Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sixteen patients with poor-prognosis acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and non-Hodgkin's lymphoma (NHL) underwent conditioning with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) (BUCY-2) plus melphalan (90 or 135 mg/m2) and autologous bone marrow transplantation (AuBMT) in a phase I study. At the melphalan dose of 90 mg/m2, grade greater than or equal to 3 regimen-related toxicity (RRT) was observed in five patients (31%; 95% confidence interval [CI], 11% to 59%), with hepatic (venoocclusive disease [VOD]) and urinary (hemorrhagic cystitis) RRT being the most frequent complications. Further escalation of the melphalan dose to 135 mg/m2 was deemed excessively toxic, as three of five patients had grade greater than or equal to 3 RRT. Following this experience, 21 patients with multiple myeloma (MM) and chronic myelogenous leukemia (CML) were treated with BUCY-2 plus melphalan 90 mg/m2 and AuBMT in separate studies. Three of these patients--all with extensively pretreated MM--had grade greater than or equal to 3 RRT (14%; 95% CI, 3% to 36%); no others had grade greater than or equal to 3 RRT. Therefore, a total of eight of the 37 patients (22%; 95% CI, 10% to 38%) who received BUCY-2 plus melphalan 90 mg/m2 conditioning developed grade greater than or equal to 3 RRT; three of these patients (8%; 95% CI, 3% to 25%) died of RRT. Although limited by the relatively small number of patients, our analysis of the patients receiving this regimen showed that the presence of parameters denoting the lymphoid diagnostic group (ie, ALL, NHL, and MM), more extensive pretreatment, and/or more advanced disease status were associated with a higher incidence of grade greater than or equal to 3 RRT. Response data on the AML, ALL, and NHL patients who received BUCY-2 plus melphalan 90 mg/m2 were analyzed: three patients (all with AML in first or second remission) are leukemia-free at 3.0, 2.8, and 1.4 years after AuBMT. The actuarial 2-year event-free survival in this group is 17% (95% CI, 5% to 54%). Response data on the MM and CML patients will be reported subsequently. BUCY-2 plus melphalan at a dose of 90 mg/m2 before AuBMT produces acceptable toxicity in patients who are not heavily pretreated. A full evaluation of the antineoplastic effects of this regimen requires further study.
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PMID:Busulfan, cyclophosphamide, and melphalan conditioning for autologous bone marrow transplantation in hematologic malignancy. 191 38

Philadelphia chromosome1 positive (Ph1) chronic myelogenous leukemia (CML) is characterized by metamorphosis of the chronic phase to blastic crisis. However, cellular events associated with this transition are poorly understood. To examine the possible participation of hematopoietic growth factors in this process, we studied growth factor expression in adherent layers of bone marrows derived from CML Ph1 patients in various stages of the disease. Interleukin-1 beta (IL-1 beta) and IL-6 mRNA were expressed in five of six patients, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in one of six patients with myeloid/undifferentiated blast crisis. In addition, leukemia inhibitory factor (LIF) expression was increased in four of six patients with myeloid/undifferentiated blast crisis phase of the disease. IL-1 beta was also detected in bone marrow adherent layer conditioned medium from two of these patients. These results were in sharp contrast to the lack of detectable levels of uninduced IL-1 beta, IL-6, and GM-CSF mRNA, in samples derived from 4 patients in lymphoid blastic crisis, 3 in accelerated, and 11 in chronic phases of the disease, or from normal controls. The possibility of a paracrine loop formation, whereby the adherent layers representing the bone marrow stroma are induced to express hematopoietic growth factors, was supported by our finding IL-1 beta mRNA expression in the leukemic blast cells in three of four studied patients in blast crisis and IL-1 beta protein production in seven of eight patients studied. Finally, coculturing CML blast crisis cells onto pre-established adherent layers induced the expression of both IL-1 beta and IL-6 genes. From this preliminary study, it appears that abnormal expression of growth factors is a common event with CML Ph1 progression. We hypothesize that IL-1 beta generated by the transformed malignant clone stimulates the marrow stroma to produce various growth factors, and that this process may play a role in disease progression.
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PMID:Alteration in bone marrow adherent layer growth factor expression: a novel mechanism of chronic myelogenous leukemia progression. 193 51

Thirty patients with refractory lymphoid malignancies [multiple myeloma (MM): 8, plasma cell leukemia (PCL): 2, acute lymphocytic leukemia (ALL): 5, chronic myelogenous leukemia in blast crisis: 1, chronic lymphocytic leukemia in blast crisis: 1, adult T-cell leukemia: 1, non-Hodgkin lymphoma (NHL): 9, Hodgkin's disease (HD): 3] were treated with VAD regimen (vincristine, doxorubicin, dexamethasone). Of 28 evaluable patients, 4 patients achieved complete response or remission [MM1, ALL1, NHL1, HD1], 10 attained partial response or remission [MM5, PCL1, NHL3, HD1], and 2 patients with MM attained minor response. The remission duration ranged from 1 month to over 14 months. The response rate was high in patients with MM (75%) and lymphoma (60%), however 4 patients with T-cell malignancies achieved no response except one with NHL. In three patients who showed resistance to VAD, diltiazem was administered in addition to VAD and one patient with MM had response. Atrio-ventricular block was also observed in one patient during the period of diltiazem administration. Nine patients developed documented infections, 5 of which suffered from candida infections. From these observations, we concluded that VAD regimen might be useful as a salvage therapy especially in patients with MM and lymphoma.
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PMID:[The efficacy of VAD chemotherapy for refractory lymphoid malignancies]. 194 21

The development of cancer is generally believed to occur by a multistep process in which critical genetic defects accumulate in a clone of cells, confer a growth advantage, and result in the emergence of more malignant subclones. This paper describes the clonal origin of cells in a patient with Philadelphia-chromosome negative, M-bcr rearrangement-positive chronic myelogenous leukemia, observed in two episodes of lymphoid blast crisis (BC), the intervening chronic phases (CP), and following allogeneic bone marrow transplantation. Serial analysis of immunoglobulin heavy and kappa light chain (IgJH, IgCK), beta-T-cell receptor (beta-TcR) and bcr major breakpoint cluster region (M-bcr) gene rearrangements was performed. Clonal IgJH rearrangements present in cells of the first lymphoblastic crisis (BC1) were altered during the chronic phase post-treatment (CP1), and were again altered in recurrent blast crisis (BC2). In addition, the M-bcr gene rearrangement present in BC1 and CP1 was absent from cells in BC2. These observations suggest that the course of clinical neoplastic disorders may not always be characterized simply by a hierarchical process of clonal evolution, but may also involve clonal succession of malignant cells. Moreover, the deletion of M-bcr in recurrent BC suggests that bcr/abl may not be essential for the maintenance of cell growth in established BC.
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PMID:Clonal succession and deletion of bcr/abl sequences in chronic myelogenous leukemia with recurrent lymphoid blast crisis. 194 28

One hundred and seventy bone marrow biopsies from patients with chronic myeloproliferative disorders (CMPDs) were evaluated for the presence of lymphoid nodules (LNs) and were immunostained using a panel of monoclonal antibodies (UCHL1, 4KB5 and L26) recognizing different lymphocyte antigens. LNs were found in 35% of cases of idiopathic thrombocythaemia, 24.6% of myelofibrosis/osteomyelosclerosis, 18.2% of polycythaemia vera 12.1% of chronic myeloid leukaemia and 19.2% of borderline cases. Varying degrees of immunohistochemical positivity for the three antibodies tested were found. LNs were always made up of variable proportions of both T- and B-lymphocytes with a prevalence of T-cells. This latter observation suggests that bone marrow LNs in CMPDs could be an expression of reactivity.
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PMID:Immunohistochemical evaluation of bone marrow lymphoid nodules in chronic myeloproliferative disorders. 194 8

Serial cytogenetic studies were performed on 60 leukemic recipients of HLA-matched bone marrow transplants (BMT) who were prepared by high doses of alkylating agents and fractionated total body irradiation (TBI). Forty-three patients were recipients of untreated BMT and 17 were recipients of T-depleted BMT. Donor or host mitoses were identified by examination of sex chromosomes in 54 patients or by evaluation of the polymorphism of other chromosomes after specific banding in six patients. Mixed lymphoid chimerism (MLC) was identified in 29 patients and full donor lymphoid chimerism (FDLC) in 29 patients. Complete donor hematopoiesis was recovered in most patients after 12 months, but two T-depleted patients had persistent host cells at 46 and 52 months after the graft. Acute graft-versus-host disease was significantly less frequent in patients with MLC, especially when more than 10% of residual lymphoid cells were detected. The probability of relapse and survival was identical in patients with MLC and FDLC, except in patients with chronic myeloid leukemia where MLC was significantly associated with an increased risk of relapse.
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PMID:Influence of mixed chimerism on the results of allogeneic bone marrow transplantation for leukemia. 195 96

A case of Ph1+ chronic myeloid leukemia in blast crisis (CML-BC) is reported, in which the periodic acid Schiff and myeloperoxidase negative blasts displayed high terminal deoxynucleotidyl activity and coexpressed both B- (CD19, CD10, and CD24) and T- (CD7) lymphoid markers. In line with the immunophenotype, DNA analysis revealed a rearranged configuration of both the immunoglobulin and T-cell receptor (beta, gamma, and delta) genes. In spite of this dual B/T phenotype and genotype, the negativity of CyCD3 favors the suggestion that the target of the neoplastic event is an early B cell, with a cross lineage involvement of the putative common recombinase. However, taking into account that a normal counterpart of a biphenotypic B/T ALL has been recognized, it could be hypothesized that the leukemic transformation may have involved an oligopotent B/T lymphoid precursor. This case confirms the lineage heterogeneity of CML-BC and suggests that DNA analyses coupled to extensive immunophenotyping may allow further insight for a more precise recognition of both normal and leukemic ontogenesis.
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PMID:Hybrid lymphoid blast crisis of chronic myeloid leukemia with both immunoglobulin and T-cell receptor gene rearrangements. 196 Jan 35

We determined the expression levels of the mdr1 and mdr3 multidrug-resistance genes (also known as PGY1 and PGY3, respectively) in peripheral blood cells from 69 adult patients with acute and chronic leukemias, using an RNase protection assay. Expression of mdr1 was found in samples from patients with acute nonlymphocytic leukemia (13 of 17), chronic myelocytic leukemia (CML, chronic phase, 10 of 10; blast crisis, three of four), acute lymphocytic leukemia (ALL, eight of 11), B-cell chronic lymphocytic leukemia (B-CLL, 17 of 17), hairy cell leukemia (HCL, one of two), and T-cell prolymphocytic leukemia (one of one), but not in B-cell prolymphocytic leukemia (B-PLL, 0 of seven). Expression of mdr3 was only detected in samples from B-cell lymphocytic leukemias: CML, lymphoid blast crisis (one of one), B-cell ALL (two of two), B-CLL (17 of 17), B-PLL (seven of seven), and HCL (two of two). In vitro drug uptake studies by on-line flow cytometry showed that in leukemia cells expressing either mdr1 or mdr3, the steady-state accumulation of daunorubicin could be significantly increased by addition of cyclosporine and, to a lesser extent, by verapamil. Because cyclosporine and verapamil are known as inhibitors of the mdr1-encoded P-glycoprotein drug-efflux pump, and because the mdr1 and mdr3 genes are highly homologous, our data suggest that the mdr3 gene encodes a functional drug pump in B-cell lymphocytic leukemias. The results of this study may have implications for clinical therapy for acute or chronic leukemias expressing the mdr1 or mdr3 gene, in particular, treatment with combinations of cytotoxic drugs plus agents that reverse multidrug resistance. Since mdr1 and mdr3 are frequently expressed in untreated as well as treated leukemia, such combination therapy should be considered for untreated patients as well as treated patients.
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PMID:Expression of mdr1 and mdr3 multidrug-resistance genes in human acute and chronic leukemias and association with stimulation of drug accumulation by cyclosporine. 197 61

Indirect immunofluorescence staining with monoclonal antibody (MoAb) CL203.4 of malignant cells from 269 patients with hematologic malignancies showed a heterogeneous expression of CD54/intercellular adhesion molecule-1 (ICAM-1). This marker was expressed by malignant cells of 57 out of 118 patients with myeloid malignancies and 69 out of 135 with B-lymphoid malignancies. On the other hand, CD54 was not detected on malignant cells of 16 patients with T-lymphoid malignancies. In myeloid malignancies, CD54 is preferentially expressed by "stem cell-derived" malignancies, being detectable on blast cells from almost all patients affected by chronic myelogenous leukemia in blast phase or myelodysplastic syndromes and by only 34% of patients with de novo acute myeloid leukemia (AML). The expression of CD54 did not correlate with any specific myeloid FAB subtype, although three cases of highly undifferentiated AML (FAB MO) displayed maximal levels of the antigen. The expression of CD54 in AML was significantly associated with that of CD34 and HLA-DR antigens. In B-lymphoid malignancies, CD54 expression appears to correlate with the differentiation stage of malignant cells, since B-origin acute lymphoblastic leukemias and conventional B-chronic lymphocytic leukemias (B-CLL; ie, "dim SIg" CLL) expressed lower levels of CD54 than more mature lymphoproliferative disorders ("bright SIg" CLL, prolymphocytic leukemias, and lymphoplasmacytic tumors). "High-grade" B-cell non-Hodgkin's lymphomas (B-NHL) express in general a higher level of CD54 than "low-grade" ones. This finding in conjunction with the expression of CD54 in all 17 patients with "bright SIg" CLL investigated (characterized by marked organomegaly and poor prognosis) suggest that the differential expression of CD54 in lymphoproliferative disorders may also relate to their degree of malignancy.
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PMID:Differential expression of CD54/intercellular adhesion molecule-1 in myeloid leukemias and in lymphoproliferative disorders. 197 71

The aim of this work is to evaluate the relationship between P-glycoprotein expression in circulating blasts and clinical response in patients suffering from acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, and chronic myeloid leukemia in either lymphoid or myeloid blastic crisis. The results obtained show that: a) patients whose blasts express P-glycoprotein are resistant towards protocols including Doxorubicin, Daunorubicin, Etoposide, Mithramycin, Vincristine; b) P-glycoprotein can be expressed constitutively in some cases; c) P-glycoprotein does not appear to be the only mechanism responsible for resistance towards anthracyclines and Etoposide.
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PMID:P-glycoprotein and drug resistance in acute leukemias and in the blastic crisis of chronic myeloid leukemia. 198 99


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