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)

This phase I trial of idarubicin (IDA) was conducted in 32 patients with acute leukemia and chronic myelogenous leukemia (CML) in blastic crisis (CML/BC) who either had failed to achieve a complete remission (CR) after initial induction therapy or had relapsed after CR. IDA was administered at dosages ranging from an initial dose of 5 mg/m2/d for 3 days with an increment of 2.5 mg/m2/d to 15 mg/m2/d for 3 days. The dose-limiting toxicities (DLTs) were thought to be stomatitis and anorexia. The maximum tolerated dose (MTD) was determined to be 15 mg/m2/d for 3 days (45 mg/m2 per course). Bone marrow toxicity was significant when greater than 10 mg/m2/d of IDA was given. When IDA was administered at this dosage or higher, there were three CRs and four partial responses, with an overall response rate of 26.9% in 26 assessable patients. It is recommended that a phase II study be undertaken at an IDA dosage of 10 to 15 mg/m2/d for 3 consecutive days in the treatment of acute leukemia. Twenty-one of 32 patients were also studied for the pharmacokinetics of IDA. The terminal half-life (t1/2) values for IDA were 6.4 to 15.1 hours in plasma and 8.09 to 16.34 hours in blood cells. The t1/2 values for idarubicinol were much longer: 43.46 to 51.01 hours in plasma and 36.61 to 54.70 hours in blood cells. Concentrations of idarubicinol in plasma and blood cells exceeded those of IDA 2 to 4 hours after the start of treatment and remained elevated for a long time. The area under the curve (AUC) of idarubicinol in plasma was 5.16 to 8.36 times higher than that of IDA, and the AUC of idarubicinol in blood cells was 2.05 to 4.57 times higher than that of IDA. The AUCs of both IDA and idarubicinol increased dose-dependently over the dosage range of 5 to 15 mg/m2/d. When two-compartment multiple-dose models were used, plasma t1/2 alpha and t1/2 beta values of IDA were 0.25 +/- 0.13 and 9.4 +/- 3.4 hours, respectively. The steady-state volume of distribution (Vdss) was 934.9 +/- 370.7 L/m2, and the plasma clearance was 82.3 +/- 29.7 L/h/m2. The urinary excretion of IDA and its metabolite was low. The mean cumulative urinary recovery rates were 2.04% for IDA and 11.53% for idarubicinol up to 7 days.
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PMID:A phase I study of idarubicin hydrochloride in patients with acute leukemia. The Idarubicin Study Group of Japan. 891 10

Intensive chemotherapy given in early chronic phase of chronic myelogenous leukemia (CML) has resulted in high numbers of circulating Philadelphia (Ph) chromosome-negative hematopoietic progenitor cells (HPC). We have autografted 30 consecutive patients with CML in chronic phase with HPC collected in this way to facilitate restoration of Ph-negative hematopoiesis in bone marrow after high-dose therapy. Hematopoietic recovery to greater than 0.5 x10(9)/L neutrophils and to greater than 25 x 10(9)/L platelets occurred in all patients, a median of 13 (range, 9 to 32) days and 16 (range, 6 to 106) days postautograft, respectively. Regenerating marrow cells were Ph-negative in 16 (53%) patients and greater than 66% Ph-negative in 10 (33%) patients. Twenty-eight patients are alive 6 to 76 months (median, 24 months) after autografting. Three patients have developed blast crisis from which 2 have died. Eight patients are in complete cytogenetic remission at a median of 20 (range, 6 to 44) months with a median ratio BCR-ABL/ABL of 0.002 (range, <0.001 to 0.01). Eight patients are in major cytogenetic remission at a median of 22 (range, 6 to 48) months. No patient died as a consequence of the treatment. All patients had some degree of stomatitis that was severe in 15 (50%) patients. Gastrointestinal and hepatic toxicities were observed in about one fourth of patients. Thus, autografting with Ph-negative mobilized HPC can result in prolonged restoration of Ph-negative hematopoiesis for some patients with CML; moreover, most autograft recipients report normal or near normal activity levels, suggesting that this procedure need not to be associated either with prolonged convalescence or with chronic debility.
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PMID:Autografting with philadelphia chromosome-negative mobilized hematopoietic progenitor cells in chronic myelogenous leukemia. 1002 81

Cell vaccines engineered to express immunomodulators have shown feasibility in eliminating leukemia in murine models. Vectors for efficient gene delivery to primary human leukemia cells are required to translate this approach to clinical trials. In this study, second-generation lentiviral vectors derived from human immunodeficiency virus 1 were evaluated, with the cytomegalovirus (CMV) promoter driving expression of granulocyte-macrophage-colony-stimulating factor (GM-CSF) and CD80 in separate vectors or in a bicistronic vector. The vectors were pseudotyped with vesicular stomatitis virus G glycoprotein and concentrated to high titers (10(8)-10(9) infective particles/mL). Human acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic myeloid leukemia cell lines transduced with the monocistronic pHR-CD80 vector or the bicistronic pHR-GM/CD vector became 75% to 95% CD80 positive (CD80(+)). More important, transduction of primary human ALL and AML blasts with high-titer lentiviral vectors was consistently successful (40%-95% CD80(+)). The average amount of GM-CSF secretion by the leukemia cell lines transduced with the pHR-GM-CSF monocistronic vector was 2182.9 pg/10(6) cells per 24 hours. Secretion was markedly lower with the bicistronic pHR-GM/CD vector (average, 225.7 pg/10(6) cells per 24 hours). Lower amounts of CMV-driven messenger RNA were detected with the bicistronic vector, which may account for its poor expression of GM-CSF. Primary ALL cells transduced to express CD80 stimulated T-cell proliferation in an autologous mixed lymphocyte reaction. This stimulation was specifically blocked with monoclonal antibodies reactive against CD80 or by recombinant cytotoxic T-lymphocyte antigen 4-immunoglobulin fusion protein. These results show the feasibility of efficiently transducing primary leukemia cells with lentiviral vectors to express immunomodulators to elicit antileukemic immune responses. (Blood. 2000;96:1317-1326)
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PMID:Lentiviral vectors for efficient delivery of CD80 and granulocyte-macrophage- colony-stimulating factor in human acute lymphoblastic leukemia and acute myeloid leukemia cells to induce antileukemic immune responses. 1094 73

Hydroxyurea is an antimetabolite agent used in the treatment of myeloproliferative disorders and sickle cell anaemia. Although hydroxyurea is relatively well tolerated, adverse effects often involve skin and mucous membrane during long-term therapy. A group of 510 patients affected by chronic myeloid leukaemia from 1977 to 1998 has been considered. Only 158 patients were treated with hydroxyurea and fulfilled inclusion/exclusion criteria of this study. A spectrum of severe cutaneous and mucosal changes (inflammatory and neoplastic) was seen in about 13% of patients (21 patients out of 158) and was studied in detail. Cutaneous and mucosal atrophy were observed in all 21 patients. Skin atrophy was often characterized by numerous telangiectases, especially on legs and on sun-exposed sites (16/21). Cutaneous, mucosal and nail hyperpigmentation was evident, albeit with variable extent, in 10 of the 21 patients. Severe stomatitis and glossitis with flattening of papillae were another common finding. Five patients, who received a particularly long treatment with hydroxyurea, developed squamous-cell neoplasms on sun-exposed sites (both squamous-cell carcinomas and keratoacanthomas). Acral changes were characteristic and constant, including acral erythema (21/21), dermatomyositis-like changes on the dorsa of hands (7/21), ulcers localized on acral areas of legs, on genitalia and oral mucosae (20/21). The frequency and the variety of these muco-cutaneous changes are reported and the mechanisms by which hydroxyurea may induce this muco-cutaneous syndrome-like group of changes, are proposed.
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PMID:Muco-cutaneous changes during long-term therapy with hydroxyurea in chronic myeloid leukaemia. 1129 3

The availability of an i.v. form of busulfan (Bu) has prompted investigation of administration schedules other than the 4-times-daily dosage commonly used with oral Bu. We have studied an allogeneic stem cell transplantation (SCT) preparative regimen comprising fludarabine (FLU) 50 mg/m2 on days -6 to -2 plus i.v. Bu 3.2 mg/kg daily in a 3-hour infusion on days -5 to -2. The regimen was given to 70 patients aged 15 to 64 years (median, 41 years) with hematologic malignancy. Thirty-six patients (51%) had high-risk malignancy, 28 (40%) had unrelated or genotypically mismatched related donors (alternate donors [AD]) and 29 (41%) received bone marrow rather than blood as stem cell source. Acute GVHD prevention comprised antithymocyte globulin 4.5 mg/kg over 3 days pretransplantation, cyclosporin A, and short-course methotrexate with folinic acid. Hepatic toxicity was transient and there was no clinically diagnosed veno-occlusive disease. Grade II stomatitis occurred in 49 patients (70%) and hemorrhagic cystitis in 9 patients (13%). One patient with subtherapeutic phenytoin levels had a convulsion 8 hours after the third i.v. Bu dose, but no other neurotoxicity was apparent. Incidence of acute GVHD grades II to IV was 8% and incidence of grade III-IV was 3%, with no deaths from this cause. Actuarial incidence of chronic GVHD at 2 years is 38%. There were 2 cases of graft failure in unrelated donor BMT recipients, 1 of which was reversed by asecond transplantation. With a median follow-up of 16 months (range, 6-27 months), transplantation-related mortality at 100 days and 2 years was 2% and 5% for matched related donor (MRD) SCT and 8% and 19% for AD SCT, respectively (P = not significant). Relapse rates were 21% for 34 patients with acute myeloid leukemia (AML) in complete remission or chronic myeloid leukemia in chronic phase (low-risk), 66% for 19 patients with high-risk AML, and 18% for 17 patients with other active malignancy. Projected disease-free and overall survival rates at 2 years were 74% and 88% for low-risk disease, 26% and 37% for advanced AML, and 65% and 71% for other high-risk disease, respectively. Pharmacokinetic studies were done using 11 samples with the first and fourth doses of Bu. Kinetics were linear, and for the first and fourth doses, the half-lives were 2.60 +/- 0.44 and 2.57 +/- 0.36 hours, respectively. Clearances were 106.77 +/- 16.68 and 106.86 +/- 21.57 mL/min per m2, peak concentrations (Cmax) were 3.92 +/- 0.31 and 3.96 +/- 0.28 mcg/mL, and Bu areas under the plasma concentration versus time curve (AUC) were 4866.51 +/- 771.42 and 4980 +/- 882.80 microM x min, respectively. Bu was completely cleared within 24 hours and the day 4 pharmacokinetic values were very similar to those on day 1 for every patient. The cumulative AUC was comparable to the target range established for p.o. Bu. This regimen incorporating once-daily i.v. Bu is convenient to give, is relatively well tolerated, gives predictable blood levels, and deserves further study in circumstances in which cytoreduction as well as immune suppression is needed.
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PMID:Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. 1237 50

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

A phase II study of troxacitabine, a non-natural dioxolane nucleoside L-enantiomer, was conducted in patients with chronic myelogenous leukemia in blastic phase (CML-BP). Patients were untreated for BP, or treated with imatinib mesylate (IM) as sole prior therapy for BP. Troxacitabine was given as an intravenous infusion over 30 min daily for 5 days at a dose of 8.0 mg/m(2) per day. Thirty-one patients, 29 (93%) of whom had failed prior IM therapy, received 51 courses of therapy. Grade 3 or 4 toxicities included stomatitis (4%), hand-foot syndrome (18%), and skin rash (12%). Four patients (13%) responded. Troxacitabine-based combinations merit study in IM-resistant CML.
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PMID:Phase II study of troxacitabine, a novel dioxolane nucleoside analog, in patients with untreated or imatinib mesylate-resistant chronic myelogenous leukemia in blastic phase. 1292 45

A 35-year-old woman attended our hospital with chronic myeloid leukemia and was prescribed imatinib mesylate. She was admitted with lower abdominal pain, stomatitis, and hyposthenia after an increase in her dose of imatinib mesylate. When the treatment was changed to interferon-alpha and Ara-C, the lower abdominal pain, stomatitis, and hyposthenia improved, but bone marrow aspiration showed 36.4% blasts. After the treatment was changed back to an increased dose of imatinib mesylate (800 mg), the stomatitis deteriorated and intestinal bleeding reoccurred. Endoscopy demonstrated the presence of multiple ulcers in the ascending colon and 99mTc RBC scintigraphy demonstrated lesions of the large and small intestine. The patient declined any treatment except for transfusion and died suddenly after ten days. The present case suggests that we should carefully consider the possibility of intestinal bleeding when prescribing imatinib mesylate.
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PMID:[Intestinal bleeding during the treatment of chronic myeloid leukemia with imatinib mesylate]. 1644 Jul 65

Imatinib mesylate (imatinib) is a potent inhibitor of defined tyrosine kinases (TKs) and is effective in the treatment of malignancies characterized by constitutive activation of these TKs such as chronic myeloid leukemia and gastrointestinal stromal tumors. TKs also play an important role in T-cell receptor (TCR) signal transduction. Inhibitory as well as stimulating effects of imatinib on T cells and dendritic cells have been described. Here, we analyzed the effects of imatinib treatment on antiviral immune responses in vivo. Primary cytotoxic T-cell (CTL) responses were not impaired in imatinib-treated mice after infection with lymphocytic choriomeningitis virus (LCMV) or after immunization with a tumor cell line expressing LCMV glycoprotein (LCMV-GP). Similarly, neutralizing antibody responses to vesicular stomatitis virus (VSV) were not affected. In contrast, secondary expansion of LCMV-specific memory CTLs was reduced in vitro and in vivo, resulting in impaired protection against reinfection. In addition, imatinib treatment delayed the onset of diabetes in a CTL-induced diabetes model. In summary, imatinib treatment in vivo selectively inhibits the expansion of antigen-experienced memory CTLs without affecting primary T- or B-cell responses. Therefore, imatinib may be efficacious in the suppression of CTL-mediated immunopathology in autoimmune diseases without the risk of acquiring viral infections.
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PMID:Imatinib mesylate selectively impairs expansion of memory cytotoxic T cells without affecting the control of primary viral infections. 1687 71

The chronic use of hydroxyurea (HU) in some oncologic and non-oncologic diseases (psoriasis, sickle cell anemia) can be accompanied by side effects, both systemic and mucocutaneous. The most severe adverse events known in HU therapy are leg ulcers and cutaneous carcinomas. At skin level may also appear: xerosis, persistent pruritus, skin color changes (erythema, hyperpigmentation), cutaneous atrophy. Likewise, oral ulcerations and stomatitis may occur at mucosal level. Hair damage can be expressed through alopecia and nail damage through melanonychia and oncycholysis. First case, a 63-year-old woman with severe psoriasis vulgaris and chronic granulocytic leukemia, with 5 years of HU therapy, was admitted to hospital for submammary and palmoplantar ulcers, superinfected with methicillin-resistant Staphylococcus aureus and Proteus mirabilis. Clinical exam showed that the patient had also cutaneous atrophy, marked palmoplantar xerosis and melanonychia. The second case, a 72-year-old woman with primary thrombocytemia, treated with HU for 3 years, presented with necrotic leg ulcers that were superinfected with Pseudomonas aeruginosa, Enterobacter and E. Coli. The patient associates cellulitis, microbial eczema and xeroderma. In both cases, after HU discontinuation, systemic antibiotics, topical epithelizing agents and emollients, the ulcers had a slow favorable evolution. In our cases, the ulcers appeared after 5, respectively 3 years of HU therapy. It is stressed that in the first case, which had associated psoriasis, after 1 year of 1 g of HU/day, the psoriatic lesions completely disappeared. The severe progression of the ulcers was also favored by the superinfection of the ulcers with 2, respectively, 3 identified germs for which appropriate systemic antibiotics was required.
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PMID:Hydroxyurea-induced superinfected ulcerations: Two case reports and review of the literature. 3310 81


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