Cases Of Chronic Myeloid Leukemia Research Articles

Multidrug Resistance Gene (MDR1) Polymorphism and Response to Nilotinib in Egyptian Patients with Chronic Myeloid Leukemia (CML)

Introduction: Inappropriate expression of the multidrug resistance (MDR1) gene I in chronic phase chronic myeloid leukemia cases (CML-CP) encodes P glycoprotein (Pgp)that may cause resistance to second generation tyrosine kinase inhibitors (TKIs)Patients and methods: Thirty-one upfront CML-CP patients, planned to receive nilotinib, were included. Detection of MDR1 gene polymorphism C3435T, using PCR Restriction Fragment Length Polymorphisms (PCR-RFLP) was done initially for every patient. We prospectively followed up the patients between February 2012 and February 2014 with PCR for BCR-ABL1 transcripts every 3 months. The molecular response to nilotinib, according to the level of BCR-ABL1 by PCR, was compared to the different MDR1 3435 genotypes.Results: The majority of the patients carried the MDR1 3435CC genotype of Molecular response was optimal in 56%, 60% and 80% of the patients at month 3, 6 and 12 respectively.There was no statistically significant difference between MDR- C3435T genotypes and the molecular response to treatment with nilotinib. DisclosuresNo relevant conflicts of interest to declare.

Systemic lupus erythematosus and chronic myeloid leukemia: mere coexistence or association?

Systemic Lupus Erythematosus (SLE) is a multisystem connective tissue disorder associated with increased predisposition to haematological malignancies. Myeloid series malignancies are rarely associated with SLE. We here report a case of Philadelphia chromosome positive chronic myeloid leukemia (CML) associated with SLE in a 36 year old Indian housewife. This is probably the first such case to be reported from India and only a handful of such cases have been reported in World literature till now. The patient presented initially with leukopenia. She was treated with imatinib with good results.

A case of chronic myeloid leukemia with the m-bcr (p190) molecular rearrangement identified during treatment

Chronic myeloid leukemia (CML) is a hematological malignancy in which a high percentage of patients cytogenetically express the Philadelphia chromosome. This chromosome results from the reciprocal translocation, t(9;22)(q34;q11.2). During this exchange, the Abelson gene (abl) on chromosome 9 and the breakpoint cluster region gene (bcr) on chromosome 22 generate the breakpoint cluster region-Abelson murine leukemia (BCR-ABL) fusion gene. The most frequent breakpoint on chromosome 22, located between exons 12 and 16, is called the major breakpoint cluster region (M-bcr) and with its counterpart in exon 2 of chromosome 9 results in the b2a2 and b3a2 transcripts that code for a 210 kDa protein. Less frequently, a second rearrangement, minor breakpoint cluster

Cytopathology of myeloid sarcoma: a study of 16 cases

The diagnosis of myeloid sarcoma (MS) in cytology samples is challenging, especially when these tumors occur prior to a diagnosis of acute myeloid leukemia. The aim of this study was to review our cytopathology service's experience with a series of MS cases. Archival records were searched from which 16 cytology cases of MS were identified and reviewed. Clinical findings, cytomorphology, and ancillary studies were analyzed. MS was secondary to acute myeloid leukemia in 14 cases, chronic myeloid leukemia (CML) in blast crisis in 1 case, and myelodysplastic syndrome in another. Flow cytometry was supportive in 11 cases, immunostains were helpful when performed in 4 cases, and fluorescence in-situ hybridization in the CML case showed t(9;22). Cellularity was variable in all leukemia subtypes. Blasts had round or cleaved nuclei with indistinct nucleoli. Maturing granulocytes were present only in the patient with CML, or with peripheral blood contamination (4 cases). Other blood precursors were absent. Apoptosis and lymphoglandular bodies were present in almost one-half of the cases, which correlated with increased blasts. Mitoses were infrequent (6 cases) and necrosis was not seen. The diagnosis of MS in cytology specimens can be made in cases with adequate cellularity and supportive ancillary studies in the correct clinical context. MS was harder to diagnose in cytology cases with low cellularity, blood contamination, and few blasts. Cytologic features that pose diagnostic pitfalls are lymphoglandular bodies suggestive of lymphoma and maturing or mixed granulocytes that mimic infection.

Long‐term outcome of chronic myeloid leukaemia patients with p210 and p190 co‐expression at baseline

Long‐term outcome of chronic myeloid leukaemia patients with p210 and p190 co‐expression at baseline

Resistant mutations in CML and Ph(+)ALL - role of ponatinib.

In 2012, ponatinib (Iclusig®), an orally available pan-BCR-ABL tyrosine kinase inhibitor (TKI) developed by ARIAD Pharmaceuticals, Inc., was approved by the US Food and Drug Administration for use in resistant or intolerant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Ponatinib is the only approved TKI capable of inhibiting BCR-ABL with the gatekeeper T315I kinase domain mutation, known to be the cause for 20% of resistant or relapsed CML cases. In 2013, ponatinib sales were temporarily suspended due to serious side effects seen in nearly 12% of the patient population. These side effects are thought to stem from the potent nature and pan-activity of this TKI. ARIAD Pharmaceuticals, Inc. has since been permitted to resume sales and marketing of ponatinib to a limited patient population with an expanded black box warning. In the following review, the use of ponatinib in CML and Ph+ALL will be discussed. Mechanisms of resistance in CML are discussed, which provide insight and background into the need for this third generation TKI, followed by the molecular design and pharmacology of ponatinib, which lead to its success as a therapeutic. Finally, the efficacy, safety, and tolerability of ponatinib will be highlighted, including summaries of the important clinical trials involving ponatinib as well as its current place in therapy.

Environmental and occupational factors associated with chronic myeloid leukemia: a case-control study

BackgroundThe relationship between chronic myeloid leukemia (CML) and a broad range of exposures to occupational and environmental factors known to cause leukemia in general is limited. CML is by and large incurable and treatment is just palliative and life prolonging, with high case fatality rate, even in the best centers. Furthermore treatment is very expensive. Identification of leukemogenic factors is therefore important if this can lead to simple public health interventions.ObjectiveThe objective was to determine key environmental and occupational exposure factors that may be associated with CML.MethodsThis was a case-control study involving CML cases enrolled in Glivec International Patient Assistance Program (GIPAP) clinics at the Nairobi Hospital and Aga Khan University Hospital and two control groups for each case, matched for age and sex: a family- and hospital-based control, was carried out. One hundred and eight cases with ageand-gender-matched family- and hospital-based controls were recruited and a standard questionnaire was administered. Individual data on demographics, occupation, environment, and exposures to benzene and farm organochemical products were obtained. Clinical examination was carried out in control subjects. Statistical analysis was done using bivariate and multivariate analysis to look for associations between exposure factors and CML.ResultsThe median age at diagnosis of CML cases was 41.32 years with an age range of 8–81 years and a male to female ratio of 1.7:1. Most of our cases were concentrated in or around Nairobi. There was no significant correlation found for exposure to benzene or pesticides. Long duration of exposure to pesticides in the family control group was significantly associated (t-test, P = 0.017) with risk of CML.ConclusionsAssociations between exposures to organic solvents like pesticides and CML were indicated but were not entirely consistent, although no associations with benzene products were found. Nevertheless, for almost all cases of Ph chromosome-positive CML, other explanations must be sought for.

Association des polymorphismes du gène méthylène-tétrahydrofolate réductase avec la leucémie myéloïde chronique

Methylene-tetrahydrofolate reductase (MTHFR) is a key enzyme of folate metabolism. Few studies were reported about its relationship with chronic myeloid leukemia (CML). We conducted a case-control study analyzing the prevalence of the polymorphisms MTHFR C677T and MTHFR A1298C in Algerians CML patients. Using TaqMan® allelic discrimination assay, we investigate MTHFR C677T and A1298C polymorphism distribution in 90 cases of CML and 100 healthy subjects. The frequencies of 677T alleles and genotypes 677TT and 677CT were significantly higher in cases than in control (P = 1E-6; OR = 6.77 [4.22-10.86]) and (P = 1E-6; OR = 10.38 [4.56-23.6]) respectively. Also, the frequencies of 1298C alleles and genotypes 1298CC and 1298AC were higher in cases (P = 9 E-6; OR = 2.65 [1.71-4.10]) and (P = 0.008; OR = 2.22 [1.21-4.06]) respectively. We report also the higher significance of the haplotype 677T/1298A and 677T/1298C in cases (P = 0.007; OR = 2.57 [1.26-5.24]) and (P = 5 E-6, OR = 6.91 [2.7646-17.2899]) respectively. Our results demonstrate that 677T and 1298C alleles are both associated with an increased risk of CML in Algeria.

Structure, Function, and Resistance in Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is effectively treated by tyrosine kinase inhibitors (TKIs). Rarely, CML cases develop TKI resistance through acquisition of compound mutations. In this issue of Cancer Cell, Zabriskie and colleagues study how structural changes caused by compound mutations cause clinically relevant changes in TKI sensitivity.

Is survival in myeloid malignancies really improving? A retrospective 15-year population-based study

Myeloid malignancies (MMs) are heterogeneous groups of diseases which present different prognoses. Using data from the population-based Girona Cancer Registry, we estimated the relative survival (RS) rates and relative excess risk of death among patients with MMs in the province of Girona between 1994 and 2008. The 5-year RS rate was 49.7%, ranging from 20.2% for acute myeloid leukemia (AML) to 75.3% for myeloproliferative neoplasms (MPN). Marked differences in RS were observed when the age of patients was considered: an increase in RS was mainly found in younger patients with myelodysplastic syndromes and MPN. Furthermore, cases of chronic myeloid leukemia treated with imatinib had a significantly better outcome compared with those that were untreated. Despite the slight improvement in the survival rate of younger patients with AML, RS remained stable for 15 years, as no significant improvements were made in the management of the disease during that period.

BMI1 gene expression in myeloid leukemias and its impact on prognosis.

BMI1 is a polycomb group (PcG) protein and is overexpressed in leukemia. It plays a key role in the self-renewal of stem cells. Leukemic cells lacking BMI1 underwent proliferation arrest and showed signs of differentiation and apoptosis. This study was aimed to investigate the expression and impact of BMI1 in myeloid leukemias. Expression levels of BMI1 in 100 acute myeloid leukemia (AML), 100 chronic myeloid leukemia (CML) patients and 20 healthy controls were measured by real time quantitative polymerase chain reaction (RQ-PCR). The results showed that the expression of BMI1 was significantly higher in AML and CML versus control subjects (p<0.001 for both). The 2-year overall and disease free survival rates were significantly lower in patients expressing higher BMI1. Multivariate analysis showed that BMI1 was independent prognostic factor for OS for AML cases (p=0.015, HR=3.204, 95% CI=1.250-8.212). Accelerated and blastic phases in CML cases expressed higher BMI1 than chronic phase (p<0.001). We concluded that detecting BMI1 is helpful for predicting the survival in AML patients and monitoring the aggressiveness and progression in patients with CML.

A case of chronic myeloid leukemia with unusual presentation

A case of chronic myeloid leukemia with unusual presentation

Bone marrow microenvironment in chronic myeloid leukemia: implications for disease physiopathology and response to treatment

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm related to the presence of the BCR-ABL1 fusion gene, linked to t (9;22) (q34;q11). It is originated from an abnormal hematopoietic stem cell, which is characterized as its normal counterparts by long-term self-renewal and multi-lineage differentiation. Both leukemic and quiescent normal hematopoietic stem cells preferentially reside in the osteoblastic niche. Mesenchymal stromal cells (MSC) are located near them, playing a critical role in their regulation. Currently, with tyrosine kinase inhibitor (TKI) therapy, long term clinical responses are achieved in most CML cases. However, late treatment failures may be observed related to the persistence of leukemic stem cells. The interactions between the leukemic stem cell and the microenvironment may be responsible in part for these events. We review the interactions between the leukemic stem cell and BM stroma and its potential clinical and therapeutic implications.

The Safety of Specific Immunotherapy for Patients Allergic to House-Dust Mites and Pollen in Relation to the Development of Neoplasia and Autoimmune Disease: A Long-Term, Observational Case-Control Study

Background: Specific immunotherapy (SIT) safety has been well documented. However, the prolonged late side effects in patients who terminated SIT several years previously have been reported on in only a limited number of studies. The aim of this study was to perform a 20-year post-SIT observational evaluation for the assessment of any manifestation of serious immunological disease. Materials and Methods: In total, 1,144 patients (521 women and 623 men), with a mean age of 22.8 ± 16.9 years (at the moment of SIT completion) and who had atopic bronchial asthma and/or allergic rhinitis, were observed 20 years after immunotherapy. New neoplastic and autoimmune disease cases were monitored. The SIT group was compared to a control group consisting of 1,154 allergic patients who had never received SIT and had only had symptomatic treatment. Results: There was an inverse association between SIT treatment and the prevalence of new chronic myeloid leukemia and chronic lymphoblastic leukemia cases (OR 0.32, 95% CI 0.18-0.81 and OR 0.58, CI 0.44-0.78, respectively). In other neoplastic diseases, however, prevalences similar to those observed in the control group were confirmed. There were also no significant differences in the autoimmune disease prevalence between the analyzed groups. Conclusion: The results of this long-term observational study indicate a lack of a significant prevalence for new instances of neoplastic and autoimmune diseases, which suggests that SIT in the long term is indeed safe.

Pregnancy outcome in chronic myeloid leukemia patients on imatinib therapy

Imatinib is a first-line therapy to treat chronic myeloid leukemia (CML) patients. We selected 22 CML cases of pregnancies and reported 9 accidental and 13 planned pregnancies that were on imatinib therapy. Willing female patients remaining in complete hematological, cytogenetic and major molecular responses for at least 2 years planned for pregnancy and were advised to stop imatinib for 1 month prior to conception and 3 months after conception (first trimester). Willing male patients stopped therapy 1 month prior to conception of their wives. In unplanned cases, all patients were in exposure to imatinib during conception. Twenty-two pregnancies resulted in seven male children and eight female children. There were three spontaneous abortions and four elective abortions along with one case of hypospadia and another one of mild hydrocephalus. We may suggest that planned pregnancy during therapy may be encouraged but imatinib therapy in unplanned pregnancy can cause spontaneous abortion or congenital anomaly.

Molecular Monitoring of patients with Chronic Myeloid Leukemia (CML) in the state of Qatar: Optimization of Techniques and Response to Imatinib

Most cases of chronic myeloid leukemia (CML) are associated with the presence of BCR-ABL1 fusion gene; a molecular anomaly that introduced targeting therapy to CML. This study was setup primarily to optimize the real-time quantification detection of BCR-ABL1 transcripts, in order to pave the way for using this method as a diagnostic tool to support the clinical management of CML patients in Qatar. A secondary objective was to evaluate the response of CML patients to Imatinib (IM) and exploit adaption of this technique as an indicator of emerging drug resistance reported in Qatar. Peripheral blood (PB) samples from 26 CML patients receiving Imatinib, were analysed via serial Real-time quantitative polymerase chain reaction (RT-qPCR) to monitor the ratio of BCR-ABL1 to normal ABL1 transcripts. EuropeanLeukemia Net (ELN) 2006 and 2009 guidelines were employed to assess the molecular response to Imatinib. For patients to be classified as optimal responders, major molecular response (MMR) had to be achieved by 18 months of treatment. Patients responding to Imatinib achieved major molecular response (MMR) during the 1st year of treatment; while patients who resisted Imatinib treatment did not achieve any molecular response within this time frame. This was the first molecular study to evaluate the molecular response of CML patients (citizens and residents) to IM in Qatar.

Risk of myeloproliferative disease and chronic myeloid leukaemia following exposure to low-level benzene in a nested case–control study of petroleum workers

BackgroundBenzene exposure has been associated with increased risk of leukaemia and myelodysplastic syndrome. Existing studies are sparse for other lymphohaematopoietic cancer subtypes, such as myeloproliferative disease (MPD) and the related...

A Rare Case of Chronic Myeloid Leukemia At a Patient with Achondroplasia

The coincidence of chronic myeloid leukemia (CML) and achondroplastic dwarfism is very rare. A 40-year old man with achondroplastic dwarfism was diagnosed with chronic myeloid leukemia in blastic phase with a Sokal index of 1.34. Standart dose imatinib treatment was immediately started after the diagnosis.

Unusual Presentation of Chronic Myeloid Leukemia as Retroperitoneal Hematoma: A Case Report

Chronic myeloid leukemia(CML) usually remains asymptomatic and has varied clinical presentation. The disease usually has a chronic course till it goes into blast crisis when it develops fever, other constitutional symptoms and bleeding manifestations as seen in acute leukemia. Here, we present a case that came to our emergency department as a case of acute abdomen in the form of massive retroperitoneal hematoma and subsequently proved to be a case of Philadelphia positive CML with blast crisis.

Location of the BCR/ABL Fusion Genes on Both Chromosomes 9 in Ph Negative Young CML Patients: An Indian Experience.

The BCR/ABL gene rearrangement is cytogenetically visualized in most chronic myeloid leukemia (CML) cases. About 5-10% of CML patients lack its cytogenetic evidence, however, shows BCR/ABL fusion by molecular methods. We describe two CML patients with Philadelphia (Ph) negative (-ve) and BCR/ABL positive by fluorescence in situ hybridization (FISH). Both the cases were in chronic phase at diagnosis. Conventional cytogenetics and different FISH assays were adopted using BCR/ABL probes. Home-brew FISH assay using bacterial artificial clone (BAC) for BAC-CTA/bk 299D3 for chromosomal region 22q13.31-q13.32 was performed in case 1. Both the patients were Ph-ve. In first case, dual color dual fusion (DCDF)-FISH studies revealed 1 Red (R) 2 Green (G) 1 Fusion (F) signal pattern in 80% of cells indicating BCR/ABL fusion signals on chromosomes 9 instead of Ph and 2G2F signal pattern in 20% of cells indicating two BCR/ABL fusions on both chromosomes 9q34 on presentation. In second case, FISH studies revealed the 1R1G1F signal pattern indicating BCR/ABL fusion signals on chromosomes 9 instead of Ph in 100% of cells at presentation. During follow-up, both the patients exhibited 2G2F signal pattern indicating two BCR/ABL fusions on both chromosomes 9q34, which indicated a clonal evolution in 100% cells. Both the patients did not achieve therapeutic response. Relocation of BCR/ABL fusion sequence on sites other than 22q11 represents a rare type of variant Ph, the present study highlights the hot spots involved in CML pathogenesis and signifies their implications in Ph-ve BCR/ABL positive CML. This study demonstrated the genetic heterogeneity of this subgroup of CML and strongly emphasized the role of metaphase FISH, especially in Ph-ve CML cases, as it detects variations of the classical t(9;22).