Imatinib mesylate discontinuation in patients with chronic myeloid leukemia who have received front-line imatinib mesylate therapy and achieved complete molecular response

2012 ◽  
Vol 36 (6) ◽  
pp. 689-693 ◽  
Author(s):  
Ho-Young Yhim ◽  
Na-Ri Lee ◽  
Eun-Kee Song ◽  
Chang-Yeol Yim ◽  
So Yeon Jeon ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Molecular Response ◽  
Front Line ◽  
Complete Molecular Response

Imatinib Mesylate Therapy in Late Ph+ Chronic Myeloid Leukemia Patients in Stable Complete Cytogenetic Response after Interferon-Alpha Results in a Very High Complete Molecular Response Rate.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2158-2158
Author(s):  
Giuliana Alimena ◽  
Massimo Breccia ◽  
Luigia Luciano ◽  
Fabrizio Quarantelli ◽  
Daniela Diverio ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Complete Cytogenetic Response ◽  
Complete Molecular Response

Abstract Imatinib mesylate was given to 26 Philadelphia positive (Ph+) chronic myeloid leukemia (CML) patients who were in late chronic phase (CP) and in stable complete cytogenetic response (CCR) after interferon-alfa (IFN-α), but showed persistent positive residual disease at PCR analysis under this treatment. At diagnosis median age was 40 years (range 21–64) and according to Sokal’s score, 18 patients were low risk and 8 were intermediate risk. Median IFN treatment was 88 mo.s (range 15–202) and median CCR duration was 73 mo.s (range 10–148). Imatinib was administered at the standard dose of 400 mg/die, after stopping IFN for 1 week. Residual disease was measured on bone marrow (BM) cells at baseline, before starting Imatinib, at 3, 6, 12, 18 mo.s and at the last follow-up (median 32 mo.s, range 21–49), by assaying BCR-ABL transcripts using quantitative PCR (RQ-PCR). The copy number (CN) of BCR/ABL and ABL transcript were derived by the interpolation of CT values to the appropriate standard curve, and the result, for each sample, was expressed as ratio of BCR/ABL mRNA copies to ABL mRNA x 100 (normalized copy number - NCN). Imatinib treatment resulted in a progressive and consistent decline of residual disease in all but one patient, from a median of 0.89 at baseline to 0.01 at the end of follow-up. Major molecular response (BCR/ABL levels <0.1) was reached in 20 patients (77%) and BCR/ABL transcripts were undetectable in 13 (50%). Achievement of molecular response was significantly correlated with post-IFN baseline transcript level (mean 1.194 for patients achieving complete molecular response vs 18,97 for those who did not; p<0.001), but not with other clinical/biological patient characteristics. In all patients, imatinib was well tolerated with no side effects requiring drug dose reduction or dose discontinuation. Albeit obtained from an unusual subset of selected patients with favourable prognosis, and likely particularly sensitive to imatinib, present results confirm the efficacy of combining Imatinib and IFN-α and further support investigating treatment approaches employing these two drugs.

Pretherapeutic Expression of the hOCT1 Gene Predicts a Complete Molecular Response to Imatinib Mesylate in Chronic-Phase Chronic Myeloid Leukemia

2012 ◽  
Vol 127 (4) ◽  
pp. 228-234 ◽  
Author(s):  
Luciana Nardinelli ◽  
Sabri Saeed Sanabani ◽  
Alline Didone ◽  
Patricia de Barros Ferreira ◽  
Mariana Serpa ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Molecular Response ◽  
I Gene ◽  
Complete Molecular Response

Mutation Analysis of ABL1 Gene and its Relation to the Achievement of Major Molecular Response in Indonesian Chronic Myeloid Leukemia Patients

2020 ◽  
Vol 17 (1) ◽  
pp. 48-54
Author(s):  
Reni Widyastuti ◽  
Melva Louisa ◽  
Ikhwan Rinaldi ◽  
Riki Nova ◽  
Instiaty Instiaty ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Cross Sectional ◽  
Imatinib Resistance

Background: Imatinib mesylate is the first tyrosine kinase inhibitor approved for chronic myeloid leukemia (CML) therapy. Imatinib is an effective drug. However, previous studies have shown that about 20-30% of patients eventually would develop resistance to imatinib. Approximately 40% of imatinib resistance is associated with BCRABL kinase domain mutation. One of the most common and serious variations account for imatinib response is T315I of ABL1 gene. Objective: The study aimed to examine the association of T315I mutation with the ABL1 gene and its relation to major molecular response (MMR) achievement in CML patients. This study also examined other mutations adjacent to T315I, i.e., F311I, F317L, and different possible variations in the ABL1 gene. Methods: This was a cross-sectional study on Indonesian CML patients in chronic phase. We analyzed 120 blood samples from patients in chronic phase who have received imatinib mesylate (IM) for ≥12 months. Results: There were no T315I, F311I, and F317L mutations found in this study. However, we found another variation, which was 36 substitutions from A to G at position 163816 of ABL1 gene (according to NG_012034.1). Conclusions: We found no T315I, F311I, and F317L mutations in this study. Our findings suggest that there might be other factors that influenced the MMR achievement in our study patients. However, there were 36 substitutions from A to G at position 163.816 (according to NG_012034.1) that needed further examination to explore the significance of this mutation in clinical practice.

Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4497-4504 ◽  
Author(s):  
Michele Baccarani ◽  
Gianantonio Rosti ◽  
Fausto Castagnetti ◽  
Ibrahim Haznedaroglu ◽  
Kimmo Porkka ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Standard Treatment ◽  
Response Rate ◽  
Standard Dose ◽  
High Dose ◽  
Molecular Response ◽  
Front Line ◽  
To Receive

AbstractImatinib mesylate (IM), 400 mg daily, is the standard treatment of Philadelphia-positive (Ph+) chronic myeloid leukemia (CML). Preclinical data and results of single-arm studies raised the suggestion that better results could be achieved with a higher dose. To investigate whether the systematic use of a higher dose of IM could lead to better results, 216 patients with Ph+ CML at high risk (HR) according to the Sokal index were randomly assigned to receive IM 800 mg or 400 mg daily, as front-line therapy, for at least 1 year. The CCgR rate at 1 year was 64% and 58% for the high-dose arm and for the standard-dose arm, respectively (P = .435). No differences were detectable in the CgR at 3 and 6 months, in the molecular response rate at any time, as well as in the rate of other events. Twenty-four (94%) of 25 patients who could tolerate the full 800-mg dose achieved a CCgR, and only 4 (23%) of 17 patients who could tolerate less than 350 mg achieved a CCgR. This study does not support the extensive use of high-dose IM (800 mg daily) front-line in all CML HR patients. This trial was registered at www.clinicaltrials.gov as #NCT00514488.

scholarly journals BCL2L11 (BIM) Deletion Polymorphism Is Associated with Molecular Relapse after ABL Tyrosine Kinase Inhibitor Discontinuation in Patients with Chronic Myeloid Leukemia with Complete Molecular Response

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1797-1797 ◽  
Author(s):  
Seiichiro Katagiri ◽  
Tetsuzo Tauchi ◽  
Yuu Saito ◽  
Tamiko Sugro ◽  
Michiyo Asano ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Molecular Response ◽  
Deletion Polymorphism ◽  
Significant Difference ◽  
Treatment Free Remission ◽  
Tki Discontinuation ◽  
Complete Molecular Response

Abstract Background: The inhibition of BCR-ABL1 kinase with tyrosine kinase inhibitors (TKIs) has markedly improved the prognosis of chronic myeloid leukemia (CML). Recently, it has been recognized that some CML patients with a complete molecular response (CMR) are able to maintain treatment-free remission (TFR) after discontinuation of TKIs. However, no predictive prognostic factors for successful discontinuation of the treatment have yet been identified. We set out to further clarify the role of predictive biomarkers in molecular relapse and non-relapse after ABL TKI discontinuation. Materials and methods: Patients in sustained CMR (MR 4.5) undergoing TKI therapy were eligible for inclusion in the study. Molecular relapse was defined as loss of major molecular response (MMR) of at least one point. Genomic DNA was obtained from whole blood using a DNA Extractor WB Kit (Wako, Osaka, Japan), and was subjected to polymerase chain reaction (PCR) amplification using primers designed to detect a deletion site (2903 bp) in intron two of the BCL2L11 gene (forward: 5′-AATACCACAGAGGCCCACAG-3′; reverse: 5′-GCCTGAAGGTGCTGAGAAAG-3′) and JumpStart RedAccuTaq LA DNA polymerase (Sigma Aldrich, St. Louis, MO, USA). Results: 32 CML patients (17 men, 15 women, median age 58.4 years) were included in this study (Sokal category; low 24, intermediate 7, high 1). Six patients were treated with IFNα before TKI treatment, and 3 were treated with IFNα after stopping TKI. Median duration from TKI initiation to discontinuation was 79.3 months (range; 22 to 138 months); median duration of CMR before TKI discontinuation was 47.3 months (range; 5 to 97 months). Seven patients showed loss of MMR; 6 relapsed within 6 months and one showed late relapse at 25 months after discontinuation. The cumulative incidence of MMR loss was estimated as 18.8% at 12 months and at 24 months. Fluctuation of BCR-ABL transcript levels below the MMR threshold (> two consecutive positive values) was observed in 6.25% of patients at 24 months after ABL TKI discontinuation. Treatment-free remission was estimated as 81.2% at 12 months and at 24 months. The median period of restoration of second CMR was 6.0 months in re-treated patients. No patient died during the follow-up period. TKI-free remission was estimated as 78.1% at 30 months. There was only a significant difference in BCL2L11 (BIM) deletion polymorphism between the patients who maintained and those who lost MMR (p = 0.0253). No significant difference was observed in prior IFNα therapy, time to complete cytogenetic response (CCyR), time to MMR, and time to CMR between relapsing and non-relapsing patients. Conclusion: Our study shows a specific association between BCL2L11 (BIM) deletion polymorphism and clinical outcome after ABL TKI discontinuation in patients with long-lasting molecular undetectable residual disease. BCL2L11 (BIM) deletion polymorphism may predict relapse after ABL TKI discontinuation, which may have an impact on future ABL TKI discontinuation trials. These results further illustrate the importance of single nucleotide polymorphisms in successful long-term treatment of CML. Disclosures Ohyashiki: Bristol-Myers Squibb KK : Research Funding, Speakers Bureau; Novartis KK: Research Funding, Speakers Bureau.

scholarly journals Safety and efficacy of nilotinib after 10 years of interferon

2015 ◽  
Vol 6 (2S) ◽  
pp. 19-22
Author(s):  
Filippo Russo
Keyword(s):  
High Risk ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Interferon Alfa ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Safety And Efficacy ◽  
Optimal Response ◽  
Complete Molecular Response

Here we describe a case of a woman with chronic myeloid leukemia at high risk, according to the Sokal Index. The patient started interferon alfa-2b (IFN) at standard dose obtaining a major molecular response after about four years of treatment. After about 10 years the patient presented a toxicity from IFN and different comorbidities, so she was switched to nilotinib and achieved a complete molecular response (MR4). This case shows how nilotinib is effective and tolerable also in patients with multiple comorbidities. Keywords: Chronic myeloid leukemia; Optimal response; Nilotinib; Interferon alfa-2b

scholarly journals Generic Imatinib in Chronic Myeloid Leukemia: Survival of the Cheapest

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 630-630 ◽  
Author(s):  
Danthala Madhav
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Quantitative Polymerase Chain Reaction ◽  
Comparable Efficacy ◽  
Molecular Response ◽  
Free Survival

Abstract Introduction: The patent expiration of Imatinib mesylate (Glivec, ®Novaritis) on February 1, 2016, has brought the focus back on generic versions of the drug, and an opportunity to provide a safe and cost effective alternative. India has witnessed a mushrooming of home grown pharmaceutical companies, that have drawn on Darwinian theory to promote the concept of "survival of the cheapest", in pursuit of a deeper penetrance into the cash strapped population. The launch of Veenat (®NATCO pharma) at a fraction of the price of the innovator drug is a case in point. Objectives: To determine the molecular and cytogenetic responses, survival endpoints (event free survival (EFS), failure free survival (FFS), transformation free survival (TFS), overall survival (OS), and safety of innovator and generic brands of imatinib. Materials and Methods: In this retrospective analysis, data from 1,812 patients with chronic myeloid leukemia (CML) treated with frontline Imatinib mesylate (Innovator/Generic) at a single institution between 2008 and 2014 is included. Of these 1,812 patients, 445 were excluded due to inadequate data and follow up. Thus, data from 1,193 patients who were treated with Glivec (®Novartis), and 174 patients with Veenat (®NATCO) was available. Observations: A higher percentage of patients in the generic arm compared to the innovator arm, were in accelerated phase (9.7% vs 6.7%) and blast crisis (7.4% vs 3.7%), respectively.After a median follow up of 1,347 days, 805 (67.4%) patients achieved complete cytogenetic response (CCgR), 259 (21.7%) achieved major molecular response (MR3), and 205 (17.1%) achieved 4 log reduction in BCR ABL transcripts (MR4) in the innovator arm. After a median follow up of 1,220 days, 112 (64.3%), 24 (13.7%), and 42(24.1%) patients achieved a CCgR, MR3 and MR4 respectively, in the generic arm.Follow up assessments using real-time quantitative polymerase chain reaction (q-PCR) and/ or cytogenetic tests were not available in 230 (19.2%) and 40 (22.9%) patients, in the innovator and generic groups respectively, despite inclusion in a sponsorship program.Adherence to treatment was poor in 192 (16%) and 30 (17.2%) patients in the innovator and generic arms respectively. Results: In a fairly homogenous population of lower economic strata, on a free drug access program, the prime factors influencing adherence were low educational level, assumptions of "cure", recent bereavement, stigma of cancer diagnosis and repeated hospital visits. Transformation to accelerated/blast phase occurred in 7.7% and 7.4% of patients in the innovator and generic arms respectively. Testing for BCR-ABL1 mutations was done in 31 (17.8%) patients in the generic arm and 132(11%) patients in the innovator arm, after failure of treatment or suboptimal response. Mutations were identified in 14 (8%) patients in the generic arm and 52 (4.3%) patients in the innovator arm.The most common subsequent treatments chosen were, dose escalation (249 [20.8%] vs 30 [17.2%]), Nilotinib (26 [2.1%] vs 8 [4.5%]), Dasatinib (11 [0.9%] vs 9 [5.1%]) and hydroxyurea (11 [0.9%] and 4 [2.2%]) in the innovator and generic arms respectively. There was no difference in EFS (p=0.46), FFS (p=0.16), TFS (p=0.9), or OS (p=0.13) between the two groups. The frequency of reported grade 1, or 2 non-hematological adverse events which included musculoskeletal pain, muscle cramps, and peripheral edema, and hematological adverse events was comparable between the study groups. However, the incidence of grade 3 skin rash was higher in the generic group (2.8%) in comparison to the innovator group (0.2%). Conclusion: The findings of the present study showed comparable efficacy and safety of the generic and innovator versions of imatinib in the treatment of patients with chronic myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

Imatinib mesylate experience of young patients with chronic myeloid leukemia in chronic phase—Care to cure

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7072-7072
Author(s):  
D. Biswajit ◽  
R. Rejiv ◽  
N. Manjunath ◽  
G. Prasad ◽  
S. Lakshmi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Adverse Effects ◽  
Stem Cell Transplantation ◽  
Imatinib Mesylate ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Young Patients ◽  
Chronic Phase ◽  
Molecular Response

7072 Background: Chronic myeloid leukemia (CML) with introduction of imatinib has been transformed into a chronic illness. The options of treatment in a patient less than 35 years include imatinib or allogenic stem cell transplantation. Hence we studied this unique subset to look at the response rates, adverse effects, progression free survival, and overall survival with imatinib mesylate. Methods: 477 patients with Philadelphia positive CML in chronic phase were retrospectively analyzed from January 2002 to December 2007 at Cancer Institute (WIA), Chennai, India. Standard criteria were used for response evaluation and adverse effects. Results: A total of 248 young CML patients with age less than 35 years (51.9%) were diagnosed in chronic phase. The median age of study population was 27 years (4–35). The male to female ratio was 1.9: 1. Risk stratification was done using Sokal index and were classified into low (32.3%), intermediate (50.4%), and high (17.3%). All patients received imatinib 400 mg as the initial dose. Complete hematological remission (CHR) was seen in 96.7%.Cytogenetic (FISH) and molecular (RTPCR) monitoring was possible in 53.2% and 17.3%, respectively. 72% of the patients had major cytogenetic response. Major molecular response was seen in 34.8% while complete molecular response occurred in 23.2% of the patients. Primary and secondary imatinib failure was seen in 3.1% and 16.9%, respectively. 6.7% had grade 3 and grade 4 hematological toxicities. The other common non hematological toxicities included pedal edema (13.7%), hypo or hyper pigmentation (60.0%), hyalgia (14.5%), diarrhea (1.6%), and liver dysfunction (1.6%). None of the patients discontinued imatinib due to toxicities. The 3-year DFS and OS was 86.2% and 89.5%, respectively. Patients with male sex (p = 0.04), spleen > 8 cm (p = 0.02), high sokal index (p = 0.02), and loss of CHR (p < 0.001) were associated with poor outcome. Conclusions: Imatinib in young patients have an excellent tolerance and response. A small subset does not respond to therapy or develop resistance during treatment. Hence it is essential to identify these poor responders and to offer stem cell transplantation at the earliest. No significant financial relationships to disclose.

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