Novartis Pharmaceuticals Corporation.
Background: ENESTop, an ongoing, single-arm, phase 2 study (ClinicalTrials.gov, NCT01698905), is the first trial specifically evaluating treatment-free remission (TFR; ie, stopping tyrosine kinase inhibitor [TKI] treatment without a loss of response) in patients with chronic myeloid leukemia in chronic phase (CML-CP) who achieved a sustained deep molecular response after switching from imatinib (IM) to nilotinib (NIL). Of 126 patients in ENESTop who were eligible to stop NIL, 57.9% (95% CI, 48.8%-66.7%) maintained TFR at 48 weeks. Here we present results from a subgroup analysis based on reasons for switching from IM to NIL, categorized as intolerance, resistance, and physician preference. Methods:Eligible patients were adults with CML-CP who received ≥ 3 years of total TKI therapy (> 4 weeks of IM, followed by ≥ 2 years of NIL) and achieved a sustained MR4.5 (BCR-ABL1 ≤ 0.0032% on the International Scale [BCR-ABL1IS]) on NIL therapy; patients with a documented MR4.5 at the time of switch from IM to NIL were not eligible. Enrolled patients continued NIL treatment in a 1-year consolidation phase, and those without confirmed loss of MR4.5 (ie, consecutive BCR-ABL1IS > 0.0032%) were eligible to stop NIL in the TFR phase. Patients with loss of major molecular response (MMR; ie, BCR-ABL1IS > 0.1%) or confirmed loss of MR4 (ie, consecutive BCR-ABL1IS > 0.01%) during the TFR phase reinitiated NIL treatment. The primary endpoint was the proportion of patients who maintained TFR (ie, no loss of MMR, confirmed loss of MR4, or treatment reinitiation) at 48 weeks after stopping NIL. In this post hoc analysis, rates of TFR at 48 weeks after stopping NIL and a Kaplan-Meier (KM) analysis of treatment-free survival (TFS; defined as the time from the start of TFR to the earliest occurrence of any of the following: loss of MMR, confirmed loss of MR4, reinitiation of NIL due to any cause, progression to accelerated phase/blast crisis, death due to any cause) were evaluated in subgroups of patients who switched from IM to NIL due to intolerance, resistance, or physician preference. These categories were determined by grouping the reasons for switching from IM to NIL, as reported by the investigators, based on relatedness to safety (intolerance), loss of response/treatment failure (resistance), and the physician's clinical judgment (physician preference); individual reasons included within each category are presented in the Figure. Results:A total of 125 patients who entered the TFR phase were included in this analysis; 1 patient who was found to have had atypical transcripts was excluded. Among these 125 patients, the reasons for switching to NIL were categorized as intolerance in 51 patients (40.8%), resistance in 30 patients (24.0%), and physician preference in 44 patients (35.2%). The proportion of patients who maintained TFR at 48 weeks after stopping NIL was generally similar across the 3 subgroups: 30 of 51 (58.8%; 95% CI, 44.2%-72.4%) in the intolerance subgroup, 16 of 30 (53.3%; 95% CI, 34.3%-71.7%) in the resistance subgroup, and 27 of 44 (61.4%; 95% CI, 45.5%-75.6%) in the physician preference subgroup. KM analysis of TFS showed that in all 3 subgroups, the majority of TFS events occurred within the first 24 weeks after stopping NIL (Figure). There were no notable differences in the kinetics of TFS events among subgroups. The KM-estimated median duration of TFS was not reached by the data cutoff date in all 3 subgroups. Conclusion: Primary analysis from ENESTop showed that among patients with CML-CP who achieved a sustained MR4.5after switching from IM to NIL, 57.9% of those who stopped NIL maintained TFR at 48 weeks. In the present analysis, TFR was maintained at 48 weeks after stopping NIL by > 50% of patients in the intolerance, resistance, and physician preference subgroups, with generally similar results across subgroups. These findings suggest that the rate of successful TFR following second-line NIL does not differ based on the reasons for switching from IM to NIL. Figure. Figure. Disclosures Hughes: Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Australasian Leukaemia and Lymphoma Group (ALLG): Other: Chair of the CML/MPN Disease Group. Boquimpani:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Takahashi:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria. Shuvaev:Pfizer: Honoraria; BMS: Honoraria; Novartis pharma: Honoraria. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Lipton:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Moiraghi:BMS: Speakers Bureau; NOVARTIS: Speakers Bureau. Nicolini:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Ariad pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sacha:BMS: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding. Fellague-Chebra:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Krunic:Novartis: Employment, Equity Ownership. Jin:Novartis: Employment, Equity Ownership. Mahon:BMS: Honoraria; PFIZER: Honoraria; NOVARTIS PHARMA: Honoraria, Research Funding; ARIAD: Honoraria.
Background: ENESTop (NCT01698905) is an ongoing, single-arm, phase 2 study evaluating treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) who achieved sustained molecular response 4.5 (MR4.5; BCR-ABL1 ≤ 0.0032% on the International Scale [BCR-ABL1IS]) on second-line nilotinib (NIL). In the primary analysis, 57.9% (95% CI, 48.8%-66.7%) of pts who stopped NIL maintained TFR (no loss of major molecular response [MMR; ie, BCR-ABL1IS > 0.1%], confirmed loss of MR4 [ie, consecutive BCR-ABL1IS > 0.01%], or treatment reinitiation) at 48 weeks. Adverse events (AEs) were reported in 73.8% of pts during the first 48 weeks of TFR vs 77.0% during the year prior to stopping treatment. The incidence of musculoskeletal pain-related AEs was higher during TFR (42.1% vs 14.3%). To assess the potential effect of stopping NIL on quality of life (QOL), pt-reported outcomes were assessed before and during TFR. Methods: ENESTop enrolled adult pts with CML-CP with ≥ 3 years of prior tyrosine kinase inhibitor (TKI) therapy (> 4 weeks of imatinib [IM], then ≥ 2 years of NIL). Pts must have achieved sustained MR4.5 on NIL after switching from IM. Enrolled pts entered a 1-year NIL treatment consolidation phase; those without confirmed loss of MR4.5 (ie, consecutive BCR-ABL1IS > 0.0032%) entered the TFR phase and stopped NIL. Pts with loss of MMR or confirmed loss of MR4 during the TFR phase reinitiated NIL. QOL was assessed via questionnaires completed by pts at specified time points. The MD Anderson Symptom Inventory for CML (MDASI-CML) questionnaire assessed, for a defined set of symptoms, the levels of severity and interference with daily life on a scale of 0 to 10, with 0 being the lowest level. The EQ-5D-5L questionnaire assessed problems experienced by pts (no, slight, moderate, severe, or extreme [ie, interfering with functioning] problems) in 5 dimensions: mobility, self-care, usual activities, anxiety/depression, and pain/discomfort; additionally, overall level of health was assessed on a scale of 0 to 100 using the EQ VAS, with 0 being the lowest level. Results: Of 163 enrolled pts, 126 met the criteria for stopping NIL in the TFR phase; of these 126, 53 had loss of MMR or confirmed loss of MR4, of whom 51 reinitiated NIL. Among pts who completed each questionnaire at week 48 of the consolidation phase, week 12 of the TFR phase, or week 48 of the TFR phase, mean MDASI-CML severity scores were 1.7, 1.5, and 1.2, respectively; mean MDASI-CML interference scores were 1.7, 1.6, and 1.4, respectively; and mean EQ VAS scores were 82.2, 78.8, and 82.3, respectively (Table). Among pts with sustained TFR and scores at both week 48 of the consolidation phase and week 12 or 48 of the TFR phase, minimal changes were observed in MDASI-CML and EQ VAS scores during TFR vs week 48 of the consolidation phase. Among pts who reinitiated NIL, mean MDASI-CML severity and interference scores and mean EQ VAS scores at 24 weeks after the start of retreatment were 1.6, 1.5, and 78.8, respectively; changes in scores between week 24 after treatment reinitiation and week 48 of the consolidation phase were minimal among pts with scores at both time points. Among pts who completed the EQ-5D-5L questionnaire, the proportions who reported problems (any level of severity) in the 5 dimensions were generally similar across time points, although problems with mobility and pain/discomfort were more common during TFR vs week 48 of the consolidation phase, particularly at week 12 of the TFR phase (Table). Conclusion: Changes in QOL after stopping NIL, as assessed using these questionnaires, were minimal. This may be related to pts having a relatively high QOL prior to stopping treatment given that they had tolerated ≥ 3 years of TKI therapy, including ≥ 2 years of NIL, prior to enrollment. Despite the higher incidence of musculoskeletal pain-related AEs observed during TFR (42.1% vs 14.3%), the overall QOL was generally similar between the TFR and consolidation phases. This suggests that these AEs did not have a significant negative impact on QOL. Longer follow-up in ENESTop will be needed to further evaluate trends in QOL after stopping second-line NIL. Disclosures Mahon: NOVARTIS PHARMA: Honoraria, Research Funding; BMS: Honoraria; ARIAD: Honoraria; PFIZER: Honoraria. Boquimpani:BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Takahashi:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria. Shuvaev:Novartis pharma: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Lipton:Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Turkina:Novartis Pharma: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Moiraghi:NOVARTIS: Speakers Bureau; BMS: Speakers Bureau. Nicolini:Ariad: 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, Research Funding; BMS: Consultancy, Honoraria. Sacha:Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Fellague-Chebra:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Brandt:Novartis: Employment. Gnanasakthy:Novartis: Consultancy, Equity Ownership, Research Funding. Jin:Novartis: Employment, Equity Ownership. Hughes:Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Introduction. Overall survival (OS) of patients in chronic phase (CP) chronic myeloid leukemia (CML) dramatically increased in the era of tyrosine kinase inhibitors (TKI). Meanwhile nearly half of patients discontinue 1-st line Imatinib due to resistance or intolerance. Half of them subsequently failure treatment with second line TKI. It seems that 20-25% of CP CML patients need 3-d line therapy (TKI-3l). There are a few reports regarding durable outcome of TKI-3l. Materials and Methods. In our retrospective study 53 patients (20 male, 33 female) with CML CP treated either by Nilotinib 400 mg BID (n=18), Dasatinib 100 mg QD (n=33) or Bosutinib 500 mg QD (n=5) as TKI-3l were included. The median age at the time of diagnosis was 46 years (23-88 years). The main reason for previous TKIs discontinuation was resistance: 48/53 (91%) had failure of one and 42/53 (79%) patients had failure of both previous TKIs treatment. Median CML duration before TKI-3l was 55 months (2-314 months). Before TKI-3l mutation analysis was performed in 35 patients: 18 mutations were revealed in 16 (46%) patients including T315I mutation in 3 cases. At the moment of 3-d line TKIs therapy initiation, all patients were in CP and 43/53 (81%) had at least complete hematologic response (CHR), 8/53 (15%) patients had major cytogenetic response (MCyR) including 1 patient with complete cytogenetic response (CCyR). Results. At the time of analysis, the median duration of TKI-3l therapy was 21 months (1-67 months). No additional patients achieved CHR, but during observational time CHR was maintained nearly in all 40/43 (93%) patients with CHR at baseline. New cases of MCyR and CCyR were observed in 15/45(33%) and 11/52(21%) of patients, respectively. Median time to MCyR and CCyR was 3.4 (3-8) and 5.2 (3-13) months, respectively. Median duration of MCyR and CCyR was 9.3 (1-43) months and 4.5 (3-6) months, respectively. Patients with resistant mutations did not obtain any cytogenetic response. TKI-3l treatment was discontinued in 21 patients. Intolerance was the reason of treatment discontinuation in 5/53(10%) cases. Progression to accelerated or blastic phases during therapy or after discontinuation occurred in 8/53 (15%) patients. Median time to progression was 14.7 months (1-46 months). There were 13 deaths in overall group of 53 patients. Two-year OS in TKI-3l was 67%. All patients with MCyR were alive and preserved CP phase. Concluson: Our results showed that 20% of patients might obtain at least CCyR and benefit with TKIs as third line. Therefore, after two TKI lines patients, who are not eligible for allogeneic transplantation and without resistant mutations should be treated with one more line of TKI therapy. Disclosures Lomaia: Novartis: Consultancy. Zaritskey:University of Heidelberg: Research Funding; Novartis: Consultancy.
Background: PF-114 is a 4th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCR-ABL1 isoforms including BCR-ABL1T315I. We present data from a phase-1 study in patients with chronic or accelerated phase chronic myeloid leukaemia (CML) failing ≥2 TKIs or with BCR-ABL1T315I (NCT02885766) with ≥6 months therapy. Methods: 3+3 dose-escalation study to determine maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included safety and efficacy based on haematological, cytogenetic, and molecular criteria. Adverse events (AEs) were graded using NCI-CTCAE v4.03. Results: 51 patients were enrolled. Daily doses were 50 mg (n=3), 100 mg (n=3), 200 mg (n=9), 300 mg (n=11), 400 mg (n=12), 500 mg (n=3), 600 mg (n=6), 750 mg (n=4) given continuously. Median age was 50 years (range, 29-82 years). Median CML duration pre-study was 10 years (range, 0.3-23 years). All patients had baseline ECOG performance scores 0-1. Twelve patients had BCR-ABL1T315I. Patients were heavily pre-treated: 25 received ≥3 prior TKIs; 5 patients with BCR-ABL1T315I received 1 prior TKI. Interim analysis was conducted at follow-up of ≥6 months (cut-off date January 16th 2019). Therapy was ongoing in 17 patients at doses 200 mg (n=4), 300 mg (n=9), 400 mg (n=3) and 600 mg (n=1) with median duration of exposure of 7,4 (range, 4,6-26), 9,2 (range, 7,4-26), 9,2 (range, 8,3-9,2) and 9,2 months. Other patients discontinued because of progression (n=18), adverse events (n=6), consent withdrawal (n=4), participation in another study (n=3) or other reasons (n=3). The MTD was 600 mg with the grade-3 psoriasis-like skin lesions the DLT, which occurred during the first 28 days of treatment. Reversible grade-3 skin toxicity occurred in 11 patients at doses ≥400 mg. There were no other drug-related non-hematologic grade-3 toxicities except 1 grade-3 toxic hepatitis at 400 mg and there were no detectable effects on ankle-brachial index or vascular occlusive events. The best safety/efficacy dose was 300 mg/d with 6 of 11 patients achieving a major cytogenetic response (MCyR) and 4 of them - a major molecular response (MMR). Higher doses were less effective probably because of toxicity-related therapy interruptions and discontinuations. Five of 12 patients with BCR-ABL1T315I responded, 3 of which achieved a complete hematologic response and 4 achieved MCyR. Conclusion: PF-114 was safe and effective in patients with CML failing ≥2 TKIs or with BCR-ABL1T315I. The most effective dose was 300 mg/d. Five of 12 patients with BCR-ABL1T315I responded. A pivotal study is beginning. Disclosures Turkina: Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; fusion pharma: Consultancy; Novartis: Consultancy, Speakers Bureau. Vinogradova:Novartis: Consultancy; Fusion Pharma: Consultancy. Lomaia:Novartis: Other: Travel Grant;Lecture fee; Pfizer: Other: Travel Grant. Shukhov:Pfizer: Consultancy; Novartis: Consultancy. Chelysheva:Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Shikhbabaeva:Novartis: Consultancy; Fusion Pharma: Consultancy. Shuvaev:Fusion Pharma: Consultancy; Novartis: Consultancy; Pfize: Honoraria; BMS: Consultancy. Cortes:Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; BiolineRx: Consultancy; Sun Pharma: Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy. Ottmann:Roche: Honoraria; Pfizer: Honoraria; Fusion Pharma: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Mikhailov:Fusion Pharma: Employment. Novikov:Fusion Pharma: Employment. Shulgina:Fusion Pharma: Employment. Chilov:Fusion Pharma: Consultancy.
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