Additional Cytogenetic Abnormalities and/or Philadelphia Chromosome Metaphase Mosaicism Might Adversely Influence Survival and Imatinib Response in Chronic Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4783-4783
Author(s):  
Andrew P. Landstrom ◽  
Rhett P. Ketterling ◽  
Ryan A. Knudson ◽  
Gordon W. Dewald ◽  
Ayalew Tefferi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Median Length ◽  
Cytogenetic Abnormalities ◽  
Kaplan Meier ◽  
Ph Chromosome ◽  
Cytogenetic Remission ◽  
Additional Chromosomal Abnormalities

Abstract Background: Chronic myeloid leukemia (CML) is invariably associated with the reciprocal translocation of BCR and ABL to form the Philadelphia chromosome (Ph), t(9;22)(q34;q11). At diagnosis, a small proportion of patients display additional cytogenetic abnormalities and/or a variable proportion of cytogenetically normal metaphases that coexist with Ph-positive metaphases. The objective of the current study was to examine the prognostic relevance of these two scenarios. Methods: The study population consisted of 65 (47.7% female) consecutive, newly diagnosed CML patients seen at the Mayo Clinic with a median age of 59 years. 44.5 percent were initially treated with interferon alpha (IFN) resulting in complete cytogenetic remission in 10.7 percent for a median length of 5.83 years, partial cytogenetic remission in 3.57 percent for a median length of 2 years. 55.5 percent were treated with imatinib (Gleevec) resulting in complete cytogenetic remission in 54.1 percent for a median length of 3.08 years, partial cytogenetic remission in 13.5% for a median length of 1.08 years. Results: Survival at five years through Kaplan-Meier analysis was approximately 92 percent in patients demonstrating only the Ph chromosome (n = 53), versus 60 percent in patients with additional chromosomal abnormalities (n = 12; p < 0.0001 by both Logrank and Breslow-Gehan-Wilcox analysis). Furthermore, patients with additional chromosomal abnormalities demonstrated lower rates of either complete or partial cytogenetic remission with imatinib therapy. Similarly, five year survival of patients with less than 90% Ph-positive metaphases at diagnosis (n = 4) was approximately 60% compared to 92% in patients with greater than 90% Ph-positive metaphases (n = 61; p = 0.01 by Logrank and p = 0.001 by Breslow-Gehan-Wilcox analysis). Additionally, the former group of patients was significantly less responsive to imatinib. Finally, there was significant correlation between Ph-positive metaphase mosaicism and the presence of additional chromosomal abnormalities (p = 0.05). Conclusion: Although it is tempting to speculate the possibility that Ph-chromosome mosaicism and/or additional cytogenetic abnormalities at presentation of CML is a surrogate for the presence of Ph-negative imatinib-resistant clones, the preliminary results from the current study require validation from a larger study. Figure Figure Figure Figure

scholarly journals Additional chromosomal abnormalities in Philadelphia positive chronic myeloid leukemia

2019 ◽  
Vol 36 (2) ◽  
Author(s):  
Sunila Tashfeen Arif ◽  
Rafia Mahmood ◽  
Saleem Ahmed Khan ◽  
Tahir Khadim
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cytogenetic Analysis ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Newly Diagnosed ◽  
Cytogenetic Abnormalities ◽  
Conventional Cytogenetic Analysis ◽  
Major Route ◽  
Additional Chromosomal Abnormalities

Objective: To determine the frequency of additional chromosomal abnormalities in Philadelphia chromosome positive Chronic Myeloid Leukemia (CML) by conventional cytogenetic analysis. Methods: This descriptive cross sectional study was conducted at Armed Forces Institute of Pathology (AFIP), Rawalpindi, from January 2012 to December 2016. A total number of 528 newly diagnosed CML patients were included in the study. The subjects were tested for the presence of Philadelphia (Ph) chromosome and other additional cytogenetic abnormalities by conventional cytogenetic analysis interpreted according to International System of Human Cytogenetic Nomenclature (ISCN) criteria. Molecular analysis for BCR-ABL was also performed for each patient. The additional cytogenetic abnormalities were then classified into major route abnormalities and minor route abnormalities. Results: Out of the 528 newly diagnosed CML patients, 378 (71.6%) were males and 150 (28.4%) were females. The age of patients ranged between 18 to 74 years. Four hundred and ninety-eight (94.3%) patients showed Philadelphia chromosome on karyotyping while 30 (5.7%) were negative for the Philadelphia chromosome. On analysis of these 498 Philadelphia positive patients, additional cytogenetic aberrations were detected in 26 (4.9%) patients. Of these, 7 (1.3%) had major route abnormalities while 19 (3.6%) had minor route abnormalities. Conclusion: The frequency of additional chromosomal abnormalities in our study were not in accordance with previous local and international studies. doi: https://doi.org/10.12669/pjms.36.2.1384 How to cite this:Tashfeen S, Mahmood R, Khan SA, Khadim T. Additional chromosomal abnormalities in Philadelphia positive chronic myeloid leukemia. Pak J Med Sci. 2020;36(2):---------. doi: https://doi.org/10.12669/pjms.36.2.1384 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Additional Chromosomal Abnormalities in Philadelphia Chromosome-Negative Metaphases Appearing during Therapy with Imatinib, Dasatinib, Nilotinib and Ponatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1577-1577 ◽  
Author(s):  
Ghayas C. Issa ◽  
Hagop M. Kantarjian ◽  
Elias Jabbour ◽  
Gautam Borthakur ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Clinical Outcomes ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Banding Technique ◽  
First Year ◽  
Additional Chromosomal Abnormalities

Abstract Background Additional chromosomal abnormalities (ACAs) in the Philadelphia chromosome (Ph)-negative metaphases that emerge as patients with chronic myeloid leukemia (CML) are treated with tyrosine kinase inhibitors (TKIs) have been reported during treatment with imatinib. It has been suggested that these might be associated with an inferior outcome and in rare instances lead to the emergence of a new malignant clone resulting in myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (Jabbour et. al, Blood 2007). This phenomenon has not been well characterized when other TKIs are used. We conducted a retrospective analysis of patients treated on imatinib, dasatinib, nilotinib, and ponatinib frontline trials to assess the frequency and prognostic impact of ACAs appearing during the treatment after achieving cytogenetic response. Patients and Methods A total of 524 patients with CML were evaluated with a median age at diagnosis of 48 years (range 15 to 86). These included 236 patients treated with imatinib, 125 with nilotinib, 118 with dasatinib and 45 with ponatinib. All the patients were treated in clinical trials approved by the institutional board review and signed an informed consent in accordance with institutional guidelines and in accordance with the declaration of Helsenki. Conventional cytogenetic analysis was done in bone marrow cells using standard G-banding technique at baseline, every 3 months during the first year, then every 6-12 months. Clonal ACAs were identified as abnormalities present in ≥2/20 metaphases or, if only one metaphase, present in ≥2 consecutive assessments. Results After a median follow-up of 83.8 months (range 0.3-176.6 months) 13% (72/524) patients had ACAs, of which 7% (41/524) were clonal. ACAs were seen in 11% (27/236) of patients on imatinib compared to 11% (13/118, p=0.9) on dasatinib, 19 % (24/125, p= 0.04) on nilotinib, and 17% (8/45, p=0.2) on ponatinib. Six patients had both clonal evolution (CE) and ACAs at different times. The median number of metaphases containing ACAs was 5/20 (range 1 to 20) with an average of 7/20. Most appeared within the first year of the start of the TKI (median 6 months, range 3-72 months); they first appeared after 12 months of therapy in 21 of the 72 (29%) patients. ACAs were transient and were detected in 2 or less time points in 52 of the 72 (72%) cases. The most common clonal ACAs were - Y (13/41) and +8 (4/41). The rates of cytogenetic and molecular responses were similar for patients with and without clonal ACAs (CCyR: 88% vs 91%; p=0.55) (MMR: 78% vs 86%, p=0.20). Having clonal ACAs did not affect the rate of deep molecular response either (MR4.5 71% vs 67%; p =0.65). There was no significant difference in EFS and OS (5y EFS 73% vs 86%; p=0.19) (5y OS 77% vs 93%; p=0.06) although there was a trend for lower rates for both. Responses and clinical outcomes were similar between different TKIs for patients with and without clonal ACAs. One patient with -7 treated with ponatinib developed MDS. Monosomy 7 appeared 9 months from the start of treatment in 9/20 metaphases and persisted. He was taken off ponatinib because of pancytopenia. He subsequently received bosutinib, achieved and maintained a CCyR. A high-risk MDS was documented approximately 1 year after appearance of the -7 clone. He was started on decitabine and achieved a partial cytogenetic response for MDS. Another patient in the imatinib cohort with -7 developed secondary AML (CCyR for CML) and died from a multiple organ failure after allogeneic stem cell transplant from a one antigen-mismatched unrelated donor. There was a third patient with -7 that later had CE and developed Ph+ CML blast phase. Conclusion ACAs are rare and mostly transient events that appear during the treatment of CML with TKIs. These changes do not affect responses or clinical outcomes, independent of what TKI is used. A small subset of patients with -7 may develop AML or MDS warranting close monitoring of patients with changes that are reminiscent of those diseases. Molecular analysis after appearance of ACAs could help identify mutations driving the Ph-clone into AML or MDS. Disclosures Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:BerGenBio AS: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

Highly Sensitive Fluorescence In Situ Hybridization Method to Detect Double BCR/ABL Fusion and Monitor Response to Therapy in Chronic Myeloid Leukemia

Blood ◽  
1998 ◽  
Vol 91 (9) ◽  
pp. 3357-3365 ◽  
Author(s):  
Gordon W. Dewald ◽  
William A. Wyatt ◽  
Amy L. Juneau ◽  
Richard O. Carlson ◽  
Alan R. Zinsmeister ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Chronic Myeloid Leukemia ◽  
Fluorescence In Situ Hybridization ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Response To Therapy ◽  
Chromosome 9 ◽  
Ph Chromosome ◽  
Cytogenetic Remission

Abstract We investigated a new method using fluorescence in situ hybridization and DNA probes that span the common breakpoints of t(9;22)(q34;q11.2) and that detect double BCR/ABL fusion (D-FISH) in bone marrow cells with this translocation, one on the abnormal chromosome 9 and one on the Philadelphia chromosome (Ph chromosome). D-FISH patterns were abnormal in 30 of 30 specimens with classic, simple, complex, and masked Ph chromosomes. Based on 200 nuclei from each of 30 normal specimens, the mean percentage of false-positive cells was 0.25 ± 0.39. Thirty-seven specimens from 10 patients were studied before treatment and two or more times at 4-month intervals after treatment with interferon-α2b (IFN-α2b) with or without ara-C. Based on 200 nuclei, the results of D-FISH in these specimens correlated closely with quantitative cytogenetics and accurately quantified disease within a few percent. We studied 6,000 nuclei for each of six specimens, three normal and three from patients with chronic myeloid leukemia (CML) in cytogenetic remission. The normal cutoff for 6,000 nuclei was 0.079% and patients in cytogenetic remission had residual disease ranging from 7 (0.117%) to 53 (0.883%) Ph-positive nuclei. We conclude that D-FISH can detect the Ph chromosome and its variant translocations and accurately quantify disease in CML at diagnosis and at all times after treatment, including cytogenetic remission.

scholarly journals Highly Sensitive Fluorescence In Situ Hybridization Method to Detect Double BCR/ABL Fusion and Monitor Response to Therapy in Chronic Myeloid Leukemia

Blood ◽  
1998 ◽  
Vol 91 (9) ◽  
pp. 3357-3365 ◽  
Author(s):  
Gordon W. Dewald ◽  
William A. Wyatt ◽  
Amy L. Juneau ◽  
Richard O. Carlson ◽  
Alan R. Zinsmeister ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Chronic Myeloid Leukemia ◽  
Fluorescence In Situ Hybridization ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Response To Therapy ◽  
Chromosome 9 ◽  
Ph Chromosome ◽  
Cytogenetic Remission

We investigated a new method using fluorescence in situ hybridization and DNA probes that span the common breakpoints of t(9;22)(q34;q11.2) and that detect double BCR/ABL fusion (D-FISH) in bone marrow cells with this translocation, one on the abnormal chromosome 9 and one on the Philadelphia chromosome (Ph chromosome). D-FISH patterns were abnormal in 30 of 30 specimens with classic, simple, complex, and masked Ph chromosomes. Based on 200 nuclei from each of 30 normal specimens, the mean percentage of false-positive cells was 0.25 ± 0.39. Thirty-seven specimens from 10 patients were studied before treatment and two or more times at 4-month intervals after treatment with interferon-α2b (IFN-α2b) with or without ara-C. Based on 200 nuclei, the results of D-FISH in these specimens correlated closely with quantitative cytogenetics and accurately quantified disease within a few percent. We studied 6,000 nuclei for each of six specimens, three normal and three from patients with chronic myeloid leukemia (CML) in cytogenetic remission. The normal cutoff for 6,000 nuclei was 0.079% and patients in cytogenetic remission had residual disease ranging from 7 (0.117%) to 53 (0.883%) Ph-positive nuclei. We conclude that D-FISH can detect the Ph chromosome and its variant translocations and accurately quantify disease in CML at diagnosis and at all times after treatment, including cytogenetic remission.

scholarly journals Chromosomal Aberrations in Chronic Myeloid Leukemia: Response to Conventional TKIs and Risk of Blastic Transformation

2021 ◽  
Vol 6 (1) ◽  
pp. 35-39
Author(s):  
Shafaq Maqsood ◽  
Fatima Ali ◽  
Abdul Hameed ◽  
Neelam Siddiqui
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chromosomal Abnormalities ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
Trisomy 8 ◽  
Additional Chromosomal Abnormalities

Background and Purpose: Chronic Myeloid Leukemia (CML) is a common hematological malignancy. The characteristic molecular abnormality is the presence of Philadelphia chromosome or BCR-ABL fusion gene which is the result of 9:22 translocation. Tyrosine kinase inhibitors (TKIs) form the main stay of treatment in CML with excellent responses. The purpose of this study was to determine the impact of additional chromosomal abnormalities on outcomes in CML.Methods: This is a retrospective chart review of all patients who were diagnosed with CML in chronic phase (CP) with additional chromosomal abnormalities (ACAs) over a period of 5 years from 2010 to 2015 at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan. Results: A total of 283 patients were diagnosed with CML from January 2010 to January 2015. 31 patients out of these were found to have additional chromosomal abnormalities at the time of diagnosis in addition to BCR-ABL fusion gene or Philadelphia chromosome detection. Out of these 31 patients, 23 (74.2%) were males whereas 8 (25.8%) were females. 13 (41.9%) were in the age group of 31 to 50 years whereas the other two groups that is 18 to 30 years and 51 to 70 years had 9 patients each. After approval from the government which usually takes a standard 2-3 weeks’ time, these patients were started on tyrosine kinase inhibitors which was Imatinib in 30 (96.8%) and Nilotinib in 1 (3.2%) patient. Conventional cytogenetic analysis performed for each patient at the time of diagnosis revealed that 11 (35.5%) of patients had variant Philadelphia chromosome followed by 7 patients (22.6%) with trisomy 8. 5 patients (16.1%) had multiple chromosomal abnormalities including trisomy 8, deletion 1 and isochrome 17q. 2 patents each had isochrome 17q, inversion 3 and deletion 9 abnormalities. 1 patient had deletion 7 whereas 1 had variant Philadelphia chromosome with other chromosomal abnormalities. Conclusion: It was evident that frequently occurring ACAs In our CML population were Variant Philadelphia chromosome and trisomy 8.

scholarly journals Autografting with cultured marrow in chronic myeloid leukemia: results of a pilot study [see comments]

Blood ◽  
1994 ◽  
Vol 84 (3) ◽  
pp. 724-732 ◽  
Author(s):  
MJ Barnett ◽  
CJ Eaves ◽  
GL Phillips ◽  
RD Gascoyne ◽  
DE Hogge ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Intensive Therapy ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Phase Group ◽  
Cytogenetic Remission ◽  
Group 2 ◽  
Group 1

Abstract Incubation of chronic myeloid leukemia (CML) marrow for 10 days in vitro causes a marked and selective loss of very primitive Philadelphia chromosome (Ph)+ as compared with Ph- progenitors. We have autografted 22 patients with CML (16 in first chronic phase [group 1] and 6 with more advanced disease [group 2]) with marrow treated in this way to facilitate restoration of Ph- hematopoiesis after intensive therapy. Hematologic recovery to greater than 0.5 x 10(9)/L neutrophils occurred in 16 patients, and to greater than 20 x 10(9)/L platelets in 15 of 21 evaluable patients at a median of 29 and 48 days postautograft, respectively. Regenerating marrow cells were 100% Ph- in 13 patients and 75% to 94% Ph- in 3. Between 4 and 36 months (median 12) postautograft, Ph+ cells became detectable in all but 1 (who died in remission) of the 13 patients who achieved complete cytogenetic remission. Four of 7 evaluable patients treated with low-dose interferon alpha were returned to complete cytogenetic remission. Thirteen group 1 patients (81%) are alive 1.0 to 5.7 years (median 2.6) after autografting: 4 in complete cytogenetic remission, 2 in hematologic remission, 6 in chronic phase, and 1 in myeloid blast phase. Three group 2 patients (50%) are alive at 2.6, 3.8, and 4.3 years after autografting: 1 in partial cytogenetic remission, 1 in chronic phase, and 1 in accelerated phase. Thus, autografts of cultured marrow can result in prolonged restoration of Ph- hematopoiesis for some patients with CML.

Cytogenetic Clonal Evolution in Chronic Myeloid Leukemia during Imatinib Mesylate Treatment.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4844-4844
Author(s):  
Hana Klamova ◽  
Jana Brezinova ◽  
Kyra Michalova ◽  
Zuzana Zemanova ◽  
Marek Trneny
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Imatinib Treatment ◽  
Cytogenetic Abnormalities ◽  
Ph Chromosome ◽  
Cytogenetic Evolution

Abstract Cytogenetic clonal evolution (CE) - the presence of cytogenetic abnormalities in addition to the Ph chromosome in chronic myeloid leukemia (Ph+ CML) is a known poor prognostic factor associated with disease progression. Occurence of additional cytogenetic abnormalities in both Ph positive and Ph negative mitoses was also described in imatinib treated CML patients and was associated with occuring therapy resistance. The long - term significance is so far poorly understood. Objective. To monitor cytogenetic abnormalities in chronic phase CML patients on imatinib treatment, following long-term interferon alfa (IFN) or hydroxyurea treatment. To compare the haematological disease progression in patients with or without cytogenetic evolution Patients and methods: Cytogenetic evolution was analyzed in 57 patients (median age 56, range 18–73) treated with imatinib in chronic phase, following interferon resistance or intolerance. The duration of IFN application was 22 months (range 3 – 46 months), duration of imatinib treatment was 16 months (range 6 – 55 months). Cytogenetic abnormalities were detected by conventional cytogenetics - caryotype analysis and fluorescence in situ hybridisation (FISH). Results: Complete cytogenetic remission was accomplished in 55 of 57 pts (96%) on imatinib, significant or complete cytogenetic response was observed in 36 of 57 patients (66%). Cytogenetic evolution was observed in 11 patients (19%) treated with imatinib: in the Ph+ clone (9 cases) and in the Ph− clone (2 cases). Median duration of imatinib treatment before the CE identification was 16 months (range 7–36 months). The most common additional abnormality was trisomy 8 (8 pts), second Ph chromosome (4 pts), and del (17) (4 pts). In 5 cases we observed the simultaneous occurence of two different cytogenetic abnormalities. Haematological progression was observed in 7 of 11 patients (63%) following 2 – 22 months imatinib treatment (median 9 months). 5 pts (46%) exited. Six patients live 8–22 months from the detection of cytogenetic evolution. Secondary malignancy was diagnosed in 1 patient. In the group of patients without cytogenetic evolution haematological progression was observed only in 9 of 46 (19.5%) cases, 4 patients died (14.3%). Conclusion: The role of IM concerning the cytogenetic evolution occurence in CML patients is not so far clear, the suppression of the Ph+ clone could enhance the proliferation of resistant ones. In our group of patients CE was documented in 11 patients (19%), in both Ph+ and Ph− cells. Significantly higher was the risk of haematological progression. CML patients treated with imatinib should be regularly monitored with conventional cytogenetic techniques, not only to follow the decrease in the proportion of Ph-positive cells, but also to look for new especially Ph-negative clonal chromosomal abnormalities. A longer follow-up time and systematic monitoring of cytogenetics is needed to establish the prognostic impact of clonal evolution in CML patients treated with imatinib.

A Translocation (9;22)(p24;q11.2) In a Patient With CML

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5184-5184
Author(s):  
Daniele Costa Abreu ◽  
Ana Paula Castilho, Bachelor ◽  
Vivian Dionísio Niewiadonski, Bachelor ◽  
Mauricio Drummond ◽  
Nelson Gaburo
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Medical Information ◽  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
Chromosome Analysis ◽  
Chromosome 9 ◽  
Fish Analysis ◽  
Ph Chromosome

Abstract Introduction In January 2013 was received in our lab service a bone marrow sample for cytogenetic analysis. The 61 years old female patient presents an elevated white blood cell count (118,000 x10³/mm³) and clinical diagnosis as Chronic Myeloid Leukemia (CML). According the medical information the treatment began with hydroxyurea 3g daily and allopurinol 300mg daily. Methods We proceeded with cytogenetic examination of the patient’s bone marrow aspirate by conventional G-banding analysis performed on unstimulated short-term cultures (24 hrs). FISH for BCR/ABL translocation was tested using a dual fusion dual color probe. Because of the sample stability we were unable to performed RT-PCR test. Results Chromosome analysis showed the translocation (9;22)(p24;q11.2) as a sole abnormality in 100% (20/20) of analyzed metaphases. Chronic myeloid leukemia presents as a specific chromosomal abnormality the Philadelphia chromosome, t(9;22)(q34;q11) which is different from the results obtained where the region of translocation of chromosome 9 was p24 instead of the classic q34. This result suggests it is BCR/JACK2 translocation. The FISH analysis showed the presence of a complex Ph chromosome: ABL con BCRx1 (one fusion) and BCRx2;ABLx2. Conclusion The patient took imatinib without answer. She is still in clinical monitoring with persistent hyperleucocytosis and the treatment is following with hydroxyurea 500mg daily and Interferon 5000 UI three times a week. Further molecular and cytogenetic tests will be performed in a second sample to contribute with evaluation of disease progression and monitoring treatment response. Disclosures: No relevant conflicts of interest to declare.

Studying the Impact of Imatinib Mesylate (IM) Adherence in Chronic Myeloid Leukemia (CML) patients’ Responses in the State of Qatar

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5537-5537
Author(s):  
Nader I Al-Dewik ◽  
Hisham Morsi ◽  
Rola Ghasoub ◽  
Mohamed A. Yassin
Keyword(s):  
Risk Factors ◽  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Monitoring System ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Patient Adherence ◽  
Poor Adherence ◽  
Additional Chromosomal Abnormalities

Abstract Background: The introduction of Imatinib Mesylate (IM) has revolutionized the outcome of Chronic Myeloid Leukemia (CML) patients. However, the success of the rationally designed therapy is tempered by the understanding that a substantial proportion of CML patients fail treatment. In Qatar, 54% of CML patients do fail IM according to European leukemia net (ELN) recommendations 2013. Point mutation & unique tri-nucleotide insertions explained only 14% of treatment failure. Additional chromosomal abnormalities were the most common cause of IM failure in our patients’ cohort & were documented in 50% of cases. 14% of patients stopped IM due to intolerance & the mechanisms of resistance remained unknown in 28% of patients. Other cause such as patients’ adherence to IM is being prospectively investigated. Therefore, Non adherence to IM must be ruled out as a possible cause of lack of optimal response before considering such patients to be IM-resistant & switching them to next-line treatment. Aim: To correlate between CML patients’ adherence to IM treatment & their responses and identify the factors affecting non-adherence. Methods: 36 CML patients (5 citizens & 31 residents) are consented into the study. adherence to Imatinib was assessed using four different techniques: calculation of the Medication Possession Ratio (MPR), electronic Medical Records (eMR), survey questionnaire & Medication Event Monitoring System (MEMS). MPR is defined as the sum of the days' supply of medication divided by the number of days between the first fill & the last refill. Patients medications history was obtained from questionnaire, pharmacy electronic Medical record (eMR) & studying drug – drug interactions was done using MICROMEDEX® 1.0 (Healthcare Series). The Questionnaire used to identify potential factors revolving around the patient's lifestyle, affordability & knowledge related to IM, in addition to standardized evaluation based on the 9-item Morisky Medication Adherence Scale (MMAS) ranging from 1 to 13. Scores ≤10 indicates non adherence whereas ≥ 11 indicates adherence. Patient adherence was tracked electronically using the Medication Electronic Monitoring System (MEMS) that provided real time measures of adherence for a period up to 4 months. 95 Peripheral blood (PB) samples were collected & the level of BCR-ABL1 transcripts was measured via RT-QPCR. The ELN 2013 recommendations for the management of CML was adopted & employed in this study to assess the response/resistance of patients to treatment. Responses were defined at the haematological, cytogenetic & molecular levels. Patients responses were classified into optimal, suboptimal or failure. Results: Out of 36 patients, 23 patients were adherent (MMAS, MPR &MEMS were ≥ 80%) & 13 patients were classified as non-adherent (MMAS, MPR &MEMS were <80 % ) All adherent patients were optimally responded to the treatment (achieved CCyR & MMR) while the 13 non-adherent patients failed the treatment (2 patients were intolerant, 9 patients did not achieved CCyR & molecular response & 2 patients developed additional chromosomal abnormalities. Questionnaire feedback results showed that 69% patients could not afford to pay the remaining 10% of its cost, the other factors such as lack of knowledge (comprehensive & insight of illness) & illiteracy were observed in 35% & 30% of patients respectively. Discussion & conclusion: Due to high rate of Imatinib failure in Qatar, patient’s adherence to treatment was studied. Non adherence to the treatment was one of the most common causes of Imatinib failure in our patients’ cohort & was documented in 36% of cases. Economic factor (Unaffordable drug price) was one of the main causes of non-adherence & efforts should be made locally to improve access to medications for cancer diseases. Other risk factors associated with poor adherence can be improved by close monitoring & dose adjustment. Monitoring risk factors for poor adherence in combination with patient education that includes direct communication between the health care teams doctors, nurses pharmacists & patients are essential components for maximizing the benefits of TKI therapy & could rectify this problem. Our preliminary results showed that patients’ response to treatment may be directly linked to patient adherence to the treatment. However, further in-depth & specific analysis may be necessary in a larger cohort. Disclosures Al-Dewik: Hamad Medical Corporation (HMC): Employment, HMC Medical Director's Grant Competition (GC) 1013A Patents & Royalties, Research Funding. Morsi:HMC: Employment, Research Funding. Ghasoub:HMC: Employment, Research Funding.

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