Optimal duration of imatinib treatment/deep molecular response for treatment‐free remission after imatinib discontinuation from a Canadian tyrosine kinase inhibitor discontinuation trial

2021 ◽  
Author(s):  
Dennis D. H. Kim ◽  
Igor Novitzky‐Basso ◽  
Taehyung S. Kim ◽  
Eshetu G. Atenafu ◽  
Donna Forrest ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Optimal Duration ◽  
Deep Molecular Response ◽  
Treatment Free Remission ◽  
Tyrosine Kinase Inhibitor Discontinuation

scholarly journals Tyrosine kinase inhibitor resistance in pediatric chronic myeloid leukemia: a case report

2020 ◽  
Vol 29 (4) ◽  
pp. 427-30
Author(s):  
Mururul Aisyi ◽  
Ayu Hutami Syarif ◽  
Nur Asih ◽  
Agus Kosasih
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Imatinib Resistance ◽  
Hematopoietic Malignancy ◽  
Optimal Response

Pediatric chronic myeloid leukemia (CML) is a hematopoietic malignancy, treated by tyrosine kinase inhibitor (TKI). Previously, imatinib resistance in CML was treated with nilotinib as a second line. However, in Indonesia, where the options of TKIs are limited, no case has been reported. We describe TKI-resistance of a pediatric CML case in Dharmais Cancer Hospital, Jakarta. A 17-year-old boy presented with loss of complete hematologic response after 4 years of imatinib treatment. Diagnosis of relapsed CML with blast crisis was confirmed, and nilotinib was given accordingly. He achieved hematological and optimal response after 2 weeks and 3 months of treatment, respectively. However, in the 12-month evaluation, he failed to achieve major molecular response and acquired the second resistance to TKI. Since imatinib resistance marks the poor prognosis, initial optimal response of nilotinib treatment remains inconclusive to predict the final outcome.

scholarly journals Results of following up patients with chronic myeloid leukemia and a deep molecular response without tyrosine kinase inhibitor therapy

2017 ◽  
Vol 89 (12) ◽  
pp. 86-96 ◽  
Author(s):  
A G Turkina ◽  
E Yu Chelysheva ◽  
V A Shuvaev ◽  
G A Gusarova ◽  
A V Bykova ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Therapy Discontinuation ◽  
Deep Molecular Response ◽  
Tki Discontinuation

Aim. To assess the results of following up patients with chronic myeloid leukemia (CML) and a deep molecular response (MR) without tyrosine kinase inhibitor (TKI) therapy. Subjects and methods. The reasons for TKI discontinuation in 70 patients with CML and a deep MR of more than 1 year’s duration were adverse events, pregnancy, and patients’ decision. Information was collected retrospectively and prospectively in 2008-2016. Results. The median follow-up after TKI therapy discontinuation was 23 months (2 to 100 months). At 6, 12 and 24 months after TKI therapy discontinuation, the cumulative incidence of major MR (MMR) loss was 28, 41 and 48%, respectively; the survival rates without TKI therapy were 69, 50, and 39%, respectively. MMR loss was noted in 28 (88%) patients at 12 months; it was not seen without TKI therapy at 2-year follow-up. Deaths due to CML progression were absent. The Sokal risk group was a reliable factor influencing MMR loss (p ≤ 0.05). The cumulative recovery rate for deep MR after resumption of TKI use was 73 and 100% at 12 and 24 months, respectively, with a median follow-up of 24 months (1 to 116 months). Deep MR recovered at a later time when the therapy was resumed more than 30 days after MMR loss. Conclusion. Safe follow-up is possible in about 50% of the patients with CML and stable deep MRs without TKI therapy. The introduction of this approach into clinical practice requires regular molecular genetic monitoring and organizational activities. Biological factors in maintaining remission after TKI discontinuation need to be separately studied.

Minimal Residual Resistance In CML: Stable BCR-ABL Gene Expression at Levels 0.01–0.1% (IS) In the Consecutive Samples May Be Associated with BCR-ABL Mutation Development and MMoR Lost In a Small Number of Tyrosine Kinase Inhibitor Responders.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3419-3419
Author(s):  
Katerina Machova Polakova ◽  
Sylvie Nadvornikova ◽  
Karla Zemanova ◽  
Hana Klamova ◽  
Tomas Jurcek ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Standard Dose ◽  
Direct Sequencing ◽  
Transcript Level ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
High Resolution Melt

Abstract Abstract 3419 In our previous study we showed that constant levels of BCR-ABL gene expression ≥ 0.1% (IS) in minimally 3 consecutive samples were associated with the mutation development and disease progression in small proportion of patients with chronic myeloid leukemia (CML) in complete cytogenetic remission after the imatinib treatment (Polakova KM et al. Exp Hem 2010;38:20). Here we aimed to reveal whereas the BCR-ABL transcript stable levels below the 0.1% but higher than 0.01% for minimally 9 months may be attributed to the resistance development. From 212 patients with major molecular response (MMoR) after the imatinib (n=169) and dasatinib (n= 43) treatment in standard dose, 10 of them (9 pts on imatinib and 1 pt on dasatinib) reached a plateau of BCR-ABL gene expression at levels between 0.01 and 0.1% (IS) by median 26 months (range 5–46) and remained unchanged for a median of next 22 months (range 9–41). High resolution melt curve analysis (HRM; Polakova KM et al. Leuk Res 2008;32:1236) was applied to analyze mutations in BCR-ABL kinase domain because of higher sensitivity in comparison to direct sequencing. The last 2–3 consecutive samples of peripheral blood total leukocytes of all 10 patients were analyzed. Good quality sequencing is dependent on the amount of total BCR-ABL transcript. The minimum for optimal direct sequencing performance is 0.1% (Polakova KM et al. Exp Hem 2010;38:20). Direct sequencing was in this study however possible applied in some low level BCR-ABL samples. The HRM positivity was found within the region spanning the P-loop in 2 patients and within the region of the activation loop in 1 patient. Two patients on imatinib lost MMoR with the significant BCR-ABL rise over the 0.1% and sequencing confirmed presence of M244V (100%) and M351T (100%) in 2 and 7 consecutive samples, respectively. In patient with M244V mutation, sequencing revealed the development of other mutation F359V during the next 10 months of follow-up with BCR-ABL transcript level rise from 0.6% to 2% in 3 subsequent samples, i.e. 9 months. The F359V mutant clone seemed to have proliferation advantage over the M244V. The patient on dasatinib has not shown any rise of BCR-ABL transcript up to now, i.e. 5 months after positive HRM. However in two out of the last three consecutive HRM positive samples P-loop mutation E255K (100%) was detected by direct sequencing. Based on our results it seems that BCR-ABL transcript level fluctuation at values within the range of 0.01% to 0.1% may be associated with mutation development and the MMoR lost in a number of CML patients after the tyrosine kinase inhibitor treatment. Supported by MZOUHKT2005, MSM0021622430, research grant from Bristol-Myers Squibb and CELL the Czech Leukemia Study Group for Life. Disclosures: Machova Polakova: Bristol-Myers Squibb: Research Funding.

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