ALBERT

Description: Background: Activating mutations of NRAS and KRAS genes are common in newly diagnosed acute myeloid leukemia (AML), occurring in 11-16% and 4-5% of patients, respectively. RAS mutations are frequently acquired at time of progression from MDS to AML and are associated with poor survival. Next generation sequencing (NGS) at diagnosis and during complete remission has shown that RAS mutations have high clearance rates with induction chemotherapy. In the CALGB 8525 study, RAS-mutant younger patients (age

Description: Background Measurable residual disease (MRD) is associated with inferior outcomes in patients with acute myeloid leukemia (AML). MRD monitoring enhances risk stratification and may guide therapeutic intervention. Post-induction MRD is frequently cleared with further therapy and the clearance may lead to better outcomes. In contrast, persistent MRD is associated with poor outcomes. At present it is not possible to predict which patients are likely to clear MRD with further therapy. Here we report a simple, objective, widely applicable and quantitative MFC approach using the ratio of blast/PDC to predict persistent MRD and poor outcomes in AML. Patients and Methods A cohort of 136 adult patients with a confirmed diagnosis of AML by WHO criteria who underwent standard induction therapy at a single center between 4/2014 and 9/2017 was initially included. 69 patients achieved complete morphologic remission (36 MRD-neg. and 33 MRD-pos.). MRD status was assessed by MFC using a different from normal (DfN) approach. PDC were quantified as the percent of total WBC by flow cytometry based on low side scatter, moderate CD45, CD303, bright CD123 and HLA-DR expression. Results The proportion of PDC was markedly decreased in patients with AML (≥20% blasts) (N=136) with a median of 0.016% (interquartile range IQR: 0.0019%-0.071%, Figure 1A), more than 10-fold lower than observed in normal controls (median 0.23%, IQR 0.17%-0.34%) (N=20). While there was no difference between MRD-neg. and normal control groups (median 0.31%, IQR: 0.17%-0.49%; vs. 0.28%, IQR: 0.17%-0.34%), MRD-pos. group had significantly reduced PDC proportion compared to the control (median 0.074%, IQR: 0.022%-0.33%, Wilcoxon rank sum, p=0.019). In an attempt to achieve better separation and to eliminate possible effects of hemodilution, the ratio of blast/PDC was calculated by using the proportions of blasts and PDCs out of total WBCs as quantitated by flow cytometry. A cut-off threshold of the blast/PDC ratio of 10 was chosen to separate each group (Figure 1B). Importantly, a ratio cut-off of 10 had a corresponding specificity of 97.4% for predicting MRD positivity status. MRD positivity was significantly associated with inferior overall survival (OS) and relapse-free survival (RFS) in our study cohort (OS HR 4.11 (95% CI: 1.30-13.03), p=0.016; RFS HR 4.20 (95% CI: 1.49-11.82), p=0.007, Figure 1C and D). The 2-year cumulative incidence of relapse in the MRD-neg. group compared to MRD-pos. group was 10% (95% CI: 2-24%) vs. 37% (95% CI: 18-56%, p=0.014). Importantly, blast/PDC ratio ≥10 was also strongly associated with inferior OS and RFS (OS HR 3.12 (95% CI: 1.13-8.60), p= 0.028; RFS HR 4.05 (95% CI: 1.63-10.11), p=0.003, Figure 1E and F), which is similar in magnitude to MRD positivity. Furthermore, MRD-pos. patients with blast/PDC ratio

Description: Background: CPX-351 (Vyxeos) is a liposomal combination of daunorubicin and cytarabine that was FDA approved in 2017 for treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Genomic predictors of response to CPX-351 have not been described. TP53 mutations are uncommon in de novo AML, but relatively enriched in the t-AML and AML-MRC populations for which CPX-351 is approved (Christiansen DH et al. JCO 2001; Devillier R et al. Oncotarget 2015). As TP53 mutations confer resistance to conventional daunorubicin and cytarabine chemotherapy, we sought to determine whether TP53 mutations confer resistance to CPX-351. Methods: This is a retrospective, multi-center review of patients who received at least 1 cycle of induction chemotherapy with CPX-351 at Memorial Sloan Kettering Cancer Center (MSKCC), Moffitt Cancer Center (MCC), and Weill Cornell Medical College (WCMC). 101 patients were identified at MSKCC (n=22), MCC (n=44), and WCMC (n=35). Responses to CPX-351 were graded using European Leukemia Net (ELN) response criteria. (Döhner H et al Blood 2017) Immunophenotypic minimal residual disease (MRD) was identified in bone marrow aspirates (BMA) by multiparameter flow cytometry in 43 patients (MSKCC n=22, WCMC n=21). Any level of residual disease was considered MRD+. Molecular analysis was obtained from pre-induction BMA by next-generation sequencing using 21, 32, 49, or 400 gene panels, all of which included TP53. Cytogenetics/FISH were performed using standard techniques. Fisher's exact tests were used to determine significance and are two-tailed. Kaplan-Meier (KM) analysis with log-rank test was performed to estimate overall survival (OS). Results: Patient characteristics are in Table 1. 84/101 (83.1%) had baseline molecular profiling prior to CPX-351. TP53 mutations were identified in 18/84 (21.4% of patients). Analysis of additional co-mutations and responses will be presented by our collaborators (Talati et al., ASH 2018 submitted). TP53 mutations (19/20 distinct mutations) clustered in the DNA binding domain (Figure 1A). TP53 mutations are significantly associated with complex or monosomal karyotypes (p

Description: Background Hypomethylating agents (HMAs) are the current standard of care therapy in high-risk MDS. However, only ~50% of patients with MDS respond to HMAs and most responding patients eventually progress. Outcomes after HMA failure in patients with high-risk MDS are especially poor, with median survival of 4 to 6 months. Venetoclax in combination with HMAs led to deep and durable remissions in elderly patients with newly diagnosed AML with CR+CRi rate of 67% and median survival of 17.5 months.Here, we performed a multicenter retrospective analysis to determine outcomes in patients with MDS receiving HMA + venetoclax (off-label) and identified risk factors associated with response and survival. Methods After obtaining institutional review board approval(s), we retrospectively reviewed charts of patients receiving HMA and venetoclax between January 1, 2018 to July 15, 2019. Criteria for inclusion were a pathologically confirmed diagnosis of MDS and treatment with either decitabine or azacitidine in combination with venetoclax. Patients with progression to AML prior to treatment with HMA+ venetoclax were excluded. Bone marrow response assessments were evaluated per WHO 2006 criteria. For subjects who required a delay in study treatment for blood count recovery after bone marrow evaluation, hematology values for up to 2 weeks were used to determine response. When available, cytogenetics, next generation sequencing, and flow cytometry data were included for analysis. HMA failure was defined as progression to a higher IPSS-R risk MDS while on HMA or lack of response after 4 cycles of HMA treatment. On univariate analysis, Fisher's exact test and Student t tests were used for overall response and Kaplan-Meier estimates were used to summarize OS and RFS. Results 42 patients met criteria for inclusion. The patient population was predominantly male, elderly, R-IPSS very poor cytogenetics, R-IPSS very high risk, MDS-EB2, and with HMA failure prior to initiation of HMA + venetoclax (Table 1.) Median blast count was 13% (range 2-18%). MDS was classified as therapy-related (t-MN) in 13 (31%) patients. TP53 mutations with complex karyotype occurred in 9 out of 34 (26%) patients (Figure 2). Azacitidine was the most common HMA used in combination with venetoclax (63%). Median follow up from the start of the combination was 5.4 months. Out of 40 patients evaluable for response, the ORR and marrow CR rate was 55%, median RFS and OS were not reached. Patients who achieved a marrow CR had a significantly prolonged OS in comparison to non-responders (median OS not reached vs. 5.64 months, p= 0.002). Among HMA naïve patients, the marrow CR rate was 73%. Furthermore, the marrow CR rate was 47% for patients with HMA failure and there was no significant difference in response or survival based on HMA exposure (Table 2). Median time to initial response was 1.6 months. On univariate analysis, therapy related disease and very poor risk cytogenetics were significantly associated with decreased response and a delay in starting cycle 2 or 3 was associated with increased response. Female gender, t-MN, very poor risk cytogenetics and a TP53 mutation were significantly associated with inferior OS. Very poor risk cytogenetics, a TP53 mutation, and the decitabine combination was significantly associated with decreased RFS (Table 3). Of note, neither a dose delay of venetoclax 〉 7 days or

Description: Background: Patients with AML harboring FLT3 mutations have poor clinical outcomes. Furthermore, FLT3 mutations frequently co-occur with other driver mutations, such as NPM1 with DNMT3A, WT1, and RUNX1, that are associated with poor prognosis. Crenolanib is a highly potent and specific type-I FLT3 inhibitor, which has shown promising safety and efficacy in combination with chemotherapy. Here we report the outcomes of newly diagnosed FLT3 mutated AML patients treated with crenolanib and intensive 7 + 3 based chemotherapy (NCT02283177) by baseline genomic profile. Methods: Patients were treated on clinical trial with 7+3 induction chemotherapy combined with crenolanib, consolidation with high-dose cytarabine (HiDAC) combined with crenolanib, and/or allo-HCT followed by crenolanib maintenance. Of 44 pts enrolled and treated, 36 had sequencing performed at baseline. The median survival follow-up for these patients was 20.7 months with data cut off July 25, 2018. A post hoc analysis was performed to assess the impact of genomic profile on patient outcomes using published data from the German-Austrian AML Study Group as a historical control. Results: Concurrent FLT3-ITD, NPM1, and DNMT3A mutations ("triple mutant") were present in 10 pts. These patients demonstrated improved OS with crenolanib treatment compared with historical controls. Similarly, patients with FLT3-ITD and WT1 mutations (n = 6) showed dramatically improved outcomes, with no deaths occurring by 18 months. Patients with FLT3 (ITD or TKD) and RUNX1 mutations (n = 10) also had improved OS. Conclusions: This analysis suggests that adding a potent pan-FLT3 inhibitor can overcome the poor prognostic implication of adverse mutations co-occurring with mutated FLT3. These data support the combination of crenolanib with chemotherapy to improve the overall outcome of FLT3 mutated AML with diverse mutational profiles. Hence, a randomized trial has been initiated of standard chemotherapy combined with either crenolanib or midostaurin in newly diagnosed patients with FLT3-mutant AML (NCT03258931). Table. Table. Disclosures Goldberg: AROG: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; Abbvie: Research Funding. Collins:Arog Pharmaceuticals: Research Funding; Celgene Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Agios: Research Funding. Stone:Ono: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Argenx: Other: Data and Safety Monitoring Board; Arog: Consultancy, Research Funding; Merck: Consultancy; Fujifilm: Consultancy; Jazz: Consultancy; Orsenix: Consultancy; Astellas: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; AbbVie: Consultancy; Amgen: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Sumitomo: Consultancy; Cornerstone: Consultancy. Walter:Actinium Pharmaceuticals, Inc: Other: Clinical Trial support , Research Funding; Amgen Inc: Other: Clinical Trial Support, Research Funding; Amphivena Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Aptevo Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Covagen AG: Consultancy, Other: Clinical Trial Support, Research Funding; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy; Pfizer, Inc: Consultancy; Seattle Genetics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding. Wang:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Jazz: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau. Tallman:AROG: Research Funding; AbbVie: Research Funding; Orsenix: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; ADC Therapeutics: Research Funding; Cellerant: Research Funding; BioSight: Other: Advisory board.

Description: Background Outcomes in patients (pts) with secondary acute myeloid leukemia (sAML) (therapy related myeloid neoplasms and AML with myelodysplasia related changes (MRC) per WHO 2016 classification (Arber et al, Blood 2016)) are poor. Pts treated with hypomethylating agents (HMAs) have suboptimal responses to induction chemotherapy (IC) upon transformation to AML. Previously, it was retrospectively demonstrated that the IC with cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M) yields significantly higher response rates (64%) than 7+3 (cytarabine and anthracycline) (29%) in pts with prior HMA exposure (Jaglal et al, Leukemia Research 2014). Following the recent approval of CPX-351 for induction in sAML subgroup, we investigated outcomes after CPX-351 to cladribine based regimens and 7+3 in pts with sAML with prior HMA exposure. Methods We identified pts with sAML who had prior HMA treatment for an antecedent hematologic malignancy (AHM) and later received induction chemotherapy upon AML transformation from Moffitt Cancer Center (MCC) (n=229), Memorial Sloan Kettering Cancer Center (n=11) and Roswell Park Comprehensive Cancer Center (n=2). Patients were divided into 3 cohorts based on induction regimen: (A) cladribine based (CLA+/-G+/-M) (B) standard 7+3 and (C) CPX-351. Demographics, disease-specific variables, and outcomes were collected in accordance with the institutional review board approved protocol. Responders (R) were defined as pts achieving CR or CRi as defined by the 2003 International Working Group (IWG) criteria after 1 or 2 cycles of the either induction regimen whereas non-responders (NR) were defined as responses other than CR/CRi. Pts receiving a second induction with a different regimen were considered NR. Fisher's exact test and the ANOVA test were used to determine significance for continuous and categorical variables. Kaplan-Meier analysis with log-rank test was performed to estimate overall survival (OS). Results Among 242 pts who received IC for AML after HMA failure for prior AHM, 114 were treated with (A) cladribine based regimen (B) 94 pts with standard 3+7 and (C) 34 pts with CPX-351 (Cohort C). Baseline characteristics for all 3 cohorts are outlined in Table 1A. Median age for cohort A, B, and C were 65 (33-82), 66 (26-81), and 69 (36-82), respectively. Males comprised of 68.4%, 63% and 52.9% of the cohorts A, B and C, respectively. No pts had favorable-risk karyotype as defined by European LeukemiaNet (ELN) 2017 criteria. Adverse risk karyotype was noted in 42.1% of cohort A, 34.6% of cohort B and 22.7% of cohort C (p=.337). The majority of pts received azacitidine as their HMA for their AHM (88.7%, 84.9% and 82.4% in cohorts A, B, C, respectively) and median number of cycles administered prior to transformation to AML were 6, 4 and 5 for cohorts A, B, and C, respectively. Response rates in each cohort are summarized in Table 1B. The CR/CRi rate was 53% in cohort A, 32% in cohort B and 41.1% in cohort C (p=.005 between cohort A and B) (p=.329 between cohorts A and C) (p=.526 between cohorts B and C). The early death rates (4 cycles of HMAs (25.0%) (p=.0397). Cohort A (56.5% vs. 50.0%, p=.288) and B (39.1% vs. 25.5%, p=.175) did not demonstrate such a difference (Table 1C and 1D). There was a trend towards better OS (19.9 vs. 5.5mo) with CPX-351 treated pts with ≤ 4 cycles of HMAs compared to 〉4 cycles (p=.092) (Figure 1). To date, 70.0% of responding pts in cohort A have undergone an allogeneic stem cell transplant compared to 31.0% in cohort B and 28.6% in cohort C (p=.15). There was no significant difference in median OS among the 3 groups, cohort A (7.27 months), cohort B (7.63 months) and cohort C (7.07 months) (p=.887). Among responders, the mOS did not differ (12.93, 21.7, and 19.9 months for cohorts A, B, and C respectively, p=.635). Conclusions We demonstrate that cladribine-based induction regimens and CPX-351 yield higher CR/CRi rates compared to 7+3 in pts with sAML after HMA failure. Prolonged duration of HMA exposure may lower response potential with CPX-351 upon AML transformation. Median OS remains poor and did not differ among the 3 groups illustrating the unmet need for therapy for sAML pts after HMA failure. Disclosures Goldberg: AROG: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Pfizer: Research Funding. Sallman:Celgene: Research Funding, Speakers Bureau. List:Celgene: Research Funding. Wang:Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau. Tallman:AROG: Research Funding; Cellerant: Research Funding; AbbVie: Research Funding; ADC Therapeutics: Research Funding; Orsenix: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; BioSight: Other: Advisory board. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Sweet:Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Agios: Consultancy; Astellas: Consultancy; Phizer: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Phizer: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy; Jazz: Speakers Bureau; BMS: Honoraria; Agios: Consultancy; Celgene: Honoraria, Speakers Bureau; BMS: Honoraria.

Description: Background: Approval of CPX-351 has changed the treatment landscape for therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) and has become the new standard-of-care. Response rates (RR) (complete remission (CR) and CR with incomplete count recovery (CRi)) with CPX-351 in the phase 3 clinical trial were 47.7%, however, comprehensive molecular characterization to investigate impact on response was lacking. Herein, we annotated the molecular profiles of patients (pts) treated with CPX-351 to identify outcome interaction with specific somatic mutations. Methods: We retrospectively analyzed a combined cohort of 111 pts treated with CPX-351 from Moffitt Cancer Center, Weill Cornell Medical College, and Memorial Sloan Kettering Cancer Center. A total 85 pts that had next-generation sequencing (NGS) prior to treatment were included in the analysis. Those genes analyzed with 〉5% mutation frequency are summarized in Figure 1A. Demographics, disease-specific variables, and overall outcomes were analyzed and responders (RES) were defined as pts achieving CR/CRi after 1-2 cycles of CPX-351 compared to nonresponders (NR). AML patients with diagnosis of antecedent myeloid malignancy are defined as sAML. Pts receiving a second cycle of induction (reinduction) with a different regimen were considered to be NR to CPX-351. We utilized Fisher's exact test to determine two-tailed significance with p-value

Description: We have previously reported that cytarabine/daunorubicin as well cytarabine/idarubicin can be safely combined with crenolanib at the full monotherapy dose (100mg TID) and administered throughout induction, consolidation and maintenance in newly diagnosed FLT3-mutated AML (Walter et al., EHA 2018). We hypothesize that crenolanib plasma levels might correlate with long term outcome in these patients. Methods: Twenty-seven newly diagnosed AML patients with FLT3 mutations, aged 18-60 years old enrolled in a phase II study of crenolanib combined with chemotherapy (NCT02283177) were included in this analysis. Patients received 7+3 induction with cytarabine 100 mg/m2 for 7 days and either daunorubicin 90 mg/m2 (n=16) or idarubicin 12 mg/m2 (n=11) for 3 days. Crenolanib 100 mg TID was administered continuously starting 24-48 hours after induction until 72 hours prior to the next chemotherapy cycle. Consolidation could consist of up to four cycles of high-dose cytarabine (HiDAC): 3 g/m2 for 〈 60 years and 1 g/m2 for 60 years) q12 hours on days 1, 3, and 5 with crenolanib starting 24 hours after the final HiDAC dose in each cycle. Eligible patients proceeded to allogeneic hematopoietic stem cell transplant (HSCT). Maintenance crenolanib at 100mg TID was started after HiDAC or 30-90 days after HSCT for up to 12 cycles. Crenolanib levels (total and free) were measured 2-4 hours following the first dose of crenolanib and after two weeks of continuous crenolanib administration. Crenolanib levels were also measured on first day of crenolanib treatment following HiDAC consolidation. Free crenolanib was measured by rapid equilibrium dialysis. Durability of clinical remissions were documented by routine follow up every 3-4 months (as per institutional practice). Results: As of July 2019, all patients have completed all protocol therapy (one patient has continued crenolanib maintenance for 25 months per patient request). Twenty-three of 27 patients (85%) achieved complete remission, all of whom required only 1 cycle of induction chemotherapy. Nineteen of 27 patients remain alive and free of disease with a median follow-up of 29.3 months (Figure 1). Three relapses have occurred, all within the first year of treatment and no relapses have occurred in patients who completed at least 1 cycle of crenolanib maintenance. Seven patients received HiDAC consolidation along with crenolanib but did not receive HSCT. Six of these patients remain in long term remission. While the number of patients is small, we observed similar overall survival and cumulative incidence of relapse in patients who underwent HSCT as compared to those who did not (Figure2). Pharmacokinetic studies demonstrate that despite increases in acute phase reactants and AGP levels, both total and free crenolanib rapidly achieve sufficient levels to provide the continuous inhibition required to eradicate FLT3-ITD, FLT3-D835, and other FLT3 mutations including FLT3-N841, A680, V592, V491, and D839. Total levels of crenolanib exceeded 500 nM at steady state, and the majority of patients showed clearance of FLT3 mutations after combination therapy. Summary/Conclusion: These pharmacokinetic data show that crenolanib when given with chemotherapy can achieve sufficient levels to inhibit multiple FLT3 mutations, despite rises in FLT3 ligand and acute phase reactants. These clinical data suggest that this combination might improve outcomes in younger patients with newly diagnosed FLT3-mutant AML. With 29 months median follow up, median overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR) have not been reached. No relapses have been observed in patients after completing crenolanib maintenance. A phase III randomized multicenter trial has been initiated to compare the efficacy of crenolanib versus midostaurin combined with standard chemotherapy for newly diagnosed patients with FLT3-mutant AML (NCT03258931). Figure Disclosures Goldberg: Abbvie: Research Funding; ADC Therapeutics: Research Funding; American Society of Clinical Oncology: Research Funding; American Society of Hematology: Research Funding; Arog Pharmaceuticals: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Pfizer: Research Funding; DAVA Oncology: Honoraria; Abbvie: Consultancy; Celgene: Consultancy. Coombs:Abbvie: Consultancy; Covance: Consultancy; Dedham Group: Consultancy; H3 Biomedicine: Honoraria; Cowen & Co.: Consultancy; Octopharma: Honoraria; Pharmacyclics: Honoraria; Loxo: Honoraria; Medscape: Honoraria. Wang:Kite: Other: Advisory role; Abbvie: Other: Advisory role; celyad: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; Jazz: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Walter:Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding. Messahel:Arog Pharmaceuticals: Employment. Stone:Astellas: Consultancy; Biolinerx: Consultancy; Arog: Consultancy, Research Funding; Trovagene: Consultancy; Macrogenics: Consultancy; Argenix: Other: DSMB; Argenix: Other: DSMB; Otsuka: Consultancy; Takeda: Other: DSMB; Trovagene: Consultancy; Biolinerx: Consultancy; Daiichi-Sankyo: Consultancy; Celgene: Consultancy, Other: DSMB; Pfizer: Consultancy; Jazz: Consultancy; Roche: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Arog: Consultancy, Research Funding; Stemline: Consultancy; Biolinerx: Consultancy; Pfizer: Consultancy; Astra-Zeneca: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees; Biosight: Consultancy; Arog: Consultancy, Research Funding; Otsuka: Consultancy; Abbvie: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Roche: Consultancy; Argenix: Other: DSMB; Macrogenics: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy; Biosight: Consultancy; Otsuka: Consultancy; Agios: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Other: DSMB; Astellas: Consultancy; Agios: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy; Trovagene: Consultancy; Celgene: Consultancy, Other: DSMB; Stemline: Consultancy.

Description: Background: Older AML patients often present with comorbidities and may have a compromised ability to tolerate intensive chemotherapy. These patients are more likely to have AML secondary to MDS/MPN and are considered to have a biologically distinct disease compared to their younger counterparts, with more frequent occurrence of adverse-risk cytogenetic abnormalities and mutations in genes regulating epigenetic modifications. In addition, the heterogeneity of driver mutations within a single patient contributes to limited responses to standard induction chemotherapy. While FLT3 mutations occur in this population, they are often subclonal, adding to the challenge of eradicating AML in older adult patients. Studies combining sorafenib or midostaurin with standard induction chemotherapy have shown relatively modest improvements in response rates and survival, and relapses, both early and late, remain a major concern. There is a major unmet need for optimizing chemotherapy and TKI treatment in this medically fragile population. We here report the safety and efficacy results in newly diagnosed older patients with FLT3 mutant AML treated with crenolanib, a type I FLT3 inhibitor, in combination with intensive induction and consolidation chemotherapy (NCT02283177). Methods: Fifteen consecutively treated patients, aged 61-75 (median age: 68), at four academic cancer centers were included in this analysis. Patients received 7+3 induction with cytarabine 100 mg/m2 for 7 days and either daunorubicin 60 mg/m2 or idarubicin 12 mg/m2 for 3 days. Crenolanib 100 mg TID was administered continuously starting 24 hours after chemotherapy until 72 hours prior to the next chemotherapy cycle. Consolidation consisted of up to 4 cycles of high-dose cytarabine (HiDAC: 1 g/m2) q12h on days 1, 3, and 5 with crenolanib starting 24 hours after the final HiDAC dose. Eligible patients proceeded to allogeneic hematopoietic stem cell transplant (HSCT). Maintenance with crenolanib at 100mg TID was started after HiDAC or 30-90 days after HSCT for up to 12 cycles. Results: Fourteen patients completed induction chemotherapy (one patient withdrew consent at day 19). Crenolanib could be safely combined with either daunorubicin or idarubicin based induction chemotherapy. The most common adverse events (grade ≥3) were diarrhea, nausea, and febrile neutropenia. Ten of 14 patients were able to receive full doses of crenolanib during induction. The major reason for dose reduction was edema in 3 patients and GI bleeding in 1 patient. There was one treatment-related death, with 93% survival at 30 and 60 days and 87% survival at 100 days. Complete remissions with full count recovery (CR) were achieved in 10 of 15 patients after just one cycle of induction chemotherapy. Two patients achieved a complete remission after reinduction for an overall CR rate of 86%. Of the 12 patients who achieved CR, 10 patients received HiDAC consolidation, with two patients unable to receive consolidation therapy on study. Three patients received crenolanib maintenance after multiple cycles of HiDAC consolidation. Six patients underwent HSCT and 3 received crenolanib maintenance. As of July 2019, median OS for the intent to treat population is 20.2 months. One-year survival was 67% and 5 patients remain alive and in remission. All 5 long term survivors were ≤70 years old. All surviving patients received either multiple cycles of HiDAC or HiDAC plus transplant, and 4/5 underwent crenolanib maintenance. The patient who did not receive transplant completed 3 cycles of HiDAC consolidation and a full year of crenolanib maintenance. Summary/Conclusion: This safety study shows that crenolanib can be combined at full doses (100mg TID) for the duration of 7+3 induction, consolidation, and maintenance in older patients with FLT3 mutant AML. Therapy was relatively well tolerated, with less than one third of patients requiring dose reductions. Long-term survival rates are encouraging in this high-risk population, but additional studies are needed to confirm the efficacy of this combination older adults. Figure 1 Disclosures Wang: Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Griffiths:Abbvie, Inc.: Consultancy; Genentech, Inc.: Research Funding; Celgene, Inc: Consultancy, Research Funding; Onconova Therapeutics: Other: PI on a clinical trial; Novartis Inc.: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; New Link Genetics: Consultancy; Partner Therapeutics: Consultancy; Genentech, Inc.: Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Abbvie, Inc.: Consultancy, PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Boston Scientific: Consultancy; Boston Scientific: Consultancy; Persimmune: Consultancy; Persimmune: Consultancy; New Link Genetics: Consultancy; Partner Therapeutics: Consultancy; Novartis Inc.: Consultancy. Walter:Jazz Pharmaceuticals: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Boston Biomedical: Consultancy; Covagen: Consultancy; BiVictriX: Consultancy; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy. Tallman:Hematology Oncology of Indiana: Honoraria; Salzberg Weill Cornall MSKCC Seminar in Hematologic Malignancies: Honoraria; University of Oklahoma Medical Center: Honoraria; Bioline: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Nohla: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; Cellerant Therapeutics: Research Funding; Orsenix: Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Mayo Clinic: Honoraria; New Orleans Summer Cancer Conference: Honoraria; Indy Hematology Review: Honoraria; Amgen: Consultancy; 14th Annual Miami Cancer Meeting: Honoraria; Danbury Hospital Tumor Board: Honoraria; International Conference in Leukemia: Honoraria. Goldberg:ADC Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; American Society of Clinical Oncology: Research Funding; American Society of Hematology: Research Funding; Celgene: Consultancy; Abbvie: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; DAVA Oncology: Honoraria. Messahel:Arog Pharmaceuticals: Employment. Stone:Pfizer: Consultancy; Stemline: Consultancy; Astra-Zeneca: Consultancy; Argenix: Other: DSMB; Otsuka: Consultancy; Astellas: Consultancy; Argenix: Other: DSMB; Celgene: Consultancy, Other: DSMB; Stemline: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Biolinerx: Consultancy; Biosight: Consultancy; Trovagene: Consultancy; Arog: Consultancy, Research Funding; Takeda: Other: DSMB; Novartis: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy; Celgene: Consultancy, Other: DSMB; Abbvie: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Takeda: Other: DSMB; Biolinerx: Consultancy; Daiichi-Sankyo: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy; Jazz: Consultancy; Trovagene: Consultancy; Astra-Zeneca: Consultancy; Novartis: Consultancy, Research Funding; Roche: Consultancy; Macrogenics: Consultancy; Agios: Consultancy, Research Funding; Biosight: Consultancy; Abbvie: Consultancy, Research Funding; Arog: Consultancy, Research Funding; Pfizer: Consultancy; Trovagene: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Arog: Consultancy, Research Funding; Macrogenics: Consultancy; Otsuka: Consultancy; Argenix: Other: DSMB; Astellas: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy; Biolinerx: Consultancy.