ALBERT

Description: Key Points No overall clinical benefit was seen after the addition of lestaurtinib to standard chemotherapy for newly diagnosed FLT3-mutated AML. Lower rates of relapse and improved overall survival were seen in patients who achieved sustained levels of FLT3 inhibitory activity.

Description: Background: Financial Toxicity (FT) is increasingly recognized as a major contributor to morbidity and mortality in a variety of cancers. Treatment of acute leukemia is associated with heavy healthcare utilization and high costs. The purpose of this study was to define rates, risk factors, and mortality implications for FT in patients with acute leukemia using patient reported data. Methods: All patients seen at the Levine Cancer Institute, a tertiary hospital-based leukemia practice, were surveyed prior to each visit over a six-month period. All patients were aged ≥18 years and were diagnosed with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). The survey consisted of the PROMIS Global-10 measure and two questions from the COST measure. FT was defined as scoring 4 or less (maximum: 10) in agreement with the COST questions: "I know that I have enough money in savings, retirement, or assets to cover the costs of my treatment" and "I am satisfied with my current financial situation." Demographic data and disease characteristics were abstracted from the medical record. Model selection was carried out using logistic regression to identify factors impacting the incidence of financial toxicity. Correlation of numerical financial toxicity scores with PROMIS scores and with mortality data was assessed using linear regression. Results: Of the 106 patients, 58 (54%) met the definition of exhibiting FT. The factors associated with incidence of FT included: age, race, and insurance type. The odds of FT in those patients 4 compared to patients with FT scores

Description: Background:Patients with polycythemia vera (PV) often present with a broad range of clinical characteristics that may contribute to increased risks of cardiovascular (CV) morbidity and mortality, including thrombotic events (TE). Limited contemporary real-world data have been reported about the clinical burden of PV and treatment patterns in the United States. The ongoing REVEAL study collects data on disease burden, clinical management, patient-reported outcomes, and healthcare resource utilization for patients with PV in the United States. This analysis reports clinical characteristics, including underlying CV risk factors, for patients enrolled in the REVEAL study as of April 28, 2016. Methods: REVEAL is a multicenter, nonrandomized, prospective, observational study enrolling patients ≥18 years of age with a PV diagnosis who are actively managed in an academic or community setting. For this analysis, data regarding PV disease and diagnosis, clinical characteristics, and treatment patterns were collected at enrollment during usual-care visits and were based on physician assessment, electronic medical records, and local laboratory values. Ten-year CV risk factors selected for this analysis were adapted from the Framingham Heart Study for CV diseases. Results: At data cutoff, 2307 patients were available for this analysis. Mean (SD) age was 66.3 (12.2) years, 54.4% were male, 89.9% were white, 62.7% had at least some college education, and 51.1% were retired. Approximately 6% of patients had a family history of PV, primarily in parents (35.1%) and siblings (33.8%). A history of second malignancies was reported for 344 patients (14.9%). The majority of patients (84.6%) were diagnosed with PV based on an abnormal blood test alone or in combination with a bone marrow test. Among patients who were diagnosed with a mutational test (n=1078), 95.2% were diagnosed via an abnormal JAK2V617F test result. Abnormal hemoglobin (57.3%), hematocrit (55.4%), or both (47.5%) were among the most common blood values assessed for PV diagnosis. At diagnosis, 58.5% of patients were classified with high-risk PV (age ≥60 years or history of a TE); this percentage increased to 77.3% at REVEAL enrollment. The average (SD) disease duration from diagnosis to enrollment was 5.8 (6.1) years. At enrollment, 91.5% of patients were under active management for PV (phlebotomy ± aspirin, 34.0%; hydroxyurea ± aspirin, 27.0%; and phlebotomy + hydroxyurea ± aspirin, 23.2%). Underlying CV risk factors that were either diagnosed or treated in 86.0% of enrolled patients included hypertension (66.5%), history of smoking (46.2%), current smoking at enrollment (10.9%), obesity (34.2%), hyperlipidemia (27.4%), and diabetes (14.8%). At enrollment, 431 (18.7%) patients reported having ≥1 TE, including 181 patients who had a TE between PV diagnosis and enrollment. Venous and arterial TEs were reported in 11.1% and 8.6% of patients, respectively. Most commonly reported venous TEs were deep vein thrombosis (5.9%) and pulmonary embolism (2.5%); most common arterial TEs were cerebrovascular arterial thrombosis including transient ischemic attack (5.1%) and acute myocardial infarction (1.7%). Increased rates of TEs were observed among patients with hyperlipidemia (23.6%) and hypertension (21.0%; Table 1), compared with patients who did not have any risk factors (10.5%). Conclusion: A large proportion of patients in the REVEAL study had 1 or more underlying CV risks, including age, hypertension, smoking, obesity, hyperlipidemia, and diabetes, which may contribute to the risk of thrombosis. Longitudinal data from REVEAL will provide a better understanding of how these factors affect CV outcomes over time. Disclosures Stein: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Naim:Incyte Corporation: Employment, Equity Ownership. Grunwald:Janssen: Research Funding; Forma Therapeutics: Research Funding; Medtronic: Equity Ownership; Alexion: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Oh:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; CTI: Research Funding. Paranagama:Incyte Corporation: Employment, Equity Ownership. Cordaro:Incyte Corporation: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Parasuraman:Incyte Corporation: Employment, Equity Ownership. Boccia:Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau; Gilead: Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; Eisai: Consultancy, Honoraria, Speakers Bureau. Mesa:Ariad: Consultancy; CTI: Research Funding; Gilead: Research Funding; Galena: Consultancy; Novartis: Consultancy; Promedior: Research Funding; Celgene: Research Funding; Incyte Corporation: Research Funding.

Description: Abstract 2479 FLT3/ITD mutations are present in approximately one quarter of adult AML cases. Patients with these mutations carry a particularly poor prognosis. For this reason, a number of small molecule FLT3 inhibitors are being evaluated in clinical trials. In AML patients with FLT3/ITD mutations, it has become an increasingly common practice to pursue allogeneic bone marrow transplantation quickly during first remission. Among this patient population, as with other AML patients, relapse following transplant occurs frequently. As a result, there are numerous ongoing efforts to investigate a potential role for maintenance therapy with FLT3 inhibitors in the post-transplant setting. Historically, post-transplant remission in AML patients has been assessed using bone marrow morphology as well as hematologic recovery. Better methods are needed to assess minimal residual disease in AML patients. The standard method of detecting the FLT3/ITD mutation (Murphy KM, J Mol Diagn 2003) with PCR has a limit of detection of approximately 1 in 100 cells. In many FLT3/ITD AML patients who ultimately relapse with FLT3-mutated disease after transplant, the FLT3 mutation is still not detectable by standard PCR assay at time points before and after transplant, because their burden of disease is lower than the detection threshold of the assay. We report here a new PCR technique for detecting the presence of a FLT3/ITD mutation with a high level of sensitivity and specificity. The technique is referred to as tandem duplication PCR (TD-PCR). Instead of using inward-facing primers that flank the juxtamembrane domain of FLT3, TD-PCR uses outward-facing, overlapping primers within the expected region of mutation. The TD-PCR primers will not amplify any product when annealed to a wild type FLT3 template. However, if a tandem duplication is present, the primers will anneal at two distinct sites and will amplify a product, provided the duplication is long enough (roughly 30 to 40 base pairs). A duplication under this size does not allow enough room to anneal both primers. To investigate the potential clinical utility of TD-PCR, we performed a chart review at our institution and found that between December 2004 and May 2012 there were 62 patients diagnosed with FLT3/ITD AML who subsequently underwent allogeneic bone marrow transplant while in morphologic remission. Of those 62 patients, 50 were alive and in remission 60 days after the transplant. DNA samples prepared from bone marrow collected on or around Day 60 following the transplant were available for 36 of these 50 patients. Based on the size of the duplications, the TD-PCR assay was informative for 26 of these 36 (72%). Of the 26 patients whose TD-PCR results were informative, seven (27%) had positive TD-PCRs on their day 60 bone marrow specimens. The standard clinical PCR was performed on six of these seven patients and was negative in all six cases. Of the seven patients with positive post-transplant TD-PCRs, five (71%) have relapsed to date, while two still remain in remission (one of whom is on sorafenib maintenance). Nineteen of the 26 (73%) had negative TD-PCRs on their day 60 bone marrow specimens. Of these 19 patients, only two (11%) have relapsed thus far, one of whom relapsed with FLT3 wild type AML and one of whom relapsed with the FLT3/ITD mutation 29 months after the transplant. TD-PCR is thus highly predictive (p = 0.001; log-rank) for relapse risk for FLT3/ITD AML following allogeneic transplant (Figure 1). It is possible that this technique will identify patients who might benefit from post-transplant therapy such as FLT3 inhibition or donor lymphocyte infusion. We are currently examining the use of TD-PCR prospectively in an ongoing clinical trial using post-transplant sorafenib in FLT3/ITD AML patients. Larger studies are necessary to validate this technique as a prognostic tool and as a means of guiding therapy. Disclosures: No relevant conflicts of interest to declare.

Description: Background: APL is a highly curable malignancy with reported survival above 90% in many co-operative group studies. However these spectacular results are not evident in the general population. US SEER data and other population based studies from Swedish Cancer Registry and Brazil showed that early deaths (ED) can be as high as 30%, leading to a considerably lower survival compared to clinical trials where ED is around 5-10%. Decreasing ED remains a global challenge and the highest priority at all leukemia treatment centers and will result in population wide survival in this most curable leukemia. We report results of our prospective trial using a set of simplified treatment guidelines along with expert support designed to decrease ED. Methods: A network of leukemia treatment centers was established in Georgia, South Carolina and neighboring states. An aggressive outreach effort was made by visiting most of the leukemia treatment centers to publicize the concept and educate treating physicians in the community about ED in APL. The protocol provides a simplified two page treatment algorithm that emphasizes quick diagnosis, prompt initiation of therapy and proactive and aggressive management of the major causes of death during induction. Expert and treating physician communication was established very early when a diagnosis of APL was suspected and was maintained until the completion of induction. Study was approved by local IRBs (if applicable) and funded by the Lymphoma Leukemia Society (LLS). Informed consent was obtained upon confirmation of a diagnosis of APL and there were no exclusion criteria. Patient accrual was initiated in July 2013 and continued till May 2016 when the accrual goal of 120 was met on an intent to treat basis. Statistics are descriptive. Results: Between 7/2013 and 5/2016, 120 patients were enrolled at 5 large leukemia centers (n=54, 45%) and 24 community hospitals (n=66, 55%). Only 3 hospitals treated more than 3 APL patients/year. Median age was 54 years (range 21-84 years). 68 were male. 84% were low risk (WBC 〈 10,000/mm3) and median WBC count was 4.3 (range 0.3-170,000/mm3). ATRA was initiated at suspicion of APL diagnosis in 100% of patients and was the only treatment in 2(1.5%) patients. Arsenic was combined with ATRA in 93 (81.5%) patients while the other 17% received chemotherapy. 15(13%) had bleeding complications at presentation. Treatment course was complicated by infection and differentiation syndrome (DS) in 31(28%) and 40(34%) patients respectively. There were 12 early deaths, of which 1 was a Jehovah's Witness who declined transfusions and 1 who enrolled 12 days after diagnosis while in multi-organ failure. Incidence of ED was 10/118 (8.5%). The cause of death was disseminated intravascular coagulation (DIC) (n=4), DS (n=2), infection (n=1), anemia (n=1), multi-organ failure (n=4). With a median follow-up of 10.6 months, 2 low risk patients relapsed: I due to non-compliance 1 year after diagnosis and 1 with CNS relapse 3 months after completing consolidation. With a median follow up of 320 days (range 1-965) overall survival (Figure 1) was 87%. There were four late deaths; relapse (n=1), second cancer (n=1) and non-APL related comorbidities (n=2). Conclusions: Results of this prospective trial showed that a simplified treatment algorithm along with support from experts and co-management with treating physicians in the community decreased induction mortality (8.5%) and improved survival (87%) compared to SEER data (1 year relative survival of 71%). We believe our experience warrants large scale implementation and is presently approved as an ECOG/ACRIN trial (EA9131). This model can be applicable to other cancers and life-threatening diseases. Figure Overall Survival Figure. Overall Survival Disclosures Jillella: Leukemia Lymphoma Society: Research Funding. Heffner:AbbVie: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Stuart:Astellas: Research Funding; Celator: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Agios: Research Funding; Bayer: Research Funding; Incyte: Research Funding. Gerber:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding. Grunwald:Medtronic: Equity Ownership; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Amgen: Research Funding; Janssen: Research Funding. Kota:Pfizer: Membership on an entity's Board of Directors or advisory committees; Ariad Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 1519 Background: The outcome of patients (pts) with acute myeloid leukemia (AML) and FLT3-ITD mutation is poor, particularly in the relapse setting. Sorafenib is a potent inhibitor of FLT3 kinase with reported clinical activity as a single agent (Metzelder S, Blood, 2009), and in combination with chemotherapy (Ravandi F, JCO, 2010). A potential mechanism of resistance to FLT3 kinase inhibitors is high levels of FLT3 ligand (FL) as seen after myelosuppressive chemotherapy. We hypothesized that combining sorafenib with a less myelosuppressive agent, such as 5-azacytidine (AZA), may lead to higher and more durable responses than cytotoxic chemotherapy. Furthermore, both drugs have demonstrated a potential for inducing differentiation in AML cells, thereby providing further rationale for the combination. Methods: Pts were eligible if they had relapsed or refractory AML, were 18 years of age or older, and had adequate performance status (ECOG ≤ 2) and organ function. Older pts without prior therapy were also eligible, if they were deemed unsuitable to receive chemotherapy. Presence of FLT3-ITD was not a requirement but these pts were targeted for enrollment. Treatment regimen included AZA 75 mg/m2 daily for 7 days together with sorafenib 400 mg twice daily for 28 days; cycles were repeated in approximately 4 to 5-week intervals. Overall responses were assessed after the completion of at least one cycle of therapy and at the time of the best peripheral blood and bone marrow response. Plasma samples were collected on approximately Day 1 and Day 10 of each cycle. To assess the degree of FLT3 inhibition, the plasma inhibitory activity (PIA) assay was performed using the Molm-14 cell line (Levis M, Blood, 2006). Plasma FL concentrations were measured using an ELISA kit (R&D Systems). Results: 43 pts with AML with a median age of 64 years (range, 24–87) were enrolled. They included 19 (44%) pts with diploid cytogenetics, 11 (26%) with chromosome 5/7 or complex cytogenetic abnormalities, and 13 (30%) with miscellaneous abnormalities. Prior to the initiation of treatment, FLT3-ITD was detected in 40/43 (93%) pts with a median allelic ratio of 0.28 (range, 0 – 0.93). They had received a median of 2 prior treatments (range, 0–7). 16 (37%) pts had received ≥3 prior regimens and 9 had failed therapy with FLT3 kinase inhibitors (5 with AC220, 1 with PKC412, and 6 with sorafenib, either as monotherapy or with chemotherapy or plerixafor); 3 had failed 2 prior FLT3 inhibitors. 6 pts were inevaluable as they discontinued therapy before response assessment at one month and 3 are too early for response assessment. The overall CR/CRi/PR rate among the 34 evaluable pts is 44%, including 10 (29%) with CRi and 4 (12%) with CR and 1 (3%) with PR (in this pt, bone marrow blast declined from 51% to 6% with normalization of blood counts). Overall, pts have received a median of 3 (range, 1–9) treatment cycles with the median number of cycles to response among the responders being 2 (range, 1 – 4) and the median time to achieving response, 2.1 months (range, 0.9 – 4.6 months). The median duration of CR/CRi Is 2.3 months (range, 1 – 12.2+ months). Six pts have proceeded to allogeneic stem cell transplant. The most common study drug-related adverse events were rash and fatigue with no deaths attributable to study medications. One pt developed grade 3 cardiomyopathy suspected to be related to the study regimen. Of the 34 pts included in the clinical analysis, there were 22 pts from whom plasma samples spanning at least one cycle of therapy were available. Among them, 64% achieved FLT3 inhibition to a targeted level of less than 15% of baseline during their first cycle of therapy. Median survival in pts who achieved this degree of inhibition was 238 days, while median survival in pts who did not reach this level was 154 days (p=0.13). Mean FL levels at cycle 1, day 1 and cycle 1, day 10 were 9 pg/mL and 17 pg/mL, respectively. Mean FL levels at cycle 2, day 0 and cycle 2, day 10 were 27 pg/mL and 54 pg/mL, respectively. Conclusions: Combination of AZA and Sorafenib is effective for the treatment of older pts and pts with relapsed and refractory AML and FLT3-ITD mutation. While not statistically significant, there was a trend toward improved survival in pts with adequate FLT3 inhibition during cycle 1. FL levels did not rise to the levels seen in pts receiving cytotoxic chemotherapy. Disclosures: Ravandi: Bayer/Onyx: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Off Label Use: Off-label use of sorafenib and 5-azacytidine in patients with acute myeloid leukemia. Levis:Astellas Pharma: Consultancy; Plexxikon: Consultancy; Symphogen: Consultancy. Garcia-Manero:Celgene: Research Funding. Andreeff:Hoffmann-La Roche: Research Funding; Karyopharm Therapeutics: Unrestricted gift, Unrestricted gift Other. Cortes:Celgene: Research Funding.

Description: Background: Financial Toxicity (FT) is increasingly recognized as a major contributor to morbidity and mortality in a variety of cancers. Previous research has demonstrated patients with myeloproliferative neoplasms (MPNs) exhibit a substantial comorbidity burden and have an increased risk of mortality. The purpose of this study was to define rates of FT and the implications on morbidity and mortality in this population using patient reported data. Methods: All patients seen at the Levine Cancer Institute, a tertiary hospital-based specialty practice, were surveyed prior to their visit over a six-month period. All patients were aged ≥18 years and diagnosed with Philadelphia chromosome−negative classical MPNs including myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). The survey consisted of the PROMIS Global-10 measure and two questions from the COST measure. FT was defined as scoring 4 or less (maximum: 10) in agreement with the COST questions: "I know that I have enough money in savings, retirement, or assets to cover the costs of my treatment" and "I am satisfied with my current financial situation." Patient disease and treatment characteristics were summarized with frequencies and proportions for categorical variables and medians and ranges for continuous variables. Correlation of numerical FT scores with PROMIS scores was assessed with Pearson correlation coefficients and ANOVA regression. Additionally, model selection was carried out using logistic regression to identify factors impacting the incidence of financial toxicity (where FT score 4 compared to patients with FT scores 4 (p =.287). There also appeared to be a separation of the survival curves when looking at both time from diagnosis and time from survey administration (Figures 2 and 3). Age, race, gender, insurance type, distance from the hospital, disease type, disease specific risk classification, medications utilized, and history of blood/marrow transplant were not found to be significantly different in the two groups. Conclusions: Patients with myeloproliferative neoplasms represent an extremely vulnerable population for financial toxicity with quantifiably increased distress related to this toxicity increasing morbidity and potentially mortality. These findings should be validated in a larger patient cohort and interventions devised to reduce financial distress. Disclosures Knight: Foundation for Financial Planning: Research Funding. Ai:InCyte: Speakers Bureau; Amgen: Speakers Bureau. Trivedi:Incyte: Speakers Bureau. Avalos:Best Practice-Br Med J: Patents & Royalties: receives royalties from a coauthored article on evaluation of neutropenia; Juno: Membership on an entity's Board of Directors or advisory committees. Symanowski:Boston Biomedical: Membership on an entity's Board of Directors or advisory committees; Carsgen Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Immatics: Membership on an entity's Board of Directors or advisory committees. Grunwald:Amgen: Consultancy; Novartis: Research Funding; Genentech/Roche: Research Funding; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Trovagene: Consultancy; Agios: Consultancy; Incyte: Consultancy, Research Funding; Cardinal Health: Consultancy; Forma Therapeutics: Research Funding; Abbvie: Consultancy; Celgene: Consultancy; Merck: Consultancy; Medtronic: Equity Ownership; Janssen: Research Funding.

Description: Background: The hypomethylating agents (HMAs) azacitidine and decitabine have been increasingly used in the frontline setting for elderly and/or unfit patients with acute myeloid leukemia (AML). While these therapies are oftentimes used in the palliative setting, HMAs have also been used with curative intent in some patients, as a bridge to allogeneic hematopoietic cell transplantation (HCT). It is well known that 4-6 cycles of HMA therapy can be necessary to achieve a response; however, it is still common in practice for treating physicians to stop HMAs earlier when a rapid response is not observed. Few studies have investigated time to response in the setting of frontline HMA treatment for AML. Methods: We retrospectively evaluated all patients who were initiated on frontline HMAs for AML at our institution from September 2013 to April 2018. HMAs were administered without dose reduction or treatment delays. Responses were evaluated and categorized as hematologic response (HR; defined by neutrophils 〉 1000/µL, platelets 〉 100k/µL, transfusion independence, and no peripheral blasts), complete remission (CR), CR with incomplete platelet recovery (CRp), CR with incomplete hematologic recovery (CRi), and no response. Patient, cytogenetic, and treatment characteristics were summarized and described. We evaluated patients exhibiting a response before receiving 4 cycles of HMA therapy ("early" responders) and compared these patients to those achieving a response after receiving at least 4 cycles of HMA ("late" responders). The Kaplan-Meier method estimated overall survival (OS). Odds of early response were estimated with logistic regression models. Results: During the study period, 137 patients received frontline HMAs. 122 (89.1%) patients received azacitidine, and 15 (10.9%) were treated with decitabine. Mean age at HMA start was 70.1 years (range 39.8-94.3). Most patients (62.8%) were male, and most (77.4%) were Caucasian. 21 (15.3%) patients were NCCN favorable-risk, 52 (38.0%) were intermediate-risk, and 64 (46.7%) were poor-risk. At first testing, 21.4% of the patients were positive for the FLT3/ITD mutation, 0.8% the FLT3/TKD mutation, and 21.4% the NPM1 mutation. Some patients received concomitant therapies along with the HMA; these included hydroxyurea, lenalidomide, and sorafenib. Median survival in the entire population was 11.6 (95% CI 8.3, 15.2) months. Overall response rate (ORR) was 60.6%. Among responders, 80.7% achieved HR as their first response; 19.3% were first noted to have marrow responses (1.2% CR, 4.8% CRp, and 13.3% CRi). Most patients did not undergo bone marrow evaluation to assess response. Among responding patients, 60.2% responded "early", whereas 39.8% responded "late". Median overall survival was 15.2 (9.3, 17.7) months in early responders, and 22.2 (11.7, 38.9) months in late responders. There was no difference in survival between the groups (p=0.108, log-rank test; Figure 1), although there was a trend toward improved survival in late responders. Nineteen patients underwent allogeneic HCT. Time to response was not associated with odds of receiving HCT (p=0.812). Conclusions: HMAs have a high ORR as frontline therapy in elderly and unfit AML patients. Among AML patients receiving frontline HMAs, later responders have equivalent survival to earlier responders. Physicians should consider exercising patience when treating AML patients with HMAs. These findings warrant validation in a larger, prospective study. Figure. Figure. Disclosures Avalos: Juno: Membership on an entity's Board of Directors or advisory committees. Grunwald:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Janssen: Research Funding; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medtronic: Equity Ownership.

Description: Background: Guideline recommendations from the Infectious Diseases Society of America (IDSA) and the 4th European Conference on Infections in Leukemia (ECIL-4) for the optimal duration of empiric antimicrobial therapy in patients with hematological malignancies and febrile neutropenia (FN) of unknown origin (FUO) vary given limited available evidence. Recent studies involving hematology patients and hematopoietic cell transplantation (HCT) recipients with FN have demonstrated that de-escalation of broad-spectrum antimicrobials (BSA) prior to hematopoietic recovery is associated with greater antibiotic-free days, but without increased risks, such as recurrent fever, bacteremia, intensive care unit (ICU) admission, or inpatient mortality. However, the safety of this de-escalation approach has not been extensively studied in autologous and haploidentical HCT recipients within the United States as most prior studies were conducted in Europe. The main purpose of this study was to compare rates of recurrent fever, re-escalation of therapy, and Clostridium difficile-associated infection (CDI) in autologous and allogeneic HCT recipients with FUO who received early de-escalation of BSA prior to hematopoietic recovery versus those who continued BSA until hematopoietic recovery. Methods: This retrospective, observational study assessed HCT recipients with FN admitted to Carolinas Medical Center in Charlotte, North Carolina between March 2014 to April 2018. Patients were included if they were ≥ 18 years of age, had an active hematologic malignancy and underwent allogeneic or autologous HCT, experienced their first episode of FN after HCT, and were initiated on appropriate BSA for ≥ 48 hours. Patients were excluded if they had microbiological or radiological diagnosis of active bacterial, fungal, or viral infection during the FN episode. Patients were enrolled into either cohort 1, which represented patients who were de-escalated to prophylactic antimicrobials prior to hematopoietic recovery (early de-escalation group), or cohort 2, which represented patients who continued BSA until hematopoietic recovery (hematopoietic recovery de-escalation group). Fisher's exact test was conducted to make cohort comparisons for categorical patient characteristics, while Mann-Whitney U test was employed for continuous variables. Multivariate logistic regression was utilized to evaluate rates of recurrent fever, re-escalation of therapy, and CDI between the 2 cohorts. Results: A total of 107 patients were included with 24 (22.4%) in cohort 1 and 83 (77.6%) in cohort 2. Most patients (87.5%) in cohort 1 received haploidentical HCT, whereas 84.3% of patients in cohort 2 received autologous HCT (P 〈 0.001). The median duration of neutropenia following the first FN episode was significantly shorter in cohort 2 (15 vs 4 days in cohorts 1 and 2, respectively, P 〈 0.001). There were no significant differences in rates of recurrent fever (4.2% vs 7.2%, adjusted OR (AOR) = 0.63,P = 0.684) and re-escalation of therapy (4.2% vs 4.8%, AOR = 1.26, P = 0.853) within 72 hours following de-escalation between the 2 cohorts. Rates of CDI within 30 days from hematopoietic recovery were also similar (4.2% vs 2.4%, AOR = 2.25, P = 0.582). No patients experienced inpatient mortality, ICU admission, or bacteremia. There were no significant differences in days of antimicrobial use per 1000 transplant days (P = 0.071). In a subgroup analysis of only allogeneic HCT recipients, haploidentical was the most common transplant type with 91.3% (n = 21/23) in cohort 1 and 69.2% (n = 9/13) in cohort 2. Recurrent fever was very infrequent among allogeneic HCT recipients (n = 1 in cohort 1 vs n = 0 in cohort 2, P 〉 0.999). However, a significant reduction in days of antimicrobial use per 1000 transplant days (P = 0.002) was observed in cohort 1 compared to cohort 2. Conclusion: HCT recipients with FUO who received de-escalation of BSA prior to hematopoietic recovery did not experience increased rates of recurrent fever, re-escalation of therapy, CDI, bacteremia, ICU admission, or inpatient mortality. These results concur with recently published studies and the ECIL-4 guidelines. An early de-escalation approach in haploidentical HCT recipients specifically appears to be safe and may result in a reduction in antimicrobial utilization. Disclosures Grunwald: Forma Therapeutics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medtronic: Equity Ownership; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees. Avalos:Juno: Membership on an entity's Board of Directors or advisory committees. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy.

Description: Background: BET inhibitors have demonstrated therapeutic potential in hematologic malignancies; however low therapeutic margins have limited clinical development. FT-1101 (also known as CC-95775) is a BET bromodomain inhibitor of all 4 BET family members BRD4, BRD2, BRD3, and BRDT (Kd ≤20 nM) and shows additional activity towards several non-BET bromodomain proteins (including CECR2 and BRD9). In vitro, FT-1101 displayed potent anti-proliferative activity across a broad panel of human leukemia cell lines. In xenograft and syngeneic models, FT-1101 achieved superior tumor growth inhibition (including regressions) relative to JQ1, another BET inhibitor (Millan 2015). Methods: A Phase 1 study evaluated the safety, PK/PD, and clinical activity of FT-1101 in patients (pts) with relapsed/refractory (R/R) AML/MDS, or non-Hodgkin lymphoma (NHL) (NCT02543879). Oral FT-1101 (10 mg - 600 mg) was dosed once a week (QW), every other week (QOW), or monthly (QM) during dose escalation. Safety was assessed via treatment-emergent AEs (TEAEs) for all pts; efficacy (response) was assessed in evaluable pts by investigators. Pharmacodynamic biomarkers (CCR1 and HEXIM1 mRNA expression) were assessed in whole blood. Results: Between 17-Nov-2015 and 05-Mar-2019, a total of 84 AML/MDS pts and 10 NHL pts received FT-1101 in dose escalation with a median of 2 (range 1-13) treatment cycles and median exposure of 43 (1-401) days for AML/MDS and 51.5 (1-183) days for NHL pts. Most AML/MDS pts (n=80) received FT-1101 monotherapy; a small cohort (n=4) received FT-1101 200 mg QOW in combination with azacitidine. FT-1101 appeared to demonstrate dose-proportional PK (10-600 mg/dose) with a median Tmax of 4 (1-24) hrs and a mean T1/2 of 52 (18-123) hrs. Pharmacodynamic responses correlated with FT-1101 concentrations; preliminary analysis indicated that PD biomarker modulation (↓ CCR1 and ↑ HEXIM1) was seen with FT-1101 doses as low as 80 mg, with more robust modulation observed at FT-1101 doses 〉180 mg. The most common (〉20%) TEAEs (all grades) were diarrhea (32%), fatigue (30%), dyspnea (29%), nausea (27%), anemia (24%), and platelet count decreased (21%) among AML/MDS pts and diarrhea (60%), nausea or pleural effusion (40% each), and cough, decreased appetite or dyspnea (30% each) among NHL pts. The most common (〉10%) severe (≥ grade 3) TEAEs were anemia (21%), decreased platelets (19%), pneumonia (16%), sepsis (13%), febrile neutropenia (12%), and disease progression (11%) among AML/MDS pts and pleural effusion or disease progression (20% each) among NHL pts. AEs led to treatment discontinuation in 22 AML/MDS pts (26%) and 2 NHL pts (20%). Twenty AML/MDS pts (24%) and 2 NHL pts (20%) died due to AEs, all assessed as unrelated to study treatment. Disease progression was the most common fatal TEAE in AML/MDS and NHL pts (10% and 20%, respectively). The maximum tolerated dose (MTD) on the QOW schedule was 400 mg FT-1101; MTDs were not determined for other schedules. Among evaluable AML/MDS pts who received 〉180 mg FT-1101 monotherapy (n=30), one pt (3%) on the 400 mg QOW schedule achieved complete remission with incomplete hematologic recovery (CRi) and 19 pts (63%) achieved stable disease, including 2 pts receiving 〉7 cycles of treatment. Among evaluable NHL patients who received 〉180 mg FT-1101 monotherapy (n=3), one pt (33%) achieved stable disease. Conclusions: FT-1101, as monotherapy, shows acceptable safety, PK, and modest clinical activity in R/R AML/MDS and NHL pts. Intermittent (QOW) dosing within a tolerable range elicits PD activity (CCR1 suppression and HEXIM1 upregulation) consistent with preclinical observations indicating antitumor activity, and provides a rationale for testing FT-1101 in combination with standard therapies in AML/MDS and NHL. Disclosures Patel: Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: 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, Speakers Bureau. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Dinner:Agios: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy. Grunwald:Forma Therapeutics: Research Funding; Novartis: Research Funding; Celgene: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Daiichi Sankyo: Consultancy; Incyte: Consultancy, Research Funding; Medtronic: Equity Ownership; Cardinal Health: Consultancy; Merck: Consultancy; Genentech/Roche: Research Funding; Trovagene: Consultancy; Janssen: Research Funding. Ribadeneira:FORMA Therapeutics: Employment. Schroeder:FORMA Therapeutics: Employment. Brevard:FORMA Therapeutics: Employment. Wilson:FORMA Therapeutics: Employment. Sweeney:FORMA Therapeutics: Employment. Kelly:FORMA Therapeutics: Employment. Lancet:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy.