MEANING OF MOLECULAR RESPONSES FLUCTUATION IN CHRONIC MYELOID LEUKEMIA PATIENTS TREATED WITH LONG-TERM IMATINIB
(Abstract release date: 05/19/16)
EHA Library. Breccia M. 06/09/16; 132647; E1098
Disclosure(s): Honoraria from Novartis, Bristol-Myers Squibb, Pfizer, Ariad
Dr. Massimo Breccia
Contributions
Contributions
Abstract
Abstract: E1098
Type: Eposter Presentation
Background
Prognostic significance of molecular response fluctuation in the long-term outcome during imatinib treatment in chronic phase chronic myeloid leukemia (CP-CML) patients have not been so far reported in details.
Aims
Aim of our study was to correlate, over a median follow-up period of 7 years, how instability of molecular response can affect overall survival (OS) and failure-free survival (FFS).
Methods
A series of 208 patients treated with imatinib first-line was retrospectively analysed. There were 144 males and 94 females, median age was 57.7 years. According to the IS, we considered as MR3 a BCR-ABL/ABL ratio of ≤ 0.1%, as MR4 a ratio ≤0.01% and as MR4.5 a ratio ≤ 0.0032%; stable response was defined as a response that persisted over 3 consecutive RQ-PCR tests, whereas fluctuation, was defined as the alternation of a test that reached or was below the threshold ratio according to IS and the consecutive was above the threshold. We considered OS the time elapsed from diagnosis to death for any cause, and FFS the timespan that follows therapy without signs of recurrence (loss of hematologic and/or cytogenetic response, acquisition of clonal cytogenetic abnormalities or mutations).
Results
At a median follow-up of 7 years, overall incidence of MR3 was 64.4%: during the course of treatment, 17 patients (11.6%) had a fluctuation above and then below the cut-off of 0.1%. Of these 17 patients, 13 (76%) lost the response and 3 subsequently developed secondary resistance (17.6%) with an estimated FFS of 82.4% and an OS of 94.6% at 7 years. Considering the threshold of MR3, of the remaining 117 patients that never had a fluctuation and maintained a stable response over time, only 3 (2.5%) subsequently lost the response and developed secondary resistance with an estimated FFS of 93.2% (p=0.02) and OS of 94% (p=ns). All patients were analysed for mutational screening according to Sanger sequencing analysis: only two patients were found to develop a mutation of the ABL1 kinase domain, in particular 1 patient a E255K and 1 patient a M351T. Cumulative incidence of MR4 was 51% and of MR4.5 was 34.6%, obtained after a median time of 3.8 and 5.4 years, respectively. Overall, 7 patients (6.5%) showed a fluctuation of MR4 response and 4 subsequently lost the response. None of these patients showed secondary resistance or acquired mutations in the ABL kinase domain and main reason for loss of response was confirmed to be low adherence to long-term treatment. Eighteen patients (25%) showed an unstable MR4.5, but none of them developed secondary resistance or progressed to blast phase. Considering the threshold of MR4, fluctuation of molecular burden was associated to FFS of 100% and to OS of 98.2% as compared to patients with stable response that had a FFS of 99.4% and OS of 97.8%, without any statistical significance.
Conclusion
Our results showed that unstable MR3 was indeed associated to an increased probability to develop resistance, whereas long-term fluctuation of deeper molecular response (MR4-4.5) did not influence the long-term outcome of CML patients treated with imatinib.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia, RQ-PCR
Type: Eposter Presentation
Background
Prognostic significance of molecular response fluctuation in the long-term outcome during imatinib treatment in chronic phase chronic myeloid leukemia (CP-CML) patients have not been so far reported in details.
Aims
Aim of our study was to correlate, over a median follow-up period of 7 years, how instability of molecular response can affect overall survival (OS) and failure-free survival (FFS).
Methods
A series of 208 patients treated with imatinib first-line was retrospectively analysed. There were 144 males and 94 females, median age was 57.7 years. According to the IS, we considered as MR3 a BCR-ABL/ABL ratio of ≤ 0.1%, as MR4 a ratio ≤0.01% and as MR4.5 a ratio ≤ 0.0032%; stable response was defined as a response that persisted over 3 consecutive RQ-PCR tests, whereas fluctuation, was defined as the alternation of a test that reached or was below the threshold ratio according to IS and the consecutive was above the threshold. We considered OS the time elapsed from diagnosis to death for any cause, and FFS the timespan that follows therapy without signs of recurrence (loss of hematologic and/or cytogenetic response, acquisition of clonal cytogenetic abnormalities or mutations).
Results
At a median follow-up of 7 years, overall incidence of MR3 was 64.4%: during the course of treatment, 17 patients (11.6%) had a fluctuation above and then below the cut-off of 0.1%. Of these 17 patients, 13 (76%) lost the response and 3 subsequently developed secondary resistance (17.6%) with an estimated FFS of 82.4% and an OS of 94.6% at 7 years. Considering the threshold of MR3, of the remaining 117 patients that never had a fluctuation and maintained a stable response over time, only 3 (2.5%) subsequently lost the response and developed secondary resistance with an estimated FFS of 93.2% (p=0.02) and OS of 94% (p=ns). All patients were analysed for mutational screening according to Sanger sequencing analysis: only two patients were found to develop a mutation of the ABL1 kinase domain, in particular 1 patient a E255K and 1 patient a M351T. Cumulative incidence of MR4 was 51% and of MR4.5 was 34.6%, obtained after a median time of 3.8 and 5.4 years, respectively. Overall, 7 patients (6.5%) showed a fluctuation of MR4 response and 4 subsequently lost the response. None of these patients showed secondary resistance or acquired mutations in the ABL kinase domain and main reason for loss of response was confirmed to be low adherence to long-term treatment. Eighteen patients (25%) showed an unstable MR4.5, but none of them developed secondary resistance or progressed to blast phase. Considering the threshold of MR4, fluctuation of molecular burden was associated to FFS of 100% and to OS of 98.2% as compared to patients with stable response that had a FFS of 99.4% and OS of 97.8%, without any statistical significance.
Conclusion
Our results showed that unstable MR3 was indeed associated to an increased probability to develop resistance, whereas long-term fluctuation of deeper molecular response (MR4-4.5) did not influence the long-term outcome of CML patients treated with imatinib.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia, RQ-PCR
Abstract: E1098
Type: Eposter Presentation
Background
Prognostic significance of molecular response fluctuation in the long-term outcome during imatinib treatment in chronic phase chronic myeloid leukemia (CP-CML) patients have not been so far reported in details.
Aims
Aim of our study was to correlate, over a median follow-up period of 7 years, how instability of molecular response can affect overall survival (OS) and failure-free survival (FFS).
Methods
A series of 208 patients treated with imatinib first-line was retrospectively analysed. There were 144 males and 94 females, median age was 57.7 years. According to the IS, we considered as MR3 a BCR-ABL/ABL ratio of ≤ 0.1%, as MR4 a ratio ≤0.01% and as MR4.5 a ratio ≤ 0.0032%; stable response was defined as a response that persisted over 3 consecutive RQ-PCR tests, whereas fluctuation, was defined as the alternation of a test that reached or was below the threshold ratio according to IS and the consecutive was above the threshold. We considered OS the time elapsed from diagnosis to death for any cause, and FFS the timespan that follows therapy without signs of recurrence (loss of hematologic and/or cytogenetic response, acquisition of clonal cytogenetic abnormalities or mutations).
Results
At a median follow-up of 7 years, overall incidence of MR3 was 64.4%: during the course of treatment, 17 patients (11.6%) had a fluctuation above and then below the cut-off of 0.1%. Of these 17 patients, 13 (76%) lost the response and 3 subsequently developed secondary resistance (17.6%) with an estimated FFS of 82.4% and an OS of 94.6% at 7 years. Considering the threshold of MR3, of the remaining 117 patients that never had a fluctuation and maintained a stable response over time, only 3 (2.5%) subsequently lost the response and developed secondary resistance with an estimated FFS of 93.2% (p=0.02) and OS of 94% (p=ns). All patients were analysed for mutational screening according to Sanger sequencing analysis: only two patients were found to develop a mutation of the ABL1 kinase domain, in particular 1 patient a E255K and 1 patient a M351T. Cumulative incidence of MR4 was 51% and of MR4.5 was 34.6%, obtained after a median time of 3.8 and 5.4 years, respectively. Overall, 7 patients (6.5%) showed a fluctuation of MR4 response and 4 subsequently lost the response. None of these patients showed secondary resistance or acquired mutations in the ABL kinase domain and main reason for loss of response was confirmed to be low adherence to long-term treatment. Eighteen patients (25%) showed an unstable MR4.5, but none of them developed secondary resistance or progressed to blast phase. Considering the threshold of MR4, fluctuation of molecular burden was associated to FFS of 100% and to OS of 98.2% as compared to patients with stable response that had a FFS of 99.4% and OS of 97.8%, without any statistical significance.
Conclusion
Our results showed that unstable MR3 was indeed associated to an increased probability to develop resistance, whereas long-term fluctuation of deeper molecular response (MR4-4.5) did not influence the long-term outcome of CML patients treated with imatinib.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia, RQ-PCR
Type: Eposter Presentation
Background
Prognostic significance of molecular response fluctuation in the long-term outcome during imatinib treatment in chronic phase chronic myeloid leukemia (CP-CML) patients have not been so far reported in details.
Aims
Aim of our study was to correlate, over a median follow-up period of 7 years, how instability of molecular response can affect overall survival (OS) and failure-free survival (FFS).
Methods
A series of 208 patients treated with imatinib first-line was retrospectively analysed. There were 144 males and 94 females, median age was 57.7 years. According to the IS, we considered as MR3 a BCR-ABL/ABL ratio of ≤ 0.1%, as MR4 a ratio ≤0.01% and as MR4.5 a ratio ≤ 0.0032%; stable response was defined as a response that persisted over 3 consecutive RQ-PCR tests, whereas fluctuation, was defined as the alternation of a test that reached or was below the threshold ratio according to IS and the consecutive was above the threshold. We considered OS the time elapsed from diagnosis to death for any cause, and FFS the timespan that follows therapy without signs of recurrence (loss of hematologic and/or cytogenetic response, acquisition of clonal cytogenetic abnormalities or mutations).
Results
At a median follow-up of 7 years, overall incidence of MR3 was 64.4%: during the course of treatment, 17 patients (11.6%) had a fluctuation above and then below the cut-off of 0.1%. Of these 17 patients, 13 (76%) lost the response and 3 subsequently developed secondary resistance (17.6%) with an estimated FFS of 82.4% and an OS of 94.6% at 7 years. Considering the threshold of MR3, of the remaining 117 patients that never had a fluctuation and maintained a stable response over time, only 3 (2.5%) subsequently lost the response and developed secondary resistance with an estimated FFS of 93.2% (p=0.02) and OS of 94% (p=ns). All patients were analysed for mutational screening according to Sanger sequencing analysis: only two patients were found to develop a mutation of the ABL1 kinase domain, in particular 1 patient a E255K and 1 patient a M351T. Cumulative incidence of MR4 was 51% and of MR4.5 was 34.6%, obtained after a median time of 3.8 and 5.4 years, respectively. Overall, 7 patients (6.5%) showed a fluctuation of MR4 response and 4 subsequently lost the response. None of these patients showed secondary resistance or acquired mutations in the ABL kinase domain and main reason for loss of response was confirmed to be low adherence to long-term treatment. Eighteen patients (25%) showed an unstable MR4.5, but none of them developed secondary resistance or progressed to blast phase. Considering the threshold of MR4, fluctuation of molecular burden was associated to FFS of 100% and to OS of 98.2% as compared to patients with stable response that had a FFS of 99.4% and OS of 97.8%, without any statistical significance.
Conclusion
Our results showed that unstable MR3 was indeed associated to an increased probability to develop resistance, whereas long-term fluctuation of deeper molecular response (MR4-4.5) did not influence the long-term outcome of CML patients treated with imatinib.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia, RQ-PCR
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