Home About us Contact
|
Home About us Contact | ||
|
|
||
Philadelphia Chromosome (philadelphia + chromosome)
Selected AbstractsAn 85-Year-Old Japanese Woman with Philadelphia Chromosome,Positive Chronic Myelogenous Leukemia with Del (5q) Successfully Treated by Intermittent Imatinib TherapyJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 10 2004Toyoki Maeda MD No abstract is available for this article. [source] Novel agents to override imatinib resistance mechanismsDRUG DEVELOPMENT RESEARCH, Issue 7 2008Asumi Yokota Abstract Chronic myelogenous leukemia (CML) is a disorder of hematopoietic stem cells that results from the Philadelphia chromosome (Ph) created through translocation of human chromosomes 9 and 22. The resulting Bcr-Abl fusion protein has constitutively high tyrosine kinase activity that causes transformation of hematopoietic stem cells. Imatinib mesylate (IM) was developed as a specific Bcr-Abl kinase inhibitor and is efficacious in treating Ph-chromosome-positive (Ph+) leukemias such as CML and Ph+ acute lymphoblastic leukemia (ALL). Within a few years of its introduction to the clinic, IM has dramatically altered the first-line therapy for CML. Although most newly diagnosed CML patients in the chronic phase (CP) achieved durable responses when treated with IM, resistance to IM has become a major problem in patients with advanced-stage disease. The most important mechanism of IM resistance are point mutations within the Abl kinase domain; therefore, there is an urgent need for novel agents that can inhibit mutated Bcr-Abl. In this review, we describe novel Bcr-Abl tyrosine kinase inhibitors, the so-called "Super Gleevec" inhibitors. Drug Dev Res 69:398,406, 2008. © 2008 Wiley-Liss, Inc. [source] Chronic basophilic leukemia: a distinct clinico-pathologic entity?EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2003Animesh D. Pardanani Abstract: Objective: We sought to better define a group of rare and poorly understood myeloproliferative disorders that are characterized by prominent chronic basophilia in the absence of the Philadelphia chromosome (Ph) or its molecular equivalent. Methods: We screened our institution's electronic database from 1975 onwards, and identified four such cases. Clinical data and bone marrow pathology were carefully reviewed for these patients. Results: Two patients had prominent manifestations of basophil mediator-release and another presented with pituitary dysfunction. Bone marrow examination uniformly revealed trilineage hyperplasia with basophilia and eosinophilia, dysplastic megakaryocytic hyperplasia, and the absence of megakaryocyte clustering. An abnormal pattern of atypical mast cells was noted in two cases. While disease palliation was effectively achieved with hydroxyurea for one patient, transformation to acute myeloid leukemia was eventually observed in this case. Another patient has achieved long-term disease-free survival after undergoing allogeneic stem cell transplantation. Conclusions: Our observations reveal a striking pathologic similarity among all four cases, and suggest this disease, which may be aggressive with the potential to transform into acute leukemia, to possibly represent a distinct clinico-pathologic entity (chronic basophilic leukemia). [source] Integration of amplified BCR/ABL fusion genes into the short arm of chromosome 17 as a novel mechanism of disease progression in chronic myeloid leukemiaGENES, CHROMOSOMES AND CANCER, Issue 1 2001Simone Metzke-Heidemann We describe the cases of two patients with Philadelphia chromosome,positive chronic myeloid leukemia (CML), in whom the extramedullary blastic phase developed during disease progression. The similar clinical presentations of these patients was accompanied by gain of identical secondary chromosome abnormalities, that is, monosomies 9, 14, and 22, and by a clustered amplification of the BCR/ABL fusion gene. The additional copies of the BCR/ABL fusion gene were integrated into the short arm of structurally abnormal chromosomes 17 in both patients. The conformity of these genetic features in two patients with a rare disease manifestation leads us to the assumption that either the clustered amplification of the BCR/ABL fusion gene or the integration of this cluster into the short arm of chromosome 17 or both are associated with extramedullar disease progression in CML. Furthermore, the insertion of amplified BCR/ABL fusion genes into structurally abnormal chromosomes provides a novel mechanism of disease progression in BCR/ABL -positive CML. © 2001 Wiley-Liss, Inc. [source] Leukaemic infiltration of the mandible in a young girlINTERNATIONAL JOURNAL OF PAEDIATRIC DENTISTRY, Issue 2 2007RACHAEL E. BENSON Background., This report presents a case of leukaemic infiltration of the mandible in a 10-year-old female of Sudanese extraction. Case report., The patient was in remission from acute lymphoblastic leukaemia when she presented with pain localized to the alveolar ridge overlying the unerupted lower right second permanent molar. Two days later, she developed right inferior alveolar nerve paraesthesia. Radiographic imaging demonstrated cortical line absence around the developing lower right second and third permanent molars, and distal displacement of the lower right third molar. In addition, the cortical outline of the right inferior dental canal lacked clarity. Biopsy confirmed leukaemia recurrence demonstrating the Philadelphia chromosome. Tailored chemotherapy was commenced, and a bone marrow transplant was carried out 12 weeks later. At 6-month dental review, the patient remained exceptionally well with no bone pain and normal sensation in the right lower lip. Conclusion., The importance of regular and long-term dental examination of patients with leukaemia is discussed. [source] Late-appearing Philadelphia chromosome in childhood acute myeloid leukemiaPEDIATRIC BLOOD & CANCER, Issue 5 2008Niketa Shah MD Abstract A 3-year-old female was diagnosed with acute myeloid leukemia (AML-M2). The disease was refractory to various chemotherapeutic agents. Cytogenetic analysis revealed a clone with trisomy 8 at diagnosis that was replaced by a clone containing a t(11;15) and del(20q) by the end of the second induction. A new clone, characterized by a Philadelphia chromosome, with the minor BCR/ABL p190 transcript, emerged 14 months after diagnosis and remained to the end of disease course. The late occurrence of the Philadelphia chromosome in AML has been documented rarely in adults. Pediatr Blood Cancer 2008;50:1052,1053. © 2008 Wiley-Liss, Inc. [source] Technical aspects and clinical applications of measuring BCR-ABL1 transcripts number in chronic myeloid leukemia,AMERICAN JOURNAL OF HEMATOLOGY, Issue 8 2009Letizia Foroni Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by a triphasic clinical course, the morphologic expansion of a terminally differentiated myeloid cell and the presence of the BCR-ABL1 fusion gene, the hallmark of CML. The fusion gene is usually, but not always, associated with a Philadelphia chromosome, the result of a reciprocal exchange of genetic material between chromosome 22 and chromosome 9, which leads to the production of the activated BCR-ABL1 gene and oncoprotein. The breakpoint in the BCR gene occurs commonly downstream of exons e13 or e14 (M-BCR) and less frequently downstream of exons e1 and e2 (m- BCR). Less than 1% of cases carry a breakpoint downstream of exon 6 or 8 ("variant fusion genes") or exon 19 (,- BCR). Breakpoints in the ABL1 gene cluster upstream of exon a2 (or of exon a3 in less than 5% of patients with CML). Conventional cytogenetic, fluorescence in situ hybridization, and molecular testing for the BCR-ABL1 fusion gene are key investigations for the diagnosis and monitoring of CML. Treatment using tyrosine kinase inhibitors has revolutionized the management of CML with hematologic and cytogenetic response within 12,18 months observed in >85% of patients. Nevertheless, between 15 and 20% of patients may evolve to blastic phase. Measurement of low level or "minimal" residual disease using molecular tests is becoming the gold-standard approach to measure response to therapy due to its higher sensitivity compared to other routine techniques. The technical aspects and clinical applications of molecular monitoring will be the main focus of this article. Am. J. Hematol., 2009. © 2009 Wiley-Liss, Inc. [source] Acute lymphoblastic leukemia without the Philadelphia chromosome occurring in chronic myelogenous leukemia with the Philadelphia chromosomeAMERICAN JOURNAL OF HEMATOLOGY, Issue 3 2003Hee Jin Huh Abstract The blast crisis in chronic myelogenous leukemia (CML) is related to the evolution of a Philadelphia chromosome (Ph)-positive clone. Secondary chromosomal abnormalities accompanied by t(9;22) are found in 70,80% of blast crises. Here we describe a patient with Ph-positive CML, who developed Ph-negative acute lymphoblastic leukemia (ALL). A 52-year-old man was diagnosed with CML with the Ph chromosome in the chronic phase. He achieved a partial cytogenetic response after 4 months of imatinib mesylate therapy. After 8 months, common ALL occurred. At that time his karyotype was normal and the Ph chromosome was not noted. Am. J. Hematol. 74:218,220, 2003. © 2003 Wiley-Liss, Inc. [source] Cytogenetic and molecular responses and outcome in chronic myelogenous leukemiaCANCER, Issue 4 2008Need for new response definitions? Abstract BACKGROUND. Response rates in chronic myeloid leukemia (CML) are now reported based on the cumulative incidence of a single-time best response. The study aim was to examine the significance of different response criteria for CML on imatinib therapy. METHODS. In all, 276 patients with chronic phase CML on imatinib therapy were analyzed. Cytogenetic and molecular responses were coded as to single best response and response at specific intervals of treatment. RESULTS. The cumulative incidence of complete cytogenetic response (CGCR) with imatinib was 91%; however, the incidence of CGCR at 48 months into therapy was only 78%. Similarly, the incidence of major molecular responses (best cumulative vs landmark at 48 months) were 74% versus 62%, and of undetectable BCR-ABL transcripts 38% versus 24%. There was a strong association between achievement of major cytogenetic response (Philadelphia chromosome [Ph]-positivity ,35%) at 6 months to 12 months and survival as well as progression-free survival (PFS). Achievement of major molecular response (vs lesser molecular response) in patients in complete cytogenetic response was not associated with significant differences in survival, but showed some association with PFS. Durable CGCR and major molecular responses (documented continuously for ,12 months) were associated with longer PFS duration but not with survival duration differences. Of interest, major molecular responses documented at least twice were noted in 71% of patients on imatinib therapy; undetectable BCR-ABL transcripts documented at least twice were noted in 34%. CONCLUSIONS. Achievement and durability of CGCR and of major and complete molecular responses at landmark times predict outcome in CML, and may help in comparing the efficacy of different treatments. Cancer 2008. © 2007 American Cancer Society. [source] Results of decitabine (5-aza-2,deoxycytidine) therapy in 130 patients with chronic myelogenous leukemiaCANCER, Issue 3 2003Hagop M. Kantarjian M.D. Abstract BACKGROUND General and site-specific DNA methylation is associated with tumor progression and resistance in several cancers, including chronic myelogenous leukemia (CML). Decitabine is a hypomethylating agent that has shown encouraging preliminary anti-CML activity. This study evaluated the activity and toxicity of decitabine in different phases of CML. METHODS One hundred and thirty patients with CML were treated: 123 with Philadelphia chromosome (Ph)-positive CML (64 blastic, 51 accelerated, 8 chronic) and 7 with Ph-negative CML. Decitabine was given at 100 mg/m2 over 6 hours every 12 hours × 5 days (1000 mg/m2 per course) in the first 13 patients, 75 mg/m2 in the subsequent 33 patients, and 50 mg/m2 in the remaining 84 patients. RESULTS A total of 552 courses were given to the 130 patients. Only four patients (3%) died during the first course from myelosuppressive complications (three patients) or progressive disease (one patient). Of 64 patients in the CML blastic phase, 18 patients (28%) achieved objective responses. Of these 18 patients, 6 achieved complete hematologic responses (CHR), 2 achieved partial hematologic responses (PHR), 7 achieved hematologic improvements (HI), and 3 returned to the second chronic phase (second CP). Five patients (8%) had cytogenetic responses. Among 51 patients in the accelerated phase, 28 patients (55%) achieved objective responses (12 CHR, 10 PHR, 3 HI, and 3 second CP). Seven patients (14%) had cytogenetic responses. Among eight patients treated in the chronic phase, five (63%) had objective responses. Of seven patients treated for Ph-negative CML, four (57%) had objective responses. There was no evidence of a dose-response effect. The estimated 3-year survival rate was less than 5% in the blastic phase and 27% in the accelerated phase. The only significant toxicity reported was severe myelosuppression, which was delayed, prolonged, and dose dependent. With decitabine 50,75 mg/m2, the median time to granulocyte recovery above 0.5 × 109/L was about 4 weeks. Myelosuppression-associated complications included febrile episodes in 37% and documented infections in 34%. CONCLUSIONS Decitabine appears to have significant anti-CML activity. Future studies should evaluate lower-dose, longer-exposure decitabine schedules alone in imatinib-resistant CML, as well as combinations of decitabine and imatinib in different CML phases. Cancer 2003;98:522,8. © 2003 American Cancer Society. DOI 10.1002/cncr.11543 [source] Neutrophilic-chronic myeloid leukemiaCANCER, Issue 9 2002Low levels of p230 BCR/ABL mRNA, undetectable p230 BCR/ABL protein may predict an indolent course Abstract BACKGROUND Neutrophilic-chronic myeloid leukemia (CML-N) has been described as a CML variant associated both with a distinctive molecular defect of the Philadelphia chromosome and with a more benign clinical course than classic CML. The translocation (9;22) in CML-N results in the transcription of an e19/a2 type BCR/ABL mRNA that codes for a 230-kD BCR/ABL protein (p230). The indolence of the clinical course of patients with CML-N has been disputed. METHODS The objectives of this study were to quantify and correlate with clinical outcome the p230 mRNA and protein in patients with CML-N, to describe six new patients and the follow-up (with molecular analysis) of five previously reported patients with CML-N, and to review characteristics of all patients with CML-N and p230 BCR/ABL reported to date in the literature. RESULTS Quantitative polymerase chain reaction assays on specimens from the great majority of patients with CML-N revealed minimal numbers of molecules of p230 BCR/ABL transcripts per total RNA. This also was associated with a lack of detectable p230 BCR/ABL protein in patient specimens, even in one patient who was followed for 16 years after diagnosis. This may explain the milder leukemic phenotype in most patients with CML-N. A review of all 23 patients who had an e19/a2 type BCR/ABL translocation suggested that the low level of p230 BCR/ABL mRNA and the lack of detectable p230 BCR/ABL protein in patients with no additional cytogenetic abnormalities may predict their indolent clinical course. CONCLUSIONS Patients with p230 positive CML-N have indolent course, probably as a result of low p230 mRNA and protein levels. This supports the need to conduct additional molecular studies, even if cytogenetic studies have revealed t(9;22), because of the prognostic importance of the molecular findings. Cancer 2002;94:2416,25. © 2002 American Cancer Society. DOI 10.1002/cncr.10490 [source] | ||||||||||||||||||||||