Alteration of methotrexate uptake in human leukemia cells by other agents. (73/5352)

The uptake of methotrexate (MTX) and the effect of drugs known to either inhibit or enhance MTX transport in L1210 murine leukemia were studied in man using blast cells from patients with acute myelogenous leukemia in vitro. MTX uptake was found to proceed slowly, requiring at least 160 min for cells to reach a "steady state" when extracellular MTX concentrations were 1 muM. Efflux of MTX from preloaded cells required 80 to 120 min and the nonexchangeable or tightly bound fraction was 40% of the total intracellular drug. Utilizing doses that are estimates of achievable peak blood levels following single i.v. injection, cephalothin (21 mug/ml) and hydrocortisone (20 mug/ml) inhibited net MTX accumulation by 20 and 28%, respectively. Vincristine sulfate at 8.3 and 0.083 mug/ml enhanced MTX uptake by 54 and 33%, respectively, by inhibiting MTX efflux, thus increasing the level of intracellular drug in excess of the tightly bound fraction. The potential clinical implications of using MTX in combination with the aforementioned drugs for cancer chemotherapy are discussed.  (+info)

Management of acute myeloid leukemia in elderly patients. (74/5352)

Acute myeloid leukemia (AML) at older age is associated with several biologic and clinical characteristics. Hence, it may arise from an early level of hematopoietic stem cells and has a high frequency of blast cells with multidrug resistance glycoprotein MDR1 expression and particularly a high incidence of poor prognostic karyotypes. These factors, rather than age per se, underlie the poorer outcome as compared with younger cases. Prospective randomized studies clearly demonstrate, however, that elderly patients benefit from more intensive induction therapy and particularly from full-dose application of anthracyclines and possibly also cytarabine. Hematopoietic growth factors accelerate the recovery from treatment-induced neutropenia and may improve the remission rate, remission duration, and even overall survival. New treatment strategies need to be developed, however, for poor-prognosis AML subtypes in order to further improve the therapeutic perspectives for elderly patients with AML.  (+info)

Impact of immunophenotyping on management of acute leukemias. (75/5352)

BACKGROUND AND OBJECTIVE: The diagnosis of acute leukemias (AL) requires a multiparametric approach in order to apply risk-adapted therapeutic protocols and appreciate the potential outcome of any given patient. Blast cells immunophenotyping is a key test in this issue, yet the information provided by immunophenotyping has become staggering, and it may be difficult to identify relevant characteristics clearly. This manuscript provides a critical review of the literature regarding the importance of immunophenotyping in acute leukemia diagnosis and management. DATA SOURCES AND METHODS The information given here is based on the experience of the authors, on their literature files and on additional material retrieved through articles and reviews covered by the Institute for Scientific Information (ISI) and the Medline database. Studies with proper definition of the patients and sufficient information regarding follow-up were considered. RESULTS: Immunophenotyping allows an early confirmation of AL diagnosis and establishes lineage assignment. Adequate and comprehensive panels of monoclonal antibodies also allow detection of aberrant immunophenotypic profiles of prognostic value or of use in detecting minimal residual disease. A number of unusual immunophenotypic features are also associated with prognosis. The development of new antibodies, new insights in the functional properties of differentiation antigens, and the quantimetric approach of immunophenotyping will keep this field changing. Moreover, as therapeutic protocols evolve, some earlier results need to be reconsidered. INTERPRETATION AND CONCLUSIONS: Immunophenotyping, together with cytologic, karyotypic and molecular approaches, retains a crucial place in the diagnosis and management of acute leukemias. It remains a rather specialized approach and should be interpreted in a multidisciplinary perspective, considering for each patient the idiosyncrasies possibly relevant to prognosis.  (+info)

Hematopoietic stem cell transplantation for childhood myeloid malignancies after high-dose thiotepa, busulfan and cyclophosphamide. (76/5352)

Seventeen children with advanced myeloid malignancies (induction failure, relapse, myelodysplasia, secondary AML, or CR >1) received thiotepa 750 mg/m2 i.v., busulfan 12 mg/kg or 640 mg/m2 p.o., and cyclophosphamide 120 mg/kg i.v. as a preparative regimen for allogeneic or autologous hematopoietic stem cell (HSC) transplantation. Of the 15 allogeneic transplants, eight were from matched siblings, one was from a mismatched sibling, and six were from unrelated donors. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine or tacrolimus and methotrexate. Regimen-related toxicity was common but tolerable, affecting mainly the skin and gastrointestinal tract. Three patients died early and were not evaluable for engraftment; engraftment occurred in the remaining patients. Nine patients with active disease at the time of transplant were evaluable for response; all achieved remission. With a median follow-up of 40 months (range, 10-71 months), nine patients are alive and disease-free. The 3-year actuarial event-free survival was 51% (95% confidence interval (CI) 27-76%). Seven patients died of transplant-related complications: infection (n = 4), chronic GVHD (n = 1), veno-occlusive disease, VOD, (n= 1) and pulmonary alveolar hemorrhage (n = 1). Only one patient had leukemia relapse and died. We conclude that the use of high-dose thiotepa, busulfan and cyclophosphamide is an effective conditioning regimen for childhood myeloid malignancies and may be tested in patients with less advanced disease (eg CR1).  (+info)

Acute leukemia in adults: assessment of remission induction with combination chemotherapy by clinical and cell-culture criteria. (77/5352)

Remission induction was assessed by clinical and cell-culture criteria for 65 patients with acute myelogenous leukemia (AML), 11 patients with chronic myelogenous leukemia (CML) in blast crisis and 19 patients with acute lymphoblastic leukemia (ALL). Cyclophosphamide, cytosine arabinoside and vincristine (CAV) therapy resulted in complete remission in 23 of 50 previously untreated patients with AML and in 3 of the 11 patients with CML. Fourteen patients with ALL responded to vincristine-prednisone induction therapy and two to induction therapy with CAV. The median duration of survival of the responding patients was 2.2 years, compared with 4 months for the patients who did not respond to treatment. Granulopoietic colony formation, assessed by assay of colony-forming units dependent on colony-stimulating activity in culture (CFU-C), was abnormal in 37 of 42 bone marrow aspirates from patients with AML before treatement. CFU-C concentration increased when leukocyte-conditioned medium (LCM) was added to the cultures; 13 cultures had normal or elevated CFU-C concentration with LCM. Marrow cells of patients with ALL or CML in blast crisis demonstrated a similar pattern. Serial studies of marrow CFU-C concentration of 31 patients with AML demonstrated a change to a normal pattern with successful remission induction. Results of this study suggest that administration of purified LCM to leukemic patients might increase granulocyte production from potential but unstimulated granulopoietic precursors. This therapy would lessen the probability of death from infection during remission induction.  (+info)

Adenosine deaminase activity in leukaemia. (78/5352)

Adenosine deaminase (EC 3.5.4.4., ADA) has been measured in the blast cells of 36 patients with acute lymphoblastic, acute myeloid, chronic myeloid and chronic myeloid blast crisis leukaemia. Particularly high levels were found in acute lymphoblastic and chronic myeloid blast crisis patients. The measurement of ADA may be useful diagnostically in the undifferentiated acute leukaemias and in detecting the early onset of blast crisis in chronic myeloid leukaemia. Possible reasons for the elevation of ADA in malignant cells are discussed.  (+info)

Antigens shared by leukemic blast cell and lymphoblastoid cell lines detected by lymphocyte-dependent antibody. (79/5352)

Lymphocyte-dependent antibodies (LDA's) directed against antigenic determinants present on lymphoblastoid cell lines as well as human leukemia blast cells were demonstrated in heterologous antisera obtained by immunizing rabbits with a membrane fraction from RPMI-4265 (a lymphoblastoid cell line derived from a patient with chronic myelogenous leukemia). LDA was present at high titers against B-lymphoblastoid, myelomonocytic, and stem cell lines. The T-lymphoblastoid cell line MOLT-4, however, did not react. LDA was demonstrated against acute myelogenous as well as lymphoblastic leukemia cells. The reactivity was not directed against phytohemagglutinin-induced blastoid antigens, fetal antigens, or fetal calf serum. Absorptions with lymphoblastoid cell lines removed all LDA reactivity. Similar results were obtained by absorbing the rabbit antiserum with acute lymphoblastic and/or acute myelogeneous leukemia cells. These findings indicate the presence of cross-reactive antigens between lymphoblastoid cell lines and leukemia cells. Furthermore, cross-reactivity between acute lymphoblastic and acute myelogenous leukemia cells was demonstrated.  (+info)

Patients with t(8;21)(q22;q22) and acute myeloid leukemia have superior failure-free and overall survival when repetitive cycles of high-dose cytarabine are administered. (80/5352)

PURPOSE: To examine the effect of single compared with repetitive (at least three) cycles of high-dose cytarabine after induction therapy for patients with acute myeloid leukemia (AML) who have the t(8;21)(q22;q22) karyotype. PATIENTS AND METHODS: Patients entered onto the study had AML and t(8;21) and attained a complete remission on four successive Cancer and Leukemia Group B studies. In these studies, either > or = three cycles of high-dose cytarabine or one cycle of high-dose cytarabine was administered, followed by sequential cyclophosphamide/etoposide and mitoxantrone/diaziquone with or without filgrastim support. Outcomes of these two groups of t(8;21) patients were compared. RESULTS: A total of 50 patients with centrally reviewed AML and t(8;21) were assigned to receive one (n = 29) or > or = three cycles (n = 21) of high-dose cytarabine as postinduction therapy. The clinical features of these two groups of patients were similar. Initial remission duration for t(8;21) patients assigned to one cycle of high-dose cytarabine was significantly inferior (P =.03), with 62% of patients experiencing relapse with a median failure-free survival of 10.5 months, compared with the group of patients who received > or = three cycles, in which only 19% experienced relapse and failure-free survival is estimated to be greater than 35 months. Furthermore, overall survival was also significantly compromised (P =.04) in patients assigned to one cycle of high-dose cytarabine, with 59% having died as a consequence of AML, compared with 24% of those who received > or = three cycles of high-dose cytarabine. CONCLUSION: These data demonstrate that failure-free survival and overall survival of patients with t(8;21)(q22;q22) may be compromised by treatment approaches that do not include sequential high-dose cytarabine therapy.  (+info)