scholarly journals Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-Fatigue): Cognitive Debriefing in Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4777-4777
Author(s):  
Helena Chung ◽  
Daniel Eek ◽  
Calvin Krogh ◽  
Matthew Blowfield ◽  
Oren Meyers ◽  
...  
Keyword(s):  
General Population ◽  
Content Validity ◽  
Cognitive Debriefing ◽  
Employment Equity ◽  
Response Options ◽  
Concept Elicitation ◽  
The Past ◽  
Fit For Purpose ◽  
Equity Ownership ◽  
The Impact

Introduction: The FACIT-Fatigue is a 13-item patient-reported outcome instrument (PRO) that was designed to assess fatigue-related symptoms and impacts on daily functioning. This study assessed the content validity of the FACIT-Fatigue in patients with CLL to help determine if it is fit-for-purpose in this population. Methods: Forty adults with first-line (1L) or relapsed or refractory (R/R) CLL took part in an interview study comprising concept elicitation and cognitive debriefing. All participants had experienced CLL-related symptoms (fatigue, weight loss, fever or night sweats) in the past week. For concept elicitation, interviewers used a standardized semi-structured interview guide with open-ended and prompted questions to explore patients' experiences of the signs, symptoms and impacts of CLL and its treatments. Patients were asked to provide a disturbance rating of these concepts on a 0-10 scale of severity. All interviewed patients completed the FACIT-Fatigue. Item scores can range from 0 ("not at all") to 4 ("very much"), and the total score from 0 to 52; lower scores indicate greater fatigue. The recall period for each item is the past 7 days. The general population mean score is 43 (Cella et al. 2002; Montan et al. 2018). During cognitive debriefing, the clarity of the FACIT-Fatigue items, their relevance to the patients, and the comprehensiveness of the response options were assessed. Interviews were carried out by telephone and lasted about 60-75 minutes. De-identified audio-recorded interviews were transcribed, coded and analyzed using qualitative data analysis software. Results: Median age of participants was 58 years (range: 28-73 years), and gender distribution was equal. During concept elicitation, fatigue was identified as the most prominent and impactful concept. It was the only concept mentioned by 100% of patients, and almost all (1L: 95%; R/R: 85%) mentioned it spontaneously without prompting. Fatigue had a high mean disturbance rating (1L: 7.1; R/R: 6.9). Seven fatigue-related sub-components were identified from the way that patients described their fatigue, covering symptoms (tiredness/need for sleep, lack of energy, weakness, cognitive fatigue) and impacts (decreased ability to maintain social/familial/professional role, decreased physical functioning, frustration). Mean (standard deviation) FACIT-Fatigue score was 28.9 (13.6) for patients with 1L CLL and 29.3 (11.5) for those with R/R CLL, indicating greater fatigue than the general population and providing further evidence that fatigue is a core component of CLL. The items that scored highest were: "I feel fatigued" (item 1; mean score: 2.4) and "I feel tired" (item 4; mean score: 2.4). The items that scored lowest were: "I am too tired to eat" (item 10; mean score: 0.4) and "I need help doing my usual activities" (item 11; mean score: 1.0). During cognitive debriefing, 100% of patients confirmed that the FACIT-Fatigue was reflective of their experiences with fatigue resulting from CLL. All patients found the response options provided by the FACIT-Fatigue to be sufficient. Patients confirmed that most of the FACIT-Fatigue terminology was clear. An exception was the item "I feel listless/washed out" (item 3), which was not consistently understood: most patients linked it to an absence of both physical and mental energy, but some interpreted it just as a lack of physical energy. Overall, patients considered the FACIT-Fatigue items to be relevant and distinct from each other, and found that the impact items captured both the mental and physical impacts of fatigue. One item, "I am too tired to eat", was not considered to be highly pertinent because, although respondents could imagine that some patients with CLL might be too tired to eat, they themselves could only recall being too tired to prepare a meal, not being too tired to eat. However, respondents felt that the item was still relevant and that it did not detract from the applicability or clarity of the FACIT-Fatigue. Conceptual relevance of the FACIT-Fatigue was supported by mapping of its items to the 7 fatigue-related sub-components identified during concept elicitation (Table). Conclusions: Results from concept elicitation and cognitive debriefing interviews demonstrated content validity of the FACIT-Fatigue in patients with CLL with 1L or R/R disease, thus providing evidence that it is fit-for-purpose in this population. Disclosures Chung: AstraZeneca: Employment, Equity Ownership. Eek:AstraZeneca: Employment, Equity Ownership. Eyre:Janssen: Honoraria; Gilead: Consultancy, Honoraria, Other: commercial research support; Abbvie: Honoraria; Roche: Honoraria.

scholarly journals Evaluation of the Content Validity and Cross-Cultural Validity of the Study Participant Feedback Questionnaire (SPFQ)

2020 ◽  
Vol 54 (6) ◽  
pp. 1522-1533
Author(s):  
Alison Greene ◽  
Mary Elmer ◽  
Sean Ludlam ◽  
Kathyjo Shay ◽  
Sarah Bentley ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Content Validity ◽  
Study Participant ◽  
Cross Cultural ◽  
Cognitive Debriefing ◽  
Response Options ◽  
Cultural Validity ◽  
Concept Elicitation ◽  
Feedback Questionnaire ◽  
English Speaking

Abstract Objectives The Study Participant Feedback Questionnaire (SPFQ) is a patient-completed tool designed to assess patient experiences and satisfaction with aspects associated with being involved in a clinical trial. Originally developed in oncology and among English-speaking participants, the aim of the current study was to evaluate the content and cross-cultural validity of the SPFQ in other indications and non-English-speaking countries. Methods Semi-structured qualitative telephone interviews were conducted with 80 participants across eight non-English-speaking countries (in Europe, South America and Asia) who had received an investigational medicinal product as part of a clinical trial in the past three years. Interviews comprised concept elicitation to identify concepts of importance to participants’ trial experiences, and cognitive debriefing to assess understanding and perceived importance of SPFQ instructions, items and response options. Results Concept elicitation findings supported the content validity of the SPFQ. During cognitive debriefing, SPFQ instructions and the majority of items were well understood by participants. Participants generally considered the SPFQ items important to their clinical trial experience, albeit a handful of items assessed concepts that had not been experienced by trial participants or were redundant with other SPFQ items. The instructions, response options and recall period of the SPFQ were generally well understood. No country-level differences in understanding or importance were apparent. Conclusion Study findings provide evidence for the content and cross-cultural validity of the SPFQ and support implementation of the SPFQ as a means of obtaining participant feedback across global development programmes in a variety of indications.

scholarly journals Impact of Amotosalen/UVA Pathogen Inactivated Platelet Components on Outcomes after Allogeneic Hematopoetic Stem Cell Transplantation: A Single Center Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1167-1167
Author(s):  
Andreas S. Buser ◽  
Laura Infanti ◽  
Andreas Holbro ◽  
Joerg Halter ◽  
Sabine Gerull ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Risk Scores ◽  
Employment Equity ◽  
Stem Cell Source ◽  
Equity Ownership ◽  
The Impact

Background: Platelet component (PC) transfusion is required for allogeneic hematopoietic stem cell transplantation (HCT) recipients. Contamination with infectious pathogens (bacteria, viruses, or protozoa) and T-cells is a risk factor for transfusion-transmitted infection (TTI) and transfusion associated graft-versus-host disease (TA-GVHD). Pathogen inactivation (PI) treatment of PC with amotosalen-UVA (PI-PC, INTERCEPT Blood System, Cerus Corp) in platelet additive solution (PAS) without bacterial screening, gamma irradiation, CMV serology, and with 7-day storage has been the standard of care in Switzerland since 2011 to manage risk of TTI and TA-GVHD. PI-PC have replaced conventional PC (C-PC) prepared in PAS with gamma irradiation and 5 day storage. We previously reported platelet usage in two consecutive five year periods at the University Hospital of Basel. Mean PI-PC dose was higher (3.0 vs. 2.8 x 1011, p=0.001) and mean storage duration longer (4.2 vs. 3.4 days: p=0.001) than with C-PC. PC expiration wastage was reduced with 7-day PI-PC storage vs. 5-day storage (1.5% vs. 8.7%). For HCT recipients, days of PC support; PC use per patient; and RBC use per patient were similar, despite 24.3% lower corrected count increments (CCI) with PI-PC. Now, we report the impact of these observations on treatment related mortality (TRM) and overall survival (OS) 100 days after HCT. Patients and Methods: A two-period retrospective cohort study was conducted to evaluate PI-PC impact on outcomes of consecutive first allogeneic HCT recipients from January 2006 to December 2010 (Period 1, P1), when gamma-irradiated apheresis C-PC were used, and Period 2 (P2) from January 2011 to December 2017, when apheresis and whole blood-derived PI-PC were used. The review utilized 100-day OS and 100-day TRM to determine the impact of PI-PC on HCT outcomes. Descriptive statistics were used for continuous variables and log-rank analysis for survival outcomes. Univariate analysis was performed using Pearson χ2 statistics. Multivariate Cox regression modelling analyses included: PC period (P1, P2), donor match (HLA identical/twin, matched related, matched unrelated), disease state (early, intermediate, late), and conditioning regimen (reduced intensity, myeloablative) with TRM as the outcome. This was an IRB approved single-center analysis. Results: In P1 and P2, 256 and 557 consecutive first-time allogeneic HCT recipients were included, respectively. By univariate analysis, the distribution of European Group for Bone Marrow Transplantation (EBMT) risk scores (grouped 0-2, 3-4, 5-7) and mean patient age were higher during P2 (p = 0.001 and p <0.001, respectively). Primary disease status (p = 0.039); stem cell source (p <0.001); GVHD prophylaxis with ATG (p <0.001); total body irradiation (p <0.001); and conditioning regimen (p <0.001) were different between P1 and P2. Donor match (p=0.084) and disease status (p = 0.628) were similar in P1 and P2. TRM at day 100 post HCT was significantly less (31/557, 5.5%) for PI-PC recipients in P2 vs. C-PC recipients in P1 (37/256, 14.5%, p<0.001). Overall proportion of survivors at day 100 post HCT was significantly greater for PI-PC recipients (507/557, 91.0 %) compared to C-PC recipients (209/256, 81.6%, p <0.001). By multivariate Cox regression analysis, P2 with PI-PC component support was associated with improved TRM (p = 0.001; adjusted hazard ratio 0.433; 95% confidence interval: 0.262, 0.716). Donor match (p = 0.019), disease state (p = 0.022), and myeloablative conditioning (p = 0.034) were associated with significantly poorer TRM (Table). Stem cell source was not significant (p=0.157) in the model. Hemorrhage was reported as cause of death in 1/50 (2.0%) patients during P2 with PI-PC and 4/47 (8.5%) patients during P1 with C-PCs. Conclusions: Universal implementation of PI-PC in routine with extended storage to 7 days in P2 was associated with reduced TRM and better overall survival 100 days post HCT, despite transplantation of older patients with higher EBMT risk scores. Multivariate analysis revealed an adjusted hazard ratio of 0.433 (95% C.I. 0.262, 0.716) for TRM by 100 days, suggesting better outcomes in P2. This retrospective analysis at a single site indicated that PI-PC treated with amotosalen /UVA stored up to 7 days did not have a negative impact on TRM and OS in HCT recipients, and was an integral part of improving clinical outcomes at our institution. . Table. Disclosures Heim: Novartis: Research Funding. Irsch:Cerus Corporation: Employment, Equity Ownership. Lin:Cerus Corporation: Employment, Equity Ownership. Benjamin:Cerus Corporation: Employment, Equity Ownership. Corash:Cerus Corporation: Employment, Equity Ownership.

Variation in Health-Related Quality of Life by ECOG Performance Status and Fatigue Among Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4591-4591 ◽  
Author(s):  
Chris L. Pashos ◽  
Christopher R Flowers ◽  
Mark Weiss ◽  
Nicole Lamanna ◽  
Charles M Farber ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Performance Status ◽  
Clinical Practices ◽  
Employment Equity ◽  
Ecog Performance Status ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Ecog Ps ◽  
The Impact

Abstract Abstract 4591 Introduction: Clinicians and investigators appreciate the value of measuring HRQOL for monitoring CLL and the impact of treatments, and commonly use ECOG performance status (PS) and clinician-reported patient fatigue as surrogates for HRQOL in clinical practice. However, limited data exist on the relationships between PS, fatigue, and HRQOL in CLL patients (pts) undergoing treatment in clinical practices. We examined the associations between these measures and 3 psychometrically validated, patient-reported, HRQOL instruments: the Brief Fatigue Inventory (BFI), EQ-5D, and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Methods: Data were collected as part of Connect CLL®, a prospective observational registry initiated in March 2010 involving US practices. Data on pt demographics and clinical characteristics were provided by clinicians. HRQOL was self-reported by pts at enrollment using the BFI, EQ-5D, and FACT-Leu. Mean BFI, EQ-5D and FACT-Leu scores were analyzed by ECOG PS and clinician-reported fatigue. Differences in HRQOL scores between sub-cohorts were assessed by ANOVA. Results: HRQOL data were reported by 604 pts enrolled from 10 academic, 148 community, and 3 government centers. Pts were predominantly male (62%) and white (90%); mean age was 70 (standard deviation 11) years. BFI data (scale: 0 [no fatigue] - 10 [worst fatigue]) indicated that on average pts report that global fatigue, fatigue severity and fatigue-related interference worsen by ECOG severity (Table 1) and are statistically associated with clinician-reported fatigue (Table 2). Mean EQ-5D overall HRQOL as measured by a Visual Analogue Scale (VAS) from 0 (worst) to 100 (best) worsens by ECOG severity and is significantly worse in pts with fatigue. Mean EQ-5D domain scores (scale: 1 [no problem], 2 [some problems], 3 [incapacity]) indicated that pain/discomfort, mobility and usual activities increase in severity as ECOG worsens and in pts with fatigue. FACT-Leu domains except social/family were statistically worse with worse ECOG PS and in pts with fatigue. Conclusions: Initial results from Connect CLL® indicate that HRQOL worsens with worsening ECOG PS, especially in physical / functioning domains, pain/discomfort, and mobility, and worsens across multiple domains among pts whose physicians reported fatigue. Future analyses should be conducted on how HRQOL, PS and fatigue may change over time with changes in CLL, and how they are influenced by therapies. These results may serve as baseline reference. Disclosures: Pashos: Celgene: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Weiss:Celgene: Membership on an entity's Board of Directors or advisory committees. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees. Farber:Celgene: Membership on an entity's Board of Directors or advisory committees. Kipps:Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbot Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Lerner:Celgene: Membership on an entity's Board of Directors or advisory committees. Kay:Celgene: Membership on an entity's Board of Directors or advisory committees. Sharman:Celgene: Membership on an entity's Board of Directors or advisory committees. Grinblatt:Celgene: Membership on an entity's Board of Directors or advisory committees. Flinn:Celgene: Membership on an entity's Board of Directors or advisory committees. Kozloff:Celgene: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. Kahn:Celgene Corporation: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Sullivan:Celgene: Employment, Equity Ownership. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees.

Intensive Asparaginase Therapy in Young Adult Patients with Acute Lymphoblastic Leukemia: Treatment Patterns and Barriers to Asparaginase Use

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4913-4913
Author(s):  
Leonard S Sender ◽  
Tina Doede ◽  
Megan P. Hall ◽  
Celine Bernard
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Young Adult ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Employment Equity ◽  
Term Survival ◽  
The Past ◽  
Equity Ownership

Abstract Background : Although considerable progress has been made in treating acute lymphoblastic leukemia (ALL) in the pediatric population, with long-term survival exceeding 80%, the prognosis for adolescents, young adult, and adult patients with ALL remains poor, with only 30%-45% of patients achieving long-term survival. Several studies suggest that young adult patients have superior overall survival when treated with intensive "pediatric-inspired" regimens that include the use of asparaginase [Dombret H, et al. Curr Hematol Malig Rep. 2014;9(2):158-164]. Despite these results, many young adult patients with ALL continue to be treated with chemotherapy regimens that include little or no asparaginase. The goal of this study was to assess the views and practices of hematologists and oncologists with respect to asparaginase use in young adult patients with ALL. Methods : This study was conducted between May 14 and June 22, 2015, and consisted of a 10-minute online quantitative survey, with a 10-minute per-patient chart audit component for up to 4 charts provided by participating physicians. The survey targeted physicians treating young adult patients (aged 18-40 years) with ALL. To be included in the final analysis, physicians were required to be board certified with 2-30 years in practice, with ≥75% of their time spent in direct patient care and ≥20% of their time spent in an academic setting (NCCN/NCI or academic/teaching hospital). Inclusion criteria also required that physicians' total ALL patient volume (young adults and adults aged &gt;40 years) was greater than 5 over the past 2 years, that the physician primarily treats adult patients, and has personally managed and treated at least 1 young adult ALL patient in the past 2 years. Results: The study included results reported by a total of 63 practicing physicians for 189 young adult patients with ALL (62% were aged 25-40 years). Sixty percent (114/189) of young adult patients were treated with a protocol that included asparaginase, and only 29% (55/189) on a pediatric-inspired protocol. The most common protocols reported for patients receiving asparaginase included the pediatric-inspired CALGB 10403 (18%, 21/114), as well as regimens with more limited asparaginase use, including augmented hyper-CVAD (29%, 33/114) and CALGB 8811 (12%, 14/114). Overall 40% (75/189) of young adult patients were treated with protocols that did not include asparaginase, most commonly hyper-CVAD (77%, 58/75). Fifty percent (18/36) of responding physicians using hyper-CVAD reported the perception of similar outcomes with nonasparaginase regimens as with asparaginase-intensive regimens. When questioned about the greatest barrier to the use of intensive asparaginase-containing regimens, 88% (7/8) of responding physicians reported safety and tolerability concerns. Conclusion: Only 6 out of 10 patients in the study were treated with an asparaginase-containing regimen; of all patients, less than 1 out of 3 received a pediatric-inspired regimen. Fifty-three percent (60/114) of asparaginase-receiving patients were treated on a regimen that structures asparaginase dosing intermittently between alternating courses. Pediatric-inspired regimens include intensive asparaginase therapy and have consistently shown improvements in overall survival when compared with traditional adult protocols in clinical trials [Dombret H, et al. Curr Hematol Malig Rep. 2014;9(2):158-164]. Support: This study was funded by Jazz Pharmaceuticals. Disclosures Sender: Jazz Pharmaceuticals: Research Funding, Speakers Bureau. Doede:Jazz Pharmaceuticals: Employment, Equity Ownership. Hall:Jazz Pharmaceuticals: Employment, Equity Ownership. Bernard:Jazz Pharmaceuticals: Employment, Equity Ownership.

scholarly journals Could Patients with Multiple Myeloma (MM) Derive Additional Benefit from Their Treatments? Real-World Evidence for Carfilzomib Dosing Intensity on Survival and Treatment Progression

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 836-836 ◽  
Author(s):  
Rohan Medhekar ◽  
Dionne Hines ◽  
Sumeet Panjabi ◽  
Tim Welliver ◽  
Xin Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Real World ◽  
Lower Risk ◽  
Index Date ◽  
Cox Model ◽  
Weekly Dose ◽  
Employment Equity ◽  
K Index ◽  
Equity Ownership ◽  
The Impact

Abstract Introduction: Carfilzomib (K) was first approved in 2012 for the treatment of relapsed/refractory multiple myeloma (RRMM) at a dose of 27 mg/m2 twice weekly (27 BIW). The K dose has since been optimized; carfilzomib plus dexamethasone (Kd) is approved for patients with RRMM at a recommended K dose of 56 mg/m2 twice weekly (56 BIW) since 2016. Recently, the A.R.R.O.W trial showed that Kd 70mg/m2 once weekly (70 QW) significantly improved progression free survival compared to Kd 27 BIW. Considering the study time-period, however, patients are still treated with 27 BIW in the real-world leaving them possibly under-treated. The Kd 27 BIW, corresponds to a cumulative weekly dose (CWD) of K <120mg, while both Kd 56 BIW and Kd 70 QW (optimized dose-56 BIW/70 QW) correspond to a CWD of K >120mg. Therefore, in order to understand the relationship between dose and outcomes we examined the impact of K-dosing (CWD >120mg [optimized dose-56 BIW/70 QW] vs. CWD ≤120 mg [27 BIW]) on time to next treatment (TTNT) and overall survival (OS) among patients treated with Kd regimen. Methods: IQVIA's Oncology Electronic Medical Records database was used to identify patients ≥18 years of age, with a diagnosis of MM between 1/1/2010 and 10/31/2017, receiving Kd regimen in any line of therapy, with ≥ 3 doses of K on or after their K-index date (first administration of K in the Kd regimen, between 1/1/2013 and 10/31/2017). Patients were required to have ≥ 3 doses of K in order to establish continuity and for calculating CWD. CWD was calculated as the cumulative sum of weekly dose of K received by the patient divided by the number of weeks with Kd administration. The first two K doses were excluded from the calculation of CWD as these represent the loading dose. OS and TTNT were compared between patients receiving optimized dose-56 BIW/70 QW vs. 27 BIW. OS was evaluated among the subset of patients with a recorded deceased or alive status and measured from the K-index date until death due to any cause or the end of the study period, where they were censored. TTNT was defined as the time from initiation of the Kd regimen until the start of a subsequent regimen that did not contain Kd (treatment progression). Additionally, a landmark analysis at 12 months from initiation of Kd regimen was conducted to measure the proportion of patients alive and the proportion of patients with treatment progression. Kaplan-Meier analysis was used to estimate OS and TTNT and the log-rank test was used to compare the groups. Adjusted hazard ratios for OS and TTNT were evaluated using Cox models. Results : A total of 1,469 eligible MM patients with ≥3 Kd administrations were identified, of which 129 (8.8%; mean age: 63.5, SD: 9.8) received optimized dose-56 BIW/70 QW and 1,340 (91.2%; mean age: 67.0, SD: 10.4) received 27 BIW. The median follow-up time was slightly over a year for patients in both cohorts. The median K dose was 147.0 mg among patients in optimized dose-56 BIW/70 QW group and 88.1 mg among patients in 27 BIW group. Median OS was not estimable (NE), however, OS for the optimized dose-56 BIW/70 QW group (n=78) was significantly longer than that of the 27 BIW group (n=771; p=0.002) (Fig. 1). The proportion of patients in optimized dose-56 BIW/70 QW group alive at 12 months was 90.3% compared to 79.7% for patients in 27 BIW group respectively. Covariate-adjusted cox model showed that patients in optimized dose-56 BIW/70 QW group had a 64% lower risk of death than patients in 27 BIW group (adjusted HR: 0.364; 95% CI: 0.178-0.745; p = 0.0057, Table 1). TTNT was significantly longer for patients in optimized dose-56 BIW/70 QW group compared to patients in 27 BIW group (p=0.023; median TTNT: 17.5 [95% CI: 14.8-NE] and 13.2, [95% CI: 12.4-14.4], respectively) (Fig. 2). Covariate-adjusted cox model showed that patients in optimized dose-56 BIW/70 QW group had a 33% lower risk of treatment progression than patients in 27 BIW group (adjusted HR: 0.669; 95% CI: 0.483-0.927; p=0.0155, Table 1). Conclusion: Among patients treated with Kd regimen, a smaller proportion were prescribed K at optimized dose-56 BIW/70 QW. Patients receiving the optimized dose-56 BIW/70 QW had significantly improved OS and TTNT compared to those receiving 27 BIW. Our findings suggest that these patient-relevant outcomes may be improved in a vast majority of RRMM patients currently under-treated with carfilzomib by optimizing the dose, taking into consideration patients' comorbidities and ability to tolerate therapy. Disclosures Medhekar: Amgen: Employment, Equity Ownership. Hines:Amgen: Consultancy. Panjabi:Amgen: Employment, Equity Ownership. Welliver:Amgen: Employment, Equity Ownership. Wang:Amgen: Consultancy. Wade:Amgen: Consultancy.

scholarly journals Imerge: A Study to Evaluate Imetelstat (GRN163L) in Transfusion-Dependent Subjects with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) That Is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4248-4248 ◽  
Author(s):  
Uwe Platzbecker ◽  
David P. Steensma ◽  
Koen Van Eygen ◽  
Azra Raza ◽  
Valeria Santini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Phase 2 ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Equity Ownership ◽  
The Impact ◽  
Rbc Transfusion

Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase and is a competitive inhibitor of telomerase enzymatic activity (Asai et al, Cancer Res 2003; Herbert et al, Oncogene 2005). Preclinical, in vivo xenograft models (Dikmen et al, Cancer Res 2005; Hochreiter et al, Clin Cancer Res 2006) and preliminary clinical data from a pilot study conducted at Mayo Clinic (Tefferi et al, Blood Cancer Journal 2016) supported initiation of a study in TD LR MDS patients. A Phase 2 study of imetelstat, IMerge, demonstrated an 8-week RBC transfusion independence (RBC-TI) rate of 42%, 24-week RBC-TI rate of 29%, and 68% erythroid hematologic improvement (HI-E) rate in 38 heavily TD patients (median prior RBC transfusion burden 8 units / 8 weeks over the 16 weeks pre-study period) with LR MDS. Responses were durable with median duration of 8-week RBC-TI of 85.9 weeks by Kaplan Meier estimates (range 8.0-140.9) (Steensma ASH 2018, Fenaux EHA 2019). These Phase 2 results provided further evidence of potential clinical benefit of imetelstat treatment in TD LR MDS, and supported initiation of a Phase 3 trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 2 portion of the study described above is closed for enrollment. The Phase 3 portion of the study is open for enrollment of adult patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS, who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo that will enroll approximately 170 patients and will be conducted at approximately 90 centers in North America, Europe, Asia and Middle East. Imetelstat will be administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics and effect of treatment on quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. Disclosures Platzbecker: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Steensma:Astex: Consultancy; Arrowhead: Equity Ownership; Summer Road: Consultancy; Onconova: Consultancy; Aprea: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; H3 Biosciences: Other: Research funding to institution, not investigator.. Santini:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Font:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Sherman:Geron Corporation: Employment, Equity Ownership. Dougherty:Geron Corporation: Employment, Equity Ownership. Feller:Geron Corporation: Employment. Sun:Geron Corporation: Employment, Equity Ownership. Wan:Geron Corporation: Employment, Equity Ownership. Huang:Geron Corporation: Employment, Equity Ownership. Rizo:Geron Corporation: Employment, Equity Ownership. Fenaux:Celgene Corporation: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.

scholarly journals Carfilzomib Dosing Patterns and Survival in Patients with Relapsed and Refractory Multiple Myeloma: An Analysis from US Community Oncology Practices

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2084-2084
Author(s):  
Robert M. Rifkin ◽  
Eileen Fonseca ◽  
Yaozhu J. Chen ◽  
Patricia S. Fox ◽  
James E. Browning ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Employment Equity ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Community Oncology ◽  
Social Security Death Index ◽  
Equity Ownership ◽  
The Impact ◽  
Dosing Patterns

Abstract Introduction While novel agents have improved survival over the last decade, multiple myeloma (MM) remains incurable. Carfilzomib (CFZ), a second-generation proteasome inhibitor, was approved in July 2012 by the US Food and Drug Administration and had a label change in July 2015. During this study's data period, the label recommended Cycle 1 dose at 20 mg/m2/day and if tolerated increase Cycle 2 dose and subsequent cycles doses to 27 mg/m2/day. The purpose of this study is to assess baseline characteristics, CFZ dosing patterns and survival among MM patients in a US community oncology setting. Methods A retrospective study of MM patients from US Oncology Network practices that fully implemented McKesson Specialty Health's iKnowMed (iKM) oncology-specific electronic health records database was conducted on patients whose first treatment of CFZ (index) occurred between Jul-2012 and Nov-2014. Patients were eligible if they had a documented initial MM diagnosis date and had their first CFZ cycle documented in the database. Additionally, patients were required, before Dec-2014, to have either another visit to the practice post-index or a record of death and not have participated in interventional clinical trials during the previous 6 years. Data on eligible patients were collected up to March 2015. The death event was defined by the Social Security Death Index, supplemented by iKM; patients without the event were censored at the date of last observed visit. To adjust for clinical practice variations, a 10% variability was allowed for the recommended daily dose levels of 20 mg/m2 and 27 mg/m2. A subgroup was defined for patients with a 2nd cycle: "escalators" if they received 20 mg/m2/day doses throughout Cycle 1 and increased to 27 mg/m2/day on the first dose of Cycle 2; "non-escalators" if they received only 20 mg/m2 doses throughout Cycle 1 and did not increase to 27 mg/m2 on the first dose of Cycle 2; receiving any dose not equal to 20 or 27 mg/m2 were classified into "other". Survival after index was estimated using the Kaplan-Meier method with 95% confidence intervals (CI). A multivariable Cox proportional hazards (PH) model was conducted to evaluate the impact of escalation on survival accounting for selected baseline demographic and clinical characteristics. Results The cohort of 718 CFZ patients were identified with a median (interquartile range [IQR]) age of 68 (61-75) years at index, 57% (n=409) were male, and 12% (n=87) were Black and 77% (n=551) were Caucasian. At initial MM diagnosis, 19%, 27% and 42% were ISS Stage I, II, and III, respectively. Median (IQR) time from MM diagnosis to index was 3.6 (1.9-5.8) years. At index, 66% of patients had an ECOG performance status of 0-1, 21% of 2, and 2% of 3+; 54% (n=369) had moderate to severe renal impairment (eGFR<60 mL/min per 1.73 m2). Ninety percent (n=644) of patients started CFZ at 20 mg/m2, 4% (n=27) at 27 mg/m2 and 4% (n=25) at 15 mg/m2. Patients had a median (IQR) of 4 (2-7) cycles of CFZ and 45% (n=321) escalated to ≥27 mg/m2. Among these 321 patients, median (IQR) time to first escalation was 30 (28-56) days with 60% escalating in Cycle 2. The subgroup defined in "Methods" included 605 patients: 148 (24%) escalators, 342 (57%) non-escalators, and 115 (19%) other. Median (95% CI) duration from index to death was 21 (17.5-23.2) months. Unadjusted overall survival (OS) was significantly lower among non-escalators compared to escalators (log-rank p=0.024) [Figure 1]. Survival rates (95% CI) for non-escalators and escalators were 68% (62-74%) and 75% (66-82%) at year 1 and 42% (33-50%) and 61% (49-71%) at year 2, respectively. Within the multivariable Cox model, escalators showed a 33% significantly lower risk of death compared to non-escalators (HR=0.67, p=0.03) while also accounting for race, sex, age group, renal function per EGFR, and MM chain type. Other significant variables in this model were: EGFR < 15 and 15-29 vs 30-59 ml/min per 1.73m2 (HR=2.79, p<0.01; HR=1.64, p=0.04, respectively) and lambda vs kappa light chain (HR=1.55, p=0.03). Conclusions These results indicate escalation of CFZ at first dose of Cycle 2 is associated with better survival than dosing at 20 mg/m2 in Cycle 1 but not escalating at the start of Cycle 2. More research is needed to assess factors that impact physician decision-making on dose escalation to better inform physicians to improve the quality of multiple myeloma care. Disclosures Rifkin: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Fonseca:McKesson Specialty Health, which received funding to conduct this research: Employment, Equity Ownership. Chen:Onyx Pharmaceuticals: Employment. Fox:McKesson Specialty Health, which received funding to conduct this research: Employment. Browning:Onyx Pharmaceuticals, An Amgen Subsidiary: Employment. Cong:Onyx Pharmaceuticals: Employment, Equity Ownership.

scholarly journals Population Pharmacokinetics of Ivosidenib (AG-120) in Patients with IDH1-Mutant Advanced Hematologic Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1394-1394 ◽  
Author(s):  
Kha Le ◽  
Russ Wada ◽  
David Dai ◽  
Bin Fan ◽  
Guowen Liu ◽  
...  
Keyword(s):  
Body Weight ◽  
Steady State ◽  
Eastern Cooperative Oncology Group ◽  
Hematologic Malignancies ◽  
Employment Equity ◽  
Disease Characteristics ◽  
Population Pk ◽  
Cyp3a4 Inhibitors ◽  
Equity Ownership ◽  
The Impact

Abstract BACKGROUND: Ivosidenib, a potent mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is being assessed in a phase 1 study of mIDH1 advanced hematologic malignancies (NCT02074839). We characterized the pharmacokinetics (PK) of ivosidenib in this population, and the effects of patient/disease characteristics and concomitant medications. METHODS: Ivosidenib was given in continuous 28-day cycles at 100 mg twice daily and 300 mg, 500 mg, 800 mg, and 1200 mg once daily (QD). Enrollment is complete; 258 patients received ≥1 ivosidenib dose (78 in escalation, 180 in expansion); samples were available from 253 patients (223 received ivosidenib 500 mg QD). Ivosidenib concentrations were determined using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based methods. Population PK modeling was conducted using NONMEM software. The impact of demographics, renal and hepatic function, disease type, Eastern Cooperative Oncology Group (ECOG) performance status, and concomitant cytochrome P450 3A4 (CYP3A4) inhibitors/inducers and gastric acid reducers on ivosidenib PK was explored. RESULTS: Ivosidenib PK were best described using a 2-compartment model with first-order absorption, dose-dependent bioavailability, and a time-dependent change in relative bioavailability and clearance between Day 1 and steady state. Mean steady-state apparent clearance (CL/F) was 5.39 L/h (between-patient variability ~35%) and mean central volume of distribution (Vc/F) was 234 L (~47%). Less than dose-proportional bioavailability was observed, with a dose doubling translating to a ~40% increase in exposure. The moderate/strong CYP3A4 inhibitors voriconazole, fluconazole, and posaconazole were associated with 36%, 41%, and 35% reductions in CL/F, and hence 57%, 69%, and 53% increases in area under the plasma ivosidenib concentration-time curve (AUC), respectively (Figure 1). Baseline body weight had a significant impact on Vc/F. Low albumin at baseline and during treatment correlated with decreased CL/F and Vc/F. However, the effects of body weight and albumin did not appear to be clinically relevant. No effects of creatinine clearance or measures of liver function (alanine aminotransferase, aspartate aminotransferase, bilirubin, within the range studied) on ivosidenib CL/F were detected. Concomitant use of pantoprazole or famotidine did not affect ivosidenib CL/F. CONCLUSION: This population PK model of ivosidenib suggests that no dose adjustments are needed based on the range of patient and disease characteristics analyzed. Disclosures Le: Millennium: Patents & Royalties; Agios: Employment, Equity Ownership. Wada:Certara: Employment; Agios: Consultancy. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Attar:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Yang:Agios: Employment, Equity Ownership.

scholarly journals Role of hnRNP K and Interacting mRNAs in Pathogenesis of AML with 9q Deletion

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1531-1531
Author(s):  
Kerstin Rahn ◽  
Isabel Naarmann-de Vries ◽  
Yvonne Sackmann ◽  
Felicitas Klein ◽  
Antje Ostareck-Lederer ◽  
...  
Keyword(s):  
Research Funding ◽  
Transcriptional Control ◽  
Mrna Level ◽  
Rna Seq ◽  
Employment Equity ◽  
Knock Out ◽  
Hnrnp K ◽  
Qpcr Analysis ◽  
Equity Ownership ◽  
The Impact

Abstract Introduction: Acute myeloid leukemia (AML) is characterized by heterogeneous cytogenetic and molecular aberrations. Deletions on the long arm of chromosome 9 (del(9q)) are observed in 2% of AML patients. In about 24% of the cases, del(9q) is observed as sole karyotypic abnormality, while in the remaining 76%, it is associated with a t(8;21) translocation or other aberrations. Among all del(9q) AML cases, 36%-50% exhibit an additional t(8;21), whereas 7%-14% of AML cases with t(8;21) show del(9q) as an additional aberration. A commonly deleted region (CDR) of del(9q) was defined and further analysis specified a minimally deleted region (MDR) composed of seven annotated genes (GKAP1, KIF27, C9ORF64, HNRNPK, RMI1, SLC28A3 and NTRK2) (Kronke J et al. Blood. 2013). However, the function of these genes and their impact on the pathogenesis of AML remain elusive. A recent study demonstrated that reduced expression of the HNRNPK gene product can contribute to leukemogenesis in AML (Gallardo M, Cancer Cell. 2015). The multifunctional protein hnRNP K interacts with other proteins, DNA and RNA, to modulate gene activity and gene expression on different levels. For example, hnRNP K not only regulates SRC gene transcription, but as well SRC mRNA translation and the activity of c-Src kinase. In the context of AML, hnRNP K was shown to interact with the mRNAs encoding C/EBPa (CEBPA) and p21 (CDKN1A). We analyzed a cohort of 31 del(9q) AML patients in order to further analyze the deleted region and to analyze the impact of HNRNPK deletion on leukemogenesis. Methods: 31 del(9q) patients were used for the characterization of the deleted region. mRNA level (determined by RT-qPCR analysis) and clinical parameters were compared with a cohort of 24 normal karyotype (NK) AML patients. HnRNP K immunoprecipitation was combined with RNA-Seq, a whole transcriptome shotgun sequencing application based on next generation sequencing and validated by RT-qPCR analysis. CRISPR-Cas9 genome editing has been applied to functionally characterize the impact of post-transcriptional control by hnRNP K in pathogenesis of AML. Results: Our analysis confirmed the MDR in a cohort of 31 AML del(9q) patients. Survival of patients and clinical parameters were not correlated with deletion size, further supporting the importance of the MDR, while other deleted genes seem to be less important for leukemogenesis. As demonstrated by qPCR analysis, the mRNA level of HNRNPK and other genes located in the MDR was reduced in patients carrying a del(9q) compared to NK patients. To further dissect a potential function of hnRNP K in AML del(9q), we characterized hnRNP K interacting mRNAs in the AML cell line KG-1a. Therefore, hnRNP K was immunoprecipitated from cytoplasmic extracts of KG-1a cells and interacting RNAs were identified by RNA-Seq analysis. This analysis revealed that 1076 RNAs are potentially associated with hnRNP K, among them the C/EBPa mRNA. Panther Protein Class analysis identified a high number of transcripts encoding nucleic acid binding proteins, mainly transcription factors. KG-1a cell lines harboring either a complete knock out of hnRNP K or a deletion of the RNA-binding KH-domain are currently generated by CRISPR-Cas9 genome editing to functionally analyze the impact of hnRNP K-mediated post-transcriptional control in AML. Conclusion and Outlook: The deletion of seven genes (GKAP1, KIF27, C9ORF64, HNRNPK, RMI1, SLC28A3 and NTRK2) in the MDR is indispensable, indicating a crucial function for the development of AML del(9q). Among them HNRNPK seems to be a particularly important factor in this process. The identification of hnRNP K interacting RNAs provides the basis to further improve our insight in molecular mechanisms, which drive the pathogenesis of AML del(9q). HNRNPK knock out cell lines will be used to analyze the effect of HNRNPK deletion on post-transcriptional control of identified target genes. Disclosures Ehninger: Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; GEMoaB Monoclonals GmbH: Employment, Equity Ownership; Bayer: Research Funding. Brümmendorf:Merck: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy. Rollig:Janssen: Research Funding; Bayer: Research Funding. Thiede:Novartis: Honoraria, Research Funding; AgenDix: Other: Ownership.

scholarly journals AG-221, a Small Molecule Mutant IDH2 Inhibitor, Remodels the Epigenetic State of IDH2-Mutant Cells and Induces Alterations in Self-Renewal/Differentiation in IDH2-Mutant AML Model in Vivo

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 437-437 ◽  
Author(s):  
Alan H. Shih ◽  
Kaitlyn R Shank ◽  
Cem Meydan ◽  
Andrew M. Intlekofer ◽  
Patrick Ward ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Clinical Trials ◽  
Small Molecule ◽  
Leukemia Cells ◽  
Employment Equity ◽  
Advisory Committees ◽  
Self Renewal ◽  
Equity Ownership ◽  
The Impact

Abstract Somatic mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are observed in patients with acute myeloid leukemia (AML). Leukemia-associated IDH1/2 mutations result in aberrant accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). The observation that IDH1/2 mutations are mutually exclusive with TET2 mutations led to the finding that IDH1/2-mutant production of 2-HG inhibits TET2 function and induces changes in DNA methylation. These data suggested that small molecule inhibition of mutant IDH enzymes might reverse the aberrant epigenetic remodeling of IDH-mutant leukemia cells and restore normal hematopoietic differentiation. We therefore investigated the in vivo efficacy of AG-221, a potent and selective mutant IDH2 inhibitor in early-phase clinical trials, in murine models of IDH2-mutant leukemia. We first assessed the impact of AG-221 on 2-HG production in hematopoietic cells expressing mutant IDH2-R140Q. AG-221 treatment (10mg/kg or 100mg/kg bid) led to a reduction in 2-HG in vivo (96.7% below pre-treatment levels). Moreover, AG-221 treatment restored megakaryocyte-erythroid progenitor (MEP) differentiation that is suppressed by mutant IDH2 expression in vivo (mean MEP% mean, 39% Veh vs 50% AG-221). We next investigated the impact of mutant IDH2 inhibition with AG-221 on DNA methylation in vivo. We used eRRBS, a bisulfite-based next-generation sequencing platform, to assess the effect of AG-221 therapy on DNA methylation. AG-221 or vehicle therapy treated LSK stem cells (lin- Sca+ c-Kit+) were sorted from mice expressing IDH2-R140Q and evaluated by eRRBS. AG-221 therapy reversed the effects of mutant IDH2; we observed a significant reduction in DNA methylation, including 180 genes that had 20 or more hypomethylated differentially methylated cytosines (DMCs) following treatment. 84 of these genes had reduced methylation at 10 or more DMCs in the gene promoter with AG-221 therapy compared to vehicle. Mutant IDH2 inhibition with AG-221 reversed aberrant methylation at many genes with a known role in hematopoietic proliferation and differentiation, including the master transcriptional factor RUNX1. We next assessed in vivo effects of the small-molecule IDH2-R140Q inhibitor in a mouse model of IDH2-mutant leukemia. We generated mice that simultaneously expressed a constitutive Flt3ITD knock-in allele and a conditional mutant IDH2R140Q knock-in allele. As reported recently using retroviral/transgenic models, Mx1-Cre IDH2R140QFlt3ITD developed fully penetrant, transplantable AML with expansion of c-Kit+ positive blasts in the peripheral blood, and widespread leukemic infiltration. AG-221 inhibited the serial replating capacity of IDH2R140QFlt3ITD expressing cells in vitro. We competitively transplanted IDH2R140QFlt3ITD AML cells and normal bone marrow cells into secondary recipients, and then assessed the effect of AG-221 therapy on leukemia in vivo and on disease burden. AG-221 (100mg/kg bid) treatment of mice engrafted with Mx1-Cre IDH2R140QFlt3ITD AML cells markedly reduced 2HG levels consistent with on target inhibition in vivo. AG-221 therapy induced differentiation of leukemic cells, with an increase in the CD11b+ population and a decrease in the c-Kit+ population in the peripheral blood at 2wks. We next assessed the impact of treatment with both AG-221 therapy with AC220, a potent, specific Flt3 inhibitor in late phase clinical trials. Combined IDH2R140Q and Flt3ITD inhibition resulted in a marked decrease in leukemic burden to vehicle-treated mice, with a significant reduction in leukemic cell chimerism in vivo in the setting of combined inhibition at 2 wks, (mean 45.2 fraction 88% veh, 73% AG-221, p<.01). These data demonstrate that AG-221 inhibits mutant IDH2-mediated 2-HG production in vivo and reverses the effects of mutant IDH2 on DNA methylation in mutant stem/progenitor cells. AG-221 induces differentiation and impairs self-renewal of IDH2-mutant leukemia cells, effects that are further enhanced by simultaneous inhibition of Flt3ITD. Clinical trials combining IDH2 inhibitors with other targeted AML therapies are warranted in order to increase therapeutic efficacy. Disclosures Intlekofer: Foundation Medicine, Inc: Consultancy. Thompson:Agios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Travins:Agios Pharmaceuticals: Employment, Stockholder Other. Straley:Agios: Employment, Equity Ownership. Gliser:Agios Pharmaceuticals: Employment, Stockholder Other. Yen:Agios: Employment, Equity Ownership. Levine:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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