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)

Chronic myeloid leukemia (CML) appears an ideal and exciting immunological target. Novel and rational immunotherapy may therefore play an important adjuvant role in the treatment of CML patients. Peptides derived from the BCR-ABL fusion region have been shown to be immunogenic and are able to stimulate the production of BCR-ABL-specific T cell lines and clones. In this study, A 280 bp multiple epitope region of BCR-ABL fusion antigen was designed and synthesized. This region contains three BCR-ABL antigen epitopes which can bind to HLA-A2, HLA-A3 and HLA-DR11 molecules, respectively, and epitopes of cholera toxin B (CTB) and tetanus toxoid (TT) which are able to elicit vigorous T cell responses. The fusion antigen gene has highly been expressed in E. coli and the purified fusion protein reserved satisfied activity and antigenicity. The results of this investigation provided a basis for further research on the developing specific T cell immunotherapy of CML.
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PMID:[Synthesis, Cloning and Expression of a Multiple Epitope Antigen of BCR-ABL Fusion Gene] 1257 95

Immunotherapy in the form of donor lymphocyte infusions in early-phase relapse might be advantageous as it induces a higher response, but this may be offset by increased toxicity, especially during the early period after transplantation. Among 45 consecutive patients receiving an allograft for CML, 13 patients were diagnosed to have molecular relapse (MRel), as defined by real-time quantitative reverse transcriptase-polymerase chain reaction, and another four patients were diagnosed to have cytogenetic relapse (CRel) within 6 months. Patients with MRel were randomly assigned to either a 'no therapy' group (group A, n=6), in which immunotherapy was reserved until CRel, or an 'immunotherapy' group (group B, n=7). In group A, all MRel progressed to CRel, and molecular remission (MR) was achieved in four (67%) after immunotherapy. The remaining two patients died of extensive GVHD and fungal pneumonia. In group B, only two MRel progressed to CRel and the remaining five (71%) achieved MR. Two patients died in the absence or loss of response. In patients relapsing directly into CRel (n=4), immunotherapy induced MR in two patients (50%). Earlier intervention played a role in preventing disease progression but this effect was not translated into better survival, which could have been overcome by imatinib mesylate, which induced MR and cytogenetic remission in nonresponders without toxicity.
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PMID:Preemptive treatment of minimal residual disease post transplant in CML using real-time quantitative RT-PCR: a prospective, randomized trial. 1471 40

The management of CML has recently become increasingly complex. The Scotland Leukaemia Registry (SLR) sent questionnaires to all 26 Scottish haematology units, of which 18 (69%) responded. From January 1999 to December 2000, 64 new cases of CML were identified by the audit (incidence 0.64/100,00/yr), of which 46 were registered with the SLR. At diagnosis, all 18 units combined bone marrow examination with cytogenetics/FISH, but only 13 performed RT-PCR. Of four units that calculated the Hasford Score, only two used it to inform clinical decisions. 52% of patients entered clinical trials, 57% involving imatinib mesylate (IM). Of the 23 patients who were tissue typed, suitable donors were found for 18, 11 sibling, and 7 unrelated, representing 28% of the total patient population. Only 13/64 patients (20%) did not have a BMT donor identified or enter a clinical trial. Although 38% of units would consider reduced intensity allografting in patients > 60 years, no centres currently routinely tissue-type such patients. For first line therapy 56% of patients received hydroxyurea +/- interferon. Of the newer agents, 83% of units believed imatinib mesylate should be reserved for clinical trials, 83% would consider using oral ara-C and 89% pegylated-interferon.
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PMID:The Scotland Leukaemia Registry audit of incidence, diagnosis and clinical management of new patients with chronic myeloid leukaemia in 1999 and 2000. 1546 21

As part of our routine work-up in the diagnosis of lymphoproliferative disease, we used a rapid polymerase chain reaction (PCR) assay to amplify the DNA fragments of the framework 3 (FR3) region of the immunoglobulin heavy (IgH) chain genes. The assay does not involve hybridization, nested priming, or sequencing of the amplified PCR product. It was performed on 66 specimens of B-cell lymphoproliferative disease, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, hairy cell leukemia and follicular lymphoma. Twenty-six specimens of negative controls, including acute myeloid leukemia, chronic myeloid leukemia in myeloid transformation and idiopathic thrombocytopenic purpura, were also analyzed. The assay was performed with 77% sensitivity and 100% specificity. The standard IgH chain gene rearrangement by Southern blot analysis is reserved for the remaining negative cases if clinically indicated.
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PMID:Application of polymerase chain reaction to detect rearrangement of immunoglobulin heavy chain genes in lymphoproliferative disease. 1735 88

Chronic myeloid leukaemia (CML) was the first human cancer linked to an acquired chromosomal abnormality, subsequently shown to be a reciprocal translocation between chromosomes 9 and 22. The resulting fusion gene product, BCR-ABL, was shown to be the causative agent of the disease. CML has an incidence of around 1-2 cases per 100,000; in Australia, there are probably more than 200 new cases per year and more than 1300 prevalent cases. Treatment of CML with imatinib has been a powerful vindication of the concept of rational, gene-targeted drug design. Five-year published experience with imatinib at 400 mg orally daily demonstrates 89% overall survival and an estimated 93% freedom from disease progression. Adverse effects are mostly mild and transient. Higher doses of imatinib may be more efficacious and will be studied in upcoming clinical trials in Australia; however, imatinib is almost certainly not curative. Up to 28% of patients may have to stop imatinib because of intolerance or disease resistance, mostly due to point mutations of BCR-ABL. In this situation, many patients will respond to second- and third-generation tyrosine kinase inhibitors. Management of CML patients should involve close monitoring, especially in the first 2 years, with regular cytogenetics and quantitative polymerase chain reaction to optimise response and identify suboptimal responders as early as possible. Bone marrow transplantation remains the only known cure, but is reserved for patients whose kinase inhibitor therapy has failed, or who have advanced disease (accelerated phase or blastic transformation).
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PMID:Chronic myeloid leukaemia: the evolution of gene-targeted therapy. 1875 27

Since the introduction of imatinib mesylate, the role of allogeneic hematopoietic cell transplantation (allo-HCT) for CML has essentially been reserved for patients with advanced disease or imatinib resistance. In addition, there have been concerns regarding imatinib associated cardiac toxicity. We investigated the outcome of 61 patients with CML who received a myeloablative allo-HCT at the University of Minnesota between 1999 and 2006. The median age at HCT was 38.4 (range; 6.9-56.9) years. Thirty-seven patients were in first chronic phase and twenty-four patients in a second chronic or accelerated phase at the time of HCT. Twenty-six patients received imatinib therapy before or after HCT, and thirty-five patients either never received imatinib (n=32) or received it only at the time of relapse after HCT (n=3). OS and relapse-free survival (RFS) at 2 years was 69 and 55% for the imatinib group, and 57 and 49% for the non-imatinib group (P=0.57 and 0.95, respectively). There was no difference in the risk of relapse at 2 years between the groups. Symptomatic cardiac toxicity at 1 year was reported in three imatinib group (12%) and two non-imatinib group (6%) patients (P=0.44). Thus, patients treated with imatinib either before or after myeloablative allo-HCT had no increase in cardiac toxicity.
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PMID:Imatinib use either pre- or post-allogeneic hematopoietic cell transplantation (allo-HCT) does not increase cardiac toxicity in chronic myelogenous leukemia patients. 1920 9

Chronic myeloid leukemia (CML) is a progressive and often fatal malignancy of the blood. The harbinger of CML is a chromosomal translocation that results in the synthesis of the BCR-ABL fusion protein, a constitutively active tyrosine kinase. The advent of imatinib, an inhibitor targeted specifically for BCR-ABL, represented a significant medical advance in CML therapy. However, patients with CML can exhibit varying responses to first-line treatment with imatinib. While most patients respond to treatment, some may experience a loss of response or require treatment discontinuation due to toxicity. Frequent monitoring for resistance or intolerance is a requirement for recognition of suboptimal response. Mutational analysis of the patient's BCR-ABL alleles is also informative and may be predictive of a response to therapy. Published physician guidelines have highlighted these recommendations, but it is not clear if these guidelines are universally followed. One option in patients showing poor response to standard-dose imatinib of 400 mg is to escalate the dose. However, this option should be reserved for patients with minimal disease burden. Clinically available options mainly include second-generation tyrosine kinase inhibitors, such as dasatinib and nilotinib. Allogenic stem cell transplantations (for eligible patients) also should be considered. The disease and patient characteristics at the time of imatinib failure should be evaluated before choosing second-line therapy to optimize the therapeutic benefit without unnecessary delay.
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PMID:Treatment selection after imatinib resistance in chronic myeloid leukemia. 1934 97

Allogeneic stem cell transplantation (ASCT) is a potentially curative treatment for patients with chronic myelogenous leukemia (CML) and was previously considered the preferred treatment for newly diagnosed CML. The success of imatinib has changed treatment recommendations, and allogeneic transplants are now reserved for imatinib treatment failures. Previous imatinib treatment does not compromise the results of ASCT, but patients with overt transformed disease have poor results. It is unclear whether patients whose disease is considered to have failed imatinib should be referred immediately for ASCT or receive treatment with a second-generation tyrosine kinase inhibitors (TKI). Patients whose disease fails 2 TKIs should receive ASCT if possible. Nonmyeloablative preparative regimens reduce the toxicity and treatment-related mortality associated with the transplantation procedure and allow transplantations to be performed in older and medically infirm patients. This approach, including posttransplantation treatment with TKIs and donor lymphocyte infusion, produces a high fraction of durable molecular complete remissions.
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PMID:Nonmyeloablative allogeneic stem cell transplantation for chronic myelogenous leukemia in the imatinib era. 1977 50

Allogeneic hematopoietic stem cell transplantation (HSCT) is well-established as a potentially curative treatment for patients who have chronic myeloid leukemia. The success of imatinib and other tyrosine kinase inhibitors (TKI) as initial therapy has changed the treatment paradigm for this disease. Allogeneic hematopoietic transplants are now reserved for patients whose disease does not respond optimally to TKI treatment. Patients whose disease does not have an optimal response to imatinib may respond to a second-generation TKI, dasatinib or nilotinib, and many achieve major or complete molecular and cytogenetic responses. The indication for allogeneic HSCT versus continued second-line therapy is not well-defined and is the subject of ongoing study. There has been continued progress in reducing the toxicity and risks of HSCT with development of reduced-intensity regimens; transplants can be routinely performed in patients up to the age of 75 years who are in fair general medical condition. Transplantation results from unrelated donors have improved, with survival rates similar that achieved with matched siblings. Results with haploidentical and cord blood transplants have markedly improved, and should be considered for patients lacking a matched donor. Allogeneic hematopoietic transplants have the best chance to be curative in patients with chronic phase that is under hematologic control with 80% disease-free survival; patients progressing to the accelerated phase or blast crisis have a much poorer prognosis. Thus, HSCT should be considered for patients with imatinib failure. Patients receiving second-line TKI therapy must be closely monitored and referred for transplantation if a complete cytogenetic response and major molecular response is not achieved. HSCT should be performed if feasible in patients without a continued response to TKI treatment.
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PMID:Allogeneic stem cell transplantation for chronic myeloid leukemia resistant to tyrosine kinase inhibitors. 2203 58

The introduction of tyrosine kinase inhibitor (TKI) therapy has markedly reduced the use of allogeneic (allo) hematopoietic stem cell transplantation (HSCT), which is no longer standard practice in the first chronic phase in chronic myelogenous leukemia and is currently reserved after failure of TKI or in advanced phase of disease. We compared the outcome of Philadelphia chromosome-positive (Ph+) leukemia patients who received a first allo-HSCT in our center in both the pre-TKI era and the TKI era. The primary end point was to compare the 2 groups' overall survival (OS), leukemia-free survival (LFS), cumulative incidence of nonrelapse mortality, and relapse incidence. The secondary end point was to underline in the TKI era the impact of the pretransplantation minimal residual disease (MRD) on the outcomes. A total of 69 patients with Ph+ leukemia were included and their outcomes analyzed. For the purpose of this analysis, we defined 2 groups: group A (n = 39) included patients treated in the pre-TKI era, treated from January 1989 until December 2001, and group B (n = 30) included patients treated in the TKI era, treated from January 2002 until December 2013. Additional analysis was performed in group B for whom detailed TKIs and MRD data were collected. The study took place in our cancer center in the department of HSCT, Villejuif, France. The median follow-up duration for group A was 116.1 months (range, 1.1 to 240.1 months) and for group B was 8.3 months (range, 3.5 to 141.7 months). At 3 years, the LFS and OS were higher in group B (respectively, 66% and 71%) than in group A (respectively, 63% and 57%) (P > .05). The LFS and OS at 3 years of the pretransplantation MRD-negative (< 0.01%) patients were significantly (P < .05) higher (respectively, 83% and 94%) than the pretransplantation MRD-positive patients (respectively, 43% and 46%). Our data, although statistically not significant, suggest better outcomes for Ph+ leukemia patients undergoing allo-HSCT in the TKI era. Mostly TKI does not adversely affect the transplantation outcomes and can be used successfully as a bridge to allo-HSCT, especially in advanced disease. In addition, we highlight the importance of obtaining deep pretransplantation MRD negativity.
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PMID:Retrospective Study of Allogeneic Hematopoietic Stem Cell Transplantation in Philadelphia Chromosome-Positive Leukemia: 25 Years' Experience at Gustave Roussy Cancer Campus. 2629 65


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