Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Busulfan (BU) is a widely used myeloablative and antineoplastic agent in clinical bone marrow transplantation (BMT). The lower incidence of BU-associated toxicities and lower therapeutic effectiveness in young children given BU doses based on body weight (ie, 16 mg/kg) is associated with altered pharmacokinetics of BU; the area under the curve (AUC) of BU concentration versus time is significantly less in these patients than those observed in older children and adults. To optimize BU dosage in young BMT recipients, we developed a dosage regimen based on body surface area (BSA) and determined BU pharmacokinetics and BU-associated toxicities. Seven children (median age, 3.9 years, range, 1.1 to 5.7) undergoing allogeneic or autologous BMT for leukemia received 40 mg/m2/dose BU every 6 hours for 16 doses; BU concentrations were measured in the plasma, and AUCs were determined for each patient after the first and 13th doses. Expressed as a function of body weight, the median BU dosage was 26.4 mg/kg (range, 24.3 to 28.2), a 60% increase over the BU dosage based on body weight. Four patients developed mucositis, and one of them also developed nonfatal hepatic veno-occlusive disease (VOD). No patients receiving 40 mg/m2 BU developed neurotoxicity (eg, seizures) or interstitial pneumonitis. Prompt and sustained engraftment was observed in the allogeneic BMT recipients, and late graft failure was not seen. The mean BU AUCs were 1,105 mumol/L.min (range, 790 to 2,080) after the first dose and 1,022 mumol/L.min (range, 632 to 1,860) after the 13th dose of BU, comparable to the AUCs in adults given 16 mg/kg of BU. These studies suggest that, in young children, BSA-based dosing of BU (40 mg/m2) provides drug exposures (AUCs) closer to adult values with acceptable toxicities and may improve therapeutic effects.
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PMID:Optimization of busulfan dosage in children undergoing bone marrow transplantation: a pharmacokinetic study of dose escalation. 142 15

Second transplants need to be considered in two clinical situations after marrow transplantation. Firstly, failure of sustained engraftment; secondly, recurrence of the underlying malignancy. In patients with failure of sustained engraftment a trial of recombinant human GM-CSF is indicated first with a chance of improving blood counts in a significant proportion of patients. If this is unsuccessful a second transplant utilizing a preparative regime aimed primarily at further minimizing host immune competence such as a combination of antithymocyte globulin (ATG) and cyclophosphamide or ATG alone followed by a T-replete marrow infusion should be employed. A second marrow transplant can also be utilized for recurrence of the underlying haematological malignancy after first transplant. However, several large multi-institutional studies have now shown a striking difference in the long-term leukemia-free survival rate between those relapsing early (for example, less than six months) after the first transplant compared to those relapsing later after the first transplant. Leukemia-free survival post second transplant for those relapsing within six months of first transplant is less than 10%, whereas for those relapsing greater than six months from first transplant it is approximately 30%. Transplant-related mortality, particularly from complications influenced by chemotherapy, such as interstitial pneumonitis and hepatic veno-occlusive disease, are more common after second than after first transplant.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Who should get a second marrow transplant? 152 Oct 96

We analysed data from 114 recipients of HLA-identical sibling transplants who relapsed and received a second transplant between 1978 and 1989. Twenty-nine patients had acute lymphoblastic leukemia, 46 acute myeloid leukemia and 39 chronic myelogenous leukemia. Median (range) interval between first and second transplants was 15 (1-80) months. Following the second transplant, graft failure occurred in 2%, acute graft-versus-host disease (GVHD) in 27% and chronic GVHD in 21% of patients at risk. Risks of interstitial pneumonia and hepatic veno-occlusive disease were higher after the second than the first transplant. Two-year probabilities (95% confidence interval) of treatment-related mortality, relapse and leukemia-free survival were 41% (30-53%), 65% (53-75%) and 21% (14-30%), respectively. Leukemia-free survival was 7% (2-19%) among patients relapsing less than 6 months after their first transplant, with high rates of both relapse, 77% (49-92%), and treatment-related mortality 69% (46-85%). In contrast, leukemia-free survival was 28% (19-41%) in those relapsing more than 6 months after the first transplant; in this group the probability of relapse was 59% (45-72%) and treatment-related mortality 30% (20-43%). Factors correlated with better outcome included a diagnosis of chronic myelogenous leukemia, relapse more than 6 months after the first transplant, acute leukemia in remission prior to the second transplant and good performance status.
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PMID:Second HLA-identical sibling transplants for leukemia recurrence. 160 Apr 15

We performed a retrospective analysis of the incidence, risk factors, and clinical outcome of hepatic veno-occlusive disease (VOD) in 50 children prepared for bone marrow transplantation with busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg). The overall incidence of VOD was 28% (14/50). The incidence of VOD among patients transplanted for leukemia was 36% (14/39). In contrast, no patient transplanted for a genetic disease developed VOD. Neither patient age, sex, remission status, type of graft (i.e. allogeneic or autologous), past history of liver disease nor pretransplant liver function tests were associated with an increased risk of VOD. In addition, 23 of 50 patients had pretransplant samples available for antihepatitis C virus (HCV) testing; 3/23 were reactive (two of nine patients with VOD and one of 14 patients without VOD were positive for anti-HCV). We found a high incidence of pleural effusion in patients with VOD (7/14), an association that has previously not been described. VOD was manageable and resolved in all patients.
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PMID:Hepatic veno-occlusive disease post-bone marrow transplantation in children conditioned with busulfan and cyclophosphamide: incidence, risk factors, and clinical outcome. 190 40

The toxicity of the conditioning regimen of high dose busulphan (Bu) (16 mg/kg) and cyclophosphamide (Cy) (120 mg/kg) has been compared to cyclophosphamide (Cy) (120 mg/kg) and fractionated total body irradiation (TBI) 12-14 Gy. Since 1985, 67 patients have received conditioning of Bu and Cy for HLA-identical sibling bone marrow transplants. 166 patients have received Cy and TBI since 1981. Veno-occlusive disease of the liver occurred in 19% in the Bu-Cy group and was fatal in 1/12 cases, but only in 1.3% of Cy-TBI group (P less than 0.0005) and was fatal in 1/2. 30% of evaluable patients developed haemorrhagic cystitis in the Bu-Cy group and 14% in the Cy-TBI group (P = 0.008). A multiple logistic regression analysis demonstrated the preparative regimen as the only significant risk factor for the development of veno-occlusive disease or haemorrhagic cystitis. Interstitial pneumonia was diagnosed in 12/56 evaluable patients (21%) in the Bu-Cy group and was fatal in 75%. It occurred in 39/137 evaluable patients (28%) in the Cy-TBI group with a 54% case mortality. Within the Bu-Cy group, the incidence of veno-occlusive disease and haemorrhagic cystitis was similar in chronic myeloid leukaemia (CML) and acute leukaemia (AL) groups, but there was a significant (P = 0.003) incidence of interstitial pneumonia in the CML group 36% as compared to 7% in the AL group. Preparative regimen and age were significant risk factors in the development of interstitial pneumonia in patients with CML. A flexural and acral rash ranging from pigmentation to severe erosion was noted in the Bu-Cy group, but not in the Cy-TBI group. Thus, veno-occlusive disease, haemorrhagic cystitis and cutaneous changes were more common in patients receiving Bu-Cy. Interstitial pneumonia was more common in patients receiving Bu-Cy for CML than for AL.
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PMID:The toxicity of busulphan and cyclophosphamide as the preparative regimen for bone marrow transplantation. 202 79

Autologous bone marrow transplantation, using unpurged cryopreserved autologous marrow, was performed on ten adult patients with acute myeloid leukaemia in remission. Seven patients were in first chemotherapy-induced remission of their disease, while three were in later remission. Patients ages ranged from 24 to 52 years, with a median of 38.5 years. Conditioning therapy consisted of oral busulphan 16 mg/kg over four days and intravenous cyclophosphamide 60 mg/kg on two days. Bone marrow cells were thawed and infused two days later. All patients showed signs of marrow engraftment, however this was delayed in comparison with patients receiving allogeneic transplants. All patients developed fever requiring antibiotic therapy and one patient died of overwhelming sepsis. Another patient died of hepatic veno-occlusive disease two months after transplant. Serious, but non-fatal, hepatic complications occurred in two other patients. One patient, transplanted in third remission, relapsed 16 months post-autograft. No other relapses have been seen, with one second remission patient remaining leukaemia-free at 24 months, and six first remission patients in continuing remission 11 to 23 (median 20) months post transplant. These encouraging results require confirmation in a randomised clinical trial comparing autologous marrow transplantation versus standard chemotherapy.
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PMID:Autologous bone marrow transplantation for acute myeloid leukaemia in remission: a preliminary report. 232 97

Two short-lived vitamin K-dependent factors, factor VII and protein C, were measured by both functional and antigenic techniques in 3 hematological conditions known for their risk of hepatotoxicity: Following use of asparaginase and bisantrene, and patients at high risk of hepatic veno-occlusive disease after allogenic bone marrow transplantation for relapse of acute leukemia of accelerated phase of evoluted chronic myelogenic leukemia. In these 3 conditions functionally measured levels of protein C and factor VII, and antigenically measured levels of both these factors proved to be early markers of incipient hepatic involvement. These tests were easy to use routinely were reproducible, and proved to be predictive of veno-occlusive disease in grafted patients at the preconditioning stage. In the follow-up of bone marrow grafted patients plasma markers of endothelial function (von Willebrand's factor, tissue type plasminogen activator, and plasma activity of angiotensin converting enzyme) were significantly altered at the time of overdose with cyclosporin A, probably due to a drug-induced in vivo lesion of the endothelium. In the search for cytoprotective drugs for the prevention of veno-occlusive disease in bone marrow grafted patients prostaglandin E1 (PGE1) was given prior to and for at least 4 weeks after transplantation and proved to be effective by biological criteria (the level of protein C mainly). This deserves further study in a prospective clinical trial of the potential usefulness of PGE1 in preventing liver veno-occlusive disease in bone marrow grafted patients.
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PMID:[Hemostasis tests as markers of hepatic and endothelial toxicity in chemotherapy]. 329 Aug 34

One-hundred-and-forty-three patients with haematological malignancy or severe aplastic anaemia received HLA-identical sibling bone marrow transplants. In 111 of these patients who had haematological malignancy and who were prepared for transplant with cyclophosphamide 120 mg/kg and fractionated total body irradiation 12-14 Gy, the incidence of haemorrhagic cystitis and hepatic veno-occlusive disease was 13% and 3%, respectively. In contrast, the incidence in 15 leukaemic patients prepared for transplant with chemotherapy regimens containing high-dose busulphan was 47% and 20%, respectively (p less than 0.001). Two patients in this latter group who developed fatal veno-occlusive disease had chronic myeloid leukaemia and had received long-term low-dose busulphan pre-transplant. Neither complication occurred in 26 patients prepared by cyclophosphamide alone (20 patients with severe aplastic anaemia) or with cyclophosphamide and melphalan (six patients with leukaemia). The regimen of busulphan 16 mg/kg in combination with cyclophosphamide 120 mg/kg was associated with a short duration of total leucopenia with a significantly higher leucocyte count on the day of marrow transplant compared to other regimens. Furthermore, oro-pharyngeal mucositis was not severe even when methotrexate was utilised as post-transplant prophylaxis for graft-versus-host disease. Thus, while the busulphan-cyclophosphamide regimen appeared useful, we suggest that (1) high-dose busulphan should not be used as a preparative regimen for patients previously exposed to busulphan, and (2) bladder irrigation (as well as intravenous hydration) is necessary to minimise haemorrhagic cystitis in patients given regimens that incorporate high-dose busulphan.
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PMID:Preparative regimens for marrow transplantation containing busulphan are associated with haemorrhagic cystitis and hepatic veno-occlusive disease but a short duration of leucopenia and little oro-pharyngeal mucositis. 333 86

Lesions of hepatic veno-occlusive disease were found in the needle biopsy specimen of one patient suffering from chronic granulocytic leukaemia and in the liver at necropsy of a second patient suffering from acute myeloid leukaemia. The treatment included administration of 6-thioguanine which was the only relevant compound used in the first patient and which was combined with cytosine arabinoside in the second patient.
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PMID:6-thioguanine as a cause of toxic veno-occlusive disease of the liver. 695 19

Liver dysfunction occurs after bone marrow transplantation but the relative importance of graft versus host disease and other factors, such as infection, radiation, and drugs, has not been clearly established. We have studied liver status before and after bone marrow transplantation in 43 consecutive patients and have related this to survival and factors that are recognised to cause liver injury. Minor abnormalities of liver tests occurred in 21% of patients before grafting but this did not influence survival or the development of liver disease after transplantation. During the first 50 days after grafting, 83% of patients had abnormal liver tests which were more severe in patients who subsequently died. Alanine transaminase was significantly higher in non-survivors and appeared to predict survival early after transplantation. Only non-survivors developed clinical signs of liver disease. Severe liver disease was always associated with graft versus host disease and atypia of the small bile ducts was the most useful histological marker of hepatic involvement with this disease. Two of the patients with hepatic graft versus host disease also has hepatic veno-occlusive disease and three fatalities had opportunistic infection of the liver, although, in the latter, death was not due primarily to liver dysfunction. Previous hepatitis and androgen therapy could not be implicated as important causes of hepatic damage but chemotherapy for acute leukaemia and conditioning regimens for bone marrow transplantation appear to be the most important factors in the development of hepatic veno-occlusive disease.
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PMID:Liver disease after bone marrow transplantation. 704 84


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