Features Of Chronic Myelogenous Leukemia Research Articles

Chronic myelogenous leukemia combined with solid malignant neoplasms: report of eight cases and review of literature

Objective To explore the clinical features of chronic myelogenous leukemia (CML) combined with solid malignant neoplasms. Methods The clinical data of 8 CML patients with solid malignant neoplasms who were admitted to the Affiliated Tumor Hospital of Zhengzhou University, the Central Hospital of Nanyang City, the First Affiliated Hospital of Science and Technology University of Henan, and the Central Hospital of Xinxiang City from August 2006 to August 2018 were analyzed retrospectively. The clinical features, treatment and prognosis of the patients were summarized with the review of literature. Results Among the 8 patients, 3 were male and 5 female, aged 40-76 years, with a median of 50 years old. Seven cases were in CML chronic phase, and 1 was in accelerated phase. Seven patients were treated with tyrosine kinase inhibitor (TKI), and only 1 patient was treated with hydroxyurea. In 8 patients, two cases presented with synchronous multiple primary cancer (SMPC), 6 cases presented with heterochrony multiple primary cancer (HMPC). two patients received the operation, 1 patient received the operation and chemotherapy, 4 patients received chemotherapy, and 1 patient received the isotope treatment. One SMPC patient died and another one was under treatment, and 6 HMPC patients were under treatment. Conclusions The relationship between CML and solid malignant neoplasm is under discussion, but patients with CML and solid malignant neoplasm are not unusual. Clinicians should raise awareness to avoid misdiagnosis. The treatment should follow the two main lines that are comprehensive treatment and individualized treatment. Key words: Leukemia, myelogenous, chronic; Neoplasms, multiple primary; Treatment; Prognosis

Expression and Activity of Fyn Mediate Proliferation and Blastic Features of Chronic Myelogenous Leukemia

The BCR-ABL1 oncogene is a tyrosine kinase that activates many signaling pathways, resulting in the induction of chronic myeloid leukemia (CML). Kinase inhibitors, such as imatinib, have been developed for the treatment of CML; however, the terminal, blast crisis phase of the disease remains a clinical challenge. Blast crisis CML is difficult to treat due to resistance to tyrosine kinase inhibitors, increased genomic instability and acquired secondary mutations. Our recent studies uncovered a role for Fyn in promoting BCR-ABL1 mediated cell growth and sensitivity to imatinib. Here we demonstrate that Fyn contributes to BCR-ABL1 induced genomic instability, a feature of blast crisis CML. Bone marrow cells and mouse embryonic fibroblasts derived from Fyn knockout mice transduced with BCR-ABL1 display slowed growth and clonogenic potential as compared to Fyn wild-type BCR-ABL1 expressing counterparts. K562 cells overexpressing constitutively active Fyn kinase were larger in size and displayed an accumulation of genomic abnormalities such as chromosomal aberrations and polyploidy. Importantly, loss of Fyn protected mouse embryonic fibroblast cells from increased number of chromosomal aberrations and fragments induced by BCR-ABL1. Together, these results reveal a novel role for Fyn in regulating events required for genomic maintenance and suggest that Fyn kinase activity plays a role in the progression of CML to blast crisis.

Clinical and Hematological Features of 335 Patients of Chronic Myelogenous Leukemia Diagnosed at Single Centre in Northern Pakistan

There are no studies regarding analysis of clinical and haematological features of chronic myelogenous leukemia (CML) from Pakistan. This study analyzes the data of patients suffering from CML, reporting to a major referral Institute in Northern Pakistan in the past 6 years and 3 months. CML constitutes approximately 80% of all myeloproliferative disorders, with a peak incidence between 21-50 years of age, and a male:female ratio of 2:1. Anaemia and massive splenomegaly were the main clinical features found in 92% and 47% patients respectively. There was significant correlation between anaemia and WBC counts with degree of splenomegaly. Three percent of all CML patients presented as de novo accelerated phase, and another 3% presented as blast crises without any previous history of chronic phase. The ratio of myeloid and lymphoid blast crisis was 2:1. Median duration of chronic phase in patients on hydroxyurea treatment was 6 years. Thirty six percent of patients in chronic phase of CML belonged to intermediate and high risk according to Sokal and Hasford scoring systems. In contrast to the Caucasian populations where the peak incidence of the disease is in 6th to 7th decade, CML occurs in Pakistan in a much younger population, with a broad peak between 21-50 years of age. Patients present in fairly advanced disease because of poor access to health care facilities, due to non-affordability and lack of health insurance coverage.

Gender and ethnic differences in chronic myelogenous leukemia prognosis and treatment response: a single-institution retrospective study

BackgroundIn the last decade the importance of ethnicity, socio-economic and gender differences in relation to disease incidence, diagnosis, and prognosis has been realized. Differences in these areas have become a major health policy focus in the United States. Our study was undertaken to examine the demographic and clinical features of chronic myelogenous leukemia (CML) patients presenting initially at the LAC+USC Medical Center, which serves an ethnically diverse population.ResultsPatients were evenly split by gender, overwhelmingly Hispanic (60.9%), and quite young (median age 39, range 17–65) compared with previously reported CML patient populations. Previous CML studies identified significant anemia (Hgb <12 g/dl), significant thrombocytosis (platelets >450 × 109/l), and significant leukocytosis (WBC >50 × 109/l) as significant adverse pretreatment prognostic factors. Using these indicators, in addition to the validated Hasford and Sokal scores, patients were stratified and analyzed via gender and ethnicity. A significantly greater proportion of women presented with significant anemia (p = 0.019, Fisher's exact test) and significant thrombocytosis (p = 0.041, Fisher's exact test) compared to men, although no differences were found in risk stratification or treatment response. MCV values for women were significantly (p = 0.02, 2-sample t-test) lower than those for men, suggesting iron deficiency anemia. Focusing on ethnicity, Hispanics as a whole had significantly lower Hasford risk stratification (p = 0.046, Fisher's exact test), and significantly greater likelihood (p = 0.016, Fisher's exact test) of achieving 3-month complete haematological remission (CHR) compared with non-Hispanics at LAC+USC Medical Center, though differences in treatment outcome were no longer significant with analysis limited to patients treated with first-line imatinib.ConclusionFemale CML patients at LAC+USC Medical Center present with more significant adverse pre-treatment prognostic factors compared to men, but achieve comparable outcomes. Hispanic patients present with lower risk profile CML and achieve better treatment responses compared to non-Hispanic patients as a whole; these ethnic differences are no longer significant when statistical analysis is limited to patients given imatinib as first-line therapy. Our patients achieve response rates inferior to those of large-scale national studies. This constellation of findings has not been reported in previous studies, and is likely reflective of a unique patient population.

The Cytologic Features of Chronic Myelogenous Leukemia and Its Lymphoid Blast Phase in Body Fluid - A Case Report -

The Cytologic Features of Chronic Myelogenous Leukemia and Its Lymphoid Blast Phase in Body Fluid - A Case Report -

Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies.

The chronological history of the important discoveries leading to our present understanding of the essential clinical, biological, biochemical, and molecular features of chronic myelogenous leukemia (CML) are first reviewed, focusing in particular on abnormalities that are responsible for the massive myeloid expansion. CML is an excellent target for the development of selective treatment because of its highly consistent genetic abnormality and qualitatively different fusion gene product, p210(bcr-abl). It is likely that the multiple signaling pathways dysregulated by p210(bcr-abl) are sufficient to explain all the initial manifestations of the chronic phase of the disease, although understanding of the circuitry is still very incomplete. Evidence is presented that the signaling pathways that are constitutively activated in CML stem cells and primitive progenitors cooperate with cytokines to increase the proportion of stem cells that are activated and thereby increase recruitment into the committed progenitor cell pool, and that this increased activation is probably the primary cause of the massive myeloid expansion in CML. The cooperative interactions between Bcr-Abl and cytokine-activated pathways interfere with the synergistic interactions between multiple cytokines that are normally required for the activation of stem cells, while at the same time causing numerous subtle biochemical and functional abnormalities in the later progenitors and precursor cells. The committed CML progenitors have discordant maturation and reduced proliferative capacity compared to normal committed progenitors, and like them, are destined to die after a limited number of divisions. Thus, the primary goal of any curative strategy must be to eliminate all Philadelphia positive (Ph+) primitive cells that are capable of symmetric division and thereby able to expand the Ph+ stem cell pool and recreate the disease. Several highly potent and moderately selective inhibitors of Bcr-Abl kinase have recently been discovered that are capable of killing the majority of actively proliferating early CML progenitors with minimal effects on normal progenitors. However, like their normal counterparts, most of the CML primitive stem cells are quiescent at any given time and are relatively invulnerable to the Bcr-Abl kinase inhibitors as well as other drugs. We propose that survival of dormant Ph+ stem cells may be the most important reason for the inability to cure the disease during initial treatment, while resistance to the inhibitors and other drugs becomes increasingly important later. An outline of a possible curative strategy is presented that attempts to take advantage of the subtle differences in the proliferative behavior of normal and Ph+ stem cells and the newly discovered selective inhibitors of Bcr-Abl. Leukemia (2003) 17, 1211-1262. doi:10.1038/sj.leu.2402912

A model of human p210bcr/ABL-mediated chronic myelogenous leukemia by transduction of primary normal human CD34+ cells with a BCR/ABL-containing retroviral vector

AbstractMost insights into the molecular mechanisms underlying transformation by the p210BCR/ABL oncoprotein are derived from studies in which BCR/ABL cDNA was introduced into hematopoietic or fibroblast cell lines. However, such cell line models may not represent all the features of chronic myelogenous leukemia (CML) caused by additional genetic abnormalities and differences in the biology of cell lines compared with primary hematopoietic progenitor and stem cells. A primary human hematopoietic progenitor cell model for CML was developed by the transduction of b3a2 BCR/ABL cDNA in normal CD34+cells. Adhesion of BCR/ABL-transduced CD34+ cells to fibronectin was decreased, but migration over fibronectin was enhanced compared with that of mock-transduced CD34+ cells. Adhesion to fibronectin did not decrease the proliferation of BCR/ABL-transduced CD34+ cells but decreased the proliferation of mock-transduced CD34+ cells. This was associated with elevated levels of p27Kip in p210BCR/ABL-expressing CD34+ cells. In addition, the presence of p210BCR/ABLdelayed apoptosis after the withdrawal of cytokines and serum. Finally, significantly more and larger myeloid colony-forming units grew from BCR/ABL than from mock-transduced CD34+ cells. Thus, the transduction of CD34+ cells with the b3a2-BCR/ABL cDNA recreates most, if not all, phenotypic abnormalities seen in primary CML CD34+ cells. This model should prove useful for the study of molecular mechanisms associated with the presence of p210BCR/ABL in CML.

Growth factor stimulation enhances integrin-mediated migration but not adhesion of cml progenitors

Abnormal progenitor circulation and extramedullary hematopoiesis are characteristic features of chronic myelogenous leukemia (CML). These abnormalities could be related to altered β1 integrin function in CML progenitors. β1 integrins play an important role in growth factor (GF) induced mobilization of normal progenitors from the bone marrow into the circulation. Although expressing β1-integrins at normal levels, CML progenitors demonstrate significantly reduced adhesion to stroma and fibronectin (FN). We evaluated the effect of GF stimulation on CML progenitor adhesion and migration on FN. GF modulation of β1 integrin-mediated adhesion was impaired in CML CFC. Normal CFC incubated with physiological concentrations of GF had significantly enhanced adhesion to FN compared with cells incubated without GF (30.4±4.6% vs. 14±3.6%, p<0.01), whereas CML CFC adhesion to FN was poor regardless of the presence or absence of GF (7.6±1.8% vs. 7.9±2.1%). Addition of IL-3, FL and other GF rapidly enhanced β1 integrin-mediated adhesion of normal CFC to FN, but did not increase CML CFC adhesion. On the other hand, CML CFC demonstrated increase migration across FN-coated transwells (5μm pores) compared with normal CFC (15.7±3.4% vs. 7.3±1.4%, p<0.05) as well as increased spontaneous migration across uncoated transwells (9.9±2.2% vs. 3.2±0.7%, p<0.05). Addition of SCF enhanced migration of normal CFC through uncoated and FN-coated transwells (9.2+1.8% and 19.1+4.1%). In contrast to its lack of effect on adhesion, SCF also enhanced CML CFC migration (FN-: 15.3±4.3% and FN+: 23.9±6.1%). The presence or absence of GF did not affect cell viability or integrin expression. Differential enhancement of migration but not adhesion in response to GF simulation could play a role in abnormal progenitor circulation and localization in CML.

New translocations [t(6;15)(p25;q22) and t(6;19)(q16;q13.3)] with t(9;22)(q34;q11) in a Ph-positive chronic myelogenous leukemia

A case with typical features of chronic myelogenous leukemia (CML) with two complex aberrations in addition to the standard t(9;22) is reported. Cytogenetic evaluation of the patient's bone marrow cells (BMC) showed 46,XX,t(6;19)(q16;p13.3),t(9;22)(q34;q11) in 60% of the mitotic cells and 46,XX,idem, t(6;15)(p25;q22) in the remaining 40% dividing cells. The patient's peripheral blood smear exhibited the usual differential observed in chronic-phase CML and was clinically indistinguishable from patients with the t(9;22) as the only translocation. We performed Southern blotting on BglII-digested DNA with the Trans-Probe (OSI) and in addition to the 4.8-, 2.3-, and 1.1-kilobase (kb) germline fragments, we detected an additional fragment at 7 kb. This probe spans the entire 5.8-kb M-breakpoint cluster region ( BCR), and a single breakpoint in this region will appear as either one or two additional fragments. Because only one additional fragment was observed, both cell lines apparently share the same breakpoint in the ABL/BCR gene. Apparently the second aberrant cell line with the additional t(6;15) represents clonal evolution of the original abnormal clone.

The Philadelphia chromosome and chronic myelogenous leukemia.

Sixty of 73 consecutive patients with clinical and laboratory features of chronic myelogenous leukemia had the Philadelphia (Ph1) chromosome abnormality, as revealed by bone marrow and peripheral blood studies of chromosome morphology. The 13 Ph1-negative patients differed from the larger Ph1-positive group by having lower white blood cell and platelet counts and by having a larger proportion of young children under the age of 7. However, the most significant difference was the finding that the Ph1-negative patients responded poorly to chemotherapy and had a median survival of 18 months as compared to 45 months for the Ph1-positive population (P < 0.01). The Ph1 chromosome was observed during all phases of the disease and was unaffected by treatment. In addition to the Ph1 chromosome, aneuploidy, manifested usually by hyperdiploid Ph1-positive cell lines, was present in 20 percent of the patients. In 2 patients, 2 Ph1 chromosomes were seen in the same cell. A single patient with marked aneuploidy had the only chromosome abnormality seen in the 13 Ph1-negative patients.

Leukemia in Atomic Bomb Survivors: II Observations on Early Phases of Leukemia

Abstract 1. The ten cases of leukemia occurring among 3480 atomic bomb survivors in this study present convincing evidence of the high incidence of leukemia in atomic bomb survivors. 2. In all but one case blood studies were carried out prior to the development of pathognomonic features of leukemia. One case of reticulum cell leukemia was encountered on routine examination in a preclinical stage but with primitive or blast cells in the peripheral blood smears. 3. Of the ten cases, seven were acute or subacute leukemia and three were chronic myelogenous leukemia. 4. Observations on the acute cases of leukemia were of limited value because of the long interval in most cases between routine blood studies and the development of leukemia. However, in one case, examination ten weeks before clinical onset revealed no hematologic or physical findings suggestive of leukemia. 5. In contrast to acute leukemia, the long preclinical stage in two cases of chronic myelogenous leukemia allowed repeated hematologic and biochemical studies which were of considerable interest. 6. In these cases the long latent period and prolonged preclinical course were similar to those reported in cases of chronic myelogenous leukemia occurring spontaneously and following exposure to x-ray and other forms of radioactivity. 7. In the preclinical stage, disturbances in the red cells and platelets as well as leukocytosis with immature neutrophilic granulocytes were noted. The consistent presence of increased numbers of basophils, many of them atypical, was an outstanding feature of the peripheral blood smears in early myelogenous leukemia. 8. In two cases of preclinical myelogenous leukemia, studies on the separated leukocytes of the peripheral blood gave extremely low values for alkaline phosphatase. 9. Certain features of chronic myelogenous leukemia following irradiation suggest that the disorder may be due to a loss of growth-promoting or regulating factors.