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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In many ways, chronic myeloid leukaemia (CML) serves as a paradigm for the utility of molecular methods in the diagnosis of malignancy or for monitoring the response of the patient to therapy. The Philadelphia (Ph) translocation provides an elegant example of how cytogenetic findings provided the starting point for understanding the genetic mechanisms involved in leukaemogenesis. The degree of reduction in tumour load after therapy is an important prognostic factor for CML patients. Several approaches have been introduced that can specifically detect the Ph translocation or its products; these approaches include fluorescent in situ hybridization, Southern blotting, western blotting and reverse transcriptase polymerase chain reaction (RT-PCR). Because non-quantitative RT-PCR analysis after therapy gives only limited information, quantitative or semiquantitative RT-PCR assays have been developed that enable the kinetics of residual BCR-ABL transcripts to be monitored over time in patients after allogeneic stem cell transplantation, interferon-alpha, or STI571 therapy.
Best Pract Res Clin Haematol 2002 Mar
PMID:Minimal residual disease in chronic myeloid leukaemia patients. 1198 22

Hematological malignancies are phenotypically organized into lymphoid and myeloid disorders, although such a distinction might not be precise from the standpoint of lineage clonality. In turn, myeloid malignancies are broadly categorized into either acute myeloid leukemia (AML) or chronic myeloid disorder (CMD), depending on the presence or absence, respectively, of AML-defining cytomorphologic and cytogenetic features. The CMD are traditionally classified by their morphologic appearances into discrete clinicopathologic entities based primarily on subjective technologies. It has now become evident that most CMD represent clonal stem cell processes where the primary oncogenic event has been characterized in certain instances; Bcr/Abl in chronic myeloid leukemia, FIP1L1-PDGFRA or c-kit(D816V) in systemic mastocytosis, rearrangements of PDGFRB in chronic eosinophilic leukemia, and rearrangements of FGFR1 in stem cell leukemia/lymphoma syndrome. In addition, Bcr/Abl-negative classic myeloproliferative disorders are characterized by recurrent JAK2(V617F) mutations, whereas other mutations affecting the RAS signaling pathway molecules have been associated with juvenile myelomonocytic leukemia. Such progress is paving the way for a transition from a histologic to a semi-molecular classification system that preserves conventional terminology, while incorporating new information on molecular pathogenesis.
Best Pract Res Clin Haematol 2006
PMID:Classification of chronic myeloid disorders: from Dameshek towards a semi-molecular system. 1678 78

Donor leukocyte infusion (DLI) provides direct and potent graft-versus-leukemia (GVL) activity to treat relapse after allogeneic stem-cell transplantation. DLI is dramatically effective for relapsed chronic myelogenous leukemia (CML), but has been less effective for relapse of other myeloid malignancies. Nevertheless, most recipients of DLI for relapsed CML, and many patients with relapsed acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), will experience prolonged remissions and probable cure. Graft-versus-host disease remains the major complication of DLI. New strategies for GVL induction explore novel dosing regimens and both methods of enhancing GVL activity of donor T cells and of minimizing toxicity from graft-versus-host disease. Ultimately, the identification of the effector cells and target antigens for GVL induction will lead to the use of tumor-specific adoptive immunotherapy to both prevent and treat relapse with minimal toxicity. Although many issues remain unsettled, the potential to harness the graft-versus-leukemia activity of allogeneic donor cells provides a powerful new paradigm for the immunotherapy of cancer.
Best Pract Res Clin Haematol 2006
PMID:Donor leukocyte infusions in myeloid malignancies: new strategies. 1699 80

In 1951, William Dameshek speculated on the common origin of the chronic myeloproliferative disorders--polycythemia vera (PV), essential thrombocythemia (ET), chronic idiopathic myelofibrosis (IMF), and chronic myelogenous leukemia (CML). Subsequent work suggested that all arose from the hematopoietic stem cell. About 20 years ago the oncogene responsible for CML, bcr-abl, was identified, and more recently the mutant genes that cause hypereosinophilic syndrome and systemic mast cell disorder have been discovered. However, until very recently, the origin of PV, ET, and IMF have defied molecular explanation. In 2005, four separate groups working on tyrosine kinase signal transduction reported a gain-of-function, valine-to-phenyalanine, mutation at position 617 in the JH2 domain of the Janus kinase (JAK) 2 cytoplasmic tyrosine kinase. This mutation requires the presence of the erythropoietin, thrombopoietin, or granulocyte-colony stimulating factor receptor/s for function, the mutation leads to functional hyperactivity and appears responsible for hematopoietic growth factor hypersensitivity, the most characteristic finding in these disorders. Virtually all patients with PV and substantial proportions of those with ET and IMF have now been shown to harbor this mutation. The mutant kinase appears to be a useful diagnostic test for myeloproliferative disorders and may have prognostic value. Future research will undoubtedly focus on the development of specific inhibitors as therapeutic agents as well as answering a number of questions that remain regarding the role of signal intensity, genotypic and phenotypic expression and the possible involvement of additional as yet unidentified mutations in these disorders.
Best Pract Res Clin Haematol 2007 Mar
PMID:The chronic myeloproliferative disorders and mutation of JAK2: Dameshek's 54 year old speculation comes of age. 1733 49

To what degree has targeted therapy succeeded in acute myeloid leukemia (AML)? Targeted therapy has become a buzzword, with its meaning lost from overuse. In chronic myeloid leukemia (CML), gastrointestinal stromal cell tumor, and a small subset of patients with non-small cell lung cancer, a validated target has been identified and a highly specific therapeutic agent has been developed. Targeted therapy generally requires a pathophysiological Achilles heel in a tumor that can be exploited by nontoxic therapy. In most cases, the validated target has been a tyrosine kinase enzyme critical for tumor growth and survival. Are similar "drugable" targets available in AML? While our understanding of the pathophysiology of AML has advanced over the past decade, and some potential targets have been identified, no single agent will likely produce a significant proportion of remissions. On the other hand, nascent attempts with mild success have been achieved, yielding hope that this strategy will bear real fruit in the future.
Best Pract Res Clin Haematol 2007 Mar
PMID:Targeted agents in AML: much more to do. 1733 53

In allogeneic transplantation the donor-recipient sex combination plays a role in outcome. In large retrospective registry studies of several thousands of patients with aplastic anemia, chronic myelocytic leukemia (CML), acute myelocytic leukemia (AML), and multiple myeloma, chronic graft-versus-host disease (cGVHD) was more frequent and transplant-related mortality (TRM) higher in males with a female donor (F-->M) than in other donor-recipient sex combinations. Graft rejection was more frequent in females with a male donor (M-->F) in aplastic anemia, and a graft-versus-tumor effect (GVT) was documented as a reduced relapse rate in F-->M in CML, AML and multiple myeloma. The overall survival was adversely affected in F-->M in aplastic anemia, AML and CML and in M-->F in aplastic anemia. These results support the view that donor T cells specific for male minor histocompatiblity antigens encoded by Y-chromosome genes contribute to GVHD, graft rejection, GVT and survival in sex-mismatched transplants.
Best Pract Res Clin Haematol 2007 Jun
PMID:Risk assessment in haematopoietic stem cell transplantation: impact of donor-recipient sex combination in allogeneic transplantation. 1744 58

Disease relapse is the commonest cause of treatment failure after allogeneic haematopoietic stem-cell transplantation. Adoptive immunotherapy based on donor lymphocyte infusions (DLI) has a prominent role in the management of disease recurrence. Although the highest remission rates are achieved in chronic myeloid leukaemia (CML), encouraging results have also been reported in chronic lymphoproliferative disorders. However, the experience of DLI in CML is not necessarily applicable to the management of lymphoproliferative diseases because of the heterogeneity of the conditioning regimens used in chronic lymphoid malignancies. We will review the role of DLI for different disease types in the context of conventional and reduced-intensity conditioning regimens. The factors influencing response and graft-versus-host disease as well as the optimal cell dose will be discussed. Finally, we will describe the main avenues currently being explored to improve the selectivity and efficacy of DLI.
Best Pract Res Clin Haematol 2007 Jun
PMID:Disease relapse after haematopoietic stem cell transplantation: risk factors and treatment. 1744 64

The success of donor lymphocyte infusion (DLI) in treating chronic myeloid leukaemia that had recurred after allogeneic haematopoietic stem cell transplantation provided direct evidence for the existence of an immunologically mediated graft-vs-leukaemia effect and led to the development of non-myeloablative transplantation. For patients with acute myeloid leukaemia (AML), DLI has been less effective, both as a result of its rapid growth kinetics and its decreased susceptibility to alloimmune-mediated effects. This chapter reviews the historical experience with DLI for AML, both as treatment for and prophylaxis of relapse. New approaches aimed at improving the efficacy of DLI are discussed, including administration of chemotherapy prior to DLI, use of immunomodulatory cytokines to bolster the cytotoxic effector response, priming of donor lymphocytes to recipient tumour antigens ex vivo, and infusions of alloreactive natural killer cells.
Best Pract Res Clin Haematol 2008 Sep
PMID:Donor lymphocyte infusions for acute myeloid leukaemia. 1879 Apr 49

Philadelphia-positive chronic myeloid leukemia (Ph+ CML) patients who are resistant to imatinib are commonly treated with second-generation tyrosine kinase inhibitors (TKIs). Limited data exist on the possible effects of these drugs on subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT).The outcome of 12 imatinib-resistant CML patients treated with dasatinib or nilotinib or both before allo-HSCT, was retrospectively analyzed. Patients were treated with second-generation TKIs for 1-17 months (median, 8). At the time of transplant, 3 patients were in complete cytogenetic response (CCgR), 3 patients in partial cytogenetic response (PCgR) and 6 patients were in less than PCgR. Donors were HLA-matched related in 4 cases and unrelated in 8 cases. Stem cell source was peripheral blood, bone marrow or cord blood in 6, 5 and 1 cases, respectively. All patients engrafted successfully and all but one achieved a full donor chimerism. Three patients experienced acute and chronic graft-versus-host disease. No cases of transplant-related mortality were recorded. Best response to allo-HSCT was complete molecular response (CMR) in 9 patients, major molecular response (MMR) in 1 patient and CCgR in 2 patients. Median follow-up was 16.5 months. At the last evaluation, 9 patients were in continuous CMR and 1 patient was in MMR; 2 patients had died of disease progression. Second-generation TKIs given before allo-HSCT do not negatively affect transplant engraftment and response rate, nor increases transplant-related toxicity.
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PMID:Second-generation tyrosine kinase inhibitors before allogeneic stem cell transplantation in patients with chronic myeloid leukemia resistant to imatinib. 1965 41

The use of microarray technology in chronic myeloid leukaemia (CML) has increased our understanding of the biology of this disease. From early studies of gene expression profiling in BCR-ABL-positive cell lines to samples from patients in different disease phases of CML, using resting cells or cells treated with a variety of therapeutic agents, the field has now moved on to profiling microRNA and single nucleotide polymorphisms of CML cells. With the advent of tyrosine kinase inhibitors, several groups have also attempted to use microarray profiling to ascertain if particular gene expression profiles pre-existing in patients' CML cells, which could reflect intrinsic disease biology, would predict for response to treatment. This could streamline patients for alternative treatments upfront should a poor risk profile be found. In this article, we provide an overview of the progress made so far in this field, and outline the more substantial results of available microarray studies to date.
Best Pract Res Clin Haematol 2009 Jun
PMID:The impact of gene profiling in chronic myeloid leukaemia. 1969 27


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