Pharmerit International Research Articles

Economic Burden of Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) in the US

Introduction: A majority of AML patients ultimately relapse after achieving remission or exhibit refractory disease. Some patients, e.g., those carrying FLT3 -ITD mutation or other risk factors, may relapse early, i.e., within 6 months of initial diagnosis. Limited data exist regarding the economic impact of R/R AML. The present study was conducted to assess the economic burden associated with R/R AML, including early relapse, among commercially insured US patients.Methods: Adults (≥18 years) with ≥2 independent claims of new AML diagnosis code not in remission or relapse (ICD-9-CM: 205.00) were identified from 2006-2016 in the QuintilesIMS Real-World Data Adjudicated Claims - US representing a large commercially insured US population. Included patients had continuous enrollment in a health plan for ≥6 months prior to and at ≥3 months after a new AML diagnosis and were longitudinally followed up until end of continuous enrollment or end of follow-up. Patients were categorized as R/R or non-R/R AML during the follow-up period, based on a validated algorithm (Earle et al, Med Care . 2002;40(8), IV-75), augmented by including ICD-9/-10 AML relapse diagnosis codes. R/R patients were further stratified as rapid progressors (RP) if the R/R event occurred within 6 months of first AML diagnosis. Healthcare resource utilization (HCRU) and costs were compared between: (1) R/R and non-R/R cohorts, and (2) RP and non-RP groups within the R/R cohort. HCRU was compared using adjusted incidence rate ratios (IRR) derived from multivariate generalized linear models (GLM) controlling for baseline demographic characteristics (age, sex, region, payer type) and Charlson comorbidity index (CCI), and was reported as the likelihood of using a defined healthcare resource over a patient month. The burden of total cost and its components was compared using mean total per patient per month (PPPM) healthcare costs to account for variable follow-up. The adjusted cost differences were derived from separate GLMs.Results: 5,274 newly diagnosed AML patients were included. Median age was 58 years, 52% were male, 12% had CCI ≥3, and median follow-up time was 16 months. Forty percent (2,088 out of 5,274) had R/R AML. Among R/R patients, the median (95% CI) time from AML diagnosis to R/R was 7.5 (7.4-7.8) months. Compared to non-R/R patients, R/R patients had 71% more transfusions (IRR: 1.71 [95% CI: 1.53-1.91]), 45% more hospitalizations (IRR: 1.45 [95% CI: 1.29-1.62]), 14% longer median days in hospital (IRR: 1.14 [95% CI: 1.05-1.24], 87% more outpatient visits (IRR: 1.87 [95% CI: 1.73-2.03]), and almost 3 times more hospice admissions (IRR: 2.70 [95% CI: 1.40-5.19]); all P <0.001. ER admissions were not significantly different (IRR: 1.19 [95% CI: 0.87-1.61]), P= 0.278. Unadjusted PPPM total costs were significantly higher for R/R vs non-R/R patients ($28,148 vs $25,077; adjusted difference of $3,368; P <0.001), with the main driver being hospitalizations ($16,867 vs $14,551; adjusted difference of $2,036; P <0.001). In the R/R cohort, RP patients had 44% more transfusions (IRR: 1.44 [95% CI: 1.23-1.68]), 62% more hospitalizations (IRR: 1.62 [95% CI: 1.37-1.92]), 92% longer median days in hospital (IRR: 1.92 [95% CI: 1.73-2.14]), 32% more outpatient visits (IRR: 1.32 [95% CI: 1.18-1.48]), 86% more ER admissions (IRR: 1.86 [95% CI: 1.16-2.99]), and over 3 times more hospice admissions (IRR: 3.11 [95% CI: 1.35-7.17]); all P <0.001, than non-RP patients. Unadjusted PPPM total costs were significantly higher in the RP versus non-RP patients ($38,755 vs $22,153; adjusted difference of $17,588; P <0.001), with the main driver being hospitalizations ($24,196 vs $12,725; adjusted difference of $11,427; P <0.001). See Table for cost components comparison.Conclusions: Compared to the non-R/R AML patients, the R/R patients experienced significantly higher monthly healthcare resources and costs. This economic burden was particularly high among those progressing early. Hospitalization was the key driver of this increased burden. Delaying relapse in rapidly progressing patients may reduce the burden to the health care system. [Display omitted] DisclosuresAly:Pharmerit International: Employment; Daiichi Sankyo, Inc.: Other: Grant; BMS: Other: Grant; Celgene: Other: Grant; Amgen: Other: Grant; AstraZeneca: Other: Grant; Pharmacyclics: Other: Grant; Celldex Therapeutics: Other: Grant. Bapat:Daiichi Sankyo, Inc.: Other: Grant; Pharmerit International: Employment. Ray:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Chen:Pharmerit International: Employment; Daiichi Sankyo, Inc.: Other: Grant. Botteman:Daiichi Sankyo, Inc.: Other: Grant; Pharmerit International: Employment.

Second Line Systemic Treatments Including Extracorporeal Photopheresis Among Patients with Chronic Graft Versus Host Disease (cGVHD) in the United States, 2009-2016

Introduction: Extracorporeal photopheresis (ECP) is a cell-based immunomodulatory therapeutic procedure approved by the FDA for cutaneous T-cell lymphoma (CTCL) among individuals who have not been responsive to other forms of treatment in the United States (US). As clinical evidence accumulated over the years, Centers for Medicare & Medicaid Services (CMS) issued several Medicare National Coverage Decisions (NCDs) for coverage of ECP in patients with acute cardiac allograft rejection or chronic graft versus host disease (cGVHD), who are, refractory to standard immunosuppressive drug treatment. In contrast, per British Committee for Standards in Haematology (BCSH) guidelines on treatment of cGVHD, ECP is recommended as the first option over other 2nd-line systemic treatments including rapamycin (mTOR) inhibitors, pentostatin, rituximab, and imatinib. The objective of this analysis was to describe real-world use of ECP in patients with cGVHD in the US between 2009 and 2016.Methods: A retrospective analysis was conducted using the Truven Health MarketScan® Commercial and Medicare Supplemental claims databases (2009-2016). Adult (≥18 years) cGVHD patients receiving 2nd-line systemic treatments, with continuous health plan enrolment 3 months prior to first cGVHD diagnosis (i.e., baseline period) and 6 months following the initiation of 2nd-line systemic treatment were included. Patient demographic and clinical characteristics were summarized by type of 2nd-line systemic treatment (ECP vs. non-ECP). In addition, treatment patterns including the time from cGVHD diagnosis to initiation of 2nd-line systemic treatment, duration of ECP treatment (ie, time from initiation to end of ECP treatment), and ECP use (proportion of patients receiving ECP treatment among those receiving 1 of the 5 2nd-line systemic treatments) by year were reported. Annual per person all-cause cost for cGVHD patients for emergency room (ER) visits, office visits, and inpatient visits incurred after receiving 2nd-line systemic treatment (ie, the follow-up period) were also reported.Results: Of the 3086 adult cGVHD patients, 663 (21.5% of patients with cGVHD) patients had ≥2 claims for 2nd-line systemic treatments, of which 464 met the continuous enrollment criterion and were included in the study (mean age=49.7 years; 60.1% males). The most commonly reported underlying conditions at baseline were bone marrow transplant (268 [57.8%]), stem cell transplant (280 [60.4%]) and CTCL (25 [5.4%]). The average time from first cGVHD diagnosis to initiation of 2nd-line systemic treatment was 5.4 months. Among patients receiving 2nd-line systemic treatments, 210 (45.3%) received ECP treatment for an average duration of 11.1 months. ECP and non-ECP patients were similar in terms of demographic and clinical characteristics, with organ transplant as the most common underlying condition during the baseline period. As the number of cGVHD patients increased from 16 in 2009 to 100 in 2016, ECP use increased from 31.3% in 2009 to 54.0% in 2016. The total annual all-cause per patient cost was $190,148, including $4619 for ER visits, $8,673 for office visits, and $176,856 for hospitalizations during the follow-up period.Conclusions: Results from the latest US commercial administrative claims data pointed to an increase rate of cGVHD between 2009 and 2016. Of the 464 study patients with cGVHD, 2nd-line systemic treatment was initiated 5.4 months following the first diagnosis of cGVHD. As the number of cGVHD patients increased the rate of ECP use increased over time as well. During the study period, ECP was used by 45.3% of study patients with average duration of 11.1 months. In addition, high economic burden was reported among cGVHD patients receiving 2nd-line systemic treatments. DisclosuresJoshi:Pharmerit International: Employment; Mallinckrodt Pharmaceuticals: Research Funding. Luo:Mallinckrodt Pharmacueticals: Research Funding; Pharmerit International: Employment. Huang:Mallinckrodt Pharmaceuticals: Employment. Mitri:Mallinckrodt: Employment. Lovelace:Mallinckrodt Pharmaceuticals: Employment. Pham:University of California, School of Pharmacy: Employment; Mallinckrodt Pharmaceuticals: Employment. Gao:Mallinckrodt Pharmaceuticals: Consultancy, Employment.

The Direct Medical Costs of Treatment Discontinuation Among Higher-Risk Myelodysplastic Syndrome Patients Receiving Hypomethylating Agents

Introduction: Non-persistence to treatment with hypomethylating agents (HMA) in higher-risk myelodysplastic syndrome (HR-MDS) patients can result in loss of response or ability to achieve a primary response. HMA treatment is recommended to be given to HR-MDS patients for least 4-6 treatment cycles to elicit a clinical response and premature termination is likely to result in poor outcomes and considerable healthcare spending. The study objective was to assess direct medical costs associated with HMA treatment non-persistence among HR-MDS patients. Methods: Using a retrospective cohort design, MDS patients with refractory anemia with excess blasts (RAEB) were analyzed using 2010-2016 Surveillance, Epidemiology and End Results-Medicare linked database. RAEB diagnosis is considered to substantially overlap with HR-MDS and has been used as a surrogate for HR-MDS. The study cohort included RAEB patients diagnosed between 01/2011 and 12/2015. Patients were included if they had ≥ 1 year of continuous Medicare enrollment prior to diagnosis and did not receive stem cell transplant or lenalidomide in the follow-up period. HR-MDS patients receiving HMAs were stratified into HMA persistent (receiving 4 or more HMA cycles without any gap of ≥90 days between cycles) and HMA non-persistent (receiving less than 4 cycles or a gap of ≥90 days between cycles) groups. Healthcare resource use (HCRU) and associated direct medical costs incurred during the follow-up period were described as per-patient-per-month (PPPM). To account for baseline differences between HMA persistent and non-persistent groups, propensity score-based inverse probability of treatment weights (IPTW) were calculated. Weighted HCRU and costs (PPPM) were further estimated using generalized linear models (GLMs). Costs were inflated to 2019 USD using medical component of consumer price index. Results: There were 664 patients identified with RAEB, of which 295 (44.4%) patients were classified in the HMA non-persistent group and 369 (55.6%) patients in the HMA persistent group. HMA persistent and non-persistent groups were similar in baseline demographic and clinical characteristics; however, non-persistent HMA users were older at diagnosis and a lower proportion of patients were married. Results from weighted GLM analysis indicated higher PPPM resource utilization in HMA non-persistent patients compared to HMA persistent patients specifically for hospitalizations (Incident rate ratio [IRR], 1.543, 95% Confidence interval [CI]: 1.181 - 2.018]), ER visits (IRR= 1.322, 95% CI: 1.146 - 1.524), SNF use (IRR = 2.158, 95% CI: 1.308 - 3.560), home health (IRR = 1.335, 95% CI: 1.039 - 1.714] and hospice care use (IRR = 2.555, 95% CI:1.972 - 3.309) (Table 1). Further, HMA non-persistent patients had significantly (P&amp;lt;0.05) higher total PPPM costs than HMA persistent patients ($18,039 vs. $13,893, p&amp;lt;0.05); particularly for hospitalizations ($3,375 vs. $2,131), and ER costs ($5,517 vs. $2,867) (Figure 1). Conclusions: A significant proportion of HR-MDS (RAEB) patients discontinue guideline-recommended HMA treatment. Non-persistence with HMA treatments was associated with substantial cost burden. The study findings call for closer care management by healthcare providers to ensure HMA treatment is completed as scheduled (unless directed otherwise by the provider) to manage outcomes and healthcare spending. Disclosures Joshi: Pharmerit International: Current Employment. Kale:Pharmerit International: Current Employment. Corman:Pharmerit International: Current Employment. Hill:Taiho Oncology: Current Employment, Current equity holder in publicly-traded company. Wert:Taiho Oncology: Current Employment, Current equity holder in publicly-traded company. Zeidan:Otsuka: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding; Leukemia and Lymphoma Society: Other; Epizyme: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Astex: Research Funding; CCITLA: Other; Takeda: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; BeyondSpring: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; MedImmune/Astrazeneca: Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding.

Patients' and Caregivers' Preferences for Different Hemophilia a Treatment Attributes

Introduction: The treatment landscape for hemophilia A has evolved since the introduction of extended half-life (EHL) factor/non-factor VIII products, which allows for treatment personalization as per individual need, such as a less frequent infusion schedule and increased protection. Many different treatment attributes (e.g. safety, efficacy, and treatment burden) can influence patients' and caregivers' decisions in their choice of treatment. We used a discrete choice experiment (DCE) to elicit preferences from hemophilia A patients and caregivers for the treatment attributes of new EHL/non-factor products. Methods: Adult patients and caregivers providing care for a young patient (&lt;18 years) were recruited via a hemophilia A patient panel to complete an online survey with 2 components: (1) sociodemographic and treatment experience; (2) DCE with 12 treatment choice questions. Each question required respondents to choose between 2 hypothetical treatment profiles varying in terms of 6 attributes (Figure): safety concerns with too much clotting, bleed protection, dosing frequency, length of time the product has been approved for use, product type, and joint health studies. These attributes were selected based on a targeted literature review, 10 in-depth interviews with patients and caregivers, and clinical expert input. The results from the qualitative work have been previously published. The DCE survey was pilot tested with patients (N=3) and caregivers (N=3) for comprehensibility and revised prior to data collection. We used random parameters logit models to estimate preference weights and relative attribute importance scores. Results: 113 patients (mean age: 35.5 years) and 96 caregivers (mean age of the child they cared for: 10.3 years) were included in the analysis. Among them, 88 patients (77.9%) self-reported having severe hemophilia while 81 (84.4%) caregivers reported that the child (&lt;18 years) they cared for had severe hemophilia. Of these, 43 patients (38.1%) and 37 caregivers (38.5%) reported that their child with hemophilia used EHL/non-factor products. Among both patients and caregivers, the attributes from most to least important were as follows: (1) no safety concerns with too much clotting; (2) reducing annual bleeds from 5 to 0; (3) reducing weekly dosing from 4 to 1; (4) longer length of time the product has been approved for use (&gt;6 years vs. &lt;1 year); (5) factor product (vs. non-factor product), and (6) having studies demonstrating joint health improvement (vs. no studies) (Figure). The importance assigned to dosing frequency and bleed protection depended on the extent of improvement. For example, patients and caregivers valued having studies demonstrating joint health improvement more than they valued (a) a small improvement in bleed protection (i.e., 1/year to 0/year), or (b) a small improvement in dosing frequency (i.e., 2/week to 1/week). Lastly, further stratified analysis by patient and caregiver subgroups showed that patients viewed dosing frequency as the most important attribute influencing their treatment choices while caregivers valued safety the most. Among those who were not currently using EHL/non-factor products, the majority were willing to switch to EHL/non-factor products (81.4% of both cohorts). Bleed protection and dosing frequency were the most common reasons cited by respondents willing to switch treatments. Conclusions: Besides safety, other attributes of products such as bleed protection and reducing dosing frequency had an important influence on hemophilia A patients' and caregivers' treatment choices in the DCE survey. The importance that patients and caregivers placed on these attributes also depended on the extent of bleed protection improvement or dosing reduction. Adult patients and caregivers making treatment decisions for their young patients may value dosing and safety of treatments differently. With more treatment options becoming available for people with hemophilia, it is important that patients and caregivers are well-informed about the comprehensive benefit-risk profile of different products to make the most optimal decisions to improve their current treatment and outcomes. Figure Disclosures Joshi: Pharmerit International: Employment. Ng:Pharmerit International: Employment. Botteman:Alnylam Pharmaceuticals: Consultancy; Pharmerit International: Employment, Equity Ownership; Daiichi Sankyo: Consultancy, Research Funding. Li:Bioverativ, a Sanofi Company: Employment. Shah:Pharmerit International: Employment. Jain:Sanofi Genzyme: Employment, Equity Ownership. Lyn:Sanofi Genzyme: Employment. Su:Sanofi Genzyme: Employment, Equity Ownership.

Quality-Adjusted Survival for Low-Dose Cytarabine (LDAC) Versus Glasdegib+LDAC Among Newly Diagnosed Acute Myeloid Leukemia Patients Who Are Not Candidates for Intensive Chemotherapy: A Q-TWiST Analysis

Introduction: The efficacy and safety of glasdegib (a selective oral inhibitor of hedgehog signaling pathway) in combination with low-dose cytarabine (LDAC) was evaluated in a randomized, phase 2 trial of newly diagnosed acute myeloid leukemia (AML) patients (BRIGHT AML 1003; NCT01546038). Patients receiving glasdegib+LDAC experienced statistically significant and meaningful gains in overall survival (OS) compared with patients receiving LDAC alone (median OS [95% CI]): 8.3 months [4.7-12.2] vs 4.3 months [1.9-5.7]). This analysis examined whether quality-adjusted survival improvements were similarly observed using a quality-adjusted time without symptoms of disease progression or toxicities (Q-TWiST) approach to evaluate possible trade-offs between time with adverse events (toxicities), time in relapse/progression (i.e., with symptoms of disease), and 'good' survival (i.e., time without toxicities or symptoms of progression [TWiST]) when comparing regimens. Methods: OS in BRIGHT AML 1003 data, restricted to a follow-up of 20 months, was partitioned into time with toxicity (TOX: grade 3+ adverse events prior to progression), TWiST, and time post-progression (REL). Progression was defined as treatment discontinuation due to insufficient clinical response or death; patients who discontinued for other reasons (including adverse events) were censored at the date of discontinuation unless death occurred within 28 days of discontinuation. Q-TWiST was calculated by multiplying restricted mean time in each state by respective utilities (U) and then summing up the utility-adjusted time. Base case analysis used U(TOX)=U(REL)=0.5 and U(TWiST)=1.0; threshold analyses were performed varying U(TOX) and U(REL) jointly each from 0 to 1. Relative gains in Q-TWiST (i.e., Q-TWiST difference (combination vs LDAC) / OS in LDAC arm) of ≥15% were considered clearly clinically meaningful per the clinical literature. Sensitivity analysis varied the length of follow-up and AE definitions; subgroup analyses were also performed. 95% confidence intervals were obtained using the bootstrap procedure. Results: At 20 months of follow-up, the survival rate for glasdegib+LDAC and LDAC arm was 28.2% and 7.9%, respectively. Glasdegib+LDAC patients (n=78) compared with LDAC patients (n=38) had significantly longer mean time in TWiST (+3.4 [95% confidence interval: 1.8, 5.2] months) and TOX (+0.8 [0.1, 1.6] months), and longer but non-significant REL (+0.3 [-1.9, 2.3] months). Q-TWiST was 4.0 [2.1, 5.8] months longer for glasdegib+LDAC, translating into a 75% relative improvement in quality-adjusted survival relative to LDAC alone. In threshold analyses, absolute and relative Q-TWiST gains ranged from 3.5 to 4.5 months and 66% to 85%, respectively (Table 1). They exceeded the clinically meaningful threshold for gains in Q-TWiST and were statistically significant across all combinations of U(TOX) and U(REL). Results were robust to length of follow-up 6 to 24 month and remained significant when including all adverse events regardless of grade. Discussions/Conclusions: Glasdegib+LDAC is an add-on therapy that has demonstrated significant survival benefits for newly diagnosed AML patients who are unable to receive intensive chemotherapy. While patients can experience a longer time with toxicities from receiving glasdegib+LDAC (as expected since it is given as an add-on therapy), the trade-off can still be favorable as the treatment provides added time spent in 'good' health (i.e., a significantly longer time in TWiST). In the BRIGHT AML 1003 cohort, the relative gains in OS greatly exceeded previously established thresholds for being clearly clinically meaningful, which suggests that the benefits of glasdegib+LDAC vs LDAC alone outweigh the risks. Table 1 Disclosures Kwon: Pfizer Inc.: Research Funding; Pharmerit International: Employment. Bell:Pfizer Inc.: Employment, Equity Ownership. Solem:Pharmerit International: Employment; Pfizer Inc.: Research Funding. Cappelleri:Pfizer: Employment, Equity Ownership. Johnson:Pfizer Inc.: Research Funding; Pharmerit International: Employment. Bhattacharyya:Pfizer Inc: Employment, Equity Ownership. Hoang:Pfizer Inc.: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

Quality-Adjusted Time without Symptoms or Toxicity (Q-TWiST) Analysis of Quizartinib Vs Salvage Chemotherapy in Patients with Relapsed/Refractory (R/R) FLT3-ITD Acute Myeloid Leukemia (AML)

Quality-Adjusted Time without Symptoms or Toxicity (Q-TWiST) Analysis of Quizartinib Vs Salvage Chemotherapy in Patients with Relapsed/Refractory (R/R) FLT3-ITD Acute Myeloid Leukemia (AML)

687P - Evaluation of minimal important difference (MID) for the European organisation for research and treatment of cancer (EORTC) pancreatic cancer module (PAN26) in patients with surgically resected pancreatic adenocarcinoma

BackgroundPAN26 was developed as a supplement to the EORTC QLQ-C30 to assess pancreatic cancer–specific health-related quality of life (HRQoL) issues. Despite its use in clinical trials, PAN26 MID has not been established. In undertaking the most comprehensive evaluation to date of PAN26’s measurement properties in patients with surgically resected pancreatic cancer receiving adjuvant therapy, we used distribution-based minimum detectable change (MDC) and anchor-based methods to determine PAN26 scale MIDs using the data collected during the Adjuvant Pancreatic Adenocarcinoma Clinical Trial (APACT).Table687P PAN26 anchor (QLQ-C30 overall health) and distribution-derived MIDTableScale/ItemAnchorDistributionEstimateSE1/2 BLSDSEMAltered bowel habit–a12.511.8Body image6.40.313.113.5Digestive symptoms6.00.313.416.2Hepatic– a7.611.4Pancreatic pain5.60.29.79.7Satisfaction with health care– a12.115.3Sexual dysfunction5.40.417.319.7Bloated4.90.312.815.9Dry mouth5.10.313.415.6Gas– a14.516.2Indigestion4.80.312.815.7Limited activities8.00.315.421.7Low weight5.30.314.820.5Taste different7.50.313.619.7Troubled by tx adverse events8.80.312.615.8Weak arms/legs9.10.313.115.7Worried about future health6.30.315.516.3BLSD, baseline standard deviation; SE, standard error; SEM, standard error of measurement (based on intraclass correlation).aLow r (< 0.3) with overall health. MethodsPAN26 and QLQ-C30 scores were assessed in 12-week intervals at screening (BL), middle and end of treatment, and up to 2.5 years of follow-up. MDC values were calculated via BL standard deviation (SD) and reliability-biased standard error of measurement approaches. Anchor-based values were determined via a linear mixed model in which QLQ-C30 overall health (OH; Item 29) served as a serial patient global impression of severity anchor for predicting PAN26 scores. Pattern-mixture models (PMM) were fit to assess the impact of attrition on estimates. ResultsMDC values were in the 12 to 15 range (Table). These findings were consistent with SD-based values inferred from earlier studies, although our results extended to standalone items. Anchor-based MIDs were almost twice as sensitive as MDC, with values in the 5 to 9 range (PMM values almost identical). Anchor values could not be inferred for the PAN26 bowel, hepatic, and healthcare scales and gas item due to their low (r<0.30) correlation with OH. ConclusionsThe MID estimates for PAN26 subscales can help clinicians and researchers interpret the changes in HRQoL and determine sample sizes in the design of future clinical trials. Editorial acknowledgementPharmerit International. Legal entity responsible for the studyThe authors. FundingCelgene Corporation. DisclosureM. Reni: Non-remunerated activity/ies, Personal Fees: Celgene, Baxalta, Shire, Eli Lilly, Pfizer, Novocure, Novartis, AstraZeneca. J. Braverman: Full / Part-time employment: Celgene Corporation. T. Macarulla Mercade: Honoraria (self): Roche, Sanofi, Tesaro, Shire, Genzyme; Advisory / Consultancy: Baxalta, Celgene, H3B, QED, Shire; Speaker Bureau / Expert testimony: Celgene, Sanofi/Aventis, Shire; Research grant / Funding (self): Agios, Aslan, AstraZeneca, Bayer, Celgene, Genetech, Hallozyme, Immunomedics, Lilly, Merimarck, Millennium, Novartis, Novocure, Pfizer, Pharmacyclics, Roche; Travel / Accommodation / Expenses: Bayer, H3B, Merck, Sanofi. D. Oh: Advisory / Consultancy: Genentech/Roche, AstraZeneca, Novartis, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks; Research grant / Funding (institution): AstraZeneca, Novartis, Array, Eli Lilly. H. Riess: Non-remunerated activity/ies, Personal Fees: Celgene, Roche, Shire. M.A. Tempero: Advisory / Consultancy: AbbVie, Advance Medical, BioPharm Communications, BMS, Celgene, Eisai, Ignyta, Pharmacyslics, Pharmcyte Biotech, Tocagen; Advisory / Consultancy: AstraZeneca, CPRIT, Immunovia; Research grant / Funding (institution): Halozyme. B. Lu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Celgene Corporation. J. Marcus: Full / Part-time employment: Pharmerit international; Advisory / Consultancy, Research grant / Funding (self): Celgene Corporation. N. Joshi: Full / Part-time employment: Pharmerit International; Advisory / Consultancy: Celgene Corporation. M. Botterman: Honoraria (institution): Celgene, Bayer, Daiichi, BMS. All other authors have declared no conflicts of interest.

684P - Impact of adjuvant treatment with nab-paclitaxel and gemcitabine (nab-P+GEM) vs gemcitabine alone (GEM) on health-related quality of life (QoL) in patients (pts) with surgically resected pancreatic adenocarcinoma (PA) in the adjuvant pancreatic adenocarcinoma clinical trial (APACT)

684P - Impact of adjuvant treatment with nab-paclitaxel and gemcitabine (nab-P+GEM) vs gemcitabine alone (GEM) on health-related quality of life (QoL) in patients (pts) with surgically resected pancreatic adenocarcinoma (PA) in the adjuvant pancreatic adenocarcinoma clinical trial (APACT)

Real-World Differences in Characteristics and Survival of Relapsed AML Patients with and without Transplant

Background: Some AML patients, particularly those relapsing rapidly, may not get a chance to receive a potentially curative stem cell transplant (SCT) due to early death, among other reasons. This study compares the differences in characteristics and survival of relapsed AML patients with and without SCT, as observed in a real-world setting.Methods: Relapsed AML patients aged 66-75 years were identified from the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database by medical claims associated with ICD-9 code 205.02 (2009-2014). Patients were followed from relapse to the earliest of death, SCT, or end of follow-up. Baseline characteristics were compared between relapsed AML patients with and without SCT. The SCT rates were estimated after adjusting for the competing risk of death. The Fine and Gray method was used to identify predictors of receiving SCT and were reported in terms of sub-distribution hazard ratios (SHR) and 95% confidence intervals (CI). Kaplan-Meier estimates (reported in terms of median and 6-, 12-, and 24-months survival rates, tested with a log Rank test statistic) and a Cox proportional hazards model adjusting for age, sex, race, Census region, marital status, urban location, Charlson comorbidity index (CCI), and diagnosis year (reported in terms of hazard ratios (HR) and 95% CI) was used to assess the difference in survival between patients with and without SCT.Results: Of the 474 relapsed AML patients (median age, 70 years, median follow up, 4.4 months, male, 55%) included in the study, 8% received SCT, 80% died without having SCT and 12% were administratively censored. Patients were less likely to receive SCT if they were 71-75 years old (SHR 0.28, 95% CI (0.19 to 0.41; P <.001) and had higher comorbidity with CCI >3 (SHR 0.16, 95% CI (0.06 to 0.44; P <.001). The median overall survival was 16.1 months for patients with SCT vs. 4.1 months for those without SCT (log rank P <.001; adjusted HR 0.52, 95% CI (047 - 0.57; P <.001)). The 6-, 12-, and 24-month overall survival for all relapsed AML patients was 42%, 26%, and 12%, respectively. For patients with SCT, the 6-, 12-, and 24-month overall survival was 84%, 59%, and 43%, respectively. For patients without SCT, the 6-, 12-, and 24-month overall survival was 39%, 23%, and 12%, respectively.Conclusions: Relapsed AML patients who received SCT experienced significantly longer survival compared to those who did not receive SCT in this elderly study population. However, only 8% of all relapsed AML patients received SCT. Therapies that bridge more patients to SCT are expected to improve overall survival in this high unmet need population. DisclosuresAly:AstraZeneca: Research Funding; Celgene: Research Funding; BMS: Research Funding; Pharmerit International: Employment, Research Funding; Daiichi Sankyo Incorporated: Research Funding. Ray:Daiichi Sankyo Incorporated: Employment, Equity Ownership. Shah:Celgene: Research Funding; Pharmerit International: Employment, Research Funding; Daiichi Sankyo Incorporated: Research Funding; BMS: Research Funding. Botteman:Daiichi Sankyo Incorporated: Research Funding; BMS: Research Funding; Celgene: Research Funding; Pharmerit International: Employment, Equity Ownership, Research Funding; Bioverativ: Consultancy, Other: Provided consulting to Bioverativ, Research Funding.

Evaluating Time to Pain Progression in Multiple Myeloma

Patient-reported outcomes (PROs) are increasingly assessed as part of trials for new medical treatments for multiple myeloma. Pain, particularly bone pain, is an important symptom for patients with myeloma. Although time to pain progression has been evaluated as an endpoint in prostate cancer trials, this endpoint has yet to be applied in multiple myeloma despite the importance of this symptom. We sought to evaluate key issues for defining time to pain progression endpoints using two trials of anti-myeloma products submitted to the FDA.We combined data from two trials, each of which used the 0-10 point worst pain intensity numeric rating scale (0=best, 10=worst) from the Brief Pain Inventory (BPI). We evaluated changes of +1 to +5 points from pre-treatment baseline as deterioration thresholds. We considered deterioration events to be durable if patient scores did not improve by the threshold at the next visit. Event timing and frequency were evaluated using descriptive statistics. Opioid analgesia and pain-relieving procedures such as palliative radiotherapy were also assessed.We evaluated data from 1,368 patients in the pooled intention-to-treat (ITT) populations. At lower threshold levels (+2 to +3 points), 37 - 49% of patients experienced deterioration events. Of the patients with deterioration at lower threshold levels (+2 to +3 points), 39% - 44% had durable deterioration. Deterioration was less durable at higher threshold levels (+4 to +5 points), where 28% - 33% of patients with deterioration had durable deterioration. Additionally, fewer patients had deterioration events at higher threshold levels (16% - 25%). However, even if patients improved by the next visit and did not have durable deterioration, they often deteriorated again at a later timepoint; at a threshold of +5 points, >40% of patients experienced a second deterioration of +5 points after improving.Among those patients who deteriorated but then subsequently improved, pain relief through either opioid analgesia or pain-relieving procedures was used by 52% - 63% in the ITT population. For patients with minimal pain (score of <=4) or no pain (score of 0) at baseline, pain-relieving measures were used less frequently at lower deterioration thresholds (<50% of patients in either population for thresholds of +1 to +3), but more frequently at higher deterioration thresholds (47% - 62%).In conclusion, lower deterioration thresholds result in more frequent and durable events. However, patients often deteriorate, improve, and then deteriorate again. As patients may remain on clinical trials for long periods, researchers interested in assessing time to the first (durable) deterioration should clearly justify this approach. Additionally, the assessment of deterioration durability may be complicated by measures such as the use of opioid analgesia, vertebroplasty, and palliative radiotherapy. As pain is an important myeloma symptom and capturing the patient's experience while on therapy is critical, further research to better characterize patient pain while on trial is needed. DisclosuresKing-Kallimanis:Pharmerit International: Employment.

Economic Impact of Immune Tolerance Induction (ITI) with Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) Compared to Conventional Recombinant Factor VIII (rFVIII)

Introduction:Hemophilia A results from a clotting protein factor VIII (FVIII) deficiency, which leads to the need for the use of exogenous FVIII. Such therapy is effective unless alloantibodies (inhibitors) develop and render FVIII replacement ineffective. Patients with high-titer inhibitors may try to eradicate the presence of these inhibitors by undergoing ITI, an often costly process that requires the prolonged use of frequent doses of FVIII to induce FVIII antigen-specific tolerance. There is no consensus on the best approach to achieve tolerance and no product has been approved by any regulatory agency for ITI treatment in hemophilia A patients with inhibitors. The Fc portion of rFVIIIFc has shown immunomodulatory properties in mice, and chart reviews and case reports suggest that tolerization with rFVIIIFc in first-attempt ITI patients can potentially be achieved rapidly (i.e., ≤18 months) and therefore may possibly offer cost savings compared to conventional rFVIII. This analysis assessed the economic consequences and budget impact of using rFVIIIFc vs. conventional rFVIII for first-attempt immune tolerance induction (ITI) in hemophilia A patients with inhibitors.Methods:A literature-based model was developed to estimate the effect of rFVIIIFc vs conventional rFVIII on drug cost of first-attempt ITI, based on modelled ITI duration and outcome (rates and time to ITI success or failure) for US patients with varying clinical profiles (e.g., historical peak titer, FVIII dose) over a 3-year period. In the model, at any given time after ITI initiation (on either rFVIIIFc or rFVIII), a patient was categorized as ongoing ITI, post-ITI as success, or post-ITI as failure. The duration and outcomes for patients treated with rFVIIIFc ITI were based on observed data for first-attempt ITI patients with varied clinical profiles and ITI regimens from in chart reviews and case reports (n = 9). In the absence of direct head-to-head observations, the duration and outcome of ITI for the exact same patients in a scenario in which they received rFVIII (instead of rFVIIIFc) at the same doses were estimated indirectly using a previously published regression model (Bojke et al. 2009, Value in Health, 12(7), A378-A379) based on data for 113 patients from international and national registries that adjusts for historical and pre-ITI titer levels, time from inhibitor diagnosis to ITI start, and ITI factor dose. To place the cost comparison results in the perspective of a third-party US payer, a budget impact analysis was undertaken on a population of typical hemophilia A patients (after adjusting for patient characteristics) who are embarking on first-attempt ITI in a plan of 10 million insured members. In this analysis, the number of patients starting ITI each year was assumed constant, and patients who successfully eradicated inhibitors with ITI would transition back to FVIII prophylaxis.Results:The model predicted that, compared to rFVIII, rFVIIIFc would result in a reduction in estimated time to ITI success (rFVIIIFc: 9.43 months, rFVIII: 16.80 months), increased success probability at 20 months (rFVIIIFc: 67%, rFVIII: 25%), and lower 3-year per-patient costs (rFVIIIFc: $1,709,000, rFVIII: $3,630,000), respectively. In the budget impact analysis for a US health plan of 10 million insured members, 11.2 patients were expected to be newly diagnosed hemophilia A patients, among whom 1.17 patients were expected to develop inhibitors to FVIII and initiate ITI each year. By year 3, the predicted number of successful ITI patients increased by 23% and the budget savings for the plan were $103,738 per patient per year (for the ~1 patient who started ITI each year) after the inclusion of rFVIIIFc for ITI and subsequent prophylaxis when patients successfully eradicated inhibitors.Conclusions:Based on this mathematical economic model of first-attempt ITI patients, the modeled faster time to tolerization with rFVIIIFc vs. rFVIII, resulted in estimated per-patient and overall budget savings in ITI from a US payer perspective. Current prospective studies (e.g. verITI-8) will provide additional evidence on the efficacy of rFVIIIFc for ITI in Hemophilia A patients with inhibitors. DisclosuresLi:Bioverativ: Employment. Wilson:SOBI: Employment. Botteman:Daiichi Sankyo Incorporated: Research Funding; BMS: Research Funding; Pharmerit International: Employment, Equity Ownership, Research Funding; Celgene: Research Funding; Bioverativ: Consultancy, Other: Provided consulting to Bioverativ, Research Funding. Nicoloso:Bioverativ: Other: an employee of Pharmerit, which provided consulting to Bioverativ. Krishnan:Bioverativ: Employment. Su:Bioverativ: Employment.

Real-World Health Care Costs Based on Medication Adherence and Risk of Stroke and Bleeding in Patients Treated with Novel Anticoagulant Therapy.

With the lack of real-world evidence, the challenge for drug reimbursement policy decision makers is to understand medication adherence behavior among users of novel oral anticoagulants (NOACs) and its effect on overall cost savings. No study has examined and quantified the burden of cost in high-risk patients taking NOAC therapy. To examine the association of cost with adherence, comorbidity, and risk of stroke and bleeding in patients taking NOACs (rivaroxaban and dabigatran). A retrospective cohort study used deidentified data from a commercial managed care database affiliated with Optum Clinformatics Data Mart (January 1, 2010-December 31, 2012). Patients aged 18 years and older with ≥ 1 diagnosis of atrial fibrillation/flutter, > 1 NOAC prescription, 6-month pre-index and 12-month post-index continuous enrollment, and CHA2DS2-VASc score ≥ 1 were included. Adherence was calculated using proportion of days covered (PDC ≥ 80%) over an assessment period of 3, 6, and 12 months and compared based on level of comorbidity, stroke, and bleeding risk. The adjusted annual health care costs per patient (drug, medical, and total) were calculated using multivariable gamma regression controlling for demographic and clinical characteristics and compared across groups based on adherence over 12 months, baseline level of comorbidity, and risk of stroke and bleeding. Of 25,120 NOAC patients, 2,981 patients were included in the final cohort. Based on a PDC threshold of ≥ 80%, the adherence rate over 3, 6, and 12 months was 72%, 65%, and 54%, respectively. For all time periods, the level of adherence significantly increased (P < 0.001), with an increase in stroke risk (based on CHA2DS2VASc scores of 1, 2-3, and 4+); comorbidity (Charlson Comorbidity Index scores of 0, 1-2, and 3+); and risk of bleeding (HAS-BLED scores of 0-1, 2, and 3+). Adjusted all-cause total cost calculated for a 12-month period was significantly lower ($29,742 vs. $33,609) among adherent versus nonadherent users. Drug cost was higher ($5,595 vs. $2,233) among adherent versus nonadherent patients but was offset by lower medical costs ($23,544 vs. $30,485) costs. The overall cost significantly increased for patients with a high risk of bleeding and a high level of comorbidity. Adherence to NOAC therapy led to a reduction in overall health care cost, since higher drug costs were offset by lower medical (inpatient and outpatient) costs among adherent patients. Cost information based on adherence and risk of stroke and bleeding can help formulary decision makers to assess risk-benefit and help clinicians in developing interventions to reduce patient burden. Funding to acquire the data source was provided by the University of Rhode Island College of Pharmacy, Kingston, to support PhD dissertation work. Deshpande is currently an employee of Pharmerit International.

The Importance of Economic Perspective and Quantitative Approaches in Oncology Value Frameworks of Drug Selection and Shared Decision Making.

No funding was received for conceptualizing, writing, and/or editing this manuscript. Waldeck and White are employees of, and received stock option grants from, Celldex Therapeutics. Van Hout and Botteman are employees and shareholders of Pharmerit International. Pharmerit International is a research contractor for Celldex. All authors have retained editorial control of the content of the manuscript. Conceptualization of this viewpoint article was contributed primarily by Waldeck, along with Botteman, White, and van Hout. Data analysis and revision of the manuscript was contributed equally by all the authors. The manuscript was written by Waldeck, Botteman, van Hout, and White.

Budgetary Impact of Cabazitaxel Use After Docetaxel Treatment for Metastatic Castration-Resistant Prostate Cancer.

With the approval of several new treatments for metastatic castration-resistant prostate cancer (mCRPC), budgetary impact is a concern for health plan decision makers. Budget impact models (BIMs) are becoming a requirement in many countries as part of formulary approval or reimbursement decisions. Cabazitaxel is a second-generation taxane developed to overcome resistance to docetaxel and is approved for the treatment of patients with mCRPC previously treated with a docetaxel-containing regimen. To estimate a 1-year projected budget impact of varying utilization rates of cabazitaxel as a second-line treatment for mCRPC following docetaxel, using a hypothetical U.S. private managed care plan with 1 million members. A BIM was developed to evaluate costs for currently available treatment options for patients with mCRPC previously treated with docetaxel. Treatments included in the model were cabazitaxel, abiraterone acetate, enzalutamide, and radium-223, with utilization rates derived from market research data. Medication costs were calculated according to published pricing benchmarks factored by dosing and duration of therapy as stated in the prescribing information for each agent. Published rates and costs of grade 3-4 adverse events were also factored into the model. In addition, the model reports budget impact under 2 scenarios. In the first base-case scenario, patient out-of-pocket costs were subtracted from the total cost of treatment. In the second scenario, all treatment costs were assumed to be paid by the plan. In a hypothetical 1 million-member health plan population, 100 patients were estimated to receive second-line treatment for mCRPC after treatment with docetaxel. Using current utilization rates for the 4 agents of interest, the base-case scenario estimated the cost of second-line treatment after docetaxel to be $6,331,704, or $0.528 per member per month (PMPM). In a scenario where cabazitaxel use increases from the base-rate case of 24% to a hypothetical rate of 33%, the PMPM cost would decrease to $0.524, reflecting a cost saving of $0.004 PMPM and equating to incremental savings of $49,546, or $497 per patient per year (PPPY). In the second scenario, when out-of-pocket costs were not considered, the cost of second-line treatment after docetaxel was estimated as $6,733,594, or $0.561 PMPM. With a hypothetical increase in cabazitaxel use (24%-33%), the PMPM cost would decrease to $0.554, reflecting savings of $0.007 PMPM and equating to incremental savings of $86,136, or $864 PPPY. The primary driver of cost savings with increased cabazitaxel use was lower acquisition cost. One-way sensitivity analyses revealed that the model results were robust over a wide range of input values (utilization, prevalence, and population parameters). In the presented BIM, an increase in cabazitaxel use is expected to result in modest cost savings to the health plan. Patient coinsurance savings may also be realized based on applicable Medicare Part B and Part D calculations. This BIM presents an objective, comprehensive, robust, and user-adaptable tool that health plans and medical decision makers may use to evaluate potential economic impact of formulary and reimbursement decisions. Research and analysis were funded by Sanofi US. The sponsor had the opportunity to review the final draft; however, the authors were responsible for all content and editorial decisions. Flannery, Drea, Hudspeth, and Miao are employees of Sanofi. Miao is an owner of stock in Sanofi. Corman, Gao, and Xue are employees of Pharmerit International and served as consultants to Sanofi during this study. All authors contributed to study design and data collection and analysis. The manuscript was written by Flannery, along with the other authors, and revised by all the authors.

Attainment of Complete Remission Is Significantly Associated with Longer Survival Outcomes in Relapsed/Refractory (R/R) CLL: A Meta-Analysis

Introduction: Chronic lymphocytic leukemia (CLL) is an incurable, indolent neoplasm of B lymphocytes, associated with a heterogeneous clinical course. Complete response (CR) with or without minimal residual disease in first-line chemoimmunotherapy has been associated with more favorable progression-free survival (PFS) and overall survival (OS). However, patients with R/R CLL and/or those with TP53 abnormalities (ie, 17p deletion and/or TP53 mutation) are less likely to achieve deep responses and experience poorer outcomes. Therefore, less is known about the relationship between complete response and survival outcomes in R/R CLL patients. To quantify this association, we generated meta-analytic estimates of PFS and OS reported in clinical trials using the proportion of study patients with CR as a predictor variable.Methods: We performed a systematic literature review of PubMed and EMBASE up to November 2014 and congress abstracts between 2012 and 2014. Randomized controlled trials and observational studies evaluating any treatment in R/R CLL patients were eligible for inclusion. Data were extracted from publications as median survival, the proportions of patients surviving at specific follow-up times, or individual event or censoring times from reported Kaplan-Meier (KM) curves, along with the proportion of patients with CR. Data were synthesized to estimate overall OS and PFS including population-level CR as a covariate using a Weibull proportional hazards model within a Bayesian meta-analysis framework.Results: 74 published studies of treatment outcomes in R/R CLL patients were identified from the peer-reviewed literature and congress abstracts. 56 of these studies reported the proportion of CRs together with either OS or PFS outcomes and were included in the analysis. Individual patient data were extracted from KM curves of 29 studies generating 5176 individual patient OS and PFS data points in addition to 54 study-level data points including 3638 patients. There were no clinically meaningful differences in study or patient characteristics among the included studies that were not also associated with CR, our variable of interest. The hazard ratio (HR; and 95% credible interval, the Bayesian analog to confidence intervals) of survival for each 10% increase in CR among a study population was estimated to be 0.64 (0.60, 0.68). Estimated median OS for hypothetical populations with 0% CR, 25% CR, or 50% CR were 20.4 mo, 44.7 mo, and 61.9 mo. Corresponding median PFS estimates were 10.0 mo, 21.9 mo, and 30.3 mo. (Figure)Conclusions: We have demonstrated that the attainment of CR is significantly associated with longer OS and PFS outcomes in R/R CLL at the study level. Moreover this can be expressed linearly, with each 10% increase in CR rate corresponding to a 36% reduction in the risk of progression or death. To our knowledge, this is the first meta-analysis to quantify the relationship between CR and survival outcomes in R/R CLL patients. It must be noted that these results reflect the study (population) level CR versus survival association and therefore do not necessarily represent the expected survival gain associated with an individual achieving CR. Further, CR is less likely to be achieved in patients with TP53 abnormalities, a factor not explicitly considered in our analysis. These results synthesize data from 56 clinical trials and strongly support the importance of achieving CR to improve long-term outcomes in R/R CLL patients. In particular, given the negative association between CR and TP53 abnormalities, treatments focused on improving the likelihood of CR in these hard-to-treat patients are likely to confer the greatest impact on survival outcomes. [Display omitted] DisclosuresEktare:Pharmerit International, paid consultants to AbbVie: Employment. Fox:AbbVie: Consultancy; Gilead: Honoraria, Other: travel funding; Takeda: Honoraria, Other: travel funding; Janssen: Honoraria, Other: travel funding; Adienne: Honoraria, Research Funding. Taylor:AbbVie: Consultancy. Timothy:Pharmerit International, paid consultants to AbbVie: Employment. Pena:AbbVie: Employment, Equity Ownership. Maher:AbbVie: Employment, Equity Ownership. Snedecor:Pharmerit International, paid consultants to AbbVie: Employment.

Erratum to: 'Costs of treating cardiovascular events in Germany: a systematic literature review'.

Unfortunately, the original version of this article [1] contained an error. The full author list and affiliations was not included. The correct author list and affiliations can be found below. Tamara Schmida, Weiwei Xub, Shravanthi R Gandrac, Galin V Michailova a Amgen GmbH, Munich, Germany b Pharmerit International, Rotterdam, The Netherlands c Amgen Inc., Thousand Oaks, CA, USA

Increased Eligibility for Attempting Treatment-Free Remission (TFR) with Frontline Nilotinib (NIL) vs Imatinib (IM) in Patients with Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia (CML): Results of a Stochastic Simulation Model

▪Background: Tyrosine kinase inhibitors (TKIs) have dramatically improved outcomes in patients with Ph+ CML, in part by allowing achievement of sustained, low levels of BCR-ABL1 transcripts (quantified on the International Scale [IS]). TFR studies (eg, STIM, ENESTfreedom) evaluate whether some of these patients can stop TKI therapy and maintain a therapeutic molecular response off treatment. Here, we evaluated BCR-ABL1IS transcript levels of patients treated with frontline NIL 300 mg twice daily or IM 400 mg once daily for ≥ 1 year to predict time to TFR eligibility according to the ENESTfreedom trial criteria.Methods: A statistical model was developed to predict the probability of future premature treatment discontinuation (due to adverse events, progression, or suboptimal response) and BCR-ABL1IS transcript levels at any time point after 1 year of treatment. The 5-year data from the ENESTnd clinical trial, in which BCR-ABL1IS transcript levels were assessed every 3 months, were the basis for this model. Probabilities of premature treatment discontinuation were modeled using parametric survival methods; early molecular response (EMR; BCR-ABL1IS ≤ 10% at 3 months) status was used as a predictor. For patients remaining on treatment, a second-order Markov chain model was used to predict probabilities of BCR-ABL1IS transcript levels being in each of 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%) at any time point after 1 year of therapy. Probabilities were a function of EMR status, the proportion of previous BCR-ABL1IS observations at or below MR4, and BCR-ABL1IS categories from the previous 2 assessments. A simulated cohort of 1000 patients was created to match the distribution of EMR status and BCR-ABL1IS categories in the first year of therapy in each of the trial populations (NIL or IM). Premature treatment discontinuation and BCR-ABL1IS categories were randomly drawn at each 3-month interval based on their corresponding predicted probabilities. Time to eligibility criteria for TFR was defined as: last BCR-ABL1IS assessment of MR4.5, none of the prior 3 assessments worse than MR4, and no more than 2 of the prior 3 assessments between MR4 and MR4.5.Results: For years 2 to 5 of the ENESTnd trial, the observed distribution of BCR-ABL1IS categories over time had reasonable agreement with the computer-simulated cohort. Simulation results (Figure) demonstrated that more patients on NIL than on IM were eligible for TFR by year 5 (52% vs 38%, respectively) and by year 10 (72% vs 64%, respectively; P < .0001 for both time points).Conclusion: Patients in our simulated cohort received a minimum of 3 years of frontline treatment with NIL or IM prior to TFR eligibility evaluation, similar to the current consensus in clinical disease management. Treatment with NIL resulted in significantly more patients becoming eligible for TFR by all time points vs treatment with IM. These data suggest that TFR as a therapeutic goal may be more attainable with NIL than IM. Studies evaluating the duration of TFR are presently being conducted. [Display omitted] DisclosuresMahon:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD: Consultancy; Pfizer: Consultancy. Tran-Duy:Pharmerit International: Consultancy. 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. Snedecor:Pharmerit International: Employment, Other: Institution received payment to conduct this study. Saglio:Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis Pharmaceutical Corporation: Consultancy, Honoraria.

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. [Display omitted] DisclosuresSaglio: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.

Linezolid for the treatment of hospital-acquired pneumonia in a Chinese tertiary hospital.

Disclosure BAL and XG are employees of Pharmerit International which received funding from Pfizer Investment Co, Ltd. ZL has served as a speaker for Pfizer Investment Co, Ltd. YC is an employee of Pfizer Investment Co, Ltd. The authors report no other conflicts of interest in this communication. Disclosure Yuanlin Song received honorariums for travel and expenses of the study. Wei Liu, Ke Wang, Manny Papadimitropoulos, and William Montgomery are employees of Eli Lilly. Contributions from Yicheng Yang and Kai Wang were made whilst they were employees of Eli Lilly. Wendong Chen and Xuehai Li received a project consulting fee from Eli Lilly to compensate for their time on the project. The authors report no other conflicts of interest in this communication.

ANALYSIS OF THE INFLUENCE OF THROMBOEMBOLIC COMPLICATIONS PREVENTION WITH ORAL ANTICOAGULANTS ON BUDGET IN PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION

Atrial fibrillation (AF) is a risk factor for thromboembolic complications, requiring administration of vitamin K antagonists (warfarin) or the new oral anticoagulants (apixaban, dabigatran and rivaroxaban). Aim. To assess the influence of apixaban use on the budget as an alternative to warfarin, dabigatran or rivaroxaban use in patients with non-valvular AF in the Russian Federation (RF). Material and methods. The analysis was performed with the perspective of the health care budget with 5 year horizon period and by the pharmacoeconomic model developed by Pharmerit International (Rotterdam, Netherlands) and adapted for the RF. The cardiovascular complications rate in the model was in line with the results of comparative clinical trials: ARISTOTLE, AVERROES, RE-LY, ROCKET-AF. The analysis suggested that 100% of patients with atrial fibrillation were transferred on apixaban instead of warfarin, dabigatran or rivaroxaban. The analysis was based on the assumption that patients were fully committed to the therapy over the horizon of the study, ie, refusal of treatment was not considered. The possibility of episodes of ischemic and hemorrhagic strokes, the severity of which corresponded to previously published data for the Russian population, was considered in the study. The present study was performed based on two scenarios. In the first of them the cost of anticoagulation therapy was determined on the basis of the average weighted prices of public procurement for the period from 04.01.2014 to 01.04.2015. The alternative scenario purported to demonstrate potential savings of the budget of the health care system on the inclusion of apixaban in the list of essential drugs. This scenario took into account that the cost of dabigatran and rivaroxaban corresponded to registered maximum selling price including 10% VAT and 10% of the wholesale allowance and the cost of apixaban - presumed maximum selling price which the producer intends to register in case the drug is included in the essential drugs list, subject to 10% VAT and 10% wholesale mark. The cost of complications treatment corresponded to the rate of compulsory health insurance for the city of St. Petersburg for 2015. Results. The estimated number of patients with non-valvular AF who require anticoagulation therapy in the RF is 1,196,600 people according to the epidemiological data. Treatment with apixaban significantly reduces the incidence of cardiovascular events as compared with warfarin and rivaroxaban. The results of the budget impact analysis, taking into account the price obtained at auction from 01.04.14 through 01.04.15, show a decrease in the load on the budget when the apixaban is included in the therapy regimen of non-valvular atrial fibrillation. Potential savings of resources of the health care system reached 10.9 billion rubles as compared with dabigatran and 39.2 billion rubles as compared with rivaroxaban. This advantage can be explained by both the lower cost of apixaban in comparison with reference drugs, and a reduction of the in-hospital expenses on complications treatment. Switching from warfarin to apixaban increases the budget load in 2.81 times. However, previous data demonstrate the economic feasibility of the additional costs of apixaban, that help to achieve significant advantages from a clinical point of view. The results obtained on the basis of prices, intended to include apixaban in the list of essential drugs, showed that in this case the savings of the budget of the health care system will reach 127-129 bln. rubles for 5 years (average 26%) as compared with dabigatran and rivaroxaban. The comparison of apixaban with warfarin showed an increase in total costs of therapy in 2.72 times. Conclusion. The inclusion of apixaban in the therapy regimen of non-valvular atrial fibrillation can significantly reduce the burden on the budget of the health care system as compared with dabigatran and rivaroxaban, as well as reduce the incidence of cardiovascular events compared with warfarin. This allows recommending the inclusion of the drug in the federal and regional programs for the prevention of thromboembolic complications in this group of patients.