ALBERT

Description: Acid-sensing ion channels (ASICs) are proton-activated Na+ channels expressed in the nervous system, where they are involved in learning, fear behaviors, neurodegeneration, and pain sensation. In this work, we study the role in pH sensing of two regions of the ectodomain enriched in acidic residues: the acidic pocket, which faces the outside of the protein and is the binding site of several animal toxins, and the palm, a central channel domain. Using voltage clamp fluorometry, we find that the acidic pocket undergoes conformational changes during both activation and desensitization. Concurrently, we find that, although proton sensing in the acidic pocket is not required for channel function, it does contribute to both activation and desensitization. Furthermore, protonation-mimicking mutations of acidic residues in the palm induce a dramatic acceleration of desensitization followed by the appearance of a sustained current. In summary, this work describes the roles of potential pH sensors in two extracellular domains, and it proposes a model of acidification-induced conformational changes occurring in the acidic pocket of ASIC1a.

Description: Background: Hypomethylating agents (HMA), azacitidine (AZA) and decitabine (DEC), are the current standard of care in patients with intermediate-2 and high risk myelodysplastic syndromes (MDS) by IPSS prognostic category (higher-risk MDS) based on clinical trials showing increased response rates and overall survival with these agents. However, the outcomes of patients with MDS treated with HMAs have not been comprehensively assessed in real-world practice. This study describes real-world treatment patterns and outcomes among patients with MDS treated with HMAs. Methods: Adult patients with a confirmed MDS diagnosis between 01/2009-12/2015 treated with HMA were identified in the SEER-Medicare database (01/2006-12/2016). The index date was the date of HMA initiation; the first HMA was defined as the index HMA. Patients were required to have Medicare Parts A and B coverage for ≥12 months pre-index and ≥1 month post-index date. Patients with evidence of stem cell transplant (SCT) or acute myeloid leukemia (AML) pre-index, or enrollment in a clinical trial at any time were excluded. Patients meeting the aforementioned criteria formed the study population. An algorithm, based on timing of HMA initiation, timing of diagnosis of pancytopenia (low counts for red blood cells, white blood cells, and platelets), and diagnosis of refractory anemia with excess of blasts (RAEB)-1 and RAEB-2, was developed to categorize patients into specific MDS risk groups using claims data (Figure A). Patients with RAEB-1/2 diagnosis who initiated HMA within 1 month prior to or 4 months post-RAEB diagnosis, or pancytopenia diagnosis within 3 months prior to HMA initiation (regardless of types of MDS diagnosis) were classified into the higher-risk MDS group. Patients with non-RAEB MDS diagnosis and HMA initiation within 1 month prior to or 4 months post-MDS diagnosis were classified into the intermediate-1-risk MDS group; remaining, unclassified patients from the study population were assigned into the unknown-risk MDS group. OS and time to AML transformation (determined by a diagnosis of AML in claims) were assessed for each risk stratum post-index using Kaplan-Meier (KM) analyses. HMA treatment patterns were measured up to 12 months post-index or until the first event among the following: SCT, AML-like intensive chemotherapy use, AML, or end of data/Medicare Parts A and B coverage (follow-up period). Results: A total of 3,046 patients with MDS treated with HMA were included. On average, patients were aged 77.4 years, and 36.8% were female. The majority of patients were classified in the higher-risk MDS group (70.9%), 8.0% in the intermediate-1-risk MDS group, and 21.1% in the unknown-risk MDS group. Median OS was 11.6 months among patients in the higher-risk MDS group, whereas median OS was 18.4 and 19.1 months for patients in the intermediate-1 and unknown-risk MDS groups, respectively (Figure B). Median time to AML transformation was 19.3 months in the higher-risk MDS group, 50.4 months in the intermediate-1-risk MDS group, and was not reached for the unknown-risk MDS group (Figure C). Overall, patients received an average of 5.1 HMA cycles (median = 4.0 cycles) and the majority were complete cycles (90.9%; as indicated per label or, for AZA, also including the commonly used alternative regimens of 5-day 5-0-0 or 7-day with a weekend break 5-2-2). The mean duration of HMA cycles was 32.6 days (median = 28.0 days). As many as 45.3% of patients received

Description: Background : Regular monitoring of MR by real-time quantitative polymerase chain reaction (RQ-PCR) on the International Scale (IS) is critical for proper management of pts with CML-CP, and achievement of deep MR is a key criterion for enrollment in treatment-free remission studies. In addition, newer techniques have been developed for evaluating residual disease below the level of detection of conventional RQ-PCR. The BCR-ABL1 tyrosine kinase inhibitor NIL elicits higher rates of deep MR than imatinib (IM) in pts with newly diagnosed CML-CP. Prior results from ENESTnext in this pt population demonstrated rapid achievement of deep MR by conventional RQ-PCR and further reductions in BCR-ABL1 transcript levels using a microfluidic digital PCR platform in pts who achieved confirmed MR4.5 (BCR-ABL1IS ≤ 0.0032%) with NIL. Final results are presented here. Methods : ENESTnext (NCT01227577) was a single-arm, open-label, multicenter study in adult pts with Philadelphia-chromosome-positive CML-CP (diagnosed within ≤ 6 months of enrollment) treated with NIL 300 mg twice daily (BID) for up to 2 years. The primary endpoint was the rate of confirmed (≥ 2 samples taken 3 months apart) MR4.5 with up to 2 years of NIL therapy. Secondary endpoints included the rate of major MR (MMR; BCR-ABL1IS ≤ 0.1%). RQ-PCR evaluation of peripheral blood samples was performed monthly for the first 3 months and every 3 months thereafter by a central laboratory and according to the IS. In an exploratory analysis, samples from pts with confirmed MR4.5 (limit of detection of the RQ-PCR assay used) were also evaluated using the Fluidigm digital PCR platform (detection limit is approximately 1 positive cell in 1,000,000 negative cells), which is 〉 1 log more sensitive than conventional RQ-PCR. Samples were analyzed by both digital PCR and RQ-PCR for each pt upon achievement of confirmed MR4.5. Results : A total of 128 pts were enrolled (median age, 56.5 years; male, n = 64 [50.0%]; Caucasian, n = 103 [80.5%]), and 93 pts (72.7%) completed the study per protocol. With up to 2 years of treatment, 94 pts (73.4%) achieved MMR and 34 pts (26.6%) achieved confirmed MR4.5 (Table). Overall, 13 of 94 pts (13.8%) lost MMR and 6 of 34 pts (17.6%) lost MR4.5; among the pts who gained and lost MMR (n = 13) or MR4.5 (n = 6), the mean duration of response was 4.9 and 8.0 months, respectively. All pts who achieved MR4.5 had BCR-ABL1IS ≤ 10% at 3 months. Digital PCR analysis was performed on 195 samples from 33 pts with confirmed MR4.5 by RQ-PCR. Results of digital PCR detection of BCR-ABL1 transcripts in the first and last time point samples from each pt are shown in the Table; among pts for whom both the first and last time point samples showed detectable BCR-ABL1 transcripts by digital PCR, levels decreased over time with continued NIL therapy. The most common (≥ 4 pts) all-cause grade 3/4 adverse events were increased lipase (n = 16), thrombocytopenia (n = 11), neutropenia (n = 8), hypophosphatemia (n = 5), and nausea (n = 5). The most common cardiac disorders were palpitations (6.3%) and atrial fibrillation, myocardial infarction, and tachycardia (2.3% each). Ischemic cardiovascular events included myocardial infarction (2.3%) and cerebrovascular accident and transient ischemic attack (0.8% each). Conclusions : Rapid achievement of MR4.5 was observed in pts with newly diagnosed CML-CP receiving frontline NIL 300 mg BID in ENESTnext; rates of MR were also consistent with those from the ENESTnd study of frontline IM vs NIL with 2 years of follow-up. In ENESTnext, 39% of samples analyzed by digital PCR had detectable levels of BCR-ABL1 transcripts that were not detectable by conventional RQ-PCR, suggesting the potential for detection of even deeper levels of MR using this novel method. Disclosures Berdeja: BMS: Research Funding; Abbvie: Research Funding; Takeda: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Acetylon: Research Funding; MEI: Research Funding; Curis: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Array: Research Funding. Heinrich:BMS: Research Funding; Pfizer: Consultancy, Other: Consulting or Advisory Role; Blueprint Pharmaceuticals: Consultancy, Other: CONSULTING OR ADVISORY ROLE; ARIAD Pharmaceuticals Inc.: Consultancy, Other: Consulting or Advisory Role, Research Funding; Novartis: Consultancy, Other: Consulting & Advisory Role, Research Funding; MolecularMD: Other: Consulting or Advisory Role; MolecularMD: Other: Stock/Shareholder ; Novartis: Other: Expert Testimony; Onyx: Other: Consulting or Advisory Role; Bayer: Research Funding. Goldberg:BMS: Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; COTA: Employment, Equity Ownership, Other: Leadership, Stock; Novartis: Research Funding, Speakers Bureau; Pfizer: Research Funding. Kuriakose:Kedrion: Speakers Bureau. Cortes:Astellas: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Rizzieri:Novartis: Membership on an entity's Board of Directors or advisory committees. Bonifacio:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Dautaj:Novartis Pharmaceutical Corporation: Employment. Warsi:Novartis Pharmaceutical Corporation: Employment. Mauro:Ariad: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis Pharmaceutical Corporation: Consultancy, Research Funding; Pfizer: Consultancy.

Description: Introduction: Midostaurin was the first multikinase inhibitor approved in combination with daunorubicin and cytarabine induction and high-dose cytarabine (HiDAC) consolidation chemotherapy for the treatment of adults with newly diagnosed FLT3-mutation-positive (mut+) acute myeloid leukemia (AML). Approval was largely based on the results from the phase 3 RATIFY trial; patients who received midostaurin had significantly improved overall and event-free survival than those who received placebo (Stone et al, N Engl J Med, 2017). RADIUS-X (NCT02624570) is an expanded treatment protocol (ETP) designed to provide access to midostaurin during the US Food and Drug Administration's review process and to extend the understanding of the safety and tolerability of midostaurin in patients with newly diagnosed FLT3-mut+ AML. The safety profile of midostaurin in preliminary data from RADIUS-X was consistent with that in the RATIFY study (Roboz et al, Blood, 2017 [abstract 1338]). Here we report updated safety data for midostaurin during induction and consolidation and safety data during the maintenance phase. Methods: In this open-label, single-arm ETP, patients (aged ≥18 years) received 1-2 cycles of induction therapy (cytarabine plus daunorubicin [60-90 mg/m2/day] or idarubicin [12 mg/m2/day]) and up to 4 cycles of HiDAC consolidation chemotherapy plus midostaurin (50 mg twice daily [bid] on days 8-21 of each 28-day cycle), followed by up to 12 months of single-agent midostaurin (50 mg bid on days 1-28). Patients could enroll at any point before completion of a second cycle of consolidation. Patients achieving complete remission (CR) or CR with incomplete hematologic recovery (CRi) after induction proceeded to consolidation; patients who maintained a response were eligible to proceed to maintenance. The primary endpoints were safety and tolerability of midostaurin. Results: Of 111 patients screened, 103 were enrolled in the study: 47 during induction (46%) and 56 during consolidation (54%) (Figure). The median age was 58 y (range, 19-79 y); all patients were FLT3-mut+ (Table). Of 47 patients enrolled during induction, 15 received daunorubicin and 32 received idarubicin as the anthracycline. Of 35 patients who completed consolidation and entered maintenance, 9 had completed the protocol treatment and 3 remained on therapy at the data cutoff date (March 30, 2018). The CR/CRi rate for the induction phase was 74% (57% CR, 17% CRi). The relapse rate was 14% overall. The most common reason for study discontinuation was proceeding to transplant (overall, 52%; induction, 11%; consolidation, 42%; maintenance, 34%). The median duration of midostaurin exposure was 35 days (range, 3-426 days). Dose adjustment or interruption due to adverse events (AEs) occurred in 26 patients, most commonly due to febrile neutropenia (n=9) and gastrointestinal disorders (n=6). No new safety events were observed with longer follow-up. Most patients (99%) experienced ≥1 any-grade AE, mostly during induction and/or consolidation. Due to the timing of patient enrollment (up to the second cycle of consolidation), hematologic AEs were lower than reported in comparable studies. The most common AEs occurring in ≥20% of patients were febrile neutropenia (53%), nausea (42%), diarrhea (37%), anemia (36%), platelet count decreased (31%), fatigue (23%), headache (22%), and vomiting (22%). Serious AEs occurred in 50% of patients overall, most commonly febrile neutropenia (37%). AEs during induction were generally similar, regardless of anthracycline received. Overall, 9 patients discontinued due to AEs: 5 during induction (febrile neutropenia, blood bilirubin increased, electrocardiogram QT prolonged, renal impairment, and respiratory distress), 1 during consolidation (sepsis), and 1 during maintenance (leukocytosis). During maintenance, 16 of 35 patients (46%) reported any-grade AEs with midostaurin monotherapy; the most common any-grade and grade 3/4 AEs occurring in 〉1 patient were platelet count decrease (11% and 3%), nausea (9% and 0%), and oropharyngeal pain (6% and 0%).The rate of death during the study was low, with 1 death reported (disease progression). Conclusions: Midostaurin continued to demonstrate a manageable safety profile with longer follow-up and was associated with high transplant and low relapse rates. Maintenance therapy with midostaurin was well tolerated; no new safety signals were observed. Disclosures Perl: Daiichi Sankyo: Consultancy; Arog: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees. Sweet:Agios: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Incyte: Research Funding; Bristol Myers Squibb: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Speakers Bureau. Roboz:Novartis: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Eisai: Consultancy; Janssen Pharmaceuticals: Consultancy; Argenx: Consultancy; Orsenix: Consultancy; Aphivena Therapeutics: Consultancy; Daiichi Sankyo: Consultancy; Roche/Genentech: Consultancy; Orsenix: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Jazz Pharmaceuticals: Consultancy; Celltrion: Consultancy; Cellectis: Research Funding; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; Otsuka: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy; Janssen Pharmaceuticals: Consultancy; Bayer: Consultancy; Astex Pharmaceuticals: Consultancy; Eisai: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Astex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy. Strickland:Astellas Pharma: Consultancy; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis Pharmaceuticals: Consultancy, Research Funding; Tolero Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bonifacio:Novartis: Employment. Haines:Novartis: Employment. Barbera:Novartis: Employment. Purkayastha:Novartis Pharmaceuticals Corporation: Employment.

Description: Introduction Midostaurin is an orally available multikinase inhibitor that blocks FLT3 kinase activity. FLT3 mutations are associated with more frequent and earlier relapses and worse survival. The phase 3 RATIFY trial showed that midostaurin compared with placebo improved overall and event-free survival in newly diagnosed pts with FLT3-mutated AML when administered in combination with standard chemotherapy and as single-agent maintenance (Stone et al, ASH 2015). The ongoing RADIUS trial (NCT01883362) is investigating whether adding midostaurin to SOC after alloHSCT reduces the risk of relapse in pts with FLT3-ITD-mutated AML. Here we report safety data from the first 56 enrolled pts. Methods RADIUS is a randomized, open-label, phase 2 study comparing SOC vs midostaurin + SOC after alloHSCT in adult pts with AML with FLT3-ITD mutations (planned enrollment, N = 60). Study treatment started 28-60 days after alloHSCT. SOC was dictated by the treating physician. Pts were randomized to either SOC or midostaurin 50 mg twice daily + SOC (hereafter called the midostaurin arm) continuously for ≤ 12 months and will be followed up for ≥ 24 months. The study was designed to look for any safety or efficacy signals and not powered to find differences between study treatments. The primary endpoint is relapse-free survival at 18 months after alloHSCT. Adverse events (AEs) were followed up for 30 days after treatment. Key inclusion criteria are documented FLT3-ITD mutation, age 18-70 years, and first complete remission status. Pts could enroll after the date of engraftment and hematologic recovery to an absolute neutrophil count 〉 1000/μL and platelet count ≥ 20,000/μL without requiring transfusion. Results Pts were randomized from Feb 5, 2014, to Jun 13, 2016. The 2 arms (n = 28 each) were balanced regarding age, sex, and race. Most pts (93%) had de novo AML. At data cutoff (Jun 3, 2016), data were not mature enough to evaluate efficacy. Median (range) follow-up in the SOC and midostaurin arms was 240 (3-786) and 234 (3-656) days, respectively. Overall, 18 pts (64%) in the SOC arm and 19 pts (68%) in the midostaurin arm stopped treatment. Of these, 10 (36%) and 8 (29%) in the SOC and midostaurin arms, respectively, completed 12 months of treatment. Other reasons for stopping treatment were relapse (2 [7%] and 2 [7%]), death (2 [7%] and 0 [0%]), administrative problems (2 [7%] and 1 [4%]), withdrawn consent (1 [4%] and 3 [11%]), abnormal test results (1 [4%] and 0 [0%]), and AEs (0 [0%] and 4 [14%]). In the 24 pts who received ≥ 1 dose in the midostaurin arm, the median midostaurin dose was 76.2 (range, 25-100) mg daily. In the 15 pts (54%) who required a dose change, the reasons for dose changes were AEs (13 [46%]), dosing error (3 [11%]), re-escalation (3 [11%]), abnormal test results (2 [7%]), per protocol (2 [7%]), use of concomitant strong CYP3A4 inhibitors (1 [4%]), and other reasons (4 [14%]). The most common any-grade (Gr) AEs were fatigue (29%) and AST, headache, nausea and vomiting (all 25%) in the SOC arm and nausea and vomiting (both 64%) and diarrhea (43%) in the midostaurin arm (Figure 1). The most common Gr 3/4 AEs were nausea and hypertension in the SOC arm (all 3 [11%] each) and diarrhea, increased ALT, neutrophil count decreased (all 3 [11%] each) and platelet count decreased (5 [18%]) in the midostaurin arm. No on-treatment deaths occurred in the midostaurin arm. AEs led to discontinuation of midostaurin in 4 pts and included Gr 1 nausea, Gr 2 nausea and vomiting, Gr 3 lung infection, and Gr 2 elevated liver enzymes (n = 1 each). All of these except the lung infection were considered related to midostaurin. Graft-vs-host disease (GVHD) occurred in 16 pts (57%) in the SOC arm and 18 pts (64%) in the midostaurin arm (Figure 2). No stage ≥ 3 organ involvement occurred. Most cases of GVHD (11 [39%] in the SOC arm and 17 [61%] in the midostaurin arm) were acute. The most commonly affected organ was the skin (11 [39%] and 13 [46%], respectively, of which 5 [18%] and 4 [14%], respectively, were stage 2). Conclusions The preliminary safety data in the post-alloHSCT setting was consistent with data from other studies. Rates of Gr 1/2 nausea, vomiting, and diarrhea were higher in the midostaurin arm. Midostaurin did not change rates of GVHD. Because of the limited duration of follow-up, effects on chronic GVHD are unknown. Follow-up is ongoing, with efficacy data anticipated in 2017. Disclosures Maziarz: Athersys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Deol:Jazz Pharmaceuticals: Consultancy. Haines:Novartis: Employment. Bonifacio:Novartis: Employment. Rine:Novartis: Employment. Fernandez:Fate Pharmaceuticals: Honoraria; Chimerix: Honoraria; Sanofi: Speakers Bureau.

Description: INTRODUCTION: Mutation of FLT3, a tyrosine kinase receptor, is one of the most common molecular alterations in AML. In 2017, the FDA approved midostaurin for treatment of newly diagnosed AML adult patients with FLT3 mutation. Understanding of utilization and costs associated with AML pre and post Midostaurin approval is warranted. The objectives of this study were to evaluate healthcare utilization and costs between FLT3-mutated AML patients and FLT3-wildtype AML patients, pre-midostaurin approval and among initial FLT3-mutated AML patients treated with midostaurin. METHODS: FLT3-tested AML patients treated with 7+3 induction chemotherapy prior to midostaurin approval, were identified retrospectively from 2007-2016 at Huntsman Cancer Institute. A separate sample of FLT3-mutated patients treated with midostaurin from May 2017 to June 2018 were also identified. Healthcare charges, which are the individual list prices set by the medical facility, were computed for inpatient, outpatient and emergency services in this study. Since cost data were not available, charges were converted to imputed costs by applying the 2013 CMS charge-to-cost ratio of 0.492. Health care utilization through inpatient, outpatient and emergency room visits were also evaluated for FLT3-mutated and FLT3-wildtype patients. RESULTS: Pre-midostaurin: One hundred patients (39 FLT3-mutated, 61 FLT3-wildtype) prior to the availability of midostaurin were identified with a median age of 53 years. Median number of AML related inpatient visits for the total sample was 5 (FLT3-mutated [5] vs FLT3-wildtype [6] p=0.1]. Median outpatient visits were 43 for the total sample (FLT-mutated [47] vs FLT3-wildtype [51], p=0.4). Healthcare costs were categorized as AML related and all-cause related costs. AML related costs, which included transplant costs, contributed to nearly 70% of all-cause healthcare costs on an average. Approximately 38% of total AML-related costs were attributable to induction therapy among FLT3-mutated patients, while 29% of total AML-related costs among wildtype patients were related to induction (p

Description: Introduction: Fms-like tyrosine kinase 3 (FLT3) gene mutation occurs in approximately 25-30% of acute myeloid leukemia (AML) cases and is associated with poor prognosis. Decreased overall survival is reported in FLT3-mutated vs. FLT3-wildtype. Midostaurin, a pan-targeted kinase inhibitor that inhibits activated FLT3 received FDA approval in April 2017 for adult patients with newly diagnosed FLT3-mutated AML in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. We report descriptive US clinical treatment patterns and outcomes in FLT3-mutated early midostaurin-users, historical FLT3-mutated patients prior to midostaurin approval, and historical FLT3-wildtype AML patients all treated with 7+3 induction therapy at an academic cancer specialty hospital to support the development of a larger database across several comprehensive cancer centers. Methods: This retrospective, observational study utilized ICD codes, tumor registry data, and pharmacy records from the Huntsman Cancer Institute (HCI) to identify AML patients treated with 7+3 induction chemotherapy from 2007 to July 2018. FLT3-mutated midostaurin-users treated with 7+3 induction including midostaurin from May 2017 to July 2018 comprise Group 1. Historical FLT3-mutated patients prior to midostaurin approval (non-users) and FLT3-wildtype patients comprise Groups 2 and 3, respectively. Complete response (CR), relapse rates, overall survival and treatment patterns were described. Results: A total of 105 patients met eligibility for inclusion in the study. Groups 1, 2, and 3 included five, 39 and 61 patients, respectively. Off-label midostaurin use in Group 1 after induction therapy was observed in one patient with post-consolidation monotherapy and salvage therapy in combination with ATRA (tretinoin) and CLAG (cladribine, cytarabine, and filgrastim). Following midostaurin approval, two FLT3-mutated patients received induction therapy without midostaurin due to enrollment in clinical trials that excluded midostaurin use for induction and consolidation therapy. These two patients were excluded from the study. Descriptive results of the comparative groups are summarized in Table 1. CR rate from induction therapy was 100% for Group 1, 90% for Group 2, and 77% for Group 3. The proportion of patients who received consolidation therapy was 60%, 74%, and 67%, and patients who maintained CR during consolidation therapy was 100%, 83%, and 49% for Groups 1, 2, and 3, respectively. Sixty-six percent of eligible Group 1 patients, 74% of Group 2 patients, and 54% of Group 3 patients received transplant. Median time from diagnosis to transplant was 81, 99, and 145 days for Groups 1, 2, and 3, respectively. The proportion of patients who received salvage therapy in Groups 1, 2, and 3 was 20%, 38%, and 56% respectively. Median follow-up was 6 months for Group 1, 14 months for Group 2, and 24 months for Group 3. After CR, 20% of Group 1, 49% of Group 2, and 59% of Group 3 relapsed. All Group 1 patients were alive at time of analysis while four Group 2, and eight Group 3 patients died during the study period. Discussion: Similar CR and relapse rates were observed between the comparative groups, although early use observations indicate improved response rates of induction therapy and consolidation therapy in a limited Group 1 sample. Patients in Group 1 and Group 2 underwent transplant earlier and more frequently than patients in Group 3, which may explain the higher relapse rate in Group 3. As this data resource is expanded across similar institutions, statistical comparisons of FLT3-mutated AML patients treated with and without midostaurin can be made. Sponsorship: Funding for this study was provided by Novartis Pharmaceuticals. Disclosures Unni: Novartis: Research Funding. Ndife:Novartis: Employment. Joseph:Novartis Pharmaceuticals Corporation: Employment; Amgen: Equity Ownership; Pfizer: Equity Ownership; Express Scripts: Equity Ownership. Bonifacio:Novartis: Employment. Stein:Novartis: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Bayer: Consultancy; Celgene: Consultancy; Pfizer: Consultancy. Shami:Lone Star Biotherapies: Equity Ownership; Pfizer: Consultancy; JSK Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees. Kovacsovics:Amgen: Honoraria, Research Funding; Abbvie: Research Funding. Brixner:BD: Consultancy; Abbott: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Millcreek Outcomes Group: Equity Ownership; University of Utah: Research Funding. Stenehjem:Novartis: Research Funding.

Description: Oral mucositis (OM) is an acute, severe and often dose-limiting toxicity in patients undergoing HSCT. OM significantly affects functional status and patients’ quality of life; however no effective therapy was available for this condition. Palifermin (Kepivance®) is a human keratinocyte growth factor (KGF) produced by recombinant DNA technology. KGF binds to its receptor on epithelial cells, stimulating their proliferation, differentiation, and migration. Palifermin has been shown to decrease the incidence and duration of severe OM in patients with hematologic malignancies receiving myelotoxic therapy and HSCT. In Italy, compassionate use protocols are considered EAP and are regulated by a decree issued by the Ministry of Health (MoH) on May 8th 2003. The objective of the Decree is to ensure that patients have access to experimental therapies outside clinical trials, when no valid therapeutic alternative exists. Approval is granted in case of serious or rare diseases or life-threatening conditions. After Ethical Committee (EC) approval and notification to MoH, the drug can be supplied in response to an unsolicited request from a physician. The drug is then administered under the physician’s direct responsibility. During EAP, the Decree allows collection of the patient’s data similar to an observational trial. From July 2005 through July 2006 a total of 26 centers have requested the drug and obtained approval from local EC. Each center collected the following data on a case report form: vital signs, disease status and treatment, palifermin administration, mucositis, analgesic use, parenteral supplementation, common laboratory tests and duration of hospitalization. A total of 175 adults patients with hematological malignancies treated with autologous SCT participated in the EAP. In an interim analysis, data from 41 patients (24 men; 17 women; median age 52.44) were analyzed. The most common diagnoses were multiple myeloma (MM) (n=16) and non-Hodgkin lymphoma (NHL) (n=15). Conditioning therapy and supportive care were administered according to standard institutional practice (high-dose melphalan for MM and the BEAM regimen for NHL). Palifermin 60 mcg/kg/day was given intravenously on 3 consecutive days before the conditioning regimen and on 3 days starting on the day of stem cell infusion. OM was evaluated daily for 28 days after transplantation or until severe OM resolution using the five-grade World Health Organization (WHO) oral-toxicity scale. Safety was assessed on the basis of the incidence of adverse events. The incidence of severe OM (Grade 3–4) was 17% and the mean duration was 2.2 ± 3.5 days (CI, 1.1–3.3) in patients with OM Grade 0–4 while in patients with OM G3-4 the mean duration was 6.9 ± 2.5 (CI, 4.5–9.2). Adverse events (mainly rash, pruritus, erythema, mouth and tongue disorders, and taste alteration) were mild to moderate in severity and were transient. The frequency of adverse events was consistent with those observed in clinical trials. In conclusion, the Italian EAP experience with palifermin suggested that results were consistent with those of pivotal studies in patients with hematologic malignancies undergoing HSCT. From the results of the interim analysis of the Italian EAP, the use of palifermin in this setting appears to be feasible and was widely accepted by participating physicians and patients.

Description: Introduction: Midostaurin, a multitargeted tyrosine kinase inhibitor (TKI), plus induction and consolidation chemotherapy followed by single-agent midostaurin maintenance therapy resulted in significant benefits in event-free and overall survival (OS) in adults with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) compared with placebo (RATIFY study; Stone et al, N Engl J Med, 2017). In RATIFY, patients who received allogeneic hematopoietic stem cell transplant (alloSCT) did not receive midostaurin maintenance. Despite alloSCT providing the highest likelihood of sustained remission, relapse rates remain high (30%-59%; Schiller et al, Biol Blood Marrow Transplant, 2016), especially in patients with FLT3-internal tandem duplication-positive (ITD+) AML. Posttransplant maintenance therapy may improve this outcome. Here, we report the primary results from RADIUS, a randomized, open-label, phase 2 exploratory trial (NCT01883362) that investigated whether the addition of midostaurin to standard of care (SOC) after alloSCT could reduce the risk of relapse in patients with FLT3-ITD+ AML. Methods: Adults (aged 18-70 y) who had undergone myeloablative alloSCT in first complete remission (CR1), had achieved hematologic recovery, and were transfusion independent were eligible. Patients enrolled postengraftment and were randomized to receive SOC with or without midostaurin 50 mg twice daily continuously (4-week cycles) for up to 12 cycles. Study treatment started 28 to 60 days post-alloSCT and patients were followed for ≥24 months post-alloSCT. The primary endpoint was relapse-free survival (RFS) at 18 months post-alloSCT. Secondary endpoints included safety and disease-free survival (DFS), OS, and RFS at 24 months post-alloSCT. The study was not adequately powered to detect a statistical difference between the 2 arms; a sample size of 60 was calculated to detect a 50% reduction in the risk of relapse. Results: 60 patients were randomized (30 per arm). Baseline characteristics were generally balanced between the 2 arms. Overall, 30 patients completed 12 cycles of study treatment (14 with SOC; 16 with midostaurin). The median exposure to midostaurin was 10.5 months (range, 0.2 to 12.0 months) and the median dose intensity was 93 mg/day (range, 15-100 mg/day). Early treatment discontinuations were similar between arms (15 in the SOC arm; 13 in the midostaurin arm), frequently due to adverse events (AEs; 3% vs 23%) and consent withdrawal (20% vs 7%). Among 6 patients who withdrew consent in the SOC arm, 2 did so to pursue other TKI therapies. Midostaurin dose modifications occurred in 19 patients (63%), mostly due to AEs (84%); 1 instance was due to receiving a concomitant CYP3A4 inhibitor. With an estimated 18-month RFS (95% CI) of 76% (54%-88%) in the SOC arm and 89% (69%-96%) in the midostaurin arm, estimated relapse rates were 24% and 11%, respectively, which is a 46% relative reduction in the risk of relapse with the addition of midostaurin (Figure 1). At 18 months, the median RFS was not reached in either arm. Longer follow-up at 24 months (data not yet matured) will be presented, including RFS, OS, and DFS. In the SOC and midostaurin arms, AEs were reported in 87% and 100% of patients, respectively (the most common any-grade AE was vomiting: 23% vs 73%; Figure 2); serious AEs were reported in 57% and 30% of patients, respectively, with diarrhea (7% vs 13%), nausea (10% vs 3%), vomiting (10% vs 3%), and pyrexia (7% vs 7%) being the most common. Overall, 8 patients discontinued midostaurin therapy due to AEs (mostly gastrointestinal related) and 12 died on study (all during the follow-up phase; 8 in the SOC arm and 4 in the midostaurin arm [n=4 vs n=2 due to AML disease progression]). Rates of graft-vs-host disease (GVHD) were generally similar between the SOC and midostaurin arms (overall, 70% vs 73%; acute GVHD, 53% vs 57% [grade 2/3 events: 37% vs 30%; no grade 4 events]; chronic GVHD, 47% vs 37% [most events were mild or moderate; severe events: 1 with SOC and 2 with midostaurin]). Conclusions: Adding midostaurin to SOC reduced the risk of relapse at 18 months post-alloSCT by 46% (vs SOC). The safety profile of single-agent midostaurin was consistent with previous reports; no major safety concerns were identified when adding midostaurin to SOC following alloSCT. These data suggest that midostaurin monotherapy can be safely administered for ≤1 year and may improve outcomes in patients who undergo alloSCT in CR1. Disclosures Maziarz: Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria; Kite Therapeutics: Honoraria; Athersys, Inc.: Patents & Royalties. Scott:Agios: Consultancy; Novartis: Research Funding; Celgene: Consultancy, Research Funding; Alexion: Consultancy. Deol:Kite Pharmaceuticals: Consultancy; Novartis: Consultancy. Kim:Novartis: Consultancy, Honoraria, Research Funding; Briston-Meyers Squibb: Consultancy, Honoraria, Research Funding; Paladin: Consultancy; Pfizer: Consultancy. Haines:Novartis: Employment. Bonifacio:Novartis: Employment. Rine:Novartis: Employment. Purkayastha:Novartis Pharmaceuticals Corporation: Employment.

Description: Background: There is a scarcity of data about healthcare resource utilization (HRU), costs, and treatment patterns of patients (pts) with newly diagnosed AML, despite the prolonged hospitalizations associated with induction and consolidation chemotherapy. The initial decision whether to treat with intensive induction chemotherapy depends, primarily, on pt age, comorbidities, and performance status. For pts deemed eligible for induction chemotherapy, treatment generally consists of induction with an intensive chemotherapy regimen (e.g., cytarabine + anthracycline "7+3") and post-induction therapy (consolidation) for those who achieve a complete remission. Post-induction therapy may consist of repeated rounds of further cytotoxic chemotherapy or allogeneic HSCT. Methods: Adult pts with newly diagnosed AML who received induction chemotherapy in an inpatient (IP) setting within 14 days of diagnosis were identified from a US administrative claims database (2006-2015). Pts with acute promyelocytic leukemia (APL) or in clinical trials were excluded. Outcomes were analyzed between the beginning of the induction episode and an HSCT, death (IP discharge status of death), end of health plan enrollment/ data availability, or 180 days after the discharge date of the induction episode, whichever occurred first (i.e., observation period). Induction and consolidation episodes were identified using diagnosis related group (DRG) codes for chemotherapy with acute leukemia (DRG 837, 838, or 839) or procedure/drug codes for specified/unspecified chemotherapy for AML. Outcomes included treatment patterns (setting and duration of AML treatment episodes, and time between episodes), HRU (IP admissions, HSCT), and costs (USD 2015, amount reimbursed by private payers, coordination of benefits, and beneficiaries contributions [deductibles and copayments]). AML treatment costs are reported during induction and consolidation episodes and IP costs are reported between episodes. Results: A total of 631 pts (mean age = 56 years; 48% female) met the sample selection criteria. Among these, during the 12-month period preceding the index date, 18% had a diagnosis for MDS, 15% had a diagnosis for a malignancy other than lymphoid/hematopoietic neoplasms (mainly breast or skin malignancies), 14% received chemotherapy, 1% received radiation therapy, and the average Charlson comorbidity index score was 2.3. During the observation period, 2 out of 631 pts had a HSCT during the IP stay of the induction therapy (and were excluded from the cost analysis). A total of 73 (12%) pts had initial induction and subsequent re-induction therapy during the same IP episode. The median duration of IP episodes for pts who required initial induction therapy only was 27 days, the mean total healthcare cost was $113,969, and the mean cost per day was $5,177. The median duration of IP episodes for pts who required induction and re-induction therapy was 43 days, the mean total healthcare cost was $182,328, and the mean cost per day was $4,147. Among pts with post-induction treatment episodes, the first consolidation cycle occurred, on average, 26 days after the discharge date of the induction episode; 75% was in an IP setting, and 25% in an OP setting. In the IP setting, the median duration of the first cycle was 6 days, the mean total healthcare cost was $48,723, and the mean cost per day was $4,292. In the OP setting, the median duration of the first cycle was 4 days of treatment over 5 days, the mean total healthcare cost was $11,253, and the mean cost per day of treatment was $2,751. A proportion of 25% of pts had an IP admission between the end of the induction episode and the first consolidation cycle, and 43% between the first and second consolidation cycles. In addition, during the observation period, a total of 97 (15%) pts had an allogeneic HSCT; 31 (5%) after the induction episode, 39 (6%) after the first consolidation cycle, and 27 (4%) after the second consolidation cycle. (Table) Conclusions: This is the first exploratory study reporting treatment patterns, HRU, and costs of AML management. Despite lack of granular information on the type of treatment administered, this study describes the setting, duration, and HRU and costs associated with induction and consolidation therapy for AML. Study findings suggest that in a sample of commercially insured pts with newly diagnosed AML, there is substantial heterogeneity in the management and costs of AML. Table Table. Disclosures Stein: Agios Pharmaceuticals: Other: Advisory Board, Research Funding; Seattle Genetics: Research Funding; Celgene: Other: Advisory Board, Research Funding; Novartis: Consultancy. Latremouille-Viau:Analysis Group: Employment; Novartis: Other: Author is an employee of Analysis Group which has received consulting fees from Novartis. Guerin:Novartis: Other: I am an employee of Analysis Group, Inc., which has received consulting fees from Novartis for the conduct of this study; Analysis Group, Inc.: Employment. Shi:Novartis: Other: I am an employee of Analysis Group, Inc., which has received consulting fees from Novartis for the conduct of this study; Analysis Group, Inc.: Employment. Gagnon-Sanschagrin:Analysis Group, Inc: Employment; Novartis: Other: Author is an employee of Analysis Group which has received consulting fees from Novartis. Bonifacio:Novartis: Employment. Joseph:Novartis: Employment; Amgen: Other: Stocks/stock option; Pfizer: Other: Stock/stock option.