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

Leukemia has been treated with chemotherapy for the past 40 years with only moderate success. A growing body of evidence suggests that by augmenting the immune system more effective results may be obtained. This is highlighted by T cell reinfusions resulting in durable remissions in patients with chronic myelogenous leukemia who have relapsed after an allogeneic transplant. Interleukin-2 is the primary growth factor for T lymphocytes and is a stimulator of natural killer cell activity. It has now been shown that a limited number of otherwise refractory leukemias can be effectively treated with interleukin-2. However, there remains a lack of correlation between the biologic and clinical effects of interleukin-2. The clinical activity of interleukin-2 appears to be greatest in myeloid leukemias. A variety of dose schedules and routes of administration make it difficult to determine if interleukin-2 given to patients in clinical remission is of benefit. Large randomized studies are necessary to explore the role of interleukin-2 in leukemia.
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PMID:Interleukin-2 and leukemia. 982 39

Chronic myeloid leukemia (CML) is usually treated with either alpha-interferon or hydrea. Median survival is 6 years. Eventually, in most CML patients, the disease evolves to blast phase with clinical and morphologic characteristics of an acute leukemia. This phase is commonly associated with systemic symptoms and the appearance of new cytogenetic abnormalities. Therapy for this phase is of limited value, resulting in a mean survival of 4 months. We describe four consecutive patients seen at our clinic with advanced stage CML (three blast, one accelerated phase) who were treated with interleukin-2 (Proleukin). The mean survival in these patients was 22 months (range 9-35 months) and two are still alive 25 and 35 months after the start of therapy. One patient had a complete cytogenetic response and another a partial response. Toxicity was minimal and no patient had to discontinue therapy because of it.
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PMID:Interleukin-2 therapy for advanced chronic myeloid leukemia. 982 41

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.
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PMID:Treatment of chronic myelogenous leukemia with interleukin-2: a phase II study in 21 patients. 1009 42

Nine patients with onco-hematological malignancies with a poor prognosis due to high risk of relapse received immunotherapy with interleukin-2 (IL-2) and interferon (IFN(alpha 2b)) s.c. as maintenance therapy after receiving autologous bone marrow or peripheral blood stem cell transplantation (ABMT/PBSCT). All the patients were considered at very high risk of relapse. We attempted to assess the efficiency, toxicity and clinical effects of these cytokines in these patients. Five patients were treated with high-dose of IL-2 and the other four patients with escalating doses every month. Side-effects in the first group of patients consisted of fever, chills, weakness, nausea, anorexia, loss of weight and local dermatitis in the injection site. Toxicity on the WHO scale was grade II in three patients and grade IV in the other two patients. In the second group of patients, the same clinical signs of toxicity appeared, but these were grade I on the WHO scale in all patients. None of the patients had infections or died in relation to administration of IL-2. Four patients died of relapse or progression of their hematological malignancies. The other five patients are alive, one in chronic phase of CML and the other four patients are in complete remission of their malignancies.
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PMID:Treatment with interleukin-2 (IL-2) and interferon (IFN(alpha 2b)) after autologous bone marrow or peripheral blood stem cell transplantation in onco-hematological malignancies with a high risk of relapse. 1019 3

Chronic myelogenous leukemia in more than 90% of patients is associated with the abnormal Philadelphia chromosome, which results in aberrant BCR-ABL chimeric gene expression. The mean overall survival on standard chemotherapy (which is not curative) ranges between 54-72 months. Selected patients with CML can be cured by allogeneic hemopoietic stem cell transplantation. Only 30% of patients has an optimal HLA-identical sibling donor. It is possible to find well-matched unrelated donor for another 20-30% of patients, however matched-unrelated donor transplantation is still associated with relative high risk of complications and cannot be used in elderly patients. Interferon alpha treatment in monotherapy or in combination with ARA-C can induce a cytogenetical and molecular remission in selected group of patients, which benefits with significantly prolonged survival. Nevertheless the cost of this treatment is high and long period of therapy is required to assess its efficacy. In patients lacking matched related or unrelated donors for allogeneic transplantation, autologous stem cell transplantation could be the alternative method of treatment. Discussed in the paper method of mobilization and transplantation of Philadelphia-negative peripheral-blood progenitor cells collected during early phase of bone marrow regeneration after "mobilizing" chemotherapy (mini-ICE) enables to achieve a complete or major cytogenetical response in about 77% of patients. There is only minimal morbidity and no transplant-related mortality. This procedure and the post-transplant immunotherapy (IFN alpha, interleukin-2) can considerably suppress the pathological clone and significantly prolong the overall survival in CML patients not eligible for allogeneic transplantation.
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PMID:[Autologous hemopoietic stem cell transplantation in treatment of chronic myelogenous leukemia]. 1049 85

The infusion of lymphocytes from the original marrow donor (donor lymphocyte infusions [DLI]) is remarkably effective in treating chronic myeloid leukemia in relapse after allogeneic stem cell transplantation. DLI are less effective in acute leukemia and other hematologic tumors, but the use of interleukin-2 in conjunction with DLI after allograft may increase the response rate. The use of DLI to treat certain solid tumors is under investigation. In contrast, the value of donor lymphocytes for treating infectious complications post-transplant and graft failure has been established. The major drawback of DLI remains graft-versus-host disease, but novel regimens of administration and/or selective manipulation of donor cells prior to infusion have reduced its incidence. Further progresses in this area will help to establish the role of nonmyeloablative conditioning for allografting.
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PMID:Donor lymphocyte infusions. 1054 93

Natural killer (NK) cells are deficient in patients with chronic myelogenous leukemia (CML), but the mechanisms responsible for the dysfunction are not completely understood. This study reports that CML cells effectively inhibit the baseline and interleukin-2 (IL-2)-induced NK cell cytotoxicity against a CML cell-derived line (K562). A sizable fraction of NK cells subsequently acquired features characteristic of programmed cell death/apoptosis. The CML cell-mediated inhibition of NK cells required triggering of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated formation of reactive oxygen species (ROS) and was prevented by catalase, a scavenger of ROS, and by histamine, acting via H(2)-receptor-mediated inhibition of ROS production in CML cells. In contrast, nonmalignant neutrophilic granulocytes inhibited NK cells via ROS production without the requirement of exogenous NADPH oxidase-triggering stimuli. We propose that paracrine production of ROS may contribute to the dysfunction of NK cells in CML and that histamine may serve as an autocrine inhibitor of ROS formation in leukemic granulocytes. (Blood. 2000;96:1961-1968)
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PMID:Natural killer cell dysfunction and apoptosis induced by chronic myelogenous leukemia cells: role of reactive oxygen species and regulation by histamine. 1096 1

The first line therapy for CML is IFN-alpha and/or allogeneic hematopoietic stem cell transplantation(HSCT). The indication of autologous HSCT is limited for patients with no HLA-matched donor, and is recognized as an experimental therapy. Major problems of autologous HSCT for CML are contamination of Ph1-positive cells to graft and no GVL effects. To concur these problems, many attempts have been made such as the collection of peripheral blood stem cells after high dose chemotherapy, ex vivo purging using antisense, administration cyclosporin to induce GVL effect, and post-HSCT therapy by IFN-alpha +/- Interleukin-2. Autologous HSCT for CML is still to be a hopeful candidate for pursuing cure.
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PMID:[Autologous bone marrow transplantation for CML]. 1176 41

Interleukin-2 (IL-2) is able to generate nonspecific cytotoxic effectors from hematopoietic precursors. We evaluated the feasibility and efficacy of chronic myeloid leukemia (CML) treatment with autologous hematopoietic stem cell transplantation (HSCT) using grafts cultured in IL-2 followed by immunotherapy with IL-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon (IFN)-alpha. Eight patients with CML were enrolled: five in an accelerated phase and three in a chronic phase. They received peripheral blood stem cells (PBSC) or bone marrow (BM) cultured in a medium containing IL-2 for 24 h. A median of 1.29 x 10(6) CD34+ cells/kg were infused after conditioning with busulfan (12 16 mg/kg) in PBSC recipients. BM was infused without prior myeloablative therapy. The engraftment occurred with a median of 15 d. Engraftment failure developed in one patient. The transplantation was followed by a 1-mo regimen of IL-2 (0.5 x 10(6) IU/m(2) daily) and GM-CSF, and 6 mo of IFN-alpha. One complete and one transient minor cytogenetic remission were observed. At 24 mo after transplantation, two patients had died of progressive disease and one of infection. Five patients had stable disease in the chronic phase. Autologous transplantation using IL-2-activated graft is feasible and the subsequent IL-2, GM-CSF, and IFN-alpha administration has acceptable toxicity. However, no benefits in comparison with conventional autologous transplantation for CML were identified in our study.
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PMID:Treatment of chronic myeloid leukemia with autologous transplantation using peripheral blood stem cells or bone marrow cultured in IL-2 followed by IL-2, GM-CSF, and IFN-alpha administration. 1266 87

The understanding of the use of donor lymphocyte infusions (DLI) for graft-versus-leukaemia (GVL) in the treatment of chronic myeloid leukaemia (CML) post haemopoietic stem cell transplant (HSCT) has advanced during the last years. In relapsed leukaemia post-stem cell transplant, DLI can achieve durable remissions in 60-73% patients. Technical improvements in molecular methods of detection of the BCR-ABL transcripts permit the prediction of relapse with increased sensitivity and reproducibility. Use of DLI early at relapse is important since responses to DLI are less likely in the face of bulky or blast-phase disease. Exogenous interleukin-2 may enhance the response to DLI but total cell dose is also relevant to the efficacy of DLI with the effective cell dose (ECD) required being lower in HLA matched unrelated DLI donors compared to siblings. Donor T-lymphocytes target minor histocompatibility (H) antigens and the relative tissue distribution of these may influence the toxicity of DLI, which includes graft-versus-host-disease (GVHD). Modified methods of delivery such as selective deletion of CD8+ cells or escalating cell dosage regimens have reduced the incidence of serious morbidity due to GVHD without compromising the GVL effect mediated by DLI. These approaches have not removed the risk of GVHD entirely and conditional suicide protocols utilising the HSV-tk or fas receptor derived genes are being developed in the clinic. Since significant morbidity and mortality is attributable to the conditioning regimen used prior to HSCT, awareness of the potency of DLI has driven the development of reduced intensity conditioning (RIC) regimens. The purpose of RIC is to enhance tolerisation of the host to the graft while permitting the establishment of donor haemopoiesis. DLI may then be used subsequently to enhance the GVL effect.
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PMID:Donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukaemia. 1269 Nov 39


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