Philadelphia-negative chromosomal evolution during treatment for chronic myeloid leukemia

Chromosome evolution is one of the major mechanisms of disease progression and resistance in chronic myeloid leukemia (CML) patients. However, the clinical significance of chromosomal evolution in the Philadelphia (Ph)-negative clone during therapy is not fully understood. We evaluated 94 CML patients in the chronic phase of CML during treatment of the disease. Six of them had Ph-negative chromosome abnormalities during treatment. Four patients with a single abnormality and a good molecular response showed no obvious complications from the chromosomal changes, while two other patients who had complex abnormalities and previous treatment had poor outcomes. Our results highlight the need for close monitoring of this kind of patient, not only on a molecular level but also at the cytogenetic level.     

Minute chromosomes in a case of chronic Ph1-positive myeloid leukemia

Minute chromosomes (mins) were found in all bone marrow cells in a 62-year-old woman with Ph1 positive chronic myeloid leukemia. The cells had a range of 39 to 50 chromosomes with a mode of 46. The examined metaphases had a variety of numerical and structural chromosome abnormalities, as well as 2 to 6 minute chromosomes. Our case supports the assumption that there may be a correlation between the presence of mins in leukemias and the resistance of the cells to chemotherapy or the rapid progression of the disease.     

The allometry of chronic myeloid leukemia

Chronic myeloid leukemia (CML) is an acquired neoplastic hematopoietic stem cell (HSC) disorder characterized by the expression of the BCR-ABL oncoprotein. This gene product is necessary and sufficient to explain the chronic phase of CML. The only known cause of CML is radiation exposure leading to a mutation of at least one HSC, although the vast majority of patients with CML do not have a history of radiation exposure. Nonetheless, in humans, significant radiation exposure (after exposure to atomic bomb fallout) leads to disease diagnosis in 3-5 years. In murine models, disease dynamics are much faster and CML is fatal over the span of a few months. Our objective is to develop a model that accounts for CML across all mammals. In the following, we combine a model of CML dynamics in humans with allometric scaling of hematopoiesis across mammals to illustrate the natural history of chronic phase CML in various mammals. We show how a single cell can lead to a fatal illness in mice and humans but a higher burden of CML stem cells is necessary to induce disease in larger mammals such as elephants. The different dynamics of the disease is rationalized in terms of mammalian mass. Our work illustrates the relevance of animal models to understand human disease and highlights the importance of considering the re-scaling of the dynamics that accrues to the same biological process when planning experiments involving different species.     

Molecular genetics of chronic neutrophilic leukemia,chronic myelomonocytic leukemia and atypical chronic myeloid leukemia

According to the 2008 World Health Organization classification, chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia are rare diseases. The remarkable progress in our understanding of the molecular genetics of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms has made it clear that there are some specific genetic abnormalities in these 3 rare diseases. At the same time, there is considerable overlap among these disorders at the molecular level. The various combinations of genetic abnormalities indicate a multi-step pathogenesis, which likely contributes to the marked clinical heterogeneity of these disorders. This review focuses on the current knowledge and challenges related to the molecular pathogenesis of chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia and relationships between molecular findings, clinical features and prognosis.     

Complex cytogenetic abnormalities in a patient with chronic myeloid leukemia: a case report

A case of multiple chromosome aberrations in a patient with CML (chronic myeloid leukemia) in the accelerated phase was described. Cytogenetic and molecular genetic studies revealed the presence of a t(9; 22)(q34; q11) translocation and some additional abnormalities such as t(1; 2)(p36; p21), del(6)(q21), +del(8)(q22), del(18)(q21), and +der(22), part of which is not typical for this kind of pathology. The correlation between the obtained data and the data presented in different publications is considered. A probable connection of the detected changes with previously received treatment and a possible effect of these changes on CML progression are discussed.     

The origin and evolution of mutations in acute myeloid leukemia

Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is "captured" as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse.     

Morbidity of chronic myeloid leukemia

In 129 patients with chronic myeloid leukemia recorded in our files between 1955 and 1978, the sex ratio showed a slight decrease of the previously higher proportion of males. The morbidity rates of the two sexes are approaching. A shift of the incidence peak in males to a younger age is a striking feature, in contrast to a shift to the opposite direction in females. The incidence peak of women shifted from 35 years in the first to 65 yr in the second period, for men from 55 to 35 yr. The mean age at diagnosis was higher in women than in men. A decrease of frequency was observed during the second period 1970-1978. Whether this is a real improvement and consistent trend has to be ascertained by further studies.     

Investigations on karyotype evolution in patients with chronic myeloid leukemia (CML)

In an attempt to relate karyotype evolution to clinical and hematological data serial chromosomal analyses were performed in 31 patients with chronic myeloid leukemia (CML), both in chronic and acute phases. Our results in Philadelphia chromosome (Ph1)-positive CML are in line with karyotype profiles described in the literature. In addition, we report on chromosomal findings in 4 cases of Ph1-negative disease, one presenting with an iso17q chromosome in the positive CML. The same chromosomal abnormality was observed in a small population of Ph1-negative cells present in one of two patients with mixed Ph1-positive/Ph1-negative CML. The first case of a female patient with the loss of a sex chromosome in Ph1-positive cells is reported. Two patients with unusually long and mild chronic phases despite the presence of trisomy 8 in their karyotypes are described. Our findings suggest that the order of appearance of additional chromosomal changes of CML is of prognostic significance for the progression and the clinical picture of the disease.     

The role of interferon-alpha in the treatment of chronic myeloid leukemia

Biological agents have long been used in the treatment of cancer, and interferon-alpha was the first human cytokine to be widely studied in this setting. Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder for which interferon-alpha has demonstrated substantial activity. In the 1980s interferon-alpha became first-line therapy for patients with chronic-phase CML, not eligible for allogeneic stem cell transplantation. Following the discovery of the leukemic oncogene BCR/ABL and its causal association with CML, the potent BCR/ABL tyrosine kinase inhibitor imatinib mesylate was developed. Imatinib proved to be superior to interferon-alpha in all outcome measures, making imatinib the new standard of care for patients with CML. There is both clinical and laboratory evidence suggesting imatinib therapy alone is not curative in CML, whereas IFN has induced a low but reproducible curative effect in some patients. This unique activity may be the basis for the reincorporation of IFN into the management of CML. These observations may be best explained by imatinib's negligible activity against the leukemic stem cell (LSC) population. This review discusses the history of interferon-alpha in the treatment of CML, the evolution of molecularly targeted therapies, and some of the lessons we have learned from years of informative research in CML. It also explores the new challenge of managing minimal residual disease in the imatinib era, and addresses the promising role for LSC-directed therapies in the future treatment of CML.     

Blast crisis in chronic myeloid leukemia

Although the worst prognosis among acute forms of leukemia is persistently attributed to the blast crisis of chronic myeloid leukemia, a therapeutic nihilism seems to us to be unreasonable. Even in the developing stage of a blast crisis we consider an aggressive chemotherapy to be justified particularly in younger patients. In this connection, value and necessity of supporting of therapy are especially emphasized. Remissions can be achieved in about one third of patients during the blast crisis of CML. As in other forms of tumour therapy, the initial status, age, and secondary diseases have to be taken into account and a careful, individual therapy planning has to be made. For the future there is the hope that the increasing possibilities of differentiating blasts will allow more systematic therapeutic conclusions to be made. According to the present knowledge the greatest hopes for achieving long-term remissions or even healings can, in our opinion, be expected by bone-marrow transplantation.     

Serum factors in chronic myeloid leukemia

Mononuclear cells from the peripheral blood of healthy test persons were cultivated in a methylcellulose medium with serum samples taken from 13 patients with chronic myeloid leukemia (CML) and with osteomyelosclerosis (OMS) as well as with serum samples of 6 healthy test persons. From evaluating the proliferation of granulopoietic cells quantitatively, conclusions were made concerning the concentrations of granulopoietic stimulating substances in these sera. In all cultures with the serum of patients the number of granulopoietic cell colonies was greater than that in cultures with the serum of normal persons. The stronger proliferation of granulopoietic precursor cells in cultures with serum of patients is seen to be due to an enhanced production of the granulocyte-macrophage colony stimulating factor (GM-CSF) by leukemic cells. The differential hemograms and curves indicating the course of leukocytes in patients are compared with the corresponding results of cultures. In patients with CML an increased output of GM-CSF will apparently influence the increase in size of the granulopoietic stem cell pool, which is evident in the steep increase of those curves indicating the course of leukocytes. In patients with OMS, however, there is a discrepancy between granulopoietic serum activity and proliferation in vivo. From these investigations the hypothesis is derived that an increased synthesis of GM-CSF in patients with CML may be one of the causes underlying hyperplastic granulopoiesis. A direct advantage of leukemic cells in proliferation cannot be derived from it.(ABSTRACT TRUNCATED AT 250 WORDS)     

Imatinib mesylate in chronic myeloid leukemia

Chronic myeloid leukemia has become a paradigm for the discovery of target therapeutic approaches in the field of onco-hematology. Recognition of the tyrosine kinase activity of the p210Bcr-Abl oncoprotein led to the development of compounds targeting against BCR-ABL and then controlling the leukemic proliferation. Imatinib mesylate, one of the first tyrosine kinase inhibitors developed, was found effective and safe. According to five-years experience with this drug, it is recommended that the golden standard for initial treatment of newly diagnosis chronic myeloid leukemia patients should be 400 mg Imatinib daily. In this brief review, we discuss the current tools for the effective management of chronic myeloid leukemia with Imatinib, providing the updated results of IRIS and RIGHT clinical trials and then the suggestions how Imatinib-treated patients should be monitored.