Supplemental Methods Supplemental Table 1 Supplemental Figures 1-6 1. Pretreatment with cytarabine potentiates the effects of FED in AML xenografts. Supplemental Figure 2. PF cytometry analysis of AML samples. Supplemental Figure 3. Immunophenotypic and phosphoprotein signaling heterogeneity of AML patient samples. Supplemental Figure 4. PF analysis of validation cohort samples Supplemental Figure 5. Effects of FED treatment on FLT3 activity. Supplemental Figure 6. Effects of FED and DAS treatment on pSTAT5, pSRC and pTyr in BCR-ABL1+ AML samples. Supplemental Table 1: Characteristics of patient samples studied in initial and validation cohorts.

CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). In a pivotal phase 3 study, patients aged 60 to 75 years with newly diagnosed, high-risk/secondary AML were randomized to receive CPX-351 or conventional 7+3 chemotherapy. In the primary endpoint analysis, CPX-351 demonstrated significantly prolonged median overall survival (OS) vs 7+3. These exploratory post hoc subgroup analyses evaluated the impact of achieving complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) with CPX-351 (73/153 [48%]) vs conventional 7+3 (52/56 [33%]) on outcomes. CPX-351 improved median OS vs 7+3 in patients who achieved CR or CRi (25.43 vs 10.41 months; hazard ratio = 0.49; 95% confidence interval, 0.31, 0.77). Improved median OS was seen across AML subtypes (t-AML, AML-MRC), age subgroups (60 to 69 vs 70 to 75 years), patients with prior hypomethylating agent exposure, and patients who did not undergo transplantation. Patients who achieved CR or CRi with CPX-351 also had a higher rate of transplantation, a longer median OS landmarked from the date of transplantation (not reached vs 11.65 months; hazard ratio = 0.43; 95% confidence interval, 0.21, 0.89), and a safety profile that was consistent with the known safety profile of 7+3. These results suggest deeper remissions may be achieved with CPX-351, leading to improved OS. This study was registered at www.clinicaltrials.gov as #NCT01696084.

As more clinically-relevant genomic features of myeloid malignancies are revealed, it has become clear that targeted clinical genetic testing is inadequate for risk stratification. Here, we develop and validate a clinical transcriptome-based assay for stratification of acute myeloid leukemia (AML). Comparison of ribonucleic acid sequencing (RNA-Seq) to whole genome and exome sequencing reveals that a standalone RNA-Seq assay offers the greatest diagnostic return, enabling identification of expressed gene fusions, single nucleotide and short insertion/deletion variants, and whole-transcriptome expression information. Expression data from 154 AML patients are used to develop a novel AML prognostic score, which is strongly associated with patient outcomes across 620 patients from three independent cohorts, and 42 patients from a prospective cohort. When combined with molecular risk guidelines, the risk score allows for the re-stratification of 22.1 to 25.3% of AML patients from three independent cohorts into correct risk groups. Within the adverse-risk subgroup, we identify a subset of patients characterized by dysregulated integrin signaling and RUNX1 or TP53 mutation. We show that these patients may benefit from therapy with inhibitors of focal adhesion kinase, encoded by PTK2 , demonstrating additional utility of transcriptome-based testing for therapy selection in myeloid malignancy.

Background Daunorubicin and cytarabine are used as standard induction chemotherapy for patients with acute myeloid leukaemia. CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. Primary analysis of the phase 3 trial in adults aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia provided support for approval of CPX-351 by the US Food and Drug Administration and European Medicines Agency. We describe the prospectively planned final 5-year follow-up results. Methods This randomised, open-label, multicentre, phase 3 trial was done across 39 academic and regional cancer centres in the USA and Canada. Eligible patients were aged 60-75 years and had a pathological diagnosis of acute myeloid leukaemia according to WHO 2008 criteria, no previous induction therapy for acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned 1:1 (stratified by age and acute myeloid leukaemia subtype) to receive up to two induction cycles of CPX-351 (100 units/m(2) administered as a 90-min intravenous infusion on days 1, 3, and 5; on days 1 and 3 for the second induction) or standard chemotherapy (cytarabine 100 mg/m(2) per day continuous intravenous infusion for 7 days plus intravenous daunorubicin 60 mg/m(2) on days 1, 2, and 3 [7+3]; cytarabine for 5 days and daunorubicin on days 1 and 2 for the second induction [5+2]). Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery could receive up to tw cycles of consolidation therapy with CPX-351 (65 units/m(2) 90-min infusion on days 1 and 3) or chemotherapy (5+2, same dosage as in the second induction cycle). The primary outcome was overall survival analysed in all randomly assigned patients. No additional adverse events were collected with long-term follow-up, except data for deaths. This trial is registered with ClinicalTrials.gov, NCT01696084, and is complete. Findings Between Dec 20, 2012, and Nov 11, 2014, 309 patients with newly diagnosed high-risk or secondary acute myeloid leukaemia were enrolled and randomly assigned to receive CPX-351 (153 patients) or 7+3 (156 patients). At a median follow-up of 60.91 months (IQR 60.06-62.98) in the CPX-351 group and 59.93 months (59.73-60.50) in the 7+3 group, median overall survival was 9.33 months (95% CI 6.37-11.86) with CPX-351 and 5.95 months (4.99-7.75) with 7+3 (HR 0.70, 95% CI 0.55-0.91). 5-year overall survival was 18% (95% CI 12-25%) in the CPX-351 group and 8% (4-13%) in the 7+3 group. The most common cause of death in both groups was progressive leukaemia (70 [56%] of 124 deaths in the CPX-351 group and 74 [53%] of 140 deaths in the 7+3 group). Six (5%) of 124 deaths in the CPX-351 group and seven (5%) of 140 deaths in the 7+3 group were considered related to study treatment. Interpretation After 5 years of follow-up, the improved overall survival with CPX-351 versus 7+3 was maintained, which supports the previous evidence that CPX-351 can contribute to long-term remission and improved overall survival in patients aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

Introduction: Patients (pts) with newly diagnosed, secondary AML (sAML) may have previously received hypomethylating agent (HMA) therapy for an antecedent hematologic malignancy (eg, myelodysplastic syndrome [MDS]). Outcomes for pts with MDS who progress following HMA therapy are typically poor, with remission rates <30% and median overall survival (OS) of ~6 months (Prébet T, et al. J ClinOncol. 2011; Jabbour E, et al. Cancer 2010). CPX-351 (Vyxeos®; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of cytarabine [C] and daunorubicin [D] at a synergistic 5:1 molar ratio, is approved by the US FDA and the EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. In a large randomized, open-label, multicenter, phase 3 study (NCT01696084) in older pts with newly diagnosed, high-risk/sAML, induction followed by consolidation with CPX-351 significantly improved OS (9.56 vs 5.95 months; hazard ratio [HR] = 0.69; 1-sided P = 0.003) versus conventional 7+3, with a safety profile comparable to that of 7+3. An exploratory subgroup analysis of the phase 3 study was performed to compare outcomes in pts with any prior HMA exposure who achieved complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) with CPX-351 versus 7+3. Methods: Pts were randomized 1:1 to receive 1-2 induction cycles with CPX-351 (100 units/m2 [C 100 mg/m2 + D 44 mg/m2] as a 90-minute infusion on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m2/day continuously for 7 days [2nd induction: 5 days] + D 60 mg/m2 on Days 1-3 [2nd induction: Days 1-2]). Pts achieving CR+CRi could receive up to 2 consolidation cycles with CPX-351 (65 units/m2 [C 65 mg/m2 + D 29 mg/m2] on Days 1 and 3) or 5+2 (as in 2nd induction). Pts could receive hematopoietic cell transplantation (HCT) at the discretion of the treating physician. This exploratory subgroup analysis included pts with any prior HMA exposure who achieved CR+CRi to study treatment. Results: A total of 309 pts were enrolled in the study, including 133 (43%) pts who had received prior HMA therapy. Among pts with any prior HMA exposure, 23/62 (37%) receiving CPX-351 and 20/71 (28%) receiving 7+3 (odds ratio [OR] = 1.50 [95% CI: 0.73-3.12]) achieved CR+CRi and were included in this analysis. Baseline characteristics for these pts were generally balanced between treatment arms; 9% and 5% of pts in the CPX-351 and 7+3 arms, respectively, were classified as having therapy-related AML, 78% and 90% had antecedent MDS, and 13% and 5% had antecedent chronic myelomonocytic leukemia. In pts with any prior HMA exposure who achieved CR+CRi to CPX-351 or 7+3, median OS was longer with CPX-351 (14.72 vs 10.17 months; HR = 0.55 [95% CI: 0.26-1.15]; Figure 1). More of the pts with prior HMA exposure who achieved CR+CRi and received CPX-351 underwent HCT versus those who received 7+3 (57% vs 35%; relative risk = 1.39 [95% CI: 0.73-2.67]), and OS landmarked from the HCT date was longer with CPX-351 versus 7+3 (not reached vs 14.09 months; HR = 0.43 [95% CI: 0.12-1.51]; Figure 2). In pts without prior HMA exposure, 50/91 (55%) receiving CPX-351 and 32/85 (38%) receiving 7+3 (OR = 2.02 [95% CI: 1.11-3.69]) achieved CR+CRi; among those who achieved CR+CRi to CPX-351 versus 7+3, median OS was also longer with CPX-351 (26.32 vs 10.43 months). The most common treatment-emergent adverse events (TEAEs) in pts with any prior HMA exposure who achieved CR+CRi were febrile neutropenia (CPX-351: 83%; 7+3: 75%), nausea (48%; 55%), fatigue (48%; 45%), diarrhea (43%; 70%), constipation (43%; 50%), peripheral edema (39%; 65%), and dizziness (13%; 50%). The most common grade ≥3 TEAEs were febrile neutropenia (CPX-351: 83%; 7+3: 75%) and fatigue (22%; 0%). The most common serious TEAEs were febrile neutropenia (CPX-351: 13%; 7+3: 10%), ejection fraction decreased (9%; 10%), and subdural hemorrhage (0%; 10%). There was no early mortality by Day 60 in either arm. Conclusions: Pts with prior HMA exposure for an antecedent hematologic malignancy typically have poor outcomes and are a challenging subgroup of AML. Among pts in this study who had any prior HMA exposure and achieved CR+CRi, CPX-351 increased median OS, the rate of HCT, and median OS landmarked from the HCT date versus 7+3. The safety profile for CPX-351 in this subgroup was consistent with the overall study population and the known safety profile of 7+3. Disclosures Lin: Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ryan:University of Rochester: Patents & Royalties; AbbVie: Equity Ownership. Ritchie:Ariad, Celgene, Incyte, Novartis: Speakers Bureau; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Celgene, Novartis: Other: travel support; Jazz Pharmaceuticals: Research Funding; Genentech: Other: Advisory board; Tolero: Other: Advisory board; agios: Other: Advisory board; Pfizer: Other: Advisory board, travel support; Celgene: Other: Advisory board; Celgene, Incyte, Novartis, Pfizer: Consultancy. Strickland:Astellas Pharma: Consultancy; Sunesis Pharmaceuticals: Research Funding; AbbVie: Consultancy; Jazz: Consultancy; Kite: Consultancy; Pfizer: Consultancy. Kolitz:Astellas: Research Funding; Boeringer-Ingelheim: Research Funding; Roche: Research Funding. Schiller:Astellas: Research Funding; Amgen: Other, Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; FujiFilm: Research Funding; Eli Lilly and Company: Research Funding; Daiichi Sankyo: Research Funding; Constellation Pharmaceutical: Research Funding; Celgene: Research Funding, Speakers Bureau; Agios: Research Funding, Speakers Bureau; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding. Wieduwilt:Celgene: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Reata Pharmaceuticals: Equity Ownership; Amgen, Leadiant, Merck, Servier: Research Funding. Ryan:Jazz Pharmaceuticals: Employment, Equity Ownership. Faderl:Jazz Pharmaceutics: Employment, Equity Ownership. Cortes:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; Takeda: Consultancy, Research Funding.

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]

Guideline-recommended day 14 (D14) bone marrow (BM) examinations during induction therapy for acute myeloid leukemia have uncertain benefit. The present study evaluated the prognostic significance of D14 BM samples for 486 patients undergoing induction therapy for acute myeloid leukemia and the subsequent outcomes for induction strategies. D14 BM samples have prognostic significance but no observed clinical benefit for directing induction therapy. Introduction: The 2017 National Comprehensive Cancer Network guidelines for acute myeloid leukemia have recommended performing bone marrow (BM) aspiration and BM trephine biopsy (BMTB) 14 to 21 days after starting induction therapy (commonly referred to as "day 14 [D14] marrow"). Those who do not achieve a hypoplastic marrow, with cellularity < 20% and blasts < 5%, are recommended to undergo 2-cycle induction (2CI). We performed a retrospective analysis to determine the impact of D14 BM characteristics in predicting for remission, association with overall survival (OS), and the effect of 2CI according to the D14 BM results. Patients and Methods: Patients aged 18 to 70 years undergoing induction therapy with standard "7 + 3" regimens were included. D14 cellularity was determined from BMTB samples and the blast percentage was assessed by morphology on BM aspiration and BMTB samples. The outcomes evaluated included the rates of complete remission (CR) and OS. Results: A total of 486 patients with results from D14 BM evaluation were included in the present study. On multivariate analysis, cytogenetic risk and D14 blasts < 5% were predictive of CR/CR with incomplete count recovery (P <.001). Cytogenetic risk (P <.001), age < 60 years (P = .001), and D14 blasts < 5% (P = .045) predicted for OS. 2CI was performed in 131 patients (27%). Patients with hypocellular D14 BM but residual blasts (n = 106) underwent 2CI in 46% of cases, with improved remission rates (43.9% vs. 72.0%; P = .004) but no difference in OS. Conclusions: The results from D14 BM evaluations are predictive of subsequent remission and OS. Our findings did not show a survival benefit with D14 BM-driven 2CI. (C) 2020 Elsevier Inc. All rights reserved.

Understanding how patient-reported quality of life (QoL) and socioeconomic status (SES) relate to survival of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) may improve prognostic information sharing. This study explores associations among QoL, SES, and survival through administration of the Euro-QoL 5-Dimension, 3-level and Functional Assessment of Cancer Therapy-Leukemia and financial impact questionnaires to 138 adult participants with newly diagnosed AML or MDS in a longitudinal, pan-Canadian study. Cox regression and lasso variable selection models were used to explore associations among QoL, SES, and established predictors of survival. Secondary outcomes were changes in QoL, performance of the QoL instruments, and lost income. We found that higher QoL and SES were positively associated with survival. The Lasso model selected the visual analog scale of the EQ-5D-3L as the most important predictor among all other variables (P = .03; 92% selection). Patients with AML report improved QoL after treatment, despite higher mean out-of-pocket expenditures compared with MDS (up to $599 CDN/month for AML vs $239 for MDS; P = .05), greater loss of productivity-related income (reaching $1786/month for AML vs $709 for MDS; P < .05), and greater caregiver effects (65% vs 35% caregiver productivity losses for AML vs MDS; P < .05). Our results suggest that including patient-reported QoL and socioeconomic indicators can improve the accuracy of survival models.

Introduction: t-AML is generally defined as AML arising from prior cytotoxic therapy, ionizing radiotherapy, or immunotherapy for an unrelated disease and is associated with poorer outcomes relative to de novo AML, with a median overall survival (OS) of ~6 mo following conventional induction chemotherapy. CPX-351 (Vyxeos®; daunorubicin and cytarabine liposome for injection) is a dual-drug liposomal encapsulation of cytarabine [C] and daunorubicin [D] at a synergistic 5:1 molar ratio. In a phase 3 study (NCT01696084) in older patients (pts) with newly diagnosed, high-risk/secondary AML, induction followed by consolidation with CPX-351 significantly improved OS (9.56 vs 5.95 mo; hazard ratio [HR] = 0.69; 1-sided P = 0.003) vs conventional 7+3, with a comparable safety profile. CPX-351 is approved by the FDA and EMA for the treatment of adults with newly diagnosed t-AML or AML with myelodysplasia-related changes. An exploratory analysis of the phase 3 study was performed to compare outcomes in the subgroup of pts with t-AML who achieved complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi). Methods: Pts aged 60-75 y with newly diagnosed, high-risk/secondary AML were randomized 1:1 to receive 1-2 induction cycles with CPX-351 (100 units/m2 [C 100 mg/m2 +D 44 mg/m2] as a 90-min infusion on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m2/day continuously for 7 d [2nd induction: 5 d] + D 60 mg/m2 on Days 1-3 [2nd induction: Days 1-2]). Pts achieving CR+CRi could receive up to 2 consolidation cycles with CPX-351 (65 units/m2 [C 65 mg/m2 + D 29 mg/m2] on Days 1 and 3) or 5+2 (as in 2nd induction). Pts could receive hematopoietic cell transplantation (HCT) at the physician's discretion. This exploratory analysis compared outcomes for CPX-351 vs 7+3 in the subgroup of t-AML pts who achieved CR+CRi. Results: Of 309 enrolled pts, 63 (20%) were diagnosed with t-AML. Among t-AML pts, 14/30 (47%) receiving CPX-351 and 12/33 (36%) receiving 7+3 achieved a CR+CRi (odds ratio = 1.53 [95% CI: 0.56-4.20]). Fewer pts treated with CPX-351 vs 7+3 received prior treatment with non-anthracycline chemotherapy alone (CPX-351: 14%; 7+3: 42%) whereas prior radiation therapy alone was less frequent in 7+3 pts (36%; 17%). Prior exposure to non-anthracycline chemotherapy with radiation (29%; 25%) and non-anthracycline chemotherapy with anthracycline chemotherapy and radiation (21%; 17%), as well as other baseline characteristics, were balanced between arms (Table). Median OS was longer with CPX-351 vs 7+3 in t-AML pts who achieved a CR+CRi (not reached [NR] vs 9.15 mo; HR = 0.19 [95% CI: 0.06-0.62]; Figure 1). While the rate of HCT in pts with CR+CRi was similar with CPX-351 and 7+3 (57% vs 58%; relative risk = 0.97 [95% CI: 0.50-1.90]), OS landmarked from the HCT date was longer with CPX-351 (NR vs 6.60 mo; HR = 0.08 [95% CI: 0.01-0.67]; Figure 2). No pt relapsed prior to HCT. Additional antileukemia therapy was received during follow-up prior to HCT by 7/8 (88%) pts in the CPX-351 arm and 7/7 (100%) pts in the 7+3 arm. Median OS in CR+CRi pts who did not receive a HCT was NR (95% CI: 7.43-NR) with CPX-351 vs 8.48 mo (95% CI: 5.49-NR) with 7+3. The most common treatment-emergent adverse events (TEAEs) in t-AML pts who achieved CR+CRi were febrile neutropenia (CPX-351: 100%; 7+3: 67%), rash (64%; 25%), epistaxis (57%; 25%), nausea (50%; 67%), diarrhea (43%; 67%), decreased appetite (43%; 58%), chills (29%; 50%), and fatigue (21%; 50%). A cardiac TEAE occurred in 4 (29%) pts in the CPX-351 arm and 4 (33%) pts in the 7+3 arm; the most common cardiac TEAEs were mitral valve incompetence (14%; 0%) and atrial fibrillation (7%; 17%). The most common grade ≥3 TEAEs were febrile neutropenia (CPX-351: 93%; 7+3: 67%), pneumonia (21%; 8%), and bacteremia (21%; 0%). The most common serious TEAEs were febrile neutropenia (CPX-351: 43%; 7+3: 0%), cellulitis (14%; 0%), and syncope (14%; 0%). There was no early mortality by Day 60 in either arm for t-AML pts who achieved a CR+CRi. Conclusions: Among t-AML pts who achieved a CR+CRi, CPX-351 improved median OS and OS landmarked from the HCT date vs 7+3 chemotherapy. Differences in outcomes may have been influenced by fewer pts treated with 7+3 who received prior radiation therapy only. The safety profile for CPX-351 in this subgroup was generally consistent with the known profile of 7+3. Exploratory analyses of baseline and post-treatment molecular (mutational) characteristics is ongoing. Figure Disclosures Lancet: Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Rizzieri:Spectrum: Consultancy; AbbVie: Consultancy; TEVA: Consultancy; Millennium: Speakers Bureau; Amgen: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Schiller:Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding. Erba:Amgen, Celgene, Daiichi Sankyo, ImmunoGen, Incyte, Jazz Pharmaceuticals, Millennium, Novartis, Ono, Pfizer, Seattle Genetics, Sunesis: Consultancy; Celgene, Incyte, Novartis: Speakers Bureau; Agios, Amgen, Astellas Pharma, Daiichi Sankyo, ImmunoGen, Janssen, Jazz Pharmaceuticals, Juno, Millennium, Seattle Genetics: Research Funding. Ryan:Jazz Pharmaceuticals: Employment, Equity Ownership. Faderl:Jazz Pharmaceutics: Employment, Equity Ownership. Cortes:Sun Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding.

Abstract Introduction: FLT3-ITD mutations are among the most common molecular abnormalities in AML, occurring in ≈ 25% of pts. These driver mutations are associated with high leukemic burden and poor prognosis, eg, high risk of relapse, decreased response to salvage therapy, and shorter overall survival (OS). Pts with R/R FLT3-ITD AML have a worse prognosis and represent a population with high unmet medical need. Q is a once-daily, oral, highly potent and selective FLT3i shown in phase 2 trials to have promising single-agent antileukemic activity and a manageable safety profile. QuANTUM-R was the first global, phase 3, randomized controlled trial (NCT02039726) to show that an FLT3i prolonged OS compared with salvage chemotherapy (SC) in pts with R/R FLT3-ITD AML. Final efficacy and safety data from this pivotal phase 3 trial are reported. Methods: Pts aged ≥ 18 years with FLT3-ITD AML refractory to or relapsed (duration of first remission ≤ 6 mo) after standard AML therapy, w/wo hematopoietic stem cell transplant (HSCT) were randomized 2:1 to receive Q (60 mg [30-mg lead-in]) or 1 of 3 preselected investigator's choice (IC) SC: low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). Up to 2 cycles of MEC or FLAG-IDA were permitted; Q and LoDAC were given until lack of benefit, unacceptable toxicity, or HSCT. Prior therapy with midostaurin was allowed, but all other FLT3i were not. Pts receiving HSCT in the Q arm could resume Q after HSCT. Primary and secondary endpoints were OS and event-free survival (EFS), respectively. Sensitivity analyses for OS and EFS were conducted: (1) using the per-protocol set (randomized and treated patients without major protocol deviations), (2) censoring at HSCT, (3) censoring at the use of other postbaseline FLT3i (for OS only). Predefined subgroup analyses of OS were also performed. Exploratory endpoints included response rates, duration of CRc, and transplant rate. Results: 367 pts were randomized; 245 to Q and 122 to IC SC (LoDAC, n=29; MEC, n=40; FLAG-IDA, n=53). Four pts randomized to Q and 28 pts randomized to SC did not receive therapy. Median follow-up was 23.5 mo. Six pts were still on initial Q treatment at data cutoff vs 0 in the SC arm. Treatment groups were well balanced for baseline characteristics, including age, response to prior therapy, transplant history, and FLT3-ITD allelic burden. OS hazard ratio (HR) of Q relative to SC was 0.76 (95% CI, 0.58-0.98; stratified log-rank test, 1-sided P=0.0177). Median OS was 6.2 (95% CI, 5.3-7.2) vs 4.7 (95% CI, 4.0-5.5) mo, with an estimated 12-mo OS probability of 27% vs 20% in Q and SC arms, respectively. EFS HR was 0.90 (95% CI, 0.70-1.16; stratified log-rank test, 1-sided P=0.1071); median EFS was 6.0 (95% CI, 0.1-8.3) vs 3.7 (95% CI, 0.4-5.9) wk, respectively. Sensitivity analyses of OS and EFS all supported benefit of quizartinib compared with SC, as did OS analyses across subgroups, including varying allelic ratio, prior HSCT, AML risk score, and response to prior therapy (Tables 1 and 2, Figure). CRc was 48% (95% CI, 42%-55%) and 27% (95% CI, 19%-36%) in Q and SC arms (nominal P=0.0001), respectively. Duration of CRc was 12.1 (95% CI, 10.4-27.1) vs 5.0 (95% CI, 3.3-12.6) wk. Transplant rate was 32% and 12% in Q and SC arms (nominal P<0.0001), respectively; of 79 eligible pts, 49 (62%) resumed single-agent Q after HSCT (15 ongoing Q treatment at data cutoff). Median duration of post-HSCT Q was 129 d. Rates of treatment-emergent adverse events (TEAEs) were comparable between the 2 arms, despite higher total drug exposure in Q vs SC arms (101.9 vs 3.7 patient-years [pt-y], respectively). Exposure-adjusted TEAEs were 2.3 vs 25.2 per pt-y, respectively. Most common grade ≥ 3 TEAEs in both arms were infections and those associated with cytopenia. Only 2 pts discontinued Q due to QTcF prolongation. QTcF >500 ms (grade 3) by central laboratory was 3% in the Q arm; no grade 4 QTcF occurred. Q-treated pts post-HSCT had a similar AE profile to those overall. Conclusions: This report confirms the survival benefit observed with single-agent Q compared with SC in pts with R/R FLT3-ITD AML and the favorable Q safety profile, providing evidence of meaningful clinical benefit in pts who have few options. These results are paradigm changing in the R/R FLT3-ITD AML treatment setting. Disclosures Cortes: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. Khaled:Juno: Other: Travel Funding; Daiichi: Consultancy; Alexion: Consultancy, Speakers Bureau. Perl:Arog: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Ganguly:Amgen: Consultancy; Janssen: Consultancy; Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau. Russell:Daiichi Sankyo: Consultancy; Jazz Pharma: Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Kramer:Daiichi Sankyo: Consultancy; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding. Dombret:Daiichi Sankyo: Honoraria; Roche/Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Ariad: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria; Jazz Pharma: Honoraria, Research Funding; Agios: Honoraria; Sunesis: Honoraria; Karyopharm: Honoraria; Kite Pharma: Honoraria, Research Funding; Menarini: Honoraria; Astellas: Honoraria; Janssen: Honoraria; Servier: Honoraria; Seattle Genetics: Honoraria. Jonas:Accelerated Medical Diagnostics: Research Funding; Incyte: Research Funding; Esanex: Research Funding; LP Therapeutics: Research Funding; AbbVie: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Kalobios: Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Research Funding; Genentech/Roche: Research Funding; Glycomimetics: Research Funding; Tolero: Consultancy; Amgen: Consultancy; Forma: Research Funding. Leung:Novartis: Speakers Bureau; Daiichi: Research Funding. Mehta:Daiichi Sankyo: Honoraria. Montesinos:Daiichi Sankyo: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Radsak:Novartis: Consultancy, Honoraria; Jazz Pharmaceuticals: Other: Travel grant; TEVA: Consultancy; Daiichi Sankyo: Honoraria, Other: Travel grant; Gilead: Other: Travel grant; Celgene: Honoraria, Other: Travel grant; Takeda: Consultancy. Arunachalam:Daiichi Sankyo: Employment. Holmes:Daiichi Sankyo: Employment. Kobayashi:Daiichi Sankyo: Employment. Namuyinga:Daiichi Sankyo: Employment. Ge:Daiichi Sankyo: Employment. Yver:Daiichi Sankyo: Employment. Zhang:Daiichi Sankyo: Employment.

Autologous stem cell transplantation (SCT) remains a frontline standard in eligible multiple myeloma (MM) patients (pts). Maintenance with Lenalidomide (Len) following SCT improves progression free survival (PFS). In del17p MM bortezomib (Bort) pre and post transplant was shown to improve PFS and OS. This led to the approval of len maintenance for all pts and of bort maintenance as an option for pts with high risk cytogenetics (HRC) in 2014 in British Columbia. Uptake of maintenance options was dependent on pt and physician preference. We compare the influence of maintenance regimen on outcome in pts with HRC after their first SCT for MM and compared this group to non-HRC MM pts.

Aims: Acute myeloid leukemia (AML) treatment typically involves remission induction chemotherapy followed by consolidation chemotherapy. New treatments for AML have recently been introduced, including a chemotherapy formulation called CPX-351, which is administered via less time-intensive IV infusion than the standard 7+3 continuous infusion regimen of cytarabine plus an anthracycline. The purpose of this study was to estimate utilities that could be used in economic modeling of AML treatment.Materials and methods: In time trade-off interviews, participants from the UK general population valued 12 health states drafted based on literature and clinician interviews. To identify disutility associated with chemotherapy, two types of induction and four types of consolidation were added to an otherwise identical health state describing AML. The decrease in utility when adding these chemotherapy regimens represents the disutility of each regimen. Five additional health states were valued to estimate utilities associated with other AML treatments.Results: Two hundred participants completed interviews. Mean (SD) utilities were 0.55 (0.31) for pre-treatment AML and 0.66 (0.29) for AML in temporary remission. Adding any chemotherapy significantly decreased utility (p<0.0001). Induction had a mean disutility of -0.11 with CPX-351 and -0.15 with 7+3. Mean disutility for consolidation ranged from -0.03 with outpatient CPX-351 to -0.11 with inpatient 5+2. Utilities are also reported for other AML treatments (e.g. transplant, low-intensity chemotherapy).Limitations: One limitation is that the differences in adverse event profiles between the treatment regimens were based on clinician opinion. Future use of CPX-351 in clinical trials or clinical settings will provide additional information on its adverse event profile.Conclusions: While all chemotherapy regimens were associated with disutility, regimens with shorter hospitalization and less time-intensive infusion were generally perceived as preferable. These utilities may be useful in cost-utility models comparing the value of AML treatments.

Background Patients with relapsed or refractory FLT3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia have a poor prognosis, including high frequency of relapse, poorer response to salvage therapy, and shorter overall survival than those with FLT3 wild-type disease. We aimed to assess whether single-agent quizartinib, an oral, highly potent and selective type II FLT3 inhibitor, improves overall survival versus salvage chemotherapy. Methods QuANTUM-R is a randomised, controlled, phase 3 trial done at 152 hospitals and cancer centres in 19 countries. Eligible patients aged 18 years or older with ECOG performance status 0-2 with relapsed or refractory (duration of first composite complete remission <= 6 months) FLT3-ITD acute myeloid leukaemia after standard therapy with or without allogeneic haemopoietic stem-cell transplantation were randomly assigned (2: 1; permuted block size of 6; stratified by response to previous therapy and choice of chemotherapy via a phone-based and webbased interactive response system) to quizartinib (60 mg [30 mg lead-in] orally once daily) or investigator's choice of preselected chemotherapy: subcutaneous low-dose cytarabine (subcutaneous injection of cytarabine 20 mg twice daily on days 1-10 of 28-day cycles); intravenous infusions of mitoxantrone (8 mg/m(2) per day), etoposide (100 mg/m (2) per day), and cytarabine (1000 mg/m (2) per day on days 1-5 of up to two 28-day cycles); or intravenous granulocyte colony-stimulating factor (300 mu g/m (2) per day or 5 mu g/kg per day subcutaneously on days 1-5), fludarabine (intravenous infusion 30 mg/m (2) per day on days 2-6), cytarabine (intravenous infusion 2000 mg/m (2) per day on days 2-6), and idarubicin (intravenous infusion 10 mg/m (2) per day on days 2-4 in up to two 28-day cycles). Patients proceeding to haemopoietic stem-cell transplantation after quizartinib could resume quizartinib after haemopoietic stem-cell transplantation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials. gov, number NCT02039726, and follow-up is ongoing. Findings Between May 7, 2014, and Sept 13, 2017, 367 patients were enrolled, of whom 245 were randomly allocated to quizartinib and 122 to chemotherapy. Four patients in the quizartinib group and 28 in the chemotherapy group were not treated. Median follow-up was 23.5 months (IQR 15.4-32.3). Overall survival was longer for quizartinib than for chemotherapy (hazard ratio 0.76 [95% CI 0.58-0.98; p=0.02]). Median overall survival was 6.2 months (5.3-7.2) in the quizartinib group and 4.7 months (4.0-5.5) in the chemotherapy group. The most common non-haematological grade 3-5 treatment-emergent adverse events (within <= 30 days of last dose or > 30 days if suspected to be a treatment-related event) for quizartinib (241 patients) and chemotherapy (94 patients) were sepsis or septic shock (46 patients [19%] for quizartinib vs 18 [19%] for chemotherapy), pneumonia (29 [12%] vs eight [9%]), and hypokalaemia (28 [12%] vs eight [9%]). The most frequent treatment-related serious adverse events were febrile neutropenia (18 patients [7%]), sepsis or septic shock (11 [5%]), QT prolongation (five [2%]), and nausea (five [2%]) in the quizartinib group, and febrile neutropenia (five [5%]), sepsis or septic shock (four [4%]), pneumonia (two [2%]), and pyrexia (two [2%]) in the chemotherapy group. Grade 3 QT prolongation in the quizartinib group was uncommon (eight [3%] by central reading, ten [4%] by investigator report); no grade 4 events occurred. There were 80 (33%) treatment-emergent deaths in the quizartinib group (31 [13%] of which were due to adverse events) and 16 (17%) in the chemotherapy group (nine [10%] of which were due to adverse events). Interpretation Treatment with quizartinib had a survival benefit versus salvage chemotherapy and had a manageable safety profile in patients with rapidly proliferative disease and very poor prognosis. Quizartinib could be considered a new standard of care. Given that there are only a few available treatment options, this study highlights the value of targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor.