trisomy 11.

Adult↗
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↗
PubMed2000

Geographic heterogeneity of cellular characteristics of acute myeloid leukemia: a comparative study of Australian and Japanese adult cases.

We assessed a large number of adults (368 from Australia and 494 from Japan) with de novo acute myeloid leukemia (AML) to define the biological differences between the two populations. In this study, AML was classified using the French-American-British (FAB) criteria into seven groups (M1-M7). M2 was more common in Japan than in Australia, whereas M4 occurred more frequently in Australia than in Japan. Other FAB subtypes were evenly distributed. Cytogenetically, Japanese M2 displayed a higher frequency of t(8;21) than Australian (33.1% vs 15.3%, P < 0.05). The t(15;17), inv/del(16), 11q23 aberrations and 5/7/8 abnormalities were seen at similar frequencies. Immunophenotypically, Japanese M4/M5 more frequently displayed CD13 and CD14 than Australian, whereas the stem cell markers, CD34 and HLA-DR were observed at a relatively higher rate in Australian M3 than in Japanese M3. The B cell antigen, CD19 was more frequently seen in Japanese M2 than in Australian M2, but found more often in Australian M5 than in Japanese M5. In both populations, a close relationship was observed between the expression of CD19 and t(8;21). These findings suggest different biological characteristics of AML between the two populations, the main differences being generated by a higher frequency of t(8;21) chromosomal abnormality in Japanese AML. Leukemia(2000) 14, 163-168.

Acute Disease↗
PubMed1999

Disseminated nocardiosis in a bone marrow transplant recipient with chronic GVHD.

We describe a case of disseminated nocardiosis in a 53-year-old male allogeneic marrow recipient with chronic GVHD, 15 years post BMT. Six months prior to admission he was treated for recurrent chronic GVHD with corticosteroids with a good response. He deteriorated subsequently while still on steroids requiring admission for fever, anorexia, weight loss, productive cough and progressive dyspnoea. On admission he had multiple nodular lesions on chest roentgenogram and subsequently grew Nocardia farcinica in blood culture. N. farcinica is rare post BMT, has a high mortality, is resistant to various antibiotics and needs prolonged antimicrobial therapy. We report the successful management of our patient with single agent trimethoprim-sulphamethoxazole.

Adrenal Cortex Hormones↗
PubMed1999

Factors affecting the outcome of allogeneic bone marrow transplantation for adult patients with refractory or relapsed acute leukaemia.

We evaluated the outcome of allogeneic bone marrow transplantation (BMT) for advanced acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) in 383 adult patients in nine Australian adult BMT centres between 1981 and 1997. The median overall survival for the group was 4.8 months, with an estimated 5-year survival of 18%. 28% of patients died of transplant-related toxicities within the first 100 d. Progressive disease was responsible for 48% of deaths. Multi-factor analysis demonstrated that AML (v ALL), disease status (second complete remission [CR2] v others), age (< 40 years) and duration of prior first complete remission (CR1) (> 6 months) were pre-transplant variables significantly associated with improved survival. Acute graft-versus-host disease (GVHD) of any grade reduced the rate of relapse in both AML and ALL, but only grades I-II were associated with improved survival. Both limited and extensive chronic GVHD were associated with increased survival. Only patients with AML in untreated first relapse or CR2, with a duration of CR1 > 6 months, or patients with T ALL, had a 5-year survival > 20%. Transplants for AML in induction failure or pre-B ALL in untreated first relapse or CR2 had an intermediate outcome, with 5-year survival of 10-20%. A 5-year survival of < 10% was observed for patients transplanted for ALL in induction failure or for pre-B ALL or AML in refractory first relapse or beyond CR2. These results suggest that for most adult patients with advanced acute leukaemia an allograft offers only a small chance of cure.

Adolescent↗
PubMed1998

VLA-4 is involved in the engraftment of the human pre-B acute lymphoblastic leukaemia cell line NALM-6 in SCID mice.

Attachment of human pre-B leukaemic cells to human or murine bone marrow stromal cells in vitro is largely mediated by the beta1 integrin VLA-4 binding to VCAM-1. Cells subsequently migrate within the stroma, a process also involving VLA-4. A variant of the pre-B acute lymphoblastic leukaemia cell line NALM-6, designated 4A1, lacking expression of VLA-4, was generated by radiation-induced mutagenesis followed by several rounds of negative selection with immunomagnetic beads, fluorescence activated cell sorting and clonal expansion. In vitro assays using 4A1 cells showed reduced binding to, and migration under, the murine stromal line M2-10B4. Sublethally irradiated mice (n=19) with severe combined immunodeficiency were injected intravenously with NALM-6 cells. Animals developed signs of leukaemia with hind-limb paralysis at a median of 30 d (95% confidence interval 28-30). Although there were no gross abnormal findings at autopsy, histological analysis revealed extensive marrow replacement and focal liver infiltration with leukaemic blasts, which were confirmed to be of human origin by flow cytometry. 12 mice were injected with a similar number of cells from the VLA-4-negative variant cell line 4A1. Six mice developed signs of leukaemia after 43-74d, with the remaining six being free of signs of disease after > 100d (P<0.001). Mice in this group with leukaemia had a lower incidence of hind-limb paralysis and less leukaemic infiltration in the marrow, but in some cases had large tumour nodules elsewhere. After a single 500 microg intraperitoneal injection of anti-murine VCAM-1 monoclonal antibody (MK2.7), five additional mice were injected with an identical number of wild-type (VLA-4+) NALM-6. All animals developed signs of leukaemia after a similar period to those injected with wild-type NALM-6 only. These results demonstrate that the beta1 integrin VLA-4 is involved in the engraftment of the pre-B-cell leukaemic cell line NALM-6 in SCID mice, although the interaction with VCAM-1 is unlikely to be the sole explanation.

Animals↗
PubMed1998

Antileukemic effects of rapid cyclosporin withdrawal in patients with relapsed chronic myeloid leukemia after allogeneic bone marrow transplantation.

The results of rapid tapering of Cyclosporin therapy in 7 patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) in relapse after allogeneic bone marrow transplantation are reported. All patients had cytogenetically-documented relapse within 6 months of transplant, and were on oral Cyclosporin therapy. Rapid tapering of Cyclosporin resulted in moderately severe acute GVHD in 2 cases, and in extensive chronic GVHD in a further 2 patients (fatal in 1 case). An antileukemic effect was observed in 6 patients, with complete haematological and cytogenetic remission observed in all cases. The seventh patient did not respond, and died after infusion of donor leucocytes. Four of the responders remain in complete remission of CML 30 to 120 months after BMT. One patient died in remission of chronic GVHD, and one patient had a complete response lasting 5 months, but relapsed and died 13 months post transplant. Rapid withdrawal of Cyclosporin therapy appears to be an effective means of treatment of early relapse of CML after transplant, and is an alternative to the use of donor leucocyte infusions for those patients still receiving Cyclosporin at the time of relapse.

Adolescent↗
PubMed1998

Intensified induction chemotherapy with high dose cytarabine and etoposide for acute myeloid leukemia: a review and updated results of the Australian Leukemia Study Group.

Induction therapy of acute myeloid leukemia (AML) with standard dose chemotherapy will result in approximately 55-75% of patients achieving a complete remission (CR). Intensification of induction treatment with etoposide and high dose cytarabine does not alter the CR rate but appears to significantly improve the subsequent outcome. Updated results of the comparison of high dose cytarabine with daunorubicin and etoposide in induction (HIDAC-3-7) versus a standard dose combination (7-3-7) demonstrated a highly significant increase in relapse free survival, (RFS) on the high dose arm (p = 0.007) with RFS of 48% at 5 years with HIDAC-3-7 and 25% on 7-3-7. The high dose arm had a more modest survival advantage at 5 years of 33% compared with 25% on standard treatment, possibly because of a higher initial death rate with HIDAC-3-7. The improvement seen in patients with CR after high dose induction appear to parallel results obtained with post-remission therapies intensified with high dose cytarabine. These studies provide clinical evidence that a dose-response effect is present for cytarabine in AML. Intensified treatment is more toxic, gives more profound myelosuppression post-remission and has been shown to benefit younger patients only. Issues of patient selection and the optimal placement of intensification in the treatment sequence require further study. In the future, it is likely that remission duration may be a useful clinical tool to study the influence of new induction therapies on residual resistant leukemia.

Acute Disease↗
PubMed1997

Effect of the Philadelphia chromosome on minimal residual disease in acute lymphoblastic leukemia.

The Philadelphia translocation is associated with a poor prognosis in adults and children with acute lymphoblastic leukemia, even though the majority of patients achieve remission. To test the hypothesis that the translocation leads to drug resistance in vivo, we studied 61 children and 20 adults with acute lymphoblastic leukemia and used the level of minimal residual disease at the end of induction as the measure of drug resistance in vivo. In children the presence of the translocation was associated with a significant increase in residual disease, indicating higher drug resistance in vivo; five of seven Philadelphia-positive children but only five of 54 Philadelphia-negative children had a minimal residual disease level >10(-3), a level which is associated with a high risk of relapse in childhood acute lymphoblastic leukemia of standard risk. By contrast, in adults, residual disease and hence drug resistance was already higher than in children, and the presence of the Philadelphia translocation in seven patients had no obvious additional effect. We conclude that the Philadelphia chromosome may increase resistance to drugs in vivo in children, but not detectably in adults.

Adolescent↗
PubMed1997

Australian Leukaemia Study Group myeloma II: a randomized trial of intensive combination chemotherapy with or without interferon in patients with myeloma.

The Australian Leukaemia Study Group has performed a randomized trial of interferon alpha-2A (Roferon-A) as a co-induction agent together with intensive combination chemotherapy and as maintenance following completion of 12 cycles of induction treatment. When used as a co-induction agent, interferon-alpha did not improve response rates, time-to-treatment failure, or overall survival. Patients who had interferon together with intensive combination therapy (PCAB: prednisone 60 mg/m2 days 1-5, cyclophosphamide 600 mg/m2 day 1, BCNU 30 mg/m2 day 1, doxorubicin 30 mg/m2 day 1, repeated every 28 d for a total of 12 cycles) had more leucocyte and granulocyte toxicity and received a lower dose intensive of cytotoxic drugs than those patients who received PCAB without interferon. There was a trend towards prolongation of plateau phase which did not reach significance. Interferon, however, did improve the survival of patients who achieved plateau; for those patients interferon was associated with a 33% decrease in the rate of death after adjusting for initial beta-2 microglobulin level.

Activities of Daily Living↗