Regulation of miR-126 and miR-122 Expression and Response of Imatinib Treatment on Its Expression in Chronic Myeloid Leukemia Patients

2021 ◽  
pp. 1-7
Author(s):  
Mirza Masroor Ali Beg ◽  
Sameer Ahmad Guru ◽  
Saleh Mohammed Abdullah ◽  
Irfan Ahmad ◽  
Aliya Rizvi ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Internal Control ◽  
Myeloid Leukemia ◽  
Expression Patterns ◽  
Chronic Phase ◽  
Fold Change ◽  
Imatinib Therapy ◽  
Taqman Probe ◽  
Imatinib Treatment ◽  
Altered Expression

<b><i>Background:</i></b> MicroRNAs (miRNAs) have been observed to exhibit altered expression patterns in chronic myeloid leukemia (CML). Therefore, this study was aimed to evaluate the clinical importance of miR-126 and miR-122 expression in concert to imatinib response in CML patients. <b><i>Methods:</i></b> The present study included 100 CML and 100 healthy subjects. The expression of the 2 miRNAs was performed using TaqMan probe chemistry, and snU6 was used as internal control. <b><i>Results:</i></b> The expression of miR-126 and miR-122 was downregulated in CML patients, with a mean fold change ± SD 0.20 ± 0.33 and 0.22 ± 0.37, respectively. While the expression of both miRNAs was analysed before and after imatinib treatment, it was observed that the expression levels of both were increased after imatinib treatment by 26.25-fold (5.33 against 0.20) and 13.95-fold (3.07 against 0.22) and the increase was statistically significant (<i>p</i> &#x3c; 0.0001 and <i>p</i> &#x3c; 0.0001, respectively). The expression of miR-126 was not conclusive when compared in different clinical stages of the CML disease as it showed a decreased expression in patients with accelerated phase compared to chronic phase (mean fold change = 0.03 and 0.27, respectively), but patients with chronic phase and blastic phase had comparable expression (mean fold change = 0.27 and 0.24, respectively). We also observed an increased expression of both miRNAs after imatinib therapy in each clinical phase. <b><i>Conclusion:</i></b> The study concludes that expression of miR-126 and miR-122 increases after imatinib treatment in CML patients and that miR-126 defines the good responders of imatinib therapy.

Evaluation Of hOCT1expression In Patients With Chronic Myeloid Leukemia (CML) Treated With Imatinib In First Line

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4041-4041
Author(s):  
Cintia Do Couto Mascarenhas ◽  
Maria Helena Almeida ◽  
Eliana C M Miranda ◽  
Bruna Virgilio ◽  
Marcia Torresan Delamain ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Taqman Probe ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
First Line ◽  
Transcript Levels

Abstract Introduction The majority of chronic myeloid leukemia (CML) patients (pts) in chronic phase (CP), present satisfactory response to imatinib treatment. However, 25-30% of these pts exhibit suboptimal response or treatment failure. The probability of achieving optimal response may be related with several factors. The human organic cation transporter 1 (hOCT1, SLC22A1), an influx transporter, is responsible for the uptake of imatinib into chronic myeloid leukemia (CML) cells The aim of this study was to analyze hOCT-1 levels at diagnosis of CML patients and correlate with cytogenetics and molecular responses. Methods hOCT-1 expression was evaluated in 58 newly diagnosed CML pts. Pts were treated with imatinib 400-600mg in first line. Samples were collected from peripheral blood at diagnosis and RNA was obtained from total leucocytes. For cDNA synthesis, 3 ug of RNA was used. hOCT-1 expression was evaluated by real-time PCR with TaqMan probe SLC22A1 (Applied Biosystems) and endogenous GAPDH control. The results were analyzed using 2-ΔΔCT. Cytogenetic analysis was performed at diagnosis, 3, 6, 12 and 18 months after starting therapy and then every 12-24 months thereafter if CCR was achieved. BCR-ABL transcripts were measured in peripheral blood at 3-month intervals using quantitative RT-PCR (RQ-PCR). Results were expressed as BCR-ABL/ABL ratio, with conversion to the international scale (IS). Major molecular response (MMR) was defined as a transcript level ≤ 0.1%. Results 58 CML pts, 60% male, median age of 46 years (19-87) were evaluated, 71% in chronic phase (CP), 21% in accelerated phase (AP) and 5% in blast crisis (BC). The mean and median of hOCT-1 transcript levels in the total group was 2.03 and 0.961 respectively (0.008–19.039) and CP pts was 1.86 and 1.00 (0.008-10.34).The median duration of imatinib treatment was 27 months (1-109) and 96.6% achieved complete hematological response, 79.3% complete cytogenetic response and 69% major or complete molecular response. The regression analysis showed correlation between higher transcript levels of hOCT-1 and BCR-ABL transcripts<10%) at 3 months analysis (p<0.0001). Albeit, there was no influence of the hOCT-1 transcript levels at diagnosis in the achievement of cytogenetic and molecular response at 24 months of treatment. Conclusions In this report, we found that high hOCT-1 expression was predictive of BCR-ABL transcripts<10% at 3 months, although we did not find correlation between hOCT-1 levels at diagnosis and the achievement of molecular response at 24 months, studies show that there is correlation between BCR-ABL log reduction in the first months of treatment and the achievement of molecular response. Disclosures: No relevant conflicts of interest to declare.

scholarly journals European Treatment and Outcome Study (Eutos) Score Predicts Early Molecular Response to Imatinib Therapy in Chronic Phase Chronic Myeloid Leukemia Patients (Cp-Cml)

2014 ◽  
Vol 25 ◽  
pp. iv337
Author(s):  
K. Sudheer Reddy ◽  
M. Manickavasagam ◽  
V. Venkata Sampath ◽  
D. Barghavi ◽  
A. Vindhyavasini ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Outcome Study ◽  
Eutos Score

Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-α treatment

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1039-1043 ◽  
Author(s):  
Andreas Hochhaus ◽  
Brian Druker ◽  
Charles Sawyers ◽  
Francois Guilhot ◽  
Charles A. Schiffer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Interferon Α ◽  
Imatinib Treatment ◽  
Serious Adverse Events ◽  
Response Level

Abstract Imatinib mesylate, a targeted inhibitor of BCR-ABL tyrosine kinase, is the standard of care for chronic myeloid leukemia (CML). A phase 2 trial of imatinib in late chronic-phase (CP) CML after interferon-α (IFNα) failure enrolled 532 patients, 454 with a confirmed diagnosis of CP CML. Median time from diagnosis was 34 months; median duration of imatinib treatment was 65 months. Cumulative best rates of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) were 67% and 57%, respectively. At the 5-year landmark, 184 (41%) of the 454 patients are in CCyR. At more than 6 years, 199 (44%) of the 454 patients remain on imatinib. Most responses occurred within 12 months of starting imatinib; however, some patients achieved initial MCyR and CCyR more than 5 years after imatinib initiation. Estimated rates of freedom from progression to accelerated phase (AP) and blastic phase (BP) and overall survival at 6 years were 61% and 76%, respectively. Both freedom from progression to AP/BP and overall survival (OS) were associated with cytogenetic response level at 12 months. No increase in rates of serious adverse events was observed with continuous use of imatinib for up to 6.5 years, compared with earlier time points. Imatinib continues to be an effective and safe therapy for patients with CP CML after failure of IFN.

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.

Outcome of Patients with Chronic Myeloid Leukemia Who Recieved an Intermittent Imatinib Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1034-1034
Author(s):  
Hyun-Gyung Goh ◽  
Soo-Hyun Kim ◽  
Jeong Lee ◽  
Sae-Eun Jang ◽  
Wan-Seok Kim ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Oral Dose ◽  
Median Duration ◽  
Myeloid Leukemia ◽  
Cytogenetic Response ◽  
Imatinib Therapy ◽  
Intermittent Therapy ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
600Mg Daily

Abstract Diagnosis of chronic myeloid leukemia (CML) is based on detection of the BCR-ABL gene or Philadelphia chromosome, and the BCR-ABL tyrosine kinase inhibitor imatinib has been the standard therapy for CML patients. Although imatinib therapy is effective in CML, it is still unclear whether imatinib can be safely discontinued without relapse. This study was designed to investigate the outcome of 26 CML patients after discontinuation of imatinib and to determine whether intermittent imatinib therapy can be employed in CML patients. Between May 2001 and Jun 2007, 555 patients have been treated with imatinib in St Mary’s Hospital of the Catholic University of Korea, and 26 patients discontinued imatinib when they achieved either complete cytogenetic response (CCyR) or complete molecular response (CMR). These 26 patients were diagnosed as Philadelphia positive (Ph+) CML between November 1995 and May 2002, and 22 patients were in chronic phase (CP) and 4 patients were in accelerated phase (AP) at diagnosis. The median age was 35 years (22–56), and 12 patients (46%) were female and 14 (54%) were male. Among 26 patients, 7 received interferon prior to imatinib therapy and 7 underwent SCT. Five patients received both interferon and SCT before imatinib therapy, and the remaining 7 patients received the imatinib as a front line therapy. Imatinib was started at oral dose of 400mg and 600mg daily for patients in CP and AP, respectively, and when they achieved CCyR or CMR, imatinib was discontinued after informed consent of the patient. In case of cytogenetic or molecular relapse, patients in all phases were retreated with imatinib at 400mg daily. Bone marrow (BM) or peripheral blood (PB) samples were obtained at regular intervals from diagnosis for hematologic response (HR), cytogenetic response (CyR) and molecular response (MR) monitorings. Eleven patients discontinued imatinib when they achieved CCyR, and 15 patients discontinued imatinib after achieving CMR. After the median duration of 7 month (4–48) observation without imatinib therapy, hematologic, cytogenetic and molecular relapses occurred in 4, 7 and 10 patients, respectively, and imatinib at oral dose of 400mg daily was reintroduced to all patients except 2 who continued to remain in CMR after imatinib discontinuation. Except 1 patient who expired and 2 patients who are in persistent molecular remission, all of 23 patients are maintaining the best response achieved after imatinib resumption with a median duration of 38 months (16–58). In conclusion, although imatinib cannot be discontinued completely, intermittent therapy can be considered for the treatment of CML patients. Intermittent imatinib treatment should not be restricted to CP patients who achieve CMR, and AP patients or patients with CCyR also can be considered for intermittent imatinib treatment. We will continue the follow-up of the patients enrolled in this study, and long-term study of intermittent imatinib treatment with expanded pool of patients will enable us to determine the accurate consequences of discontinuation of imatinib and intermittent imatinib treatment.

Inhibiting Alternative Non Homologus Endjoining (NHEJ) Pathways: Therapeutic Targets in Chronic Myeloid Leukemia (CML).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1088-1088
Author(s):  
Annahita Sallmyr ◽  
Lisa Tobin ◽  
Alan E. Tomkinson ◽  
Feyruz V. Rassool
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cell Lines ◽  
Small Molecule ◽  
Myeloid Leukemia ◽  
Therapeutic Targets ◽  
Chronic Phase ◽  
Dna Ligase ◽  
Imatinib Treatment ◽  
Dna Ligases ◽  
Dna Deletions

Abstract BCR-ABL fusion tyrosine kinase in chronic myeloid leukemia (CML), induces high levels of ROS that generate DNA double strand breaks (DSBs). We previously showed that CML cells repair DSBs by aberrant non homologous end-joining (NHEJ) that is characterized by large DNA deletions. The generation of DNA deletions represents a mechanism by which genomic alterations may be acquired in the progression of chronic phase CML to blast crisis. Recently, we demonstrated that a “back-up” or alternative NHEJ pathway is involved in aberrant repair of DSBs in CML. Proteins in this pathway include, DNA ligase IIIα, XRCC1 and poly(-ADP) ribose polymerase (PARP). We have identified that NHEJ proteins, DNA ligase IIIα and WRN are overexpressed in CML. This increased expression appears to be dependent on the presence of BCR-ABL. “Knockdown” of these proteins leads to an accumulation of unrepaired DSBs, demonstrating their essential involvement in DSB repair in CML cells. The goal of the current study is to evaluate the effect of inhibiting “back-up” DNA repair proteins in proliferation and apoptosis of BCR-ABL-positive CML compared with standard Imatinib therapy. To evaluate whether “back-up” repair proteins may be therapeutic targets, we used siRNA down-regulation and small molecule inhibition of DNA ligase IIIα and PARP in BCR-ABL positive cell lines. Importantly, we have recently identified small molecule inhibitors of DNA Ligases by computer aided drug design (CADD). Inhibition of DNA ligases and PARP result in a significant increase in apoptosis of CML cells (K562, Kasumi 4, MEG01 and KU812 and P210 MO7e), comparable with the cell death observed with imatinib treatment. Importantly, CML cell lines resistant to imatinib treatment demonstrate similar apoptotic levels in response to “back-up” repair protein inhibition. These inhibitors are in the process of being tested in CML xenografts and mouse models for therapeutic efficacy in vivo. Our data suggest that the survival of CML cells is at least in part maintained by repair of DSBs using “Back-up” NHEJ. The main proteins involved in this pathway, which include DNA ligase IIIα, XRCCI, DNA Ligase I, PARP and WRN have the potential to be novel therapeutic targets in CML patients that have acquired resistance to imatinib.

Long Term Adherence to Imatinib Therapy Is the Critical Factor for Achieving Molecular Responses in Chronic Myeloid Leukemia Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3290-3290 ◽  
Author(s):  
Alex Bazeos ◽  
Jamshid Khorashad ◽  
François-Xavier Mahon ◽  
Lina L Eliasson ◽  
Dragana Milojkovic ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Independent Predictor ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Adherence Rate ◽  
Molecular Response ◽  
Molecular Responses ◽  
Adherence To Therapy

Abstract Abstract 3290 Poster Board III-1 There is a great variability in the degree of molecular responses achieved by chronic myeloid leukemia (CML) patients treated with imatinib. These different levels of molecular response could reflect different degrees of adherence to therapy. We measured the adherence to imatinib therapy in 87 consecutive CML chronic phase patients who had received imatinib 400 mg day as first line therapy for a median of 59.7 months before enrolment (range 25–104) and therefore all them were in complete cytogenetic response. Adherence levels were monitored during a 3-month period using microelectronic monitoring devices (MEMS) and were related to levels of molecular response. MEMS consist of an electronic device fitted in the cap of a normal looking medication bottle that automatically records each time the bottle is opened. MEMS are considered as the ‘gold standard' for measuring adherence. We also measured the imatinib plasma level, the presence of TKD mutations and the following prognostic factors measured at diagnosis: hOCT1 transcripts level, polymorphism 1236C&gt;T in ABCB1, Sokal risk group, hemoglobin, leukocytes , BCR-ABL1 transcript type and BCR1-ABL1 ratio and demographic data. The study protocol was approved by the Research Ethics Committee and patients gave written informed consent to participate. The median adherence rate was 97.6% (range 22.6–103.8%). In 23 (26.4%) patients adherence was ≤90% (median 76%) and in 12 (13.8%) ≤80% (median 63%). We found a strong association between adherence rate (≤90% or &gt;90%) and the 6-year probability of major molecular response (MMR) (28.4% vs 94.5%, p&lt;0.0001) and complete molecular response (CMR) (0% vs 43.8%, p=0.002) (Fig 1). Multivariate analysis identified adherence (RR=11.7, p=0.001) and expression of the molecular transporter hOCT1, (RR=1.79, p=0.038) as the only independent predictors for MMR. Adherence was the sole independent predictor for CMR. No molecular responses were observed when the adherence was ≤20% (p=0.0001). In patients whose imatinib dose had been increased (n=32) the adherence was poor (median 86.4%). Adherence was the only independent predictor for failure to achieve a 3-log transcript reduction (RR=17.66, p=0.006) in this subgroup of patients. Patients with CML vary greatly in their response, as demonstrated originally by Sokal et al. in 1984, and the same variation is seen in patients treated with imatinib in the modern era. The basis for this variation is unknown but it has been attributed to the intrinsic biological heterogeneity of the leukemia. In contrast we show here that adherence to therapy is the major factor determining the degree of response that a CML patient treated with imatinib will achieve. Disclosures: Mahon: Novartis: Consultancy, Research Funding. Apperley:Novartis: Consultancy, Honoraria. Rezvani:Novartis: Consultancy, Honoraria, Research Funding. Marin:Novartis: Consultancy, Research Funding.

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