POS0603 ANALYSIS OF FACTORS ASSOCIATED WITH THE EFFECTIVENESS OF ABATACEPT IN THE ORIGAMI STUDY

Background:The ORIGAMI study is a multicenter, observational study to evaluate the effectiveness, safety, and patient-reported outcomes of abatacept (ABA) in Japanese patients with csDMARD-resistant, Simplified Disease Activity Index (SDAI)-moderate, biologic-naïve rheumatoid arthritis (RA). ABA has shown better effectiveness/efficacy in RA patients with anti-cyclic citrullinated peptide antibody (ACPA) positive (1) and high ACPA titer (2) compared to ACPA negative and low ACPA titer, respectively. However, more accurate predictors of effectiveness in clinical practice are needed than ACPA status.Objectives:This post-hoc analysis is aimed to determine the association between ACPA and ABA effectiveness (disease activity and physical function) or retention rate and to investigate other factors associated with the effectiveness of ABA in patients enrolled in the ORIGAMI study.Methods:Of the 279 patients in the effectiveness analysis set of the ORIGAMI study, 270 patients with baseline ACPA measurement were analyzed. The patients were divided into the ACPA-positive group (ACPA +ve, ≥4.5 U/mL at baseline) and the ACPA-negative group (ACPA –ve, <4.5 U/mL). Patients’ characteristics, changes in disease activity and physical function (Japanese Health Assessment Questionnaire; J-HAQ) through 52 weeks, and retention rates of ABA at week 52 were evaluated. Baseline characteristics and use of concomitant drugs were analyzed as independent variables by multiple regression analysis using a standard linear model adjusted by SDAI at week 0 to identify factors associated with SDAI change at week 52. In addition, the interaction effects among ACPA status, RF status, and the factor that was significantly associated with SDAI change in multiple regression analysis on changes in SDAI were explored.Results:The numbers of ACPA +ve and –ve patients were 226 and 44, respectively. ACPA values (mean ± SD, U/mL) were 280.3 ± 376.8 and 0.9 ± 0.7, and rheumatoid factor (RF) values were 174.8 ± 302.6 and 20.9 ± 61.7 in the ACPA +ve and –ve groups, respectively. Mean (95% confidence interval) changes in SDAI at week 52 were −11.3 (−12.4 to −10.3) and −8.0 (−10.5 to −5.5), and those in J-HAQ were −0.27 (−0.34 to −0.20) and −0.16 (−0.34 to 0.01) in the ACPA +ve and –ve groups, respectively. In the Kaplan–Meier analysis, the retention rates of ABA at week 52 in the ACPA +ve and –ve groups were 72.1% and 58.7%, (discontinuation for any reason), and 91.6% and 75.7% (discontinuation because of lack of effectiveness), respectively. In a multiple regression analysis, the duration of disease (< 1 year) was associated with the change in SDAI at week 52. With respect to SDAI changes, the estimated difference of ACPA +ve and disease duration (< 1 year), ACPA +ve and disease duration (≥1 year), and ACPA –ve and disease duration (< 1 year), versus ACPA −ve and disease duration (≥ 1 year), were −4.26 (p = 0.022), −0.82 (p = 0.618), and −0.93 (p = 0.716), respectively (Fig. 1). The estimated difference of ACPA +ve and RF +ve, ACPA +ve and RF –ve, and ACPA –ve and RF +ve, versus ACPA –ve and RF –ve, were −2.48 (p = 0.060), −2.77 (p = 0.107), and −5.48 (p = 0.087), respectively.Conclusion:A higher retention rate as well as better effectiveness of ABA on disease activity and physical function in ACPA +ve group versus ACPA –ve group were shown in the simple subgroup analysis. ABA effectiveness on the SDAI change was significantly better in patients with disease duration <1 year and ACPA +ve compared to those with ACPA −ve and disease duration ≥ 1 year.References:[1]Harrold LR et al. J Rheumatol 2018;45(1):32–39.[2]Sokolove J et al. Ann Rheum Dis 2016;75(4):709–714.Disclosure of Interests:Kenta Misaki Speakers bureau: Eisai Co., Ltd., AbbVie GK, Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd., Grant/research support from: Ono Pharmaceutical Co., Ltd., Eiichi Tanaka Speakers bureau: AbbVie GK, Asahi Kasei Pharma Corporation, Astellas Pharma Inc, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kyowa Pharma Chemical Co., Ltd., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Pfizer, Takeda Pharmaceutical Co., Ltd, and Teijin Pharma Ltd., Eisuke Inoue Speakers bureau: Pfizer Japan, Bristol-Myers Squibb K.K., Katsuki Tsuritani Employee of: Bristol-Myers Squibb K.K., Shigeru Matsumoto Employee of: Ono Pharmaceutical Co., Ltd., Hisashi Yamanaka Consultant of: Bristol-Myers Squibb K.K., masayoshi harigai Speakers bureau: AbbVie GK, Ayumi Pharmaceutical Corporation, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Consultant of: AbbVie GK, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., and Gilead Sciences Inc., Grant/research support from: AbbVie GK, and Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Corporation, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd. Daiichi-Sankyo, Inc., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation., Nippon Kayaku Co., Ltd., Taisho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd.

Targeted Literature Review of Patient Reported Outcomes (PROs) in Chronic Myeloid Leukemia (CML) Patients Receiving Second and Later Lines of Treatment

Background: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic CML in the last several years; however, the failure rates associated with TKIs still remain high in second line (50%) and later lines (75%-80%) treatment. Also, patients often experience adverse events associated with these TKIs, but are often left with no alternative treatment in real world practice which might result in TKI cycling. There is a need to understand the quality of life (QoL) and symptom burden among these patients, in order to better manage their disease and also to explore new treatments. The objectives of this study were to summarize the PROs among patients with CML receiving 2nd/3rd/4th line (2L/3L/4L) treatment, and the instruments used for QoL and symptom burden assessment in clinical trials and real world studies. Methods: Embase, MEDLINE, and the Cochrane Library were searched using pre-defined search terms to identify studies published from 1/1/2010 to 6/15/2020. Following the title/abstract and full-text screening based on the inclusion/exclusion criteria (see Table), one reviewer independently extracted all relevant data with random quality check (~20% of the sample) by a 2nd reviewer. Included studies reported QoL, symptom burden, or any PROs of adult CML patients who received 2L/3L/4L treatment. Only clinical trials and observational studies published in English were included, including conference abstracts. Results: Database search identified 1,377 records, which were screened to identify 20 studies (5 observational studies and 15 clinical trial-based studies) that met eligibility criteria (see Figure). Of the included studies, 16 targeted chronic phase CML patients only. More than half of the studies (n=14) focused on patients receiving 2L treatment (bosutinib, dasatinib, or nilotinib) only, and six reported QoL data on patients receiving 2L/3L/4L treatment, out of which four studies reported results by line of therapy. Out of 15 studies reporting a follow-up period, 13 observed patients ≥ 12 months with a maximum of 24 months. The duration between observations were usually 12 weeks for observational studies; while shorter duration was observed in clinical trials. Six clinical trial-based studies were associated with one trial (NCT00261846). Instruments used to assess QoL included four generic instruments [Functional Assessment of Cancer Therapy - General (FACT-G), EuroQol 5 dimension (EQ-5D), 36-Item Short Form Survey (SF-36), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)], three disease specific instruments [Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu), MD Anderson Symptom Inventory chronic myeloid leukemia (MDASI-CML), Comprehensive Symptom Profile in Chronic Myeloid Leukemia Patients (CSP Leuk-CML)], one Work Productivity and Activity Impairment (WPAI) questionnaire, and two additional general questions on QoL. Ten studies applied both generic and disease specific instruments altogether to evaluate patients' QoL and symptom burden. For 2L TKI treatment, studies have shown improvement in QoL following treatment; however, one study indicated that although patients were content with their QoL, they reported poor symptom scores on mobility, usual activities, and pain/discomfort. Among four studies examining PROs by line of therapy, only one study reported results on the 4L cohort individually, which showed lowest baseline FACT-G and FACT-Leu score in the 4L cohort compared to other cohorts, especially in terms of the physical and emotional well-being domain. Discrepancies existed in QoL between 2L- and 3L cohorts. Two studies found QoL to be similar between the 2L- and 3L cohorts, while the other two observed the QoL was lower in the 3L cohorts. In addition, three reported that QoL scores remained stable throughout observation period regardless of the line of therapy, but one study demonstrated the utility score got improved in the 2L but not the 3L cohort. Conclusions: Evidence on PROs in CML patients receiving 3L/4L treatment is very limited, especially real-world data. Existing research indicates patients with CML receiving later lines of treatment may have poor quality of life. Robust real-world studies with longer follow-up period are needed to provide evidence on later lines treatment management among CML patients. Disclosures Zhang: Novartis Pharmaceutical Corporation: Current Employment. Maegawa:Novartis Pharmaceutical Corporation: Current Employment, Current equity holder in publicly-traded company. Patwardhan:Novartis Pharmaceutical Corporation: Current Employment, Current equity holder in publicly-traded company.

Real-World Treatment Patterns, Healthcare Resource Utilization and Associated Costs Among Patients with Chronic Myeloid Leukemia in Later Lines of Therapy

Introduction: Despite advances in tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML), there remains a sizeable proportion of patients (pts) with CML in chronic phase who are refractory or intolerant to these agents. A good understanding of the most recent real-world patterns of care in these pts is necessary in order to provide context for assessing the potential benefits of new treatments undergoing clinical development. The aim of this study was to evaluate treatment patterns in CML pts cycling through TKI therapies achieving later lines of therapy, and to estimate their healthcare resource utilization (HRU) and costs. Methods: Adult pts with CML in the United States who received at least 3 lines of TKI therapy were identified in the IBM MarketScan Commercial and Medicare Supplement databases (Q1/2001-Q2/2019). Treatment patterns were observed from CML diagnosis. Pt characteristics were measured during the 6 months prior to third line (3L) initiation (baseline period). All-cause HRU (inpatient [IP] admissions and days, days with outpatient [OP] services, and emergency department [ED] visits) and costs (medical and pharmacy) were measured 1) during the course of 3L therapy (from 3L initiation to termination) and 2) between 3L initiation and end of follow-up (stem cell transplant [SCT], or end of data availability/health plan coverage). HRU was reported using monthly incidence rates per 100 pts (IR/100pts); costs (2019 USD) were evaluated per-pt-per-month (PPPM) from a payer's perspective. Results: Of the 48,168 pts identified with CML, a total of 296 CML pts initiated 3L therapy; median age was 58.5 years (30% were aged ≥65 years) and 50% were female. The mean follow-up period from CML diagnosis was 57.8 months and from 3L initiation was 24.5 months. Most pts had their first CML diagnosis in or after 2010 (71%) and achieved 3L in or after 2014 (50%). At baseline, the mean modified Charlson Comorbidity Index score (excluding CML) was 1.6 with 24% of pts with a score ≥3, 64% of pts had a moderate or severe Darkow Disease Complexity Index, and the most prevalent comorbidities were hypertension (45%) and diabetes (25%); 21% of pts (i.e., ≥1 indicator of congestive heart failure, cirrhosis, or end-stage renal disease, or ≥75 years old). The most common sequences of TKIs from first line (1L) to 3L were imatinib → dasatinib → nilotinib (28%), imatinib → nilotinib → dasatinib (16%), imatinib → dasatinib → imatinib (9%), and dasatinib → imatinib → nilotinib (5%). The mean duration of 1L, second line (2L), and 3L therapy was 14.9, 10.4, and 15.6 months, respectively; 62% of pts were still in 3L at the end of follow-up. Only one patient received SCT after 3L. The most common TKIs received at each line were imatinib in 1L (65%), dasatinib in 2L (49%), and nilotinib in 3L (36%). The mean treatment-free period (time between line of therapy termination and next line initiation) between 1L and 2L was 1.3 months, 2.6 months between 2L and 3L, and 1.5 months between 3L and 4L. During 3L therapy, pts had a monthly IR/100pts of 3.4 IP admissions, 21.2 IP days, 248.8 OP days, and 10.2 ED visits (Figure 1A). Pharmacy costs accounted for 69% of the mean total costs of $15,192 PPPM, with medical costs accounting for the remainder (Figure 1B). In 3L therapy and later, pts had a monthly IR/100pts of 3.5 IP admissions, 28.7 IP days, 252.2 OP days, and 10.0 ED visits (Figure 1A). Pharmacy costs accounted for 49% of the mean total costs of $18,767 PPPM, with medical costs mainly driven by IP costs (Figure 1B). Conclusions: This study characterized CML pts receiving later lines of therapy, a clinical population which has not been previously well studied with important unmet treatment needs as they repetitively fail TKI therapy. Although the majority of pts were likely fit for SCT, SCT was rare. In addition, pts quickly switched to the subsequent line of therapy, both facts suggesting that an important proportion of pts were intolerant to previous TKIs. While pharmacy costs accounted for nearly half of the total cost burden during 3L, the proportion of medical costs PPPM took more importance following 3L therapy, with IP costs being the primary cost drivers for this increase. These findings support the need for better treatment options in pts with CML undergoing later lines of therapy. Disclosures Atallah: Novartis Pharmaceutical Corporation: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Research Funding; Abbvie: Consultancy; Genentech: Consultancy. Maegawa:Novartis Pharmaceutical Corporation: Current Employment, Current equity holder in publicly-traded company. Latremouille-Viau:Novartis Pharmaceutical Corporation: Consultancy, Other: Dominique Latremouille-Viau is an employee of Analysis Group, Inc. which received consultancy fees from Novartis.; Sanofi Genzyme: Consultancy, Other: Dominique Latremouille-Viau is an employee of Analysis Group, Inc. which received consultancy fees from Sanofi Genzyme.. Rossi:Novartis Pharmaceutical Corporation: Consultancy, Other: Carmine Rossi is an employee of Analysis Group, Inc. which received consultancy fees from Novartis.. Guerin:Abbvie: Consultancy, Other; Sanofi Genzyme: Consultancy, Other: Annie Guerin is an employee of Analysis Group, Inc. which received consultancy fees from Sanofi Genzyme.; Novartis Pharmaceuticals Corporation: Consultancy, Other: Annie Guerin is an employee of Analysis Group, Inc. which received consultancy fees from Novartis.. Patwardhan:Novartis Pharmaceutical Corporation: Current Employment, Current equity holder in publicly-traded company.

Major Adverse Cardiac, Arterial Occlusive, and Venous Occlusive Events Among Chronic Myeloid Leukemia Patients Prescribed Ponatinib Vs Bosutinib

INTRODUCTION: Chronic myeloid leukemia (CML) is a bone marrow and blood disorder accounting for 15% of adult leukemia. Tyrosine kinase inhibitors (TKIs) have been the standard of care for CML treatment. However, an association between TKI use and cardiovascular events has been observed. Ponatinib and bosutinib are introduced to provide more options for patients who failed their first-line treatment. The incidence of major adverse cardiac events (MACEs), arterial occlusive events (AOEs), and venous occlusive events (VOEs) were assessed among CML patients who were prescribed ponatinib vs bosutinib. METHODS: A retrospective observational study was conducted among adult CML patients aged ≥18 years with use of 1 or 2 prior TKIs who were prescribed bosutinib or ponatinib. Study patients were selected from the IBM® MarketScan® Research database from July 2012-June 2017. The index date was defined as the index drug prescription date, identified based on TKI use during the identification period (January 2013-December 2016) in a hierarchical order based on the sequence of treatment lines: ponatinib and bosutinib without ponatinib. Continuous health plan enrollment for ≥6 months pre-index date (baseline period) and at least 6 months post-index date (follow-up period) was required. Cardiovascular (CV) events (MACEs, AOEs, VOEs) using ICD-9/10-CM diagnosis codes occurring through the earliest of index TKI discontinuation, switch to another TKI, or end of follow-up period, were calculated as the number of events per 100 person-years (PYs). Inverse probability of treatment weighting (IPTW) was applied to adjust for differences in baseline characteristics between the treatment cohorts. Kaplan-Meier (KM) and Cox proportional hazard model analyses were conducted on the adjusted sample to examine any difference in CV event risk. RESULTS: After applying the selection criteria, 79 and 109 patients were included in the ponatinib and bosutinib cohorts, respectively. Mean ages were 53 years (ponatinib cohort) and 58 years (bosutinib cohort). The average Charlson Comorbidity Index (CCI) scores - defined by categorizing comorbidities using diagnosis codes - were 1.23 for ponatinib and 1.81 for the bosutinib cohort. Common baseline comorbid conditions included anemia (ponatinib: 49%; bosutinib 34%), hypertension (ponatinib: 33%, bosutinib: 46%), and diabetes (ponatinib: 15%; bosutinib: 29%). Some patients were observed to have CV events, specifically MACEs (ponatinib 8%; bosutinib 16%) and AOEs (ponatinib 15%; bosutinib 28%), before index ponatinib or bosutinib use. In the follow-up period, ponatinib patients were associated with a similar incidence of MACEs (14.70 vs 10.46 per 100 PYs; p=0.464), AOEs (29.56 vs 34.50 per 100 PYs; p=0.632), and VOEs (36.21 vs 34.70 per 100 PYs; p=0.890) compared to bosutinib patients. After applying IPTW, similar risks of the CV events (MACE, AOEs, VTEs) were observed in the KM analysis (Figure 1) expressed as time to CV event. After adjusting for additional confounders using Cox models, compared to those with bosutinib use, ponatinib patients were associated with similar rate of MACEs (Hazard Ratio [HR]: 1.02; 95% CI: 0.34, 3.01), AOEs (HR: 0.90; 95% CI: 0.43, 1.85), and VOEs (HR: 0.92; 95% CI: 0.44, 1.94). CONCLUSION: Among CML patients treated with ponatinib or bosutinib in second or third line, similar risks of cardiovascular events (MACE, AOEs, VTEs) were observed in the follow-up in this study in a community setting. Figure 1 Disclosures Levy: Takeda (Millennium Pharmaceuticals): Consultancy. Xie:STATinMED Research: Other: I am a paid employee of STATinMED Research which is a paid consultant to Takeda Pharmaceutical Corporation. . Wang:STATinMED Research: Other: I am a paid employee of STATinMED Research which is a paid consultant to Takeda Pharmaceutical Company. . Neumann:Millennium Pharmaceuticals (Takeda): Employment, Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Srivastava:Millennium Pharmaceuticals (Takeda): Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Naranjo:Millennium Pharmaceuticals (Takeda): Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Xu:Millennium Pharmaceuticals (Takeda): Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Zhang:STATinMED Research: Other: I am a paid employee of STATinMED Research which is a paid consultant to Takeda Pharmaceutical Corporation.. Dalal:Millennium Pharmaceuticals (Takeda): Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd.

ANTI-MICROBIAL RESISTANCE: AN OPPORTUNITY TO COLLABORATE

Dear Reader, Many of you would have noted the announcement of the establishment of a Centre by ICMR in New Delhi, in collaboration with a multinational pharmaceutical corporation to combat anti-microbial resistance (AMR). We see large full page advertisements with the words “AMR” in the front page of the daily news papers. These advertisements are the result of the efforts to draw the attention of all to the development of Anti-microbial resistance at a much faster pace than predicted. The action is noteworthy. However, it is difficult to comprehend how these advertisements will help to reduce AMR. While many more activities are being planned, it is hoped that the holistic approach being pursued will involve many more institutions and organizations. CDSCO has notified a separate schedule of drugs, Schedule H1 consisting of antibiotics, to ensure better prescription practices by medical professionals and the requirement that retailers maintain copies of the prescriptions served

OPEN INNOVATION AS A FACILITATOR FOR CORPORATE EXPLORATION

While open innovation is a management concept of increased attention in academia as well as in industry, studies have also shown that the implementation of open innovation can be a rather difficult and challenging process. Installed organisational structures, culture and knowledge are often portrayed as hinder for change. This study provides an in-depth case study, based on 50 interviews, of how a large pharmaceutical corporation implemented an open innovation initiative. Instead of considering existing internal knowledge and structures as problematic, these resources were rather utilised as cornerstones for value offerings in open innovation. Furthermore, employees’ engagement in open innovation resulted in a more open and dynamic climate, as well as an improved entrepreneurial image of the corporation internally as well as externally. The study contributes to the open innovation literature by advancing the understanding about the organisational implications of implementing open innovation in practice. As such, it provides valuable insights for researchers and practitioners about implementing open innovation in practice.

Ongoing Phase 1a/1b Dose-Finding Study of CWP232291 (CWP291) in Relapsed or Refractory Multiple Myeloma (MM)

Background: CWP291, a novel peptidomimetic small molecule, has potent and selective inhibitory activity on a Wnt gene reporter and decreases expression of the β-catenin target genes, cyclin D1 and survivin. It has broad anti-cancer efficacy in vitro, outperforming lenalidomide and bortezomib in multiple myeloma murine xenografts and demonstrating improved survival when used in combination with lenalidomide in bone marrow engraftment models. Methods: Subjects with relapsed or refractory MM were infused CWP291 iv over at least 30 minutes twice weekly for 3 weeks out of a 4-week cycle in a 3+3 dose-escalation, Phase 1 design. Results: Results as of July 15, 2016 over a dose range of 198 - 446 mg/m2 in 9 subjects are reported. Median duration of treatment was 3 cycles (range 1.3 - 6.5 cycles) with 3 subjects ongoing. The most common (>20% of subjects) drug-related adverse events (AEs) were due to GI toxicities, including diarrhea (77.8%), nausea (55.6%) and constipation (33.3%). Toxicity was mostly ≤grade 2, however grade 3/4 events were frequently related to myelosuppression, including neutropenia (33.3%), and anemia and thrombocytopenia (22.2% each). Serious adverse events were recorded for 5 subjects with 8 separate events: 6 events in 4 subjects considered unrelated were hospitalizations for pneumonia, and 2 events in 1 subject each considered possibly related were a urinary tract infection and grade 3 hypoxia. Dose-limiting toxicities occurred in 2 patients at 446 mg/m2, which were hypoxia (grade 3) and thrombocytopenia (grade 4). Accrual at 335 mg/m2 has now been initiated. Stable disease (≥3 months on therapy with no increase in M protein as per the IMWG) was seen in 4 subjects. There was also documentation of a 34.6% decrease in bone marrow plasma cells in one subject for whom a bone marrow aspirate was available. PK in the first 3 subjectsreceiving198 mg/m2showed plasma levels of the active metabolite had very little inter-patient variability, which were comparable to patients with AML receiving this same dose in another study. There was less than 4% excreted in the urine, and there was no evidence of accumulation from Day 1 to Day 18. Changes in targeted genes in blood and BM, as well as additional PK, will be provided from expanded and escalated dosing cohorts. Furthermore, preliminary observations in the Phase 1b part of this study, which combines the administration of CWP291 with lenalidomide and dexamethasone, will be reported. Conclusions: CWP291, a novel and first in class molecule with significant preclinical activity, shows single agent safety as well as early evidence of efficacy in subjects with MM. Accrual is ongoing to establish the optimal dose level for both single agent and combination therapy. Disclosures Hauptschein: JW Theriac Pharmaceutical: Employment. Choi:JW Pharmaceutical Corporation: Employment. Lee:JW Pharmaceutical Corporation: Employment.

Early Molecular Response (EMR) with Frontline Treatment Is a Significant Predictor of Long-Term BCR-ABL Transcript Levels in Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia (CML) in Chronic Phase

Background : An emerging goal of tyrosine kinase inhibitor (TKI) therapy for patients with CML is to achieve sustained deep molecular response. Several factors, such as efficacy and tolerability of therapy and patient or disease characteristics, may impact treatment success. In this study, the correlation between specified prognostic factors and predicted molecular response levels after 1 year of treatment with nilotinib (NIL) 300 mg twice daily or imatinib (IM) 400 mg once daily was evaluated. Methods : Datafrom the ENESTnd trial comparing frontline treatment with NIL vs IM, in which BCR-ABL1 transcript levels were assessed every 3 months by real-time quantitative polymerase chain reaction on the International Scale (IS), were used to develop a statistical regression model to predict the BCR-ABL1IS category of a patient at any time point after 1 year of therapy. Potential predictors investigated were treatment, EMR status (BCR-ABL1IS ≤ 10% at 3 months), gender, age, Sokal risk score, BCR-ABL1IS categories from the previous 2 assessments, and the proportion of previous BCR-ABL1IS observations at or below MR4. BCR-ABL1IS transcript levels for patients in the NIL and IM arms of ENESTnd were stratified into 5 clinically relevant categories: ≤ 0.0032% (MR4.5), > 0.0032% to ≤ 0.01% (MR4), > 0.01% to ≤ 0.1%, > 0.1% to ≤ 10%, and > 10%. The model was specified to be a second-order Markov chain (to accommodate previous BCR-ABL1IS transcript levels) with ordinal prediction values (for ordered BCR-ABL1IS categorical outcomes). Results : Overall, 522 patients (NIL, n = 258; IM, n = 264) were included in the model, which contributed 5950 usable observations of BCR-ABL1IS transcript levels with corresponding values from the 2 prior assessments. Achievement of EMR (P = .0007), proportion of previous BCR-ABL1IS observations at or below MR4 (P < .0001), and BCR-ABL1IS categories from the previous 2 assessments (both P< .0001) were significant predictors of BCR-ABL1IS category at any time after 1 year of treatment. In our model, neither Sokal risk score nor type of therapy was a significant predictor of BCR-ABL1IS category due to their high correlations with other factors included in the model and which are measured on treatment. For example, more patients in the NIL arm than in the IM arm achieved EMR (91% vs 67%, respectively), which accounted for a lack of model statistical significance for treatment type. Model predictions had good agreement with the observed trial data (Figure). Conclusion : Patients with CML who achieve EMR after initiating frontline TKI therapy have improved long-term treatment responses and survival outcomes. Our model also demonstrates that achievement of EMR is significantly associated with BCR-ABL1IS transcript levels after 1 year. These results add to the growing body of evidence that early response to TKI treatment should be carefully considered to ensure optimal long-term treatment success. Disclosures Saglio: Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis Pharmaceutical Corporation: Consultancy, Honoraria. Snedecor:Pharmerit International: Employment, Other: Institution received payment to conduct this study. Ji:Novartis Pharmaceuticals: Research Funding. Tai:Pharmerit International: Employment. Ray:Novartis Pharmaceutical Corporation/Rutgers University: Other: I am currently a fellow with Rutgers University, conducting my "field" experience at Novartis.. Mendelson:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Buchbinder:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Edrich:Novartis Pharma AG: Employment. Mahon:Novartis: Consultancy, Honoraria; Pfizer: Consultancy; ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria.