Combined population dynamics and entropy modelling supports patient stratification in chronic myeloid leukemia

Modelling the parameters of multistep carcinogenesis is key for a better understanding of cancer progression, biomarker identification and the design of individualized therapies. Using chronic myeloid leukemia (CML) as a paradigm for hierarchical disease evolution we show that combined population dynamic modelling and CML patient biopsy genomic analysis enables patient stratification at unprecedented resolution. Linking CD34+ similarity as a disease progression marker to patientderived gene expression entropy separated established CML progression stages and uncovered additional heterogeneity within disease stages. Importantly, our patient data informed model enables quantitative approximation of individual patients’ disease history within chronic phase (CP) and significantly separates “early” from “late” CP. Our findings provide a novel rationale for personalized and genome-informed disease progression risk assessment that is independent and complementary to conventional measures of CML disease burden and prognosis

Management of Chronic Myeloid Leukemia in Advanced Phase

Management of chronic myeloid leukemia (CML) in advanced phases remains a challenge also in the era of tyrosine kinase inhibitors (TKIs) treatment. Cytogenetic clonal evolution and development of resistant mutations represent crucial events that limit the benefit of subsequent therapies in these patients. CML is diagnosed in accelerated (AP) or blast phase (BP) in <5% of patients, and the availability of effective treatments for chronic phase (CP) has dramatically reduced progressions on therapy. Due to smaller number of patients, few randomized studies are available in this setting and evidences are limited. Nevertheless, three main scenarios may be drawn: (a) patients diagnosed in AP are at higher risk of failure as compared to CP patients, but if they achieve optimal responses with frontline TKI treatment their outcome may be similarly favorable; (b) patients diagnosed in BP may be treated with TKI alone or with TKI together with conventional chemotherapy regimens, and subsequent transplant decisions should rely on kinetics of response and individual transplant risk; (c) patients in CP progressing under TKI treatment represent the most challenging population and they should be treated with alternative TKI according to the mutational profile, optional chemotherapy in BP patients, and transplant should be considered in suitable cases after return to second CP. Due to lack of validated and reliable markers to predict blast crisis and the still unsatisfactory results of treatments in this setting, prevention of progression by careful selection of frontline treatment in CP and early treatment intensification in non-optimal responders remains the main goal. Personalized evaluation of response kinetics could help in identifying patients at risk for progression

Unlocking the potential of anti-CD33 therapy in adult and childhood acute myeloid leukaemia

Acute Myeloid Leukaemia (AML) develops when there is a block in differentiation and uncontrolled proliferation of myeloid precursors, resulting in bone marrow failure. AML is a heterogeneous disease clinically, morphologically, and genetically, and biological differences between adult and childhood AML have been identified. AML comprises 15-20% of all children less than fifteen years diagnosed with acute leukaemia. Relapse occurs in up to 40% of children with AML and is the commonest cause of death.1,2 Relapse arises from leukaemic stem cells (LSCs) that persist after conventional chemotherapy. The treatment of AML is challenging and new strategies to target LSCs are required. The cell surface marker CD33 has been identified as a therapeutic target, and novel anti-CD33 immunotherapies are promising new agents in the treatment of AML. This review will summarise recent developments emphasising the genetic differences in adult and childhood AML, while highlighting the rationale for CD33 as a target for therapy, in all age groups

Cytogenetic and molecular studies in chronic myeloid leukaemia

Imperial Users onl

A Novel murine model identifies cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression

The introduction of highly selective ABL-tyrosine kinase inhibitors (TKIs) has revolutionized therapy for chronic myeloid leukemia (CML). However, TKIs are only efficacious in the chronic phase of the disease and effective therapies for TKI-refractory CML, or after progression to blast crisis (BC), are lacking. Whereas the chronic phase of CML is dependent on BCR-ABL, additional mutations are required for progression to BC. However, the identity of these mutations and the pathways they affect are poorly understood, hampering our ability to identify therapeutic targets and improve outcomes. Here, we describe a novel mouse model that allows identification of mechanisms of BC progression in an unbiased and tractable manner, using transposon-based insertional mutagenesis on the background of chronic phase CML. Our BC model is the first to faithfully recapitulate the phenotype, cellular and molecular biology of human CML progression. We report a heterogeneous and unique pattern of insertions identifying known and novel candidate genes and demonstrate that these pathways drive disease progression and provide potential targets for novel therapeutic strategies. Our model greatly informs the biology of CML progression and provides a potent resource for the development of candidate therapies to improve the dismal outcomes in this highly aggressive disease.Work in the Huntly laboratory is funded by CRUK, The European Research Council (ERC), Leukaemia Lymphoma Research, the Kay Kendall Leukaemia Fund, Wellcome Trust, the Medical Research Council (UK), the Leukemia Lymphoma Society America and the Cambridge NIHR Biomedical Research centre. David Adams is funded by Cancer Research UK and Wellcome Trust. Steffen Koschmieder has received funding from Deutsche José Carreras Leukämie-Stiftung (DJCLS; grant 10/23).This is the final published version. It first appeared at http://dx.doi.org/10.1084/jem.2014166

Myeloid Leukemia

This book comprises a series of chapters from experts in the field of diagnosis and treatment of myeloid leukemias from all over the world, including America, Europe, Africa and Asia. It contains both reviews on clinical aspects of acute (AML) and chronic myeloid leukemias (CML) and original publications covering specific clinical aspects of these important diseases. Covering the specifics of myeloid leukemia epidemiology, diagnosis, risk stratification and management by authors from different parts of the world, this book will be of interest to experienced hematologists as well as physicians in training and students from all around the globe

Chronic Myeloid Leukaemia in Advanced Phase: An Analytical Evaluation

Objective: To evaluate the clinical and morphological features in advanced phase chronic myeloid leukaemia. Methods: This descriptive observational study was conducted at the Pathology Unit of Fauji Foundation Hospital, Rawalpindi from June 2012 till June 2016. Diagnosed patients of chronic myeloid leukaemia in accelerated and blast phase of the disease were included in the study. History was taken, physical examination, complete blood counts, peripheral blood film examination, and bone marrow biopsy was done. Results: Mean age in the advanced phase was 47 years. Female to male ratio was 5:1. 19 patients were in blast phase ; 14( 74%) in myeloid transformation, 4(21%) patients in lymphoblastic transformation and 1(05%) patient transformed into acute biphenotypic leukaemia showing both lymphoid and myeloid markers. Forty six patients were in accelerated phase. Conclusion: There is usually not a single criterion for transition into accelerated phase but certain variables coexist at the same time

Epigenetic reprogramming and emerging epigenetic therapies in CML

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by BCR-ABL1, an oncogenic fusion gene arising from the Philadelphia chromosome. The development of tyrosine kinase inhibitors (TKIs) to overcome the constitutive tyrosine kinase activity of the BCR-ABL protein has dramatically improved disease management and patient outcomes over the past 20 years. However, the majority of patients are not cured and developing novel therapeutic strategies that target epigenetic processes are a promising avenue to improve cure rates. A number of epigenetic mechanisms are altered or reprogrammed during the development and progression of CML, resulting in alterations in histone modifications, DNA methylation and dysregulation of the transcriptional machinery. In this review these epigenetic alterations are examined and the potential of epigenetic therapies are discussed as a means of eradicating residual disease and offering a potential cure for CML in combination with current therapies