scholarly journals Final Study Results of Newly Diagnosed Chronic Myeloid Leukemia Chronic Phase (CML-CP) Patients Receiving Radotinib 300 Mg BID or Imatinib: Rerise 48 Months Follow-up

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1733-1733
Author(s):  
Young Rok Do ◽  
Jae-Yong Kwak ◽  
Hawk Kim ◽  
Jeong-A Kim ◽  
Hyeoung-Joon Kim ◽  
...  
Keyword(s):  
Research Funding ◽  
Safety Data ◽  
Chronic Phase ◽  
Standards Of Care ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Study Results

Abstract Background: In RERISE phase 3 study, radotinib demonstrated significantly higher and faster rates of major molecular response (MMR) than imatinib in patients with newly diagnosed CML-CP. By 36 months follow up, MMR (BCR-ABL1IS ≤ 0.1%) and MR4.5 (BCR-ABL1IS ≤ 0.0032%) in radotinib 300 mg twice daily (bid) were higher than imatinib group. Also, early molecular response (EMR) at 3 months could predict better long term outcomes in both radotinib and imatinib groups. Here, authors updated 48 months long-term benefits and risks of 300mg bid and imatinib 400mg qd from RERISE phase 3 study (NCT01511289). Methods: RERISE study was randomized trial of radotinib 300 mg bid (n=79), radotinib 400 mg bid (n=81), or imatinib 400 mg once daily (qd) (n=81) in patients with newly diagnosed CML-CP. We evaluated long-term MMR and MR4.5, overall survival (OS), and progression-free survival (PFS) including safety data by 48 months. Results: At the study completion, 53% of patients with radotinib and 44% of patients with imatinib treated were remained. MMR and MR4.5 continued to be higher in patients receiving radotinib 300 mg bid compared with imatinib 400mg qd (Table). Especially, MMR rate by 48 months was significantly higher for radotinib compared to imatinib (76% vs 56%; P=0.0070, Figure). Also, early molecular response (EMR) at 3 months were observed in 86% of patients in the radotinib 300 mg bid group and 68% in the imatinib group (P = 0.0179). More patients treated with radotinib 300mg bid who had EMR at 3 months achieved MMR and MR4.5 by 48 months: 84% and 53% in the radotinib 300 mg bid group and 71% and 44% in the imatinib group, respectively. 48 months estimated OS and PFS rate were not significantly different in two groups (99% vs 94%; P=0.3224, 97% vs 94%; P=0.4328). Treatment failure was lower in radotinib group compared with imatinib group (Table). The safety profiles were consistent with those previously reported and most of adverse events (AEs) developed within 12 months. No new or unexpected safety events were reported in both arms by 48 months and no serious CVE related with radotinib reported. Conclusions: With a minimum 48 months follow-up, radotinib continued to demonstrate higher rates of MMR and MR4.5 than imatinib in newly diagnosed CML-CP. Also, these responses with radotinib were earlier and deeper compared with imatinib. Up to 48 months, no new and serious safety events related with radotinib reported. These results demonstrate that radotinib may have higher possibility of treatment- free remission (TFR) on frontline therapy as well as it can be one of the standards of care in newly diagnosed CML-CP. Figure. Figure. Disclosures Bunworasate: IL-YANG: Research Funding. Comia:IL-YANG: Research Funding. Mun:IL-YANG: Research Funding. Caguioa:IL-YANG: Research Funding. Kim:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Ilyang: Research Funding.

scholarly journals Efficacy and Safety of Radotinib Compared with Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia Patients: 12 Months Result of Phase 3 Clinical Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 476-476 ◽  
Author(s):  
Jae-Yong Kwak ◽  
Hawk Kim ◽  
Jeong A Kim ◽  
Young Rok Do ◽  
Hyeoung Joon Kim ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Grade 3

Abstract Background Radotinib is a second generation BCR-ABL1 tyrosine kinase inhibitor (TKI) developed by IL-YANG Pharm. Co., Ltd (Seoul, South Korea) and approved by the Korea FDA for the treatment of chronic phase chronic myeloid leukemia (CML-CP) patients who have failed prior TKIs. We conducted the randomized, open-label, phase 3 study to assess the efficacy and safety of radotinib, as compared with imatinib, for the first-line treatment of newly diagnosed CML-CP. Methods Based on baseline demographics and Sokal risk score, 241 patients were randomized 1:1:1 to radotinib 300 mg twice daily (bid) (n=79), radotinib 400 mg bid (n=81), or imatinib 400 mg once daily (qd) (n=81). The primary endpoint was the rate of major molecular response (MMR) by 12 months and molecular response was assessed by RQ-PCR at baseline and every 3 months. Secondary endpoints were the rate of complete cytogenetic response (CCyR), MR4.5 by 12 months, and the rate of progression to accelerate phase or blast crisis. Results All three study groups were well balanced with baseline age, gender, race and Sokal risk score. With minimum follow-up of 12 months, the proportions of patients receiving a study drug were 86.3% (69/79) in radotinib 300 mg bid group, 71.6% (58/81) in radotinib 400 mg bid group, and 81.5% (66/81) in imatinib 400 mg qd group. By 12 months, rates of MMR were significantly higher in patients receiving radotinib 300 mg bid (51.9%, P = .0044) and radotinib 400 mg bid (45.7%, P = .0342) compared with imatinib (29.6%). The median time to MMR among responders were shorter on radotinib 300 mg bid (5.7 months) and radotinib 400 mg bid (5.6 months) than imatinib group (8.2 months). The MR4.5 rates by 12 months were also higher for both radotinib 300 mg bid (15.2%) and 400 mg bid (13.6%) compared to imatinib (8.6%). The CCyR rates by 12 months were also higher for radotinib 300 mg bid (91.1%, P = .0120) compared with imatinib (76.5%). There was no progression to accelerated phase or blast crisis in all groups by 12 months. Discontinuation due to adverse events (AEs) or laboratory abnormalities occurred in 7 (8.8%), 16 (19.8%), and 5 (6.2%) patients for radotinib 300 mg bid, radotinib 400 mg bid and imatinib, respectively. Grade 3/4 thrombocytopenia occurred in 16.5% of patients receiving radotinib 300 mg bid, in 13.6% for radotinib 400 mg bid, and in 19.8% receiving imatinib. And grade 3/4 neutropenia occurred in 19.0%, 23.5%, and 29.6% for radotinib 300 mg bid, 400 mg bid and imatinib, respectively. The most common any grade non-laboratory AEs were skin rash (35.4% and 33.3%), nausea/vomiting (22.8% and 23.5%), headache (19.0% and 30.9%), and pruritus (19.0% and 30.0%) in radotinib 300 mg bid and radotinib 400 mg bid, respectively; AEs in the imatinib group were edema (34.6%), myalgia (28.4%), nausea/vomiting (27.2%), and skin rash (22.2%). Overall, grade 3/4 non-laboratory AEs were uncommon in all groups. Conclusions With minimum 12 months follow-up, radotinib demonstrated significantly higher and faster rates of CCyR and MMR than imatinib in patients with newly diagnosed CML-CP. The safety profiles of the radotinib and imatinib were different, and most AEs were manageable with optimal dose reduction. The results of this trial support that radotinib can be one of the standard of care in newly diagnosed CML-CP. Table. Baseline Characteristics, Molecular and Cytogenetic Response Rates Radotinib 300mg BID Radotinib 400mg BID Imatinib 400mg QD (N=79) (N=81) (N=81) Age, median (range), years 45 (20-75) 43 (18-84) 45 (18-83) Gender, n (%) Male 52 (65.8) 47 (58.0) 52 (64.2) Female 27 (34.2) 34 (42.0) 29 (35.8) Sokal risk, n (%) Low 21 (26.6) 22 (27.2) 22 (27.2) Intermediate 38 (48.1) 38 (46.9) 39 (48.2) High 20 (25.3) 21 (25.9) 20 (24.7) MMR by 12 months, % 51.9 45.7 29.6 P = .0044 P = .0342 Cumulative Incidence of MMR by 12 months¢Ó, % 57.0 58.0 35.0 P = .0040 P = .0037 MR4.5 by 12 months, % 15.2 13.6 8.6 CCyR by 12 months, % 91.1 81.5 76.5 ¢Ó Kaplan-Meier estimates of MMR Disclosures Kim: IL-YANG Pharm. Co. Ltd: Research Funding. Kim:Alexion Pharmaceuticals: Research Funding. Chung:Alexion Pharmaceuticals: Research Funding. Choi:Alexion Pharmaceuticals: Research Funding.

scholarly journals Long-Term Outcome of Chronic Phase Chronic Myeloid Leukemia Patients Treated with Nilotinib Front-Line

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-45
Author(s):  
Franck E Nicolini ◽  
Vincent Alcazer ◽  
Pascale Cony-Makhoul ◽  
Stephanie Dulucq ◽  
Sandrine Hayette ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Chronic Phase ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Front Line ◽  
Advisory Committees ◽  
Long Term Outcome

Nilotinib (NIL) 600 mg daily has demonstrated its superiority over Imatinib 400 mg daily in terms of response and incidence of deep molecular response in the front-line chronic phase (CP) CML setting. In this observational study we have retrospectively analyzed the outcome of in- and out-study 202 patients (pts) treated in this setting with NIL 600 mg front-line, in "real-life" conditions. All pts with newly diagnosed adult CP-CML receiving NIL 300 mg BID alone front-line between 10/2007 and 06/2020, were eligible for this study. Data were retrospectively collected according to the current French regulations with pts' information. All pts were assessed and followed according to ELN recommendations 2003, 2006, and 2009 along treatment and to the recommendations from the French group of CML (D. Rea et al., Cancer 2018) in case of TFR. In this regard, a TKI was resumed if loss of MMR. All BCR-ABL1 assessments were performed in the 3 reference laboratories, standardised and expressed in % (IS) with ≥32,000 copies of ABL1 as control. The primary endpoints were the rate of molecular responses in the long-term and the (vascular) safety of Nilotinib. Secondary endpoints were the kinetics of molecular response, survival and safety of Nilotinib. Survival (OS, PFS & EFS) was defined according to ELN (J. Guilhot et al. Blood 2012). Two hundred and two patients were reported with 44% females and 56% males with a median age at diagnosis of 50.4 (17.5-83) years, and 26% of them had cardiovascular risk factors at onset (tobacco abuse 11%, hypercholesterolemia 9.3%, diabetes 1.45%, none with past history of cardiovascular events [CVE]). ELTS scores were high in 14%, intermediate in 31% and low in 55% of pts. Twenty-four (12%) pts harboured additional chromosomal abnormalities at diagnosis. The median follow-up after NIL initiation was 61.5 (1-147.5) months. At last follow-up 113 pts (55%) are not on NIL anymore for toxicities, TFR or resistance reasons. Twenty-eight (14%) pts present an arterial event on NIL (18% PAOD, 14% angina pectoralis, 7% myocardial infarction, 14% stroke, 47% others such as atrial fibrillation, cardiomyopathy...), that occurred after a median of 26 (0.6-98.5) months on NIL. Forty-six (22.5%) pts reached TFR criteria and stopped NIL after a median of 58.5 (27-126) months. The cumulative incidence (CI) rates of MMR at 1, 2 and 5 years were 64 (57-71)%, 79.4 (75.45-83.35)% and 95 (92-98.5)% respectively. For MR4, those were 35.5 (29-42)%, 60 (52-67)% and 82 (74.5-89)% respectively; and for MR4.5, were 14 (9-19)%, 31 (24-28)% and 62 (54-70.5)% respectively. The CI of sustained MR4.5 (i. e. patients eligible for TFR: MR4.5 ≥2 years) was observed in 30 (23-37)% at 3 years, 45.5 (36-55)% at 5 years and 52.5 (41.5-64)% at 6 years (Figure). The CI of patients entering TFR was 16.75 (10.5-23)% at 5 years and 51.94 (37.31-66.57)% at 10 years with a survival without MMR loss of 70.7 (58- 86)% at 1 year and 65.26 (50.6-84)% at 5 years. Nine (4.5%) pts progressed towards accelerated phase (4 pts) or BC (2 lymphoid, 3 myeloid) responsible for 5 deaths at latest follow-up. Among NIL resistant patients screened, 15 were harbouring ABL1 mutations (5 Y253H, 3 E255K, 3 T315I, 1 M244V, 1 G250E, 1 F359V, 1 V299L). Overall, 10 patients died (5 from CML, 5 from unrelated causes). The probability of OS was 95.75 [95%CI: 92.9-98.7]% at 2 years and 94.8 [91.5-98.3]% at 5 years, for PFS it was 94.92 [91.7-98.2]% at 2 years and 89.5 [84.7-94.6]% at 5 years, and EFS it was 78 [72.3-84]% at 2 years and 60.25 [53.3-68.1]% at 5 years. Regarding sustained MR4.5, univariate analysis showed that female gender (HR=2.46 [1.50-4.02], p<0.001) and low ELTS (HR=0.41 [0.22-0.76], p<0.004) had a significant impact, while multivariate analysis confirmed the role of these 2 factors (HR=2.31 [1.41- 3.79], p=0.001 and HR= 0.52 [0.30- 0.90], p=0.02) in addition to high ELTS (HR= 0.28 [0.14- 0.58], p<0.001). Univariate and multivariate analyses demonstrated that only age impacted on the CI of CVE (HR= 1.07 [1.04-1.10], p<0.001, and HR=1.07 [1.04-1.10], p<0.001). NIL first-line efficiently limits progression of newly diagnosed CP-CML patients and provides high rates of sustained MR4.5, allowing TFR in a substantial proportion of pts. However, the onset of arterial occlusive events, especially in the elderly is a matter of concern in the choice of this compound at treatment initiation. Disclosures Nicolini: Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Sun Pharma Ltd: Consultancy. Cony-Makhoul:BMS: Speakers Bureau; Incyte Biosciences: Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy; BMS: Consultancy. Dulucq:Incyte: Speakers Bureau; Novartis: Speakers Bureau. Cayuela:Novartis: Speakers Bureau; Incyte: Speakers Bureau. Rea:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: 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. Mahon:ARIAD: Honoraria; Pfizer: Honoraria; Novartis Pharma: Honoraria, Research Funding; BMS: Honoraria. Etienne:Pfizer: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau.

Occurrence, Management, and Outcomes In Patients with Pleural Effusion During Dasatinib Treatment for Chronic-Phase Chronic Myeloid Leukemia (CML-CP) In the First-Line Setting: Analysis of the DASISION Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2282-2282 ◽  
Author(s):  
Kimmo Porkka ◽  
Michele Baccarani ◽  
Andreas Hochhaus ◽  
Hagop Kantarjian ◽  
Satu Mustjoki ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Research Funding ◽  
Chronic Phase ◽  
Risk Scores ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Once Daily ◽  
Management Interventions ◽  
Grade 3

Abstract Abstract 2282 Background: The Phase 3 DASISION trial comparing dasatinib 100 mg once daily with imatinib 400 mg once daily as initial treatment in patients (pts) with newly diagnosed CML-CP has demonstrated superior efficacy and favorable safety of dasatinib after a minimum of 12 months of follow-up (Kantarjian, H, et al. N Engl J Med 2010;362:2260). While fluid retention was more frequent with imatinib than with dasatinib, pleural effusion was seen only with dasatinib. Here, we provide a detailed analysis of pts experiencing pleural effusion, a clinically relevant adverse drug reaction. Methods: 519 pts with newly diagnosed, treatment-naive CML-CP (median disease duration of 1 month) were randomly assigned to either dasatinib 100 mg once daily (259 pts) or imatinib 400 mg one daily (260 pts). Key endpoints included complete cytogenetic response (CCyR), major molecular response (MMR) and safety. All pts were assessed by chest x-ray at baseline and at 6 months after randomization, or more frequently, if indicated clinically. Pts with pleural effusion at baseline were excluded. Pleural effusion was graded according to CTCAE version 3 (grade 1, asymptomatic; grade 2, symptomatic, up to 2 therapeutic thoracenteses; grade 3, symptomatic requiring supplemental oxygen, < 2 therapeutic thoracenteses; grade 4, life-threatening, hemodynamic instability). Results: After a minimum follow-up of 12 months with median treatment duration of 14.3 months (range, 0.3–25.8), 26 (10%, median age, 60 years) of the 258 dasatinib-treated pts (median age, 46 years) experienced pleural effusion. Of the pts with pleural effusion, 6 (23%) had low, 17 (65%) had intermediate and 3 (12%) had high Hasford risk scores. There were no grade 3 or 4 pleural effusion events. All events were grade 1(2%) or grade 2 (8%). Most events (n = 22, 85%) occurred more than 8 weeks after the start of study drug. In pts who had a pleural effusion, the median time to the event was 28 weeks (range, 4–88). Lymphocytosis (defined as peripheral blood lymphocyte count > 3.6 × 109/L) was noted in 11 (42%) of the 26 pts with pleural effusion, as compared to 46 (20%) of 232 pts with no pleural effusion. Pleural effusion was managed by dose modification and/or medical intervention. Therapy was interrupted in 19 pts, and the dose of dasatinib was reduced in 8 pts (4 pts, to 80 mg; 1 pt, to 70 mg; 3 pts, to 50 mg). Twelve pts received diuretics, 7 received corticosteroids, and only 1 pt underwent therapeutic thoracentesis. Only 3 pts (1.2%) discontinued therapy due to pleural effusion (grade 2). Eleven pts who continued dasatinib had resolution of their pleural effusion. Five pts had recurrent effusions. Of the 26 pts with pleural effusion, 24 (92%) achieved a CCyR and 17 (65%) achieved a MMR by 12 months of treatment; the corresponding CCyR and MMR rates in the total pt population were 83% and 46%, respectively Seven of the 8 pts with pleural effusion who reduced their dose achieved CCyR and MMR. Conclusion: In pts with newly diagnosed CML-CP treated with dasatinib as initial therapy, pleural effusion was mild to moderate in severity, and was manageable with dose interruption and/reduction and/or a short course of diuretics and/or corticosteroids. The occurrence of pleural effusion and management interventions did not negatively affect the achievement of CCyR or MMR. These findings are in line with data reported previously for second-line dasatinib in CML pts resistant or intolerant to imatinib (Porkka, K, et al. Cancer 2010;116:377). Furthermore, pleural effusion and peripheral lymphocytosis may be indicative of immune-mediated antitumor activity of dasatinib. Disclosures: Porkka: BMS, Novartis: Consultancy, Honoraria, Research Funding. Baccarani: Novartis, Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Brostol-Myers Squibb, Novartis: Consultancy, Research Funding. Kantarjian: BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Mustjoki: BMS, Novartis: Honoraria. Bradley-Garelik: Bristol-Myers Squibb: Employment, Equity Ownership. Zhu: Bristol-Myers Squibb: Employment. Cortes: Brostol-Myers Squibb, Novartis and Wyeth: Consultancy, Honoraria.

Seven-Year Follow-up Data on Sequential Prospective Trials of Imatinib 400mg Vs 800mg Daily Schedule for Front-Line Treatment of Chronic Myeloid Leukemia (CML).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3438-3438
Author(s):  
Naveen Pemmaraju ◽  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Srdan Verstovsek ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Chronic Phase ◽  
Annual Rate ◽  
Molecular Response ◽  
Free Survival ◽  
Cumulative Rate ◽  
Prospective Trials

Abstract Abstract 3438 Background: The standard of care for most patients (pts) with CML has been imatinib mesylate at a dose of 400mg by mouth daily. Earlier studies have suggested that there may be a benefit to pts to start treatment at a higher dose as this may result in faster and more durable responses to imatinib. It is not yet known whether long-term event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) will be impacted by the higher dosing schedule. Objectives: To determine the long term responses and clinical benefit of imatinib 800mg daily versus 400mg daily dosing when used as upfront treatment strategy in CML. Methods: We conducted sequential prospective trials using imatinib 400mg or 800mg daily as initial therapy for patients with previously untreated chronic phase CML. Results: A total of 281 pts were included in these trials: 208 treated with 800mg and 73 with 400mg. The median follow-up for each group was 79 months (range: 3–107) and 110 months (range: 2–116). The overall, cumulative rate of complete cytogenetic response (CCyR) was 91% and 87%, respectively (p=0.49) for those treated with high- and standard-dose, and the cumulative rate of major molecular response (MMR) was 87% and 78%, respectively (p=0.06). Rates of CCyR at 12 months were 90% and 66%, respectively (p < 0.001), and MMR at 18 months 82% and 68%, respectively (p=0.04). A significantly better EFS (definition per IRIS criteria) was observed for the 800 mg group compared to that in the 400mg group (log-rank test, p=0.049; estimated 7-year EFS 86% vs 76% by Kaplan-Meier method). No significant differences were seen for survival free from transformation to accelerated and blast phase (p = 0.46) and overall survival (p = 0.27). For OS, thus far 19 pts in the 800mg group have died (2 probable CML-related, 3 unknown causes, 14 non CML related) compared to 13 pts (10 probable CML-related, 3 non CML-related) in the 400mg group. The table below shows the annual rate of events and transformation for each dose group. Treatment discontinuation for toxicity occurred in 16 (8%) pts treated with 800mg and 6 (8%) pts treated with 400mg. Conclusions: At 7-year follow up, pts treated with 800mg demonstrated a significantly better EFS (by IRIS criteria) compared to those treated with 400mg. There is a trend for a lower annual rate of events and transformation with the higher dose, particualry in the earlier years, but no difference in OS. These results suggest a modest benefit for patients treated with higher dose imatinib. Disclosures: Off Label Use: imatinib at dose of 800mg po daily for CML. Kantarjian:BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Verstovsek:Incyte Corporation: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. Cortes:Pfizer: Consultancy, Research Funding; BMS: Honoraria, Research Funding; Novarits: Honoraria, Research Funding.

Long-Term Efficacy and Safety in COMFORT-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy for the Treatment of Myelofibrosis: 5-Year Final Study Results

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 59-59 ◽  
Author(s):  
Claire N. Harrison ◽  
Alessandro M. Vannucchi ◽  
Jean-Jacques Kiladjian ◽  
Haifa Kathrin Al-Ali ◽  
Heinz Gisslinger ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Spleen Volume ◽  
Phase 3 ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Final Study ◽  
Study Results

Abstract BACKGROUND: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor that has demonstrated rapid and durable improvements in splenomegaly and symptoms as well as improved survival in the two phase 3 COMFORT studies in patients (pts) with myelofibrosis (MF). In COMFORT-II, significantly more pts achieved the primary endpoint (a ≥ 35% decrease in spleen volume from baseline at wk 48) with RUX compared with best available therapy (BAT) (28% vs 0%; P ˂ .0001). The 3-year follow-up confirmed that spleen volume reductions were sustained and RUX treatment remained tolerable with long-term use. Here, we report final study results on longer-term safety and efficacy after 5 years of RUX treatment in COMFORT-II. METHODS: COMFORT-II is a randomized (2:1), open-label phase 3 study of RUX vs BAT in pts with intermediate-2- or high-risk primary MF, post-PV MF, or post-ET MF. Pts initially received RUX 15 or 20 mg bid based on their platelet counts at baseline (100-200 and > 200 x 109/L, respectively), and doses were individually titrated to maximize safety and efficacy. Pts were allowed to cross over from the BAT arm to receive RUX upon protocol-defined progression (primarily progressive splenomegaly, a ≥ 25% increase in spleen volume from on-study nadir). All pts randomized to BAT had crossed over or discontinued by Nov 2011. The date of final database lock for the study is 20 Apr 2015. RESULTS: Pts were randomized to RUX (n = 146) or BAT (n = 73). Baseline characteristics were well balanced between arms and have been described previously (Harrison, N Engl J Med, 2012); disease and hematologic characteristics were representative of a population of pts with advanced primary or secondary MF. At study completion (median follow-up, 4.3 years), 39 pts (26.7%) in the RUX arm and 11 of the 45 pts (24.4%) who crossed over from BAT completed 5 years of on-study treatment. Primary reasons for premature discontinuation before 5 years were adverse events (AEs; 24.0%) and disease progression (21.9%) in the RUX arm and withdrawal of consent and other in the BAT arm (12.3% each). Overall 78 pts (53.4%) in the RUX arm achieved a ≥ 35% reduction in spleen volume from baseline at any time during treatment; the median duration of maintenance of spleen volume reduction was 3.2 years. The K-M estimated probability of maintaining this reduction was 0.51 (95% CI, 0.38-0.62) at 3 years and 0.48 (95% CI, 0.35-0.60) at 5 years. Approximately one-third of evaluable JAK2 V617F-positive pts had a ˃ 20% reduction in allele burden at 3.2 years (38.3%) and 3.7 years (31.0%). With RUX treatment, 23 pts (15.8%) had improved fibrosis (including 4 who improved to grade 0 from baseline fibrosis grades of 1 [n = 1], 2 [n = 2], and 3 [n = 1]), 47 pts (32.2%) had stable fibrosis, and 27 (18.5%) had a worsening at their last assessment. There was no relevant increase in the incidence of AEs with longer exposure (median: RUX arm, 2.6 years; BAT arm, 0.87 years; RUX after crossover, 1.2 years) compared with previous reports. The most commonly reported AEs in pts who received RUX any time (randomized treatment, extension phase or after cross over from BAT) were thrombocytopenia (52.4%), anemia (49.2%), diarrhea (35.6%), and peripheral edema (33.0%); grade 3/4 AEs included anemia (22.5%), thrombocytopenia (15.2%), pneumonia (5.8%), general physical health deterioration (4.2%), and dyspnea (4.2%). 8 pts (5.5%) and 5 pts (6.8%) developed leukemia in the RUX and BAT arms, respectively. There were no new or unexpected AEs. Overall, 59 (40.4%) and 35 (47.9%) deaths were reported in the RUX and BAT arms, respectively. Median OS was not reached in the RUX arm and was 4.1 years in the BAT arm. There was a 33% reduction in risk of death with RUX compared with BAT (HR, 0.67; 95% CI, 0.44-1.02; P = .06). The K-M estimated probability of survival at 5 years was 56% with RUX and 44% with BAT. As expected, the confounding effect on OS of crossover from BAT to RUX became apparent in this extended follow up compared with previous analyses; an analysis of OS correcting for crossover will be presented. SUMMARY/CONCLUSIONS: The immediate benefits of RUX treatment, such as improvements in spleen size, were maintained with long-term therapy. The previously reported OS benefit was maintained, although results are confounded by extensive crossover from the BAT arm following the primary analysis at wk 48, which becomes more apparent with longer follow-up. Long term safety and tolerability was consistent with previous findings. Disclosures Harrison: Novartis: Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria; Sanofi: Honoraria, Speakers Bureau; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Shire: Speakers Bureau. Vannucchi:Shire: Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Kiladjian:Incyte Corporation: Consultancy; Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Novartis: Consultancy. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Gisslinger:AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau; Geron: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Aventis: Consultancy. Knoops:Novartis: Consultancy. Cervantes:Novartis: Consultancy, Speakers Bureau; CTI-Baxter: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy. Jones:Incyte Corporation: Employment. Sun:Incyte Corporation: Employment. Descamps:Novartis Pharma S.A.S: Employment. Stalbovskaya:Novartis Pharma AG: Employment, Equity Ownership. Gopalakrishna:Novartis Pharma AG: Employment. Barbui:Novartis: Speakers Bureau.

Treatment-free remission (TFR) following frontline (1L) nilotinib (NIL) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): 192-week data from the ENESTfreedom study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7013-7013
Author(s):  
Francis J. Giles ◽  
Tamas Masszi ◽  
María Teresa Gómez Casares ◽  
Andrzej Hellmann ◽  
Jesper Stentoft ◽  
...  
Keyword(s):  
Musculoskeletal Pain ◽  
Chronic Phase ◽  
Molecular Response ◽  
Free Survival ◽  
Study Results ◽  
Stopping Treatment ◽  
Treatment Free Remission ◽  
Event Rates

7013 Background: In ENESTfreedom (NCT01784068), which evaluated TFR following 1L NIL in CML-CP pts, 51.6% remained in TFR 48 wks after stopping treatment (primary endpoint) and durability of TFR was demonstrated at 144 wks. Data from longer follow-up (192 wks) evaluating maintenance of TFR are reported. Methods: Pts with MR4.5 ( BCR-ABL1IS ≤0.0032%) and ≥2y of 1L NIL entered a 1y consolidation; pts with sustained deep molecular response (MR) were eligible for TFR. NIL was resumed after loss of major MR (MMR; BCR-ABL1IS ≤0.1%). At the latest data cut-off (Sep 17 2018), all pts had completed ≥192 wks of TFR, resumed NIL, or discontinued the study. Results: By the data cut-off, of 190 pts entering TFR, 87 were ongoing, 91 had resumed NIL, and 12 had permanently discontinued. The TFR rate at 192 wks was 44.2% (84/190, 95% CI: 37.0–51.6%). Of 89 pts with successful TFR at 144 wks, 5 were not assessable for TFR at 192 wks as 2 had discontinued by 192 wks due to pt/physician decision, and 3 with MR4.5 previously did not have 192 wk PCR data. Of 91 pts who resumed NIL, 90 (98.9%) regained MMR and 84 (92.3%) regained MR4.5. 75/90 and 73/84 pts, respectively, had stable MMR and MR4.5 at 48 wks later. There were no cases of disease progression or new deaths. 10 deaths were reported in the 144-wk analysis, none due to CML. The 192-wk treatment-free survival rate was 48.7% (95% CI 41.4–55.6%). Of 89 pts remaining in TFR for > 144 wks (including 87 pts for > 192 wks), all-grade AE rates during consolidation and each subsequent 48 wk period of TFR were 84.3%, 77.5%, 70.8%, 48.3%, and 52.8%, respectively. All-grade musculoskeletal pain AE rates were 15.7%, 40.4%, 9.0%, 3.4% and 3.4%, respectively; cardiovascular event rates were low across these periods. Among pts who resumed NIL, most common AEs were nasopharyngitis (18.7%) and pruritus, fatigue, and increased lipase (14.3% each); the majority of AEs were grade 1/2. Conclusions: Results continue to support the long-term durability and safety of TFR at 192 wks after stopping 1L NIL; overall AE rates declined during the TFR phase and musculoskeletal pain AEs were transient. Pts should continue to be regularly monitored during TFR. Clinical trial information: NCT01784068.

ENESTop 192-week results: Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after stopping second-line (2L) nilotinib (NIL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7005-7005
Author(s):  
Timothy P. Hughes ◽  
Carla Boquimpani ◽  
Naoto Takahashi ◽  
Noam Benyamini ◽  
Nelma Cristina D. Clementino ◽  
...  
Keyword(s):  
Musculoskeletal Pain ◽  
Chronic Phase ◽  
Molecular Response ◽  
Free Survival ◽  
Study Results ◽  
Deep Molecular Response ◽  
Treatment Free Remission ◽  
Clinical Trial Information

7005 Background: In the ENESTop study (NCT01698905) of TFR in pts with CML-CP who achieved a sustained deep molecular response (MR) with 2L NIL, 57.9% remained in TFR 48 wks after stopping NIL (primary endpoint). Analyses at 144 wks showed durability of TFR. Data from longer follow-up (192 wks) evaluating the maintenance of TFR are reported. Methods: Pts treated with ≥2 y NIL after > 4 wks imatinib (≥3 y total) and achieving MR4.5 ( BCR-ABL1IS ≤0.0032%) on NIL were eligible. After a 1 y consolidation, pts with no confirmed loss of MR4.5 could attempt TFR. NIL was resumed upon loss of major MR ( BCR-ABL1IS ≤0.1%) or confirmed loss of MR4 ( BCR-ABL1IS ≤0.01%). At the data cut-off (Sep 24 2018), all pts had completed ≥192 wks of TFR, resumed NIL, or discontinued the study. Results: By the data cut-off, of 126 pts entering TFR, 56 were ongoing, 59 had resumed NIL, and 11 had discontinued. TFR rate at 192 wks was 46.0% (58/126; 95% CI, 37.1–55.1%); all but 1 of the 58 pts were in MR4.5. Only 1/61 pts in TFR at 144 wks lost response by 192 wks (confirmed loss of MR4); another 2 pts discontinued due to serious AE (polycythemia vera) and pt/guardian decision, respectively. Of 59 pts who resumed NIL, 56 (94.9%) and 55 (93.2%) regained MR4 and MR4.5, respectively. 40/56 pts (71.4%) who regained MR4 had stable MR4 at 96 wks (12 discontinued < 96 wks, and 4 remained on study with < 96 wks, after regaining MR4); 37/55 pts (67.3%) who regained MR4.5 had stable MR4.5 at 96 wks (12 discontinued < 96 wks, and 6 remained on study with < 96 wks, after regaining MR4.5). There were no disease progressions, deaths due to CML, or new deaths since the 144-wk analysis. The 192 wk treatment-free survival rate was 50.3% (95% CI, 41.2–58.7%). Of 62 pts who remained in TFR for > 144 wks, 11.3%, 53.2%, 21.0%, 14.5% and 3.2% had musculoskeletal pain AEs during consolidation and each subsequent 48 wk period of TFR. Among 59 pts who resumed NIL, most common AEs were hypertension (20.3%) and arthralgia (13.6%); the majority of AEs were grade 1/2. Conclusions: Results demonstrate long-term durability and safety of TFR following 2L NIL, with no disease progressions or CML-related deaths, and musculoskeletal pain AEs were transient. Clinical trial information: NCT01698905.

Beneficial Effects of Cytogenetic and Molecular Response on Long-Term Outcome in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib (IM): Update from the IRIS Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 166-166 ◽  
Author(s):  
Bengt Simonsson ◽  
Keyword(s):  
Blast Crisis ◽  
Chronic Phase ◽  
Risk Groups ◽  
Low Risk ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcome ◽  
Increased Risk

Abstract Background: IM was proven to be superior to IFN+Ara-C for newly diagnosed pts with CML-CP (O’Brien et al, NEJM 2003). At 42-months of follow-up, 75% of the 553 pts randomized to IM remain on treatment. Of the 553 pts randomized to IFN+Ara-C only 4% are still on IFN+Ara-C. This update analysis is focused on IM pts. Methods: Evaluation included complete hematologic response (CHR), major/complete cytogenetic response (MCyR/CCyR) - defined as 0-35% Ph+ and 0% Ph+ metaphases respectively, major molecular response (MMR) - defined as ≥3 log reduction of bcr-abl transcripts from the standardized baseline, time to progression - defined as loss of CHR/MCyR or evolution to accelerated phase/blast crisis (AP/BC) or death due to any cause, time to AP/BC - defined as evolution to AP/BC or death due to CML, and overall survival. Results: With an average duration of 38 months of IM treatment, the best observed rates of CHR, MCyR and CCyR are 96%, 88% and 81%, respectively. Although the majority of MCyRs were achieved within the first 3 to 9 months, some pts achieved a MCyR and some even a CCyR after more than one year of treatment (Figure 1). The estimated MMR rate at 12 months is 40%. Figure 1 - Observed CHR, MCyR and CCyR during treatment with IM Figure 1 -. Observed CHR, MCyR and CCyR during treatment with IM The estimated progression-free rate at 42 months is 84%; additionally 94% are estimated free of progression to AP/BC (97% of the pts with CCyR and 73% of the pts without CCyR during study, p<0.001). The risk of relapse remains low with no apparent increased risk over time. The yearly hazard for progression to AP/BC is about 2% in each of the 4 years. The overall estimated survival at 42 months is 91% (considering all deaths). The estimated survival was lowest in pts with high risk Sokal score (84%) as compared to 91% in the intermediate risk pts and 94% in the low risk pts (p<0.001). Similarly, the best observed CCyR in the high, intermediate, and low risk groups were 69%, 80% and 88% respectively (p=0.002). In the subset of pts with CCyR the estimated survival at 42 months was 92%, 93% and 97% in the high to low risk groups (p=0.30), indicating that once pts achieve a CCyR, their survival is not significantly different between the Sokal risk groups. Of the 509 pts who were still on treatment at 12 months and had achieved a MCyR by then (n=436), the rate without progression to AP/BC at 42 months was 97% whereas it was only 83% for the 73 pts who did not achieve a MCyR at 12 months (p<0.001). The estimated survival rates at 42 months were 95% and 83% in these two response groups, respectively (p<0.001). Furthermore, for pts who had achieved a MMR at 12 months, the probability of remaining free from progression to AP/BC was 100% at 42 months compared to 95% for pts in CCyR but not in MMR, and 91% for pts not in CCyR at 12 months (p=0.0013). Conclusions: The follow-up confirms the beneficial effect of cytogenetic and molecular responses on long-term outcomes with IM. These results will be further updated using data cut-off of 31-July 2005 to reflect additional 12-months of data (i.e., 54-month follow-up).

Nilotinib Versus Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd 36-Month (mo) Follow-up

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 452-452 ◽  
Author(s):  
Giuseppe Saglio ◽  
Philipp D. LeCoutre ◽  
Ricardo Pasquini ◽  
Saengsuree Jootar ◽  
Hirohisa Nakamae ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Safety Data ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Abstract 452FN2 Background: In ENESTnd, pts treated with nilotinib demonstrated higher and faster rates of major molecular response (MMR, ≤ 0.1% BCR-ABLIS), deeper molecular response (MR4, ≤ 0.01%IS and MR4.5, ≤ 0.0032%IS), and complete cytogenetic responses (CCyR) along with significantly lower rates of progression to AP/BC and fewer CML-related deaths compared with imatinib by 12 and 24 mo. Here, we report data with a minimum follow-up of 24 mo; however, efficacy and safety data based on considerably longer follow-up of ≥ 36 mo will be presented. As demonstrated in IRIS and other imatinib trials, most pts who progress on imatinib do so within the first 3 years of therapy. Thus, this 36-mo update of ENESTnd will be important to further verify the benefits of nilotinib in newly-diagnosed pts. Methods: 846 adult pts with newly-diagnosed Ph+ CML-CP were randomized to nilotinib 300 mg twice daily (BID) (n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg once daily (QD) (n = 283). MMR, MR4, MR4.5, time to progression to AP/BC on treatment, progression-free survival (PFS) on treatment, and overall survival (OS) were evaluated. Results: By 24 mo, both doses of nilotinib demonstrated significantly higher rates of MMR, MR4, and MR4.5 vs imatinib (Table). Nilotinib-treated pts achieved median BCR-ABLIS levels of 0.09% (300 mg BID) and 0.10% (400 mg BID) by 12 mo, while this level of reduction was not observed before 24 mo on imatinib. More pts with CCyR achieved MMR at 12 and 24 mo with either dose of nilotinib vs imatinib (Table). Regardless of Sokal risk, rates of MMR and MR4.5 were higher for nilotinib at both doses vs imatinib (Table). Progression to AP/BC (excluding clonal evolution [CE]) on treatment was significantly lower for nilotinib vs imatinib (2 pts and 3 pts with nilotinib 300 mg BID [P = .0059] and 400 mg BID [P =.0196]), respectively vs 12 pts with imatinib). After achieving CCyR, 4 pts treated with imatinib progressed to AP/BC and 2 pts treated with nilotinib 400 mg BID progressed after achieving both CCyR and MMR (1 also achieved MR4). No pt who achieved MR4.5 progressed at any time. All but 1 pt who progressed to AP/BC on treatment were in the intermediate and high Sokal risk groups; 1 pt treated with nilotinib 400 mg BID progressed in the low Sokal risk group who had an E255V mutation at progression. When considering progression events of pts after discontinuation of treatment, an additional 7, 2, and 6 events (excluding CE) were observed with nilotinib 300 mg BID, nilotinib 400 mg BID and imatinib, respectively. Twice as many pts had emergent mutations on imatinib (n = 20) vs nilotinib (n = 10 on 300 mg BID; n = 8 on 400 mg BID). At 24 mo, OS remained similar in all groups, but there were fewer CML-related deaths in both nilotinib 300 mg BID (5 pts) and nilotinib 400 mg BID (3 pts) arms vs imatinib (10 pts). Both drugs were well tolerated and few new adverse events (AEs) and lab abnormalities were observed between 12- and 24-mo of follow-up. Nilotinib 300 mg BID had the fewest discontinuations due to AEs/lab abnormalities (9% vs 13% and 10% with nilotinib 400 mg BID and imatinib, respectively). Conclusions: With a minimum follow-up of 24 mo, nilotinib continued to demonstrate superiority vs imatinib with faster and deeper molecular responses and a significantly decreased risk of progression. These data support the use of nilotinib as a standard of care option in newly-diagnosed adult pts with Ph+ CML-CP. Disclosures: Saglio: Novartis Pharmaceutical: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Pfizer: Consultancy. Off Label Use: Nilotinib is a safe and effective treatment for patients with CML. LeCoutre:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria. Pasquini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Nakamae:Novartis: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau. Flinn:nOVARTIS: Research Funding. Hochhaus:Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larson:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Gallagher:Novartis: Employment. Yu:Novartis: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

Impact of Treatment with Frontline Nilotinib (NIL) vs Imatinib (IM) on Sustained Deep Molecular Response (MR) in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2781-2781 ◽  
Author(s):  
Andreas Hochhaus ◽  
Giuseppe Saglio ◽  
Timothy P. Hughes ◽  
Richard A. Larson ◽  
Lilia Taningco ◽  
...  
Keyword(s):  
Treatment Duration ◽  
Research Funding ◽  
Quantitative Polymerase Chain Reaction ◽  
Chronic Phase ◽  
Molecular Response ◽  
Event Analysis ◽  
Newly Diagnosed ◽  
Consolidation Phase ◽  
Time Point

Abstract Background: For pts with CML-CP treated with frontline IM, achievement of a sustained deep MR is one of the major criteria associated with successful treatment-free remission (TFR); other factors, including long duration of IM therapy and favorable Sokal risk score, have also been shown to be important. Factors affecting successful TFR in pts treated with frontline NIL are under investigation. Ongoing studies are evaluating TFR in pts who have received different durations of TKI treatment and achieved different durations of sustained MR4 (BCR-ABL1 ≤ 0.01% on the International Scale [BCR-ABL1IS ]) or MR4.5 (BCR-ABL1IS ≤ 0.0032%). Here, 6-y data from the ENESTnd trial of frontline NIL vs IM were analyzed to evaluate rates of MR4 and MR4.5 with each agent and estimate pts' rates of sustained response for ≥ 1 y while on NIL or IM treatment. Methods: ENESTnd (NCT00471497) is an ongoing, randomized trial of NIL 300 mg twice daily (BID; n = 282) or NIL 400 mg BID (n = 281) vs IM 400 mg once daily (QD; n = 283) in pts with newly diagnosed CML-CP. Data from ENESTnd based on a minimum follow-up of 6 y for pts remaining on treatment were analyzed. Rates of deep MR were reported as cumulative incidence, with pts who achieved a response at or before each time point considered responders by that time point. Rates of sustained MR4 and MR4.5 on treatment among pts who achieved each response were estimated in each arm using a time-to-event analysis. In an exploratory analysis, the MR and treatment duration criteria for entering and attempting TFR in the ENESTfreedom trial (NCT01784068; a single-arm trial of pts with CML-CP who received ≥ 2 y of frontline NIL and achieved MR4.5 prior to enrollment) were applied a posteriori to determine the proportion of pts in each NIL arm of ENESTnd who were potential candidates for TFR, per the ENESTfreedom design (in the ENESTfreedom treatment consolidation phase, pts must maintain deep MR for 1 y [with real-time quantitative polymerase chain reaction assessments every 12 weeks, and with no assessment above MR4, ≤ 2 assessments between MR4 and MR4.5, and MR4.5 in the last assessment] on NIL 300 mg BID prior to attempting TFR). Results: With a minimum follow-up of 6 y in ENESTnd, 151 (53.5%), 155 (55.2%), and 127 (44.9%) pts in the NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively, remained on study treatment; median time on treatment was 5.8, 5.9, and 5.3 y, respectively. Cumulative rates of MR4 and MR4.5 by 6 y were higher with NIL vs IM; more pts achieved MR4.5 with NIL vs IM in all Sokal risk groups (Table). Among evaluable pts at 3 mo, more achieved BCR-ABL1IS ≤ 10% at 3 mo with NIL vs IM (NIL 300 mg BID, 234/258 [90.7%]; NIL 400 mg BID, 232/260 [89.2%]; IM, 176/264 [66.7%]); within each arm, rates of MR4.5 by 6 y were higher among pts who achieved BCR-ABL1IS ≤ 10% at 3 mo vs those with BCR-ABL1IS > 10% at 3 mo. Estimated rates of sustained MR4 and MR4.5 for ≥ 1, ≥ 2, and ≥ 3 y in pts achieving each response were high in all 3 arms; estimated rates of sustained MR4.5 for ≥ 1 y were 81.5%, 84.3%, and 84.4% in the NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively. By the data cutoff, 54.3% (153/282) and 54.8% (154/281) of pts in the NIL 300 mg BID and NIL 400 mg BID arms, respectively, had received ≥ 2 y of NIL treatment and achieved MR4.5 (the treatment duration and MR criteria for entering the ENESTfreedom treatment consolidation phase). In the 2 NIL arms, 37.9% (107/282) and 34.2% (96/281) of pts, respectively, had received ≥ 3 y of NIL treatment with sustained MRD for ≥ 1 y (the criteria for attempting TFR in ENESTfreedom). Conclusion: In ENESTnd, NIL resulted in higher rates of MR4 and MR4.5 than IM. Once achieved, these deep MRs were durable in all 3 treatment arms, with > 80% of pts who achieved MR4.5 maintaining this response for ≥ 1 y. The higher rates of deep MR achieved with frontline NIL vs IM may enable more pts to qualify to attempt experimental TFR in a clinical trial. After a minimum follow-up of 6 y, 37.9% of pts (107/282) treated with NIL 300 mg BID in ENESTnd had the treatment duration and sustained deep MR equivalent to those required for attempting TFR in ENESTfreedom. Disclosures Hochhaus: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Saglio:Novartis: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Hughes:Bristol-Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Larson:Bristol-Myers Squibb: Consultancy; Ariad: Consultancy, Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Research Funding. Taningco:Novartis Pharmaceuticals: Employment. Deng:Novartis Pharmaceuticals: Employment. Menssen:Novartis Pharma Basel Switzerland: Employment.

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