scholarly journals Adherence Is the Critical Factor for Achieving Molecular Responses in Patients With Chronic Myeloid Leukemia Who Achieve Complete Cytogenetic Responses on Imatinib

2010 ◽  
Vol 28 (14) ◽  
pp. 2381-2388 ◽  
Author(s):  
David Marin ◽  
Alexandra Bazeos ◽  
Francois-Xavier Mahon ◽  
Lina Eliasson ◽  
Dragana Milojkovic ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Independent Predictor ◽  
Chronic Phase ◽  
Critical Factor ◽  
Organic Cation Transporter ◽  
Poor Adherence ◽  
Adherence Rate ◽  
Molecular Response ◽  
Molecular Responses

Purpose There is a considerable variability in the level of molecular responses achieved with imatinib therapy in patients with chronic myeloid leukemia (CML). These differences could result from variable therapy adherence. Methods Eighty-seven patients with chronic-phase CML treated with imatinib 400 mg/d for a median of 59.7 months (range, 25 to 104 months) who had achieved complete cytogenetic response had adherence monitored during a 3-month period by using a microelectronic monitoring device. Adherence was correlated with levels of molecular response. Other factors that could influence outcome were also analyzed. Results Median adherence rate was 98% (range, 24% to 104%). Twenty-three patients (26.4%) had adherence ≤ 90%; in 12 of these patients (14%), adherence was ≤ 80%. There was a strong correlation between adherence rate (≤ 90% or > 90%) and the 6-year probability of a 3-log reduction (also known as major molecular response [MMR]) in BCR-ABL1 transcripts (28.4% v 94.5%; P < .001) and also complete molecular response (CMR; 0% v 43.8%; P = .002). Multivariate analysis identified adherence (relative risk [RR], 11.7; P = .001) and expression of the molecular human organic cation transporter-1 (RR, 1.79; P = .038) as the only independent predictors for MMR. Adherence was the only independent predictor for CMR. No molecular responses were observed when adherence was ≤ 80% (P < .001). Patients whose imatinib doses were increased had poor adherence (86.4%). In this latter population, adherence was the only independent predictor for inability to achieve an MMR (RR, 17.66; P = .006). Conclusion In patients with CML treated with imatinib for some years, poor adherence may be the predominant reason for inability to obtain adequate molecular responses.

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.

hOCT1 Gene Expression Might Predict Molecular Response In Patients with Chronic Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4838-4838
Author(s):  
Lurdes Zamora ◽  
Marta Cabezon ◽  
Concha Boqué ◽  
Silvia Marce ◽  
Jordi Ribera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Chronic Phase ◽  
Organic Cation Transporter ◽  
Initial Response ◽  
Molecular Response ◽  
Hematopoietic Malignancy

Abstract Abstract 4838 Introduction: Chronic myeloid leukemia (CML) is a clonal hematopoietic malignancy characterized by the presence of BCR/ABL fusion gene. The resulting protein has a high tyrosine kinase (TK) activity. The first-line treatment for CML is Imatinib, which allow the achievement of cytogenetic and molecular response in most of patients with CML in chronic phase. However, some patients do not respond to this treatment or lose their initial response. Imatinib has been reported to be incorporated into the cell through hOCT1 transporter (human organic cation transporter). The aim of this study was to determine whether the expression of hOCT1 at diagnosis of CML influenced the achievement of molecular response. Patients and Methods: We analyzed hOCT1 gene expression by quantitative PCR in 42 patients at diagnosis and 18 months after treatment with Imatinib. We compared the expression with the presence of compleat molecular response (CMR) at 18 months. We consider CMR when the Ratio (BCR-ABL/ABL)×100 was <0.1% (after International Scale correction). For statistical analysis methods we have used Kolmogorov-Smirnov and Mann-Whitney nonparametric methods. Results: Of the 42 patients, 2 were in hematological response, 22 were in cytogenetic response and 18 in CMR at 18 months. We found a higher hOCT1 gene expression at 18 month than at diagnosis (53.3 versus 29.6, p<0.001) in all patients (Figure 1). We have found some tendency of higher hOCT1 expression at diagnosis in patients with CMR at 18 months than in those who did not had (25.5 versus 18.8, p = 0.07) (Figure 2). Conclusions: Partially funded by FICJ-P-EF-09, RD06/0020/1056 de RTICC and Novartis. We want to thank Dr. David Marin for providing us plasmid for quantitative analysis. Disclosures: No relevant conflicts of interest to declare.

Prognostic Significance of hOCT1 and ABCG2 Expression in Chronic Myeloid Leukemia Patients Treated with Imatinib

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5033-5033
Author(s):  
Yeo-Kyeoung Kim ◽  
Hee-Nam Kim ◽  
Ri Yu ◽  
Il-Kwon Lee ◽  
Jae-Sook Ahn ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Statistical Significance ◽  
Prognostic Significance ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Organic Cation Transporter ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Mrna Levels

Abstract Background: Imatinib mesylate is a substrate for both the drug influx transporter human Organic Cation Transporter 1 (hOCT1; SLCA22) and the efflux transporter ATP-binding cassette transporters (ABCG2; BCRP). The correlation between the expression of these two transporters of imatinib and the clinical outcome of imatinib in chronic myeloid leukemia (CML) patients remain clarified. Methods: hOCT-1 and ABCG2 mRNA levels were determined by performing real-time polymerase chain reaction assays on 83 BM samples obtained at initial diagnosis from the patients with chronic phase CML treated with imatinib (started at 400mg/day). Results: Of patients with higher hOCT-1 mRNA expression than median value (≥ 34.53 a.u.) at diagnosis, 59.5% achieved complete cytogenetic response (CCyR) at 6 months, whereas of patients with no more than a median hOCT-1 expression, 33.3% could achieve CCyR at 6 months (p=0.035). Furthermore, patients with low hOCT-1 showed higher rate of suboptimal response [failed to achieve complete hematologic response (CHR) by 3 months, major cytogenetic response (MCyR) by 6 months, CCyR by 12 months, and major molecular response (MMR) by 18 months] than those with high hOCT-1 expression (55.9% vs. 33.3%. p=0.048). There was no statistical significance in progression-free survival (PFS) or overall survival (OS) according to the hOCT-1 expression levels. Patients with low ABCG2 expression (&lt; 13.53 a.u.) showed higher MMR rate at 18 months (57.1% vs. 35.5 %, p=0.09) and longer PFS (3 yr PFS, 87.2% vs. 64.1%, p=0.07) than those with high ABCG2 expression but there was no statistical significance. The time to achieving MMR was significantly shorter in patients with low ABCG2 expression than in those with high ABCG2 expression (6.9 ± 2.1 ms vs. 12.2 ± 4.2 ms, p=0.09). The patients with high hOCT-1 expression showed shorter time to achieving MMR, but there was no statistical significance (8.1 ± 1.9 vs. 10.5 ± 1.7, p=0.50). Conclusions: This study demonstrates that pretreatment assay of hOCT-1 and ABCG2 expression may help us to identify the treatment outcome in the CML patients treated with imatinib.

scholarly journals Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy

Blood ◽  
2011 ◽  
Vol 117 (14) ◽  
pp. 3733-3736 ◽  
Author(s):  
Amr R. Ibrahim ◽  
Lina Eliasson ◽  
Jane F. Apperley ◽  
Dragana Milojkovic ◽  
Marco Bua ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cytogenetic Response ◽  
Poor Adherence ◽  
Adherence Rate ◽  
Lower Probability ◽  
Term Therapy ◽  
Molecular Response ◽  
Long Term Therapy

Abstract We studied the relation between adherence to imatinib measured with microelectronic monitoring systems and the probabilities of losing a complete cytogenetic response (CCyR) and of imatinib failure in 87 CCyR chronic myeloid leukemia patients receiving long-term therapy. We included in our analysis the most relevant prognostic factors described to date. On multivariate analysis, the adherence rate and having failed to achieve a major molecular response were the only independent predictors for loss of CCyR and discontinuation of imatinib therapy. The 23 patients with an adherence rate less than or equal to 85% had a higher probability of losing their CCyR at 2 years (26.8% vs 1.5%, P = .0002) and a lower probability of remaining on imatinib (64.5% vs 90.6%, P = .006) than the 64 patients with an adherence rate more than 85%. In summary, we have shown that poor adherence is the principal factor contributing to the loss of cytogenetic responses and treatment failure in patients on long-term therapy.

scholarly journals Early BCR-ABL1 kinetics are predictive of subsequent achievement of treatment-free remission in chronic myeloid leukemia

Blood ◽  
2020 ◽  
Author(s):  
Naranie Shanmuganathan ◽  
Ilaria Stefania Pagani ◽  
David M Ross ◽  
Sahee Park ◽  
Agnes SM Yong ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Independent Predictor ◽  
Chronic Phase ◽  
Patient Specific ◽  
Molecular Response ◽  
Response Dynamics ◽  
Multiple Variables ◽  
Treatment Free Remission ◽  
The Impact

With treatment-free remission (TFR) rapidly becoming the ultimate goal of therapy in chronic myeloid leukemia (CML), there is a need to develop strategies to maximise sustained TFR by improving our understanding of its key determinants. Chronic phase CML patients attempting TFR were evaluated to identify the impact of multiple variables on the probability of sustained TFR. Early molecular response dynamics were included as a predictive variable, assessed by calculating the patient-specific halving time of BCR-ABL1 after commencing tyrosine kinase inhibitor (TKI) therapy. Overall, 115 patients attempted TFR and had ≥12 months follow-up. The probability of sustained TFR, defined as remaining in major molecular response off TKI therapy for 12 months, was 55%. The time taken for the BCR-ABL1 value to halve was the strongest independent predictor of sustained TFR: 80% in patients with a halving time of &lt;9.35 days (first quartile) compared with only 4% if the halving time was &gt;21.85 days (last quartile) (P&lt;.001). The e14a2 BCR-ABL1 transcript type and duration of TKI exposure before attempting TFR were also independent predictors of sustained TFR. However, the BCR-ABL1 value measured at 3 months of TKI was not an independent predictor of sustained TFR. A more rapid initial BCR-ABL1 decline after commencing TKI also correlated with an increased likelihood of achieving TFR eligibility. The association between sustained TFR and the time taken for BCR-ABL1 to halve after commencing TKI was validated using an independent dataset. These data support the critical importance of the initial kinetics of BCR-ABL1 decline for long-term outcomes.

scholarly journals Generic Versus Branded Imatinib As Frontline Therapy in Chronic-Phase Chronic Myeloid Leukemia Patients in Italy: A Case-Control Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5909-5909
Author(s):  
Massimiliano Bonifacio ◽  
Mario Tiribelli ◽  
Gianni Binotto ◽  
Maria Cristina Miggiano ◽  
Marco Basso ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Historical Cohort ◽  
Molecular Responses ◽  
Sokal Score

Introduction. Imatinib is the most commonly used frontline drug in chronic phase (CP) chronic myeloid leukemia (CML) patients worldwide. In early 2017 a generic formulation of imatinib was introduced in Italy and uniformly replaced branded imatinib (Glivec®), upon requirement of regional health authorities. In the last years various groups reported on the efficacy and safety of generic imatinib with conflicting results, partly related to substandard pharmaceutical quality of some products used in developing countries. In a multicenter cohort of 294 patients treated in Italy with branded imatinib for at least 6 months and then switched to generic imatinib we observed that the majority of patients maintained or improved their molecular response. Here, we analyzed patients who received generic imatinib since diagnosis. Aims. To analyze the rates of molecular responses at 3, 6 and 12 months and of treatment discontinuation in CML patients treated frontline with generic imatinib, compared to a case-matched historical cohort of CML patients who received frontline branded imatinib at our institutions. Methods. We analyzed 31 newly diagnosed CP-CML patients consecutively enrolled in a prospective observational registry between January 2017 and July 2018, treated frontline with generic imatinib 400 mg/day (diverse manufacturers) and evaluable for all the ELN2013 molecular milestones (if not discontinued earlier). They were compared to a retrospective cohort of 31 patients, matched for age, gender, and Sokal risk, diagnosed between 2007 and 2014 and treated with branded imatinib 400 mg/day for at least 24 months before eventual switching to a generic formulation. Definitions of molecular responses were made according to the ELN2013 recommendations. Results. A total of 62 patients were included in the analysis: 31 patients (21 males and 10 females) treated with generic imatinib ("cases") and 31 treated with branded imatinib ("controls"). Median age at diagnosis of the cases was 68 years (range 33-89), Sokal score was low/intermediate/high in 8 (26%), 19 (61%) and 4 (13%) patients, respectively. The controls were matched for gender, age (+/- 4 years, median age 68, range 35-85) and Sokal score. As median follow-up time for the cases was 18.6 months (range 2.2-28.5), controls were censored at 24 months after imatinib start. Optimal molecular response at 3 months was attained in 23/30 (76.7%) cases and in 18/29 (62%) controls (p=0.35); one case died after 2 months of imatinib therapy for a CML-unrelated cause, while 2 controls were molecularly not evaluable. At 6 months, 17/29 (58.6%) cases and 17/30 (56.7%) controls achieved BCR/ABL transcript <1%, respectively (p=1). At 12 months, MMR was attained by 14/30 (46.7%) cases and by 13/29 (44.8%) controls (p=1). Twelve out of 31 patients (38.7%) permanently discontinued generic imatinib due to warning/failure response (n=6), intolerance (n=4) or death while on treatment at 2 and 13 months (meningoencephalitis of unknown origin and cardiovascular event, respectively). Among patients treated with branded imatinib, 12/31 (38.7%) stopped within the 24th month of therapy for resistance (n=8), intolerance (n=3) or death at 16 months (acute renal failure). No patient receiving generic imatinib progressed to advanced phase, while one control developed a blast crisis at 6 months of branded imatinib and deceased shortly after. Estimated overall survival at 24 months in cases and controls was 92.5% and 93.1%, respectively. Conclusions. Our preliminary data suggest an equivalent efficacy of generic imatinib compared to a matched population of historical patients treated with the originator drug in Italy. A continue pharmacovigilance by reporting efficacy and safety outcomes of generic drugs is needed to ensure an optimal management of CML patients. Disclosures Bonifacio: Novartis: Honoraria, Research Funding; Amgen: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Tiribelli:Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Krampera:Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

Early Assessment of Molecular Response in Chronic Myeloid Leukemia Patients On Dasatinib After Imatinib Failure Identify Patients with Poor Cytogenetic and Molecular Responses

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3787-3787
Author(s):  
Katia B. Pagnano ◽  
Beatriz F Ribeiro ◽  
Eliana C M Miranda ◽  
Marcia T Delamain ◽  
Carmino Antonio De Souza ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Internal Control ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Molecular Response ◽  
Early Assessment ◽  
Molecular Responses ◽  
Free Survival ◽  
Dasatinib Treatment

Abstract Abstract 3787 Dasatinib is effective at inducing complete cytogenetic response (CCyR) in approximately half of chronic myeloid leukemia (CML) patients treated in the chronic phase (CP) after failing imatinib. The aim of this work was to evaluate the role of molecular monitoring in predicting the outcome of patients treated with dasatinib after imatinib therapy. Between 2008 and 2012, it was analyzed 55 consecutive patients with CML with imatinib intolerance or resistance treated in a single center. Patients received dasatinib (50–140 mg) as second or third line therapy. Cytogenetic analysis was performed at 3, 6, 12 and 18 months after dasatinib introduction. BCR-ABL1 transcripts were measured in the blood at 3 months intervals using real-time quantitative PCR (RQ-PCR). Results were expressed as percent ratios relative to an ABL1 internal control. Major molecular response (MMR) was defined as a transcript level ≤ 0.1% on the international scale. Kinase domain (KD) mutations were performed before starting therapy and/or after dasatinib resistance. The probabilities of overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) were calculated using the Kaplan-Meier method. An event was defined as the loss of a CCyR or complete hematologic response, progression to AP and BP, death, or discontinuation of dasatinib. The probabilities of cytogenetic and molecular responses were calculated using cumulative incidence (CI) and x2method. Results: 33 patients were male (60%) and 22 female (40%), with median age of 48 years (15–81). At diagnosis Sokal scores were low for 11/34 (32.4%), intermediate for 6 (17.6%) and high for 17 (50%) (21 NA). Thirteen patients had a previous CCyR with imatinib. The median time between diagnosis and dasatinib treatment was 25 (2–223) months. The median follow-up was 12 months. Disease phase at beginning of dasatinib treatment: 32 (58%) CP, 13 (24%) accelerated phase (AP) e 10 (18%) blast phase (BP). Eight-seven percent achieved RHC, 55% CCyR and 38% MMR. At 3 months 67% (25/37) had BCR-ABL1/ABL1 transcript ratio '10%, at 6 months 48% (14/29) ≤ 1% and at 12 months 27% (6/22) RQ-PCR ≤ 0.1%. After introduction of dasatinib, patients with the 3-month BCR-ABL1/ABL1 transcript ratio of >10% had a lower chance of achieving CCyR (12.5% vs 81.5%, p= 0.001) and MMR (8.3% vs. 58.3%, p= 0.005). Patients with the 6-month BCR-ABL1/ABL1 transcript ratio of >1% had a lower chance of achieving CCyR (8% vs. 75%, p= 0.01) and MMR (26.6% vs. 64.2%, p=0.06) compared with patients with ratio ≤ 1%. The probability of OS, PFS and EFS in 48 months while on treatment was 83%, 70% and 29%, respectively. PFS was 88%, 76% e 11% in CP, AP and BP respectively (p< 0.0001). EFS was 36%, 32% e 10% in CP, AP and BP (P< 0.0001). Dasatinib was discontinued in 26/55 because of resistance (12), intolerance (5) or transplant (1). BCR-ABL KD mutations were detected in 13/38 cases, two before (L387M e M351T) and 11 during dasatinib treatment (T315I-6, M244V-2, E255V-1, E499E-1, M351T-1). Patients with mutations had an inferior EFS (p=0,05). In conclusion, this study indicates that evaluation of molecular response at 3 and 6 months can identify patients with less chance of response to dasatinib in patients with imatinib failure. The early identification of patients with poor outcome is important for planning future treatments. Disclosures: No relevant conflicts of interest to declare.

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