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Biomedical subjects

J Szer

Publications and source records attributed to J Szer.

At least 19 recordsLinked to original sources
PubMed2006

The hyper-CVAD-rituximab chemotherapy programme followed by high-dose busulfan, melphalan and autologous stem cell transplantation produces excellent event-free survival in patients with previously untreated mantle cell lymphoma.

The hyper-CVAD + rituximab (R) programme consists of fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone + R alternating with high-dose methotrexate + cytarabine (HD MTX/ARA-C) + R. This regimen, when used as initial therapy for patients under 65 years of age with previously untreated mantle cell lymphoma (MCL), results in remission rates of > 85% with a median event-free survival (EFS) of > 50 months, but with a pattern of continuous relapse out to 60 months. We performed a study of hyper-CVAD + R, followed by consolidative peripheral blood progenitor cells autograft [autologous stem cell transplant (AuSCT)] with high-dose busulfan and melphalan (Bu/Mel) conditioning, in patients with responsive disease. Thirteen patients with a median age of 54 (range = 33-61) were treated. Complete remission (CR) was achieved in 12 patients (92%) after hyper-CVAD + R and 12 completed AuSCT after Bu/Mel conditioning. One patient died during the autograft and another declined AuSCT after achieving a CR with hyper-CVAD + R. With a median follow-up from diagnosis of 36 months (range = 16-53 months), the observed 36 months overall survival and EFS are both 92% for the whole cohort. These data confirm the excellent CR rates achieved by the use of hyper-CVAD + R in patients with MCL and suggest that consolidation with Bu/Mel and AuSCT may improve durable disease control when compared to published outcomes of hyper-CVAD + R alone.

Adult↗
PubMed2006

Female genital tract graft-versus-host disease: incidence, risk factors and recommendations for management.

Female genital tract graft-versus-host disease (GVHD) is an under-recognized complication of allogeneic stem cell transplantation impacting on quality of life. We describe a prospective surveillance programme for female genital GVHD to better characterize incidence, risk factors and clinical features and the impact of a structured intervention policy. A retrospective audit was conducted on the medical records of all female transplant recipients surviving at least 6 months at a single centre over a 5-year period. Patients commenced topical vaginal oestrogen early post transplant with hormone replacement as appropriate for age, prior menopausal status and co-morbidities. A genital tract management programme included regular gynaecological review and self-maintenance of vaginal capacity by dilator or intercourse. The incidence of genital GVHD was 35% (95% confidence interval (CI) (25, 50%)) at 1 year and 49% (95% CI (36, 63%)) at 2 years. Topical therapy was effective in most cases; no patient required surgical intervention to divide vaginal adhesions. The main risk factor was stem cell source with peripheral blood progenitor cells posing a higher risk than marrow (hazard ratio=3.07 (1.22, 7.73), P=0.017). Extensive GVHD in other organs was a common association. We conclude that female genital GVHD is common, and early detection and commencement of topical immunosuppression with dilator use appears to be highly effective at preventing progression.

Administration, Topical↗
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

A randomized, open-label, multicenter comparative study of the efficacy and safety of piperacillin-tazobactam and cefepime for the empirical treatment of febrile neutropenic episodes in patients with hematologic malignancies.

BACKGROUND: The empirical treatment of febrile, neutropenic patients with cancer requires antibacterial regimens active against both gram-positive and gram-negative pathogens. This study was performed to demonstrate the noninferiority of monotherapy with piperacillin-tazobactam, compared with cefepime. METHODS: We conducted a randomized-controlled, open-label, multicenter clinical trial among high-risk patients from 34 university-affiliated tertiary care medical centers in the United States, Canada, and Australia who were undergoing treatment for leukemia or hematopoietic stem cell transplantation and were hospitalized for empirical treatment of febrile neutropenic episodes. Patients received piperacillin-tazobactam (4.5 g every 6 h) or cefepime (2 g every 8 h) intravenously. The primary outcome was success (defined by defervescence without treatment modification) at 72 h of treatment, end of treatment, and test of cure in the modified intent-to-treat analysis. Secondary outcomes included time to defervescence, microbiological efficacy, the additional use of glycopeptide antibiotics, emergence of resistant bacteria, and safety. RESULTS: For 528 subjects (265 received piperacillin-tazobactam and 263 received cefepime), success rates were 57.7% and 48.3%, respectively (P = .04) at the 72-h time point, 39.6% and 31.6% (P = .06) at end of treatment, and 26.8% and 20.5% (P = .11) at the test-of-cure visit. The analyses demonstrated noninferiority for piperacillin-tazobactam at all time points (P< or = .0001). Treatment with piperacillin-tazobactam was independently associated with treatment success in multivariate analysis (odds ratio, 1.65; 95% confidence interval, 1.04-2.64; P = .035). Both regimens were well tolerated. CONCLUSIONS: This study demonstrates the noninferiority and safety of piperacillin-tazobactam monotherapy, compared with cefepime, for the empirical treatment of high-risk febrile neutropenic patients with cancer.

Adolescent↗
PubMed2006

Donor methylenetetrahydrofolate reductase genotype is associated with graft-versus-host disease in hematopoietic stem cell transplant patients treated with methotrexate.

Methotrexate (MTX), used as a graft-versus-host disease (GvHD) prophylactic agent in hematopoietic stem cell transplantation (HSCT), exerts its effect via folate cycle inhibition. A critical enzyme involved in folate metabolism is 5,10-methylenetetrahydrofolate reductase (MTHFR). We examined the association of a single nucleotide polymorphism (SNP) at position 677 in the MTHFR gene on GvHD outcomes in allogeneic HSCT patients administered MTX. MTHFR genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on 193 HSCT patients and donors. A total of 140 patients were transplanted with an HLA-matched related donor and 53 with an unrelated donor. GvHD outcomes were compared between genotypes by univariate and multivariate analysis. The combined donor 677CT and TT genotypes were associated with a decreased incidence of GvHD (acute and chronic combined) in HSCT recipients with an HLA-matched related donor (75% at 1 year in the CT and TT group compared with 91% in the wild type CC group, P=0.01), increased time to onset of first GvHD (P=0.001) and time to first GvHD treated with systemic therapy (P=0.022). Unrelated donor MTHFR genotype was not associated with outcome parameters and no associations of recipient genotype in either related or unrelated donor cohorts were observed.

Adolescent↗
PubMed2006

Reduced-intensity allogeneic haemopoietic stem cell transplantation induces durable responses in patients with chronic B-lymphoproliferative disorders.

Thirty-six patients with chronic B-lymphoproliferative disorders (B-LPD) underwent reduced-intensity allogeneic transplantation (RIT) from HLA-identical related donors. Diagnoses included follicular (n=17), mantle cell (n=9) and small lymphocytic lymphoma (n=2), and chronic lymphocytic leukaemia (n=8). Median age at transplant was 51 years (range, 30-66) and time from diagnosis was 3.4 years (range, 0.3-9.5). At transplant, 28% were in CR, 36% were in PR and 36% were chemorefractory. Conditioning therapy included fludarabine and either cyclophosphamide (n=27) or melphalan (n=9). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin (CsA)/methotrexate (n=21), CsA/mycophenolate mofetil (n=13) or CsA alone (n=2). Eight patients died owing to acute GVHD (n=3), infection in association with chronic GVHD (n=4) and intra-abdominal bleeding (n=1). Treatment-related mortality was 8% at day 100, and 17 and 20% at one and two years, respectively. The cumulative incidence of grade II-IV acute GVHD was 58%, whereas limited and extensive chronic GVHD occurred in 25 and 56%, respectively. No patient has relapsed or progressed. At a median follow-up of 48 months, overall survival probability is 80% (95% CI, 67-93%). We confirm that RIT in chronic B-LPD can result in high and durable CR rates but with significant incidences of acute and chronic GVHD.

Adolescent↗
PubMed2006

Long-term survival data from a phase 3 study of Filgrastim as an adjunct to chemotherapy in adults with de novo acute myeloid leukemia.

We previously reported the results of a double-blind, placebo-controlled study of Filgrastim in patients with de novo AML undergoing induction and consolidation chemotherapy. The study demonstrated that Filgrastim was effective and well tolerated and had no impact on complete remission or survival. We now report follow-up data on these patients, assessing long-term effects with emphasis on prognostic indicators. After a median follow-up of 7 years, 434 (83%) patients were dead, 73 (14%) were alive, and 14 (3%) were lost to follow-up. The proportions of deaths were similar in the Filgrastim (83%) and placebo (84%) groups. No differences in median time to death (1.04 years Filgrastim, 1.13 years placebo; P = 0.97) or median disease-free survival (0.86 years Filgrastim, 0.79 years placebo; P = 0.52) were evident. Proportional hazard modeling identified age, performance status, and French-American-British subtype as independent predictors for survival (P < 0.001, P = 0.005, and P = 0.036, respectively), whereas cytogenetic status was not (P = 0.118). Filgrastim had no effect on overall survival in any of these subgroup analyses as none of the treatment comparisons were statistically significant. These findings indicate that Filgrastim can be effectively used to support patients with AML undergoing induction and consolidation chemotherapy without worsening long-term disease outcome.

Acute Disease↗
PubMed2006

Zoledronic acid prevents bone loss after allogeneic haemopoietic stem cell transplantation.

Allogeneic haemopoietic stem cell transplant (alloHSCT) patients are at increased risk of osteoporosis. Zoledronic acid (ZA) is a potent i.v. bisphosphonate; however, there are few data on ZA use after alloHSCT. The aim of this study is to examine the effect of a single 4 mg ZA infusion in alloHSCT patients with either osteoporosis (T-score < -2.5) or rapid bone loss post-alloHSCT. An uncontrolled, prospective study of 12 consecutive patients receiving ZA, predominantly within the first year post-HSCT. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at the spine and proximal femur pretransplant, pre-ZA and post-ZA. The median annualized percentage change in total hip BMD between the pretransplant scan and the scan immediately before ZA was -13% (range, -51 to +3.6%). After ZA treatment, the total hip BMD increased by a median of +3.3% (range, -20.4 to +14.8%) in 75% of patients. The median annualized percentage change in femoral neck BMD between the pretransplant scan and the scan immediately before ZA was -13.2% (range, -40 to +1.0%). Post-ZA, femoral neck BMD increased by a median of +1.4% (range, -22.2 to +33.6%). Only one patient continued to lose bone from the femoral neck post-ZA infusion. The median annualized percentage change in spinal BMD pretransplant was -12.5% (range, -38 to +6.9%). Post-ZA, spinal BMD decreased by a median of -2.8% (range, -27.6 to +24.4%). Four patients continued to lose bone from the spine post-ZA. ZA reduces bone loss in most patients after alloHSCT. Our data require confirmation in a larger prospective, randomized study.

Adult↗
PubMed2005

Optimal scheduling to reduce morbidity of involved field radiotherapy with transplantation for lymphomas: a prospective Australasian Leukaemia and Lymphoma Group Study.

This study evaluated delivery of involved field radiotherapy (IFRT) with transplantation for lymphomas timed to minimise toxicity. Patients transplanted for lymphoma had infradiaphragmatic disease irradiated pre-transplant and supradiaphragmatic disease post transplant. A total of 31 patients were studied, with a median follow-up duration of 4 years. Transplant conditioning was according to clinician preference. In all, 14 patients had pre-transplant abdominopelvic IFRT and 19 had post transplant IFRT (including three who had pre-transplant IFRT). Grade III-IV haematological toxicity from pre-transplant IFRT occurred in three patients and from post transplant IFRT in 10 patients. Pre-transplant IFRT had no effect on haematological recovery post transplant, but was associated with a trend towards increased gastrointestinal toxicity (P = 0.094). Pneumonitis due to post transplant thoracic IFRT occurred in one patient. Two patients failed in involved sites after completion of protocol radiotherapy. One case of myelodysplasia has been reported. As sequenced in this study, IFRT was feasible and produced a low incidence of severe pulmonary and haematological toxicities. Patient selection, field size and radiotherapy dose warrant further study.

Adolescent↗
PubMed2005

Haemopoietic stem cell transplantation in Australia and New Zealand, 1992-2001: progress report from the Australasian Bone Marrow Transplant Recipient Registry.

BACKGROUND: Bone marrow and blood stem cell transplantation is now used as curative therapy for a range of haematological malignancies and other conditions. The Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) has recorded transplant activity in Australia since 1992; transplant centres in New Zealand have corresponded with the Registry since 1998. AIM: To describe allogeneic and autologous bone marrow and blood stem cell transplantation activity and outcomes in Australia and New Zealand from 1992 to 2001. METHODS: Each haemopoietic stem cell transplant centre in Australia and New Zealand contributes information to the Registry via a single information form compiled when a transplant is performed. An annual follow-up request is then sent from the Registry to the contributing centre at the anniversary of each individual transplant. RESULTS: Haemopoietic stem cell transplants in Australia have increased in number from 478 in 1992 to 937 in 2001, whereas in New Zealand the number has grown from 91 in 1998 to 105 in 2001, mainly as a result of an increase in autologous blood stem cell transplants. The number of hospitals contributing to the ABMTRR has grown from 20 in 1992 to 37 in 2001. The most common indication for autologous transplantation in 2001 was non-Hodgkin's lymphoma, whereas for allogeneic transplants it was acute myeloid leukaemia. The 9-year actuarial disease-free survival probability for patients aged 16 and above between 1992 and 2000 was 37% for autologous, 39% for allogeneic related donor and 30% for allogeneic unrelated donor transplants. Recurrence of the underlying disease was the main cause of death post-transplant after both allogeneic (26.3% of deaths in the first year and 68.0% of deaths in the second year) and autologous transplants (59.0% and 86.2%). Treatment-related mortality was 16.9% after allogeneic transplantation and 2.1% after autologous transplantation in 2000. CONCLUSIONS: The ABMTRR provides a comprehensive source of information on the use of bone marrow transplant, and allows for continuing analysis of changes in the application of this high-cost technology and the outcome of patients undergoing these procedures. Registry data provide a means for directing future clinical research into perceived areas of priority for improvement of outcome, such as the reduction in the risk of disease recurrence post-transplant.

Acute Disease↗
PubMed2005

Enzyme replacement therapy for Gaucher disease in Australia.

AIM: To study the effectiveness of a specific national programme of enzyme replacement therapy (ERT) for patients with severe forms of Gaucher disease, a disorder of sphingolipid metabolism resulting from an inherited deficiency of the lysosomal enzyme beta-Glucocerebrosidase. METHODS: Prospective analysis of data submitted at entry and every 6 months on therapy. The responses of haemoglobin (Hb) and platelet (plt) concentrations, liver and spleen volumes were assessed. PATIENTS: Forty-eight patients were treated with ERT for a minimum of 6 months. Forty patients had Type 1 disease and eight had Type 3B. The age range was 1-70 years (median 24 years). Duration of therapy at the time of analysis was 6-114 months. RESULTS: Thirty-six per cent of patients started with a normal Hb increasing to 76% after 6 months. The mean improvement in Hb from baseline to the end of study period was 20 g/L, when the Hb was normal in 85% (41 patients). Thirty per cent of patients had a normal plt count at the start of therapy, with a more gradual increase in the count at 6 monthly intervals of 50, 91, 108 and 142% of starting value. Seventy-five per cent of patients had a normal plt count at the end of study. Spleen volumes reduced by a mean of 56% in 33 evaluable patients, and the liver by 27% in 30 of 38 evaluable patients. Eight patients had an increase in liver volume of 28%. CONCLUSION: Enzyme replacement therapy produced a spectrum of beneficial responses in patients with Gaucher disease, but all had some evidence of reversal of haematological complications and/or reduction in visceromegaly. Future analyses will examine the effect of therapy on bone disease, prepubertal growth and quality of life.

Adolescent↗
PubMed2005

Recombinant activated factor VII in treatment of bleeding complications following hematopoietic stem cell transplantation.

BACKGROUND: Bleeding is a common complication following hematopoietic stem cell transplantation (HSCT) and standard hemostatic treatment is often ineffective. We conducted a multicentre, randomized trial of the efficacy and safety of activated recombinant factor VII (rFVIIa, NovoSeven) in the treatment of bleeding following HSCT. METHODS: 100 patients with moderate or severe bleeding (52 gastrointestinal; 26 hemorrhagic cystitis; seven pulmonary; one cerebral; 14 other) were included from days +2 to +180 post-transplant (97 allogeneic; three autologous) to receive seven doses of rFVIIa (40, 80 or 160 microg kg(-1)) or placebo every 6 h. The primary efficacy endpoint was the change in bleeding score between the first administration and 38 h. RESULTS: No significant effect of increasing rFVIIa dose was observed on the primary endpoint. A post hoc analysis comparing each rFVIIa dose with placebo showed that 80 microg kg(-1) rFVIIa improved the bleeding score at the 38 h time point (81% vs. 57%, P = 0.021). This effect was not seen at 160 microg kg(-1). There were no differences in transfusion requirements across dose groups. There was no trend in the type or number of severe adverse events observed. Six thromboembolic events were observed in the active treatment groups: three during, and three following the 96-h observation period. CONCLUSIONS: Despite no overall effect of rFVIIa treatment on primary endpoint, post hoc analysis showed an improvement in the control of bleeding for 80 microg kg(-1) rFVIIa vs. standard hemostatic treatment. The heterogeneity of the population may have contributed to the lack of an increasing effect with increased dose. Further trials should focus upon identifying the patient populations that may benefit from treatment with rFVIIa.

Adolescent↗
PubMed2004

Risk factors for post-engraftment invasive aspergillosis in allogeneic stem cell transplantation.

The majority of invasive aspergillosis (IA) in allogeneic stem cell transplantation (SCT) occurs during the post-engraftment period. We used Cox proportional hazards regression to evaluate post-engraftment IA risk in a cohort of 217 allogeneic SCT recipients from 1991 to 1998. The aim was to quantify the effects of dose-intensity and duration of corticosteroids and other risk factors. Median duration of follow-up was 330 days. There were 19 cases of IA (overall 8.8%) with 14 post-engraftment infections. In the final model, the risk of IA was greatest within 2 weeks of high-dose corticosteroids (HR 8.5, P=0.003), with risk extending to 4 weeks with doses of 0.25-1 mg/kg/day (HR 3.1, P=0.08). Ganciclovir was associated with greatest risk (HR 13.6). Grade 3 or 4 acute GVHD (HR 5.7) and secondary neutropenia (HR=1.3) were also additive risks. In the univariate analysis, corticosteroid doses of 0.25-1.0 mg/kg/day for any duration between 2 and 10 weeks demonstrated prolonged risk for IA. Moderate doses of corticosteroids can confer an increased risk for IA for extended periods which is almost as marked as that conferred by higher doses. Knowledge of these risks may facilitate the development of targeted surveillance and prophylaxis strategies for prevention of IA.

Adolescent↗
PubMed2004

A pilot study of targeted itraconazole prophylaxis in patients with graft-versus-host disease at high risk of invasive mould infections following allogeneic stem cell transplantation.

Patients with severe graft-versus-host disease (GVHD) requiring intensive immunosuppression are at high risk of invasive mould infections (IMI). Prophylaxis with an active, oral antifungal agents with reliable absorption in this context is desirable. A total of 44 patients at high risk of post-engraftment IMI received itraconazole solution 2.5 mg/kg b.d. as prophylaxis. Two of the first nine patients, in whom bioavailability was compromised due to significant vomiting and/or diarrhoea, died of probable or proven invasive aspergillus. None of the subsequent 35 patients, some of whom had severe gut GVHD and who received liposomal amphotericin B prophylaxis until itraconazole was reliably tolerated and absorbed, developed IMI. The overall incidence of IMI was substantially lower than in historical controls. Itraconazole was generally well tolerated, with five patients (11%) ceasing the drug due to intolerance or disturbed liver function. Targeted prophylaxis with oral or parenteral antifungal agents in high-risk allograft recipients appears to be effective in reducing the incidence of IMI.

Adolescent↗
PubMed2004

Guidelines for the use of antifungal agents in the treatment of invasive Candida and mould infections.

ABSTRACT Treatment of invasive fungal infections is increasingly complex. Amphotericin B deoxycholate has long been the mainstay of treatment. However, there has been increasing recognition of both the propensity for nephro-toxicity in haematology, transplant and intensive care patients as well as its adverse impact on morbidity and mortality. This has coincided with the availabilty of newer, and in certain settings, more effective antifungal agents. Although the newer agents clearly cause less nephrotoxicity than amphotericin B, drug interactions, hepatic effects and unique side-effects need to be considered. The spectrum of the newer triazoles and echinocandins varies, highlighting the importance of accurate identification of the causative organism where possible. Consensus Australian guidelines have been developed to assist clinicians with treatment choices by reviewing the current evidence for the efficacy, the toxicity and the cost of these agents.

Antifungal Agents↗
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↗