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Biomedical subjects

J Szer

Publications and source records attributed to J Szer.

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

Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose aciclovir and ganciclovir.

We examined the incidence of herpes varicella-zoster virus (VZV) infection in 151 patients undergoing allogeneic BMT between August 1990 and September 1997 and who survived at least 3 months. Median follow-up was 17 (range 3.3-80.7) months. Herpes simplex virus antibody positive (HSV+) patients received aciclovir 1200 mg p.o. daily or 750 mg i.v. daily, in divided doses from day 0 to engraftment. Ganciclovir (5 mg/kg i.v. three times per week) was given in CMV+ patients (or if the donor was CMV+) from engraftment to day 84. Ganciclovir was continued or recommenced if a dose of greater than 20 mg of prednisone was used for the treatment of GVHD otherwise aciclovir was recommenced. In HSV+ patients not receiving ganciclovir, aciclovir 600 mg p.o. daily in divided doses was given until at least 6 months after BMT. Thirty-two patients developed VZV infection from 4.1 to 28 months after transplant. The estimated cumulative incidence of VZV was 13% (95% confidence interval 6-19%) at 12 months, 32% (22-42%) at 24 months and 38% (27-50%) at 28 months, with no further cases beyond that time. No patient developed VZV whilst receiving aciclovir or ganciclovir (P < 0.0001). However, there was a rapid onset of VZV following cessation of antiviral therapy (33% (20-46%) at 1 year post cessation). The presence of GVHD and the prior duration of antiviral prophylaxis were significant and independent risk factors for the development of VZV. Age, underlying disease, conditioning therapy or donor type were not. We conclude that 3-6 months of low-dose aciclovir and ganciclovir are effective at delaying the onset of VZV after allogeneic BMT, but may not affect the overall incidence of infection. Prolonged prophylaxis may be warranted in patients at high risk of infection, for example those patients with GVHD.

2-Aminopurine↗
PubMed2000

Neurological events associated with the infusion of cryopreserved bone marrow and/or peripheral blood progenitor cells.

Reports of neurological toxicity of cryopreserved stem cell infusion are infrequent. Three of 179 consecutive patients experienced significant neurological events in this context. Transient global amnesia developed following infusion in one patient and in the other two, cerebral infarction occurred. Profound hypotension, bradyarrhythmias or hypoxia were not associated with any of these episodes. These events may have been related to infused DMSO, which in the non-transplant setting has been associated with neurological toxicity and local infusion of which has resulted in acute vasospasm in animal models. These cases suggest that infusion of cryopreserved stem cells may result in cerebrovascular ischaemia. Bone Marrow Transplantation (2000) 25, 1285-1287.

Bone Marrow↗
PubMed2000

Extramedullary relapse after allogeneic bone marrow transplantation for haematological malignancy.

We describe the risk factors for and the natural history and response to treatment of extramedullary (EM) relapse in 183 patients who underwent allogeneic bone marrow transplantation (alloBMT) for a variety of haematological malignancies at our institution over a 7 1/2 year period. Fifty-one patients relapsed; 15 had EM relapse either alone or in association with marrow involvement. A retrospective analysis found that the presence of chronic GVHD and a longer interval between transplant and relapse were independently associated with an increased risk of EM compared to marrow-only relapse. EM relapse was also associated with a longer post-relapse survival. Patients with EM relapse appeared to respond to cytotoxic therapy but not to DLI. EM relapse after alloBMT may be more common than previously thought and have a better prognosis than marrow-only relapse. While patients developing chronic GVHD after alloBMT have a lower overall relapse risk than those who do not, they may be more prone to delayed relapse at EM sites.

Adolescent↗
PubMed2000

Reproductive status in long-term bone marrow transplant survivors receiving busulfan-cyclophosphamide (120 mg/kg).

There are few published data on the recovery of fertility after 'little' Bu-Cy (busulfan 16 mg/kg, cyclophosphamide 120 mg/kg) conditioning for BMT. To address this, we identified 19 females aged less than 40 years at transplant and 47 males from a single centre who were alive a minimum of 2 years after BMT with little Bu-Cy as conditioning and who were evaluable for testing. FSH, LH, testosterone and inhibin B levels were measured in males. Twenty-six also had semen analysis, a median of 5 years post transplant; 21 had detectable sperm, with 11 having counts >20 x 10(6)/ml. There was an association between prolonged chronic graft-versus-host disease and low sperm counts. FSH and inhibin B levels correlated with sperm counts but not to the extent that they could reliably predict counts in individual patients. An additional six of seven males attempting to father children did so, a median of 3.2 years post transplant. Low testosterone levels were noted in 12% of males, most of whom had symptoms consistent with androgen deficiency. FSH, LH and oestradiol levels in the absence of hormone replacement therapy were measured in females; all remained amenorrheic with endocrine evidence of ovarian failure. These results have implications for fertility counselling and hormone replacement therapy both pre- and post BMT.

Adult↗
PubMed2000

Prolonged disease-free survival after autografting for chemosensitive non-bulky low grade non-Hodgkin's Lymphoma.

The results of autografting in patients with relapsed low grade non-Hodgkin's Lymphoma (NHL) have generally been disappointing due to the failure to maintain remission and the late development of myelodysplasia. Most series have used regimens that include total body irradiation and purged stem cells. We evaluated the outcome in 32 patients with low grade NHL autografted using chemotherapy-only busulfan-based conditioning and unpurged stem cells. Seven of 10 patients with poor prognostic features at diagnosis remain alive in CR a median of 78 months (range 14-129) post-transplant. Twenty two patients with relapsed, chemosensitive, low bulk disease, most of whom did not have marrow involvement or an elevated LDH, were transplanted. Only five of the 22 have relapsed, with an 86 +/- 8% overall survival and 72 +/- 10% event free survival (EFS) after a median follow-up of 56.5 months. All but one patient has an EFS period longer, often substantially so, than their previous longest remission. No patient has developed myelodysplasia. These data suggest that in selected patients with poor prognosis or relapsed low grade NHL autografting has a favourable impact on the natural history of their disease and may result in long-term disease control.

Actuarial Analysis↗
PubMed1999

Fludarabine-based non-myeloablative chemotherapy followed by infusion of HLA-identical stem cells for relapsed leukaemia and lymphoma.

Many patients have not been offered potentially curative allogeneic marrow transplants because of the toxicity of myeloablative regimens in the setting of advanced age or organ dysfunction. We treated five patients, ineligible for myeloablative chemotherapy due to one of these criteria, with fludarabine-based non-myeloablative chemotherapy followed by reinfusion of G-CSF-mobilised allogeneic peripheral blood progenitor cells (PBPC). Two patients died early of multi-organ failure. Another patient with massive splenomegaly was infused with a suboptimal number of PBPC; no engraftment was documented. The remaining two patients demonstrated mixed chimerism early post-transplant, but by 3 and 6 months respectively, engraftment was almost entirely of donor origin. One of these patients, transplanted with relapsed AML, remains in remission with extensive chronic GVHD at 17 months. The other patient, transplanted with chemorefractory mantle cell lymphoma, progressed early post-transplant but entered remission coincident with the onset of severe GVHD following cessation of cyclosporin A, suggesting a powerful graft-versus-mantle cell lymphoma effect. These preliminary observations suggest this approach results in engraftment and GVHD/graft-versus-tumour effects similar to myeloablative regimens and may provide an alternative in patients ineligible for conventional conditioning regimens.

Adult↗
PubMed1999

Bone marrow transplants for paroxysmal nocturnal haemoglobinuria.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare clonal haematological disorder characterized by intravascular haemolysis and increased risk of thrombosis. PNH is associated with bone marrow failure syndromes including aplastic anaemia, myelodysplasia and leukaemia. Bone marrow transplants are sometimes used to treat PNH, but small series and reporting biases make assessment of transplant outcome difficult. The outcome of 57 consecutive allogeneic bone marrow transplants for PNH reported to the International Bone Marrow Transplant Registry (IBMTR) between 1978 and 1995 was analysed. The 2-year probability of survival in 48 recipients of HLA-identical sibling transplants was 56% (95% confidence interval 49-63%). Two recipients of identical twin transplants remain alive 8 and 12 years after treatment. One of seven recipients of alternative donor allogeneic transplants is alive 5 years after transplant. The most common causes of treatment failure were graft failure and infections. Our results indicate that bone marrow transplantation can restore normal bone marrow function in about 50% of PNH patients.

Adolescent↗
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↗
PubMed1999

Mini-allografts' for haematological malignancies: an alternative to conventional myeloablative marrow transplantation.

BACKGROUND: Considerable morbidity and mortality are consequences of the myeloablative chemoradiotherapy utilised in conventional allogeneic marrow transplantation. This has generally restricted such potentially curative treatment to patients <50-55 years with normal organ function. Recent studies suggest that purine-analogue based non-myeloablative regimens are sufficiently immunosuppressive to facilitate allogeneic donor cell engraftment. AIM: To review the outcome of HLA-compatible sibling allogeneic peripheral blood progenitor cell (PBPC) transplants using fludarabine-based conditioning in patients ineligible for a conventional transplant, with emphasis on engraftment, graft vs host disease (GVHD) and graft vs tumour effects. METHODS: Eleven patients (nine > or = 47 years age) with advanced haematological malignancies received one of three different fludarabine-based chemotherapy followed by infusion of granulocyte colony-stimulating factor mobilised PBPC. Cyclosporin-methotrexate was used as GVHD prophylaxis. RESULTS: Two patients died early; minimal non-haematological toxicity apart from mucositis occurred in the other nine. Eight of the nine evaluable patients had evidence of durable donor cell engraftment in preference to recipient cells. Acute GVHD (> or = grade 2) occurred in seven of eight patients with donor engraftment who survived beyond two months. Four patients are alive in complete remission 8-28 months post-transplant; another is alive in probable remission at four months. CONCLUSIONS: Fludarabine-based non myeloablative chemotherapy facilitates rapid engraftment of allogeneic donor cells, which produce powerful GVHD and graft vs tumour effects. This approach has the potential to extend the applicability of allogeneic stem cell transplants to patients traditionally regarded as too old or sick for conventional marrow transplants.

Adult↗
PubMed1999

The addition of allogeneic peripheral blood-derived progenitor cells to bone marrow for transplantation: results of a randomised clinical trial.

BACKGROUND: The use of cytokine-mobilised peripheral-blood-derived progenitor cells (PBPC) has resulted in a significant improvement in the safety of autologous transplantation. Collections of PBPC contain large numbers of haemopoietic progenitors and T-lymphocytes when compared with bone marrow (BM). AIMS: To assess the clinical effects and safety of filgrastim-mobilised allogeneic PBPC, in particular whether PBPC would alter the kinetics of engraftment or the incidence and severity of graft-versus-host disease (GVHD). METHODS: Twenty-seven patients undergoing allogeneic transplantation were randomised to receive BM or BM supplemented by PBPC. Patients were conditioned with busulphan 16 mg/kg and cyclophosphamide 120 mg/kg. GVHD prophylaxis was with methotrexate and cyclosporin. Ganciclovir prophylaxis was administered to all cytomegalovirus seropositive patients. No haemopoietic growth factor was used after BMT. Donors of PBPC underwent a single, seven litre apheresis after four days of filgrastim, 10 microg/kg/day by subcutaneous injection. RESULTS: Donor toxicity was mild, with the most frequently reported being bone pain in the cytokine-treated donors. The patients transplanted with BM+PBPC received an eight-fold increase in CD3+ T-lymphocytes (1.65X 10(8)kg vs 0.22 x 10(8)/kg, p=0.04) and the cytokine product contained a median of 5 x 10(6) CD34+ cells/kg. BM+PBPC patients had more rapid engraftment of neutrophils to 0.5x 10(9)/L (17 days vs 19 days, p=0.02) and platelets to 50X 10(9)/L (22 days vs 35 days, p=0.04). BM megakaryocyte numbers were significantly enhanced at days 14 and 28 after BMT (both p=0.04), however platelet transfusions were not significantly different. The incidence, organ distribution, severity and time to onset of acute and chronic GVHD were not different between the treatment groups and there was no difference in overall survival or event-free survival. CONCLUSIONS: Allogeneic PBPC from HLA-identical siblings may speed engraftment of neutrophils and platelets without detrimental effects on GVHD or survival.

Adult↗
PubMed1999

Multicycle high-dose chemotherapy and filgrastim-mobilized peripheral-blood progenitor cells in women with high-risk stage II or III breast cancer: five-year follow-up.

PURPOSE: To determine the safety and efficacy of multiple cycles of dose-intensive, nonablative chemotherapy in women with poor-prognosis breast cancer. PATIENTS AND METHODS: Women with stage II breast cancer and 10 or more involved nodes or four or more involved nodes and estrogen receptor-negative tumors and women with stage III disease received three cycles of epirubicin 200 mg/m2 and cyclophosphamide 4 g/m2, with progenitor cell and filgrastim support every 28 days (n = 79) or 21 days (n = 20). Patients were reviewed at least twice yearly thereafter. Twenty-six patients had bone marrow and apheresis collections assessed for the presence of micrometastatic tumor cells. RESULTS: Ninety-nine women (median age, 43 years; range, 24 to 60 years) were treated. Ninety-two completed all three cycles of chemotherapy. The major toxicity was severe, reversible myelosuppression that was more prolonged with successive cycles, and this did not differ between patients given treatment every 28 days and those treated every 21 days. Febrile neutropenia occurred in 176 (61%) of 287 cycles. Severe mucositis (grade 3 or 4) occurred in 23% of cycles but tended to be short-lived and was reversible. The cardiac ejection fraction fell by a median of 4% during treatment, and three patients developed evidence of cardiac failure after chemotherapy. Two patients (2%) died of acute toxicity. Three of 26 patients had evidence of circulating micrometastatic tumor cells. The actuarial distant disease-free and overall survival rates at 60-month follow-up were 64% (95% confidence interval [CI], 53% to 75%) and 67% (95% CI, 56% to 78%), respectively. CONCLUSION: Multiple cycles of dose-intensive, nonablative chemotherapy is a feasible and safe approach. Disease control and survival are similar to those in other studies of myeloablative chemotherapy in poor-prognosis breast cancer. The regimen is being evaluated in a randomized trial of the International Breast Cancer Study Group.

Adult↗
PubMed1999

Mechanisms of bone loss following allogeneic and autologous hemopoietic stem cell transplantation.

A significant proportion of patients will be long-term survivors of bone marrow transplantation (BMT) and little is known about their risk of late bony complications. We therefore evaluated bone mineral density (BMD) prior to BMT, post-transplantation changes in BMD, and mechanisms of bone loss in long-term survivors. We performed two analyses. The first was a cross-sectional study of 83 consecutive BMT patients (38 F, 45 M), examining the relationship between BMD and bone turnover, measured immediately prior to transplantation, and a number of disease and patient variables. The second was a prospective study of 39 patients (19F, 20 M) followed for a median of 30 months (range 5-64 months) following either allogeneic (allo, n = 29) or autologous (auto, n = 10) BMT to determine if bone loss was related to treatment of graft versus host disease (GVHD) with glucocorticoids and cyclosporine A, high bone turnover rates, or hypogonadism. Auto BMT recipients acted as a control group for effects of GVHD therapy on BMD. Prior to BMT, spinal and femoral neck (FN) BMDs were 8.6% and 14% lower in female auto BMT recipients than in female allo BMT recipients, respectively (p = 0.12 and p = 0. 003). Urinary bone resorption markers were higher than in normal gender- and age-matched control subjects. Patients treated previously with glucocorticoids also had 8% lower FN BMD. Glucocorticoid-pretreated women with amenorrhoea had lower lumbar spine (LS) and FN BMDs than eumenorrheic women and women receiving HRT. Post-allo BMT, patients lost 11.7% of FN BMD compared with a nonsignificant decrease of 1.1% post-auto BMT (p < 0.001). Spinal BMD and total body bone mineral content (TBBMC) decreased by 3.9% and 3.5%, respectively, post-allo, compared with an increase (1.5%, p = 0.03) or nonsignificant decrease (-3.7%, p = NS), respectively, post-auto BMT. Post-allo BMT bone loss correlated best with the cumulative prednisolone dose at the LS and FN, and with average daily prednisolone dose for TBBMC. At the spine, the rate of bone loss was 4%/10 g of prednisolone, while the rate of bone loss at the FN was greater (9%/10 g of prednisolone). Bone loss was also negatively related to the duration of cyclosporine therapy for GVHD and baseline deoxypyridinoline concentrations. Avascular necrosis of the femoral head occurred in four, and vertebral and rib fractures occurred in one of the allo BMT patients, but in no auto BMT patients. In conclusion, BMT recipients are at risk of osteoporosis secondary to bone loss associated with their underlying illness and/or chemotherapy, particularly in female autograft recipients, and in allograft recipients secondary to GVHD and its treatment.

Adult↗
PubMed1998

Fatal CMV pneumonia associated with steroid therapy after autologous transplantation in patients previously treated with fludarabine.

Fludarabine has been associated with an increased risk of opportunistic infections, possibly related to the induction of profound CD4+ lymphopenia. We observed two cases of cytomegalovirus pneumonia (CMV-IP) in a total of nine patients over a 5-year period who had previously received fludarabine and who proceeded to autografting. Both patients also received steroids post-transplant. CMV-IP was observed in one of 104 other autograft recipients over this time who had not received prior fludarabine. This observation suggests that the combination of fludarabine pre-transplant and steroids post-transplant may increase the risk of invasive CMV disease in autograft recipients.

Adult↗
PubMed1998

Progress in management of acute myeloid leukaemia (AML) in Australia since 1980: a single institution retrospective study.

BACKGROUND: Much research has been conducted into the pathobiology, diagnosis, and management of acute myeloid leukaemia (AML) since 1980, with major contributions from Australian studies in this period. AIMS: To determine whether advances in basic and clinical research into AML have translated into improved survival for patients in the community. METHODS: A retrospective survey of records of all patients with AML presenting to the Royal Melbourne Hospital (RMH) over a 16 year period, analysed according to induction therapy and established prognostic factors. Between 1980 and December 1996 223 (98%) of 227 patients were evaluable. RESULTS: The probability of survival at five years for patients treated since 1990 has improved significantly compared to the cohort treated between 1980-89 (34 +/- 5% vs 4 +/- 2%; mean +/- standard error). This benefit is most evident in patients less than 60 years of age (50 +/- 7% vs 11 +/- 4%). Successive induction protocols in the context of clinical trials conducted since 1985 contributed to improved outcomes. The selective application of bone marrow transplantation, and use of retinoic acid as induction therapy for acute promyelocytic leukaemia has also improved survival. Despite increases in dose-intensity, early death rates for patients undergoing induction therapy fell during the study period. CONCLUSIONS: Participation in clinical and basic research with the development of more intense and specific treatments for patients with AML has contributed to better outcomes, underpinned by improvements in supportive care.

Acute Disease↗
PubMed1998

Rapid hematopoietic recovery after multicycle high-dose chemotherapy: enhancement of filgrastim-induced progenitor-cell mobilization by recombinant human stem-cell factor.

PURPOSE: To assess the mobilization potential and safety of recombinant human stem-cell factor (SCF) when coadministered with filgrastim to untreated women with poor-prognosis breast cancer. PATIENTS AND METHODS: Eligible women had breast cancer with 10 or more positive axillary nodes, or estrogen receptor-negative tumor with 4 positive nodes, or stage III disease. Patients were randomized to receive SCF plus filgrastim or filgrastim alone. Filgrastim 12 microg/kg daily was administered for 6 days by continuous subcutaneous infusion. SCF was administered by daily subcutaneous injection at 5, 10, or 15 microg/kg concurrent with filgrastim for 7 days, or 10 microg/kg daily starting 3 days before filgrastim for a total of 10 days (SCF pretreatment). Apheresis was performed on days 5, 6, and 7 of filgrastim administration. Patients then had three cycles of epirubicin 200 mg/m2 and cyclophosphamide 4 g/m2 every 28 days, each supported by one third of the apheresis product. RESULTS: Sixty-two women were treated. Greater yields occurred in patients who received SCF 10 microg/kg daily plus filgastim than those who received filgrastim alone (P=.013 for CD34+ cells; P=.07 for granulocyte-macrophage colony-forming cells [GM-CFCs]). The difference was more marked with SCF-pretreatment than concurrent SCF. Fewer aphereses were required to reach the predetermined target of peripheral-blood progenitor/stem cells (PBPCs) in women who received SCF. SCF was generally well tolerated. Hematologic recovery was rapid after each of the three cycles of chemotherapy. There was no difference in recovery between the different treatment groups. CONCLUSION: Mobilization of PBPCs by filgrastim is significantly enhanced by coadministration of SCF, and commencing SCF before filgrastim can optimize this effect. SCF has the potential to reduce the number of aphereses required to collect a target number of PBPCs.

Adult↗
PubMed1998

HLA-identical sibling peripheral blood cell transplants. The Australian experience and preliminary results of a randomised study.

Twenty-seven patients undergoing matched sibling BMT were randomly assigned to be infused with bone marrow alone or bone marrow supplemented with allogeneic peripheral blood cells collected by apheresis after stimulation with filgrastim. Other transplant conditions were standard and identical for the two groups. There was no difference between the groups in survival or acute or chronic GVHD, however, the patients receiving blood cells had significantly more rapid neutrophil engraftment by a median of 2 days. We conclude that filgrastim-mobilised HLA-identical sibling allogeneic blood cells are biologically active and safe.

Adolescent↗