Kooperativer Bibliotheksverbund

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 15_suppl ( 2014-05-20), p. 7084-7084

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/jco.2014.32.15_suppl.7084

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2014

detail.hit.zdb_id: 2005181-5

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 27, No. 21 ( 2009-07-20), p. 3472-3479

Abstract: Patients with chronic myelogenous leukemia in accelerated phase (CML-AP) that is resistant or intolerant to imatinib have limited therapeutic options. Dasatinib, a potent inhibitor of BCR-ABL and SRC-family kinases, has efficacy in patients with CML-AP who have experienced treatment failure with imatinib. We now report follow-up data from the full patient cohort of 174 patients enrolled onto a phase II trial to provide a more complete assessment of the efficacy and safety of dasatinib in this population. Patients and Methods Patients with imatinib-resistant (n = 161) or -intolerant (n = 13) CML-AP received dasatinib 70 mg orally twice daily. Results At a median follow-up of 14.1 months (treatment duration, 0.1 to 21.7 months), major and complete hematologic responses were attained by 64% and 45% of patients, respectively, and major and complete cytogenetic responses were achieved in 39% and 32% of patients, respectively. Responses were achieved irrespective of imatinib status (resistant or intolerant), prior stem-cell transplantation, or the presence of prior BCR-ABL mutation. The 12-month progression-free survival and overall survival rates were 66% and 82%, respectively. Dasatinib was generally well tolerated; the most frequent nonhematologic severe treatment-related adverse event was diarrhea (52%; grade 3 to 4, 8%). Cytopenias were common, including grade 3 to 4 neutropenia (76%) and thrombocytopenia (82%). Pleural effusion occurred in 27% of patients (grade 3 to 4, 5%). Conclusion Dasatinib is effective in patients with CML-AP after imatinib treatment failure.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2007.14.3339

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2009

detail.hit.zdb_id: 2005181-5

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 35 ( 2012-12-10), p. 4323-4329

Abstract: The association between initial molecular response and longer-term outcomes with nilotinib was examined. Patients and Methods Patients with imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase from the phase II nilotinib registration study with available postbaseline BCR-ABL1 transcript assessments were included (N = 237). Results BCR-ABL1 transcript levels (International Scale [IS]) at 3 months correlated with complete cytogenetic response (CCyR) by 24 months. Patients with BCR-ABL1 (IS) of 〉 1% to ≤ 10% at 3 months with nilotinib had higher cumulative incidence of CCyR by 24 months than patients with BCR-ABL1 (IS) of 〉 10% (53% v 16%). BCR-ABL1 (IS) at 3 months predicted major molecular response (MMR) by 24 months. Cumulative incidence of MMR by 24 months for patients with BCR-ABL1 (IS) of 〉 0.1% to ≤ 1%, 〉 1% to ≤ 10%, and 〉 10% was 65%, 27%, and 9%, respectively. These differences were observed for patients with or without baseline BCR–ABL1 mutations and for those with imatinib resistance or intolerance. Estimated event-free survival (EFS) rates at 24 months decreased with higher transcript levels at 3 months; patients with BCR-ABL1 (IS) of ≤ 1% had an estimated 24-month EFS rate of 82%, compared with 70% for patients with BCR-ABL1 (IS) of 〉 1% to ≤ 10% and 48% for patients with BCR-ABL1 (IS) of 〉 10%. Conclusion Patients with BCR-ABL1 (IS) of 〉 10% at 3 months had a lower cumulative incidence of CCyR and MMR and lower rates of EFS versus patients with BCR-ABL1 (IS) of ≤ 10%. Prospective studies may determine whether close monitoring or alternative therapies are warranted for patients with minimal initial molecular response.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2011.40.5217

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2012

detail.hit.zdb_id: 2005181-5

In: New England Journal of Medicine, Massachusetts Medical Society, Vol. 362, No. 24 ( 2010-06-17), p. 2251-2259

Type of Medium: Online Resource

ISSN: 0028-4793 , 1533-4406

URL: Article

DOI: 10.1056/NEJMoa0912614

Language: English

Publisher: Massachusetts Medical Society

Publication Date: 2010

detail.hit.zdb_id: 1468837-2

In: Leukemia, Springer Science and Business Media LLC, Vol. 34, No. 8 ( 2020-08), p. 2064-2073

Abstract: Early molecular response is associated with improved probability of deep molecular response and superior survival in patients with CML-CP. However, ~1 in 3 patients on first-line imatinib do not achieve this threshold. The phase 2b DASCERN trial (NCT01593254) assessed the outcome of early switch to dasatinib in patients with suboptimal response to first-line imatinib. Adult patients with CML-CP were randomized (2:1) to receive 100 mg dasatinib ( n  = 174) or continue imatinib at ≥400 mg ( n  = 86). The primary endpoint was the rate of major molecular response (MMR) at 12 months, which was 29% (dasatinib) and 13% (imatinib; P  = 0.005). After ≥2 years of follow-up, 45 patients (52%) randomized to continue imatinib had crossed over to dasatinib. Considering treatment crossover, the 2-year cumulative MMR rate was 64% with dasatinib and 41% with imatinib (66% and 67%, respectively by intent-to-treat). Adverse events were consistent with the established safety profiles of both drugs. The results of this first prospective study support early monitoring of patients treated with first-line imatinib, and suggest that switching to dasatinib in cases of suboptimal response may offer clinical benefit. Further follow-up is needed to assess the long-term clinical benefit of early switching.

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-020-0805-1

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2008023-2

In: Leukemia, Springer Science and Business Media LLC, Vol. 37, No. 3 ( 2023-03), p. 617-626

Abstract: Asciminib, the first BCR::ABL1 inhibitor that S pecifically T argets the A BL M yristoyl P ocket (STAMP), is approved worldwide for the treatment of adults with Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase (CML-CP) treated with ≥2 prior tyrosine kinase inhibitors (TKIs). In ASCEMBL, patients with CML-CP treated with ≥2 prior TKIs were randomized (stratified by baseline major cytogenetic response [MCyR]) 2:1 to asciminib 40 mg twice daily or bosutinib 500 mg once daily. Consistent with previously published primary analysis results, after a median follow-up of 2.3 years, asciminib continued to demonstrate superior efficacy and better safety and tolerability than bosutinib. The major molecular response (MMR) rate at week 96 (key secondary endpoint) was 37.6% with asciminib vs 15.8% with bosutinib; the MMR rate difference between the arms, after adjusting for baseline MCyR, was 21.7% (95% CI, 10.53–32.95; two-sided p  = 0.001). Fewer grade ≥3 adverse events (AEs) (56.4% vs 68.4%) and AEs leading to treatment discontinuation (7.7% vs 26.3%) occurred with asciminib than with bosutinib. A higher proportion of patients on asciminib than bosutinib remained on treatment and continued to derive benefit over time, supporting asciminib as a standard of care for patients with CML-CP previously treated with ≥2 TKIs.

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-023-01829-9

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 449-449

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)

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.449.449

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 792-792

Abstract: All tyrosine kinase inhibitors (TKIs) approved to treat chronic myeloid leukemia (CML) inhibit BCR-ABL1 by targeting the ATP-binding site. Some patients (pts) develop mutations (muts) conferring resistance to these TKIs. The T315I mut confers resistance to all TKIs except ponatinib (PON), which is known to be efficacious. However, pts with cardiovascular (CV) risk factors might not be eligible for PON, and pts failing PON have no other targeted therapies available; thus, new treatments are needed for pts with the T315I mut. Asciminib is a new, potent, and specific TKI targeting the BCR-ABL1 myristoyl-binding site, an allosteric regulatory domain, and has potential to treat pts carrying muts conferring resistance to ATP-binding-site TKIs, including T315I. Preclinical in vitro data showed asciminib activity in BaF3 cells expressing the BCR-ABL1 construct and various muts, including T315I; an approximately 4- to 5-fold increase in exposure was required to inhibit the T315I mut relative to other muts (Wylie et al. Nature. 2017;543:733-737; Wylie et al. Blood. 2014;124 [abstract 398] ). This phase 1 study (NCT02081378) enrolled pts ≥ 18 y old with CML in chronic phase (CP) or accelerated phase resistant to or intolerant of (R/I) ≥ 2 prior TKIs; pts carrying the T315I mut were eligible after ≥ 1 prior TKI. Pts with uncontrolled CV conditions were excluded. Previous results showed single-agent asciminib was well tolerated and demonstrated activity in pts with CML (Hughes et al. Blood. 2016;128 [abstract 625]). A dose of 40 mg twice daily (BID) was recommended for pts with CML-CP without the T315I mut. Enrolled pts carrying the T315I mut were assigned to asciminib 20 mg BID (1 pt), 40 mg BID (1 pt), 80 mg BID (4 pts), 150 mg BID (7 pts), 160 mg BID (7 pts), 200 mg BID (24 pts), 80 mg once daily (QD; 1 pt), 120 mg QD (4 pts), or 200 mg QD (1 pt) cohorts. We report results from the largest cohort: pts with confirmed T315I mut at screening (tested locally by Sanger sequencing) and treated with asciminib 200 mg BID, which showed the most robust efficacy (data cutoff: April 30, 2018). At the data cutoff, treatment was ongoing in 23/24 pts (95.8%) (Table); 1 pt (4.2%) had ended treatment. Median duration of follow-up and asciminib exposure were both 28.5 wk (range, 0.1-74.7 wk). Most pts had received multiple prior TKIs, and PON was the most recent TKI for 12/24 (50.0%). Pts who were PON naive had underlying conditions, such as CV risk factors. Eight of 24 pts achieved MMR by 24 wk; 1 achieved MMR after 24 wk. Ten of 24 pts had BCR-ABL1 〈 10% on the International Scale (IS) at screening and ≥ 1 postbaseline evaluation; 6/10 (60%) achieved a ≥ 1-log reduction in BCR-ABL1IS by 24 wk. Among PON-naive and PON-R/I pts, 5/11 and 3/13, respectively, achieved MMR by 24 wk (Figure). One PON-R/I pt with isolated T315I at screening lost MMR 3 mo after achieving it (prior TKIs: imatinib, dasatinib, and PON). Analysis of 200 mg BID pharmacokinetic data is planned. A total of 20/24 pts (83.3%) experienced any-grade AEs (grade 3/4, 8/24 [33.3%]); the most frequent any-grade AEs were arthralgia, fatigue, lipase increased, and nausea (4/24 [16.7%] each). Any-grade AEs suspected to be study drug related were reported in 15/24 pts (62.5%; grade 3/4, 3/24 [12.5%]) and most frequently included arthralgia and nausea (3/24 [12.5%] each). One pt experienced a serious AE of grade 3 peripheral arterial occlusive disease requiring angioplasty, not considered study drug related, after 17 mo of treatment. This pt was previously treated with imatinib (33 mo), dasatinib (10 mo), bosutinib (5 mo), and PON (17 mo), started asciminib 3 d after stopping PON, had history of hypertension and stroke (on PON), and was on clopidogrel; the pt had asciminib dose reductions to 160 mg BID at 1.5 mo and 120 mg BID at 4 mo due to AEs but remained on asciminib. No deaths were reported. Overall, asciminib 200 mg BID monotherapy showed a favorable safety profile and clinical efficacy in PON-naive and PON-R/I pts carrying the T315I mut. This cohort will be expanded to enroll additional pts carrying the T315I mut. Asciminib may represent a new option for pts with CML and the T315I mut who are not eligible for PON or have failed PON treatment. Disclosures Rea: Pfizer: 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; Incyte: Honoraria. Lang:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Kim:Pfizer: Research Funding; Ilyang: Research Funding; BMS: Research Funding; Novartis: Research Funding. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding. Hughes: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; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Minami:Taisho-Toyama: Research Funding; Ohtsuka: Honoraria; DaiichiSankyo: Honoraria, Other: Clinical Trial, Research Funding; Sanofi: Honoraria, Research Funding; Ono Yakuhin: Honoraria, Other: Clinical Trial, Research Funding; Eizai: Honoraria, Research Funding; Nippon Chemiphar: Honoraria, Research Funding; Nihon Shinyaku: Research Funding; Mochida: Honoraria; Merck Serono: Honoraria; Kyowa-Kirin: Honoraria, Research Funding; Kowa: Honoraria; Yakult: Research Funding; Shire Japan: Honoraria; Teijin Pharma: Research Funding; Takeda: Honoraria, Research Funding; Asahi-Kasei Pharma: Research Funding; DaiNihonSumitomo: Honoraria, Research Funding; Eizai: Honoraria, Research Funding; Lilly: Honoraria, Research Funding; MSD: Honoraria, Other: Clinical Trial, Research Funding; Bristol-Myers Squibb: Honoraria, Other: Clinical Trial, Research Funding; Celgene: Clinical Trial, Honoraria; Taiho: Honoraria, Other: Clinical Trial, Research Funding; Pfizer: Honoraria, Research Funding; Janssen: Honoraria; Astellas: Research Funding; AstraZeneca: Other: Clinical Trial; Bayer: Honoraria, Other: Clinical Trial, Research Funding; Behringer: Honoraria, Research Funding; Chugai: Honoraria, Other: Clinical Trial, Research Funding. Breccia:BMS: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Deangelo:Novartis: Consultancy. Hochhaus:Takeda: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Goh:Takeda: Other: Non-financial support, Research Funding; Novartis AG: Honoraria, Other: Non-financial support, Research Funding. le Coutre:Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Deininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy. Etienne:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Incyte: Honoraria, Patents & Royalties, Speakers Bureau. Sondhi:Novartis: Employment. Mishra:Novartis: Employment. Aimone:Novartis: Employment. Ng-Sikorski:Novartis: Employment. Mauro:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Takeda: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-113609

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 163-163

Abstract: Abstract 163 Background: Despite progress in Ph+ leukemia therapy, patients who experience failure of tyrosine kinase inhibitors (TKIs) and those with the T315I BCR-ABL mutation have limited treatment options. Ponatinib is an oral TKI developed using computational and structure-based design with optimal binding to the BCR-ABL active site. At clinically achievable concentrations, ponatinib demonstrated potent in vitro activity against native BCR-ABL and all BCR-ABL mutants tested, including T315I. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with Ph+ leukemia were evaluated in a phase 2, international, open-label clinical trial. Methods: 449 patients resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation confirmed at entry were enrolled and assigned to 1 of 6 cohorts: chronic phase (CP)-CML R/I (N=203), CP-CML T315I (N=64), accelerated phase (AP)-CML R/I (N=65), AP-CML T315I (N=18), blast phase (BP)-CML/Ph+ALL R/I (N=48), BP-CML/Ph+ALL T315I (N=46). Five patients (3 CP-CML, 2 AP-CML) without confirmed T315I and not R/I to dasatinib or nilotinib were treated, but not assigned to a cohort; they were included in safety analyses. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months for CP-CML and major hematologic response (MaHR) at any time within 6 months for advanced Ph+ leukemia. The trial is ongoing. Data as of 23 July 2012 are reported: median follow-up 11 (0.1 to 21) months; minimum follow-up 9 months. Results: Median age was 59 (18–94) yrs; 53% were male. Median time from diagnosis to ponatinib was 6 (0.3–28) yrs. Patients were heavily pretreated: 96% received prior imatinib, 84% dasatinib, 65% nilotinib; median number of prior TKIs was 3, with 53% exposed to all 3 approved TKIs. In patients previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance and 12% were purely intolerant to dasatinib or nilotinib. Best prior response to most recent dasatinib or nilotinib was 26% MCyR or better in CP-CML, and 23% MaHR or better in advanced Ph+ leukemia. Frequent BCR-ABL mutations confirmed at entry were: 29% T315I, 8% F317L, 4% E255K, 4% F359V, 3% G250E. No mutations were detected in 44%. The primary endpoint response rates (see Table) in each cohort exceeded the prespecified statistical criteria for success. In CP-CML and AP-CML R/I (the 3 largest cohorts), 95% CIs exceeded the prespecified response rate. Median time to response (for responders) was 84 days in CP-CML, 112 days in AP-CML, 55 days in BP-CML/Ph+ALL. Responses were durable; the estimated (Kaplan-Meier) probability of responders maintaining the primary endpoint at 1 yr was 91% in CP-CML, 42% in AP-CML, 35% in BP-CML/Ph+ALL. In CP-CML, 46% had complete cytogenetic response and molecular response rates were 32% MMR, 20% MR4, and 12% MR4.5. Response rates were higher in patients exposed to fewer prior TKIs and those with shorter disease duration. Similar response rates were observed in patients with and without BCR-ABL mutations. In CP-CML, response rates were higher in those with T315I; however, a post hoc analysis found that presence of T315I was not a predictor of response. Instead, the difference in response rate was explained by T315I patients' younger age, shorter duration of leukemia, and exposure to less prior therapy. At the time of analysis, 52% of patients remained on therapy (66% CP-CML). The most frequent reasons for discontinuation were progression (18%) and AEs (12%). The most common drug-related AEs were thrombocytopenia (36%), rash (33%), and dry skin (31%). Pancreatitis was the most common drug-related SAE (5%); however, it occurred early and was managed with dose modification (1 patient discontinued due to pancreatitis). Conclusions: Ponatinib has substantial activity and is generally well tolerated in these heavily pretreated Ph+ leukemia patients who have limited available treatment options. Data with a minimum follow-up of 12 months will be presented. Disclosures: Cortes: Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Kim:Novartis, BMS, Pfizer, ARIAD, Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis, Bristol-Myers Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Deciphera: Research Funding; ARIAD: Research Funding; Celgene: Research Funding; Millenium: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; 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, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:BMS, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers Squibb, Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, BMS, Pfizer, MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Briston-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.163.163

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3431-3431

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.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.3431.3431

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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detail.hit.zdb_id: 80069-7