Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transplant-related morbidity and mortality remain a major problem following stem cell transplantation (SCT). The use of high-dose single-agent busulphan before allogeneic or autologous SCT may be a reasonable compromise between maintaining cytoreductive efficacy and minimizing toxicity in patients with chronic myeloid leukaemia (CML). Seventy patients with CML have received busulphan as the only cytoreductive therapy before SCT on 79 occasions. The probability of survival of the 14 allogeneic recipients (all of whom were undergoing a second transplant from the original donor) was 78% at 5 years. Sixty-five autologous SCT were performed in 56 patients, of whom 40 were in late chronic phase. The actuarial 3-year post-autograft survival was 54% for these 56 first autografts. For patients in chronic phase, the 3-year survival was 76% compared with 30% at 2 years for those with advanced phase disease. Busulphan therapy was well tolerated, and except for mild mucositis little toxicity was experienced. None of these patients developed hepatic veno-occlusive disease (VOD). Nine patients (one allogeneic and eight autologous recipients) received several doses of an intravenous formulation of busulphan with very low toxicity. High-dose busulphan alone appears sufficient to provide adequate cytoreduction and immunosuppression in second allogeneic transplants and is also effective as cytoreduction before autologous SCT in patients with CML.
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PMID:High-dose busulphan alone as cytoreduction before allogeneic or autologous stem cell transplantation for chronic myeloid leukaemia: a single-centre experience. 1079 82

Busulfan has been previously only available in an oral formulation due to its poor water solubility. We report the results of a phase I study of multiple escalating doses of intravenous busulfan (Spartaject Busulfan, Orphan Europe, Paris, France) for myeloablation prior to stem cell transplantation (SCT) in 12 patients with chronic myeloid leukemia, acute myeloid leukemia or acute lymphocytic leukemia. One patient received allogeneic SCT; the other 11 patients received autologous SCT. The first six patients received i.v. busulfan diluted in 50 ml of 0.9% normal saline and the last six patients received busulfan in a 500-ml 5% dextrose solution. All patients experienced profound myelosuppression and all but one demonstrated hematopoietic engraftment. Toxicity was mild or moderate and there were no toxic deaths attributable to busulfan. Of note, there were no cases of veno-occlusive disease of the liver. Busulfan plasma concentrations were determined by gas chromatography with electron capture detection and showed little intrapatient variability. In most cases there was no significant difference between the first and last dose PK parameters. These data suggest that dose adjustment based on first dose PK data could allow uniformity of busulfan dosing for patients receiving SCT.
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PMID:A phase I/II study of multiple-dose intravenous busulfan as myeloablation prior to stem cell transplantation. 1106 31

Seven patients with Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) were treated with an ICE-based regimen plus G-CSF with the aim of mobilizing and collecting Ph-negative peripheral stem cells in the setting of an autologous transplant program. Five patients had CML in the first chronic phase and 2 in the accelerated phase. All patients had been previously treated with interferon-alpha. Median value and ranges for harvested mononuclear cells, CD34+ cells and CFU-GM, respectively: 5.65 x 10(8)/kg (2.61-11.38); 1.48 x 10(6)/kg (0.216-3.5), and 3.43 x 10(4)/kg (0.243-11.6). FISH was the only useful method for detection of minimal residual disease on apheresis product showing <5% t(9;22) positive cells in 2 cases and <10% positive cells in 4 other cases. Four of seven autologous grafts have been transplanted to date. Busulfan conditioning was used in 1 case and TBI/Cy conditioning in 3 other cases. All patients are alive and well following transplantation and are on interferon-alpha therapy.
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PMID:Autologous hematopoietic stem cell transplantation in chronic myeloid leukemia with different clinical stages. 1171 74

Published data suggest that the average concentration of busulfan at steady state (Bu Css) is critical for successful engraftment in children receiving busulfan as a conditioning agent for bone marrow transplantation (BMT). We previously found in children that a Bu Css <600 ng/ml correlated with autologous recovery/mixed chimerism; there was no correlation between Bu Css and regimen-related toxicity (RRT). In a cohort continuous with the previous trial, we prospectively evaluated targeted busulfan concentrations in 32 pediatric patients (age 0.6-18.5 years) with AML (n = 6), CML (n = 6) and non-malignant disorders (n = 20) receiving HLA-closely matched donor grafts. In this trial, individual busulfan pharmacokinetics were performed prior to admission. Busulfan doses were then adjusted to achieve a Bu Css target range of 600-900 ng/ml +/- 10% depending on donor source and disease. A repeat study was done following dose 1 of the conditioning regimen. Thirty of thirty-two (94%) patients achieved target concentrations. Total busulfan doses ranged from 10.9 to 29 mg/kg. Thirty of thirty-two patients (94%) have durably engrafted. Grade 3/4 RRT occurred in seven patients (21%). Targeting Bu Css ranges of 600-900 ng/ml significantly improved our rate of successful engraftment from 74% to 94% (P = 0.043). These results indicate that targeted busulfan dosing optimizes allogeneic engraftment in children.
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PMID:Target dose adjustment of busulfan in pediatric patients undergoing bone marrow transplantation. 1178 9

The graft-vs-tumor effect is an important part of the curative potential of allogeneic transplantation. We characterized the effect of transplanted donor mononuclear cells on relapse- and event-free survival after allogeneic bone marrow transplantation (BMT). We studied 113 consecutive patients with hematologic malignancies who received non-T-cell-depleted BMT from human leukocyte antigen (HLA)-matched siblings. Most patients (n = 103) received busulfan (Myleran)-based conditioning, and all patients received standard short-course methotrexate and tacrolimus (Prograf) as graft-vs-host disease prophylaxis. Sixty-four patients had low-risk diagnoses (acute lymphoblastic leukemia/acute myeloid leukemia [first complete remission], myelodysplastic syndrome [refractory anemia/refractory anemia with ring sideroblasts], and chronic myeloid leukemia [first chronic phase]); 49 patients had high-risk diagnoses (all others). Cox regression analyses evaluated risk strata, age, gender, and the numbers of nucleated cells, CD3-positive T cells, CD34-positive hematopoietic cells, and type 2 dendritic cells (DC2) as covariates for event-free survival, relapse, and nonrelapse mortality. Recipients of larger numbers of DC2 cells had significantly lower event-free survival, a lower incidence of chronic graft-vs-host disease, and an increased incidence of relapse. Recipients of larger numbers of CD34-positive cells had improved event-free survival; recipients of fewer CD34-positive cells had delayed hematopoietic engraftment and increased death from infections. In conclusion, content of donor DC2 cells was associated with decreased chronic graft-vs-host disease and graft-vs-leukemia effects consistent with Th2/Tc2 polarization of donor Tcells following allogeneic bone marrow transplantation.
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PMID:DC2 effect on survival following allogeneic bone marrow transplantation. 1182 82

For most chronic myeloid leukaemia patients the option of a potentially curative allogeneic stem cell transplantation is not available because of age or lack of donor. Alternative therapy with interferon-alpha appears to prolong survival but is probably not curative. The aim of the study is to analyse the clinical results of the first Hungarian autologous transplantations in CML. METHODS: Seven patients were treated with ICE-based regimen plus G-CSF with the aim of mobilising and collecting Ph-negative peripheral stem cells in the setting of autologous transplant program. Five patients had CML in first chronic phase and two in accelerated phase. All patients have been previously treated with interferon-alpha. RESULTS: Median value and ranges for harvested mononuclear cells, CD34(+) cells and CFU-GM were: 5.65x10(8)/kg (2.61-11.38), 1.48x10(6)/kg (0.216-3.5) and 3.43x10(4)/kg (0.243-11.6), respectively. Four out of seven autologous grafts have been transplanted. Busulfan conditioning was used in one case and TBI/Cy conditioning in three patients. All patients are alive and well post-transplant being on interferon-alpha therapy. CONCLUSIONS: Based on the clinical advantages of autologous transplantation including long-term chronic phase, achievement of second chronic phase and improved response to interferon-alpha therapy, the procedure can offer an alternative treatment in CML in lack of HLA-identical donor.
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PMID:[Autologous hematopoietic stem cell transplantation in chronic myeloid leukaemia with different clinical stages] 1205 Jul 22

We have performed a phase I dose escalation of 4-Hydroperoxycyclophosphamide (4HC) purging of autologous peripheral blood progenitor cells (PBPCs) to improve the outcome of autologous transplantation for patients with myeloid leukemia. Peripheral blood stem cells were mobilized after cytosine arabinoside of 2 g/m(2) every 12 hours x 8 doses with etoposide of 40 mg/kg total dose infused over 4 days, followed by growth factor support. The preparative regimen included Busulfan of 1 mg/kg orally every 6 hours x 16 doses, followed by etoposide of 60 mg/kg x 1 day (the patient with chronic myeloid leukemia received cyclophosphamide of 60 mg/kg/d x 2 days in lieu of etoposide). PBPCs purged with 4HC were infused following this induction. Toxicities included grade 3 or 4 skin rashes, stomatitis/mucositis, and delay in time to hematopoietic recovery. The maximum tolerated dose of 4HC used to purge PBPCs in this trial was 20 microg/mL, which resulted in an average of 18 days for white blood cells and 28 days for platelet recovery. With a median follow-up of 2.25 years in surviving patients, the 3-year disease free survival rate is 44% and the overall survival rate is 89%. These data suggest that autologous PBPCs are more sensitive than marrow purged with 4HC, tolerating less intense purging, although a survival advantage may still be seen and should be assessed in larger studies. Approaches to minimize stomatitis and protect normal stem cells from the toxicity of 4HC may improve the tolerance and efficacy of this approach.
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PMID:4-hydroperoxycyclophosphamide--purged peripheral blood stem cells for autologous transplantation in patients with acute myeloid leukemia. 1265 69

We present a case of thyroidian cancer and chronic granulocytic leukemia simultaneously found in a 28 years old patient. Initial surgical management consisted in total thyroidectomy and removal of the lymph nodes; local recurrence after 6 months required excision of the tumoral block by radical neck dissection. Hematological disease was controlled with Hydroxiureea, associated, when needed, with Busulphan and Cytosar. The patient is in acceptable general condition and free of any local recurrence or apparent metastases 2.5 years after the diagnosis.
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PMID:[Thyroid cancer and chronic granulocytic leukemia in the same patient: Cernobyl or coincidence?]. 1273 Dec 69

Allogeneic haemopoietic stem cell transplantation was initially considered as a means of delivering supralethal doses of chemotherapy with or without total body irradiation for the treatment of malignancy. However, it has become clear that this mode of therapy does not eradicate the malignancy in many patients and its benefit is largely due to the immune mediated graft versus malignancy effect. This has led to development of alternative strategy to utilize a less intensive preparative regimen pre-transplantation that provides sufficient immunosuppression to achieve engraftment of an allogeneic stem cell graft, thus allowing the evolution of a graft versus malignancy effect post-transplantation. Since September 1999, we had carried out 10 cases of allogeneic peripheral blood stem cell transplantation: one case of aplastic anaemia, four cases of acute myeloid leukemia (AML) in first remission, and five cases of chronic myeloid leukemia (CML) in chronic phase. The preparative regimen was non-myeloablative comprising Fludarabine with Cyclophosphamide or Busulphan. Recovery from transplantation was rapid with no or brief period of neutropenia or thrombocytopenia. Engraftment was established by determining donor's short tandem repeats in the recipient's bone marrow at day 30, 60 and 100 post-transplantation. Seven cases (70%) show partial or complete donor's chimerism by day 30 indicating successful engraftment. No treatment mortality was noted at day 100. Graft versus host disease was generally limited. Up to the date of reporting, two patients with CML had graft failure, one was successfully re-transplanted later. Two patients with AML had since relapsed and passed away. The others remain alive and well. The cost of transplantation on average was estimated to be about a quarter of that using a myeloablative regimen. It appears that this treatment strategy is a promising approach for the management of blood disorders.
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PMID:Allogeneic haemopoietic stem cell transplantation using non-myeloablative conditioning--a local experience. 1456 43

Busulfan (1,4-butanediol dimethanesulfonate) has been used widely for the treatment of patients with chronic myelogenous leukemia. Busulfan is bifunctional and thus may effectively induce DNA damage, which may play an important role in the cytotoxicity. In this study, we compared the cytotoxicity of bifunctional busulfan with that of monofunctional ethyl methanesulfonate (EMS) in human promyelocytic leukemia HL-60 cells. Busulfan showed a significant inhibitory effect on cell growth, whereas the cells grew in the presence of EMS. To clarify the mechanism of cytotoxicity of busulfan, we investigated DNA damage induced by busulfan using 32P-5'-end-labeled DNA fragments obtained from the human p16 tumor suppressor gene. Busulfan induced DNA damage dose-dependently, whereas EMS caused little DNA damage. DNA-sequencing experiments using piperidine and 3-methyladenine DNA glycosylase indicated that busulfan caused double-base lesions mainly at 5'-GA-3' and, to a lesser extent, at 5'-GG-3' sequences. Time of flight mass spectrometry confirmed that busulfan forms an intrastrand cross-link at the 5'-GA-3' sequence, in addition to mono-alkylation. The mechanism and the role of cross-linking at the 5'-GA-3' sequence are discussed in relation to the cytotoxicity induced by busulfan.
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PMID:DNA intrastrand cross-link at the 5'-GA-3' sequence formed by busulfan and its role in the cytotoxic effect. 1513 75


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