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At least 991 records · Page 55Linked to original sources
PubMed2003

Risk and prognosis of central nervous system leukemia in patients with Philadelphia chromosome-positive acute leukemias treated with imatinib mesylate.

PURPOSE: In patients with acute leukemias, a lymphoid phenotype, the presence of a Philadelphia chromosome (Ph), and inadequate central nervous system (CNS)-directed prophylactic therapy are risk factors for CNS involvement. Imatinib mesylate has promising single-agent antileukemic activity in patients with advanced Ph(+) acute leukemias. It was the aim of this analysis to determine the incidence of, and risk factors associated with, meningeal leukemia during imatinib monotherapy. STUDY DESIGN: We analyzed 107 consecutive patients with relapsed or refractory Ph(+) acute lymphoid leukemia (ALL; n = 65) or chronic myeloid leukemia blast crisis (n = 42) who were enrolled in successive Phase II trials of single-agent imatinib and who did not receive routine prophylactic intrathecal chemotherapy. RESULTS: CNS leukemia developed in 13 of 107 patients (12%) and was associated primarily with a lymphoid or bilineage phenotype (12 of 78; 15%) and with imatinib refractory Ph(+) ALL (5 of 19; 26%). Meningeal leukemia did not occur among patients who received prior prophylactic cranial irradiation. The median survival with combined CNS and systemic disease was 108 days (range, 58-141), with no patient surviving long term. In contrast, two of three patients with exclusively meningeal leukemia achieved prolonged molecular remissions with intrathecal chemotherapy, cranial irradiation, and continued imatinib. CONCLUSIONS: Patients with Ph(+) ALL are at considerable risk of meningeal leukemia during imatinib monotherapy and should routinely receive CNS prophylaxis. Although the prognosis with combined meningeal and systemic relapse is dismal, patients with an isolated meningeal relapse may still achieve sustained remissions. The optimal type of CNS-directed treatment and the extent of protection afforded by prophylactic cranial irradiation remain to be defined.

Adolescent↗
PubMed1989

Prevention of leukemic relapse after transplantation with lymphocyte depleted marrow by intensification of the conditioning regimen with a 6-day continuous infusion of anthracyclines.

In the present study we have evaluated the efficacy and toxicity of a 6-day continuous constant rate intravenous infusion of anthracyclines added to the standard conditioning regimen for allogeneic bone marrow transplantation (BMT). In 22 consecutive recipients of a lymphocyte depleted bone marrow graft, either demethoxydaunomycin (n = 11) or daunorubicin (n = 11) were added to high-dose cyclophosphamide and total body irradiation. Five patients had acute non-lymphoblastic leukemia in first complete remission, six patients acute lymphoblastic leukemia in first or second complete remission, nine patients chronic myelogenous leukemia in chronic phase and two patients refractory anemia with excess of blasts. After a median observation period of 18 months, only one leukemic relapse has been observed. Six patients died in the post-transplant period. In 17 of the 22 patients a severe, transient mucositis developed. No cardiac toxicity, as assessed with radioisotope studies, was observed. We conclude that anthracyclines may be effectively and safely incorporated in conditioning regimens before BMT, provided that they are administered as long-term continuous infusions in order to avoid toxicity due to excessive plasma levels.

Adolescent↗
PubMed1977

Lymphocyte-epithelium interaction during rejection of nonisogeneic rat tracheal grafts.

Rat tracheal tissues were maintained in organ culture for 1 to 2 weeks and then implanted heterotopically into syngeneic and outbred hosts. The grafts and surrounding tissues were removed at regular intervals and examined by light and electron microscopy. Allogeneic grafts were consistently rejected, and a constant pattern of immunologic response was observed during rejection. Infiltration by mononuclear cells occurred initially in the subepithelial region. Subsequently, small lymphocytes migrated through the basal lamina and insinuated themselves between the differentiated epithelial cells. Larger cells resembling activated lymphocytes were also present in the intraepithelial infiltrate. Both type of lymphocytes had cellular processes in contact with epithelial cells, but there was no associated death of epithelial cells. Later, the infiltrate in some areas of the epithelium inclded dividing cells and other large cells exhibiting ultrastructural features suggesting blast transformation. Epithelial cell death was evident during this phase. The sequence of events may reflect a process of recognition and specific cytotoxic action by lymphocytes.

Animals↗
PubMed1999

Drug resistance testing of acute myeloid leukemia in adults using the MTT assay.

OBJECTIVE: We want to evaluate the MTT in vitro assay for newly diagnosed AML in adults, in particular its prognostic significance. METHODS: MTT tests were performed according to Pieters et al., Blood 76: 2327, 1990. Up to 18 cytostatic drugs were tested in a wide range of concentrations over 4 days and compared with controls. If necessary, blasts were enriched > 80% by negative selection with dynabeads (Kaspers et al., Br. J. Cancer 70: 1047, 1994). Percent S-phase was measured at begin of assay and after 4 days. RESULTS: Technical success rate was 80-85% and the assay took about one day of work. IC50 values as a measure for drug resistance were highly reproducible with an interassay CV (range) of 28% (13-47) between days. Median cell viability of controls after 4 days was 80% (44-97);% S-phase at begin of assay was 3% (0.1-15) and after 4 days 9% (1-39). Leukemic blasts from 57 adult AML patients were prospectively tested in vitro at diagnosis. Large interindividual differences in drug resistance were observed (over 1000 fold on average). There was a trend for greater IC50 with higher cytogenetic risk and nonresponders to induction. Other clinical prognostic factors such as patient age, initial WBC, FAB subtype, prior MDS and % S-phase did not show a relationship with the in vitro data. There was a high correlation between the topoisomerase II related drugs regarding in vitro resistance. CONCLUSION: In vitro sensitivity tests like the MTT assay may provide a valuable tool for prediction of individual therapy outcome in combination with cytogenetics. However, longer follow-up is required.

Adolescent↗
PubMed1993

An overview of some studies of chronic myelogenous leukemia: biological-clinical observations and viewing the disease as a chaotic system.

While much is known about CML at both the clinical and molecular biological levels, the precise relationship between the disease at these two levels is unclear. The appearance of the fusion gene bcr-abl and disorders in the regulation of the myc gene, and perhaps other oncogenes which code for nucleoproteins, appear to play integral roles in the genesis of the chronic and blastic phases of the disease. The resistance of this disease to cytotoxic therapy appears to reflect both "classical" drug resistance and the ability of those cells which survive cytotoxic therapy to rapidly replace the killed cells thereby offsetting the effects of chemotherapy ("regrowth resistance"). The clinical evolution of the disease is compatible with two fundamentally different processes: one compatible with a deterministic chaotic model and the other involves two basically independent linear phenomena which overlap and intersect as the blastic phase appears and replaces the chronic phase.

Antineoplastic Agents↗
PubMed1991

Extramedullary blast crisis in a patient with Philadelphia chromosome-positive chronic myelogenous leukemia in complete cytogenetic remission.

Treatment of Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) with recombinant interferon-alpha (IFN-A) results in complete disappearance of the Ph chromosome in about 10% to 15% of patients in early chronic phase. This group has a long survival and very low incidence of blast crisis. The first known case is reported of extramedullary blastic transformation in a patient with medullary complete cytogenetic response (0% Ph-positive metaphases) to IFN-A. Four episodes of extramedullary blast crisis have occurred in this patient. The first three episodes were lymphoid by morphology and cytochemical stains. Molecular analysis confirmed breakpoint cluster region rearrangement. The most recent transformation was myeloid in nature and involved bone and pulmonary parenchyma. The patient is currently undergoing a second autologous transplantation with stored bone marrow that is Ph negative. The patient has survived more than 18 months since the first episode of blast crisis, and the bone marrow is normal.

Adult↗
PubMed2003

A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia.

Neoangiogenesis has been shown to play an important role in the pathogenesis of acute myeloid leukemia (AML). Autocrine and paracrine secretion of angiogenic and hematopoietic growth factors such as vascular endothelial growth factor (VEGF) and stem cell factor (SCF) in the bone marrow microenvironment may promote proliferation and survival of leukemic blasts. This concept represented the rationale for the initiation of a multicenter phase 2 trial of SU5416, a small molecule inhibitor of phosphorylation of VEGF receptors 1 and 2, c-kit, the SCF receptor, and fms-like tyrosine kinase-3 (FLT3) in patients with advanced AML. Entered into the study were 43 patients with refractory AML or elderly patients not judged medically fit for intensive induction chemotherapy; 42 patients received at least one dose of study drug. Treatment was generally well tolerated, with nausea, headache, and bone pain the most frequent treatment-related side effects. One patient had a morphologic remission (French-American-British [FAB] criteria of complete response without normalization of blood neutrophil and platelet counts) lasting for 2 months. There were 7 patients who achieved a partial response (reduction of blasts by at least 50% in bone marrow and peripheral blood) lasting 1 to 5 months. Patients with AML blasts expressing high levels of VEGF mRNA by quantitative polymerase chain reaction (PCR) had a significantly higher response rate and reduction of bone marrow microvessel density than patients with low VEGF expression consistent with the antiangiogenic effects of SU5416.

Adult↗
PubMed1993

Molecular defects associated with the acute phase CML.

Parts of the Bcr/Abl hybrid transcript supposed to be important for its transforming ability were sequenced in a series of CML blast crises, in order to evaluate the possible presence of alterations responsible for the disease transition from the chronic to the acute phase. In addition, the N- and Ki-ras as well as the p53 involvement was investigated by exploring their structure and expression in the same patients. We used traditional types of molecular analysis including Southern and Northern blot, together with methods that allow a rapid detection of point mutations and microdeletions, such as SSCP, single strand conformation polymorphism and direct sequencing. The results obtained may be summarized as follows: no alterations were found in the parts of the Bcr/Abl transcripts investigated in the present study (SH2, SH3 and the region surrounding codon 832); p53 alterations were observed in 5% and N- and Ki-RAS mutations in 5% of the cases examined. These molecular defects are therefore responsible for the clinical progression of the Ph1-positive CML only in a minority of cases.

Base Sequence↗
PubMed2001

Hypercalcemia as the presenting feature of t-cell lymphoid blast crisis of ph-positive chronic myeloid leukemia.

Hypercalcemia is a rare complication of chronic myeloid leukemia (CML), usually seen in the accelerated or blastic phases of the disease and associated with a poor prognosis. T-cell lymphoid phenotype is also an infrequent finding in the blast crisis (BC) of CML. A CML patient who had hypercalcemia as the presenting feature of a T-cell BC is reported. She was a 78 year-old woman who, at four months of CML diagnosis, developed weakness, bone pain, and mental confusion, with hypercalcemia being subsequently found. Although the peripheral blood and bone marrow were consistent with the chronic phase of CML, mediastinal enlargement, a soft tissue mass adjacent to the iliac bone, and multiple osteolytic lesions were seen. Serum levels of parathyroid hormone (PTH) and PTH-related peptide were normal, whereas the search for a second neoplasm was negative. The hypercalcemia initially responded to conventional treatment, but it reappeared two weeks later. Coincidentally, a high proportion of blast cells of T-cell origin at the cortical thymocyte stage were observed in the patient's peripheral blood and bone marrow, and she died shortly afterwards.

Aged↗
PubMed1997

Cell cycle specificity of apoptosis during treatment of leukaemias.

This review summarizes our observations on the mechanism of induction of apoptosis in vitro in leukaemic cell lines and in vivo in patients with leukaemia undergoing chemotherapy, in relation to the cell cycle. Multiparameter flow cytometric methods allowed us to identify apoptotic cells and position them with respect to their cell cycle phase. Several antitumor agents of different classes have been characterized in terms of the cell cycle phase specificity of induction of apoptosis. Three types of apoptosis could be distinguished in relation to the initial damage to the cell vis-a-vis cell cycle position: (1) homo-phase apoptosis where the cells underwent apoptosis during the same phase in which they were initially affected; (2) homo-cycle apoptosis, where the cells underwent apoptosis during the same cell cycle in which they were initially affected, i.e., prior to or during the first mitosis, and (3) post-mitotic apoptosis, where cells underwent apoptosis during the cell cycle(s) subsequent to that in which the cell was initially affected, most likely at the G1 or G2 checkpoints of these cycle(s). Four ranges of drug concentration can be distinguished in vitro for most drugs, where either: (1) no immediate effects; (2) cytostasis or post-mitotic apoptosis; (3) homo-cycle or homo-phase apoptosis; or (4) necrosis are observed. Analysis of cell death of blast cells from peripheral blood or bone marrow of over 250 leukaemia patients (AML, ALL, CML in blast crisis) treated with various drugs during routine chemotherapy reveals that in the case of DNA topoisomerase inhibitors (e.g., mitoxantrone, VP-16) apoptosis is often rapid (peaks at 1-2 days after drug administration) and has features of homo-phase apoptosis. In contrast, cell death observed after administration of paclitaxel (taxol) or cytarabine (cytosine arabinoside) occurs later and has features of post-mitotic apoptosis: the cells divide but die in G1 of the subsequent cycle(s).

Journal Article↗
PubMed2003

Genomic imbalances in CML blast crisis: 8q24.12-q24.13 segment identified as a common region of over-representation.

The acute phase of chronic myeloid leukemia (CML) is accompanied by secondary chromosomal changes. The additional changes have a non-random pattern; however, highly abnormal (marker) chromosomes are reported in some 20% of abnormal karyotypes. These marker chromosomes have proved to be beyond the resolution of conventional G-banding analysis. We used molecular cytogenetic techniques to determine the structure of complex chromosome markers in 10 CML-derived cell lines after our investigations of CML patients in blast crisis. Multicolor fluorescence in situ hybridization identified a multitude of structural chromosome aberrations. In addition, genomic gains identified by comparative genomic hybridization (CGH) were mapped to highly complex marker chromosomes in more than one cell line. The most common genomic loss detected by CGH affected chromosome 9, whereas the most common genomic gains affected, in order of frequency, the sequences of 8q, 6, and 13q. The smallest discrete amplification on 8q was identified in cell line MEG-01. This amplicon contains sequences represented by the marker D8S263/RMC08P029 but did not contain the proximal MYC gene or a more distal marker, D8S256/RMC08P025. We determined the size of the amplicon to be less than the chromosome segment 8q24.12-q24.13. The use of region- and locus-specific probes to analyze the organization of highly complex marker structures aided the identification of preferentially amplified genomic regions. The resultant amplifications could harbor gene(s) driving disease progression.

Allelic Imbalance↗
PubMed1994

Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia.

High-dose methotrexate (HDMTX) is a component of most treatment protocols for childhood acute lymphoblastic leukemia (ALL), yet recent studies of receptor-mediated transport and saturable polyglutamylation have questioned its rationale. To investigate this in vivo, methotrexate and its active polyglutamated metabolites (MTX-PG) were measured in bone marrow blasts obtained from 101 children randomized to single-agent therapy with either HDMTX (1 g/m2 per 24 h i.v., n = 47) or low-dose MTX (LDMTX, 30 mg/m2 by mouth every 6 h x 6, n = 54), before remission induction therapy. Blast concentrations of total MTX-PGs (median 460 vs 1380 pmol/10(9) cells) and of long-chain MTX-glu4-6 were both significantly higher after HDMTX (P < 0.001). With either treatment, MTX-PGs were significantly higher in B-lineage blasts than in T-lineage blasts (LDMTX P = 0.001, HDMTX P = 0.03). In a multiple regression analysis of B-lineage ALL, blast MTX-PG was significantly related to MTX dose (or plasma MTX concentration), lymphoblast ploidy (hyperdiploid > nonhyperdiploid), and percentage S-phase. This is the first evidence that HDMTX achieves higher MTX-PG concentrations in ALL blasts in vivo, establishing a rationale for HDMTX in the treatment of childhood ALL, especially T-lineage or nonhyperdiploid B-lineage ALL, disease characteristics associated with a poor prognosis on conventional therapy.

Adolescent↗
PubMed1989

Cell-mediated immune response to Coxiella burnetii antigens in Q fever convalescents and vaccinees.

Cellular immunity against phase I and II Coxiella burnetii antigens was evaluated by the lymphocyte blast transformation test in a) Q fever convalescents; b) persons immunized with a chemovaccine against Q fever; and c) control persons. The first two groups consisted of workers in a ricketsiology department. Of the 9 convalescents, all (100%) were positive against phase I antigen and 4 (44.4%) against phase II antigen. Of the 22 vaccinees, 77.3% were positive against phase I antigen and all were negative against phase II antigen. All 10 controls were negative against both antigens.

Antigens, Bacterial↗
PubMed1984

Quantitative variation of the common acute lymphoblastic leukemia antigen (gp100) on leukemic marrow blasts.

Marrow blasts from children with B cell precursor acute lymphoblastic leukemia (ALL) were studied for differences in quantitative expression of the common ALL antigen (CALLA). Of 42 untreated patients, 35 had detectable amounts of CALLA by flow cytometric (FCM) analysis of J-5 monoclonal antibody binding. Using an FCM technique that provides correlated measurements of a given cell surface antigen, cell size, and DNA content, we detected increased CALLA expression as lymphoblasts moved from G0/G1 phase through S phase of the cell cycle. The density of the antigen (per unit of blast surface area) remained relatively constant over the same interval, indicating that the change was not due to S phase-specific enhancement of CALLA expression. Eight cases had hyperdiploid cellular DNA content and in seven of these, only cells with clonal abnormalities of DNA content expressed the CALLA marker. Mean amounts of CALLA for each patient ranged widely within the study group, from very high to marginally detectable. This variation had no discernible relation to cell size, stem-line DNA content, percentage of cells in S phase, or the presence or absence of cytoplasmic immunoglobulin. Results of a univariate proportional hazards analysis showed that both quantitative level of CALLA for S phase cells (P = 0.048) and white blood cell count (P = 0.012) had made significant contributions to treatment outcome. Patients with relative amounts of CALLA less than the median value for the entire CALLA+ group had a higher rate of failure, which was virtually identical to that for the seven HLA-DR+ patients whose blasts lacked detectable CALLA. The observed interpatient variation in quantitative expression of CALLA is consistent with recognized steps in B cell precursor differentiation and may be useful in distinguishing patients with a less favorable prognosis.

Antibodies, Monoclonal↗
PubMedDate not supplied

The plicamycin and hydroxyurea combination chemotherapy for chronic granulocytic leukemia in myeloid transformation.

Between 1987-1988 we treated, in a cooperative study, 13 patients in blast crisis of CGL according to Koller and Miller's regimen. We observed no return to the chronic phase of the disease, while some patients suffered major drug-induced side effects. Six patients in accelerated phase were treated with the same combination therapy. All of them responded with a return to the chronic phase for a median of 4.5 months. In our hands the combination of plicamycin and hydroxyurea was ineffective in patients with CGL in blast crisis. This regimen could deserve further evaluation in patients with CGL in acceleration.

Adult↗
PubMed1998

Determinants of prognosis in late chronic-phase chronic myelogenous leukemia.

PURPOSE: Since interferon alfa (IFN-A) became an established treatment in chronic myelogenous leukemia (CML), more patients are referred to tertiary centers in late chronic phase (ie, > 12 months after diagnosis). Trials conducted in this phase cannot be evaluated precisely unless the features that determine prognosis in late chronic-phase CML are identified. The purpose of this study is to define the prognostic determinants of late chronic-phase CML. PATIENTS AND METHODS: From 1980 to 1997,257 consecutive CML patients referred in late chronic phase were studied. Their clinical characteristics at the time of referral and their association with survival were investigated. A staging model was designed. RESULTS: The median survival from time of referral was 43 months. Pretreatment characteristics associated with worse outcome included older age, poor performance status, splenomegaly, low albumin level, high percentage of blasts or basophils in peripheral blood (PB) or bone marrow, longer duration of chronic phase, and poor-risk group as defined by the Synthesis model. Prior exposure to IFN-A was not associated with worse outcome. By multivariate analysis, characteristics associated with shorter survival were age of 60 years or older, time from diagnosis of 3 years or greater, performance status of 1 or greater, PB basophils of 7% or greater, spleen 10 cm or greater, PB blasts 3% or greater, and albumin level less than 4 g/dL. A model that included age, duration of chronic phase, performance status, and PB basophils was generated. Patients with no, one, two, or three or greater adverse factors had median survivals of 71, 49, 26, and 19 months, respectively. CONCLUSION: A staging model for late chronic-phase CML can stratify patients in four groups with significantly different outcomes. If confirmed in independent populations, such a model could be considered in the analysis of future trials of treatment strategies in late chronic-phase CML.

Adolescent↗
PubMed1986

Blast crisis of chronic myelogenous leukemia. Morphologic and immunological features.

The morphological and immunological features of 22 patients with transformation of Philadelphia chromosome (Ph1) positive chronic myelogenous leukemia (CML) were evaluated. Patterns of differentiation in blast crisis were as follows: myeloblastic 5 cases, lymphoblastic 6 cases, basophil differentiation 4 cases, monoblastic 3 cases, megakaryoblastic 1 case, and mixed 3 cases (myeloblastic and lymphoblastic, monoblastic and lymphoblastic and panmyelosis). Three cases were diagnosed as acute lymphoblastic leukemia (ALL) in early stage. After complete remission was achieved rapidly with vincristine and prednisolone, the hematological findings showed CML features. The immunological phenotype of lymphoblasts in lymphoid crisis was Ia+, CALLA+, surface and intracytoplasmic immunoglobulin negative. It was suggested that the neoplastic cells in two cases had B cell differentiation because of B1 or B4 positive. The terminal deoxynucleodidyl transferase (TdT) activity was examined by immunoperoxidase and immunofluorescence techniques on 11 cases. All TdT+ cells were the small lymphoid cells in 5 cases of lymphoid crisis and one case in mixed type. Heterogeneity of the terminal phase of CML was recognized. It was thus suggested that blast crisis of CML occurred in the pluripotent stem cell.

Blast Crisis↗