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7510 Background: CPX-351 (Vyxeos; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of cytarabine [C] and daunorubicin [D], is approved by the FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Primary analysis of the pivotal phase 3 study (NCT01696084) that formed the basis for these approvals evaluated patients (pts) aged 60-75 y with newly diagnosed high-risk/secondary AML and found that CPX-351 significantly improved median overall survival (OS) vs conventional 7+3, with a comparable safety profile. Here, we report the prospectively planned final 5-y follow-up results from this phase 3 study. Methods: Pts were randomized 1:1 to receive ≤2 induction cycles of CPX-351 (100 units/m2 [C 100 mg/m2 + D 44 mg/m2] as a 90-min infusion on Days 1, 3, 5 [2nd induction: Days 1, 3]) or 7+3 (C 100 mg/m2/d continuously for 7 d + D 60 mg/m2 on Days 1-3 [2nd induction: 5+2]). Pts achieving complete remission (CR) or CR with incomplete platelet or neutrophil recovery could receive up to 2 consolidation cycles. Pts could receive a hematopoietic cell transplant (HCT) at the physician’s discretion. Pts were followed until death or up to 5 y following randomization. Results: In total, 309 pts were randomized to CPX-351 (n = 153) or 7+3 (n = 156). The survival rate at 5 y was higher for CPX-351 vs 7+3 (18% vs 8%; Table). Among pts who died, the most common primary cause of death was progressive leukemia in both arms (CPX-351: 56%; 7+3: 53%). After a median follow-up of 60.65 mo, improved median OS with CPX-351 vs 7+3 was maintained: 9.33 vs 5.95 mo; Kaplan-Meier (KM) OS curves plateaued at ~30 mo. HCT was received by 53 (35%) vs 39 (25%) pts after CPX-351 vs 7+3; among these pts, the survival rate at 5 y was higher for CPX-351 vs 7+3 (52% vs 23%), and median OS landmarked from the HCT date was not reached for CPX-351 vs 10.25 mo for 7+3 (Table). Conclusions: After 5 y of follow-up, improved OS was maintained in this phase 3 study, supporting that CPX-351 has the ability to produce or contribute to long-term remission and survival in older pts with newly diagnosed high-risk/secondary AML. Clinical trial information: NCT01696084 . [Table: see text]

e18514 Background: Patients (pts) sAML have poor outcomes (CR/CRi= 25-35%) with standard 7+3 induction chemotherapy (7+3). CPX-351 (liposomal encapsulated daunorubicin + cytarabine at a synergistic 5:1 molar ratio) was approved recently for sAML based on improvements in CR/CRi and survival but high cost and toxicity has discouraged its use. FLAG (fludarabine + high-dose cytarabine + granulocyte colony stimulating factor) have emerged as a lower cost, safe alternatives; however, outcomes between CPX-351 and FLAG have yet to be compared. In the absence of a direct trial, we aimed to estimate indirectly by Bayesian NMA the comparative efficacy of CPX-351, FLAG, and 7+3 therapy for sAML patients. Methods: Publications that compared FLAG or CPX-351 to 7+3 in newly diagnosed sAML were identified through a search of PubMed. CR/CRi rates were used in a Bayesian NMA to assess the direct (CPX-351 vs 7+3; FLAG vs 7+3) and indirect (CPX-351 vs FLAG) comparative efficacy of these regimens. Fixed (FE) and random effect (RE) analyses were conducted to estimate pooled odds ratios (OR) with 95% credible interval (CrI). Results: Of 169 identified articles, four studies (three RCT and one retrospective cohort) on a total of 781 pts in three treatment arms were retained. NMA showed no significant difference in pooled CR/CRi rates between CPX-351 and FLAG in both FE and RE models. However, pts receiving either FLAG or CPX-351 had significantly higher CR/CRi than those receiving 7+3 in both FE and RE models as shown in the table. Conclusions: This NMA suggests that both CPX-351 and FLAG prevail in CR/CRi efficacy over 7+3. In indirect comparison, CPX-351 and FLAG are equivalent in efficacy. The cost implications of these results remain to be established. [Table: see text]

7040Background: CPX-351, a liposomal encapsulation of cytarabine (C) and daunorubicin (D) at a synergistic ratio, is approved in the US for treatment of adults with newly diagnosed therapy-related ...

7031Background: In vitro studies demonstrate that AML cells are arginine auxotrophs and are metabolically vulnerable to arginine depletion (PMID: 24018014 & 25896651). To test the clinical utility ...

TPS7071 Background: SY-1425 (tamibarotene) is an orally available, synthetic retinoid approved in Japan for the treatment of relapsed/refractory (R/R) APL. SY-1425 is a more potent and selective retinoic acid receptor alpha (RARα) agonist with improved pharmacologic properties compared to all-trans retinoic acid (ATRA) including increased half-life and lack of metabolism by CYP26A1 resulting in extended relative exposures. SY-1425 binding to RARα relieves pathogenic repression of myeloid differentiation. Super-enhancers associated with RARA and upregulation of RARA expression correlate with increased sensitivity to SY-1425 in vitro and predict for response to SY-1425 with induced differentiation and reduced proliferation in RARA-high PDX AML models, but not in RARA-low models. SY-1425 also induces the RARα target gene DHRS3 in RARA-high AML cell lines. This study is designed to demonstrate pharmacodynamic (PD) and clinical effects of SY-1425 in non-APL AML and MDS patients (pts) positive for the RARA super-enhancer associated biomarker or exploratory RARA pathway biomarker, IRF8. Methods: This study is enrolling pts with R/R AML, R/R higher-risk MDS, newly-diagnosed AML ≥60 yrs unlikely to respond to or tolerate standard therapy, and transfusion dependent lower-risk MDS pts without del 5q who are unlikely to respond to or have failed ESAs. Pts must be biomarker positive based on centralized testing of tumor cells from blood. All pts receive SY-1425 at 6 mg/m2/day PO with continuous twice daily dosing. Primary objectives are to characterize the activity of SY-1425 by ORR in AML and higher-risk MDS pts or transfusion independence in lower-risk MDS pts. Secondary objectives include event-free and relapse-free survival, duration of response, overall survival, hematologic improvement and safety. PD evaluation includes induction of DHRS3 and expression of myeloid differentiation markers. Target enrollment is 80 pts. This trial opened in September 2016. Through a protocol amendment, SY-1425 treatment in combination with azacitidine will also be evaluated. ClinicalTrials.gov identifier: NCT02807558.

e18507 Background: FLT3+ AML patients (pts; 20%-30% of AML pts) often have rapid post-induction relapse, highlighting the need for therapies that improve the bridge to SCT. CPX-351 is a liposomal formulation that delivers a synergistic 5:1 molar ratio of cytarabine (C) and daunorubicin (D). CPX-351 demonstrated efficacy versus 7+3 in a randomized, open-label, controlled phase III trial in pts aged 60-75 years with newly diagnosed, high-risk AML; our analysis investigated outcomes in the subset of FLT3+ pts. Methods: Pts were randomized 1:1 to induction with 1-2 cycles of CPX-351 (100 u/m2 [C 100 mg/m2 + D 44 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m2/day x 7 days [2nd induction: x 5 days] + D 60 mg/m2on Days 1, 2, and 3 [2nd induction: Days 1 and 2]). Pts with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 consolidation cycles. Results: Of the pts who had FLT3 mutations assessed and received study treatment, 22/138 (16%) pts in the CPX-351 arm and 20/136 (15%) pts in the 7+3 arm had baseline FLT3 mutations. AML subtypes in FLT3+ pts were: tAML (19%); AML after MDS with (38%) or without (10%) prior hypomethylating agents; AML after CMMoL (12%); and de novo AML with MDS karyotype (21%). In FLT3+ pts, median OS was longer with CPX-351 (10.25 mo) versus 7+3 (4.55 mo; HR = 0.57 [95% CI: 0.24, 1.33]; P= 0.093) and the rate of CR+CRi was higher (68% vs 25%). A greater number of FLT3+ pts treated with CPX-351 were able to undergo SCT (n = 10/22 [45%]; 4 pts were alive as of this analysis, after a median post-SCT follow up of 692 days [range: 96-769]) compared with 7+3 (n = 2/20 [10%]; neither pt still alive). The on-study safety profile of CPX-351 in FLT3+ pts was comparable to 7+3 and consistent with the overall study population. Serious adverse events were experienced by 7 (32%) FLT3+ pts in the CPX-351 arm and 10 (50%) in the 7+3 arm. Conclusions: CPX-351 demonstrated numerical improvement in median OS in older pts with newly diagnosed, FLT3+ high-risk AML and allowed more pts to undergo SCT. The analysis was limited by small number of pts. Clinical trial information: NCT01696084.

2520 Background: GMI-1271 is a novel antagonist of E-selectin (E-sel) that down-regulates cell survival pathways and enhances chemotherapy response. We assessed GMI-1271 plus salvage chemotherapy with mitoxantrone, etoposide, and cytarabine (MEC) for the treatment of patients (pts) with relapsed/refractory (R/R) AML. Methods: A phase (Ph) 1trial in pts with R/R AML escalated GMI-1271 across pharmacologically active doses from 5-20 mg/kg combined with MEC. Safety, tolerability and anti-leukemia activity were assessed. GMI-1271 was given 24 hrs prior, then every 12 hrs during and for 48 hrs post induction/consolidation. Eligible pts had an ECOG score 0-2, received ≤2 prior inductions, WBC < 20K ( < 40K after 2 dose levels), no active CNS disease, and adequate renal/hepatic function. E-sel expression was assessed. After confirming safety and tolerability, a Ph 2 study of GMI-1271 at 10 mg/kg plus MEC was initiated. Results: To date, 47 pts have enrolled (Ph 1 = 19; Ph 2 = 28 of planned 47). The recommended Ph 2 dose is 10 mg/kg based on drug exposure, time over IC50 for E-sel binding, lack of DLT, and clinical outcomes. Ph1/Ph2 combined median age was 55yrs (range 26-84) with 70% male pts. Prior AML history included 26% primary refractory, 36% CR1 < 6 mos; 17% prior SCT; 55% unfavorable cytogenetics (by SWOG). Common Gr 3/4 AEs were febrile neutropenia (36%), sepsis (26%), bacteremia (13%), hypoxia (13%). 30 and 60 d mortality were 0 and 7%, respectively. ORR (CR/CRi/MLFS/PR) was 21/42 evaluable (50%). Remission rate (CR/CRi) was 45%. Observed/expected remission (CR/CRi) ratio was > 2.75 (Estey, Blood 1996). With a median follow-up of 11 mos, the Ph 1 median Leukemia Free Survival was not reached and Overall Survival was 7.6 mos. The median E-sel ligand binding at baseline was 35% of blasts (range, 1-75%) and was higher in those achieving remission. Conclusions: The addition of GMI-1271, a novel E-sel antagonist, to MEC chemotherapy is well tolerated with a high ORR, low induction mortality, and promising initial survival outcomes in pts with R/R AML. Furthermore, the baseline expression of E-sel ligand is predictive of response. Clinical trial information: NCT02306291.

7000Background: Older patients with secondary AML have poor outcomes following first-line cytarabine and anthracycline-based treatment. CPX-351 is a liposomal formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio with enhanced efficacy among poor risk AML patients. We report final results from a randomized open-label study of first-line CPX-351 in patients with high-risk sAML (NCT01696084). Methods: Patients 60-75 years of age with untreated AML with a history of prior cytotoxic treatment, antecedent MDS or CMML (+/- prior hypomethylator treatment), or AML with WHO-defined MDS-related cytogenetic abnormalities were eligible. 300 patients were to be randomized 1:1 to CPX-351 (100 units/m2, days 1, 3, 5) or 7+3 (cytarabine 100 mg/m2/day x 7 days, daunorubicin 60 mg/m2 days 1, 2, 3) induction therapy. Endpoints included: overall (OS, 1o) and event free survival (EFS) assessed by stratified log rank analysis, independent blinded assessment of CR+CRi, and 60-day mortality. Patient enroll...

7047 Background: PON, an approved oral tyrosine kinase inhibitor (TKI), has potent activity against native BCR-ABL and resistant mutants, including T315I. A phase 1 trial evaluated PON safety and a...

7078 Background: Ponatinib is a potent oral pan–BCR-ABL TKI that is active against native and mutated forms of BCR-ABL. The safety and anti-leukemic activity of ponatinib in pts with chronic myeloi...

7063 Background: Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) that is active against native and mutated forms of BCR-ABL. The safety and anti-leukemic activity of ponatinib in patients (pts) with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) were evaluated in a phase I clinical trial. Methods: Pts (N=81) with resistant/refractory hematologic malignancies were enrolled in this ongoing, open-label, dose escalation, phase I study. Ponatinib was dosed once daily (2–60 mg). 65 pts had Ph+ leukemia and are included in the present analysis (data as of 9 Nov 2012). Median follow-up was 25 (0.5–44) mos. Results: The median age of pts was 55 yrs; median time since diagnosis was 6.5 yrs. Pts were heavily pretreated (94% had received ≥2 prior TKIs, 62% ≥3). 65% had baseline BCR-ABL mutations. 46% (67% chronic phase [CP] CML) of pts remained on study. Progression and adverse events (AEs) were the most common reasons for discontinuation (17% each). The most common treatment-related AEs were rash (42%), thrombocytopenia (34%), arthralgia (20%), and increased lipase (20%). Significant anti-leukemic activity was observed (Table). Responses (major cytogenetic response [MCyR] for CP-CML or major hematologic response [MaHR] for accelerated phase [AP] CML, blast phase [BP] CML, or Ph+ ALL) were observed against the following mutations detected in >1 pt at baseline: 14/19 T315I, 4/7 F317L, 2/4 G250E, 2/2 M244V, 2/2 M35IT, and 1/2 F359V. Among CP-CML pts, 73% with complete cytogenetic response (CCyR) and 63% with major molecular response (MMR) are estimated to maintain response at 2 yrs (Kaplan-Meier). Of 28 CP-CML pts with CCyR, 25 remained on study (19 with continuous CCyR); of 22 pts with MMR, 21 remained on study (15 with continuous MMR). Updated data will be presented. Conclusions: Significant and durable responses were observed in heavily pretreated CP-CML pts, regardless of mutation status, and ponatinib was generally well tolerated. Clinical trial information: NCT00660920. [Table: see text]