Background and Objectives: Chronic myeloid leukemia (CML) accounts for approximately 15% of newly diagnosed cases of leukemia in adults. In this study, the efficacy of nilotinib at 400 mg BID is compared with imatinib...Background and Objectives: Chronic myeloid leukemia (CML) accounts for approximately 15% of newly diagnosed cases of leukemia in adults. In this study, the efficacy of nilotinib at 400 mg BID is compared with imatinib at 400 mg BID in CML patients with suboptimal molecular response after at least 12 months of daily dose 400 mg of imatinib therapy. Patients and Methods: This study included a total number of 50 patients, divided into two groups (25 patients each). The first group (Group I): Patients received imatinib at 400 mg BID, second group (Group II): Patients had a suboptimal molecular response to imatinib and received nilotinib at 400 mg BID in early chronic phase. During the two years period of data collection, the primary end included median survival. The secondary end included response rate, type of response, duration of response and progression free survival. Also side effects were recorded. Patients were followed up every month by complete and differential blood counts, liver function test, renal function test and (PCR) every three months for two year. Results: Nilotinib group had significantly higher frequency of major molecular response (MMR) where 23 (92%) patients achieved it while only 16 (64%) patients in Imatinib group achieved MMR (P = 0.01). Nilotinib had better toxicities profile than Imatinib. Conclusion: Both Nilotinib and high dose Imatinib achieved response in CML patients with suboptimal response with rapid and deeper molecular response, better survival outcomes and less side effects in nilotinib.展开更多
Chronic myeloid leukemia(CML)is a myeloproliferative neoplasm and was the first neoplastic disease associated with a well-defined genotypic anomaly―the presence of the Philadelphia chromosome.The advances in cytogene...Chronic myeloid leukemia(CML)is a myeloproliferative neoplasm and was the first neoplastic disease associated with a well-defined genotypic anomaly―the presence of the Philadelphia chromosome.The advances in cytogenetic and molecular assays are of great importance to the diagnosis,prognosis,treatment,and monitoring of CML.The discovery of the breakpoint cluster region(BCR)-Abelson murine leukemia(ABL)1 fusion oncogene has revolutionized the treatment of CML patients by allowing the development of targeted drugs that inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein.Tyrosine kinase inhibitors(known as TKIs)are the standard therapy for CML and greatly increase the survival rates,despite adverse effects and the odds of residual disease after discontinuation of treatment.As therapeutic alternatives,the subsequent TKIs lead to faster and deeper molecular remissions;however,with the emergence of resistance to these drugs,immunotherapy appears as an alternative,which may have a cure potential in these patients.Against this background,this article aims at providing an overview on CML clinical management and a summary on the main targeted drugs available in that context.展开更多
The acquisition of secondary chromosomal aberrations in chronic myeloid leukemia (CML) patients with Philadelphia chromosome-positive (Ph+) karyotype signifies clonal evolution associated with the progression of the d...The acquisition of secondary chromosomal aberrations in chronic myeloid leukemia (CML) patients with Philadelphia chromosome-positive (Ph+) karyotype signifies clonal evolution associated with the progression of the disease to its accelerated or blastic phase. Therefore, these aberrations have clinical and biological significance. T(3;12)(q26;p13), which is a recurrent chromosomal aberration observed in myeloid malignancies, is typically associated with dysplasia of megakaryocytes, multilineage involvement, short duration of any blastic phase, and extremely poor prognosis. We have identified a recurrent reciprocal translocation between chromosomes 3 and 12 with different breakpoint at bands 3q21 in the malignant cells from a 28-year-old man. The patient was initially diagnosed as having Ph+ CML in the chronic phase. The t(3;12)(q21;p13) translocation occurred 4 years after the patient was first diagnosed with CML while undergoing tyrosine kinase inhibitor therapy. We confirmed the t(3;12)(q21;p13) translocation via fluorescence in situ hybridization assay by using whole-chromosome paint probes for chromosomes 3 and 12. Our findings demonstrate that, similar to other recurrent translocations involving 3q26 such as t(3;3) and t(3;21), the t(3;12)(q21;p13) translocation is implicated not only in myelodysplastic syndrome and acute myeloid leukemia but also in the progression of CML. These findings extend the disease spectrum of this cytogenetic aberration.展开更多
Dasatinib is a second-line tyrosine kinase inhibitor used in patients with imatinib resistant or intolerant chronic myeloid leukemia (CML) and Philadelphia chromosomepositive acute leukemia. Gastrointestinal bleeding ...Dasatinib is a second-line tyrosine kinase inhibitor used in patients with imatinib resistant or intolerant chronic myeloid leukemia (CML) and Philadelphia chromosomepositive acute leukemia. Gastrointestinal bleeding may occur in up to 7% of patients using dasatinib, although, severe dasatinib-related acute colitis had rarely been reported. Here, we present the case of a 36-year-old female who progressed to acute myeloid leukemia after fourteen months of receiving imatinib for CML in the chronic phase and was treated with a dasatinib-containing chemotherapy regimen. On day 34 of treatment, the patient developed moderate abdominal pain and bloody diarrhea with mucous. Analyses of stool specimens were negative for parasites, Clostridium difficile , and other pathogenic bacteria. The cytomegalovirus pp65 antigen was negative in her blood leukocytes. A colonoscopy revealed acute colitis, and a mucosal biopsy showed nonspecific colitis. The patient was treated with broad-spectrum antibiotics, bowel rest and hydration, and dasatinib treatment was stopped. Her bloody diarrhea improved within 72 h. After confirming cytological remission, the patient received initial course of consolidation, and dasatinib treatment was reinstated. However, hemorrhagic colitis recurred. After discontinuing dasatinib, herhemorrhagic colitis drastically improved and did not recur following the administration of nilotinib. The characteristics of our patient suggest that dasatinib treatment can lead to hemorrhagic colitis, which typically resolves after discontinuation of the drug.展开更多
BCR-ABL fusion oncogene originates from the reciprocal translocation of chromosome 9 and 22 t(9;22) (q34;q11). It translates a chimeric protein, p210, characterized by constitutive activation of its tyrosine kinase, w...BCR-ABL fusion oncogene originates from the reciprocal translocation of chromosome 9 and 22 t(9;22) (q34;q11). It translates a chimeric protein, p210, characterized by constitutive activation of its tyrosine kinase, which triggers leukemogenic pathways resulting in onset of chronic myeloid leukemia (CML). In CML, the classic fusion is b2a2 or b3a2 fusing exon 13 (b2) or exon 14 (b3) of BCR to exon 2 (a2) of ABL. The type of bcr/abl transcripts may be associated with different prognosis and hence useful in therapeutic plan. This study was conducted to calculate the frequency of these splice variants as the frequencies of different fusion oncogenes associated with leukaemia can vary in different geographical regions due to interplay of genetic variation in different ethnic populations, diverse environmental factors and living style. A very sensitive nested RT-PCR was established to detect BCR-ABL splice variants in CML. Sensitivity of RT-PCR assay was of the order of 10–6. Thirty CML patients were subjected to BCR-ABL analysis. Out of 30 Pakistani patients, 19 (64%) expressed b3a2 while 11 (36%) expressed b2a2 transcript. This shows that BCR-ABL splice variants differ in their frequencies which may have an effect on biology and implications for prognosis and management of BCR-ABL positive Leukemias.展开更多
Philadelphia chromosome-positive acute myeloid leukemia is controversial and difficult to distinguish from the blast phase of chronic myeloid leukemia. As a myeloid neoplasm, rare cases of this leukemia manifest multi...Philadelphia chromosome-positive acute myeloid leukemia is controversial and difficult to distinguish from the blast phase of chronic myeloid leukemia. As a myeloid neoplasm, rare cases of this leukemia manifest multiple soft-tissue tumors or bone lyric lesions. In this paper, we describe a 49-year-old male patient who had an abrupt onset with sharp chest pain, fever, fatigue, emaciation, and splenomegaly. 18F-fluoro-deoxy-glucose positron emission tomography/computed tomography （18F-FDG PET/CT） result showed diffuse and uneven hypermetabolic lesions in the bone marrow with peripheral bone marrow expansion, multiple soft tissue neoplasms with high 18F-FDG uptake, and lyric bone lesions. Bone marrow smear and biopsy detected aberrant blast cells expressing myeloid rather than lymphoid immunophenotype marker. For the existence of Philadelphia chromosome and BCR-ABL1 fusion gene together with complex chromosome abnormalities, a diagnosis of Philadelphia-positive acute myeloid leukemia was made, although the type （de novo or blast crisis） remained unclear.展开更多
Background: Acute lymphoblastic leukemia (ALL) is a hematologic malignancy which results from accumulation of lymphoid progenitor cells in the bone marrow and/or extramedullary sites. Philadelphia chromosome (Ph1) pos...Background: Acute lymphoblastic leukemia (ALL) is a hematologic malignancy which results from accumulation of lymphoid progenitor cells in the bone marrow and/or extramedullary sites. Philadelphia chromosome (Ph1) positive ALL, a high-risk cytogenetic subset, accounts for 25% - 30% of adult ALL cases but occurs in less than 5% of children. We aimed with this study to detect BCR-ABL genes fusion, amplification and deletion in ALL patients, using extrasignal-fluorescence in situ hybridization (ES-FISH), and to assess their relation with other standard prognostic factors and therapeutic response. Patients and Methods: This study was carried out on 39 newly diagnosed ALL patients. All patients were subjected to: history, clinical examination and laboratory investigations, which included complete blood count (CBC), peripheral blood (PB), bone marrow (BM) examination, immunophenotyping and fluorescence in situ hybridization using extra-signal probe to detect BCR-ABL genes fusion. Results: This study showed statistical analysis of patients’ t(9;22) with other factors revealed, significant association (p 35 years, hepatosplenomegaly, absence of lymphadenopathy, TLC ≥ 50 × 109/L, absolute PB blasts ≥ 4.4 × 109/L, immunophenotyping and other aberrations. Conclusion: BCR/ABL fusion gene analysis by ES-FISH may serve as a prognostic marker in adulthood ALL. The age, TLC and t(9;22) represent the significant standard prognostic factors in relation to patients’ outcome.展开更多
The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Phila?delphia chromosome(Ph) and is a hallmark of chronic myeloid leukemia(CML).In leukemia cells,Ph not only...The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Phila?delphia chromosome(Ph) and is a hallmark of chronic myeloid leukemia(CML).In leukemia cells,Ph not only impairs the physiological signaling pathways but also disrupts genomic stability.This aberrant fusion gene encodes the breakpoint cluster region?proto?oncogene tyrosine?protein kinase(BCR?ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity.The kinase activity is responsible for maintaining proliferation,inhibiting differentia?tion,and conferring resistance to cell death.During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase,the expression patterns of different BCR?ABL1 transcripts vary.Each BCR?ABL1 transcript is present in a distinct leukemia phenotype,which predicts both response to therapy and clinical outcome.Besides CML,the Ph is found in acute lymphoblastic leukemia,acute myeloid leukemia,and mixed?phenotype acute leukemia.Here,we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph?positive leukemia and highlight key findings regarding leukemogenesis.展开更多
文摘Background and Objectives: Chronic myeloid leukemia (CML) accounts for approximately 15% of newly diagnosed cases of leukemia in adults. In this study, the efficacy of nilotinib at 400 mg BID is compared with imatinib at 400 mg BID in CML patients with suboptimal molecular response after at least 12 months of daily dose 400 mg of imatinib therapy. Patients and Methods: This study included a total number of 50 patients, divided into two groups (25 patients each). The first group (Group I): Patients received imatinib at 400 mg BID, second group (Group II): Patients had a suboptimal molecular response to imatinib and received nilotinib at 400 mg BID in early chronic phase. During the two years period of data collection, the primary end included median survival. The secondary end included response rate, type of response, duration of response and progression free survival. Also side effects were recorded. Patients were followed up every month by complete and differential blood counts, liver function test, renal function test and (PCR) every three months for two year. Results: Nilotinib group had significantly higher frequency of major molecular response (MMR) where 23 (92%) patients achieved it while only 16 (64%) patients in Imatinib group achieved MMR (P = 0.01). Nilotinib had better toxicities profile than Imatinib. Conclusion: Both Nilotinib and high dose Imatinib achieved response in CML patients with suboptimal response with rapid and deeper molecular response, better survival outcomes and less side effects in nilotinib.
文摘Chronic myeloid leukemia(CML)is a myeloproliferative neoplasm and was the first neoplastic disease associated with a well-defined genotypic anomaly―the presence of the Philadelphia chromosome.The advances in cytogenetic and molecular assays are of great importance to the diagnosis,prognosis,treatment,and monitoring of CML.The discovery of the breakpoint cluster region(BCR)-Abelson murine leukemia(ABL)1 fusion oncogene has revolutionized the treatment of CML patients by allowing the development of targeted drugs that inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein.Tyrosine kinase inhibitors(known as TKIs)are the standard therapy for CML and greatly increase the survival rates,despite adverse effects and the odds of residual disease after discontinuation of treatment.As therapeutic alternatives,the subsequent TKIs lead to faster and deeper molecular remissions;however,with the emergence of resistance to these drugs,immunotherapy appears as an alternative,which may have a cure potential in these patients.Against this background,this article aims at providing an overview on CML clinical management and a summary on the main targeted drugs available in that context.
文摘The acquisition of secondary chromosomal aberrations in chronic myeloid leukemia (CML) patients with Philadelphia chromosome-positive (Ph+) karyotype signifies clonal evolution associated with the progression of the disease to its accelerated or blastic phase. Therefore, these aberrations have clinical and biological significance. T(3;12)(q26;p13), which is a recurrent chromosomal aberration observed in myeloid malignancies, is typically associated with dysplasia of megakaryocytes, multilineage involvement, short duration of any blastic phase, and extremely poor prognosis. We have identified a recurrent reciprocal translocation between chromosomes 3 and 12 with different breakpoint at bands 3q21 in the malignant cells from a 28-year-old man. The patient was initially diagnosed as having Ph+ CML in the chronic phase. The t(3;12)(q21;p13) translocation occurred 4 years after the patient was first diagnosed with CML while undergoing tyrosine kinase inhibitor therapy. We confirmed the t(3;12)(q21;p13) translocation via fluorescence in situ hybridization assay by using whole-chromosome paint probes for chromosomes 3 and 12. Our findings demonstrate that, similar to other recurrent translocations involving 3q26 such as t(3;3) and t(3;21), the t(3;12)(q21;p13) translocation is implicated not only in myelodysplastic syndrome and acute myeloid leukemia but also in the progression of CML. These findings extend the disease spectrum of this cytogenetic aberration.
文摘Dasatinib is a second-line tyrosine kinase inhibitor used in patients with imatinib resistant or intolerant chronic myeloid leukemia (CML) and Philadelphia chromosomepositive acute leukemia. Gastrointestinal bleeding may occur in up to 7% of patients using dasatinib, although, severe dasatinib-related acute colitis had rarely been reported. Here, we present the case of a 36-year-old female who progressed to acute myeloid leukemia after fourteen months of receiving imatinib for CML in the chronic phase and was treated with a dasatinib-containing chemotherapy regimen. On day 34 of treatment, the patient developed moderate abdominal pain and bloody diarrhea with mucous. Analyses of stool specimens were negative for parasites, Clostridium difficile , and other pathogenic bacteria. The cytomegalovirus pp65 antigen was negative in her blood leukocytes. A colonoscopy revealed acute colitis, and a mucosal biopsy showed nonspecific colitis. The patient was treated with broad-spectrum antibiotics, bowel rest and hydration, and dasatinib treatment was stopped. Her bloody diarrhea improved within 72 h. After confirming cytological remission, the patient received initial course of consolidation, and dasatinib treatment was reinstated. However, hemorrhagic colitis recurred. After discontinuing dasatinib, herhemorrhagic colitis drastically improved and did not recur following the administration of nilotinib. The characteristics of our patient suggest that dasatinib treatment can lead to hemorrhagic colitis, which typically resolves after discontinuation of the drug.
文摘BCR-ABL fusion oncogene originates from the reciprocal translocation of chromosome 9 and 22 t(9;22) (q34;q11). It translates a chimeric protein, p210, characterized by constitutive activation of its tyrosine kinase, which triggers leukemogenic pathways resulting in onset of chronic myeloid leukemia (CML). In CML, the classic fusion is b2a2 or b3a2 fusing exon 13 (b2) or exon 14 (b3) of BCR to exon 2 (a2) of ABL. The type of bcr/abl transcripts may be associated with different prognosis and hence useful in therapeutic plan. This study was conducted to calculate the frequency of these splice variants as the frequencies of different fusion oncogenes associated with leukaemia can vary in different geographical regions due to interplay of genetic variation in different ethnic populations, diverse environmental factors and living style. A very sensitive nested RT-PCR was established to detect BCR-ABL splice variants in CML. Sensitivity of RT-PCR assay was of the order of 10–6. Thirty CML patients were subjected to BCR-ABL analysis. Out of 30 Pakistani patients, 19 (64%) expressed b3a2 while 11 (36%) expressed b2a2 transcript. This shows that BCR-ABL splice variants differ in their frequencies which may have an effect on biology and implications for prognosis and management of BCR-ABL positive Leukemias.
文摘Philadelphia chromosome-positive acute myeloid leukemia is controversial and difficult to distinguish from the blast phase of chronic myeloid leukemia. As a myeloid neoplasm, rare cases of this leukemia manifest multiple soft-tissue tumors or bone lyric lesions. In this paper, we describe a 49-year-old male patient who had an abrupt onset with sharp chest pain, fever, fatigue, emaciation, and splenomegaly. 18F-fluoro-deoxy-glucose positron emission tomography/computed tomography （18F-FDG PET/CT） result showed diffuse and uneven hypermetabolic lesions in the bone marrow with peripheral bone marrow expansion, multiple soft tissue neoplasms with high 18F-FDG uptake, and lyric bone lesions. Bone marrow smear and biopsy detected aberrant blast cells expressing myeloid rather than lymphoid immunophenotype marker. For the existence of Philadelphia chromosome and BCR-ABL1 fusion gene together with complex chromosome abnormalities, a diagnosis of Philadelphia-positive acute myeloid leukemia was made, although the type （de novo or blast crisis） remained unclear.
文摘Background: Acute lymphoblastic leukemia (ALL) is a hematologic malignancy which results from accumulation of lymphoid progenitor cells in the bone marrow and/or extramedullary sites. Philadelphia chromosome (Ph1) positive ALL, a high-risk cytogenetic subset, accounts for 25% - 30% of adult ALL cases but occurs in less than 5% of children. We aimed with this study to detect BCR-ABL genes fusion, amplification and deletion in ALL patients, using extrasignal-fluorescence in situ hybridization (ES-FISH), and to assess their relation with other standard prognostic factors and therapeutic response. Patients and Methods: This study was carried out on 39 newly diagnosed ALL patients. All patients were subjected to: history, clinical examination and laboratory investigations, which included complete blood count (CBC), peripheral blood (PB), bone marrow (BM) examination, immunophenotyping and fluorescence in situ hybridization using extra-signal probe to detect BCR-ABL genes fusion. Results: This study showed statistical analysis of patients’ t(9;22) with other factors revealed, significant association (p 35 years, hepatosplenomegaly, absence of lymphadenopathy, TLC ≥ 50 × 109/L, absolute PB blasts ≥ 4.4 × 109/L, immunophenotyping and other aberrations. Conclusion: BCR/ABL fusion gene analysis by ES-FISH may serve as a prognostic marker in adulthood ALL. The age, TLC and t(9;22) represent the significant standard prognostic factors in relation to patients’ outcome.
基金supported by the China Central Budget Recruitment Program of High?Level Overseas Talent (GDW 201221022066 to Q.Liu)the National Basic Research Program of China (973 Program:No.2012CB967000 to Q.Liu)+2 种基金the National Natural Science Foundation of China (NNSF No.81130040 to Q.Liu and No.81201686 to J.Xu)the Program for Changjiang Scholars and Innovative Research Team in Universities (ITR 13049 to Q.Liu)the Liaoning (NSF 2014029102 to Q.Liu)
文摘The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Phila?delphia chromosome(Ph) and is a hallmark of chronic myeloid leukemia(CML).In leukemia cells,Ph not only impairs the physiological signaling pathways but also disrupts genomic stability.This aberrant fusion gene encodes the breakpoint cluster region?proto?oncogene tyrosine?protein kinase(BCR?ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity.The kinase activity is responsible for maintaining proliferation,inhibiting differentia?tion,and conferring resistance to cell death.During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase,the expression patterns of different BCR?ABL1 transcripts vary.Each BCR?ABL1 transcript is present in a distinct leukemia phenotype,which predicts both response to therapy and clinical outcome.Besides CML,the Ph is found in acute lymphoblastic leukemia,acute myeloid leukemia,and mixed?phenotype acute leukemia.Here,we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph?positive leukemia and highlight key findings regarding leukemogenesis.
