scholarly journals Second Imatinib Discontinuation Outcomes in Patients Regaining Durable Deep Molecular Response in the Korean Imatinib Discontinuation Study; KID Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 51-52
Author(s):  
Sung-Eun Lee ◽  
Joon Seong Park ◽  
Young Rok Do ◽  
Sung-Hyun Kim ◽  
Dae Young Zang ◽  
...  
Keyword(s):  
Prospective Study ◽  
Board Of Directors ◽  
Median Duration ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Close Monitoring ◽  
Advisory Committees ◽  
Deep Molecular Response ◽  
Multicenter Prospective Study

Backgroud: Although multiple trials have shown that stopping tyrosine kinase inhibitor (TKI) treatment can be employed in CP CML patients with sustained deep molecular response (DMR) after enough TKI therapy, they emphasized the need for close monitoring because about 50-70% of patients experienced molecular relapse. However, most patients with molecular recurrence regain their initial molecular level after restarting TKI therapy. Aims: In this study, we analyzed second imatinib (IM) discontinuation outcomes in patients regaining durable DMR in the Korean multicenter prospective study (Korean Imatinib Discontinuation Study; KID Study) Methods: CP CML patients who were treated with IM for more than 3 years and maintained DMR for at least 2 years were eligible for the Korean multicenter prospective study and in cases of MMR loss on 2 consecutive assessments, IM treatment was re-introduced. After IM resumption, the molecular response was evaluated every month until re-achievement of MMR and every 3 months thereafter. The second stop was permitted in the patients who were in second DMR for at least 2 years. Results: Among the patients who maintained a second DMR for at least 2 years after IM resumption, 23 patients entered into a second IM stop. Prior to first discontinuation, the median duration of IM therapy was 73.2 months (range, 38.4-133.2 months) and the duration of sustained UMRD was 38.4 months (range, 24-102 months). After first attempt of IM discontinuation, they relapsed after a median duration of 3.7 months (range, 1.8-20.8 months) and re-achieved UMRD at a median of 5.8 months (range, 1.7-12.1 months) after IM resumption. After sustaining a second DMR for a median of 26.3 months, IM therapy discontinued for a second time. With a median follow-up of 29.5 months (range, 9-63 months) since second IM stop, 15/23 patients (65%) lost MMR after a median 2.9 months (range, 1.8-30.7 months), which was similar to those of the first IM discontinuation [median 3.7 (range, 1.8-20.8 months)]. The patients who lost MMR were retreated with IM for a median of 24.5 months (range, 1.2-49.7 months); 14 patients re-achieved MMR and one patient was in therapy for 1.2 months. Conclusion: Our data demonstrated that a second attempt might be possible and the median time to MMR loss after second discontinuation was similar to those of the first discontinuation. Further studies on the predictors to select patients for a trial of second TFR and novel strategies will be warranted. Disclosures Kim: Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: Research Funding.

scholarly journals Outcome of 472 Chronic Myeloid Leukemia Patients Treated with Frontline Nilotinib: A Gimema CML WP Analysis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 458-458 ◽  
Author(s):  
Gabriele Gugliotta ◽  
Fausto Castagnetti ◽  
Massimo Breccia ◽  
Alessandra Iurlo ◽  
Mariella D'Adda ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Age Groups ◽  
Advisory Board ◽  
Molecular Response ◽  
First Line ◽  
Advisory Committees ◽  
Deep Molecular Response ◽  
First Line Treatment

Abstract BACKGROUND: In chronic phase (CP) chronic myeloid leukemia (CML) nilotinib showed better efficacy compared to imatinib. The higher rates of deep molecular response with nilotinib may translate in more patients (pts) eligible for treatment discontinuation. On the other hand, cardiovascular toxicity may limit nilotinib use in selected groups of pts (e.g. elderly pts). AIM: To investigate the efficacy and safety, overall and according to age, of first-line treatment with nilotinib in CML pts. METHODS: We analyzed response rates, events and outcome of 472 pts ≥ 18 y of age with CP CML, enrolled in clinical trials of the GIMEMA CML WP with nilotinib frontline. Pts were treated with: nilotinib 300 mg BID (n=276); nilotinib 400 mg BID (n=73); rotation of nilotinib 400 mg BID / imatinib 400 mg OD (3-month periods for each drug)(n=123). The median follow-up was 36 (3-82) months. Pts were further analyzed considering 3 age groups: 18-39 y (98 pts); 40-59 y (217 pts); and ≥ 60 y (157 pts). Definitions: Major molecular response (MR3): BCR-ABL≤0.1% (IS), with > 10.000 ABL copies; MR4: BCR-ABL≤0.01% (IS), with > 10.000 ABL copies. Events: permanent discontinuation of nilotinib for any reason, including adverse events, progression to accelerated/blast phase (AP/BP), or deaths. Arterial thrombotic events (ATEs): peripheral arterial obstructive disease, acute coronary syndrome, chronic ischemic heart disease, significant carotid stenosis and ischemic stroke, or other significant ischemic events. RESULTS: Overall, the cumulative incidences of MR3 by 12, 24, and 36 months were 75, 88, and 93%, respectively. The cumulative incidences of MR4 by 12, 24, and 36 months were 38, 63, and 76%, respectively. Events leading to permanent nilotinib discontinuation occurred in 132 (27.9%) pts. ATEs occurred in 33 (7% of pts) ATEs, corresponding to 19.7 ATEs/1000 pt-y. Fifteen (3.1%) pts progressed to AP/BP. Overall, 23 (4.9%) pts died, 11 of them after progression to AP/BP. The estimated 5-year OS was 93%. The sub-analysis according to age showed that: MR3 and MR4 rates were similar across the 3 age groups (cumulative incidences of MR4 by 24 months were 55, 62, and 70% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively; p=0.25). Progressions to AP/BP were: 6.1% in pts 18-39 y, 2.8% in pts 40-59 y, and 1.9% in pts ≥ 60 y. ATEs were: 0 in pts 18-39y, 4.1% (11.7/1000 pt-years) in pts 40-59 y, and 15.3% (41.3/1000 pt-years) in pts ≥ 60 y (no difference in ATEs was found between pts 60-69 y and those ≥ 70 y). The 5-y OS was 91, 97, and 89% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively (p=0.065). Death was always leukemia-related in pts 18-39 y (100%), while it was mainly leukemia-unrelated (75%) in pts ≥ 60 y. SUMMARY/CONCLUSION: Nilotinib as first-line treatment of newly diagnosed CP CML pts showed high rates of deep molecular responses, few progressions to AP/BP, and a high OS. Deep molecular response were similar in all age groups; as expected, ATEs were more frequent in pts > 60 y. These data suggest that: in pts > 60 y, the high efficacy of nilotinib should be weighed against its potential toxicity; in pts < 60 years, nilotinib may be a very good choice, with high efficacy and low toxicity. Disclosures Gugliotta: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria. Castagnetti:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Breccia:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria. Levato:Novartis: Other: Advisory board. Abruzzese:Pfizer: Consultancy; Ariad: Consultancy; Novartis: Research Funding; BMS: Consultancy. Soverini:Bristol Myers Squibb: Consultancy; Incyte Biosciences: Consultancy; Novartis: Consultancy. Foà:NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; AMGEN: Other: ADVISORY BOARD. Cavo:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pane:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau; AMGEN: Speakers Bureau.

scholarly journals For Patients with Sustained MR4-MR4.5, Less Frequent Molecular Monitoring during the First 12 Months after Tyrosine Kinase Inhibitor Cessation Is Viable for Timely Detection of Loss of MMR

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1890-1890
Author(s):  
Naranie Shanmuganathan ◽  
Susan Branford ◽  
Jodi Braley ◽  
Devendra Hiwase ◽  
David T. Yeung ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Monitoring Strategy ◽  
Molecular Monitoring ◽  
Advisory Committees

Abstract Background: Discontinuation of tyrosine kinase inhibitor (TKI) treatment for chronic myeloid leukaemia (CML) patients in stable deep molecular response leads to treatment-free remission (TFR) in approximately 50% of cases. In most studies, monthly PCRs was performed for 12 months followed by 2-3 monthly testing thereafter. Around 80% of molecular relapses occur within the first 6 months after TKI cessation. The current recommendation for TKI recommencement is a single BCR-ABL1 value ≥0.1% IS (International scale), indicating loss of major molecular response (MMR). Not all institutions can offer monthly PCR monitoring due to financial constraints, particularly relevant in developing countries. For some patients, remaining on TKI is a cheaper alternative. Aim: To assess the safety of less frequent BCR-ABL1 monitoring for detection of loss of MMR for CML patients attempting TFR. Methods: We monitored 85 patients who ceased TKI with the aim of achieving TFR. Patients had a minimum of 24 months of sustained MR4 (n=3) or MR4.5 (n=82) prior to TKI cessation. At the time of TKI cessation, 64 patients were on imatinib (75%), 17 on nilotinib (20%) and 4 on dasatinib (5%). Forty of the patients were enrolled in the TWISTER study where the criteria for TKI recommencement was loss of MMR or 2 consecutively rising BCR-ABL1 positive values. The remaining patients were on a registry study and the trigger for TKI recommencement was loss of MMR. Results: TKI recommencement occurred in 49 of 85 patients. Median time to TKI recommencement was 4 months (range 2-28 months) at a median BCR-ABL1 value of 0.27% on the International Scale (IS), range 0.002-24% IS. Thirty-six of the 49 patients (73%) lost MMR prior to TKI recommencement; the median time to loss of MMR was 3 months (range 1 to 10 months). One patient lost MMR within the first month. Figure A demonstrates the time to loss of MMR in the 36 patients with PCR values ≥ 0.1%. Eighteen of the 36 patients (50%) lost MMR by the 3 month BCR-ABL1 assessment and 35 of 36 patients (97%) lost MMR by 6 months. The latest loss of MMR was at 10 months. Fourteen patients recommenced TKI at a BCR-ABL1 value of >1% and 1 recommenced at a value >10%. Clinician delay in TKI recommencement of 1 month resulted in a BCR-ABL1 rise from 0.84% to 24% with associated loss of complete hematological response. We propose monthly BCR-ABL1 testing between 2 and 6 months post TKI cessation followed by 2 monthly testing. Detection of a BCR-ABL1 value of ≥0.1% would trigger TKI recommencement. In the presence of a rising BCR-ABL1, which remains ≤0.1%, monthly monitoring should ensue in order to avoid hematological relapse. If this strategy were employed in this cohort of patients, only 1 patient would have had the trigger for TKI recommencement delayed by 1 month (estimated BCR-ABL1 at recommencement ~2.5%). This patient had loss of MMR in the first month post TKI cessation. If this molecular monitoring strategy was applied to patients in our cohort who had not lost MMR at TKI recommencement, we estimate that 1 other patient would have had TKI recommencement delayed by 1 month based on the average BCR-ABL1 doubling time of 1 log per month. A proportion of patients maintain low levels of BCR-ABL1 after TKI cessation and do not lose MMR. There were 2 such patients in our cohort. Conclusion: The critical time for molecular monitoring to trigger TKI recommencement is the first 6 months. A monthly monitoring strategy beginning 2 months after cessation would capture the majority of patients at loss of MMR. The data suggest that after 6 months, 2-monthly monitoring could follow. Monthly BCR-ABL1 testing can be re-introduced in the event of a positive result in those that ceased TKI with undetectable BCR-ABL1 or if there is a BCR-ABL1 result higher than the cessation value. This approach would reduce BCR-ABL1 testing by approximately 33% in the majority of cases while minimizing hematological relapse. Therefore this strategy would reduce the cost and inconvenience of molecular monitoring for a trial of TKI cessation, making the option of TFR available to some patients for whom it is otherwise not feasible. Disclosures Branford: Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cepheid: Consultancy; Ariad: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yeung:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Research Funding. Ross:Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria. Hughes:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Australasian Leukaemia and Lymphoma Group (ALLG): Other: Chair of the CML/MPN Disease Group.

scholarly journals PF-114 in Patients Failing Prior Tyrosine Kinase-Inhibitor Therapy Including BCR::ABL1T315I

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1482-1482
Author(s):  
Anna G. Turkina ◽  
Olga Vinogradova ◽  
Elza Lomaia ◽  
Evgeniya Shatokhina ◽  
Oleg A. Shukhov ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Board Of Directors ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Ankle Brachial Index ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Advisory Committees

Abstract Background: Not everyone with CML responds optimally to TKI-therapy, especially those with BCR::ABL1T315I. PF-114 is a 4 th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCR::ABL1 isoforms including BCR::ABL1T315I. We present final results of a phase-1 study (NCT02885766). Methods: 3+3 dose-escalation study to determine maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included safety and efficacy based on haematological, cytogenetic and molecular response criteria. Adverse events (AEs) were graded using NCI-CTCAE v4.03. Results: 51 subjects (5 with accelerated phase CML, 46 - with chronic CML), 23 males, were studied. Daily doses were 50-600 mg/d given once daily continuously. Median age was 50 y (range, 29-82 y). Median CML duration pre-study was 10 y (range, 0.3-23 y). 16 subjects had BCR::ABL1T315I. 25 subjects received ≥ 3 prior TKIs. Median follow-up was ≥ 31 mo and median exposure, 6 mo (range, 0.4-52). Therapy was ongoing in 7 subjects at study termination. Others discontinued because of progression (n = 20), AEs (n = 2), consent withdrawal (n = 5), entry into another study (n = 3) or other reasons (n = 14). The MTD was 600 mg with the grade-3 psoriasis-like skin AE as the DLT. There were no vascular occlusive events or deviations of ankle-brachial index. Complete haematologic response (CHR) was achieved in 14 of 30 subjects, major cytogenetic response (MCyR) in 15 of 44 subjects, complete cytogenetic response (CCyR) in 11 of 50 subjects and major molecular response (MMR) in 8 of 51 subjects. Median duration of CHR was 12 mo and has not been reached for MCyR, CCyR and MMR. The best safety/efficacy dose was 300 mg/d with 6 of 9 subjects achieving a MCyR, 5, a CCyR and 4, MMR. 5 of 16 subjects with BCR::ABL1T315I responded, including 4 achieving a MCyR, 2, a CCyR and 1, a MMR. 2 of 6 subjects failing ponatinib achieved a CHR. Conclusion: PF-114 was safe and effective in subjects failing ≥ 2 TKIs and those with BCR::ABL1T315I including those failing ponatinib. The PF-114 dose for further study is 300 mg/d. Disclosures Turkina: Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau. Vinogradova: Bristol Myers Squibb: Speakers Bureau; Novartis Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Chelysheva: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pharmstandart: Speakers Bureau. Petrova: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau. Cortes: Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Baccarani: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ottmann: Fusion: Honoraria; Incyte: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria. Mikhailov: Fusion Pharma: Current Employment. Novikov: Fusion Pharma: Current Employment. Shulgina: Fusion Pharma: Current Employment. Chilov: Fusion Pharma: Current Employment.

Nilotinib Lowers the Incidence of BCR-ABL Mutations and Improves the Molecular Response Kinetics Compared with Imatinib in Patients (Pts) with Newly Diagnosed Chronic Myeloid Leukemia (CML).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3431-3431 ◽  
Author(s):  
Andreas Hochhaus ◽  
Giuseppe Saglio ◽  
Richard A. Larson ◽  
Dong-Wook Kim ◽  
Ian W. Flinn ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Direct Sequencing ◽  
Rapid Decline ◽  
Molecular Response ◽  
Close Monitoring ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
New Mutations

Abstract Abstract 3431 Background: In the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Pts) trial, nilotinib demonstrated superior efficacy vs imatinib in newly diagnosed pts. Here, we examined the kinetics of molecular response and BCR-ABL mutation status in pts from ENESTnd. Methods: Pts with CML-CP were randomized to receive nilotinib 300 mg twice daily (bid) (n = 282), nilotinib 400 mg bid (n = 281), or imatinib 400 mg once daily (qd) (n = 283). BCR-ABL transcripts were quantified at baseline (BL) and every 3 months (mos); MMR was defined as ≤ 0.1% BCR-ABL on the International Scale (IS). Mutational testing of BCR-ABL was performed by direct sequencing at BL and at the occurrence of: (i) 5-fold increase in PCR levels, (ii) failure to achieve MMR at 12 mos, (iii) loss of MMR (≥ 0.1% BCR-ABLIS confirmed by a subsequent sample in association with a ≥ 5-fold rise in BCR-ABL from the lowest value achieved on study treatment), and (iv) end of treatment. Median follow-up was 18 mos. Results: During therapy, a more rapid decline in BCR-ABL levels was demonstrated in the nilotinib arms vs imatinib (Table). The median BCR-ABL levels for pts on nilotinib at 6 mos (both arms) were similar to those on imatinib at 18 mos. The median time to MMR among responders was also shorter on nilotinib (6, 8, and 10 mos in the nilotinib 300 mg bid, 400 mg bid, and imatinib arms, respectively). Loss of MMR occurred in 14 (2%) pts (6 [2%], 5 [2%], and 3 [1%] in the nilotinib 300 mg bid, 400 mg bid, and imatinib arms). Of the 14, none progressed to accelerated phase/blast crisis (AP/BC); only 1 of these pts showed a BCR-ABL mutation (M244V) in the imatinib arm, and 1 pt in the nilotinib 300 mg bid arm lost CCyR. Overall, 9 of 14 (64%) pts, including 8 of 11 on nilotinib, regained MMR within 6 mos on their assigned therapy. In 3 of these 9 pts who regained MMR, loss of MMR was concurrent with dose reduction, and MMR was regained at the time of dose re-escalation. Poor compliance may have contributed to fluctuations in BCR-ABL levels in some pts. At BL, no BCR-ABL mutations were found; 60 pts had polymorphisms which were equally distributed among the 3 arms. Mutational testing was triggered on therapy in 164, 171, and 199 pts in the nilotinib 300 mg bid, 400 mg bid, and imatinib arms, respectively, most commonly due to lack of MMR at 12 mos. Approximately twice as many BCR-ABL mutations (16 [6%]) developed in the imatinib arm vs nilotinib arms (8 [3%] and 5 [2%] for 300 mg bid and 400 mg bid), and most of these were detected within the first 12 mos. The majority of mutations in the nilotinib arms were less sensitive (Y253H, E255K, F359V) or resistant (T315I) to nilotinib, while both nilotinib-sensitive and insensitive mutations were detected in the imatinib arm (Table). The T315I mutation emerged in 5 pts: 2 on nilotinib 300 mg bid, 1 on nilotinib 400 mg bid, and 2 on imatinib; two of these 5 pts discontinued therapy. Overall, 6 of 16 pts with mutations on imatinib progressed to AP/BC vs only 1 of 13 pts on nilotinib (Table). Minimum 24 month follow-up data for all pts will be presented. Conclusions: Pts treated with nilotinib had faster and deeper molecular responses compared with imatinib. The incidence of new mutations was highest for imatinib, and most pts with mutations on nilotinib have not progressed with 18 mos of median follow-up. Loss of MMR was infrequent and was regained in the majority of cases without a change in therapy, and was not typically associated with subsequent treatment failure or the emergence of new mutations. Therefore, loss of MMR may not be an indicator for adjusting therapy, although close monitoring for further loss of response is warranted and mutation testing may be considered. Disclosures: Hochhaus: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Larson:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:Novartis: Research Funding. Goh:Novartis: Honoraria, Research Funding; Janssen Ciliag: Honoraria, Research Funding; Celgene: Honoraria; Bristol Myers Squibb: Honoraria. Dorlhiac-Llacer:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Wyeth: Research Funding. Porkka:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kurokawa:Novartis: Consultancy; Shionogi & Co., Ltd.: Consultancy. Shou:Novartis: Employment. Gallagher:Novartis Pharma AG: Employment, Equity Ownership. Haque:Novartis: Employment. Kantarjian:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Hughes:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria.

scholarly journals The Canadian Tyrosine Kinase Inhibitor Discontinuation Trial with Imatinib Discontinuation As a First Attempt and with Dasatinib Discontinuation As a Second Attempt of Treatment-Free Remission: Results of 4 Years of Follow-up

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1644-1644
Author(s):  
Dennis Dong Hwan Kim ◽  
Isabelle Bence-Bruckler ◽  
Lambert Busque ◽  
Donna L. Forrest ◽  
Lynn Savoie ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Total Duration ◽  
Transcript Level ◽  
Molecular Response ◽  
Advisory Committees ◽  
Deep Molecular Response ◽  
Treatment Free Remission ◽  
Reduced Risk

Introduction: The Canadian trial entitled "Treatment Free Remission Accomplished By Dasatinib" (BMS CA180543, NCT#02268370) is ongoing since Jan 2015, and has completed accrual of 131 patients. The study was designed to determine if using dasatinib (DA) can lead to a successful treatment-free remission (TFR) after failing a first attempt of TKI discontinuation following imatinib (IM) treatment. The preliminary results (ASH 2018) indicate: 1) The 6-month molecular relapse-free survival (mRFS) rate is estimated as 58.0%; 2) DA re-treatment is feasible and safe, with achievement of excellent rates of MMR and MR4; 3) The estimated TFR2 rate after DA discontinuation was 21.5±8.5% at 6 months [7.9-39.5%]). Herein, we report the 4-year follow-up results with updated TFR2 after second TFR attempt following DA discontinuation. Methods and materials: This prospective clinical trial has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. Molecular relapse is defined as an increase in BCR-ABL transcript level above MR4.0 on 2 consecutive occasions, or an increase in BCR-ABL transcript level above MR3.0 on a single occasion. 100mg daily of DA is started if molecular relapse is confirmed and is discontinued 12 months after achieving MR4 following a 2nd TFR attempt. Results: As of Jun 25, 2019, 58 (44.3%) of 131 enrolled patients experienced molecular relapse after IM discontinuation with a mRFS rate of 59.1% [50.1-67.0%] and 56.8% [47.8-64.8%] at 6 and 12 months, respectively. TFR using loss of MMR as an event was 69.8% at 6/12 months. Of the 58 patients who lost response, 53 patients (91.4%) lost response within 6 months after IM discontinuation: 7 (10.1%) lost response within 2 months, 20 (34.5%) within 3 months, 14 (24.1%) within 4 months, 9 (15.5%) within 5 months, and 3 (5.2%) within 5-6 months. Beyond 6 months, 5 patients (15.5%) lost response within 7, 8, 10, 20, 21 months, respectively. Only two patients experienced late relapse occuring 15 months after IM discontinuation. 54 patients started DA, of whom 49 patients (90.7%) achieved MR4.5 on DA. Median time to MMR, MR4 and MR4.5 was 0.94, 1.95, and 2.48, respectively. The incidence of MMR, MR4 and MR4.5 at 3 months was 99.0% (86.3-99.0%), 91.5% (78.4-96.7%), and 76.6% (60.9-86.0%), respectively. 32/49 patients receiving DA attained MR4.5, and discontinued DA for a 2nd TFR attempt (TFR2). 25/32 (78.1%) of these patients lost molecular response at a median of 3.67 months after DA discontinuation. The estimated TFR2 after DA discontinuation was 18.5% at 6 months [6.8-34.7%], TFR2 using loss of MMR as a definition of molecular relapse was 20.4% [7.6-37.4%], while TFR2 using two consecutive losses of MR4 was 25.4% [9.4%-45.2%]. Two patients continued to attain deep molecular response at MR4.2 and undetectable level (equivalent to MR5.5) beyond 18 months after DA discontinuation. At last follow-up of Jun 25, 2019, 30 patients are still being monitored on trial on IM discontinuation (n=20), DA rechallenge (n=4) or DA discontinuation phases (n=6). With a median follow-up duration of 36 months, risk factor analyses were performed using Cox's proportional hazard regression model suggesting a strong correlation of mRFS with total duration of IM treatment prior to IM discontinuation (p<0.001, HR 0.864), MR4 duration (p<0.001, HR 0.867), but not with time to achieve MR4 (p=0.216). When patients attained MR4 or deeper for longer than 10.59 years, their mRFS was 91.8% [71.1-97.9%] at 12 months. The group who attained MR4 duration of 6.93 years or longer had 40.3% reduced risk of mRFS (HR 0.597 [0.449-0.794], p<0.001] compared to those with MR4 duration less than 6.93 years. The group who attained 10.59 years of MR4 duration or longer had a 65.5% reduced risk of mRFS (HR 0.345 [0.171-0.699], p=0.003] compared to those with MR4 duration less than 10.59 years. Conclusion: The 4-year follow-up results suggests that DA rechallenge after failing a first IM discontinuation attempt for TFR was safe, feasible and well tolerated. It was effective in most cases rapidly regained at least MR4. Based on the two cases who successfully discontinued DA more than 18 months after DA consolidation following achievement of deep molecular response, second generation TKI therapy after imatinib discontinuation failure is a feasible option. Further follow-up is strongly warranted in order to reach a clear conclusion on this issue. Disclosures Busque: ExCellThera: Patents & Royalties; Paladin: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Savoie:Pfizer: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Keating:Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Seattle Genetics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees. Delage:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Liew:Novartis: Consultancy, Honoraria. Leber:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Achieving the Deep Molecular Response Levels Required for an Imatinib Discontinuation Trial Is Strongly Associated with the BCR-ABL Level at the First Qualifying Timepoint

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4561-4561 ◽  
Author(s):  
Susan Branford ◽  
David M Ross ◽  
David T Yeung ◽  
Jodi Braley ◽  
Timothy P. Hughes
Keyword(s):  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Molecular Response ◽  
First Line ◽  
Advisory Committees ◽  
Deep Molecular Response ◽  
Landmark Analyses ◽  
Tki Treatment

Abstract Background: Discontinuation of tyrosine kinase inhibitor (TKI) treatment for patients (pts) with CML is desirable for both clinical and economical reasons. Two studies, STIM and TWISTER, demonstrated that treatment free remission (TFR) is achievable in a proportion of pts. A qualifying period of 3 years of imatinib and sustained undetectable BCR-ABL with a sensitivity of MR5 or MR4.5 for at least 2 years was required before discontinuation. Due to the very slow clearance of BCR-ABL after an initial rapid reduction in the first year of imatinib, the number of pts meeting discontinuation criteria potentially requires many years of imatinib. New discontinuation studies may require at least 3 years of TKI treatment but are exploring less stringent molecular criteria for discontinuation. The first requirement is the achievement of MR4.5 (≤0.0032%) or even MR4 (≤0.01%), and these responses must be maintained. More potent TKIs when administered as first line or after switch from imatinib are associated with higher rates of deep molecular response, which potentially leads to a greater number of pts who qualify for a discontinuation trial. It is unknown what proportion of imatinib treated pts who have not achieved a deep molecular response at 3 years will subsequently do so, and in which subgroup of patients a switch to a more potent TKI is warranted if TFR is the goal. Aim: Since BCR-ABL levels at milestone response timepoints strongly predict long term molecular response, we determined whether the BCR-ABL level at the first qualifying timepoint for a discontinuation trial (3 years) predicts the achievement of deep molecular response. Method: 528 consecutive chronic phase pts treated with first line imatinib were examined (400, 600 or 800 mg). Those who met the following criteria at 3 years were included: CCyR or 1% BCR-ABL, no MR4.5 and at least 6 months of further imatinib therapy. Only 4 pts did not have CCyR at 3 years and were not included since they also had treatment failure. The cohort is historical so was not confounded by switching to another TKI after 3 years of imatinib. Landmark analyses according to the BCR-ABL response level at 3 years were performed for MR4 and MR4.5. These responses required confirmation at consecutive measurements. Results: 147 pts met the analysis criteria. The median follow up on imatinib after the 3 year landmark was 1.5 years, range 0.75 – 9.8. At 3 years of imatinib the median BCR-ABL was 0.03%, range 0.004% - 1.4%. The cumulative incidence of MR4 for the 116 pts without MR4 at 3 years was 52% by 5 years after the landmark. The cumulative incidence of MR4.5 for the 147 pts was 62% by 5 years after the landmark. Pts were divided into 3 BCR-ABL response levels at the landmark: MR2 (>0.1%) n=45; MMR (>0.01 – 0.1%) n=71; and MR4 (>0.0032 – 0.01%), n=31. Landmark analyses demonstrated that pts with MR2 at 3 years of imatinib had a negligible probability of achieving MR4 and MR4.5 with up to 5 additional years of imatinib, Figure. Only 2 and 1 of these 45 pts reached MR4 and MR4.5, respectively. Furthermore, pts with MMR at 3 years had a significantly lower cumulative incidence of MR4.5 compared to pts with MR4: MMR vs MR4, 61% vs 100% by 5 years after the landmark, P < .0001, Figure. Intuitively, pts with BCR-ABL close to MR4.5 could be predicted to achieve that response. However, the median time to reach MR4.5 for the pts with MR4 at 3 years was at 1.5 years of additional imatinib, demonstrating the very slow kinetics of BCR-ABL clearance. The starting dose of imatinib had no effect on the achievement of MR4 or MR4.5. Only 1 of the 147 pts lost CCyR (pt with MMR at 3 years). Conclusion: This study has further demonstrated that the BCR-ABL value is a powerful predictor of response, not only in the first months of treatment but also at later timepoints when long term management decisions are made. If the aim of therapy is to qualify for TFR studies, our data suggest that pts without an MMR at 3 years of imatinib have minimal chance of reaching the deep molecular responses required, even with up to 5 additional years of imatinib. Pts who switched to nilotinib without MMR in the ENESTcmr trial were indeed more likely to achieve MR4.5 compared to continuing on imatinib (Hughes Blood 2014). In our study, most pts with MR4 at 3 years of imatinib achieved the deep molecular response criteria with 2 additional years of imatinib. These findings may help clinical decisions when considering a switch of treatment to optimize discontinuation options. Figure 1 Figure 1. Disclosures Branford: Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Ross:Novartis: Honoraria, Research Funding; BMS: Honoraria. Yeung:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding.

Treatment-Free Remission Accomplished By Dasatinib (TRAD): Preliminary Results of the Pan-Canadian Tyrosine Kinase Inhibitor Discontinuation Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1922-1922 ◽  
Author(s):  
Dennis Dong Hwan Kim ◽  
Isabelle Bence-Bruckler ◽  
Donna L. Forrest ◽  
Mary Lynn Savoie ◽  
Stephen Couban ◽  
...  
Keyword(s):  
Tyrosine Kinase Inhibitor ◽  
Board Of Directors ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Total Duration ◽  
Transcript Level ◽  
Molecular Response ◽  
Advisory Committees ◽  
Treatment Free Remission ◽  
Tki Discontinuation

Abstract Introduction: Multiple studies have shown that tyrosine kinase inhibitor (TKI), usually imatinib (IM), can be successfully discontinued in chronic myeloid leukemia (CML) patients, achieving a 40-50% treatment free remission (TFR) rate. However, the remaining 60% of patients require reintroduction of TKI therapy. We have designed this study to answer the question if a second generation TKI, i.e. dasatinib, should be used after failing the first attempt of TKI discontinuation with IM. This prospective study attempts to evaluate whether the use of dasatinib after failure of a 1st attempt of TKI discontinuation with IM could improve TFR rate after a 2nd attempt of TKI discontinuation. Methods and materials: This is a prospective clinical trial (BMS CA180-543, Clinicaltrial.gov NCT#02268370) including all major CML centers across Canada (n=12). The primary objective is to determine the proportion of patients who remain in molecular remission (defined as maintaining ≥MR4.0) after dasatinib discontinuation following achieving ≥MR4.5. The present study has 3 phases: 1) IM discontinuation phase, 2) dasatinib rechallenge phase, 3) dasatinib discontinuation phase. A total of 135 patients is planned to be enrolled over 18-24 months. Key inclusion criteria include: 1) CML in chronic phase (CP), 2) total duration of IM therapy of minimum of 3 years, 3) total duration of MR4.5 or deeper response over 2 years with 2 consecutive confirmed MR4.5 or deeper response at the central lab with 3 months interval. Key exclusion criteria include prior allogeneic stem cell transplant or prior accelerated or blastic phase CML. Molecular recurrence was defined as an increase in BCR-ABL transcript level above MR4.0, on at least two consecutive occasions, or a single increase in BCR-ABL transcript level above MR3.0. Dasatinib is started at a dose of 100mg daily once molecular recurrence is confirmed. Results: The study was launched on March 2015. As of June 22 2016, 110 patients were entered into screening phase of whom 16 patients were not qualified due to 1) fluctuating transcripts (n=8) or 2) consent withdrawal (n=8). Two patients withdrew consent after losing their molecular response following IM discontinuation before starting dasatinib. Finally 75 patients were enrolled into IM discontinuation phase with 17 additional patients on screening in awaiting enrollment (Figure A). Of 67 patients evaluable for molecular relapse, 21 patients (31.3%) lost molecular response defined as loss of major molecular response (MMR; n=18) and loss of MR4 on 2 consecutive tests (n=3). The 6-month relapse free survival (RFS) rate was estimated as 58.0% (42.1-71.0%), while TFR rate using loss of MMR as an event was 64.7% (48.7-76.7%) at 6 months (Figure B) Of 21 patients who lost molecular response, 20 patients underwent dasatinib rechallenge phase, 14 of which were treated with dasatinib for at least 1 month and evaluated at least once with monthly BCR-ABL transcript monitoring (Figure C). Twelve patients achieved MMR at a median time of 56 days. The median time to achieve MR4.5 was 84 days. The incidence of MMR and MR4.5 at 3 months was 100% each (Figure D). Cox's proportional hazard regression model suggested strong correlation of RFS with total duration of IM therapy prior to IM discontinuation (p=0.001), duration of MR4 maintenance (p=0.004) or MR4.5 maintenance (p=0.006) prior to IM discontinuation, but not with time to achieve MR4 (p=0.289) or MR4.5 (p=0.330). Recursive partitioning method also defined the best cutoff for those variables: The group treated with IM for over 8.9 years (n=35) had RFS rate 81.1% vs 21.0% in those treated for less than 8.9 years (n=32; p<0.001, HR 0.125). The group who maintained MR4 for more than 7.7 years (n=29) had RFS rate 82.3% vs 36.3% in others (n=37; p=0.001, HR 0.192), while those who maintained MR4.5 for more than 7.9 years (n=21) had RFS rate 89.5% vs 39.2% in others (n=44; p=0.003, HR 0.141). Conclusion: Preliminary results of this Canadian TKI discontinuation trial show a RFS rate of 58-65% after IM discontinuation in CP-CML patients who attained MR4.5 for over 2 years, similar to other TKI discontinuation studies. Dasatinib can be safely administered in CML patients who lost molecular response after IM discontinuation with 100% of MMR rate at 3 months. Prolonged duration of IM treatment, or duration of MR4/MR4.5 maintenance with IM therapy could predict the chance of TFR success, but not time to achievement of MR4/MR4.5. Disclosures Bence-Bruckler: Lundbeck: Membership on an entity's Board of Directors or advisory committees. Savoie:Amgen: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy; Lundbeck: Consultancy. Busque:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Delage:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Laneuville:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Paladin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Liew:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Xenocostas:Janssen Inc.: Research Funding. Kamel-Reid:BMS: Research Funding. Leber:BMS Canada: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Chronic Myeloid Leukaemia Patients with Stable Molecular Responses (at least MR3) May Safely Decrease the Dose of Their Tyrosine Kinase Inhibitor: Data from the British Destiny Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 938-938 ◽  
Author(s):  
Richard E. Clark ◽  
Fotios Polydoros ◽  
Jane F. Apperley ◽  
Christopher Pocock ◽  
Graeme Smith ◽  
...  
Keyword(s):  
Side Effects ◽  
Chronic Myeloid Leukaemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Standard Dose ◽  
Molecular Response ◽  
Advisory Committees ◽  
Molecular Responses ◽  
Tki Treatment

Abstract Several studies have established that some chronic myeloid leukaemia (CML) patients with enduring deep molecular responses to tyrosine kinase inhibitor (TKI) therapy can discontinue treatment. However, these studies are confined to patients in stable MR4, i.e. whose BCR-ABL/ABL ratio is consistently below 0.01% (molecular response 4 logs below an arbitrary baseline). Although there are anecdotal reports of successful treatment cessation for a few months in patients in stable MR3 (i.e. BCR-ABL <0.1%; major molecular response) but not MR4, e.g. during pregnancy, such patients have not hitherto been formally studied in a stopping trial. In addition, we questioned whether some patients who experience molecular recurrence on stopping TKI might nevertheless be able to safely decrease TKI treatment without molecular recurrence. In the British De-Escalation and Stopping Therapy with Imatinib, Nilotinib or sprYcel (DESTINY) study, patients in at least stable MR3 (on the International Standard) initially decreased their TKI to half the standard dose for 12 months, followed by complete cessation. Key entry requirements included first chronic phase of CML; receiving the same TKI since original diagnosis (except that one switch was permissible if for intolerance to the initial drug); on TKI for at least 3 years; all PCR tests in the past 12 months were in at least MR3 (minimum of 3 tests, each with >10,000 ABL control transcripts). Central monitoring was carried out monthly. Molecular recurrence was defined as loss of MR3 (>0.1%) on two consecutive samples; this prompted resumption of full dose of their entry TKI. Between December 2013 and April 2015, 174 patients (male 98; female 76) were recruited after giving informed consent from 20 UK centres. At entry, 148 patients were receiving imatinib, 16 nilotinib and 10 dasatinib. After 12 months of half-dose therapy (imatinib 200mg daily, nilotinib 200mg twice daily or dasatinib 50mg daily), molecular recurrence was lower in patients with stable MR4 at entry (3 of 125 patients; 2.4%) than in those in MR3 but not MR4 (9 of 49 patients; 18.4%) (p < 0.001). The median time to relapse was shorter in the sustained MR3 group than in those in sustained MR4 at entry (4.4 months vs 8.7 months). The probability of molecular recurrence on de-escalation was not related to age, gender, performance status, prior TKI (imatinib vs second generation) or the duration of TKI therapy (median 7.0 years overall). No progression to advanced phase or loss of cytogenetic response was seen; one death and 15 serious adverse events occurred which were all unrelated to CML or TKI treatment. All 12 patients with molecular recurrence regained MR3 within 4 months of resumption of full dose TKI. During the first 3 months of de-escalation but not thereafter, the number of patient-reported common TKI side effects decreased, though interestingly 53 new musculoskeletal symptoms were reported by 36 patients (21%) which were typically mild and transient. In CML patients with stable MR3 or better, decreasing TKI treatment to half the standard dose appears safe, and is associated with improvement in TKI related side effects, implying that many patients with stable responses are being overtreated. Studies of more ambitious de-escalation are warranted. Disclosures Clark: Ariad: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Apperley:Novartis: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Ariad: Honoraria, Speakers Bureau. Pocock:Gilead Sciences: Other: Sponsorship to attend the EHA 2016 Meeting; Janssen: Speakers Bureau; Takeda: Honoraria. Smith:Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Byrne:Bristol Myers Squibb: Consultancy, Speakers Bureau. O'Brien:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Copland:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals BCR-ABL Mutations in Chronic Myeloid Leukemia (CML) Patients (pts) with Failure and Warning to First- and Second-Line Tyrosine Kinase Inhibitor (TKI) Therapy: What Is the Advantage of Next-Generation Sequencing (NGS) over Conventional Sequencing?

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 346-346 ◽  
Author(s):  
Simona Soverini ◽  
Caterina De Benedittis ◽  
Fausto Castagnetti ◽  
Gabriele Gugliotta ◽  
Manuela Mancini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Mutation Screening ◽  
Point Mutations ◽  
Kinase Domain ◽  
Screening Methods ◽  
Molecular Response ◽  
Advisory Committees ◽  
Line Therapy

Abstract Background - Point mutations in the BCR-ABL kinase domain are associated with resistance to TKI therapy. The most recent (2013) European Leukemia Net (ELN) recommendations have re(de)fined the criteria for failure in pts receiving 1st-line and 2nd-line TKI therapy and introduced the concept of warning. Assessing in how many CML patients with failure and warning mutations can be identified, especially now that more sensitive NGS-based mutation screening methods are available, would advance our knowledge of the biology of TKI resistance as well as contribute useful data to revise the ELN recommendations as to when and how BCR-ABL mutation analysis should be performed. Aims - We aimed to determine the frequency of BCR-ABL mutations as assessed by NGS vs conventional Sanger sequencing (SS) in CML pts with failure and warning to 1st- or 2nd-line TKI therapy as per the latest, 2013 ELN definitions. Methods - Between May 2013 and June 2015, 298 consecutive CML pts on TKI therapy were referred to our laboratory for BCR-ABL mutation screening by SS. One hundred and fifty-eight cases had no clinical data available, or were not in CP, or were receiving ≥3rd-line TKI therapy, or had confirmed/suspected nonadherence, or had experienced dose reductions for toxicity - leaving 140 pts who could be included in this study. Pts who were negative for mutations as determined by SS (n=105/140) were retrospectively reanalyzed by NGS on a Roche GS Junior, using a protocol already set up and optimized in the framework of the IRON II (Interlaboratory RObustness of NGS) international consortium. Sequencing depth allowed to achieve a lower mutation detection limit of 1% in all samples. Results - Failures and warnings to 1st-line therapy (imatinib, n=57; nilotinib, n=22; dasatinib, n=13) were 63 and 29, respectively. BCR-ABL mutations were found in 15/63 (24%) failures and 3/29 (10%) warnings by SS (Table 1). NGS reanalysis of the 74 pts with no evidence of mutations by SS revealed low burden (median, 6.6%; range, 1.5-11.7%) mutations in 6 failures and 1 warning, so that, overall, 21/63 (33%) failures and 4/29 (14%) warnings turned out to have mutations (Table 1). Mutations were E462K, E279K, K262R, F359I, E255K, F317L, K378R, A399T, L364I, V280A. No compound mutation was detected. Failures and warnings to 2nd-line therapy (nilotinib, n=27; dasatinib, n=21) were 35 and 13, respectively. SS identified mutations in 13/35 (37%) failures and 2/13 (15%) warnings (Table 1). NGS reanalysis of the 33 pts with no evidence of mutations by SS revealed low burden (median, 5.4%; range, 1.9-10.0%) mutations in 5 failures and 2 warnings, so that, overall, 18/35 (51%) failures and 4/13 (31%) warnings turned out to have mutations (Table 1). Mutations were T315I, E255V, F317I, E258D, P480L, Y393C, W261L, L370P, V371A, L324Q, again with no compound mutations. Table.All ptsPts positive for mutations by SSAdditional pts positive for mutations by NGSTotal pts positive for mutations1ST -LINE FAILURESNo CyR @ 3 mo9101BCR-ABL>10% @ 6 mo9000mCyR @ 6 mo1101BCR-ABL>1% @ 12 mo10022No CCyR @ 12 mo2101Loss of CCyR7314Loss of MMR20639Loss of CHR2101Progression to BP3202Total6315 (24%)621 (33%)1ST -LINE WARNINGSBCR-ABL>10% @ 3 mo7101BCR-ABL>1% @ 6 mo10112BCR-ABL>0.1% @ 12 mo12101Total293 (10%)14 (14%)2ND -LINE FAILURESNo CyR @ 3 mo3112BCR-ABL>10% @ 6 mo10224Loss of CCyR7303Loss of MMR6123Loss of CHR4303Progression to BP5303Total3513 (37%)518 (51%)2ND -LINE WARNINGSBCR-ABL>10% @ 3 mo6202BCR-ABL>0.1% @ 12 mo7022Total132 (15%)24 (31%) Conclusions 1) NGS allowed to identify BCR-ABL mutations in a greater proportion of cases as compared to SS. Low burden mutations included a T315I mutation in 2 pts on 2nd-line therapy classified as warnings: this would have turned them into failures. 2) Still, a substantial proportion of cases was found to not harbor any mutation, even when using a more sensitive NGS-based method. In particular, non-optimal achievement of the key molecular response milestones (10%, 1%, 0.1%) on 1st-line therapy was mostly not associated with BCR-ABL mutations, indicating that other mechanisms of molecular disease persistence have to be investigated in an attempt to optimize therapeutic outcomes. A national, multicenter study ('NEXT-IN-CML') aimed at the prospective assessment of NGS for routine BCR-ABL mutation screening of CML patients has just started. Supported by ELN, AIL, AIRC, FP7 NGS-PTL project, Progetto Regione-Università 2010-12 (L. Bolondi) Disclosures Soverini: Bristol-Myers Squibb: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Castagnetti:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. Bonifacio:Ariad Pharmaceuticals: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Novartis Farma: Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Novartis Pharmaceutical Corporation: Consultancy, Honoraria. Rosti:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau. Baccarani:NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martinelli:Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; ROCHE: Consultancy; BMS: Consultancy, Speakers Bureau; AMGEN: Consultancy; MSD: Consultancy; Ariad: Consultancy.

scholarly journals Updated 18-Month Results from Dasfree: A Study Evaluating Dasatinib Discontinuation in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Deep Molecular Response (DMR)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4253-4253 ◽  
Author(s):  
Neil P. Shah ◽  
Jose Valentín García Gutiérrez ◽  
Antonio Jiménez-Velasco ◽  
Sarah Larson ◽  
Susanne Saussele ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Safety Data ◽  
Chronic Phase ◽  
Molecular Response ◽  
Relapse Free Survival ◽  
Advisory Committees ◽  
Free Survival

Abstract Introduction: Tyrosine kinase inhibitor (TKI) discontinuation is being investigated in pts with CML-CP with sustained DMR (defined here as MR4.5 or BCR-ABL1 ≤ 0.0032% on the International Scale [IS]), with the goal of treatment-free remission (TFR). Successful TFR has been reported previously for pts enrolled in DASFREE (CA180-406/NCT01850004), which showed that 48% of CML-CP pts with DMR for ≥ 1 year were able to stop dasatinib and maintain major molecular response (MMR) 12 months after discontinuation. Here we present updated results from pts followed for a minimum of 18 months, in order to understand the durability of TFR beyond 12 months. Methods: DASFREE is a phase 2, open-label, single-arm study in adult pts with CML-CP on dasatinib for ≥ 2 years as 1st-line or subsequent therapy. Eligible pts had dasatinib-induced DMR (MR4.5) confirmed at a local lab for ≥ 1 year prior to enrollment, with a 1-log reduction in BCR-ABL1 from baseline within 3-6.5 months of starting dasatinib. MR4.5 was confirmed at a central lab twice within 3 months prior to dasatinib discontinuation (screening phase). BCR-ABL1 was monitored centrally after discontinuation every month in the 1st year, then every 3 months. Pts resumed dasatinib at their previous dose if MMR was lost. The primary endpoint is the rate of MMR 12 months after dasatinib discontinuation. Secondary endpoints include BCR-ABL1 kinetics, molecular relapse-free survival (MRFS; no loss of MMR), relapse-free survival (RFS; no loss of MMR, complete cytogenetic response, or complete hematologic response, or progression to accelerated/blast phase [AP/BP] CML), rate of transformation to AP/BP, progression-free survival, and overall survival. Exploratory analyses include frequency of adverse events (AEs) after discontinuation and during dasatinib treatment, and MMR after reinitiating dasatinib. Results: In total, 84 pts enrolled between February 2014 and June 2016 discontinued dasatinib; all had ≥ 18 months of follow-up after discontinuation at the time of this analysis. Pt characteristics were previously reported (the majority [64%] had low Sokal scores; no pt had prior interferon; 37 pts were on 1st-line dasatinib, 47 on subsequent lines of dasatinib). At 18 months after discontinuation, the RFS rate was 48% (95% CI 37-58) in all pts (Figure), 54% (95% CI 38, 70) in 1st-line pts, and 42% (95% CI 28, 57) in pts who received subsequent-line therapy. With longer follow-up, 1 additional pt lost MMR at 18 months following discontinuation. Of the 45 pts who lost MMR and restarted treatment, 44 regained MMR (1 pt discontinued after only 1 molecular assessment) in a median of 2 months (range 1-4) and 42 regained MR4.5 in a median of 3 months (range 2-18). Analyses of baseline pt characteristics revealed that for the 40 pts who did not lose MMR after discontinuation, 15 (37.5%) were able to maintain MR4.5. Additionally, the median time in prior MR4.5 was 28 months (range 13-116) for all pts, and was similar for 1st-line pts who maintained (27 months [range 13-56]) or lost MMR (27 months [range 15-68]) at 12 months. With longer follow-up, AEs (any cause) identified were consistent with previous reports and were found to be similar on and off treatment: 8 (10%) pts off treatment and 8 (18%) pts on treatment experienced grade 3/4 AEs of any cause after restarting dasatinib (4.4% were drug related). No transformation events or deaths occurred. Of the 13 reported withdrawal events occurring in 8 (9.5%) pts, 10 were resolved (5 off treatment, 5 resolved after restarting treatment due to loss of MMR) after a median of 5 months (range 1-12) after onset. One pt discontinued after restarting dasatinib due to malignancy unrelated to treatment. In addition to efficacy and safety data, multivariate analyses evaluating prognostic factors for MMR will be presented. Conclusions: Additional follow-up of pts enrolled in DASFREE revealed that TFR remained durable at 18 months after discontinuing dasatinib. AEs reported here were consistent with the known safety profile of dasatinib, and withdrawal was well tolerated. Collectively, this trial, the largest dasatinib discontinuation trial to date, continues to support the feasibility and practicality of TFR in pts with CML-CP in DMR treated with dasatinib in the 1st line and beyond. Figure. Figure. Disclosures Shah: ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding. García Gutiérrez:Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Larson:Bristol-Myers Squibb: Consultancy; Takeda: Speakers Bureau. Saussele:Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria. Rea:Incyte: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Mahon:Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Gómez-Casares:Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau. Pane:Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy. Nicolini:Incyte: Consultancy, Honoraria, Speakers Bureau; Sun Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Mauro:Pfizer: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding. Sy:Bristol-Myers Squibb: Employment. Martin Regueira:Bristol-Myers Squibb: Employment, Equity Ownership. Lipton:ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

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