05 / Asciminib (ABL001) in Combination With Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase Who Have Not Achieved a Deep Molecular Response With Long-Term Frontline Imatinib: A Randomized, Open-Label, Multicenter, Phase 2 Study

2018 ◽  
Author(s):  
Cortes Jorge E.
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Molecular Response ◽  
Phase 2 ◽  
Open Label ◽  
Multicenter Phase ◽  
Phase 2 Study ◽  
Deep Molecular Response

scholarly journals Randomized, Open-Label, Multicenter, Phase 2 Study of Asciminib (ABL001) As an Add-on to Imatinib Versus Continued Imatinib Versus Switch to Nilotinib in Patients with Chronic Myeloid Leukemia in Chronic Phase Who Have Not Achieved a Deep Molecular Response with Frontline Imatinib

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5910-5910
Author(s):  
Giuseppe Saglio ◽  
Timothy P. Hughes ◽  
Jan Geissler ◽  
Shruti Kapoor ◽  
Anne-Sophie Longin ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Molecular Response ◽  
Phase 2 ◽  
Atp Binding Site ◽  
Phase 2 Study ◽  
Deep Molecular Response ◽  
Ongoing Phase

Background: In patients with chronic myeloid leukemia in chronic phase (CML-CP), the efficacy of ATP-competitive tyrosine kinase inhibitors (TKIs) has resulted in treatment-free remission (TFR) as a primary treatment goal for those with a sustained deep molecular response (DMR). However, most patients treated with imatinib fail to achieve a sustained DMR, meaning that they cannot benefit from TFR. Asciminib is a potent and specific inhibitor of BCR-ABL1. Unlike BCR-ABL1 TKIs that target the ATP binding site, asciminib binds to the myristate pocket of ABL1. Preclinical data showed that the combination of asciminib with ATP-competitive TKIs may provide more potent BCR-ABL1 inhibition and prevent emergence of resistance mutations (Wylie et al. Nature. 2017;543:733-737). In an ongoing phase 1 study (NCT02081378), asciminib demonstrated clinical activity and was well tolerated as a single agent (Hughes et al. Blood. 2016;128 [abstract 625]). In the same study, asciminib in combination with imatinib showed promising preliminary efficacy and a good safety profile in patients resistant/intolerant of ≥2 prior TKIs (Cortes et al. HemaSphere. 2019;3(S1) [abstract S388]). These findings informed the dose of asciminib to be further evaluated in combination with imatinib. An ongoing phase 3 study (NCT03106779) is evaluating asciminib vs bosutinib in patients previously treated with ≥2 ATP-binding site TKIs (Mauro et al. J Clin Oncol. 2019;37 [abstract TPS7070]). Here, we describe the ASCiminib add-on 4-arm study evaluating MOlecular REsponse (ASC4MORE) in patients. This is a phase 2 study evaluating the efficacy of adding asciminib to ongoing imatinib therapy in patients with CML-CP who have not achieved DMR with long-term frontline imatinib (CABL001E2201; NCT03578367). Methods: Study participants are aged ≥18 years, have CML-CP, and have been treated with frontline imatinib for ≥12 months. Study entry requires patients to be receiving imatinib 400 mg once daily (QD) at randomization, have BCR-ABL1 transcript levels in the range of ≤1% to >0.01% on the International Scale (IS), no prior achievement of MR4 (BCR-ABL1IS ≤0.01%) confirmed by two consecutive tests, and no prior treatment failure. Overall, ~80 patients will be randomized 1:1:1:1 to one of four arms (Figure): either asciminib 40 mg QD or 60 mg QD added to imatinib 400 mg QD; continued treatment with imatinib 400 mg QD; or switch to nilotinib 300 mg twice daily. Study treatment will continue until treatment resistance or intolerance, or up to 96 weeks after the last randomized patient has begun treatment. The primary objective of this study is to assess whether asciminib add-on to imatinib is more effective than imatinib continuation; the primary endpoint is the rate of MR4.5 (BCR-ABL1IS ≤0.0032%) at 48 weeks. Secondary objectives include: to estimate the efficacy of switch to nilotinib; to estimate the difference in efficacy between asciminib add-on to imatinib and switch to nilotinib; and to characterize the safety of asciminib add-on to imatinib. Exploratory objectives include TFR eligibility at the end of the study and patient-reported outcomes. Patients in the imatinib continuation arm who have not achieved MR4.5 at 48 weeks may cross over to receive add-on asciminib. This study is ongoing, with 23 patients randomized as of 22 July 2019. Disclosures Saglio: BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Jansen: Consultancy; Celgene: Consultancy. Hughes:Novartis, Bristol-Myers Squibb, Celgene: Research Funding; Novartis, Bristol-Myers Squibb: Consultancy, Other: Travel. Geissler:Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy; Amgen: Consultancy; Incyte: Research Funding; Takeda: Research Funding; Biomarin: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; UCB: Consultancy, Speakers Bureau; Servier: Consultancy. Kapoor:Novartis: Employment. Longin:Novartis: Employment. Mukherjee:Novartis: Employment. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

scholarly journals Discontinuation of Nilotinib in Patients with Chronic Myeloid Leukemia Who Have Maintained Deep Molecular Responses for at Least 2 Years: A Multicenter Phase 2 Stop Nilotinib (Nilst) Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 790-790 ◽  
Author(s):  
Norimitsu Kadowaki ◽  
Tatsuya Kawaguchi ◽  
Junya Kuroda ◽  
Hirohisa Nakamae ◽  
Itaru Matsumura ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Treatment Discontinuation ◽  
Molecular Response ◽  
Phase 2 ◽  
Multicenter Phase ◽  
Kaplan Meier ◽  
Deep Molecular Response ◽  
Treatment Free Remission

Abstract Background Sustained treatment-free remission (TFR) has been reported in 40-60% of patients with chronic myeloid leukemia-chronic phase (CML-CP) after discontinuation of imatinib or dasatinib following at least 1-2 years of deep molecular response (MR). We investigated safety and efficacy of discontinuing nilotinib treatment after 2 years of sustained MR4.5 (BCR-ABL1IS ≤ 0.0032%) on nilotinib in patient for whom MR4.5 was achieved by prior treatment with imatinib or nilotinib. Methods The Stop Nilotinib (NILSt) trial was a single-arm multicenter phase 2 study in Japan. CML-CP patients who obtained MR4.5 by treatment with imatinib or nilotinib were enrolled, and were further treated with nilotinib for 2 years. The patients who maintained MR4.5 during those 2 years were eligible for discontinuation of nilotinib. After treatment discontinuation, maintenance of MR4.5 was monitored by quantitative RT-PCR every month during the 1st year and every 2 months during the 2nd year. Nilotinib was reintroduced in patients who lost MR4.5. The primary endpoint was the proportion of patients who maintained MR4.5 at 1 year after the discontinuation. This study is registered, number UMIN000007141. Results 112 patients were enrolled between April 11, 2012 and November 30, 2012, and were treated with nilotinib for 2 years. 90 of those patients maintained MR4.5 during the entire 2-year period and were eligible to discontinue treatment, among which 87 patients actually discontinued nilotinib to intend a treatment-free remission period. Median follow-up after the discontinuation was 13.4 months (range 4.8-20.1). At 1 year, 53 patients (58.9%, 90% CI 49.7-67.7) maintained MR4.5, whereas 34 patients experienced loss of MR4.5 mostly within 6 months after the discontinuation (Figure 1). Thirty-two of those 34 patients (94.1%) regained MR4.5 2.2 months (median, 95% CI 1.5-2.6) after reintroduction of nilotinib. The following parameters did not significantly predict the probability of MR4.5 at 1 year after the discontinuation: age, sex, Sokal, Hasford, EUTOS scores, history of IFN-a therapy, total duration of imatinib or nilotinib therapy, time to MR4.5, or trough concentrations of nilotinib in sera. Notably, the percentages of patients maintaining MR4.5 for one year without treatment did not improve significantly with longer duration of prior MR4.5 on treatment; even some patients with a duration of prior deep MR on treatment exceeding 10 years experienced loss of MR4.5 after treatment discontinuation (Table 1). The rates of all grade (grade 3/4 in parentheses) cardiovascular events were 5.5% (2.7%), fluid retention were 14.1% (0%), and musculoskeletal pain were 9.7% (1.8%) during the 2-year treatment periods. Conclusion Nilotinib can be discontinued without relapse in more than half of the patients who maintained MR4.5 for at least 2 years. However, relapse occurred after the discontinuation following even more than 10 years of sustained deep MR in the rest of the patients. This suggests that the period of deep MR after which nilotinib can be discontinued without relapse is considerably long, if any, in a substantial proportion of patients. Biomarkers to detect such patients are awaited. Furthermore, additional strategies may be required to safely discontinue nilotinib as early as possible in such patients, in order to avoid serious adverse events caused by prolonged administration. Figure 1. Kaplan-Meier estimates of TFR after discontinuation of nilotinib Figure 1. Kaplan-Meier estimates of TFR after discontinuation of nilotinib Table 1. Rates of MR4.5 maintenance at 1 year after discontinuation of nilotinib in relation to the duration of deep molecular response before the discontinuation Table 1. Rates of MR4.5 maintenance at 1 year after discontinuation of nilotinib in relation to the duration of deep molecular response before the discontinuation Disclosures Kawaguchi: Novartis: Honoraria. Kuroda:Janssen: Honoraria; Astra Zeneca: Research Funding; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Nakamae:Mochida Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis Pharma KK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation/meeting expenses, Research Funding. Matsumura:Bristol-Myers Squibb Company: Honoraria; Novartis Pharma K.K: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Consultancy, Honoraria; Pfizer Japan Inc.: Honoraria. Kanakura:Bristol Myers: Research Funding; Alexionpharma: Research Funding; Nippon Shinyaku: Research Funding; Astellas: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Chugai Pharmaceutical: Research Funding; Shionogi: Research Funding; Kyowa Hakko Kirin: Research Funding; Fujimotoseiyaku: Research Funding; Toyama Chemical: Research Funding.

scholarly journals Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis

Leukemia ◽  
2021 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Timothy P. Hughes ◽  
Richard A. Larson ◽  
Dong-Wook Kim ◽  
Surapol Issaragrisil ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Chronic Phase ◽  
Individual Treatment ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Treatment Free Remission

AbstractIn the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.

scholarly journals Dasatinib discontinuation in patients with chronic-phase chronic myeloid leukemia and stable deep molecular response: the DASFREE study

2019 ◽  
Vol 61 (3) ◽  
pp. 650-659 ◽  
Author(s):  
Neil P. Shah ◽  
Valentín García-Gutiérrez ◽  
Antonio Jiménez-Velasco ◽  
Sarah Larson ◽  
Susanne Saussele ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Molecular Response ◽  
Deep Molecular Response

scholarly journals Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results

Blood ◽  
2011 ◽  
Vol 117 (4) ◽  
pp. 1141-1145 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Francis J. Giles ◽  
Kapil N. Bhalla ◽  
Javier Pinilla-Ibarz ◽  
Richard A. Larson ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Study Endpoint ◽  
Primary Study ◽  
Molecular Response ◽  
Open Label ◽  
Imatinib Resistance ◽  
Abl Tyrosine Kinase

Abstract Nilotinib is a potent selective inhibitor of the BCR-ABL tyrosine kinase approved for use in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP), and in CML-CP and CML-accelerated phase after imatinib failure. Nilotinib (400 mg twice daily) was approved on the basis of the initial results of this phase 2 open-label study. The primary study endpoint was the proportion of patients achieving major cytogenetic response (CyR). All patients were followed for ≥ 24 months or discontinued early. Of 321 patients, 124 (39%) continue on nilotinib treatment. Overall, 59% of patients achieved major CyR; this was complete CyR (CCyR) in 44%. Of patients achieving CCyR, 56% achieved major molecular response. CyRs were durable, with 84% of patients who achieved CCyR maintaining response at 24 months. The overall survival at 24 months was 87%. Adverse events were mostly mild to moderate, generally transient, and easily managed. This study indicates that nilotinib is effective, with a manageable safety profile, and can provide favorable long-term benefits for patients with CML-CP after imatinib failure. This trial was registered at www.clinicaltrials.gov as #NCT00109707.

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