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)

We designed a phase II study to assess the activity of recombinant interleukin-2 (rIL-2) in patients with chronic myelogenous leukemia (CML). Study population included 11 patients in the chronic phase of CML (6 in hematologic remission and 5 with active disease), 6 patients in the accelerated phase, and 4 in blastic phase of CML. Patients received three 5-day cycles administrated every other week. rIL-2 was given as intravenous bolus infusions of 8 x 10(6) IU/m2 three times a day during cycle 1 and twice a day during cycles 2 and 3. Response to rIL-2 was assessed on day 45. No hematologic response was achieved in the patients with evaluable disease. One patient in hematologic remission with rIL-2 achieved a major response (from 72% to 9% Ph+ metaphases), and two patients had some degree of reduction of Ph+ metaphases. Responses were short-lived (< 6 months), but two of these three patients achieved a new cytogenetic response with interferon given post-rIL-2. A significant immune activation was achieved with rIL-2 including a marked increase in CD3+/CD25+ cells, CD56+ cells, and in natural killer/lymphokine activated killer cell cytotoxic activity. These results confirm preclinical studies, which showed that IL-2 has antileukemic activity in CML. However, the responses observed were short lived and restricted to a subgroup of patients with low disease burden. This invites further studies testing its impact in situations of minimal disease or in combination with other cytokines.
 ...
PMID:Treatment of chronic myelogenous leukemia with interleukin-2: a phase II study in 21 patients. 1009 42

Three different types of anti-T cell antibody were used in patients undergoing haematopoietic stem cell transplantation (HSCT) with an HLA-A, -B and -DR compatible unrelated donor: ATG-Fresenius (ATG-F) (n = 26), Thymoglobuline (TMG) (n = 61) and OKT-3 (n = 45). The groups were comparable regarding diagnosis, stage, age, conditioning and GVHD prophylaxis, Adverse events were less frequent after ATG-F treatment. Levels of IL-2, IL-6, IFN-gamma, TNF-alpha and GM-CSF were increased after OKT-3 infusion. In multivariate analysis OKT-3 treatment (P = 0.01), G-CSF treatment (P = 0.02) and a cell dose >/=2.7 x 108/kg (P = 0.03) gave a faster engraftment. Acute GVHD grades II-IV occurred in 25% of the ATG-F patients, 12% of the TMG-patients and 43% (P < 0.001 vs TMG) of the OKT-3 patients. OKT-3 was associated with acute GVHD in multivariate analysis. TRM was 26% using TMG as compared to 43% in the OKT-3 group (P = 0.03). Patient survival at 4 years was 63%, 50% and 45% in the ATG-F, TMG and OKT-3-treated patients, respectively (NS). Relapses were 8%, 49% and 34%, respectively (ATG-F vs TMG, P = 0.03). Relapse-free survivals were 61%, 40% and 37% (NS). Among CML patients the probability of relapse was 61% in TMG-treated patients, while no patients relapsed in the other two groups. To conclude, the type of anti-T cell antibody affects GVHD and relapse after HSCT using unrelated donors.
 ...
PMID:Effect on cytokine release and graft-versus-host disease of different anti-T cell antibodies during conditioning for unrelated haematopoietic stem cell transplantation. 1051 91

A 3-year-old girl with BCR/ABL-positive CML relapsed after related HLA-identical cord blood transplantation. She was treated with three cycles of donor lymphocyte (DLI) infusion from her 15-month-old brother. Interferon alpha was added after the second DLI, whereas a trial of IL-2 had to be discontinued because of increasing immature myeloid cells in the blood smear. No signs of GVHD were observed, but she developed myelosuppression and needed one platelet and one red blood cell transfusion. She achieved a molecular remission after 6 months with transient molecular relapse followed by sustained remission for 15 months. Thus, DLI with or without interferon alpha might prove to be a promising treatment option with tolerable side-effects in relapsed CML after cord blood transplantation. Bone Marrow Transplantation (2000) 25, 219-222.
 ...
PMID:Successful treatment of relapsed CML after cord blood transplantation with donor leukocyte infusion IL-2 and IFNalpha. 1067 86

Peptide sequences spanning the BCR-ABL protein junction potentially constitute novel leukaemia-specific antigens. 9-mer b3a2 fusion peptides have been reported to bind with high affinity to HLA-A3, -A11 and -B8. We have studied the effect of b3a2 BCR-ABL junctional peptides on the cytotoxic T-cell (CTL) response against normal and chronic myeloid leukaemia (CML) cells. Antigen-presenting cells (APCs) were prepared from HLA-A3- or -B8-positive peripheral blood mononuclear cells (PBMCs) by incubation with phytohaemagglutinin (PHA) and interleukin (IL)-2 for 7 d. These APCs were pulsed with the respective b3a2 junctional peptide in the presence of beta2-microglobulin and were then used to challenge autologous PBMCs at 7-d intervals in the presence of IL-2, IL-6, IL-7 and IL-12. On subsequent exposure to target cells (either further pulsed normal APCs or unpulsed CML cells), specific HLA-restricted CTL responses were observed against all HLA-A3/-B8 matched normal target cells tested, but not to targets that were HLA mismatched. Cytotoxicity was also induced against HLA-A3/-B8 unpulsed CML cells, but not against unmatched CML cells. These data indicate (i) that endogenous BCR-ABL junctional peptides may be presented by CML cells and (ii) that exogenous peptides are potential stimulators of autologous antileukaemic CTLs.
 ...
PMID:b3a2 BCR-ABL fusion peptides as targets for cytotoxic T cells in chronic myeloid leukaemia. 1088 12

Evidence from allogeneic hematopoietic stem cell transplantation indicates a possible immune response against leukemia-associated antigens in patients with either acute myeloid leukemia (AML) or chronic myeloid leukemia (CML). However, autologous immune responses are less evident. We have developed a method using sequential modulation of growth factors (SMGF) to generate specific anti-AML T-cells from primary cultures of mononuclear cells (MNCs) from patients with AML. This culture method induces greater degrees of antigen presentation by inducing dendritic cell (DC) differentiation of AML in the presence of autologous lymphocytes, which are then expanded by interleukin (IL)-2 and costimulatory molecule ligation. MNCs consisting of 92.3% +/- 5.1% AML blasts and 3.4% +/- 3.2% CD3+ T-cells were obtained from AML patients (n = 12) and cultured in AIM-V medium with IL-4 and recombinant granulocyte-monocyte colony-stimulating factor. Recombinant IL-2 was added on day 8. On day 21, culture conditions were changed to anti-CD3/anti-CD28 monoclonal antibodies and IL-2. By day 42, 354 +/- 182-fold CD3+ T-cell expansion had occurred. Cytotoxic T-lymphocyte assays demonstrated that these T-cells caused significant lysis of autologous leukemia cells and AML cell lines, but not of cells of other lineages, in an HLA class I-dependent manner. Specific Vbeta subgroups (Vbeta3, -7, and -12a), possibly representing T-cell clones specific to AML-specific antigens, were expanded in the cultures of cells from 3 AML patients. SMGF can be used to induce and expand autologous T-cells with HLA class I-dependent antileukemia potential from the peripheral blood of AML patients. Adoptive transfer of these expanded T-cells to patients is a possible therapeutic approach for further study.
 ...
PMID:Sequential modulation of growth factors: a novel strategy for adoptive immunotherapy of acute myeloid leukemia. 1243 51

Treatment of advanced renal cancer has made little progress in the past 30 yr. Most clinical efforts have incorporated cytokine-based therapy. The presumption has been that the cytokines may trigger a host immune response against the renal cancer. Only IFN-alpha and high-dose IL-2 seemed to have positive effects on patient outcomes. IFN has prolonged the lives of patients by a few months, and high-dose IL-2 is capable of inducing very prolonged remissions (>5 yr) for a small number of patients. Nephrectomy in the presence of metastatic disease has been established as an effective procedure for select patients, providing palliation and prolonging survival. Finally, enthusiasm has focused on the use of nonmyeloablative allogeneic stem cell transplantation and donor leukocyte infusion for the induction of graft versus tumor effects. Early results are both provocative and promising. A number of agents that target the critical gene products downstream from pVHL and hypoxia-inducible factor-1, such as vascular endothelial growth factor, PDGF, EGF receptor, and TGF-alpha, have recently become available. The new agents are capable of inhibiting specific cellular targets, and the biologic characteristics of clear cell carcinoma of the kidney support their application. If the correct targets are carefully selected for inhibition in tumors in which the targets are present (clear cell histologic features and loss of VHL expression), then results should resemble those others have observed with targeted therapy, such as the use of STI-571 (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) for treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors or anti-HER2/neu (Herceptin; Genentech, South San Francisco, CA) for treatment of breast cancer.
 ...
PMID:Targeting of the VHL-hypoxia-inducible factor-hypoxia-induced gene pathway for renal cell carcinoma therapy. 1456 78

Allogeneic bone marrow transplantation (alloBMT) is the only curative therapy for chronic myelogenous leukemia (CML). This success is explained by the delivery of high doses of antineoplastic agents followed by the rescue of marrow function and the induction of graft-versus-leukemia reaction mediated by allogeneic lymphocytes against host tumor cells. This reaction can also be induced by donor lymphocyte infusion (DLI) producing remission in most patients with CML who relapse after alloBMT. The immunological mechanisms involved in DLI therapy are poorly understood. We studied five CML patients in the chronic phase, who received DLI after relapsing from an HLA-identical BMT. Using flow cytometry we evaluated cellular activation and apoptosis, NK cytotoxicity, lymphocytes producing cytokines (IL-2, IL-4 and IFN-gamma), and unstimulated (in vivo) lymphocyte proliferation. In three CML patients who achieved hematological and/or cytogenetic remission after DLI we observed an increase of the percent of activation markers on T and NK cells (CD3/DR, CD3/CD25 and CD56/DR), of lymphocytes producing IL-2 and IFN-gamma, of NK activity, and of in vivo lymphocyte proliferation. These changes were not observed consistently in two of the five patients who did not achieve complete remission with DLI. The percent of apoptotic markers (Fas, FasL and Bcl-2) on lymphocytes and CD34-positive cells did not change after DLI throughout the different study periods. Taken together, these preliminary results suggest that the therapeutic effect of DLI in the chronic phase of CML is mediated by classic cytotoxic and proliferative events involving T and NK cells but not by the Fas pathway of apoptosis.
 ...
PMID:Immunological effects of donor lymphocyte infusion in patients with chronic myelogenous leukemia relapsing after bone marrow transplantation. 1476 74

Treatment with interferon-alpha is effective for chronic myelogenous leukemia in the chronic phase (CML-CP), but the immunological mechanisms of the antileukemic effect of this substance are still unclear. The objective of this study was to investigate the immunological effects of interferon-alpha in CML patients. Markers of cellular activation and apoptosis, natural killer (NK) cell cytotoxicity and production of intracellular cytokines (IFN-gamma, IL-2 and IL-4) were determined by flow cytometry in the peripheral blood mononuclear cells (PBMC) of 26 CML-CP patients before and 3, 6 and 9 months after IFN-alpha treatment. The results were correlated with the hematological response. In the whole group of patients, INF-alpha use was followed by a significant increase of lymphocytes producing IL-2 and IFN-gamma, an increase in NK activity and a decrease in the number of CD34+ cells. Out of 26 CML patients, 15 achieved hematological remission and 7 achieved partial cytogenetic remission after 9 months of IFN-alpha treatment. There was an increase in the percentage of CD8/FasL+, DR/CD3+, DQ/CD3+, CD34/Fas+, DR/CD56+, CD56/FasL+ cells and of IFN-gamma- and IL-2-producing lymphocytes and an increase in NK cytotoxicity only in the group of patients who achieved complete hematological remission. Our results indicate that IFN-alpha use in CML-CP reduces the number of CD34+ cells, activates T cells, enhances stem cell apoptotic markers and increases the production of intracellular IFN-gamma and IL-2 by lymphocytes. Taken together, these results indicate that the therapeutic effect of IFN-alpha in CML-CP is mediated at least in part by immunological mechanisms.
 ...
PMID:Immunological effects of interferon-alpha on chronic myelogenous leukemia. 1495 48

Chronic myelogenous leukaemia (CML) is a disorder of the haematopoietic stem cell that results in malignant expansion of myeloid cells with a cytogenetic abnormality, and translocation between chromosomes 9 and 22, known as the Philadelphia chromosome. It has been hypothesized that genetic factors other than histocompatibility disparity may play a role in predisposition to developing CML. In this regard, T helper types 1 and 2 (Th1 and Th2) cytokines and their gene polymorphism seem to be important. Overall expression and secretion of cytokines are dependent, at least in part, on genetic polymorphism (nucleotide variations) within the promoter region or other regulatory sequences of cytokine genes. The majority of polymorphisms described are single nucleotide polymorphism (SNPs). The objective of this study was to analyse the genetic profile of Th1 and Th2 cytokines in 30 Iranian patients with CML and 40 healthy subjects. In the patients and control subjects, the allelic and genotype frequencies were determined for the cytokine genes. All typing were performed with a polymerase chain reaction-sequence-specific primers (PCR-SSP) assay. Allele and genotype frequencies were calculated and compared with those of normal controls. The results showed that the most frequent genotypes in our patients were transforming growth factor (TGF)-beta TG/TG, interferon (IFN)-gamma AT, interleukin (IL)-4 CC at position -590, TT at position -33, and IL-10 ACC/ACC and ATA/ATA. In contrast, the genotypes TGF-beta CG/CG, IL-2 TT at position -330, IL-4 CT at position -590, CT at position -33, and IL-10 GCC/ACC were seen at much lower frequencies. The results suggest that production of TGF-beta in CML patients is higher and production of IL-4 and IL-10 is lower than in normal subjects.
 ...
PMID:Cytokine gene polymorphism in Iranian patients with chronic myelogenous leukaemia. 1593 21

A number of growth factors are involved in clonal haematopoietic expansion and their clinical significance in patients with chronic myeloproliferative diseases requires further evaluation. Using enzyme-linked immunosorbent assays, we analysed serum levels of interleukin (IL)-1a, IL-1b, IL-2, IL-6, the soluble IL-2 receptor alpha (sIL-2Ra), and thrombopoietin (TPO), in 25 individuals with myelofibrosis with myeloid metaplasia (MMM), 40 with essential thrombocythaemia (ET), eight with polycythaemia vera (PV), 10 patients with chronic myeloid leukaemia (CML) and 27 normal controls. These were correlated with clinicopathological characteristics including overall survival, and histopathological bone marrow features, including angiogenesis. The serum derived from patients with MMM, ET, PV and CML contained significantly higher IL-2 and sIL-2Ra than healthy subjects, while IL-6 levels were higher only in MMM and CML than controls. IL-2, sIL-2Ra and IL-6 levels were raised during the transformation phase of CML, during progression of MMM to AML, and ET and PV to myelofibrosis (P < 0.001). There was a positive correlation between IL-2, sIL-2Ra, IL-6 and angiogenesis in bone marrow samples. Cytokines may be useful markers for predicting clinical evolution, reflecting increased angiogenesis. This requires further evaluation to guide diagnostic and therapeutic options.
 ...
PMID:Serum interleukin (IL)-1, IL-2, sIL-2Ra, IL-6 and thrombopoietin levels in patients with chronic myeloproliferative diseases. 1611 26


<< Previous 1 2 3 4 5 6 7 Next >>