Exposure of CML Cells to Imatinib Results in the Post-Transcriptional Induction of Manganese Superoxide Dismutase.

Posted by rob on July 22, 2014 under Uncategorized | Comments are off for this article

Exposure of CML Cells to Imatinib Results in the Post-Transcriptional Induction of Manganese Superoxide Dismutase.

Leuk Lymphoma. 2014 Jul 21;:1-13

Authors: Reinke EN, Bera S, Diamond AM

Abstract

ABSTRACT The treatment of chronic myelogenous leukemia with specific tyrosine kinase inhibitors typically results in clinical success although therapeutic failure frequently occurs. In order to investigate the biological consequences of treating CML cells with such drugs, we previously reported that the anti-oxidant selenoprotein GPx-1 was induced by imatinib in both patient samples and cultured cells. Here, we extend these findings to demonstrate that the treatment of CML cell lines, but not non-CML cells, results in the approximately 4-fold increase in the levels of another important anti-oxidant protein, MnSOD without altering the steady state levels of the corresponding transcript.

PMID: 25039350 [PubMed - as supplied by publisher]

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[Chronic myeloid leukemia stem cells: cross-talk with the niche].

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[Chronic myeloid leukemia stem cells: cross-talk with the niche].

Med Sci (Paris). 2014 Apr;30(4):452-61

Authors: Chomel JC, Aggoune D, Sorel N, Turhan AG

Abstract

The physiological hematopoietic niche located in bone marrow is a pluricellular structure whose components are now well identified. Within this microenvironment, hematopoietic stem cells are in direct contact with mesenchymal stromal cells, osteoblasts and sinusoidal endothelial cells. These close relationships drive specialized cellular functions (proliferation/quiescence, differentiation/self-renewal) ensuring an efficient hematopoiesis. Chronic myeloid leukemia (CML) is a major model of leukemic hematopoiesis. The BCR-ABL1 tyrosine kinase, constitutively activated in CML, plays a critical role in the pathogenesis of the disease. An intensive cross-talk between CML progenitors and the components of the hematopoietic niche has recently been demonstrated. Consequently, the occurrence of the so-called leukemic niche promotes both the proliferation of myeloid cells and the maintenance of quiescent leukemic stem cells. This bone marrow niche could also protect CML stem cells from tyrosine kinase inhibitors and probably contribute to their resistance towards targeted therapies.

PMID: 24801043 [PubMed - indexed for MEDLINE]

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Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management.

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Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management.

Am J Hematol. 2014 May;89(5):547-56

Authors: Jabbour E, Kantarjian H

Abstract

DISEASE OVERVIEW: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100,000 adults, and accounts for ?15% of newly diagnosed cases of leukemia in adults.

DIAGNOSIS: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL fusion oncogene, which in turn translates into a Bcr-Abl oncoprotein.

FRONTLINE THERAPY: Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and dasatinib have been approved by the US Food and Drug Administration for the first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses; their impact on long-term survival remains to be determined.

SALVAGE THERAPY: For patients who fail frontline therapy, second-line options include second and third generation TKIs. Although second and third generation TKIs are potent and specific BCR-ABL TKIs, they exhibit unique pharmacological profiles and response patterns relative to different patient characteristics, such as patients comorbidities, disease stage, and BCR-ABL mutational status. Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib. Allogeneic transplantation remains an important therapeutic option for CML-CP who have failed at least 2 TKIs, and for all patients in advanced phase disease.

PMID: 24729196 [PubMed - indexed for MEDLINE]

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Ponatinib: A new tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.

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Ponatinib: A new tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.

Ann Pharmacother. 2013 Nov;47(11):1540-6

Authors: Shamroe CL, Comeau JM

Abstract

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trials, adverse effects, and formulary considerations of ponatinib, a pan-tyrosine kinase inhibitor (TKI).

DATA SOURCES: A literature search of articles published between January 1966 and June 2013 was performed using PubMed with the following search terms: ponatinib, AP24534, and Iclusig. ARIAD Pharmaceuticals, Inc, was contacted for unpublished information. Other sources included American Society of Hematology abstracts, the Food and Drug Administration Center for Drug Evaluation and Research Web site, and clinicaltrials.gov.

STUDY SELECTION/DATA EXTRACTION: Included articles and abstracts were published in English and contain information about ponatinib, particularly in the treatment of chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

DATA SYNTHESIS: Following the phase II PACE trial, ponatinib was approved for the treatment of patients with chronic-phase (CP), accelerated-phase (AP), or blast-phase (BP) CML or Ph+ ALL who have become intolerant or resistant to previous therapy. Unlike other BCR-ABL TKIs, ponatinib was designed to overcome the T315I mutation. At 15.3 months, 46% of patients with CP-CML achieved a complete cytogenetic response, and 34% achieved a major molecular response. Complete hematologic responses occurred in 47% of patients with AP-CML, 21% with BP-CML, and 34% with Ph+ ALL after 1 year. Severe toxicities included myelosuppression, hepatotoxicity, pancreatitis, and arterial thrombosis.

CONCLUSIONS: Ponatinib is a potent TKI that can overcome several resistance mechanisms in previously treated patients with CML and Ph+ ALL. Ponatinib should be reserved for patients who have failed first-line therapy, have the T315I mutation, or have progressed.

PMID: 24265264 [PubMed - indexed for MEDLINE]

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Imatinib-associated melanosis of the palate.

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Imatinib-associated melanosis of the palate.

Am J Hematol. 2014 May;89(5):564

Authors: Roeker LE, Wolanskyj AP

PMID: 24030927 [PubMed - indexed for MEDLINE]

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Prognostic Significance of the Lymphoblastic Leukemia-Derived Sequence 1 (LYL1) GeneExpression in Egyptian Patients with AcuteMyeloid Leukemia.

Posted by rob on July 19, 2014 under Uncategorized | Comments are off for this article

Prognostic Significance of the Lymphoblastic Leukemia-Derived Sequence 1 (LYL1) GeneExpression in Egyptian Patients with AcuteMyeloid Leukemia.

Turk J Haematol. 2014 Jun;31(2):128-35

Authors: El-Menshawy N, Shahin D, Ghazi HF

Abstract

Objective: Aberrant activation of transcription factor genes is the most frequent target of genetic alteration in lymphoid malignancies. The lymphoblastic leukemia-derived sequence 1 (LYL1) gene, which encodes a basic helix-loop helix, was first identified with human T-cell acute leukemia. Recent studies suggest its involvement in myeloid malignancies. We aimed to study the expression percent of oncogene LYL1 in primary and secondary high-risk myeloid leukemia and the impact on prognostic significance in those patients. Materials and Methods: Using quantitative real-time polymerase chain reaction for detection of LYL1 oncogenes, our study was carried out on 39 myeloid leukemia patients including de novo cases, myelodysplastic syndrome (MDS) with transformation, and chronic myelogenous leukemia (CML) in accelerated and blast crisis, in addition to 10 healthy individuals as the reference control. Results: LYL1 expression was increased at least 2 times compared to the controls. The highest expression of this transcription factor was observed in the MDS cases transformed to acute leukemia at 7.3±3.1, p=0.0011. LYL1 expression was found in 68.2%, 75%, and 77.8% of cases of acute myeloid leukemia, CML crisis, and MDS, respectively. Significant correlation of LYL1 overexpression with some subtypes of French-American-British classification was found. There was, for the first time, significant correlation between the blood count at diagnosis and LYL1 expression (p=0.023, 0.002, and 0.031 for white blood cells, hemoglobin, and platelets, respectively). The rate of complete remission was lower with very high levels of LYL1 expression and the risk of relapse increased with higher levels of LYL1 expression, suggesting an unfavorable prognosis for cases with enhanced expression. Conclusion: Overexpression of LYL1 is highly associated with acute myeloid leukemia and shows more expression in MDS with unfavorable prognosis in response to induction chemotherapy. These observations could signal a promising tool for a therapeutic target to basic helix-loop helix protein related to transcription factors, which may improve patient outcome in acute myeloid leukemia, MDS, and CML in blast crisis.

PMID: 25035669 [PubMed]

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Chronic myeloid leukemia patient with co-occurrence of BCR-ABL junction and JAK2 V617F mutation.

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Chronic myeloid leukemia patient with co-occurrence of BCR-ABL junction and JAK2 V617F mutation.

Int J Hematol. 2014 Jan;99(1):87-90

Authors: Xu W, Chen B, Tong X

Abstract

The JAK2 V617F mutation is common in patients with Philadelphia-negative chronic myeloproliferative neoplasms, but few cases of the JAK2 V617F mutation have been described in Philadelphia-positive chronic myeloid leukemia (CML) patients. Here, we report a 21-year-old female who presented with phenotype of CML in whom BCR-ABL transcript and JAK2V617F mutation co-occurred. These findings were determined through cytogenetic analysis, fluorescence in situ hybridization, and allele-specific (AS) PCR. The patient’s BCR-ABL transcript disappeared after 6 months of treatment with imatinib, while the JAK2V617F mutation remained positive. We discuss this case with reference to the current literature.

PMID: 24293258 [PubMed - indexed for MEDLINE]

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Treatment with dasatinib for chronic myeloid leukemia following imatinib-induced hepatotoxicity.

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Treatment with dasatinib for chronic myeloid leukemia following imatinib-induced hepatotoxicity.

Int J Hematol. 2014 Jan;99(1):91-4

Authors: Harbaum L, Marx A, Goekkurt E, Schafhausen P, Atanackovic D

Abstract

Treatment with the tyrosine kinase inhibitor (TKI) imatinib for chronic myeloid leukemia in chronic phase (CML-CP) of disease may cause severe hepatotoxicity in rare cases. However, it remains unclear (1) how imatinib-induced hepatotoxicity should be treated; and (2) if and how TKI treatment can be resumed after recovery. We report a 32-year-old woman with CML-CP and histology confirmed imatinib-induced liver toxicity after 6 months of treatment. In this case, the early administration of corticosteroid therapy resulted in rapid and complete hepatic recovery, and treatment for CML-CP with the second generation TKI dasatinib was continued safely after recovery. Thus, dasatinib represents an option for maintaining therapeutic response in patients in whom continuation of imatinib is not possible due to its hepatic toxicity.

PMID: 24264834 [PubMed - indexed for MEDLINE]

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Similar outcome of patients with chronic myeloid leukemia treated with imatinib in or out of clinical trials.

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Similar outcome of patients with chronic myeloid leukemia treated with imatinib in or out of clinical trials.

Clin Lymphoma Myeloma Leuk. 2013 Dec;13(6):693-9

Authors: Yilmaz M, Kantarjian H, Jabbour E, O’Brien S, Borthakur G, Verstovsek S, Garcia-Manero G, Ravandi F, Burger J, Pierce S, Quintas-Cardama A, Cortes J

Abstract

INTRODUCTION: Outcomes of CML-CP patients treated in clinical trials are frequently perceived to be not representative of those treated outside of clinical trials.

PATIENTS AND METHODS: We investigated the outcomes of patients receiving imatinib outside of a clinical trial (off protocol) or in a clinical trial (on protocol) for CML-CP.

RESULTS: We identified 65 patients treated with imatinib off protocol and 71 patients treated on protocol with standard-dose imatinib. The overall complete cytogenetic response (CCyR) rate was 83% for patients treated on and off protocol. CCyR rates 12 months after initiation of imatinib were not statistically different (61% vs. 66%, respectively; P = .15). Patients treated off protocol had similar rates of overall major molecular response (72% vs. 73%) compared with the patients treated on protocol. The 5-year event-free survival rates were 84% and 86% for off and on protocol patients, respectively. There was also no significant difference in 5-year transformation free survival (94% vs. 96%) and overall survival (96% vs. 90%).

CONCLUSION: These results suggest that patients with CML treated outside of a clinical trial might have the same excellent outcome as those treated in a clinical trial provided they are followed with the same rigor.

PMID: 24060289 [PubMed - indexed for MEDLINE]

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Detection of dormant chronic myeloid leukemia clones in the bone marrow of patients in complete molecular remission.

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Detection of dormant chronic myeloid leukemia clones in the bone marrow of patients in complete molecular remission.

Clin Lymphoma Myeloma Leuk. 2013 Dec;13(6):681-5

Authors: Quintás-Cardama A, Grgurevic S, Rozovski U, Li P, Estrov Z, Cortes J

Abstract

BACKGROUND: Several methods are available to detect MRD in patients with CML in complete molecular remission (CMR) and taking tyrosine kinase inhibitor (TKI) therapy.

MATERIALS AND METHODS: We performed clonogenic assays on mononuclear bone marrow cells from 14 patients. Of the 10 assessable samples, 6 were from patients in CMR and 4 from patients in complete cytogenetic remission but had detectable MRD using polymerase chain reaction (PCR) analysis (positive controls). At least 10 colonies per sample were microaspirated and individual colonies were subjected to PCR analysis.

RESULTS: Of the 6 patients in CMR, 5 harbored breakpoint cluster region abelson (BCR-ABL1) negative colonies but in 1 sample, 1 of the 10 colonies analyzed was positive for BCR-ABL1. Of the 4 patients with evidence of MRD in peripheral blood, 2 had negative and 2 had positive BCR-ABL1 colonies.

CONCLUSION: MRD is still detectable using clonogenic assays in some patients with CML after achieving CMR using TKI therapy, which is likely responsible for relapse on TKI discontinuation. Because of the large number of single colonies that need to be analyzed, the use of clonogenic assays in clinical practice to determine the feasibility of TKI discontinuation is not recommended.

PMID: 24060288 [PubMed - indexed for MEDLINE]

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The one-two punch: combination treatment in chronic myeloid leukemia.

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The one-two punch: combination treatment in chronic myeloid leukemia.

Crit Rev Oncol Hematol. 2013 Dec;88(3):667-79

Authors: Sweet KL, Hazlehurst LA, Pinilla-Ibarz J

Abstract

Despite the success of tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML), minimal residual disease persists, requiring indefinite treatment. Accumulated evidence has shown that leukemic stem cells (LSCs) in the bone marrow can survive TKI treatment via downstream BCR-ABL1-independent signaling pathways that are activated by soluble growth factors and interactions with the extracellular matrix in the bone marrow microenvironment. Research efforts have therefore turned to the identification and development of agents that target LSCs, and together with TKIs, have the potential to eradicate CML. A number of such agents are now under clinical investigation, and others are soon to enter early-phase studies. This review examines the pathways, molecular targets, and potential new therapeutics that, with TKIs, may provide an effective “one-two punch” to cure CML.

PMID: 23969231 [PubMed - indexed for MEDLINE]

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Use of tyrosine kinase inhibitors in a patient with Brugada syndrome and chronic myeloid leukemia.

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Use of tyrosine kinase inhibitors in a patient with Brugada syndrome and chronic myeloid leukemia.

Int J Hematol. 2013 Oct;98(4):483-6

Authors: Sgherza N, Russo Rossi AV, Colonna P, Carluccio P, Delia M, Specchia G

Abstract

The treatment and prognosis of chronic myeloid leukemia have dramatically changed since the introduction of tyrosine kinase inhibitors, but although several clinical trials have examined their safety with respect to heart function, no data are yet available about the use of these drugs in patients with Brugada syndrome. We report a case of Brugada syndrome diagnosed during tyrosine kinase inhibitor therapy in a 69-year-old Caucasian male with meningioma and chronic myeloid leukemia. This case report highlights the importance of an integrated approach among hematologists and cardiologists to ensure appropriate treatment with tyrosine kinase inhibitors in patients affected by chronic myeloid leukemia who also suffer from Brugada syndrome.

PMID: 23881644 [PubMed - indexed for MEDLINE]

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Stem cell maintenance and disease progression in chronic myeloid leukemia.

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Stem cell maintenance and disease progression in chronic myeloid leukemia.

Int J Hematol. 2013 Dec;98(6):641-7

Authors: Ito T

Abstract

Chronic myeloid leukemia (CML) is a cancer of blood cells driven by the BCR-ABL1 oncogenic protein tyrosine kinase, which is the product of a reciprocal chromosomal translocation known as the Philadelphia chromosome. Discovery of tyrosine kinase inhibitors targeting the BCR-ABL1 kinase revolutionized CML therapy, but these drugs are unable to eradicate the disease due to the presence of a drug-insensitive stem cell population that sustains continued growth of the malignant cells. Resistance to therapies also increases the risk of relapse and disease progression to a more advanced phase. This review discusses emerging issues in CML research, and describes recent progress in elucidating the mechanisms of CML stem cell maintenance and disease progression.

PMID: 23550022 [PubMed - indexed for MEDLINE]

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Bosutinib: a novel src/abl kinase inhibitor for chronic myelogenous leukemia.

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Bosutinib: a novel src/abl kinase inhibitor for chronic myelogenous leukemia.

J Adv Pract Oncol. 2013 Nov;4(6):451-5

Authors: Steinbach A, Clark SM, Clemmons AB

PMID: 25032026 [PubMed]

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Omacetaxine mepesuccinate: a new treatment option for patients with chronic myelogenous leukemia.

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Omacetaxine mepesuccinate: a new treatment option for patients with chronic myelogenous leukemia.

J Adv Pract Oncol. 2013 Jul;4(4):257-62

Authors: Kurtin SE, Matta L

PMID: 25032006 [PubMed]

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Pathologic rupture of the spleen in a patient with acute myelogenous leukemia and leukostasis.

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Pathologic rupture of the spleen in a patient with acute myelogenous leukemia and leukostasis.

Rev Bras Hematol Hemoter. 2014 Jul-Aug;36(4):290-2

Authors: De Santis GC, Oliveira LC, Ramos AF, da Silva ND, Falcão RP

Abstract

Rupture of the spleen can be classified as spontaneous, traumatic, or pathologic. Pathologic rupture has been reported in infectious diseases such as infectious mononucleosis, and hematologic malignancies such as acute and chronic leukemias. Splenomegaly is considered the most relevant factor that predisposes to splenic rupture. A 66-year-old man with acute myeloid leukemia evolved from an unclassified myeloproliferative neoplasm, complaining of fatigue and mild upper left abdominal pain. He was pale and presented fever and tachypnea. Laboratory analyses showed hemoglobin 8.3g/dL, white blood cell count 278×10(9)/L, platelet count 367×10(9)/L, activated partial thromboplastin time (aPTT) ratio 2.10, and international normalized ratio (INR) 1.60. A blood smear showed 62% of myeloblasts. The immunophenotype of the blasts was positive for CD117, HLA-DR, CD13, CD56, CD64, CD11c and CD14. Lactate dehydrogenase was 2384U/L and creatinine 2.4mg/dL (normal range: 0.7-1.6mg/dL). Two sessions of leukapheresis were performed. At the end of the second session, the patient presented hemodynamic instability that culminated in circulatory shock and death. The post-mortem examination revealed infiltration of the vessels of the lungs, heart, and liver, and massive infiltration of the spleen by leukemic blasts. Blood volume in the peritoneal cavity was 500mL. Acute leukemia is a rare cause of splenic rupture. Male gender, old age and splenomegaly are factors associated with this condition. As the patient had leukostasis, we hypothesize that this, associated with other factors such as lung and heart leukemic infiltration, had a role in inducing splenic rupture. Finally, we do not believe that leukapheresis in itself contributed to splenic rupture, as it is essentially atraumatic.

PMID: 25031169 [PubMed]

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Synthesis and anticancer effects of some novel 2-(4-phenoxyphenyl)-1H-benzimidazole derivatives on K562 cell line.

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Synthesis and anticancer effects of some novel 2-(4-phenoxyphenyl)-1H-benzimidazole derivatives on K562 cell line.

Arch Pharm Res. 2014 Jul 18;

Authors: Gurkan-Alp AS, Göker H, Alp M, Ozkan T, Sunguroglu A

Abstract

A series of novel 2-(4-phenoxyphenyl)-1H-benzimidazole derivatives was synthesized and tested in vitro on human chronic myelogenous leukemia (CML) cell line K562. Benzimidazoles containing 5-amidino (10), 5-N-isopropylamidino (11), 5-bromo (13), and 5,6-dimethyl (14) derivatives exhibited remarkable cytotoxic activity. The quantitative analysis of apoptosis by flow-cytometry demonstrated that the percentages of early and late apoptotic K562 cells treated with these compounds were significantly higher than cells without treatment. We also investigated the effects of these compounds on the expression of apoptosis-related genes BAX, BCL-2, BAD and BIM. Treatment of K562 cells wih compounds 10-14 significantly increased the expression levels of the proapoptotic genes BAX, BAD and BIM, whereas compound 20 increased BAX and BAD.

PMID: 25030856 [PubMed - as supplied by publisher]

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[Early monitoring of BCR-ABL transcript levels and cytogenetic in assessing the prognosis of chronic myeloid leukemia].

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[Early monitoring of BCR-ABL transcript levels and cytogenetic in assessing the prognosis of chronic myeloid leukemia].

Zhonghua Yi Xue Za Zhi. 2013 Oct 15;93(38):3049-53

Authors: Huang Q, Zhang XY, Li Y, Wang XM

Abstract

OBJECTIVE: To explore the prognostic significance of early monitoring of BCR-ABL transcript levels and cytogenetic evaluations for chronic myeloid leukemia in chronic phase (CML-CP).

METHODS: From July 2007 to May 2012, 56 CML-CP patients received oral imatinib 400 mg/d. The BCR-ABL transcript levels were monitored and cytogenetic examinations performed after 3 and 6 months respectively. The median follow-up time was 48 months.

RESULTS: The 3-month BCR-ABL transcript levels ? 10% of patients 5-year overall survival (OS) and progression-free survival (PFS) were better than BCR-ABL transcript levels >10% of patients (OS: 100% vs 84.6%, P = 0.011; PFS: 94.6% vs 67.7%, P = 0.045); cytogenetics: Ph(+) ? 35 % of patients 5-year OS and PFS better than Ph(+) > 35% of patients (OS: 100% vs 76.2%, P = 0.001; PFS: 95.2% vs 38.1%, P = 0.001); the 6-month BCR-ABL transcripts level ? 1% of patients 5-year OS and PFS also better than BCR-ABL transcript levels> 1% of patients (OS: 100% vs 71.4%, P = 0.000; PFS: 95.2% vs 47.6%, P = 0.001); Ph(+) = 0% and Ph(+)> 0% patients, 5-year OS and PFS were significantly different (OS: 100% vs 68.6%, P = 0.000; PFS: 95.3% vs 45.7%, P = 0.000).

CONCLUSIONS: Early molecular biology and cytogenetics monitoring have some significance in the prognostic assessment of CML-CP. And individualized treatment strategies should be based upon the monitoring results in conjunctions with comprehensive judgments.

PMID: 24417926 [PubMed - indexed for MEDLINE]

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[Treatment efficacy of imatinib mesylate versus allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia in chronic phase].

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[Treatment efficacy of imatinib mesylate versus allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia in chronic phase].

Zhonghua Yi Xue Za Zhi. 2013 Oct 15;93(38):3035-9

Authors: Gao GL, Xu N, Zhou X, Xiao YJ, Ding L, Lu QS, Wei YQ, Zhang Y, Xu D, Sun J, Liu QF, Liu XL

Abstract

OBJECTIVE: To compare the treatment efficacy of imatinib mesylate versus allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with chronic myeloid leukemia in chronic phase.

METHODS: The efficacy, overall survival, progression-free survival and adverse events were evaluated in 198 patients on these two therapies from February 2002 to December 2012 at our hospital. One hundred and fifteen cases in imatinib group (n = 115) received imatinib at an initial daily dose of 400 mg and then dose was adjusted according to blood routine test and therapy response. All patients were evaluated for hematologic, cytogenetic and molecular responses every 1-3 months. The allo-HSCT group (n = 83) received myeloablative preconditioning regimen and methotrexate (MTX) and cyclosporine A (CsA) were used for graft-versus-host disease (GVHD) partially plus mycophenolate mofetil (MMF) and antihuman thymocyte globulin (ATG). The engraftment evidence and evolution of cytogenetic and molecular response was conventionally detected after allo-HSCT.

RESULTS: In imatinib group, 59 of 86 (68.6%) cases achieved complete cytogenetic response (CCyR) in the 12 months after therapy, while 67 of 70 (95.7%) cases achieved CCyR in allo-HSCT group. The relapse rates of two groups were 14.8% (17/115) , 12.3% (10/81) respectively. The adverse reaction of imatinib in imatinib group was obviously much more tolerable for patients compared with frequently occurred GVHD and infection in allo-HSCT group. The 10-year cumulative overall survival (OS) rate was 93.9% in imatinib group and 77.1% in allo-HSCT group (P = 0.015). And the 10-year cumulative progression-free survival (PFS) rate was 86.1% in imatinib group versus 88.0% in allo-HSCT group (P = 0.508) . For Sokal rating stratified analysis, the cumulative OS rates of two groups were 96.4% and 68.0% (P = 0.049) for intermediate-risk patients, 92.6% and 57.1% (P = 0.017) for high-risk patients while the cumulative PFS rates of two groups were 89.3% and 88.0% for intermediate-risk patients (P = 0.942), 70.4% and 85.7% for high-risk patients (P = 0.405). The rates of OS and PFS were not significantly different for low-risk patients. The cumulative OS rates of two groups were 94.7% and 73.5% (P = 0.009) for those ? 30 years old and the cumulative PFS rates of two groups 84.2% and 94.1% respectively (P = 0.147).

CONCLUSION: Imatinib mesylate is superior to allo-HSCT for patients with chronic myeloid leukemia in chronic phase.

PMID: 24417923 [PubMed - indexed for MEDLINE]

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The prognostic significance of an inv(3)(q21q26.2) in addition to a t(9;22)(q34;q11.2) in patients treated with tyrosine kinase inhibitors.

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The prognostic significance of an inv(3)(q21q26.2) in addition to a t(9;22)(q34;q11.2) in patients treated with tyrosine kinase inhibitors.

Cancer Genet. 2014 May 21;

Authors: Theil KS, Cotta CV

Abstract

In chronic myelogenous leukemia, BCR-ABL1 positive detection of cytogenetic abnormalities in addition to the t(9;22) is thought to portend a poor prognosis; however, not all abnormalities associated with the t(9;22) have the same impact. Inv(3) defines a group of aggressive neoplasms with poor response to conventional treatment options. In this study, four cases with the t(9;22) and inv(3) treated with tyrosine kinase inhibitors (TKI) were investigated. In three cases, the inv(3) was not detected at the initial diagnosis and the patients initially responded to TKI therapy; the inv(3) was detected at blast crisis in all three cases, and one case had both abnormalities at the initial presentation, but this case presented as acute myeloid leukemia. In all cases, detection of an inv(3) was associated with a high blast count and a lack of response to treatment regimens including TKI. All patients died within months from the detection of inv(3). This indicates that cases with the t(9;22) and inv(3) have a clinical course similar to that of cases with an inv(3) and no other therapeutically targetable abnormality.

PMID: 25027637 [PubMed - as supplied by publisher]

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