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At least 127 records · Page 7Linked to original sources
PubMed2003

Practical aspects of the treatment of chronic myelogenous leukemia with imatinib mesylate.

Imatinib mesylate (Gleeve; formerly known as STI-571; Novartis Pharmaceuticals, Basel, Switzerland) is a protein tyrosine kinase inhibitor that has been approved by the US Food and Drug Administration for chronic-phase chronic myeloid leukemia (CML) that is refractory to or intolerant of interferon-alpha, and with accelerated and blast-phase CML. Imatinib is remarkably effective as treatment for chronic-phase and accelerated-phase CML at doses of 400 mg and 600 mg daily, respectively. Although dramatic responses are noted in patients with myeloid blast crisis, lymphoid blast crisis, and Philadelphia chromosome-positive acute lymphoblastic leukemia, the responses are usually incomplete and of short duration. The role of imatinib in relation to allogeneic stem cell transplantation is discussed, recognizing that the data on which any decisions can be made are relatively immature. At this time, it remains to be seen whether the chronic phase of CML can be extended sufficiently long in some patients so that they are functionally "cured," and whether doses of imatinib higher than 400 mg daily will improve response rates in chronic-phase CML. The feasibility of combining imatinib with other agents also needs to be examined, as does the utility of molecular monitoring of response. Finally, developing methods to overcome resistance to imatinib is a looming challenge.

Benzamides↗
PubMed1995

Cytogenetic correlation with disease status and treatment outcome in advanced stage leukemia post bone marrow transplantation: a Southwest Oncology Group study (SWOG-8612).

A retrospective cytogenetic study was performed to determine whether non-random chromosome aberrations were related to the outcome of marrow transplantation for advanced stage acute leukemia (AL) and chronic myelogenous leukemia (CML). The patients were registered on SWOG-8612, a randomized comparison of busulphan and cyclophosphamide (BU/CY) to fractionated total body irradiation and etoposide (FTBI/VP16) as preparatory regimens for allogeneic bone marrow transplant (BMT). Blume K. G., Kopecky K. J., Henslee-Downey J. P., Forman S. J., Stiff P. J., Le Maistre C. F. & Appelbaum F. R. (1987) Blood 81, 2187. Pretreatment cytogenetic studies were available for 90 (78%) of the 115 patients who proceeded to BMT. Patients were categorized by diagnosis (ALL/AML/CML), disease status ['good' risk = second complete remission (CR2) or CML-accelerated phase (AP); 'poor' risk = third complete remission (CR3), induction failure, florid relapse or CML-blast phase (BP)] and cytogenetic status (favorable = normal cytogenetics in AL or Philadelphia chromosome positive (Ph+) standard or variant translocation as the sole findings in CML; unfavorable = all other cytogenetic aberrations). Chromosomal aberrations observed in the unfavorable category included -7, t(9;22) in AL, t(8;21) in association with complex karyotypes, t(6;9), del(9q), t/del(11q), t(1;19), hypotetraploidy, and complex karyotypes (> 3 cytogenetic anomalies). Unfavorable cytogenetic status was significantly more frequent among patients with 'poor' risk clinical disease status (P < 0.0001). In multivariate analysis, disease-free survival (DFS) was significantly poorer for patients with unfavorable cytogenetic status (P = 0.002) but not significantly related to disease status (P = 0.43). These data indicate that certain secondary chromosome aberrations [+8,i(17q), duplication of Ph] should be reclassified as relatively favorable predictors of successful BMT in CML and, therefore, be separated from the unfavorable cytogenetic aberrations characteristic of drug resistant disease [-7, inv(3), complex karyotypes]. The limited number of patients precluded definitive assessment of the prognostic significance of specific cytogenetic aberrations for any single diagnosis. Nevertheless, these findings suggest that cytogenetic status may be an important and independent factor in predicting outcome following allogeneic bone marrow transplantation.

Adolescent↗
PubMed2003

Troxacitabine: BCH 4556, SPD 758, Troxatyl.

Troxacitabine [BCH 4556; SPD 758; Troxatyl] is a DNA synthesis inhibitor. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It is a member of a novel class of nucleoside analogues discovered by BioChem Pharma and is the first example of a synthetic L-nucleoside analogue to have shown anticancer activity in animal models. On 11 May 2001, BioChem Pharma was acquired by, and integrated into, Shire Pharmaceuticals Group. In February 2002 Shire announced that it intended to pursue development of troxacitabine as a treatment for solid tumours. In addition, Shire indicated that it would pursue the drug's development for acute myeloid leukaemia. In March 1999, phase II trials were initiated to investigate the efficacy and tolerability of troxacitabine in a variety of solid tumours including pancreas, prostate, colorectal, renal and non-small cell lung cancers and melanoma. The trials were conducted throughout North America and were closed to patient accrual in 2000. Two phase I combination chemotherapy trials in solid tumours (one with cisplatin and another with paclitaxel) have been initiated. One of these trials is in patients with pancreatic cancer. A phase III trial in patients with pancreatic cancer is expected to begin during the second or third quarter of 2003. In addition, further clinical development was initiated in May 2000, in the form of a combination chemotherapy trial in patients with acute leukaemia. A phase II trial in patients with acute myeloid leukaemia (AML) and chronic myeloid leukaemia-blast phase (CML-BP) has reported that troxacitabine demonstrated significant activity in these cancers. However, Shire indicated that no further development for CML-BP will be conducted. The company indicated that it would focus future development in the haematological malignancy area on AML and has initiated an exploratory phase III trial of troxacitabine in previously untreated patients with poor prognosis AML. The study will compare troxacitabine in combination with either cytarabine or idarubicin, with a control drug regimen. The aim is to identify the most promising treatment regimens in a relatively small number of patients before commencing the larger pivotal trial. A pivotal phase III trial is expected to begin in the first half of 2003. In September 2002, Shire Pharmaceuticals forecast Troxatyl to reach peak sales of $US100-200 million, for the indications of pancreatic cancer and myeloid leukaemia.

Antineoplastic Agents↗
PubMed2007

Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy.

BACKGROUND: Homoharringtonine (HHT) is a cephalotaxus alkaloid that inhibits the synthesis of proteins leading to apoptosis. Intravenous HHT has demonstrated activity in patients with chronic myeloid leukemia (CML) after failure with interferon. METHODS: A Phase I study was completed of subcutaneous (s.c.) HHT in patients with CML in accelerated or blast phases and demonstrated efficacy and good tolerance at the same doses used by intravenous (i.v.) administration. The maximal tolerated dose (MTD) was 1.25 mg/m(2) s.c. twice daily. The cohort was then expanded to treated at the MTD to include patients in late chronic phase CML after imatinib failure. Therapy consisted of an i.v. loading dose of HHT 2.5 mg/m(2) over 24 hours, followed by 1.25 mg/m(2) s.c. twice daily for 14 days every 28 days until remission, then for 7 days every 28 days. Six patients (median age, 53 years) who had failed imatinib were treated and 5 were evaluable. Patients received a median of 4.5 courses of s.c. HHT. RESULTS: Complete hematologic remission was obtained in all 5 evaluable patients and 3 had cytogenetic (CG) responses: 1 complete and 2 minor. The 2 patients with BCR-ABL kinase domain mutations at the start of therapy with HHT had a CG response and in both instances the mutations became undetectable. All patients developed myelosuppression and 3 had their HHT dose reduced due to prolonged neutropenia. Nonhematologic toxicity was mild and manageable. CONCLUSIONS: Subcutaneous HHT is well tolerated and may have clinical activity in patients with CML after imatinib failure.

Adult↗
PubMed2004

Hematologic and cytogenetic findings in eleven chronic myelogenous leukemia patients treated with imatinib mesylate at a tertiary care hospital.

OBJECTIVE: To evaluate the response of Imatinib mesylate in patients with myeloid leukemia in chronic accelerated and blast phase. PATIENTS AND METHODS: Eleven patients with established diagnosis of chronic myeloid leukemia were treated with Imatinib mesylate. Adverse events were documented with regular follow ups. Hematological and cytogenetic responses were assessed according to established criteria. Patients with zero percent Philadelphia positive metaphases were labeled as complete cytogenetic response while patients with 1% to 35% Philadelphia positive metaphases were termed as partial responders. RESULTS: Of 11 cases there were 7 males and 4 females with a mean age of 39.5 years and median age 51 years (range 21-69). Male to female ratio was 7:4. Median follow-up was 34 weeks (range 8-78). Four patients were in blast crisis, 1 in accelerated phase and remaining six patients were in chronic phase. All patients achieved hematological response. Cytogenetic response was present in six patients, 3 were responders and the remaining were non responders. Two patients achieved complete cytogenetic response and one patient had partial cytogenetic response. Both patients with complete cytogenetic response relapsed in twelve weeks time. CONCLUSION: Imatinib mesylate is a drug with curative potential and can be used as a first line drug in the management of CML, however at present the cure rate is unknown.

Adult↗
PubMed1984

Adult-type CML in childhood: case report and review.

The clinical, hematologic, and cytogenetic features of ACML in children appear to be identical to Ph1-positive CML seen in adults. From our review of the literature, one could anticipate that a child with this condition would have a response to therapy and an anticipated survival similar to that seen in adults. This situation is quite different when one compares adults with ALL to children with the same disease. It has been suggested that Ph1-positive CML is an acquired, postzygotic abnormality induced by environmental agents. It is difficult to reconcile this hypothesis with the fact that this condition can be seen in infants as young as 5 months of age and the general belief that environmental carcinogens take many years to produce malignant changes in cells. Ph1-positive CML has been associated with atomic bomb exposure and it is of interest to note that two patients in the present series had received radiation. For both children and adults, bone marrow transplantation during the chronic phase is the most successful therapy if a suitable donor is available. Recently, successful marrow transplantation during the accelerated phase has also been reported. For patients without a suitable donor, control of the disease with either busulfan or hydroxyurea and attempts to induce a remission with chemotherapy during the accelerated or blast phase is the best current alternative. For patients whose blasts have lymphoid characteristics such as TdT activity, vincristine and prednisone may be successful. For those patients with a myeloid or mixed lymphoid-myeloid transformation, no chemotherapy regimen has been successful. An aggressive approach such as that described by Weinstein et al. for the treatment of acute nonlymphocytic leukemia might prove beneficial.

Child, Preschool↗
PubMed1991

Translocation (3;21) characterizes crises in myeloid stem cell disorders.

Three patients, one with Philadelphia (Ph) chromosome positive chronic myelocytic leukemia (CML) and two with primary acquired myelodysplastic syndromes (MDS), have been identified to have a t(3;21)(q26;q22). In the patient with CML, the t(3;21) was detected only in the blast phase. The t(3;21) as the sole abnormality appeared at presentation of MDS [refractory anemia with excess blasts (RAEB)] in one patient and remained as such when progression to RAEB in transformation (RAEB-t) occurred. The other patient with MDS had the t(3;21), in addition to other changes, during the progression of the disease. Thus, t(3;21) may characterize myeloid crises of clonal hematopoietic stem cell disorders (HSCD) and indicates a poor prognosis. As a primary cytogenetic event it may be also involved in the genesis of myelodysplasia with subsequent leukemic transformation.

Aged↗
PubMed1978

Splenectomy in chronic myeloid leukemia.

We review splenectomy in chronic myeloid leukemia, emphasizing recent studies that have evaluated early splenectomy during the chronic phase of the disease. Despite current interest in splenectomy in chronic myeloid leukemia, uncontrolled clinical trials to date suggest that the operation during the early phase neither delays the onset of blastic transformation nor prolongs survival. Immediate operative mortality of splenectomy during the chronic phase is low, generally less than 1%. The morbidity of the procedure, however, remains formidable due to infectious and thromboembolic complications. Splenectomy during chronic-phase chronic myeloid leukemia permits easier control of the disease in patients who are thrombocytopenic due to busulfan toxicity or sensitivity. Splenectomy during the chronic phase may also palliate those patients who suffer from acute splenic events or massive splenomegaly. Splenectomy in blast-phase disease should be considered a heroic measure providing little benefit to most patients.

Aged↗
PubMed2001

Application of Resistance Reversal Agents in Hematologic Malignancies; Malignancy; Current Clinical Practice.

The clinical application of resistance reversal drugs for patients with hematologic malignancies is reviewed. The phenomenon of multidrug resistance versus other mechanisms are discussed. The pump-like mechanisms of P-glycoprotein, multidrug resistance associated protein, lung resistance protein and of other ATP binding cassette transporter proteins are reviewed briefly, as well as the important substrate drugs and pump-blocking compounds. The problems associated with resistance protein assays in clinical samples and the concept of prognostic versus therapeutic clinical relevance are described, within the context of selected hematologic malignancies. Toxicities and treatment outcomes of phase II and III trials of reversal agents in lymphoma, multiple myeloma, myelodysplastic syndromes, acute myeloid leukemia and blast phase of chronic myeloid leukemia are reviewed. Finally, current options for on-study management of relapsed or refractory hematologic malignancy patients are discussed.

Journal Article↗
PubMed1983

T-cell surface antigens in a patient with blast crisis of chronic myeloid leukemia.

There is little evidence to suggest that T lymphocytes are involved in the leukemic process in chronic myeloid leukemia (CML). A case of CML in blast phase is described in which T-cell surface antigens were detected by immunofluorescence on the patient's blasts using monoclonal antibodies. In order to determine that the T-cell blasts were derived from the original CML clone, cells bearing the T3 antigen were isolated by fluorescence-activated cell sorting and chromosome analysis was performed. All metaphases examined had the Philadelphia chromosome, confirming their origin from CML.

Antigens, Surface↗
PubMed1982

Clinical evaluation of succinylated Acinetobacter glutaminase-asparaginase in adult leukemia.

We treated 13 adult patients with acute leukemia or chronic myelocytic leukemia (CML) in blast phase using succinylated Acinetobacter glutaminase-asparaginase (SAGA) administered on a daily dose schedule. SAGA reduced the peripheral blast count in two patients with acute lymphoblastic leukemia and two with blastic CML; however, no patient achieved either complete or partial remission. Marked central nervous system toxic effects (encephalopathy and coma) were observed, limiting treatment in patients whose disease appeared responsive; this effect finally prompted early discontinuance of the trial. Other toxic effects observed included nausea, hyperglycemia, and respiratory alkalosis. Hypersensitivity reactions to the enzyme were not seen. Pharmacologic analyses showed that prolonged blood glutamine depletion was achieved only by daily enzyme administration; however, we noted the importance of performing amino acid analysis on blood which was deproteinized immediately following phlebotomy. Our results demonstrate excessive central nervous system toxicity when glutaminase-asparaginase is administered on a daily schedule. Because of this effect, we propose that future trials of similar enzymes be limited to short courses of enzyme therapy, possibly with the addition of antimetabolites or amino acid analogs, which could enhance the antitumor effect without increasing toxicity.

Acinetobacter↗
PubMed1994

Availability and appropriateness of allogeneic bone marrow transplantation for chronic myeloid leukemia in 10 countries.

BACKGROUND: Allogeneic bone marrow transplantation, a sophisticated and expensive procedure, is the only curative therapy for chronic myeloid leukemia (CML). We examined the availability and appropriateness of allogeneic bone marrow transplantation for CML in 10 economically advanced countries with diverse health care systems. For each country we obtained data on the likelihood of transplantation to treat CML in patients under the age of 55 years, the length of time from diagnosis to transplantation, and the stage of disease at the time of transplantation. METHODS: Data were collected on 9873 allogeneic bone marrow transplantations performed at 208 centers in 10 countries from 1989 through 1991. Data were acquired from transplantation registries and by means of a mailed survey of all centers and teams that did not contribute data to registries. Data on the incidence of disease were drawn from national and regional cancer registries. RESULTS: Among the 10 countries there was a twofold difference between the lowest and highest rates of transplantation to treat CML (0.26 to 0.54 per 100,000 population per year); Swedish patients were the most likely to receive a transplant, and German patients the least likely. The median length of time from diagnosis to transplantation ranged from 6.8 to 15.4 months. In all countries, most transplantations were performed in the chronic phase of the disease, but as many as a third of patients received transplants in the less favorable accelerated or blast phase. The values for the United States fell near the middle of those for the 10 countries on all measures. CONCLUSIONS: Our findings challenge the assumption that the United States is unique in providing broad access to high-technology treatments. On no measure of the availability or appropriateness of transplantation for CML did it surpass the other nine countries studied.

Adolescent↗
PubMed1997

Trilineage extramedullary myeloid cell tumor in myelodysplastic syndrome.

A patient with a 17-month history of myelodysplastic syndrome (refractory anemia with excess blasts that evolved into chronic myelomonocytic leukemia), which was treated with transfusions and erythropoietin, developed abdominal and inguinal lymphadenopathy. Biopsies of the abdominal nodes revealed virtual obliteration of the architecture by myeloid blasts admixed with maturing granulocytic, erythroid, and megakaryocytic precursors. The lymph node findings appeared to represent extramedullary dyshematopoiesis undergoing a tissue phase blast transformation. Four months later, the patient developed rising peripheral blast counts consistent with acute leukemia. Although the development of granulocytic sarcoma (also called extramedullary myeloid cell tumor) is well known to occur in patients with myelodysplastic syndromes, to our knowledge this is the first description of an extramedullary myeloid cell tumor associated with trilineage differentiation.

Anemia, Refractory, with Excess of Blasts↗
PubMed1996

[Chronic myeloid leukemia].

The chronic myelogenous leukemia [CML] is a clonal disease of hematopoietic stem cells with unknown etiology. The incidence is around 2/100,000/year, the median age at diagnosis about 47 years. The course of CML is characterized by a chronic phase with few symptoms and good therapeutic response of about 4 to 5 years duration and by transition to a prognostically unfavourable blast phase of about 3 months duration. Therapy of choice, at present, is early allogenous bone marrow transplantation [BMT], which is curative in 40 to 80% of transplanted cases. In patients below 55 years, a donor search should be started at the earliest possible time after diagnosis. Drug therapy of choice are interferon alpha [IFN] and hydroxyurea, which are both superior to busulfan with regard to duration of chronic phase and survival. Complete cytogenetic remissions are observed in 5 to 9% of IFN-treated patients in randomized studies, but virtually all remain positive for bcr/abl by PCR. Whether and in how far IFN is superior to hydroxyurea appears, at least in part, to depend on the treatment intensity with hydroxyurea and on patients characteristics. In analyzing median survival times, the risk profiles of the patients have to be considered. In the future, intensive chemotherapy with or without autografting might play an important role in the therapy of chronic-phase CML. Forthcoming trials have to consider both, conventional and new experimental treatment modalities. An example is the treatment strategy of the ongoing randomized study of the German CML Study Group which compares allogenous BMT with the best available drug therapy and, in addition, analyses the influence of intensified drug therapy on survival.

Adolescent↗
PubMed1975

Chromosome band analysis in 19 cases of chronic myeloid leukemia: 9 chronic, 10 blastic, two with Ph1 (22q-) translocation on 17 short arm.

The results of Giemsa band analyses of the marrow cells of 19 cases of CML in the chronic or blast phase are reported. All but one of the 14 Ph1 positive cases showed the 9q+pattern, the exceptional one being 16p+. All 10 blast cases showed additional rearrangements, which are described. In two of the cases, one blastic, one chronic, which were -22, Ph1 negative, the 22q- member was identified as a translocation on the short arm of one 17 which was dicentric.

Chromosome Aberrations↗
PubMed1995

Phase I study of continuous infusion 6-thioguanine in patients with acute leukemia.

6-Thioguanine (6-TG) was administered as a continuous i.v. infusion for 7 days to 24 patients with relapsed or refractory acute leukemia or in the blast phase of chronic granulocytic leukemia. The daily dose of 6-TG was escalated from 37.5 mg/m2 to 160 mg/m2. Stomatitis was dose-related and dose-limiting with a maximum tolerated dose of 120 mg/m2 daily. Cutaneous reactions were dose-related but not dose-limiting. The recommended dose for phase II trials in acute leukemia is 120 mg/m2 per day as a continuous infusion for 7 days. There were two complete and four partial remissions among all patients. At the suggested phase II dose of 120 mg/m2 there were two complete remissions and one partial remission in five evaluable patients.

Acute Disease↗
PubMed2002

Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia.

BACKGROUND: Chronic myelogenous leukemia (CML) is caused by the BCR-ABL tyrosine kinase, the product of the Philadelphia chromosome. Imatinib mesylate, formerly STI571, is a selective inhibitor of this kinase. METHODS: A total of 532 patients with late--chronic-phase CML in whom previous therapy with interferon alfa had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for cytogenetic and hematologic responses. Time to progression, survival, and toxic effects were also evaluated. RESULTS: Imatinib induced major cytogenetic responses in 60 percent of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95 percent. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 89 percent of patients, and 95 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were infrequent, and hematologic toxic effects were manageable. Only 2 percent of patients discontinued treatment because of drug-related adverse events, and no treatment-related deaths occurred. CONCLUSIONS: Imatinib induced high rates of cytogenetic and hematologic responses in patients with chronic-phase CML in whom previous interferon therapy had failed.

Administration, Oral↗
PubMed2003

Purine nucleoside analogues in the treatment of myleoid leukemias.

The purine nucleoside analogues (PNA), fludarabine (FA), cladribine (2-chlorodeoxyadenosine, 2-CdA) and 2'-deoxycoformycin (DCF), represent a novel group of cytotoxic agents with high activity in low-grade lymphoid malignancies. However, several investigations have revealed that these agents are active also in acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML). Synergistic interaction between FA or 2-CdA with cytarabine (Ara-C) have been demonstrated in both preclinical and clinical studies. PNA enhance the cell concentration of Ara-CTP, which is active metabolite of Ara-C. It is likely that the addition of granulocyte colony stimulating factor (G-CSF) may further improve the effects of FA (FLAG) or 2-CdA (CLAG). The addition of anthracyclines to induction therapy does not appear to result in a substantial advantage in terms of CR achievement and duration. An alternative approach to increase FLAG activity might be the addition of investigational drugs with novel mechanism of action, such as topoiromerase I inhibitors. The addition of anthracyclines to induction therapy does not appear to result in a substantial advantage in terms of CR achievement and duration. Clinical studies have confirmed the efficacy of PNA alone or in combination protocols in the treatment of AML. These regimens seem to produce superior results with acceptable toxicities in previously treated and relapsed, poor risk AML. However, early relapses remain a significant problem in a majority of refractory or relapsed patients in CR after treatment with PNA based regimens. To prolong remission duration or even cure AML, auto--or allo stem cell transplantation should be considered. However, FAMP or 2-CdA containing regimens may impair mobilization and collection of stem cells from peripheral blood for autotransplantation. Few studies have analyzed the role of PNA in CML. 2-CdA, FAMP and DCF can induce hematologic response in chronic phase of CML but cytogenetic responses have not been observed. Preliminary results suggest, that PNA used alone or in combination may be used as palliation in blast phase of the disease. However, currently, the role of these agents in CML is insignificant because of the high activity of Glivec in this disease. Finally, PNA, especially FA play an important role in non-myeloablative conditioning regimens for allogenic stem cell transplantation in high-risk patients, possibly also with myeloid malignancies.

Acute Disease↗