Response and Outcomes to Nilotinib at 24 Months in Imatinib-Resistant Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) and Accelerated Phase (CML-AP) with and without BCR-ABL Mutations.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1130-1130 ◽  
Author(s):  
Jerald P. Radich ◽  
Giovanni Martinelli ◽  
Andreas Hochhaus ◽  
Enrico Gottardi ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Advisory Committees ◽  
Imatinib Resistant

Abstract Abstract 1130 Poster Board I-152 Background Nilotinib is a selective and potent BCR-ABL inhibitor, with in vitro activity against most BCR-ABL mutants (excluding T315I) indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) CML in CPor AP resistant or -intolerant to prior therapy, including imatinib. In a previous analysis of nilotinib in patients with BCR-ABL mutations, mutations occurring at three specific amino acid residues (E255K/V, Y253H, and F359C/V) were shown to be associated with less favorable response to nilotinib. The current analysis is based on mature data with a minimum follow-up of 24-months for all patients. Outcomes of patients at 24 months were analyzed by mutation type. Methods Imatinib-resistant CML-CP (n = 200) and CML-AP (n = 93) patients were subdivided into the following mutational subsets: no mutation, sensitive mutations (including mutations with unknown in vitro IC50). or E255K/V, Y253H, or F359C/V mutations at baseline. Patients with mutations of unknown in vitro sensitivity were classified as sensitive in this analysis based on a previous finding that patients with these mutations responded similarly to nilotinib as patients with sensitive mutation. Patients with baseline T315I mutations were excluded from this analysis. Patient groups were analyzed for kinetics and durability of cytogenetic and molecular response to nilotinib, as well as event-free survival (EFS), defined as loss of hematologic or cytogenetic response, progression to AP/BC, discontinuation due to disease progression, or death, and overall survival (OS). Results In CML-CP and -AP patients with no mutation, sensitive mutations, or E255K/V, Y253H, or F359C/V mutations, hematologic, cytogenetic and molecular responses are provided in the Table. Overall, patients with no mutations responded similarly to patients with sensitive mutations, whereas patients with E255K/V, Y253H, or F359C/V mutations had less favorable responses. This correlation was observed in both CML-CP and CML-AP patients, respectively. Median time to CCyR was 3.3 months (range, 1.0–26.7) for CML-CP patients with no mutations, and 5.6 months (range, 0.9–22.1) for patients with sensitive mutations. At 24 months, CCyR was maintained in 74% of CML-CP patients with no mutation and in 84% of patients with sensitive mutations. One patient with CML-CP and an E255K mutation achieved CCyR at 25 months and maintained until last assessment at 30 months. Median time to MMR was similar at 5.6 months (range, 0.9–25.8) for CML-CP patients with no mutations and 5.6 months (range, 2.7–22.1) for patients with sensitive mutations. No patient with a less sensitive mutation achieved MMR. Median EFS and 24-month estimated OS rate are provided in the Table. Conclusions Imatinib-resistant CML-CP and CML-AP patients treated with nilotinib therapy with BCR-ABL mutations (excluding E255K/V, Y253H, or F359C/V) achieved rapid and durable cytogenetic responses, and estimated EFS and OS at 24 months similar to that of patients with no mutations, respectively. Patients with E255K/V, Y253H, or F359C/V mutations had lower and less-durable responses and shorter EFS than patients with sensitive mutations. Alternative therapies may be considered for patients with these uncommon mutations (E255K/V, Y253H, and F359C/V). Disclosures Radich: Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Branford:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Shou:Novartis: Employment. Haque:Novartis: Employment. Woodman:Novartis: Employment. Kantarjian:Novartis: Research Funding. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Kim: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; Wyeth: Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau.

scholarly journals Efficacy of Bosutinib in Imatinib-Resistant Vs Dasatinib/Nilotinib-Resistant Chronic Phase Chronic Myeloid Leukemia: Results from the Phase 4 BYOND Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1650-1650 ◽  
Author(s):  
B. Douglas Smith ◽  
Tim H Brümmendorf ◽  
Gail J. Roboz ◽  
Carlo Gambacorti-Passerini ◽  
Aude Charbonnier ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Imatinib Resistant ◽  
Equity Ownership

Introduction: The tyrosine kinase inhibitor (TKI) bosutinib is approved for patients with Philadelphia chromosome (Ph)+ chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed patients in chronic phase (CP). Methods: The ongoing phase 4 BYOND study (NCT02228382) is further evaluating the efficacy and safety of bosutinib for CML resistant/intolerant to prior TKIs. Patients were administered bosutinib at a starting dose of 500 mg once daily (QD). Primary results were previously reported. Here, we report the efficacy of bosutinib 500 mg QD in patients with Ph+ CP CML and resistance to imatinib (but not to nilotinib or dasatinib) vs patients with resistance to ≥1 second-generation TKI (dasatinib and/or nilotinib), as well as in patients with intolerance to all prior TKIs. Data are reported at ≥1 year after last enrolled patient; 85% of patients had a minimum follow-up of 2 years. Results: Of 163 patients who received bosutinib, 156 had Ph+ CP CML: 52 had resistance only to imatinib, 31 had resistance to dasatinib/nilotinib, and 73 were intolerant to all prior TKIs. Corresponding median treatment duration (range) was 24.1 (0.2-42.2), 8.9 (0.9-41.6), and 25.3 (0.4-41.9) months, and median dose intensity (range) was 360 (125-500), 431 (195-561) and 292 (80-500) mg/day. In all, 69.2%, 41.9%, and 53.4% of imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, were still receiving treatment as of the data cutoff date. The main reason for discontinuation was adverse events (AEs), with 10 (19.2%), 8 (25.8%), and 21 (28.8%) imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, discontinuing due to AEs. Corresponding discontinuations due to insufficient response occurred in 2 (3.8%), 5 (16.1%), and 1 (1.4%) patients. No patient experienced on-treatment transformation to advanced phase CML or discontinued treatment due to disease progression. In the evaluable cytogenetic population, cumulative major cytogenetic response (MCyR) rates were 85.4%, 69.0%, and 88.1% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively (Table). The majority of patients, across all cohorts, achieved a complete cytogenetic response (CCyR). In the evaluable molecular population, cumulative major molecular response (MMR) rates were 72.3%, 44.8%, and 82.2% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively; the 50th percentile of the cumulative incidence curve was 5.66 months, not reached and 3.22 months, respectively. Correspondingly, 59.6%, 24.1%, and 68.5% achieved molecular response (MR)4, and 48.9%, 17.2%, and 56.2% achieved MR4.5. In imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, Kaplan-Meier estimated overall survival rates (95% confidence interval) were 96.1% (85.2-99.0), 100% (100-100), and 98.6% (90.5-99.8) at 1 year, and 96.1% (85.2-99.0), 92.6% (73.4-98.1), and 97.2% (89.2-99.3) at 2 years with 4, 3, and 3 deaths occurring on study. Conclusions: Cytogenetic and molecular responses were seen in a high proportion of patients with Ph+ CP CML and TKI-resistance or TKI-intolerance. Response rates were similar between patients with resistance to imatinib and patients who were intolerant to all prior TKIs. Although to a lesser degree, responses were also seen in patients with resistance to second-generation TKIs, including patients achieving MR despite the shorter treatment duration. These results further support bosutinib use for patients with Ph+ CP CML and resistance/intolerance to prior TKIs. Disclosures Smith: Agios: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Jazz: Consultancy. Brümmendorf:Janssen: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy; Merck: Consultancy; University Hospital of the RWTH Aachen: Employment; Pfizer: Consultancy, Research Funding. Roboz:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Charbonnier:Novartis: Consultancy; Pfizer: Consultancy; Incyte: Speakers Bureau. Viquiera:Pfizer: Employment, Equity Ownership. Leip:Pfizer: Employment, Equity Ownership. Giles:Novartis: Consultancy; Epigene Therapeutics Inc: Consultancy, Other: leadership, stock/other ownership ; Actuate Therapeutics Inc: Employment. Ernst:Novartis: Research Funding. Hochhaus:Incyte: Research Funding; MSD: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Rosti:BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Maintaining Imatinib ≥600 Mg Daily in the First 12 Months of Chronic Phase CML Treatment Is Associated with Superior Event-Free Survival at 5 Years.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1125-1125 ◽  
Author(s):  
Michael P Osborn ◽  
Susan Branford ◽  
Deborah L White ◽  
John F Seymour ◽  
Ruth Columbus ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Event Rates

Abstract Abstract 1125 Poster Board I-147 The Australasian Leukaemia and Lymphoma Group conducted a trial (TIDEL I) in 103 patients with newly diagnosed chronic phase CML, using imatinib 600 mg/day with dose escalation to 800 mg/day for suboptimal response. This was defined as failure to achieve (1) complete haematological response (CHR) at 3 months, (2) major cytogenetic response (MCR) at 6 months, (3) complete cytogenetic response (CCR) or molecular equivalent at 9 months, or (4) less than 0.01% (IS) BCR-ABL by RQ-PCR at 12 months. Here we report the outcomes with all surviving patients having been treated for at least 60 months. We aimed to determine whether the patient outcome at 60 months was predicted by the molecular response within the first 18 months of imatinib therapy. The outcomes for patients maintaining a dose of imatinib of ≥600 mg/day in the first 12 months was compared to those who were on a reduced dose for at least part of this time. Event-free survival (EFS) was defined as death from any cause, accelerated phase/blast crisis (AP/BC), and loss of CHR, MCR or CCR. The 103 patients included 66 males and 37 females with a median (±SD) age of 49 (±14) years. All patients had an ECOG performance status of 0-2 at enrolment. The 5-year EFS was 71%, transformation (AP/BC) free survival (TFS) was 95%, and overall survival was 87%. Of the 14 patients who died, 3 died in blast crisis, 2 from transplant-related complications, 8 from CML-unrelated causes, and the cause of death of 1 patient was unavailable. The annual rates of progression to AP/BC over 5 years were 3%, 1%, 0%, 1%, and 0%, while annual event rates were 13%, 8%, 8%, 1%, and 4%. CCR was achieved by 89% of patients by 60 months, while 72% achieved a major molecular response (MMR) by this time. In the first 12 months of treatment, 55% of patients maintained an imatinib dose of ≥600 mg/day (mean ±SD dose = 604 ±10 mg/day), while 45% were on <600 mg/day for at least part of this time (mean ±SD dose = 511 ±100 mg/day). EFS at 60 months was significantly higher in patients taking ≥600 mg/day compared with those who had been dose-reduced to <600 mg/day (89% vs 56%, P<0.001). Annual event rates for the ≥600 mg/day group were 6%, 2%, 2%, 0%, and 2%, while annual event rates for those on <600 mg/day were 14%, 16%, 16%, 8%, and 4%. By 60 months, 96% of patients who had been on ≥600 mg/day within the first 12 months had achieved CCR, while only 80% of those who had been on <600 mg/day had achieved this milestone (P<0.001). Log rank analysis of the achievement of MMR was also significant (P=0.03). Overall survival and TFS after 12 months were both similar between the dosing groups. There was no difference between the dosing groups' median age (50 vs 48 years, P=0.36) or Sokal score (1.04 vs 0.94, P=0.33) that may otherwise account for these results. The outcome was also determined for all patients dependent on the BCR-ABL levels at various assessment timepoints. Patients with a BCR-ABL level of <10% (IS) at 6 months (n=92) had an EFS of 78% at 60 months, while all of those with a level >10% (IS) (n=8) had an event (P<0.001). Patients with a level of ≤1% (IS) at 12 months (equivalent to CCR) (n=81) had an EFS of 75% compared with 25% (n=13) for those with levels >1% (IS) (P<0.001). At 18 months, a level ≤0.1% (IS) (n=58) conferred an EFS of 88%, while those who had failed to attain this depth of response (n=30) had an EFS of 60%. There was a significant difference in EFS between those who had achieved an MMR at 18 months and those who had achieved a CCR, but no MMR (88% vs 67%, P=0.03). In conclusion, our data suggest that patients maintaining a dose of ≥600mg in the first 12 months of imatinib therapy are more likely to achieve CCR and MMR, and superior EFS compared to those with a lower dose. This study also confirms that achieving an MMR by 18 months is associated with improved EFS. This emphasises the value of achieving a molecular response early in the treatment course, as well as adding weight to the evidence supporting the role of molecular monitoring in CML. Disclosures Branford: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. White:Novartis and Britol-Myers Squibb: Research Funding. Seymour:Bayer Schering: Consultancy, Membership on an entity's Board of Directors or advisory committees, Travel grants; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Grants. Catalano:Roche: Honoraria, Research Funding, Travel grants. Mills:Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding.

Efficacy and Safety of Nilotinib in Elderly Patients with Imatinib-Resistant or -;Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP): A Sub-Analysis of the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3286-3286 ◽  
Author(s):  
Philipp D. le Coutre ◽  
Anna Turkina ◽  
Dong-Wook Kim ◽  
Bernadeta Ceglarek ◽  
Giuliana Alimena ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Study Drug ◽  
Cytogenetic Response ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Abstract 3286 Poster Board III-1 Introduction: Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib in adult pts with imatinib-resistant or intolerant CML in a clinical practice setting outside of a registration program. It is the largest single source of efficacy and safety information of any available tyrosine kinase inhibitor (TKI) in CML, particularly among the elderly. Methods: The present is a sub-analysis of the ENACT study on the efficacy and safety of 400 mg twice daily nilotinib in elderly (aged =60 years) pts initiating treatment in CML-CP who were resistant and/or intolerant to imatinib. Results: Of the 1,422 CML-CP pts enrolled in the ENACT study between January 2006 and October 2008, 452 (32%) were elderly (=60 years) at study initiation and 165 (37%) of these pts were =70 years [10 (2%) were =80 years]. Countries that enrolled =20 elderly pts include France, Italy, USA, Germany, UK, Spain, Canada, and Brazil. At study initiation, elderly pts had longer median durations of CML (<60: 51.1 months; =60: 69.3; =70: 66.6) and higher proportions with CML duration >5 years (<60: 43%; =60: 56%; =70: 52%). Besides imatinib, prior CML treatments received by elderly pts included dasatinib (=60: 20%; =70: 19%), cytarabine (=60: 23%; =70: 19%), busulfan (=60: 10%; =70: 7%), and interferons (=60: 50%; =70: 42%). Elderly pts were previously treated with imatinib for longer median durations (<60: 27.4 months; =60: 32.7; =70: 29.9), with higher proportions treated for >5 years (<60: 12%; =60: 19%; =70: 18%). The proportion of imatinib-intolerant to resistant elderly pts was about 1:1, which was higher than the proportion among <60 pts at about 0.6:1, such that relatively few elderly pts had prior highest imatinib dose >800 mg (<60: 34%; =60: 26%; =70: 21%). While response rates to prior imatinib were similar, among pts who required therapy after failing imatinib, elderly pts had lower cytogenetic response rates (<60: 22%; =60: 17%; =70: 19%) to prior dasatinib. During ENACT, less than 50% of elderly pts experienced nilotinib dose interruptions (=60: 46%; =70: 41%) and reductions (=60: 7%; =70: 6%) lasting >5 days, which was consistent with the overall ENACT dataset. The median duration of dose interruptions and reductions was 15 (=70: also 15) and 41 (=70: 32) days, respectively. The main reason for dose interruptions and reductions was adverse events (AEs). The median duration of nilotinib exposure was 227 days (=70: 219) and the median dose intensity was 749 mg/day (=70: 775). Efficacy was similar among elderly pts, with 39% (=70: 35%) of pts achieving complete hematologic response (CHR), 41% (=70: 39%) achieving major cytogenetic response (MCyR) and 31% (=70: 33%) achieving complete cytogenetic response (CCyR). MCyR rate was also similar among elderly hematologic responders (=60: 64%; =70: 65%). Among elderly pts requiring nilotinib therapy after both imatinib and dasatinib, and therefore have more resistant CML, CHR rate was 39% (=70: 32%), MCyR rate was 28% (=70: 29%) and CCyR rate was 20% (=70: 16%). Safety was likewise similar among elderly pts, with grade 3/4 study drug-related AEs occurring in 56% of pts (=70: 53%). The most frequent of these AEs were thrombocytopenia (=60: 24%; =70: 21%) and neutropenia (=60: 14%; =70: 11%). The most common method of managing these AEs was brief dose interruptions and/or reductions [thrombocytopenia (=60:86/108 pts; =70: 30/35), neutropenia (=60: 42/62 pts; =70: 9/18)]. Among elderly pts with prior dasatinib, 53% (=70: 58%) experienced grade 3/4 study drug-related AEs, while 7 out of 8 pts with pleural effusion on dasatinib no longer had it on nilotinib. Conclusions: In ENACT, pts aged =60 years at study initiation appear to have longer durations of CML, be more heavily pre-treated and more intolerant to imatinib than the younger cohort. Nonetheless, nilotinib induced comparable clinical responses in CML-CP pts regardless of age. Importantly, the safety profile of nilotinib is maintained in elderly pts. Disclosures: le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Kim:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Ceglarek:Novartis Pharmaceuticals: Honoraria. Shen:Novartis Pharmaceuticals: Honoraria. Smith:Novartis Pharmaceuticals: Honoraria. Rizzieri:Novartis Pharma: Honoraria, Research Funding, Speakers Bureau. Szczudlo:Novartis: Employment. Berton:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Research Funding. Nicolini:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau.

Early Switch to Nilotinib Does Not Overcome the Adverse Outcome for CML Patients Failing to Achieve Early Molecular Response On Imatinib, Despite Excellent Overall Outcomes in the TIDEL II Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3771-3771 ◽  
Author(s):  
David T Yeung ◽  
Michael Philip Osborn ◽  
Deborah L White ◽  
Susan Branford ◽  
Michael Kornhauser ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Time Dependent ◽  
Molecular Response ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Trough Levels

Abstract Abstract 3771 Background: We have previously reported promising results from the TIDEL-II trial, using imatinib (IM) treatment upfront in patients (pts) newly diagnosed with Philadelphia chromosome positive Chronic Myeloid Leukaemia in Chronic Phase (CML-CP), and switching selected pts to nilotinib (NIL) on the basis of failure to achieve time-dependent molecular response (MR). This strategy showed excellent rates of major molecular response (MMR; BCR-ABL ≤0.1% IS) at 12 months (mos) and transformation free survival. Aim: To optimise molecular outcome and survival in treatment naïve CML-CP pts by selective dose escalation of IM for pts with low trough levels and early switching to NIL for pts with poor MR. Methods: TIDEL-II enrolled 210 CML-CP pts across 23 Australasian centres in 2 equal and sequential cohorts. All pts started treatment with IM 600mg/d and dose escalated to IM 800mg/d if IM trough levels were <1000ng/mL. A series of time-dependent MR targets were set: BCR-ABL ≤10%, ≤1% and ≤0.1% (IS) at 3, 6 and 12 mos. Cohort 1 (C1) pts failing to meet these targets dose escalated to IM 800 mg/d. Pts who failed to improve molecular response, or were already on IM 800mg/d, switched to NIL 400mg BID. Pts in cohort 2 (C2) who failed these targets switched to NIL directly. Pts with grade III/IV or persistent grade II toxicity were also allowed to switch from IM to NIL. Results: Median follow up (f/u) for C1 and C2 pts were 42 & 24 mos respectively, and 31 mos for all pts (15–56 mos) – see table 1. The primary end-point, confirmed MMR at 12 mos, was achieved by 64%, with no difference between C1 and C2. This climbed to 75% at 24 mos. At 12 & 24 mos, the proportion of pts with confirmed MR4.5 (BCR-ABL ≤ 0.0032% IS) was 18% and 29% respectively. Six pts progressed to blast crisis (BC) : 4 in their 1st year of treatment, and 1 each in the 2nd and 3rd yrs, resulting in 2 deaths. Four other deaths were recorded, caused by stroke (1), pneumonia (1) and cardiac disease (2); 2 pts had NIL treatment before death. Eighteen mutations had been identified in 11 pts, including 4 pts with the highly resistant mutations T315I or E255K either singly or in combination with others. These were identified in the context of BC (3), loss of MMR (2), lack of MMR by 12 mos (4), and lack of CCR by 6 mos (2). One other pt lost MMR in the absence of a mutation and regained MMR with switching to NIL. Thirty-one pts in C1 switched to NIL: 19 for intolerance and 12 for failure to achieve targets after a trial of IM 800mg/d. Of the latter, with median f/u of 26 mos on NIL, 5/12 reached MMR subsequently. In C2, 44 patients switched to NIL, 12 for intolerance and 32 for failing targets: of the latter, 9 reached MMR with median f/u of 14 mos. In contrast, in the 31 (C1+C2) pts switching for IM-intolerance, all but 2 reached MMR (including 12 patients already in MMR at time of switch). Of the 25 pts with BCR-ABL ≥ 10% at 3mos, 3 pts progressed to BC (1 at 3.5mos), 6 more withdrew from study. Of the remainder, four pts achieved MMR, 9 more achieved BCR-ABL<1% but without MMR. None of these 25 pts have achieved MR4.5. (Table 2). Conclusion: Overall, the TIDEL-II strategy compares well with other upfront studies of CML-CP pts with regard to MR, as well as risk of death and progression to BC. A small proportion of pts experience further falls in BCR-ABL when switching from IM to NIL for failure to achieve deep MR. In the 12% of pts who fail to achieve BCR-ABL ≤10% at 3 mos, there is greater risk of BC and so far no deep MR are seen, despite intensification in kinase inhibition instituted at as early as 3 mos. Alternative approaches are needed both to identify these pts early and protect them from disease transformation. Disclosures: Yeung: Novartis Pharmaceuticals: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. White:Novartis Pharmaceuticals: Research Funding; BMS: Research Funding. Branford:Novartis : Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad : Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cepheid : Consultancy. Slader:Novartis Pharmaceuticals: Employment. Hiwase:CSL Ltd: Research Funding. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ross:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Grigg:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis Oncology: 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; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Efficacy and Safety of Nilotinib 300 Mg Twice Daily (BD) in Patients with CML in Chronic Phase (CML-CP) Who Are Intolerant to Prior BCR-ABL Tyrosine Kinase Inhibitors (TKIs): Results from the Randomized, Phase IIIb E.N.E.S.Tswift Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5447-5447
Author(s):  
Devendra K Hiwase ◽  
Peter Tan ◽  
James D'Rozario ◽  
John Taper ◽  
Anthony Richard Powell ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Myeloproliferative Disease ◽  
Advisory Committees ◽  
Log Reduction ◽  
Treatment Interruptions

Abstract Background: Philadelphia chromosome-positive (Ph+) CML is a myeloproliferative disease characterized by the presence of the abnormal Ph+ in hematopoietic cells. Imatinib, dasatinib and nilotinib are BCR-ABL TKIs commonly used in the treatment of CML-CP. Many patients on BCR-ABL TKI therapy will experience adverse events (AEs). Some of the more common AEs associated with first- and second-generation BCR-ABL TKIs include fluid retention, diarrhea, rash, musculoskeletal pain, nausea, vomiting, muscle cramps, and headache. Some patients will be unable to tolerate these AEs and will discontinue therapy. The current study aimed to assess the efficacy and safety of nilotinib in patients with CML-CP who are responsive to but intolerant of treatment with imatinib or dasatinib. Although the study was stopped early due to low recruitment, here we present results on cross-intolerance and molecular response in the patients who were switched from imatinib or dasatinib to nilotinib. Methods: Eligible adult patients had: Ph+ CML-CP associated with BCR-ABL quantifiable by real-time quantitative reverse transcriptase-polymerase chain reaction (RQ-PCR); received ≥3 months imatinib or dasatinib or both; were <1% (IS) BCR-ABL level in the blood during imatinib or dasatinib treatment; and were experiencing any non-hematological AEs (any grade) that persisted for ≥1 month or recurred at least once despite supportive care. After a washout period of ≥3 days, patients were switched to nilotinib 300 mg BD and treated for up to 24 months. The dose could be reduced to 450 mg QD for safety reasons. Treatment interruptions, dose reductions and dose re-escalation to 300 mg BD were allowed for management of AEs. The primary outcome was achievement of MR4.5 (BCR-ABL ≤0.0032%) by 24 months. Major molecular response (MMR; BCR-ABL ≤0.1%) and MR4.0 (BCR-ABL ≤0.01%) were also assessed in an exploratory capacity at each visit (month 1, 2, 3, then every 3 months to month 24). Secondary endpoints included the kinetics of molecular response. Preliminary results are summarized descriptively. Planned enrolment was 130 patients. Results: The study was stopped early due to low recruitment; 20 patients were enrolled (mean age 53.9 years [range 31-77]; 14 female). 16 patients had received prior imatinib therapy, 4 patients prior dasatinib. Median nilotinib treatment duration was 494 days (mean 480, SD 167.6 days). At screening, 30% of patients were not in MMR, 45% had MMR and 25% had MR4.0. By month 3 and 24 of nilotinib treatment, 55% (11/20) and 65% (13/20) of patients, respectively, achieved at least a 1 log reduction in BCR-ABL levels. 35% (7/20) of patients achieved MR4.5 between baseline and month 3 of nilotinib treatment, and 50% (10/20) achieved MR4.5 at any time up to month 24. The proportion of patients with a molecular response at each visit up to month 15 is shown in the Figure. AEs during prior treatment with imatinib and dasatinib included gastrointestinal events (nausea, vomiting, diarrhea), superficial edema, myalgia, fatigue, rash, and headache, among others. 68% of AEs had resolved by month 3 of nilotinib treatment. Among the 13 evaluable patients on prior imatinib, 7 (54%) had resolution of all AEs during treatment with nilotinib; of 3 evaluable patients on prior dasatinib, 3 (100%) had AE resolution on nilotinib. Grade 3/4 AEs during nilotinib therapy occurred in 3 patients: diabetes mellitus, fatigue, neutropenia, pneumonia, osteoarthritis, and hyperuricemia. Conclusions: Although early termination of the study has not allowed for a robust analysis, these results suggest that nilotinib is effective and well tolerated in most patients intolerant of imatinib or dasatinib. During the first 3 months of switching to nilotinib, 55% of patients had achieved at least a 1 log reduction in BCR-ABL levels, and 35% of patients had achieved MR4.5. The cumulative rate of MR4.5 by 24 months was 50%. Achievement of this endpoint has been linked to favorable long-term outcomes, such as treatment-free remission. Furthermore, the majority of the AEs had resolved by month 3 of nilotinib therapy. This improved tolerance to nilotinib may result in improved treatment adherence. As such, although further study in a larger population is needed for confirmation, these results provide further evidence that nilotinib is a favorable option to establish a molecular response in patients intolerant of imatinib or dasatinib. Disclosures D'Rozario: BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Branford:Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Ariad: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cepheid: Consultancy. Yeung:Ariad: Research Funding; Novartis Pharmaceuticals: 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. Anderson:Novartis Pharmaceuticals: Employment. Gervasio:Novartis Pharmaceuticals: Employment. Hughes: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; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Molecular Response at 3 Months On Nilotinib Therapy Predicts Response and Long-Term Outcomes in Patients with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia in Chronic Phase (CML-CP).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3292-3292 ◽  
Author(s):  
Susan Branford ◽  
Dong-Wook Kim ◽  
Simona Soverini ◽  
Enrico Gottardi ◽  
Lan Beppu ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Long Term Outcomes ◽  
Advisory Committees ◽  
Imatinib Resistance ◽  
Transcript Levels ◽  
Imatinib Resistant

Abstract Abstract 3292 Poster Board III-1 Background: Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor, approved for the treatment of Philadelphia positive CML patients (pts) in CP or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. A recent analysis demonstrated an association between BCR-ABL transcript levels at 3 months (mos) and response in pts treated with second-line tyrosine kinase inhibitors (Branford et al. Blood. 2008). This multi-center analysis was conducted to examine the association specifically between the initial molecular response to nilotinib with response and outcomes. Methods: CML-CP pts (N = 321) with imatinib resistance or intolerance were included and post-baseline BCR-ABL transcript levels were available for 294 patients. Intolerant pts also exhibited some degree of resistance to imatinib and were not eligible for the study if demonstrating major cytogenetic response (MCyR), the primary study endpoint. We aimed to determine if the initial molecular response to nilotinib could predict the response and outcome of patients with or without BCR-ABL mutations at baseline or those with imatinib resistance or intolerance. BCR-ABL transcript levels at 3 mos were used to perform a landmark analysis to assess the association between the initial molecular response and estimated probability of MCyR, major molecular response (MMR), and event-free survival (EFS) at 24 mos. Events were defined as loss of hematologic or cytogenetic response, progression to AP/BC, discontinuation due to progression or death. The analysis excludes patients who had already attained MCyR (n = 111) or MMR [BCR-ABL% (IS) ≤ 0.1%] (n = 28) or who had an event (n = 22) within the first 3 mos of therapy for each respective landmark analysis. Patients censored within the first 3 mos were also excluded. Patients were then grouped according to their level of BCR-ABL% (IS). Results: BCR-ABL% (IS) at 3 mos correlated with MCyR rates at 24 mos; pts with BCR-ABL% (IS) ≤ 10 had better probability of response compared with pts with BCR-ABL% (IS) > 10 (62% vs 35%, respectively). This difference in MCyR rate was most significant for pts with baseline mutations (60% vs 19%, P = .006) and those with imatinib resistance (63% vs 33%, P = 0.0007). A similar trend was observed for patients without baseline mutations (64% vs 47%) and imatinib intolerance (57% vs 40%). BCR-ABL% (IS) at 3 mos was highly predictive of MMR rates at 24 mos (Table). Pts with BCR-ABL% (IS) values > 0.1 - ≤ 1 had significantly higher probability (65%) of achieving MMR for all patient groups, whereas those with BCR-ABL% (IS) > 10 had estimated rates of 10% or less. The BCR-ABL% (IS) value at 3 mos was also found to correlate with EFS at 24 mos (Table). The estimated EFS rate at 24 mos was highest for pts with BCR-ABL% (IS) values of ≤ 1 at 3 mos for each patient group and ranged from 75% to 100%. Patients with BCR-ABL% (IS) values > 10 at 3 mos had the poorest outcome and the estimated EFS rates ranged from 36% for patients with baseline mutations to 57% for those without baseline mutations. Conclusion: BCR-ABL% (IS) at 3 mos predicts response and long-term outcomes of imatinib-resistant and intolerant pts regardless of baseline mutation status at 24 mos on nilotinib therapy. Rapid reduction of BCR-ABL may be important for optimal response and outcome. Pts whose BCR-ABL % (IS) levels decreased below 10% at 3 mos demonstrated a high probability of achieving MMR and MCyR at 24 mos. Pts who achieve early molecular response may also have an increased probability of improved long-term outcomes on nilotinib therapy, while pts with BCR-ABL% (IS) value > 10 at 3 mos may have poorer prognosis. Disclosures: Branford: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Kim: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; Wyeth: Research Funding. Haque:Novartis: Employment. Shou:Novartis: Employment. Woodman:Novartis: Employment. Kantarjian:Novartis: Research Funding. Radich:Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding.

scholarly journals Ponatinib and Chemotherapy in Young Adults with De Novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Results of Ponalfil Clinical Trial after Completion of Recruitment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Josep-Maria Ribera ◽  
Olga García ◽  
Pau Montesinos ◽  
Pilar Martinez ◽  
Jordi Esteve ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Central Artery

Background and objective. The combination of tyrosine kinase inhibitors (TKI) and chemotherapy (intensive, attenuated or minimal) has improved the prognosis of patients (pts) with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The combination of HyperCVAD and ponatinib has improved the molecular response and survival compared with other combinations of chemotherapy with first or second generation TKI (Jabbour E, et al, Lancet Haematol. 2018; 5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same induction and consolidation schedule of the ALL Ph08 trial (Ribera JM et al. Cancer 2019;125:2810-2817) The results of this trial after completed recruitment are herein reported. Patients and method. The PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin and prednisone) followed by consolidation (high-dose methotrexate, ARA-C, mercaptopurine, etoposide) and allogeneic HSCT. TKI use as maintenance was only scheduled for pts with persistence or reappearance of MRD. By July 2020 the 30 scheduled pts were recruited. The response to therapy (complete morphological [CR], molecular [complete, CMR or major, MMR] after induction and before allogeneic HSCT) (assessed by centralized BCR-ABL/ABL ratio),event-free survival (EFS), overall survival [OS]) and toxicity are herein analyzed. Results. Median age was 50 (20-59) years and 14/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score at diagnosis was &lt;2 in 86% of pts. Median of WBC count was 6.4 (0.6-359.3) x109/L, Hb 90 (63-145) g/L, platelets 38 (11-206) x109/L. The immunologic phenotype was common in 26 cases, with molecular isoform p190 in 20 patients (67%), p210 in 9 (30%) and p230 in 1 (3%). CR was attained 26/26 patients (100%) (4 are still on induction therapy), with CMR in 11/26 cases (42%), MMR in 6/26 (23%) and no molecular response in 9/26 (35%)).Two patients withdrew the trial (thrombosis of the central retina artery and severe intestinal infection, one case each). Consolidation was given to 24 patients, 2/24 are receiving consolidation and 22 patients received allogeneic HSCT (14 in CMR, 6 in MMR, 2 without molecular response). No relapses before HSCT were detected. No transplant-related mortality was observed to date, but 1 patient withdrew the trial by severe GVHD. Ponatinib was given after HSCT in 4 pts due to loss of molecular response. Three pts relapsed after HSCT, one of them after documented loss of molecular response. All pts are alive (median follow-up of 4.5 months, range 0.5-26.2.2). The EFS probability at 30 months was 91% (79%, 100%) (Figure 1). One hundred and two adverse events (AE) have been registered in 20 patients, 25 of whom were severe (SAE) and occurred in 14 patients, prompting to withdrawn of the trial in 3 (thrombosis of the central artery of the retina, severe bowel infection, grade IV aGVHD, one case each). The most frequent AE were hematologic (26%), gastrointestinal (15%), infections (10%), hepatic (8%) and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina, one case each). Conclusions. The preliminary results of the PONALFIL trial after recruitment completed show a high short-term antileukemic efficacy with acceptable toxicity profile. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. Event free survival (EFS) of the whole series. Figure 1 Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau; Pfizer, Amgen: Research Funding. Martinez-Lopez:Incyte: Consultancy, Research Funding; Novartis: Consultancy; BMS: Consultancy, Research Funding; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Garcia-Sanz:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Gilead: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Pharmacyclics: Honoraria; Takeda: Consultancy, Research Funding.

Second-line bosutinib (BOS) for patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML): Final 10-year results of a phase 1/2 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7009-7009
Author(s):  
Carlo Gambacorti-Passerini ◽  
Tim H. Brümmendorf ◽  
Dong-Wook Kim ◽  
Yeow Tee Goh ◽  
Irina S Dyagil ◽  
...  
Keyword(s):  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Second Line ◽  
Prior Therapy ◽  
Kaplan Meier ◽  
Imatinib Resistant

7009 Background: BOS is approved for Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed Ph+ CP CML. In a phase 1/2 study, second-line BOS showed durable efficacy and manageable toxicity in pts with imatinib-resistant (IM-R) or -intolerant (IM-I) Ph+ CP CML. Methods: This final efficacy and safety analysis of the phase 1/2 study and extension study was based on ≥10 y of follow-up (FU). Ph+ CP CML pts who received BOS starting at 500 mg/d after prior treatment (Tx) with imatinib only were included. Results: 19% of pts were on BOS at y 10, and 13% were still on BOS at study completion after ≥10 y; 19% completed ≥10 y of FU. Median duration of Tx and FU were 26 and 54 mo, respectively. Median (range) dose intensity was 436 (87–599) mg/d. The most common primary reasons for permanent Tx discontinuation were lack of efficacy (unsatisfactory response or disease progression; 27%) and adverse events (AEs; 26%). In pts with a valid baseline assessment, cumulative complete cytogenetic response (CCyR), major molecular response (MMR) and MR4 rates (95% CI), respectively, were 50% (43–56), 42% (35–49) and 37% (30–44) (IM-R: 48% [41–56], 46% [37–55] and 39% [31–48]; IM-I: 53% [41–64], 36% [25–48] and 33% [22–45]). Responses were durable, with estimated probabilities of maintaining CCyR, MMR and MR4 > 50% after ≥10 y (Table). At 10 y, cumulative incidence of on-Tx progression/death was 24% and Kaplan-Meier (K-M) overall survival 72% (Table); 55 deaths (IM-R: n = 41; IM-I: n = 14) occurred on study, none BOS-related. Any grade Tx-emergent AEs (TEAEs) in ≥40% of pts were diarrhea (86%), nausea (46%) and thrombocytopenia (42%). Pleural effusion, cardiac and vascular TEAEs occurred in 13%, 12% and 11% of pts, respectively. 28% of pts had AEs leading to permanent Tx discontinuation; most common (≥2% of pts) were thrombocytopenia (6%), neutropenia (2%) and alanine aminotransferase increased (2%). Conclusions: These 10-y data are consistent with prior results of durable efficacy and manageable toxicity with second-line BOS and support long-term BOS use in CP CML pts after imatinib failure. Clinical trial information: NCT00261846 and NCT01903733. [Table: see text]

Dasatinib Efficacy in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Pre-Existing BCR-ABL Mutations

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 449-449 ◽  
Author(s):  
Martin C Müller ◽  
Jorge Cortes ◽  
Dong-Wook Kim ◽  
Brian J. Druker ◽  
Philipp Erben ◽  
...  
Keyword(s):  
Amino Acids ◽  
Median Time ◽  
Chronic Phase ◽  
Response Rates ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Imatinib Resistant ◽  
Dasatinib Treatment

Abstract Dasatinib (SPRYCEL®) is an effective BCR-ABL inhibitor that is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. Across a series of phase II and III trials, dasatinib has demonstrated durable efficacy in patients with CML following resistance, suboptimal response, or intolerance to imatinib. BCR-ABL mutations are an important cause of imatinib failure and suboptimal response. Here, the efficacy of dasatinib in patients with CML-CP who had baseline BCR-ABL mutations following imatinib treatment was analyzed using data from three trials (CA180-013, -017, and -034). Mutational assessment of the BCR-ABL kinase domain was performed using RT-PCR and direct sequencing of peripheral blood cell mRNA. Hematologic, cytogenetic, and molecular response rates were reported after ≥24 mos of follow-up. Duration of response, progression-free survival (PFS), and overall survival (OS; in 013/034) were calculated using Kaplan-Meier analysis, and rates were estimated at the 24-mo time point. Of 1,150 patients with CML-CP who received dasatinib, 1,043 had a baseline mutational assessment and were analyzed further. Of these, 402 patients (39%) had a BCR-ABL mutation, including 8% of 238 imatinib-intolerant and 48% of 805 imatinib-resistant patients. Excluding known polymorphisms, 64 different BCR-ABL mutations were detected affecting 49 amino acids, with G250 (n=61), M351 (n=54), M244 (n=46), F359 (n=42), H396 (n=37), Y253 (n=26), and E255 (n=25) most frequently affected. Dasatinib treatment in patients with or without a baseline BCR-ABL mutation, respectively, resulted in high rates of major cytogenetic response (MCyR; 56% vs 65%), complete cytogenetic response (CCyR; 44% vs 56%), major molecular response (MMR; 33% vs 45%); PFS (70% vs 83%), and OS (89% vs 94%) (Table). After 24 mos, CCyRs in patients with or without a BCR-ABL mutation had been maintained by 84% vs 85%, respectively, of those achieving this response. Among patients with mutations who received dasatinib 100 mg once daily, which has a more favorable clinical safety profile, efficacy and durability were similar (MCyR: 55%; CCyR: 41%; MMR: 36%; PFS: 73%; OS: 90%). In general, high response rates and durable responses were observed in patients with different mutation types, including highly imatinib-resistant mutations in amino acids L248, Y253, E255, F359, and H396. When responses were analyzed according to dasatinib cellular IC50 for individual BCR-ABL mutations, dasatinib efficacy was observed in 44 patients who had any of 5 imatinib-resistant mutations with a dasatinib cellular IC50 &gt;3 nM (Q252H, E255K/V, V299L, and F317L, excluding T315I), including MCyR in 34%, CCyR in 25%, MMR in 18%, PFS in 48%, and OS in 81%. Among patients whose mutations had a dasatinib IC50 ≤3 nM (n=254) or unknown IC50 (n=83), responses and durability were comparable to patients with no BCR-ABL mutation. As expected, few patients with a T315I mutation (IC50 &gt;200 nM; n=21) achieved a response. Among 70 patients with &gt;1 mutation, a MCyR was achieved in 53% and a CCyR in 37%. Among patients with mutational analysis at last follow-up (n=162), 42 (26%) retained a BCR-ABL mutation (20 retained a mutation with IC50 &gt;3 nM), 42 (26%) lost a mutation (5 lost a mutation with IC50 &gt;3 nM), and 44 (27%) developed a new mutation (39 developed a mutation with IC50 &gt;3 nM), with some patients counted in more than one category. Overall, this analysis demonstrates that dasatinib has broad efficacy against all BCR-ABL mutations except for T315l. For patients with BCR-ABL mutations, dasatinib treatment is associated with durable responses and favorable long-term outcomes. Table Analysis by dasatinib IC50 No BCR-ABL mutation BCR-ABL mutation BCR-ABL mutation treated with 100 mg QD &gt;3 nM (excl. T315I) 3 nM* Unknown IC50** Some patients had &gt;1 mutation. *Excluding patients with a concurrent mutation with dasatinib IC50 &gt;3 nM. **Excluding patients with a concurrent mutation with known dasatinib IC50. Patients, n 641 402 49 44 254 83 Response rates (≥24 mos of follow-up), % CHR 93 90 90 82 94 96 MCyR 65 56 55 34 58 73 CCyR 56 44 41 25 47 54 MMR 45 33 36 18 34 43 Median time to MCyR, mos 2.8 2.9 2.8 5.7 2.9 2.8 Median time to CcyR, mos 3.0 5.3 3.0 5.7 5.4 3.4 24-mo PFS (95% CI), % 83 (79.8–86.5) 70 (65.3–75.2) 73 (60.1–86.3) 48 (31.2–64.7) 73 (66.6–78.9) 89 (82.3–96.3) 24-mo OS (95% CI), % 94 (91.4– 95.7) 89 (85.1– 92.1) 90 (81.2– 98.3) 81 (68.8– 93.8) 90 (85.8– 94.2) 96 (91.2–100)

Outcome of Patients with Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) with Relapse After Tyrosine Kinase Inhibitor (TKI) Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1518-1518
Author(s):  
Hun Ju Lee ◽  
Susan O'Brien ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Salvage Therapy ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Advisory Committees ◽  
Cns Relapse ◽  
Complete Hematologic Response

Abstract Abstract 1518 Background: Treatment with TKIs has greatly improved the outcome of patients with Ph+ ALL. However, many patients treated with TKI-based therapy eventually have a relapse. The response to salvage therapy and long-term outcomes of these patients are unknown. Aims: Describe the outcomes of patients with Ph+ ALL with resistance to or relapse after frontline TKI-based chemotherapy. Methods: We analyzed the outcome of patients who were treated in clinical trials at our institution between February 2001 and July 2008 with TKI-based chemotherapy for newly diagnosed Ph+ ALL who had refractory or relapsed disease. Results: One hundred thirteen patients were treated with frontline hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone (HCVAD) plus imatinib (HCVAD+I; n=54) or HCVAD plus dasatinib (HCVAD+D; n=59). Of these, 35 (31%) experienced primary resistance (n=1) or relapse (n=34). The median age was 51 years [range (r): 20–85]; 12 patients (34%) were older than 60 years. Median follow-up was 21.1 mo (r: 4.2–56.7). Median white blood cell and platelet counts at diagnosis were 14.4 × 109/L (r: 1.2–292.9) and 48 × 109/L (r: 4–425), respectively. White blood cell count was >30 × 109/L in 13 patients (37%). Median peripheral and bone marrow blast percentages were 53% (r: 0–97%) and 80% (r: 1–98%), respectively. Twenty-two patients (63%) had received HCVAD+I and 13 (37%) HCVAD+D. Twenty-three patients (66%) had experienced first complete remission (CR1) with 1 cycle of induction. Median CR1 duration was 12 mo (r: 1.9–42). Four patients underwent allogeneic stem cell transplantation (ASCT) in CR1. ABL kinase domain mutations were investigated in 28 patients (80%) at relapse; 16 (57%) had mutations, including 5 (14%) with T315I (all had received HCVAD+D). Upon relapse, 31 patients received first salvage therapy (S1), 24 with chemotherapy [HCVAD+D, n=8; HCVAD+I, n=3; HCVAD+nilotinib (N), n=1; HCVAD+asparaginase (Asp), n=1; methotrexate, vincristine, Asp, and dexamethasone (MOAD), n=2; others, n=9]; 6 with a TKI only (I, n=2; D, n=1; N, n=1; others, n=2); and 1 with ASCT. Three patients were unfit for treatment. Median cycles of S1 were 2 (r: 1–8). Thirteen patients (42%) had second complete remission (CR2) (HCVAD+D, n=6; HCVAD+I, n=2; HCVAD+N, n=1; HCVAD+Asp, n=1; others, n=3). Median time to CR2 was 1.5 mo (r: 0.7–8.8). Five patients underwent ASCT in CR2. Median CR2 duration was 7.3 mo (r: 1.4–36.2). Complete cytogenetic response was seen in 11 patients (35%); major molecular response (BCR-ABL/ABL ratio <0.05%) in 9 (29%); and complete molecular response in 7 (22%); and complete hematologic response in 15 (48%). Times to complete cytogenetic response and complete molecular response were 1.3 mo (r: 0.7–10.6) and 3 mo (r: 1.5–8.7), respectively. Seven patients had second relapse. Fifteen patients (7 relapse, 8 refractory) received second salvage therapy (S2) with systemic chemotherapy (MOAD, n=2; phase I/single-agent TKI, n=8; others, n=5); 1 patient had solitary central nervous system (CNS) relapse treated with intrathecal cytarabine and methotrexate. CR3 was obtained in 1 patient, the patient with sole CNS relapse. Median disease-free survival (DFS) and overall survival (OS) after S1 were 6.5 mo (r: 0.5–45) and 7.3 mo (r: 1.4–36.2), respectively. At last follow-up, 2 patients (6%) were alive and 33 had died, 11 (33%) of infectious complications, 5 (15%) of organ failure, 3 (9%) of bleeding complications, 2 (6%) of graft-versus-host disease complications, 2 (6%) of CNS relapse, and 10 (30%) of other or unknown causes. Median OS after S2 was 2.1 mo (r: 1.4–2.6). In univariate analysis, age >60 years was associated with worse OS after S1 [4.2 vs. 12.7 mo; 95% confidence interval (CI) 1.8 to 6.7 vs. 7.5 to 17.9 (P=0.006)]. Complete hematologic response was associated with improved OS after S1 [15.4 vs. 4.3 mo; 95% CI 9.1 to 21.8 vs. 2.5 to 6.0 (P<0.001)]. Major molecular response was associated with improved OS after S1 [18.1 vs. 5.7 mo; 95% CI 9.3 to 26.8 vs. 3.6 to 7.8 (P=0.003)]. Choice of prior TKI (HCVAD+I vs. HCVAD+D) did not significantly influence CR and OS after relapse. Conclusion: Patients with refractory or relapsed Ph+ ALL after TKI-based therapy have poor outcome, particularly those who are older or have persistent BCR/ABL transcripts. New agents are needed to improve the outcome in this population. Disclosures: Kantarjian: BMS: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Cortes:Chemgenex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: 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.

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