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At least 649 records · Page 36Linked to original sources
PubMed2006

Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia.

PURPOSE: ABL kinase domain mutations have been implicated in the resistance to the BCR-ABL inhibitor imatinib mesylate of Philadelphia-positive (Ph+) leukemia patients. EXPERIMENTAL DESIGN: Using denaturing high-performance liquid chromatography and sequencing, we screened for ABL kinase domain mutations in 370 Ph+ patients with evidence of hematologic or cytogenetic resistance to imatinib. RESULTS: Mutations were found in 127 of 297 (43%) evaluable patients. Mutations were found in 27% of chronic-phase patients (14% treated with imatinib frontline; 31% treated with imatinib post-IFN failure), 52% of accelerated-phase patients, 75% of myeloid blast crisis patients, and 83% of lymphoid blast crisis/Ph+ acute lymphoblastic leukemia (ALL) patients. Mutations were associated in 30% of patients with primary resistance (44% hematologic and 28% cytogenetic) and in 57% of patients with acquired resistance (23% patients who lost cytogenetic response; 55% patients who lost hematologic response; and 87% patients who progressed to accelerated phase/blast crisis). P-loop and T315I mutations were particularly frequent in advanced-phase chronic myeloid leukemia and Ph+ ALL patients, and often accompanied progression from chronic phase to accelerated phase/blast crisis. CONCLUSIONS: We conclude that (a) amino acid substitutions at seven residues (M244V, G250E, Y253F/H, E255K/V, T315I, M351T, and F359V) account for 85% of all resistance-associated mutations; (b) the search for mutations is important both in case of imatinib failure and in case of loss of response at the hematologic or cytogenetic level; (c) advanced-phase chronic myeloid leukemia and Ph+ ALL patients have a higher likelihood of developing imatinib-resistant mutations; and (d) the presence of either P-loop or T315I mutations in imatinib-treated patients should warn the clinician to reconsider the therapeutic strategy.

Adolescent↗
PubMed1992

Capability of various cytokines to induce quiescent myeloid leukemia cells to the proliferative stage.

In order to investigate the capability of cytokines to induce myeloid leukemia cells from G0 phase to the proliferative stage, blasts from 9 patients with AML and 1 patient with CML-MC were cultured with various cytokines (IL-3, GM-CSF, IL-3 + GM-CSF, G-CSF) for 48 hours or 96 hours in a serum-free culture system. Cells were analyzed by two-color flow cytometry, using PI and the monoclonal antibody Ki-67. The percentage of cells in G0 phase was reduced significantly when the cells were cultured with IL-3 (p < 0.01), GM-CSF (p < 0.01), and IL-3 + GM-CSF (p < 0.01) for 48 hours, as compared with the percentage of cells in G0 phase before culture. Moreover, the percentage of cells in S phase increased significantly when the cells were cultured with IL-3 (p < 0.01), GM-CSF (p < 0.02), and IL-3 + GM-CSF (p < 0.01) for 48 hours, as compared with the percentage of cells in S phase before culture. It is well known that many drugs which are widely used in the treatment of acute leukemia are cytotoxic mainly to proliferating cells, so that if quiescent G0 phase cells can be induced to the proliferative stage, the treatment of acute leukemia would become more effective. The present findings showed that a considerable variation was observed among individual patients in the induction of the G0 component to the proliferative stage.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1995

The diverse effect of topoisomerase I specific inhibitor (camptothecin) on normal and BCR/ABL-dependent hematopoietic cells proliferation: therapeutic implications.

Camptothecin (CPT), a specific topoisomerase I inhibitor, in the presence of hematopoietic growth factors exerted an antiproliferative effect against normal bone marrow cells (NBMC) as well as chronic myelogenous leukemia-chronic phase (CML-CP) and blast crisis (CML-BC) cells. In the absence of growth factors, however, only the colony formation by CML-BC cells was inhibited by CPT, leaving NBMC and CML-CP cells intact or much less affected. Analysis of the cellular DNA content revealed that CPT induced specific changes in cell cycle distribution: decrease in S and G2/M fraction with simultaneous accumulation of the cells in G1 phase and the appearance of "sub-diploid" (apoptotic) peak. To determine if CPT is able to exert selective antileukemic effect, 1:1 mixture of NBMC and CML-BC cells was exposed to CPT in the absence of growth factors and assayed for growth ability in clonogenic assay and for expression of BCR/ABL transcript in single colonies. BCR/ABL transcript was not detected in colonies incubated with CTP, in contrast, most of colonies arising from untreated cells possessed leukemic origin (BCR/ABL expression). Our results indicate that CPT is selectively effective in vitro against the leukemia cells. This offers the prospect of a novel and more selective treatment of CML.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Expression and function of the megakaryocyte growth and development factor receptor in acute myeloid leukemia blasts.

The receptor for megakaryocyte growth and development factor (MGDF), also known as thrombopoietin, has recently been cloned. MGDF stimulates platelet production and maturation both in vitro and in vivo. MGDF may thus have a role in attenuating the thrombocytopenia associated with acute myeloid leukemia (AML) and its therapy. However, there is concern that MGDF might induce AML blast proliferation and thereby increase the risk of treatment failure. To address this concern, we studied the expression of c-mpl mRNA and c-Mpl protein by blasts from AML patients. In addition we examined the in vitro effect of MGDF as well as the combined effect of MGDF and granulocyte colony-stimulating factor (G-CSF) or stem cell factor (SCF) on leukemic blast proliferation, recruitment into S-phase, induction of programmed cell death and activation of signal transducers and activators of transcription (STAT) proteins. Our results demonstrate that blasts from a substantial proportion of cases of AML express the receptor at either the mRNA or protein level. Moreover, the function of the MGDF receptor was demonstrated by activation of STAT proteins following exposure to MGDF. Nevertheless, blast proliferation in response to MGDF was rare, and the proliferative effect of MGDF was less than that of G-CSF or SCF. Furthermore, MGDF did not prevent programmed cell death induced by cytarabine. Finally, there appeared to be no correlation between receptor expression by AML blasts and functional response to MGDF. Based on these data, it would appear that clinical trials of MGDF may be undertaken safely in patients with AML.

Acute Disease↗
PubMed1977

[Eosinophilic infiltration in chronic myeloid leukemia].

Specific infiltrations in myelogenous leukemia are rare and occur mostly in the course of an acute blast crisis often representing the terminal phase of the disease. A 50 year-old female patient is described who developed specific cutaneous lesions during such a blast crisis. The infiltrates consisted to a major part of eosinophilic myelocytes although the peripheral blood smear showed only relatively few mature eosinophils.

Eosinophils↗
PubMed1981

Emperipolesis of hematopoietic cells in myelocytic leukemia. Electron microscopic and phase contrast microscopic studies.

In case of blast crisis of chronic myelocytic leukemia, the blast cells contained several kinds of normal hematopoietic cells. The peroxidase reaction was strongly positive in the neutrophilic granules of the engulfed neutrophils. These engulfed cells appeared to be normal and the limiting membranes of the engulfing cells seemed to be intact. We speculated therefore that this phenomenon might be emperipolesis. In a case of chronic myelocytic leukemia and a case of acute myelocytic leukemia, some megakaryoblasts showed the same phenomenon. These megakaryoblasts did not phagocytize latex particles. The limiting membranes of the engulfing megakaryoblasts were stained with ruthenium red but those of the engulfed hematopoietic cells were not stained. By phase microscopy, the engulfed cells were actively moving inside the megakaryoblasts and it was observed that the engulfed cells were actually living within the engulfing cells. These results demonstrated that this phenomenon was emperipolesis. Observations with an electron microscope and the phase microscope are indispensable for distinguishing emperipolesis from phagocytosis.

Adult↗
PubMed1997

Antithymocyte globulin for patients with myelodysplastic syndrome.

Twenty-five transfusion-dependent myelodysplastic syndrome (MDS) patients (with < 20% blasts) were treated in a phase II study with antithymocyte globulin (ATG) at 40 mg/kg/d for four doses and then followed with blood counts every 2 weeks and clinic visits every 3 months, for a median of 14 months (range 1-38 months). 11 (44%) patients responded and became transfusion-independent after ATG, including three complete responses, six partial responses, and two minimal responses. Responses were observed in 9/14 patients (64%) with refractory anaemia (RA) and 2/6 patients (33%) with refractory anaemia with excess blasts (RAEB). Median response duration was 10 months (range 3-38 months). The Kaplan-Meier estimate of overall survival was 84% at 38 months, with one early death due to pneumonia and two deaths from disease progression to leukaemia. Side-effects consisted mainly of mild serum sickness in all patients. A single course of ATG restored haemopoiesis in some patients with MDS and was well tolerated.

Adult↗
PubMed1991

Gene-targeted specific inhibition of chronic myeloid leukemia cell growth by BCR-ABL antisense oligodeoxynucleotides.

Philadelphia-chromosome positive chronic myeloid leukemia cells in chronic phase (CML-CP) or blast crisis (CML-BC) and normal bone marrow cells (NBMC) were incubated in vitro with antisense oligonucleotide specific against the BCR/ABL breakpoint junction to examine the possibility of selective inhibition of leukemia growth. Growth capability was determined in vitro by colony assay in semisolid medium in the presence of interleukin 3 (IL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF). The 18-mer antisense directed against the specific BCR/ABL mRNA breakpoint region diminished the colony formation by CML-CP and CML-BC cells, but not by NBMC. Scrambled oligomer did not affect significantly the growth of leukemic and normal cells. If CML-BC cells were mixed with NMBC and incubated with specific BCR/ABL antisense oligomer, leukemic colonies were selectively inhibited, as was shown by reverse, transcriptase-polymerase chain reaction (RT-PCR) performed to detect BCR/ABL mRNA in single colonies. These results confirm the possibility of selective inhibition of leukemia cells by antisense treatment.

Base Sequence↗
PubMedDate not supplied

High-dose cytarabine for the treatment of blastic phase chronic myelogenous leukemia.

High-dose cytarabine chemotherapy regimens were given to 22 patients for the treatment of blastic phase chronic myelogenous leukemia. Bone marrow aplasia occurred in 21 of these patients; in one patient the marrow was not cleared of blasts. In five patients (26%), blastic phase promptly recurred. Eight patients (37%) died of infection or hemorrhage during the period of marrow aplasia before bone marrow recovery. Seven patients achieved complete remission and one achieved partial remission, but the duration of the remission was brief [median, 98 days (range, 52-345)]. One patient received consolidation therapy with an additional course of high-dose cytarabine and maintained remission for 345 days. These results suggest that alternative approaches to the treatment need to be explored.

Adult↗
PubMed1985

Bone marrow transplantation for chronic granulocytic leukaemia.

Twenty-one patients with chronic granulocytic leukaemia underwent marrow transplantation. The donors were human-lymphocyte antigen-identical siblings in 19 cases. In the remaining 2 cases the donor was a parent in one and an identical twin in the other. The preparatory regimen included cyclophosphamide and 8.6 Gy total body irradiation given at either a dose of 0.1 Gy/min or 0.04 Gy/min. Five patients were in the accelerated phase of the disease, one was in remission following blast crisis, and the rest were all in the chronic phase. After chemotherapy and irradiation, all patients received bone marrow transplants. To date, nine patients are still alive, with a median survival of 64 days (range 28-683 days). One patient continued to have leukaemic cells and in another, the leukaemia recurred 18 months following transplantation. Interstitial pneumonitis was the cause of death of eight patients (38%). Graft-versus-host disease occurred in ten patients (47%).

Adolescent↗
PubMed1994

Lymphoid blast crisis at the onset of chronic myelogenous leukaemia: molecular evidence.

A patient with a typical haematological pattern of acute lymphoblastic leukaemia with BCR and IgH rearrangements was brought into complete remission by treatment. A few weeks later she developed the typical peripheral and bone marrow pattern of chronic myelogenous leukaemia (CML) with persistence of the BCR rearrangement and disappearance of the IgH rearrangement, suggesting that this case is an example of CML presenting in blast crisis without a detectable chronic phase.

Adult↗
PubMed2002

Safety and efficacy of STI-571 (imatinib mesylate) in patients with bcr/abl-positive chronic myelogenous leukemia (CML) after autologous peripheral blood stem cell transplantation (PBSCT).

We examined safety and efficacy of STI-571 in 24 bcr/abl-positive patients with CML post PBSCT. At start of STI-571 therapy, nine patients presented in blast crisis (BC) or in accelerated phase (AP), and 15 in chronic phase (CP). Patients were evaluated for hematologic, cytogenetic and molecular response, survival and toxicity. In general, STI-571 was well tolerated in this heavily pretreated group of patients with a non-hematologic and hematologic toxicity profile similar to that observed in a previous phase I trial at comparable doses. Five of nine patients with CML in transformation (AP, BC) were evaluable for hematologic response. Two of five patients had transient reductions in WBC and blasts, and three patients achieved a sustained hematologic response (>4 weeks). Cytogenetic analysis in these patients revealed numerical and/or structural responses. In CML chronic phase, STI-571 induced complete hematologic responses in all patients and major cytogenetic responses in 61% of patients with a complete cytogenetic response rate of 46%. This report indicates that STI-571 is a safe and effective drug in heavily pretreated patients. No apparent additional side-effects were noted in this patient cohort. The high rate of complete hematologic and complete cytogenetic responses in CP patients is remarkable, as intensive treatment approaches plus IFN-alpha failed to be efficient in achieving long-term stabilization of CML in this patient cohort.

Adult↗
PubMed2005

Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: a 4.5-year follow-up.

BACKGROUND: The advent of imatinib has considerably changed the treatment of chronic myeloid leukemia (CML). Early studies demonstrated high rates of hematologic and cytogenetic responses in all phases of the disease after limited observation periods. METHODS: The authors evaluated long-term outcome, rates of response, and resistance in 300 patients with BCR-ABL-positive leukemias (CML in chronic phase after failure to respond to interferon-alpha [CP], n = 139; accelerated phase [AP], n = 80; myeloid blast crisis [BC], n = 76; lymphoid BC and Philadelphia chromosome-positive acute lymphoblastic leukemia, n = 5) who entered clinical trials with imatinib in a single center after an observation time of 4.5 years. RESULTS: In CP, hematologic remission was achieved in 97% and major (MCR) and complete cytogenetic remission (CCR) in 61% and 49% of patients, respectively. The chance to achieve MCR was higher in patients commencing imatinib earlier in the course of CML. In AP, the median survival period after the start of imatinib was 44 months, and MCR and CCR were observed in 31% and 26% of patients, respectively. In myeloid BC, the median survival period after the start of imatinib and after diagnosis of BC was 6 and 9 months, respectively. Hematologic resistance occurred in 25%, 41%, and 92% of patients in CP, AP, and myeloid BC, respectively, and was associated with BCR-ABL mutations in 45% of patients and with clonal evolution in 58% of patients. CONCLUSIONS: The data emphasized the need for a prolonged follow-up of patients treated with imatinib to define the clinical potential of the drug and to establish methods to optimize therapy.

Adolescent↗
PubMed1994

Effect of granulocyte-macrophage colony-stimulating factor on the metabolism of arabinosylcytosine triphosphate in blasts during therapy of patients with chronic myelogenous leukemia.

Because in vitro studies have indicated that granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates arabinosylcytosine (ara-C) metabolism in leukemia blasts, we analyzed the pharmacokinetics of ara-C triphosphate (ara-CTP) in the blasts of patients with chronic myelogenous leukemia who were undergoing therapy with GM-CSF and ara-C. Patients received a 2-h infusion of 1.0 g/m2 ara-C followed by daily infusions of GM-CSF (125 micrograms/m2/day i.v. over 6 h) for 2-4 days. After the last GM-CSF infusion, a second, identical dose of ara-C was administered. The cellular pharmacokinetics of ara-CTP in circulating blasts were determined during and after each ara-C dose, and the area under the accumulation and elimination curve (AUC) measured over 12 h was compared before and after GM-CSF. Ara-CTP accumulation peaked within 1 h after the end of each ara-C infusion. Comparison of the AUC of ara-CTP before and after GM-CSF administration suggested that in the blasts of three of four patients, GM-CSF treatment decreased the ara-CTP AUC; the AUC values were altered only slightly in a fourth patient. Studies of these patients' blasts incubated in vitro with ara-C before and after clinical infusion of GM-CSF revealed similar ara-CTP accumulation patterns. Together, these studies suggest that 2-4 days of GM-CSF administration does not increase the accumulation of ara-CTP in the circulating blasts from patients in the blastic phase of chronic myelogenous leukemia.

Arabinofuranosylcytosine Triphosphate↗
PubMed1987

Myeloproliferative disorders terminating in acute megakaryoblastic leukemia with chromosome 3q26 abnormality.

Two cases of myeloproliferative disorders terminating in acute megakaryoblastic leukemia are reported. One case began as primary myelofibrosis and the other as chronic myelogenous leukemia. Blast cells in the acute leukemic phase were identified as megakaryoblasts by the presence of platelet peroxidase. The clinical course is described, and the morphology, immunologic studies, and ultrastructure studies of the blast cells are reported. On cytogenetic analysis both cases had a translocation involving the No. 3 chromosome locus q26.2. The present data suggest that 3q26 may be associated with transformation of the megakaryocytic lineage.

Adult↗
PubMed1999

Multilineage outgrowth of both malignant and normal hemopoietic progenitor cells from individual chronic myeloid leukemia patients in immunodeficient mice.

In this study the ability of malignant and normal progenitors in peripheral blood (PB) and bone marrow (BM) of CML patients in chronic phase to proliferate and produce mature progeny after transplantation into hereditary immunodeficient (SCID and NOD/SCID) mice was examined. Engraftment in NOD/SCID mice preconditioned by total body irradiation (TBI) alone was 10-fold higher than in SCID mice preconditioned by macrophage depletion and TBI, demonstrating that NOD/SCID mice are more suitable for engraftment of chronic phase CML cells. Low-density cells at cell doses of 10-30 x 10(6) and purified CD34+ cells at doses of approximately 0.2 x 10(6) engrafted NOD/SCID mice, with levels of 2 to 20% CD45+ cells with production of monocytes, granulocytes, erythroid cells, B-lymphocytes, CD34+ cells and variable frequencies of erythroid and myeloid colony-forming cells. As demonstrated by fluorescent in situ hybridization (FISH) analysis, purified human myeloid, B-lymphoid, erythroid and CD34+ cells from chimeric mouse BM contained Philadelphia-chromosome (Ph)-positive cells and Ph- cells in similar frequencies as primary cells from the CML patients. These results demonstrate that production of mature normal as well as malignant cells of multiple lineages were supported with similar efficiency. In contrast, all human erythroid and myeloid clonogenic cells detected in the mice were Ph-, which can be attributed to less efficient maintenance or more rapid differentiation of immature Ph+ cells in the mouse microenvironment. CML blast crisis cells also grew well in NOD/SCID mice, with 80-90% of human cells produced containing the Ph- chromosome. The availability of an in vivo assay that supports outgrowth of normal and malignant stem cells from chronic phase and blast crisis CML patients will facilitate examination of differential effects of growth factors, inhibitory cytokines and cytotoxic drugs on survival of normal and malignant stem cells in vivo and on progression of chronic phase CML towards blast crisis.

Animals↗
PubMed2003

Clinical and genetic studies of ETV6/ABL1-positive chronic myeloid leukaemia in blast crisis treated with imatinib mesylate.

Most chronic myeloid leukaemia (CML) patients are genetically characterized by the t(9;22)(q34;q11), generating the BCR/ABL1 fusion gene. However, a few CML patients with rearrangements of 9q34 and 12p13, leading to ETV6/ABL1 chimaeras, have also been reported. Here we describe the clinical and genetic response to imatinib mesylate treatment of an ETV6/ABL1-positive CML patient diagnosed in blast crisis (BC). A chronic phase was achieved after acute myeloid leukaemia induction therapy. Then, treatment with imatinib mesylate (600 mg/d) was initiated and the effect was assessed clinically as well as genetically, including by repeated interphase fluorescence in situ hybridization studies. Until d 71 of imatinib mesylate therapy, stable improvements in the clinical and laboratory features were noted, and the frequency of ABL1-rearranged peripheral blood cells decreased from 56% to 11%. At d 92, an additional t(12;13)(p12;q13), with the 12p breakpoint proximal to ETV6, was found. The patient relapsed into BC 126 d after the start of the imatinib mesylate treatment and succumbed to the disease shortly afterwards. No mutations in the tyrosine kinase domain of ABL1 of the ETV6/ABL1 fusion were identified in the second BC. However, whereas the ETV6/ABL1 expression was seemingly the same at diagnosis and at second BC, the expression of ETV6 was markedly lower at the second BC. This decreased expression of wild-type ETV6 may have been a contributory factor for the relapse.

Adult↗
PubMed1981

Acidic isoferritins (leukemia-associated inhibitory activity) fail to inhibit blast proliferation in acute myelogenous leukemia.

Cell-free extracts of bone marrow and blood cells from patients with leukemia contain an inhibitor of normal granulocyte/macrophage progenitor (CFU-GM) proliferation (leukemia-associated inhibitory activity, LIA) identified as acidic isoferritins. A comparison was made of the action of crude LIA prepared from frozen-thawed leukemic blood cells and purified spleen ferritin from a patient with chronic myelogenous leukemia, on the proliferation of blast progenitors from patients with acute myelogenous leukemia (AML), and on the promyelocytic leukemia cell line, HL-60. Crude LIA showed no inhibition of blast progenitor or HL-60 proliferation at low concentrations, but inhibited the proliferation of CFU-GM. At higher concentrations, crude LIA inhibited both blast cells and CFU-GM. Purified spleen ferritin failed to inhibit blast progenitors or HL-60 cells at any concentration tested, but inhibited both 70-day and 14-day CFU-GM. Using the thymidine "suicide" technique, the action of LIA was confirmed as being on CFU-GM in S-phase, but it failed to affect the proliferation of blast cell in S-phase. It is concluded that acidic isoferritins inhibit normal CFU-GM but not blast cells from patients with AML. Acidic isoferritins could confer a proliferative advantage of the leukemic clone over its normal counterparts.

Cell Differentiation↗