SEARCH · PubMed Health

Results for “Myeloablative Agonists”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 91 records · Page 5Linked to original sources

PubMed2001

Infectious complications within the first year after nonmyeloablative allogeneic peripheral blood stem cell transplantation.

Nonmyeloablative peripheral blood stem cell transplantation (PBSCT) is a novel therapeutic strategy for patients with malignant and non-malignant hematologic diseases. Infectious complications of this procedure have not been previously well described. Data on 12 patients transplanted at a tertiary care center were collected prospectively and verified retrospectively. Neutropenia developed in a third of patients, lasting for a median of 5 days. All patients developed some degree of graft-versus-host disease, as intended. Most patients achieved full chimerism by week 5. Bacterial infections occurred in two patients (17%). Cytomegalovirus (CMV) viremia occurred in five patients (42%) at a median of 80 days; none had received CMV prophylaxis. Viremia was associated with fever and fatigue in three patients, possible gastrointestinal involvement in one patient and was asymptomatic in one patient. All viremic patients responded to intravenous ganciclovir therapy. No fungal infections were documented. No patients died as a result of infection. The incidence of CMV viremia in our patients was high, but the incidence of invasive disease due to CMV was low. The best strategy to prevent CMV in patients undergoing nonmyeloablative PBSCT remains to be determined, but strategies employed in traditional allogeneic bone marrow transplantation should be considered in these patients.

Adult↗

PubMed2002

Isolation and transplantation of highly purified autologous peripheral CD34(+) progenitor cells: purging efficacy, hematopoietic reconstitution and long-term outcome in children with high-risk neuroblastoma.

We have investigated the purging efficacy of positive selection of autologous mobilized CD34(+) peripheral stem cells in 22 children with high-risk neuroblastoma. CD34(+) cell selection was performed using the method of magnetic-activated cell sorting (MACS). The median purity of the CD34(+) cells post selection was 97.6% (range 81.7-99.7). For detection of contaminating neuroblastoma cells before and after CD34(+) selection, the chimeric anti-disialoganglioside GD2 antibody delta ch 14.18 was used. Prior to positive selection, various numbers of contaminating neuroblastoma cells were found in 17 patients. After positive CD34(+) cell selection, low numbers of neuroblastoma cells were only detectable in four patients. In 18 patients, high-dose chemotherapy was performed and the isolated CD34(+) cells were reinfused. In all patients, a rapid neutrophil recovery was seen with a median time to reach 0.5 x 10(9)/l neutrophils of 12 days (range 8-24 days). Nine of the 18 patients are free of progression with a median follow-up of 55 months (range 45-70 months). Two patients are alive with relapse, six patients died due to progression or relapse and one patient died due to secondary AML 10 months after transplant while in remission from neuroblastoma. In summary, we show that, through a highly effective positive selection method, a high purging efficacy can be obtained without compromising the hematopoietic reconstitution capacity of the graft.

Antigens, CD34↗

PubMed2002

Synergistic cytotoxicity of buthionine sulfoximine (BSO) and intensive melphalan (L-PAM) for neuroblastoma cell lines established at relapse after myeloablative therapy.

Patients with high-risk neuroblastoma (NB) initially respond to aggressive, alkylator-based therapy only to die from recurrent disease that is refractory to chemotherapy, including alkylating agents. We examined the ability of buthionine sulfoximine (BSO)-mediated glutathione (GSH) depletion to modulate melphalan (L-PAM) resistance in five NB cell lines established after progressive disease following myeloablative therapy (high-dose melphalan, carboplatin, etoposide and total body irradiation) supported by autologous hematopoietic stem cell transplant (AHSCT), and in 15 NB cell lines established at diagnosis or after non-myeloablative therapy (pre-AHSCT). Four of five post-AHSCT NB cell lines and 10 of 15 pre-AHSCT NB cell lines were sensitive to single agent BSO (LC(90) <300 microM BSO), while two of five post-AHSCT lines and one of 15 pre-AHSCT lines showed high-level resistance to L-PAM (LC(90)>30 microM). Fixed ratio analysis demonstrated BSO/L-PAM synergy (combination index <1) for all five post-AHSCT and for all 15 pre-AHSCT cell lines tested. Multi-log cytotoxicity (often exceeding four logs of cell kill) was observed in post-AHSCT L-PAM-resistant cell lines (including p53 non-functional lines) only when clinically achievable concentrations of BSO were combined with myeloablative concentrations of L-PAM. We conclude that most neuroblastoma cell lines, including post-AHSCT NB cell lines that are highly resistant to myeloablative levels of L-PAM and lack p53 function, are sensitive to clinically achievable concentrations of L-PAM and BSO. However, some L-PAM-resistant NB cell lines (especially those lacking p53 function) require dose escalation of L-PAM to myeloablative concentrations in order to demonstrate significant synergistic cytotoxicity. Thus, optimal clinical application of BSO/L-PAM may require AHSCT.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

Semen analysis following allogeneic bone marrow transplantation. Additional data for evidence-based counselling.

Knowledge of the impact of different conditioning regimens used in bone marrow transplantation on spermatogenesis is important in pre-BMT counselling for three reasons: (1) Most young patients who have not had children are concerned with their subsequent fertility; (2) For a number of diseases there are competing therapeutic options that may affect spermatogenesis more or less seriously; (3) Since spontaneous recovery of spermatogenesis is rare, it would be necessary to offer cryopreservation as soon as possible after diagnosis and prior to any treatment. This retrospective study evaluates 99 semen samples obtained in 64 patients who underwent BMT between 1982 and 1996. Recovery of spermatogenesis was observed in 90% of patients conditioned with cyclophosphamide (CY), in 50% of patients with CY plus busulphan (BU) or thiotepa and in 17% of patients with CY plus total body irradiation (TBI) or thoracoabdominal irradiation (TAI). Sperm quality following CY was within the normal range (WHO) in the majority of patients, whereas it was consistently severely impaired in patients who received irradiation or two alkylating agents. Following CY, spermatogenesis recovery was observed in 60% of patients tested 1 year post transplant and it was accomplished within the third year in 80% of cases. Following CY + TBI/TAI recovery of spermatogenesis never occurred before the 4th year post transplant and was demonstrated as late as 9 years in one patient who was azoospermic 1 year earlier. No statistical correlation between age and recovery of spermatogenesis could be demonstrated. The overall high incidence of azoospermia (70.3%) supports the indication for semen cryopreservation in young patients undergoing BMT. These results have implications for semen sample timing before and after BMT and underline a need to collect further data through prospective multi-center studies.

Adolescent↗

PubMed2002

Tyrosine kinase inhibitor STI571 in the treatment of Philadelphia chromosome-positive leukaemia failing myeloablative stem cell transplantation.

Eight patients with Philadelphia chromosome-positive (Ph(+)) leukaemia relapsing from stem cell transplantation (SCT) (one syngeneic and seven allogeneic) were treated with the tyrosine kinase inhibitor STI571. Five patients relapsing as chronic myeloid leukaemia (CML) in chronic phase achieved a complete haematological response, with complete and major cytogenetic responses occurring in four and one cases, respectively. One patient became negative for BCR/ABL in the bone marrow. Three patients relapsed as acute leukaemia (two CML in myeloblastic crisis and one Ph(+) acute lymphoblastic leukaemia), all of whom achieved haematological and cytogenetic responses. One patient also became BCR/ABL negative. However, pancytopenia and graft-versus-host disease led to cessation of treatment in the remaining two cases, which was followed by disease recurrence refractory to further STI treatment. Our results showed that Ph(+) leukaemic relapses after SCT might respond well to STI571 therapy.

Adolescent↗

PubMed2003

Electrocardiogram is very useful for predicting acute heart failure following myeloablative chemotherapy with hematopoietic stem cell transplantation rescue.

A prospective study was conducted in 71 evaluable patients who received myeloablative hematopoietic stem cell transplantation (HSCT) at our facility from 1995 to 2002, to find a sensitive marker for post-transplant heart failure, including echocardiographic systolic and diastolic markers and QTc interval. QTc was found to be an independent and significant risk factor for acute heart failure (AHF) on multivariate logistic regression analysis (OR 1.5, P=0.01, 95% confidence interval (CI) 1.1-2.0), while no significant differences between patients with AHF and those without AHF were found in age, sex, treatment history, type of conditioning regimen, and echocardiographic systolic and diastolic markers. On further analysis, post-transplant risk of AHF appeared to be increased as QTc was prolonged. The post-transplant risk of AHF in the group with longest QTc on multivariate logistic regression analysis was found to be 9.8 times that in the group with shortest QTc (P=0.04, 95% CI 1.0-100). These results suggest that echocardiographic markers are less valuable predictors of post-transplant AHF, but that prolongation of the QTc, an ECG marker, before HSCT is strongly associated with onset of AHF after HSCT.

Acute Disease↗

PubMed2003

Towards a myeloablative regimen with clinical potential: I. Treosulfan conditioning and bone marrow transplantation allow induction of donor-specific tolerance for skin grafts across full MHC barriers.

To investigate whether we could create a radiation-free conditioning regimen to induce permanent mixed and multilineage chimerism and donor-specific tolerance, we treated recipient mice with anti-T-cell antibodies, varying and fractionated doses of Treosulfan and fully MHC disparate bone marrow cells. Treosulfan is mainly used in the treatment of ovarian cancer. It is a structural analog of busulfan, but it does not induce severe hepatotoxicity or veno-occlusive disease at or above the maximum tolerated dose, lacks significant nonhematological toxicity and has limited organ toxicity. We report here the successful induction of permanent mixed multilineage chimerism and donor-specific tolerance as was proven by skin transplantation and IFN-gamma ELISPOT. In conclusion, because of its lower nonhematological toxicity, compared with other myeloablative regimens (eg irradiation or busulfan admin- istration), Treosulfan could be a better candidate for conditioning to induce donor-specific allograft tolerance.

Animals↗

PubMed2003

Myeloablative therapy and bone marrow transplantation in Jehovah's Witnesses with malignancies: single center experience.

Hematological malignancies in Jehovah's Witnesses are often difficult to cure since these patients deny transfusions. By a retrospective analysis, we report the possibility of treating some tumors, mostly hematological, with either autologous or allogeneic bone marrow transplantation (BMT) without blood support. Eight patients were evaluated, including lymphoma (two patients), acute lymphoblastic (one patient) and myeloblastic (one patient) leukemia, chronic lymphocytic leukemia (one patient), refractory anemia with blasts in transformation (one patient), chronic myeloid leukemia (one patient) and metastatic breast cancer (one patient). All patients experienced a severe cytopenia with no major side effects or life-threatening complications. We had four deaths: three from relapse and progression of the disease (at 5, 8 and 15 months after the stem cell infusion), and one from acute intestinal GVHD (at 2 months after the stem cell infusion). Four patients are in complete clinical remission (at 8, 10, 16 and 26 months after the stem cell infusion), and this was related to the disease outcome. We conclude that autologous and allogeneic BMT are feasible without the support of transfusions. We believe that this should be performed as soon as possible in the course of the disease.

Adolescent↗

PubMed2003

Influence of human platelet antigen match on the success of stem cell transplantation after myeloablative conditioning.

Mismatches between donor and recipient for human platelet antigens (HPA) may affect the success of transplantation due to: (a) serving as minor histocompa-tibility antigens and therefore render recipients at risk for graft-versus-host disease (GvHD), (b) inhibition of thrombopoiesis due to platelet antibodies. We therefore evaluated the occurrence of GvHD and need of platelet support by prospective analysis of donor-recipient pairs (n=53) for HPA-1, -2, -3, and -5 allotypes and screening for platelet antibodies prior to transplantation and in weekly intervals until day 100 after transplantation. Neither the incidence of GvHD nor the onset of thrombopoiesis, nor the CCI after platelet transfusions, nor the frequency of platelet transfusions was affected by HPA mismatches. Settings of homozygous donors vs heterozygous recipients or homozygous recipients vs heterozygous donors were not associated with any adverse effects on the outcome of the transplantation. Thus, the HPA-match does not affect the success of transplantation.

Adolescent↗

PubMed2003

Are predictive factors clinically useful in bone marrow transplantation?

Variables that accurately predict the clinical outcome of any procedure, including bone marrow transplantation (BMT), are of paramount importance when assessing the risks and benefits of the procedure. This review of the world's literature of variables affecting overall outcome after myeloablative BMT critically appraises the value of many bone marrow transplant dogmas. There is a relative paucity of data supporting many commonly used transplant practices, including having an upper age limit for eligibility criteria, and absolute requirements for cardiac and pulmonary function pre transplant. In contrast, recently published literature suggests that several parameters occurring soon after a BMT has been performed may accurately predict transplant outcome. Ultimately, given the rapidly evolving nature of BMT, renewed clinical research of variables predictive of transplant outcome is needed.

Bone Marrow Transplantation↗

PubMed2003

Lack of cytoprotective effect of amifostine following HLA-identical sibling transplantation for advanced myelodysplastic syndrome (MDS): a pilot study.

The objective of this prospective study was to determine whether amifostine (Ethyol) reduced conditioning-related toxicity following a regimen of busulfan (7 mg/kg) and fractionated total body irradiation (6 x 200 cGy). In all, 12 patients with advanced myelodysplastic syndrome transplanted from HLA-identical siblings were enrolled. Patients received 340 mg/m(2) amifostine i.v. twice daily during conditioning (days -7 through -1). All patients developed oropharyngeal mucositis. Six patients had evidence of sinusoidal obstruction syndrome of the liver. Six patients experienced pulmonary toxicity of grades II-III. A total of 11 patients died, one with relapse and 10 with infectious complications or regimen-related toxicity. Nonrelapse causes of death included invasive aspergillosis in three, multiorgan failure in three, and idiopathic interstitial pneumonitis in two patients. One patient each died of organizing pneumonia and CMV pneumonia. One patient is alive in complete remission 31 months after transplantation. These results were not superior to those in patients conditioned with busulfan plus fractionated total body irradiation and not given amifostine, and suggest that amifostine, as administered here, has no protective effect against toxicity from this myeloablative regimen.

Adult↗

PubMed2003

Myeloablative conditioning regimens for AML allografts: 30 years later.

During the last three decades, several myeloablative conditioning regimens have been used for AML allografts. In this review, we systematically examine the data from studies reporting on myeloablative conditioning regimens for AML allografts. High-dose busulfan combined with cyclophosphamide (BuCy) and cyclophosphamide in combination with total body irradiation (CyTBI) are the two most commonly used conditioning regimens for AML allografts. From the available data, there are no significant differences in survival with these two regimens. A small benefit of decreased relapse rate with CyTBI is counterbalanced by a nonsignificant increase in treatment-related mortality. The incidence of veno-occlusive disease is significantly higher in patients treated with BuCy. Therapeutic monitoring of busulfan was not reported in any of the studies comparing the regimens. Either of the regimens can be used for AML allografts, and the choice may ultimately depend on local availability and expertise. Further improvements may be possible from modifications of the standard regimens. Data from these latter studies seem to be encouraging, but are not based on comparative randomized trials.

Acute Disease↗

PubMed2004

Toward a myeloablative regimen with clinical potential: II. Treosulfan induces specific skin graft tolerance across haploidentical MHC barriers.

Treosulfan is a water-soluble structural analog of busulfan, acting as a prodrug of alkylating epoxide species. It does not induce severe hepatotoxicity or veno-occlusive disease at or above the maximum tolerated dose, lacks significant nonhematological toxicity and has a limited organ toxicity. It is mainly indicated for the treatment of patients with ovarian cancer. In the present study, we report that permanent donor-specific tolerance and stable mixed multilineage chimerism can successfully be achieved across haploidentical MHC barriers when Treosulfan is administered in combination with anti-T-cell mAb and T-cell-depleted donor bone marrow cells. Furthermore, we show that less T-cell suppression is required when Treosulfan is included in the conditioning regimen. In conclusion, Treosulfan is a well-tolerated myeloablative agent with a low toxicity, and is a promising candidate drug for conditioning prior to bone marrow transplantation.

Animals↗

PubMed2004

Pharmacokinetics of high-dose chemotherapy.

There is considerable variation in the severity of preparative regimen-related toxicity (RRT) in hematopoietic stem-cell transplantation (HSCT). This variation has been recognized to be due, in part, to the wide variation in the pharmacokinetics (PK) of high-dose chemotherapy (HDC). Consequently, therapeutic drug modeling and pharmacokinetic-directed therapy (PKDT) represents an attractive strategy in this setting. Advances in our understanding of drug metabolism, the nature of the active metabolites, and the ability to measure drug concentrations have led to the point where for some agents it is now possible to treat to a given PK end point with a great deal of reliability. In-depth knowledge of the PK and pharmacodynamics (PD) associations of the agents employed in the high-dose setting will make possible more efficient research into preparative regimen dosing intensity and comparisons of different preparative regimens as well as safer HSCT overall. In this review, we discuss PK and PD studies of high-dose cyclosphamide, melphalan, thiotepa, carmustine, cisplatin, carboplatin, paclitaxel, docetaxel, and busulfan.

Antineoplastic Agents↗

PubMed2004

Implications of early airflow decline after myeloablative allogeneic stem cell transplantation.

The clinical significance of early airflow decline after myeloablative allogeneic hematopoietic SCT is uncertain. We performed a retrospective cohort analysis to determine if airflow decline by day 100 is associated with later development of transplant-related airflow obstruction (AFO) and increased mortality risk. Overall, 750 (40%) patients had airflow decline by day 100. Development of airflow decline by day 100 was associated with an increased risk for AFO at 1 year (relative risk 2.6, 95% confidence interval 2.1-3.1) but not with an increase in mortality risk (hazard ratio (HR) 0.86, P=0.05). However, patients with the fastest rate of decline between day 100 and 1 year (12.5% per year +/-24) had the highest mortality risk (HR 3.2, P<0.001). In conclusion, airflow measurements made on day 100 do not predict the rate of airflow decline between day 100 and 1 year, and therefore are not useful as a single measurement for determining mortality risk associated with development of AFO. Closer monitoring of the rate of airflow decline during the first year may facilitate the timely detection and treatment of early airflow decline and prevent the development of fixed AFO and increased mortality risk after hematopoietic stem cell transplant.

Adolescent↗

PubMed2004

Allogeneic myeloablative transplantation for patients aged 50 years and over.

Allogeneic hematopoietic stem cell transplantation (HSCT) has been performed mainly for young patients due to concern about the high incidence of treatment-related mortality (TRM). Recent advances to reduce TRM by using peripheral blood stem cells or nonmyeloablative conditioning regimens have increased the age limit for this procedure, and correctly identifying the indication for transplant is essential for older patients. In this study, we analyzed data from 398 patients aged 50 or over selected from 5147 patients, who received conventional allogeneic HSCT (c-HSCT). Patients aged 50 or older showed inferior outcomes for TRM and overall survival (OS). Mulitivariate analyses confirmed that an age of 50 or over was an independent risk factor for TRM (P<0.0001) and OS (P<0.0001). Among patients aged 50 or older, increasing age remained an adverse factor for OS (P=0.0213). Regimens including total-body irradiation (TBI) correlated with a higher risk of TRM and a lower OS for older patients (P=0.0095 and 0.0303, respectively). These findings indicate that allogeneic c-HSCT should be offered to patients over 50 years only if the increased risk of TRM is acceptable, and that a non-TBI regimen is preferable when the transplant is performed.

Adolescent↗

PubMed2004

A randomized trial of amifostine as a cytoprotectant for patients receiving myeloablative therapy for allogeneic hematopoietic stem cell transplantation.

We initiated a randomized study of amifostine (the organic thiophosphate formerly known as WR-2721) given to patients during myeloablative conditioning therapy for allogeneic bone marrow transplantation. Amifostine was given at a dose of 1000 mg/day of conditioning and was well tolerated if attention was given to serum calcium levels, blood pressure and antiemetics. Since August 1998, 60 patients (30 on each arm) have completed the study. There was no significant difference in the days to neutrophil or platelet engraftment in either arm of the study. Significantly, the duration of grade I-IV mucositis was decreased in the group that received amifostine (P=0.02). Also grade III or IV infections (P=0.008), duration of antibiotic therapy (P=0.03) and duration of fever (P=0.04) were significantly reduced with amifostine. However, there were no differences in the incidence of grade III or IV mucositis, liver toxicity or renal toxicity. There were also no differences in early mortality, relapse and long-term survival. We conclude that amifostine, while reducing the duration of mucositis and infections (possibly through some preservation of gut mucosal integrity), has a modest effect in allogeneic bone marrow transplants given the multiplicity of factors influencing organ toxicity and survival in this setting.

Adolescent↗

PubMed2005

Prospective evaluation of gut mucosal barrier injury following various myeloablative regimens for haematopoietic stem cell transplant.

We determined gut mucosal barrier injury (MBI) among 129 recipients of an allogeneic or autologous haematopoietic stem cell transplant (HSCT) who had been given different myeloablative regimens by measuring integrity using the lactulose/rhamnose (RHA) ratio and absorption using the ratios of rhamnose/3-O-methylglucose and xylose/3-O-methylglucose. Regimens that did not contain idarubicin induced oral mucositis and disturbed gut integrity and absorption earlier than did those containing the anthracycline. By contrast, regimens containing idarubicin induced more severe and prolonged oral and gut MBI. Gut integrity and absorption of most patients were still abnormal at discharge from hospital. These results confirm that the integrity and absorptive capacity of the gut is affected adversely by myeloablative regimens in general, although only two patterns of mucosal injury emerged depending on whether or not idarubicin was used.

Adult↗