ARIAD Pharmaceuticals Research Articles

The cost-effectiveness of brigatinib in adult patients with ALK inhibitor-naive ALK-positive non-small cell lung cancer from a US perspective.

BACKGROUND: The discovery of specific oncogenic drivers in non-small cell lung cancer (NSCLC) has led to the development of highly targeted anaplastic lymphoma kinase tyrosine kinase inhibitors (ALKis). Brigatinib is a next-generation ALKi associated with prolonged progression-free survival in patients with ALKi-naive ALK+ NSCLC. OBJECTIVE: To estimate the cost-effectiveness of brigatinib compared with crizotinib and alectinib in patients with ALKi-naive ALK+ NSCLC, from a US payer perspective. METHODS: A lifetime area under the curve-partitioned survival model with 4 health states was used to evaluate the relative cost-effectiveness of brigatinib in the ALKi-naive ALK+ NSCLC setting. Brigatinib was compared with crizotinib within a cost-effectiveness framework and compared with alectinib in a cost-comparison framework, where all efficacy outcomes were assumed equal. The efficacy of brigatinib and crizotinib was informed by the ALTA-1L trial, and an indirect treatment comparison was performed to inform the efficacy of brigatinib vs alectinib owing to a lack of head-to-head data. Costs were derived from public sources. The main outcomes of the model were total costs, quality-adjusted life-years (QALYs), life-years, and incremental cost-effectiveness ratios. Univariate and probabilistic sensitivity analyses, in addition to multiple scenario analyses, were conducted to assess the robustness of the model outcomes. RESULTS: The improved outcomes observed in ALTA-1L translated into QALY gains (+0.97) in the comparison of brigatinib vs crizotinib. The superior efficacy profile was associated with increased time on treatment with brigatinib, which drove the increase in costs vs crizotinib (+$210,519). The resulting base-case incremental cost-effectiveness ratio was $217,607/QALY gained. Compared with alectinib, brigatinib was associated with a cost difference of -$8,546. Sensitivity analysis suggested that extrapolation of overall survival, the assumptions relating to time on treatment, and subsequent therapy costs were the most influential determinants of results. Probabilistic sensitivity analysis suggested brigatinib had the highest probability of being cost-effective beyond willingness-to-pay thresholds of $236,000 per QALY vs crizotinib and alectinib. CONCLUSIONS: At list prices and under base-case assumptions in the current analysis, brigatinib was associated with cost-savings vs alectinib, and QALY gains but at higher costs vs crizotinib. Additional research into the real-world efficacy of ALKis is warranted to further understand the comparative cost-effectiveness of these therapies. DISCLOSURES: Ms Cranmer and Ms Kearns are employees of Takeda UK Ltd. Dr Young is a former employee of Takeda Pharmaceuticals America, Inc. Dr Humphries is an employee of Takeda Pharmaceuticals U.S.A., Inc. Mr Trueman is an employee of Source Health Economics, the consultancy company that provided health economic and writing services. This work was funded by ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Work by Source Health Economics was funded by ARIAD Pharmaceuticals, Inc. Professional medical writing assistance was provided by Phillipa White, of Source Health Economics, and funded by ARIAD Pharmaceuticals, Inc.

Safety and Efficacy of Lower Intensity Induction Therapy with Intravenous Prexigebersen (BP1001) in Patients with High-Risk and Relapsed/Refractory Acute Myeloid Leukemia (AML)

Safety and Efficacy of Lower Intensity Induction Therapy with Intravenous Prexigebersen (BP1001) in Patients with High-Risk and Relapsed/Refractory Acute Myeloid Leukemia (AML)

Hematopoietic Stem and Progenitor Cell Fitness As a Novel Prognostic and Monitoring Biomarker for JAK2 V617F Myeloproliferative Neoplasms (MPNs)

Hematopoietic Stem and Progenitor Cell Fitness As a Novel Prognostic and Monitoring Biomarker for JAK2 V617F Myeloproliferative Neoplasms (MPNs)

Community Versus Academic Practice in Essential Thrombocythemia and Myelofibrosis: Differences in Clinical Characteristics, Diagnosis, Treatment Patterns, and Symptom Burden (Analysis of Data from the MOST Study)

Community Versus Academic Practice in Essential Thrombocythemia and Myelofibrosis: Differences in Clinical Characteristics, Diagnosis, Treatment Patterns, and Symptom Burden (Analysis of Data from the MOST Study)

Venetoclax in Combination with Gilteritinib Demonstrates Molecular Clearance of FLT3 mutation in Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia

Venetoclax in Combination with Gilteritinib Demonstrates Molecular Clearance of FLT3 mutation in Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia

Comparing Outcomes between Liposomal Daunorubicin/Cytarabine (CPX-351) and HMA+Venetoclax As Frontline Therapy in Acute Myeloid Leukemia

Comparing Outcomes between Liposomal Daunorubicin/Cytarabine (CPX-351) and HMA+Venetoclax As Frontline Therapy in Acute Myeloid Leukemia

Impact of Peri-Transplant Molecular Mutations on Outcomes of AML Patients Undergoing Fludarabine/Melphalan Conditioned Allogeneic Stem Cell Transplant

Impact of Peri-Transplant Molecular Mutations on Outcomes of AML Patients Undergoing Fludarabine/Melphalan Conditioned Allogeneic Stem Cell Transplant

Clinical Outcomes of Non-Small Cell Lung Cancer Brain Metastases Treated With Stereotactic Radiosurgery and Immune Checkpoint Inhibitors, EGFR Tyrosine Kinase Inhibitors, Chemotherapy and Immune Checkpoint Inhibitors, or Chemotherapy Alone

Immune checkpoint inhibitors (ICI) and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have shown responses in the management of non-small cell lung cancer (NSCLC) brain metastases (BM). However, optimizing control with stereotactic radiosurgery (SRS) and various systemic therapies in the management of NSCLC BM remains an area of investigation. We evaluated clinical outcomes in NSCLC BM treated with SRS and ICI, EGFR-TKI, ICI and chemotherapy, compared to conventional chemotherapy.A total of 174 NSCLC BM patients, treated between 2015 and 2019, to a total of 660 intact (non-operative) BM over 239 single-fraction SRS sessions within 3 months of receiving ICI (n = 58; 33%), EGFR-TKI (n = 30; 17%), chemotherapy and ICI (n = 22; 13%) or standard chemotherapy (n = 64; 37%) were identified. Time-to-event analysis was conducted with the Kaplan-Meier method, and outcomes included distant intracranial control (DIC), local control (LC), and overall survival (OS) from SRS. Cox proportional hazards model was utilized for multivariate analysis (MVA) to identify correlations of clinical variables with outcomes.Median follow-up from BM diagnosis was 8.9 months (0.26-126.5 months) and 7.3 months from SRS (2.5-17.6 months). No significant differences in age (P = 0.55), gender (P = 0.49), treated gross tumor volume (P = 0.31), presence of systemic metastasis (P = 0.1), SRS dose (P = 0.61), or KPS (0.35) were noted between treatment groups. The 12-month DIC was 35%, 53%, 41%, and 20% (P = 0.02) for ICI, EGFR-TKI, ICI and chemotherapy, and chemotherapy alone groups, respectively. No differences were noted in LC (P = 0.1) and OS (P = 0.5) between treatment groups. Upon MVA, factors found to be significant for improved DIC included treatment with EGFR-TKI therapy compared to conventional chemotherapy (HR 0.4; 95% CI 0.25-0.76; P = 0.04) and treatment with SRS before systemic therapy (HR 0.6; 95% CI 0.3-0.9; P = 0.03). Factors found to be significant for improved LC on MVA included treatment with SRS before (HR 0.4; 95% CI 0.2-0.9; P = 0.03) or concurrent (HR 0.3; 95% CI 0.1-0.6; P = 0.003) compared to following receipt of systemic therapy. Rates of radiation necrosis (RN) did not differ between treatment groups and were 6% (n = 12), 5% (n = 12), 3% (n = 3), 3% (n = 3), for ICI, EGFR-TKI, ICI and chemotherapy, and chemotherapy alone groups, respectively, P = 0.43. In addition, no differences were noted in RN between timing of SRS and receipt of systemic therapy, (P = 0.81).In our analysis of NSCLC BM patients treated with single session SRS alongside systemic therapy, we found significant differences in DIC based on receipt of systemic therapy. In addition, treatment with SRS before or concurrent with systemic therapy improved control rates. No differences in RN were noted between treatment groups or by timing of SRS and systemic therapy. Prospective evaluation of the potential synergistic effect between systemic therapy and SRS in NSCLC BM management is warranted.A.E. Dohm: None. J. Tang: None. M.N. Mills: None. B.A. Perez: Research Grant; BMS.T.J. Robinson: None. B. Creelan: Research Grant; NGenomics Laboratories, Adaptive Biotechnologies Corp. Consultant; Xilio Inc, E.R. Squibb LLC, F. Hoffmann-La Roche AG, AstraZeneca plc, AbbVie, KSQ Therapeutics Inc, GlaxoSmithKline plc, Gilead Sciences Inc, Celgene corp. Speaker's Bureau; AstraZeneca plc, ARIAD Pharmaceuticals, Hoffmann-La Roche AG.J. Gray: None. A.B. Etame: None. M. Vogelbaum: Honoraria; Celgene, Tocagen. Stock Options; Infuseon Therapeutics. Royalty; Infuseon Therapeutics. P. Forsyth: Research Grant; Pfizer, Celgene. Advisory Board; Novocure, BTG, Inovio, AbbVie, Ziopharm, Tocagen, Pfizer. H.M. Yu: Honoraria; UpToDate. Speaker's Bureau; BrainLab. Advisory Board; Novocure, AbbVie. D.E. Oliver: None. K.A. Ahmed: Research Grant; Bristol-Myers Squibb, Genentech.

CML-129: OPTIC Primary Analysis: A Dose-Optimization Study of 3 Starting Doses of Ponatinib (PON)

Context: PON, a third-generation tyrosine kinase inhibitor (TKI), demonstrated deep, long-lasting responses/survival in patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant/intolerant to second-generation TKI therapy (PACE; NCT01207440); post hoc analysis suggested a relationship between dose and adverse events/response. We present the primary analysis of OPTIC (NCT02467270), an ongoing, randomized, phase 2 trial in resistant/intolerant CP-CML to evaluate safety and efficacy of PON response–based dosing regimens. Methods: Patients with CP-CML resistant/intolerant to ≥2 TKIs or with the BCR-ABL1 T315I mutation were randomized to PON starting doses of 45 mg (cohort A), 30 mg (B), and 15 mg (C) once daily. Doses were reduced to 15 mg with achievement of ≤1% BCR-ABL1IS in cohorts A and B. Primary endpoint is Results: 283 patients were randomized (A/B/C: n=94/95/94) and had the following baseline characteristics: median age 48 y (18–81 y); 98% received ≥2 (55% ≥3) TKIs; 99% had resistant disease; 40% had ≥1 baseline mutations (23% T315I). At 32-mo median follow-up, 134 patients (47%; n=50/41/43) remained on treatment and 204 patients (72%) had PON exposure ≥12 mo. At 12 mo, 44% (41/93) in A, 29% (27/93) in B, and 23% (21/91) in C achieved ≤1% BCR-ABL1IS; cohort A met the primary endpoint. Progression-free survival/overall survival at 36 months was 73/89% (A), 66/89% (B), and 70/92% (C). Most common grade ≥3 treatment-emergent adverse events (TEAEs) were thrombocytopenia, 27%; neutropenia, 17%; and anemia, 7%. Arterial occlusive events (AOEs)/serious AOEs were reported in cohorts A (10%/4%), B (5%/4%), and C (3%/3%). Dose reductions or discontinuations for TEAEs (A/B/C) were 46/35/32% and 19/16/14%, respectively. Conclusions: The OPTIC primary analysis demonstrates the optimal benefit/risk profile for PON was achieved with a response-based dosing regimen starting with 45 mg/d, followed by dose reduction to 15 mg/d upon achieving ≤1% BCR-ABL1IS. Observed ≤1% BCR-ABL1IS responses are supported by robust survival outcomes in patients with and without BCR-ABL1 mutations. The OPTIC study is sponsored by ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, with additional funding from Incyte Corporation (Wilmington, DE).

The Target UK Study: Real-World Evidence of Molecular Response to Tyrosine Kinase Inhibitors Supports European Leukemianet 2013 Recommendations for the Management of Chronic Myeloid Leukaemia

Abstract Introduction: Several recent studies have shown the speed and depth of response to tyrosine kinase inhibitor (TKI) treatment to be an important indicator of patient outcomes in chronic myeloid leukaemia (CML) as reviewed in the most recent European evidence based recommendations for CML management (European LeukemiaNet [ELN] 2013; Baccarani et al, 2013). ELN2013 focuses on monitoring of molecular responses, describing “optimal”, “warning” and “failure” at specific milestones to guide changes in therapy. An early molecular response (EMR; BCR-ABL1 IS Methods: TARGET is an observational, retrospective study conducted at 14 UK secondary/tertiary care centres. Data on Pt's characteristics, TKI choice, and molecular responses were collected by review of medical records for adult Pts (≥18 years) with chronic phase CML. Pts first prescribed a TKI between January 2013 and October 2015 were eligible and were required to have at least 6 months follow-up. Data were analysed using descriptive statistics. Results: At data collection, median follow-up was 21.5 (range 6.0 to 40.5) months. Median age at first TKI was 53.7 (range 18.7 to 86.8) years and 52% Pts were male. Imatinib was used first line (1L) in 107 (85%) Pts, and a second generation (2G) TKI in 19 (15%) (nilotinib=18, dasatinib=1). During the observation period 52/126 (41%) Pts switched TKI at least once; 29/52 switched early (within 6 [+1] months) and 23/52 switched later. The documented main reason for first switch was resistance (for 36/52) while 16/52 Pts were switched for intolerance (n=13) or other reasons (n=3). The median time to switch was 5.5 (range 0.5 to 34.3) months for Pts switched due to intolerance and 6.7 (range 2.8-16.0) months for resistance. Molecular responses at ELN2013 milestones and rates of EMR, MMR and DMR achieved 1L and 2L during the observation period are shown in Table 1. In the 52 Pts who switched TKI during the observation period, an ELN 2013 “warning” or “failure” response was observed prior to switch in 19/52 and 21/52 Pts, respectively (note: 4/52 Pts had an “optimal” response and switched for intolerance; 8/52 had no evaluable test at ELN milestone). In the 74 Pts who remained on 1L TKI with no observed switch, 25/74 had a “warning” response and a further 6/74 had a “failure” response at one or more ELN2013 milestones. Rates of MMR and DMR (at any time) for Pts who switched TKI following a prior “warning” or “failure” response (40/52 Pts with median follow-up of 13.6 [range 0.3 to 35.4] months) were 48% (19/40) and 23% (9/40), respectively. In Pts with a “warning” or “failure” response who stayed on 1L TKI (31/74 with median follow-up of 18.0 months [range 6.0 to 37.9]), 29% (9/31) achieved a MMR and 10% (3/31) a DMR. Conclusions: Interim findings in this real-world UK cohort suggest that a higher proportion of Pts treated with 2G TKI (either 1L or 2L) achieve an EMR, MMR or DMR than Pts treated with imatinib. Early indications suggest that the probability of achieving an optimal response is greater in Pts who switch TKI following an ELN “warning” or “failure” response than those with suboptimal responses who remain on 1L therapy, and that an early switch to 2L TKI may be beneficial. The results also highlight that optimal responses can be achieved even in Pts with prior resistance to 1L. Overall, the results support the use of ELN2013 recommendations to guide TKI management. Further recruitment and extended follow-up are planned to enable more detailed analyses of UK real-world monitoring and management patterns against ELN2013 recommendations and molecular response. Download : Download high-res image (224KB) Download : Download full-size image Disclosures Milojkovic: ARIAD: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau. Clark: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ariad Pharmaceuticals: Honoraria. Byrne: Novartis: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Raghavan: Novartis: Honoraria; Pfizer: Honoraria. Wandroo: Pfizer: Honoraria; BMS: Honoraria; Bayer: Honoraria. Ali: Novartis: Honoraria; BMS: Honoraria. Ryan: Novartis: Employment; Novartis: Employment. Friedrich: Novartis: Employment. Cross: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Qiagen: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Mead: Pfizer: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria.

Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: 12-Month Patient-Reported Outcomes from the BFORE Trial

Introduction: Since many patients with chronic phase chronic myeloid leukemia (CP CML) achieve long-term survival, health-related quality of life (HR-QOL) as assessed by PROs is an important consideration. Bosutinib is a SRC/ABL tyrosine kinase inhibitor approved for Philadelphia chromosome-positive CML treatment in adults resistant or intolerant to prior therapy. In the BFORE trial (NCT02130557) of bosutinib versus imatinib a significantly higher major molecular response rate at 12 months (the primary endpoint) occurred with bosutinib. Here we report initial PRO results from BFORE.Methods: BFORE is an ongoing, multinational, phase 3, open-label study in patients with newly diagnosed CP CML. Patients are randomized 1:1 to bosutinib 400 mg once daily or imatinib 400 mg once daily. PROs, assessed as exploratory endpoints, included functional status using the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) and the European Quality of Life-5 Dimensions-Visual Analog Scale (EQ-5D-VAS) instruments. Assessments were conducted at baseline and every 3 to 6 months, to continue for up to 5 years after treatment initiation. Outcomes at month 12 are reported herein.Results: Bosutinib and imatinib mean FACT-Leu scores were similar at baseline and at month 12 (Table). At month 12, significant improvement from baseline in FACT-Leu total score was observed for both bosutinib (mean change 3.1, P=0.0425) and imatinib (mean change 4.8, P=0.0008). For bosutinib at month 12, all FACT-Leu combined and subscale scores demonstrated either improvement (emotional well-being; leukemia symptoms; FACT-Leu total score) or maintenance (physical, functional, social well-being; FACT-General total score; trial outcome index).Bosutinib and imatinib mean EQ-5D-VAS scores were similar at baseline and at month 12 (Table). At month 12, significant improvement in mean EQ-5D-VAS was observed for both bosutinib (mean change 4.4, P=0.0014) and imatinib (mean change 9.3; P <0.0001). Additional FACT-Leu and EQ-5D analyses yielded similar findings. For example, mean [SD] Functional Health Status as measured using the EQ-5D Utility Score was similar between groups at baseline (bosutinib: 0.688 [0.2710] and imatinib: 0.657 [0.2929]) and improved from baseline for subjects in both treatment arms, with comparable scores seen at Month 12 (bosutinib: 0.722 [0.2953] and imatinib: 0.724 [0.2717]).Conclusion: In the BFORE trial of first-line CP CML therapy, PROs for bosutinib indicated improvement or maintenance of HRQoL at month 12, with effects comparable to those observed for imatinib, the standard of care for first-line CML treatment. These exploratory PRO results indicate fewer symptoms, better HRQoL, and improved functional health status at month 12 relative to baseline for both therapies. [Display omitted] DisclosuresCortes:ARIAD: Consultancy, Research Funding; Sun Pharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Teva: Research Funding. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Deininger:Novartis: Consultancy, Research Funding; Incyte: Consultancy; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; BMS: Consultancy, Research Funding; Celgene: Research Funding; Gilead: Research Funding. Mauro:Bristol-Myers Squibb: Consultancy. Chuah:Chiltern: Honoraria; BMS: Honoraria, Other: Travel; Novartis: Honoraria; Avillion: Honoraria. Kim:Il-Yang: Consultancy, 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; Pfizer: 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; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Milojkovic:ARIAD: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria. le Coutre:Incyte: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; ARIAD: Honoraria. García Gutiérrez:BMS: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Reilly:Avillion LLP: Employment. Jeynes-Ellis:Avillion LLP: Employment, Equity Ownership. Crescenzo:Pfizer: Employment, Equity Ownership. Mamolo:Pfizer: Employment, Equity Ownership. Reisman:Pfizer: Employment. Bardy-Bouxin:Pfizer: Employment, Equity Ownership. Hochhaus:Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Ariad: Research Funding; MSD: Research Funding; BMS: Research Funding. Brümmendorf:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Evaluation of an Automated Immunoassay for Quantification of Imatinib in Plasma

INTRODUCTIONImatinib mesylate is a first-line tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia (CML). Therapeutic drug monitoring (TDM) of imatinib is an important tool for evaluating patient adherence to therapy, particularly in the setting of therapeutic failure, and for dose optimization. It has been proposed that the therapeutic range for pre-dose (trough) plasma imatinib concentration (C₀) is 1000 - 3000 ng/mL (Biol Pharm Bull 38:645-54, 2015). TDM for imatinib is not widely available in the United States. Automated analysis of imatinib concentrations in plasma may improve accessibility of testing to support routine TDM. OBJECTIVEThe objective of this study was to evaluate an automated immunoassay for quantification of imatinib in plasma. METHODSImatinib concentrations were determined using a laboratory developed test based on reagents provided by Saladax Biomedical, Inc. (Bethlehem, NJ), and a Beckman Coulter AU5800 automated chemistry analyzer. Accuracy at 4 concentrations (350, 1000, 1600 and 2700 ng/mL), linearity over 11 concentrations (251 - 3315 ng/mL) and precision at 3 concentrations (604, 1120, 1932 ng/mL; 4 replicates per concentration, 2 runs per day over 4 days) were evaluated using fortified plasma samples. Residual authentic plasma samples from 21 CML patients treated with imatinib were also obtained based on protocols approved by the University of Utah Institutional Review Board. The samples were split for a method comparison with the Oregon Health & Science University in Portland, OR, where imatinib quantification is performed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Statistical analysis was performed by EP Evaluator. RESULTSThe immunoassay was found to be linear with a p=0.143 and a regression equation of y = 1.016x - 29.5. Mean recovery (n=20 results) ranged from 85.1% at 350 ng/mL to 90.3% at 2700 ng/mL. Within run, between run and total imprecisions, as measured by percent coefficient of variation (%CV) were <3.5% (n=32 per concentration). Qualitative agreement of patient sample results was 100%; concentrations of the patient specimens using the immunoassay ranged from 453 - 2543 ng/mL for positive samples (n=18), and 534 - 2929 ng/mL by LC-MS/MS. There were 3 samples that were negative by both methods. The correlation coefficient (R) was 0.9911 and regression equation was y = 0.901x - 35.3. When compared to the LC-MS/MS method, the immunoassay was associated with a 12.9% negative bias. CONCLUSIONThe automated immunoassay described here for determination of plasma imatinib concentrations performed with excellent linearity, accuracy and precision, and with an approximate 13% negative bias as compared to LC-MS/MS. DisclosuresDeininger:BMS: Consultancy, Research Funding; Incyte: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Research Funding; Gilead: Research Funding; ARIAD: Consultancy.

Efficacy and Safety of Ponatinib in Chronic Phase-Chronic Myeloid Leukemia (CP-CML) According to the Extent of Treatment with Prior Tyrosine Kinase Inhibitors (TKIs): Final (5-Year) Results of the PACE Study

Efficacy and Safety of Ponatinib in Chronic Phase-Chronic Myeloid Leukemia (CP-CML) According to the Extent of Treatment with Prior Tyrosine Kinase Inhibitors (TKIs): Final (5-Year) Results of the PACE Study

The Bone Marrow Niche Uses Mir-300 As a Biological Rheostat to Selectively Control Stem Cell-Driven Malignant Hematopoiesis and Innate Anti-Cancer Immunity

Inhibition of protein phosphatase 2A (PP2A) tumor suppressor is essential for chronic myelogenous leukemia (CML) stem cell (LSC) maintenance, disease evolution and innate anti-cancer immunity. In CML, persistence of ABL tyrosine kinase inhibitor (TKI)-resistant quiescent LSCs, disease development and inhibition of natural killer (NK) cell growth and anti-cancer activity depend on cell-autonomous and bone marrow (BM)-generated signals.Here we show that expression profiling of CD34+ BM progenitors from healthy individuals and CML patients in chronic (CP) and blastic (BC) phase identified a discrete number of microRNA (miRs) altered in CML and/or during blastic transformation. Among the miRs downregulated in CML, we focused on miR-300 because it directly inhibited expression of multiple components of the PP2A inhibitory pathway (i.e. Jak2, hnRNPA1, SET) and of other factors essential for LSC maintenance and disease progression (e.g. CCND1/2, b-catenin, Myc, Twist-1), when ectopically expressed in CML but not in normal CD34+ cells.MiR-300 acted as a potent tumor suppressor in leukemic CD34+ progenitors by inducing cell cycle exit and promoting spontaneous and (TKI)-induced apoptosis, whereas no effects were exerted in normal miR-300-transduced CD34+ cells. In CD34+ CML-BC progenitors miR-300 downregulation required the BCR-ABL1 kinase-dependent inhibition of C/EBPb, which was capable of binding and transcriptionally activating miR-300 promoter.Conversely, low O2 levels and mesenchymal stromal cell (MSC)-derived exosomes abnormally increased miR-300 expression in a TKI-insensitive manner to induce and/or preserve LSC quiescence and suppress NK cell growth. Indeed, lentiviral-mediated miR-300 inhibition in MSCs significantly prevented the MSC growth inhibitory activity on CD34+ CML-BC and NK cells. Accordingly, miR-300 levels were found higher in CD56+CD3- NK cells from CML patients at diagnosis compared to healthy individuals.Induction/maintenance of high miR-300 levels in LSCs (CD34+ CFSEMAX and CD34+CD38- cells) required the hypoxia-induced inhibition of BCR-ABL1 activity and induction of C/EBPb expression/activity. However, MSC-derived exosomal miR-300 also contributed to increase miR-300 expression in LSCs.LSCs escaped from the miR-300 pro-apoptotic activity through an autocrine/paracrine mechanism that required the release by CD34+ CML stem/progenitors of TGFb1 that, in turn, induced the expression of TUG1, a lncRNA acting as a miR-300 sponge. In fact, shRNA-mediated TUG1 suppression or Ab-dependent TGFb1 inhibition decreased the quiescent (CFSEMAX) CD34+ LSC number. By contrast, miR-300 inhibition did not alter LSC survival and self-renewal, further supporting a role for TUG1 as a miR-300 sponge. Accordingly, TUG1 was markedly induced in CFSEMAX but not dividing CD34+ CML cells. In fact, low ectopic miR-300 expression induced growth arrest (decreased LTC-ICs and CD34+CD38- CFC/replating activities) without affecting the number of CFSEMAX LSCs.By contrast, high doses of miR-300 (CPG-miR-300; 500nM) but not scramble oligonucleotides impaired LSC survival (LTC-IC) and self-renewal (CFC/replating), induced a marked killing of quiescent LSCs (decreased CD34+ CFSEMAX cells) and dividing CD34+ CML progenitors, and impaired CML-BC engraftment in NRG-SGM3 mice. Notably, the association of high CPG-miR-300 with TUG1 silencing (CPG-anti-TUG1) further reduced CD34+ CFSEMAX LSC number. Notably, TUG1 was highly expressed in normal CD34+ stem/progenitor cells; in fact, neither low nor high miR-300 levels altered their survival and/or self-renewal.Altogether our results indicate that while loss of miR-300 expression is essential for survival/proliferation of leukemic progenitors and, therefore, for development of a full-blown leukemia, increased miR-300 expression is necessary for reduced NK cell number/activity and maintenance of the LSC reservoir. In this scenario, induction of TUG1 may occur to preserve LSC survival after migration into the BM endosteal niche where quiescence is induced by MSCs and low O2 levels through marked induction of intracellular (endogenous and exosomal) miR-300 levels. Thus, disrupting the miR-300/TUG1 balance may represent a potential therapeutic approach for treatment/eradication of LSC-derived leukemias and restoration of innate immunity.This work is supported in part by NHI-NCI R01CA163800-01 DisclosuresGambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Deininger:ARIAD: Consultancy; Incyte: Consultancy; BMS: Consultancy, Research Funding; Celgene: Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding. Milojkovic:ARIAD: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau. Apperley:Pfizer: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Therakos: Honoraria; Incyte: Honoraria; Sun Pharma: Honoraria; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses , Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding.

Results from the U.S. Life after Stopping TKIs (LAST) Study

Background: Several studies have demonstrated the safety of stopping tyrosine kinase inhibitors (TKIs) for patients with chronic myeloid leukemia (CML) with a sustained deep molecular response. The LAST study is an NIH-funded multi-institutional trial aiming to improve the evidence for clinical decision-making regarding TKI discontinuation in the United States.Methods: LAST is a non-randomized, prospective, longitudinal study. The primary objectives of the study are to determine the proportion of patients who develop molecular recurrence after discontinuing TKIs and to compare patient-reported outcomes (PROs) before and after discontinuation. Molecular recurrence is defined as loss of MMR (> 0.1% BCR-ABL using the International Scale) once. Key inclusion criteria are age > 18, patient currently taking imatinib, dasatinib, nilotinib, or bosutinib, on TKI therapy for at least 3 years with a documented BCR-ABL transcript level < 0.01% by QR-PCR for at least 2 years per the patient's local lab, 2 screening PCRs with results BCR-ABL is < 0.01% in a central lab, and no previous TKI resistance. Patients with prior allogeneic stem cell transplantation are excluded. Monitoring is monthly for the first 6 months, then every 2 months for 18 months, then every 3 months until 36 months. In addition, blood samples for BCR-ABL transcript levels measured by digital PCR are collected at the same time points as for RQ-PCR.Results: From December 2014 to December 2016, 208 patients were screened and 173 patients were enrolled from 14 sites in the US. The median age was 61 (range, 50-68) and 90 (52%) were females. Median duration of TKI prior to enrollment was 79 months (range, 51-117). At the time of enrollment, 60%, 23%, 15%, and 2% were on imatinib, nilotinib, dasatinib, and bosutinib respectively. With a median follow up of 12.3 months (range, 0.9-27) and a minimum follow up of 6 months for all patients remaining on study, 115 (66%) patients remain in a treatment-free remission (TFR). Of the 58 who restarted TKI, 46 patients restarted based on loss of MMR by central lab, and 12 restarted by patient choice. Of the 46 patients who restarted drug based on loss of MMR by central lab, 38 (82%) again achieved MMR by central lab, 3 withdrew consent before confirmation of MMR, 4 patients have had less than 6 months follow up, and one patient died (from causes unrelated to CML) before confirmation of MMR. PROs will be reported separately. Of note, 3 patients restarted TKI because of withdrawal syndrome. The proportion of patients who remained in TFR at 6 and 12 months is 73% (127/173) and 60% (76/127) respectively.Conclusion: Our results add to the evidence that stopping TKIs in a select group of patients is safe and feasible with close monitoring. Updated results will be presented at the meeting. DisclosuresAtallah:ADC Therapeutics: Research Funding. Radich:Amgen: Consultancy; Novartis: Consultancy, Other: lab contracts for bid and service assays; Pfizer: Consultancy; Ariad: Consultancy; BMS: Consultancy; Gilliad: Consultancy. Kota:Takeda Pharmaceuticals: Consultancy; Pfizer: Consultancy; Leukemia Lymphoma Society: Research Funding; Incyte: Consultancy; Xcenda: Consultancy; Novartis: Consultancy. Pinilla-Ibarz:Pfizer: Honoraria, Speakers Bureau; ARIAD: Consultancy, Honoraria; BMS: Honoraria, Speakers Bureau. Larson:Novartis: Consultancy, Research Funding; Amgen Inc.: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy, Research Funding. Mauro:Bristol-Myers Squibb: Consultancy. Deininger:Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Incyte: Consultancy; BMS: Consultancy, Research Funding; ARIAD: Consultancy; Gilead: Research Funding; Pfizer: Consultancy; Celgene: Research Funding. Shah:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; ARIAD: Research Funding; Daiichi-Sankyo: Research Funding. Ritchie:Pfizer: Consultancy, Other: Research funding to my institution; NS Pharma: Other: Research funding to my institution; Novartis: Consultancy, Other: Research funding to my institution, and travel, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Celgene: Consultancy, Other: Travel, Speakers Bureau; Astellas Pharma: Other: Research funding to my institution; Bristol-Myers Squibb: Other: Research funding to my institution. Cortes:Teva: Research Funding; Pfizer: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding.

Imatinib (IM) in Combination with Hydroxyurea Showed Significantly Lower Major Molecular Response Rates at 6 Months but Similar MMR at 18 Months in Patients with CML1st CP Compared to IM Alone. Final Results of the CML2004 Study. NCT 02480608

Introduction: Imatinib (IM) monotherapy remains an important option to treat newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase (CP). Hydroxyurea (HU) is effective in controlling elevated white blood cell counts and was widely used to treat CML prior to the era of tyrosine kinase inhibitors (TKIs). After combinations of IM and HU showed additive effects on Ph+ cells in vitro the East German Study Group conducted a study in patients with CML first chronic phase.Methodes: Starting in 2002, 20 adult patients with newly diagnosed CP-CML were included in the phase I study to identify the dose of HU in combination with standard dose IM (400mg daily) that would result in mild myelosuppression (white blood cell count 3,000-4,000/mL). Starting dose of HU was 500mg daily increasing by 500mg every 3 weeks to a maximum of 3,000 mg daily. In line with the protocol, 500mg HU was chosen as the starting dose for the randomized phase II study which tested the combination vs. standard dose IM, with the rate of major molecular response (MMR) at 18 months as the primary endpoint.Additional 93 patients were enrolled in the phase II of the study, 5 of whom were excluded, leaving 88 patients to be randomized 2:1 to the IM/HU (n=59) and IM (n=29) arm, respectively. Three patients (2 IM/HU, 1IM) were lost to follow-up. As prospectively designed, IM/HU patients (n=77) from the phase I and II were analyzed in combination with patients from the CML study IV (n=49) selected by propensity score matching. The median age of the 154 patients was 55 years (range 18 - 82). The EUTOS long-term survival prognostic score was available for 141 patients and was high in 8 (5.7%), intermediate in 35 (24.8%) and low in 98 (69.5%), with no significant differences between treatment groups. The median HU dose was 500mg (range 152-3000); the median IM dose was 400 mg (range 145-617mg) in both arms.Results: The 5-year overall survival (OS) was 90.4% and 84,9% in the IM/HU and IM arm respectively (not significant). Similarly, progression-free survival (PFS) at 5 years amounted to 86.7% in the IM/HU and 84.9% in the IM arm.With IM/HU, the probabilities of complete cytogenetic response (CCR) at 6, 12, and 18 months were 54.3, 84.0, and 93.7%, respectively. In the IM arm, the corresponding numbers were 70.4, 84.9, and 83.3% (p=not significant).Molecular Response Rates (MMR) in the two arms were evaluated at 6 months with 21.6 (IM/HU) vs. 41.1% (IM) (p=0.0383) and at 12 months with 41.9 (IM/HU) vs. 58.9% (IM; not significant). The primary endpoint of the study (MMR rate at 18 months) did not significantly differ between the IM/HU (65.8%) and the IM (66.0%) arms.No significant differences were detected in time to event analyses of OS and PFS or in group comparisons between the probabilities of CCR and MMR.The gross numbers of adverse events in general or of adverse events of grade 4 were not different between the two arms. However, cumulative incidences showed an earlier occurrence in the IM/HU than in the IM arm (p= 0.0343, Gray test)Conclusion: Compared to Imatinib only, the combination of Imatinib and HU resulted in a lower MMR rate at 6 months but a similar MMR rate at 18 months. Furthermore, IM/HU was associated with more early adverse events. There was no indication of a beneficial effect in the treatment of CML patients in 1st chronic phase using the combination of IM with HU. DisclosuresLange:Novartis: Honoraria, Research Funding. Al-Ali:Gilead: Consultancy, Honoraria; Alexion: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Pfirrmann:Novartis: Honoraria; BMS: Honoraria. Hehlmann:Novartis: Research Funding; BMS: Consultancy. Deininger:Incyte: Consultancy; BMS: Consultancy, Research Funding; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; ARIAD: Consultancy; Gilead: Research Funding; Celgene: Research Funding; Novartis: Consultancy, Research Funding.

Randomized Phase II Study of R-CHOP-14 Versus R-CHOP-14 Followed By Chaser As Induction Therapy for High-Dose Chemotherapy (HDT), LEED, and Autologous Stem-Cell Transplantation (ASCT) in Poor-Risk Diffuse Large B-Cell Lymphoma (DLBCL): Japan Clinical Oncology Group (JCOG) Study (JCOG0908)

Randomized Phase II Study of R-CHOP-14 Versus R-CHOP-14 Followed By Chaser As Induction Therapy for High-Dose Chemotherapy (HDT), LEED, and Autologous Stem-Cell Transplantation (ASCT) in Poor-Risk Diffuse Large B-Cell Lymphoma (DLBCL): Japan Clinical Oncology Group (JCOG) Study (JCOG0908)

Clinical Activity in a Phase 1 Study of Blu-285, a Potent, Highly-Selective Inhibitor of KIT D816V in Advanced Systemic Mastocytosis (AdvSM)

Clinical Activity in a Phase 1 Study of Blu-285, a Potent, Highly-Selective Inhibitor of KIT D816V in Advanced Systemic Mastocytosis (AdvSM)

Phase I/II Trial of Glasdegib in Heavily Pre-Treated Patients with Primary or Secondary Myelofibrosis

Background: Characterized by the clonal proliferation of bone marrow stem cells and myeloid progenitors, patients with myelofibrosis (MF) have hepatosplenomegaly, abnormal blood counts, bleeding or thrombosis, and suffer debilitating disease-related symptoms. In preclinical models of MF, inhibitors of the Hedgehog (Hh) pathway were shown to inhibit growth and self-renewal of bone marrow stem/progenitor cells that differentiate into cells of the myeloid lineage and to reduce splenic fibrosis. Glasdegib is a potent and selective oral inhibitor of the Hh pathway, acting through the inhibition of Smoothened. Expression of Hh target genes has been shown to be upregulated in granulocytes isolated from MF patients. Here we present recent data from the lead-in cohort of a single arm, open-label phase 1b/2 trial of glasdegib in MF.Methods: Patients ≥18 years with primary/secondary MF previously-treated with ≥1 Janus Kinase inhibitor (JAKi) were enrolled and received glasdegib 100 mg orally once daily until there was no further clinical benefit. Primary endpoints include adverse events and laboratory abnormalities, as graded by National Cancer Institute Common Terminology Criteria for Adverse Events v 4.03. Secondary endpoints include the proportion of patients with spleen volume reduction ≥35% and the proportion of patients with hematologic improvement. All 21 subjects in the lead-in cohort provided plasma samples for pharmacokinetic (PK) analysis, with 19 subjects providing evaluable glasdegib samples (at steady state) for the purposes of glasdegib PK analysis.Results: Between October 2014 and October 2015, 21 patients were enrolled in this ongoing study. Mean age was 69 years (range 58-83) and the median duration of treatment with glasdegib was 85 days (range 22-512). Of the 21 subjects, 52% (n=11) were refractory patients who had shown an inadequate response to prior JAKi treatment. A total of five patients achieved a reduction in spleen volume, with a maximum reduction from baseline of 2.3% to 32.9% (Fig A). One patient on study had a positive anemia response, showing improvement from Grade (G) 3 to G2 and became transfusion independent while on treatment. One patient also had an improvement in absolute neutrophil counts (from G2 to G0). Dysgeusia (n=13, 62%), muscle spasms (n=12, 57%), alopecia (n=8, 38%), decreased appetite, fatigue (n=7 each, 33%), increased lipase, decreased weight (n=5 each, 24%), nausea, pyrexia, hyperuricemia, anemia (n=4 each, 19%), asthenia, constipation, cough, dehydration, prolonged electrocardiogram QT, decreased lymphocyte count, myalgia, pain in extremity, thrombocytopenia, and upper respiratory tract infection (n=3 each, 14%) occurred in ≥10% of patients. Despite the high frequency of muscle spasms, there were no significant changes in creatine kinase; only one patient showing a G1 increase compared with baseline. Following administration of 100 mg daily oral dose of glasdegib for 15 days, at steady state, the peak plasma concentrations (Cmax) generally occurred at 1 hour post dose (Fig B). The geometric mean (%CV of geometric means) values for AUCtau and Cmax were 13150 ng.hr/mL (50%) and 996.8 ng/mL (45%), respectively (Fig C). The pre-dose concentrations (Ctrough) following daily dosing were consistent over multiple cycles, with geometric mean Ctrough values of 204.1 ng/mL, 176.1 ng/mL and 189.5 ng/mL respectively, on Cycle 1 day 15, Cycle 2 day 1 and Cycle 3 day 1.Conclusions: Although some toxicities were observed, these data highlight the potential for glasdegib in patients with primary/secondary MF previously treated with JAKi. Following oral administration of 100 mg oral glasdegib once daily to steady state, peak plasma concentrations generally occurred at 1 hour post dose and glasdegib exposures were consistent over multiple cycles of dosing. Modest clinical activity was seen in some patients. [Display omitted] DisclosuresGerds:CTI BioPharma: Consultancy; Incyte: Consultancy. Tauchi:Pfizer Inc: Research Funding. Ritchie:Novartis: Consultancy, Research Funding; Incyte: Honoraria; Celgene: Speakers Bureau; Pfizer Inc: Honoraria. Deininger:Gilead: Research Funding; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy, Research Funding. Jamieson:Johnson and Johnson: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding; Wintherix: Equity Ownership; Impact Biomedicines: Equity Ownership. Mesa:Novartis: Consultancy; Ariad: Consultancy; Galena: Consultancy; Incyte: Research Funding; Gilead: Research Funding; CTI: Research Funding; Promedior: Research Funding; Celgene: Research Funding. Heaney:Onconova Therapeutics: Research Funding; Novartis: Consultancy. Shaik:Pfizer Inc: Employment. Zhang:Pfizer Inc: Employment. DiRienzo:Pfizer Inc: Employment. Zeremski:Pfizer Inc: Employment. Chan:Pfizer Inc: Employment. Talpaz:Pfizer Inc: Consultancy, Other: Travel, Research Funding; ARIAD: Other: Travel, Research Funding.

Results from Enestgoal: A Phase 2 Study of Treatment-Free Remission (TFR) in Patients (pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Who Switched from Imatinib to Nilotinib

Results from Enestgoal: A Phase 2 Study of Treatment-Free Remission (TFR) in Patients (pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Who Switched from Imatinib to Nilotinib