Abstract Background CPX-351 (United States: Vyxeos®; Europe: Vyxeos® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved by the US FDA and the EMA for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In a pivotal phase 3 study that evaluated 309 patients aged 60 to 75 years with newly diagnosed high-risk/secondary acute myeloid leukemia, CPX-351 significantly improved median overall survival versus conventional 7 + 3 chemotherapy (cytarabine continuous infusion for 7 days plus daunorubicin for 3 days), with a comparable safety profile. A Quality‐adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of the phase 3 study was performed to compare survival quality between patients receiving CPX-351 versus conventional 7 + 3 after 5 years of follow-up. Methods Patients were randomized 1:1 between December 20, 2012 and November 11, 2014 to receive induction with CPX-351 or 7 + 3. Survival time for each patient was partitioned into 3 health states: TOX (time with any grade 3 or 4 toxicity or prior to remission), TWiST (time in remission without relapse or grade 3 or 4 toxicity), and REL (time after relapse). Within each treatment arm, Q-TWiST was calculated by adding the mean time spent in each health state weighted by its respective quality-of-life, represented by health utility. The relative Q-TWiST gain, calculated as the difference in Q-TWiST between treatment arms divided by the mean survival of the 7 + 3 control arm, was determined in order to evaluate results in the context of other Q-TWiST analyses. Results The relative Q-TWiST gain with CPX-351 versus 7 + 3 was 53.6% in the base case scenario and 39.8% among responding patients. Across various sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 to 57.6%, remaining well above the standard clinically important difference threshold of 15% for oncology. Conclusions This post hoc analysis demonstrates that CPX-351 improved quality-adjusted survival, further supporting the clinical benefit in patients with newly diagnosed high-risk/secondary acute myeloid leukemia. Trial registration This trial was registered on September 28, 2012 at www.clinicaltrials.gov as NCT01696084 ( https://clinicaltrials.gov/ct2/show/NCT01696084 ) and is complete.

Background: CPX-351 is a liposomal encapsulation of daunorubicin and cytarabine in a 1:5 molar ratio. In a randomized phase 3 study (CPX-351-301) conducted in older adults (60 to 75 years old) with newly diagnosed, high-risk and/or secondary AML, CPX-351 induction therapy was superior to standard 7+3 with improved rates of complete remission (CR) and overall survival (OS). In both older adults and high-risk AML, allogeneic hematopoietic cell transplantation (HCT) is frequently the preferred post-remission strategy owing to the high rates of relapse and poor overall survival with conventional chemotherapy approaches. After a median follow-up of 20.7 months, the primary pre-planned analysis found that more patients randomized to CPX-351 underwent HCT and an exploratory landmark survival analysis from the time of HCT favored CPX-351 (HR = 0.46 [95% CI: 0.24, 0.89]; one-sided P = 0.009). However, the initial protocol did not collect data related to HCT and the basis for improved HCT outcomes with CPX-351 was previously unknown. Here we present a detailed analysis of HCT outcomes in patients enrolled in the CPX-351-301 study with 5-years of follow-up. Methods: Patients age 60 to 75 years with high-risk and/or secondary AML were randomized in a 1:1 fashion to receive CPX-351 or 7+3 as induction and consolidation chemotherapy (Lancet J et al, JCO 2018). The protocol was amended to collect additional HCT-specific information, including donor and HCT characteristics and post-HCT outcomes, including rates of relapse and GVHD. Post-HCT outcomes including relapse, GVHD, and death were analyzed as competing events. Results: Of 309 randomized patients in the CPX-351-301 study, more patients achieved CR/CRi with CPX-351 vs 7+3 (48% vs 33%) allowing more patients to proceed to HCT (35% vs 25%) and more patients to proceed to HCT in remission (CPX-351: 41/73 [56%]; 7+3: 24/52 [46%]). The median age was 66 years with CPX-351 vs 65 years with standard induction among the transplanted cohorts; 16 patients in the CPX-351 transplanted arm were over the age of 70 compared to only 6 in the 7+3 arm. Other pre-HCT patient characteristics were balanced between the CPX-351 and 7+3 groups, including ECOG performance status (8% vs 5% with ECOG PS of 2), HCT-CI (median 4 vs 3), donor type (matched unrelated donor 49% vs 49%), and conditioning regimen intensity (myeloablative [17% vs 13%] vs reduced-intensity conditioning [43% vs 46%]). The Kaplan-Meier-estimated 3-year survival rate among transplanted patients was 56% with CPX-351 vs 23% with 7+3 (Figure 1A). The differences in survival consistently favored CPX-351 across patient age, AML subtype, disease status, donor type, and conditioning intensity (Figure 1B). Differences in OS were driven by a large reduction in non-relapse mortality (HR = 0.42 [95% CI: 0.21, 0.86]; Figure 1D). The cumulative incidence of acute GVHD with death as a competing event at 6 months from HCT date was 0.49 (95% CI: 0.35, 0.62) in the CPX-351 arm and 0.38 (95% CI: 0.23, 0.53) in the 7+3 arm. Conclusions: Analysis of HCT outcomes in patients enrolled in the CPX-351-301 study demonstrated that treatment with CPX-351 in older adults with high-risk and/or secondary AML resulted in more patients bridged to HCT and more patients transplanted in CR/CRi compared to 7+3, with improved OS in transplanted patients. The pattern of HCT outcomes suggests improved disease control with CPX-351 induction allowing higher HCT rates, but more importantly improved tolerability with less non-relapse mortality; this data supports the development of CPX-351 in other high-risk AML populations in which allogeneic HCT is the preferred post-remission strategy. Figure Disclosures Uy: Genentech: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Astellas Pharma: Honoraria; Jazz Pharmaceuticals: Consultancy. Lin:Abbvie: Research Funding; Pfizer: Research Funding; Trovagene: Research Funding; Prescient Therapeutics: Research Funding; Tolero Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Ono Pharmaceutical: Research Funding; Genetech-Roche: Research Funding; Incyte: Research Funding; Jazz: Research Funding; Mateon Therapeutics: Research Funding; Gilead Sciences: Research Funding; Celyad: Research Funding; Celgene: Research Funding; Bio-Path Holdings: Research Funding; Astellas Pharma: Research Funding; Aptevo: Research Funding. Wieduwilt:Reata Pharmaceuticals: Current equity holder in publicly-traded company; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Shire: Research Funding; Merck: Research Funding; Leadiant: Research Funding; Amgen: Research Funding; Macrogeneics: Research Funding. Ryan:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Faderl:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Lancet:Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy.

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.

Severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT). This multinational, prospective, observational study (NCT03032016), performed by the EBMT, enrolled patients treated with defibrotide from April 2015 to July 2018. This analysis focused on defibrotide-treated patients with VOD/SOS post-HCT. The primary endpoint was incidence of serious adverse events (SAEs) of interest up to 12 months post-HCT in patients with severe VOD/SOS. Overall, 104 defibrotide-treated patients with VOD/SOS post-HCT were enrolled: 62 had severe VOD/SOS and comprised the primary study population, including 36 with multi-organ dysfunction/failure (MOD/MOF). SAEs of interest occurred in 20 of 62 (32%) severe VOD/SOS patients; the most common by category were infection (24%) and bleeding (13%). In patients with severe VOD/SOS, the Kaplan–Meier–estimated Day 100 survival rate was 73% (95% CI: 60%, 82%) with VOD/SOS resolution by Day 100 in 45 of 62 (73%) patients. MOD/MOF resolved in 19 of 36 (53%) patients with MOD/MOF at VOD/SOS diagnosis. Results from this multicentre registry study build on prior defibrotide studies supporting the utility of defibrotide for the treatment of VOD/SOS post-HCT. These results provide additional real-world evidence of the effectiveness and safety of defibrotide in patients with VOD/SOS post-HCT.

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT) that is traditionally diagnosed using Baltimore or modified Seattle criteria. Whereas the Baltimore criteria require the presence of hyperbilirubinemia (bilirubin ≥2 mg/dL) for a diagnosis of VOD/SOS, the modified Seattle criteria do not. Before approval by the US Food and Drug Administration, defibrotide was available in the United States through an expanded-access study (T-IND). The T-IND protocol initially required post-HCT diagnosis of VOD/SOS by the Baltimore criteria or biopsy but was later amended to include patients diagnosed using the modified Seattle criteria. This post hoc analysis examined the incidence of VOD/SOS with a bilirubin level <2 mg/dL before and after Day 21 post-HCT in T-IND patients enrolled following the amendment allowing for diagnosis by the modified Seattle criteria. Survival of adult and pediatric patients with or without hyperbilirubinemia and with or without multiorgan dysfunction (MOD) was also evaluated. Of 803 post-HCT patients with VOD/SOS enrolled following the protocol amendment, 181 (23%) had a bilirubin level <2 mg/dL and would not have been diagnosed if hyperbilirubinemia was required. The bilirubin level at diagnosis was <2 mg/dL in 165 of 331 patients (50%) diagnosed by the modified Seattle criteria and in 16 of 23 patients (70%) diagnosed by biopsy. VOD/SOS with a bilirubin level <2 mg/dL was more common in pediatric patients (29%), although it also occurred in adult patients (15%). Patients with hyperbilirubinemia had lower Day 100 survival (54% versus 87% in patients with bilirubin <2 mg/dL) and a higher incidence of MOD (41% versus 26% in patients with bilirubin <2 mg/dL). The incidence of treatment-emergent adverse events and serious adverse events was lower in patients with a bilirubin level <2 mg/dL. These results indicate that anicteric VOD/SOS occurs in both adult and pediatric patients post-HCT and can be diagnosed before and after Day 21 in both groups. The worse survival in patients with bilirubin ≥2 mg/dL suggests that requiring hyperbilirubinemia may result in a progressed disease stage associated with worse outcomes. Taken together, these results highlight the importance of awareness and the possibility of VOD/SOS in the absence of elevated bilirubin level.

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.

To determine the time course and duration of common, early-onset treatment-emergent adverse events (TEAEs) associated with sodium oxybate (SXB) use in adults with narcolepsy. These were post hoc analyses of two 8-week, randomized, double-blind, placebo-controlled trials. In SXB-15, participants (n = 246) received daily placebo (n = 60) or SXB (n = 186) initiated at 4.5 g. Participants assigned to SXB 6 or 9 g were titrated in 1.5-g increments. In SXB-22, participants entering on modafinil (n = 231) received placebo (n = 56), SXB (n = 55), modafinil (n = 63), or SXB and modafinil (n = 57). SXB was initiated at 6 g for weeks 1–4 and increased to 9 g for weeks 5–8. TEAEs reported more frequently in SXB-treated participants than placebo and in ≥5 ClinicalTrials.gov ; Names: Safety and Efficacy of Xyrem Oral Solution (Sodium Oxybate) Compared With Placebo in Narcoleptic Patients; Trial Comparing Effects of Xyrem Taken Orally and Modafinil With Placebo in Treating Daytime Sleepiness in Narcolepsy; URLs: https://clinicaltrials.gov/ct2/show/NCT00049803 and https://clinicaltrials.gov/ct2/show/NCT00066170 ; Identifiers: NCT00049803 and NCT00066170. Husain AM, Bujanover S, Ryan R, Scheckner B, Black J, Profant J. Incidence and duration of common, early-onset adverse events occurring during 2 randomized, placebo-controlled, phase 3 studies of sodium oxybate in participants with narcolepsy. J Clin Sleep Med. 2020;16(9):1469–1474.

Aims: Treatment of acute myeloid leukemia (AML) requires significant healthcare resource utilization (HRU), including lengthy hospitalizations. In a phase 3 study (NCT01696084), CPX-351 (Vyxeos) showed significant benefits to overall survival and complete remission versus conventional 7 + 3 cytarabine/daunorubicin. This analysis evaluated HRU in patients aged 60-75 years with newly diagnosed high-risk/secondary AML treated with CPX-351 versus 7 + 3 in the phase 3 study. Materials and methods: Patients were randomized to receive up to two induction cycles with CPX-351 or 7 + 3. Responders could receive up to two cycles of consolidation. To normalize HRU to length of treatment, patients were assessed on a per patient-year (PPY) basis. HRU analyses included hospital and intensive care unit (ICU) stays, anti-infective use, transfusions, and white blood cell colony-stimulating factor (CSF). Results: The median (range) total duration of hospitalization was 39 (3-110) days with CPX-351 (n = 153) and 32 (2-83) days with 7 + 3 (n = 151); the estimated durations of hospitalization PPY were 198.4 and 240.5 days, respectively. The median (range) total duration of ICU stays was 0 (0-45) days with CPX-351 and 0 (0-17) days with 7 + 3; the estimated durations of ICU stays PPY were 6.7 and 10.5 days, respectively. When comparing supportive care use during CPX-351 and 7 + 3 treatment, the estimated number PPY of bags of platelets used (24.6 vs 26.9, respectively), bags of packed red blood cells used (13.0 vs 13.9), days of anti-infectives (162.0 vs 159.2), and days of CSF (4.0 vs 2.4) were not notably different. Limitations: This clinical study analysis may not represent real-world HRU patterns or be generalizable to a broader AML population. Conclusions: These PPY data, showing shorter durations of hospitalization and similar use of supportive care with CPX-351 versus 7 + 3, suggest CPX-351 is not associated with increased HRU in older patients with newly diagnosed high-risk/secondary AML.

For patients with untreated hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) with multi-organ dysfunction (MOD), mortality is >80%. We conducted a pooled analysis of three studies that assessed Day 100 survival in relationship to MOD severity, with dialysis and/or ventilator dependence representing the most severe organ dysfunction. All patients in the analysis were diagnosed using Baltimore criteria/biopsy. This analysis of patients with VOD/SOS and MOD after haematopoietic cell transplantation (HCT; n = 651) demonstrated higher Day 100 survival rates amongst defibrotide-treated patients with VOD/SOS with less versus more severe forms of MOD. Even patients with severe forms of MOD post-HCT benefitted from defibrotide.

Severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT). Clinical guidelines endorse prompt defibrotide initiation after VOD/SOS diagnosis. In order to collect safety and outcomes data and assess patterns of defibrotide utilization in the post-approval setting, a registry of patients who received defibrotide was established. This multicenter, multinational, prospective, observational study (NCT03032016), performed by the European Society for Blood and Marrow Transplantation, enrolled defibrotide-treated patients from April 2015 to July 2018. Investigators diagnosed VOD/SOS using classical/standard criteria (including, but not limited to, hyperbilirubinemia, hepatomegaly, ascites, and weight gain >5%). Severity grading criteria were not predefined in the protocol; investigators graded VOD/SOS severity based on their clinical expertise. The primary endpoint was incidence of serious adverse events (SAEs) of interest up to 12 months post-HCT in patients with severe VOD/SOS. This analysis evaluated time to diagnosis, treatment initiation, and resolution of VOD/SOS, as well as treatment duration and survival, in patients given defibrotide for the treatment of severe or non-severe VOD/SOS post-HCT. Overall, 104 defibrotide-treated patients with VOD/SOS post-HCT were included (62 with severe VOD/SOS [45% adults, ≥18 years] and 42 with non-severe VOD/SOS [40% adults]). The median age was 14.4 (range: 0, 69) years; 90 (87%) patients received allogeneic HCT. Most (89%) patients had received 1 HCT and most (82%) were given a myeloablative conditioning regimen. HCT type and conditioning regimen were similar between adult and pediatric patients. The median time from HCT to VOD/SOS diagnosis was 14 (range: 2, 123) days and 13 (range: 2, 36) days in patients with severe VOD/SOS or non-severe disease, respectively. Defibrotide treatment for VOD/SOS was generally initiated on the same day as diagnosis (median days from diagnosis was 0 days in both severe [range: 0, 8] and non-severe [range: 0, 11] VOD/SOS patients). Among patients with severe VOD/SOS, 73%, 13%, and 15% received defibrotide at 0, 1, and ≥2 days after diagnosis; correspondingly this was 74%, 21%, and 5% for patients with non-severe VOD/SOS. Most patients (severe: 79%; non-severe: 76%) received the recommended dose of 25 mg/kg/day. The median duration of treatment was similar for both severe and non-severe VOD/SOS (16.5 [interquartile range [IQR]: 11, 25] days and 15.5 [IQR: 13, 21] days, respectively). Resolution of VOD/SOS was achieved in 47 (76%) patients with severe VOD/SOS and 40 (95%) with non-severe VOD/SOS. The median time from diagnosis to resolution of VOD/SOS was 20.0 (range: 5, 112) days and 15.5 (range: 2, 29) days in patients with severe VOD/SOS or non-severe disease, respectively. Resolution of VOD/SOS occurred after Day 21 in 19 (40%) and 11 (28%) patients with severe VOD/SOS or non-severe disease, respectively. Among patients with severe VOD/SOS, the Kaplan-Meier (KM)-estimated Day 100 post-HCT survival rate was 89% (95% confidence interval [CI]: 76%, 95%) in patients who achieved resolution of VOD/SOS and 20% (95% CI: 5%, 42%) in those who did not. In patients with non-severe VOD/SOS, the KM-estimated Day 100 post-HCT survival rate was 95% (95% CI: 82%, 99%) in patients who achieved resolution of VOD/SOS; the two patients with non-severe disease who failed to achieve resolution of VOD/SOS were not alive at Day 100 post-HCT. A SAE of interest occurred in 32% (95% CI: 21%, 44%) of patients with severe VOD/SOS and in 21% (95% CI: 9%, 34%) of patients with non-severe VOD/SOS. The most common individual SAEs of interest (≥5% of patients) were pneumonia, sepsis, gastrointestinal bleeding, and urinary tract bleeding. Few patients discontinued defibrotide due to an adverse event: 1 (2%) patient with severe VOD/SOS and 0 patients with non-severe VOD/SOS. These results highlight the importance of prompt diagnosis and of continuing treatment until a response is achieved. These findings are consistent with the product labeling, which recommends continued administration for at least 21 days and until full resolution of VOD/SOS signs and symptoms. The safety profile of defibrotide in the real-world setting was consistent with reports from previous studies. Disclosures Locatelli: Jazz Pharmaceeutical: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria; Janssen: Honoraria; Gilead/Kite: Honoraria, Other: travel support. Ryan:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Hanvesakul:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Mohty:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. OffLabel Disclosure: The abstract describes outcomes in patients with non-severe VOD/SOS, who are not included in the indicated population in the product label.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication that occurs after hematopoietic cell transplantation (HCT). The mortality associated with untreated VOD/SOS with multiorgan dysfunction (MOD) has been reported to be >80%. The recommended dose of defibrotide is 6.25 mg/kg every 6 hours, administered as a 2-hour i.v. infusion, for a minimum of 21 days or until resolution of VOD/SOS signs and symptoms. The objective of this analysis was to evaluate the time to complete response (CR) in patients with post-HCT VOD/SOS treated with defibrotide. The time to defibrotide discontinuation due to a CR served as a surrogate for time to CR in an expanded access study (T-IND; ClinicalTrials.gov NCT00628498; n = 1000), and was analyzed separately from the time to CR data pooled from a phase 2 randomized dose-finding study (NCT00003966; n = 74 patients who received 25 mg/kg/day) and a phase 3 historically controlled study (NCT00358501; n = 102). For all studies, a CR was defined as total serum bilirubin <2 mg/dL with resolution of VOD/SOS-related MOD (renal and/or pulmonary dysfunction); the phase 2 study also required resolution of central nervous system dysfunction. In the T-IND, 390 patients discontinued treatment due to a CR and had sufficient data for analysis. The median time to discontinuation was 22 days (range, 2 to 64 days). Discontinuation due to CR occurred beyond 21 days in 235 patients (60%) and beyond 28 days in 57 patients (15%). The pooled phase 2 and 3 studies included 60 patients who achieved a CR, with a median time to CR of 24.5 days (range, 7 to 123 days). A CR was achieved beyond 21 days in 32 patients (53%) and beyond 28 days in 24 patients (40%). The Kaplan-Meier estimate of day +100 survival rate was substantially higher in patients who discontinued due to a CR compared with those who did not (92.5% versus 37.3%). Treatment-emergent adverse events occurred in 185 of 390 patients (47%) who discontinued due to a CR in the T-IND and in 55 of 60 patients (92%) who achieved a CR in the pooled phase 2 and 3 studies, and rates did not differ according to duration of treatment (≤21 days versus >21 days). Taken together, these results highlight the importance of continued defibrotide therapy until resolution of VOD/SOS signs and symptoms, as currently indicated in the approved product labels, which may occur beyond the recommended minimum of 21 days.

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.

7537 Background: CPX-351 (Vyxeos; daunorubicin [D] and cytarabine [C] liposome for injection) is approved by the FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. In a phase 3 study (NCT01696084) in patients (pts) aged 60-75 y with newly diagnosed high-risk/secondary AML, CPX-351 demonstrated significantly longer overall survival (OS) and higher rates of remission and hematopoietic cell transplant (HCT) vs conventional 7+3, with a comparable safety profile. To better understand the impact of treatment on outcomes in pts who did not undergo HCT, this exploratory analysis evaluated outcomes in the subgroup who achieved complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) with CPX-351 vs 7+3 but did not undergo HCT. 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 CR or CRi could receive up to 2 consolidation cycles. Pts could receive HCT at the physician’s discretion. Results: CR+CRi was achieved by 73/153 (48%) pts with CPX-351 vs 52/156 (33%) with 7+3; of these pts, 33/73 (45%) vs 28/52 (54%) did not subsequently undergo HCT. The baseline characteristics of these pts were generally balanced between arms; however, the CPX-351 arm had more male pts vs 7+3 (64% vs 43%) and pts with ECOG PS of 1 (82% vs 54%), and fewer pts with antecedent MDS and HMA exposure (21% vs 39%). Median OS was longer with CPX-351 vs 7+3 (14.72 vs 7.59 mo; HR = 0.57 [95% CI: 0.31-1.03]; Table). There was no early mortality by Day 60 in either arm (see Table for additional data). Conclusions: CPX-351 improved median OS vs 7+3 in pts who achieved CR+CRi but did not undergo HCT, suggesting a treatment benefit with CPX-351 even among pts who do not undergo HCT. The CPX-351 safety profile in this subgroup was consistent with the overall study population and known profile of 7+3. Clinical trial information: NCT01696084 . [Table: see text]

Background:CPX‐351 (Vyxeos®; daunorubicin and cytarabine powder for concentrate for solution for infusion), a dual‐drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, is approved by the EMA and US FDA for the treatment of adults with newly diagnosed, therapy‐related AML or AML with myelodysplasia‐related changes. In a randomized phase 3 study, induction followed by consolidation with CPX‐351 significantly improved median overall survival (OS) versus conventional 7+3 cytarabine/daunorubicin chemotherapy (9.56 vs 5.95 months; HR = 0.69 [95% CI: 0.52–0.90; 1‐sided P = 0.003) and had a safety profile comparable to 7+3 in adults aged 60–75 years with newly diagnosed, high‐risk/secondary AML (Lancet, et al. J Clin Oncol 2018). CPX‐351 was also associated with significantly higher rates versus 7+3 of complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CR+CRi; 73/153 [48%] vs 52/156 [33%]; OR = 1.77 [95% CI: 1.11–2.81]; 2‐sided P = 0.016) and CR (57/153 [37%] vs 40/156 [26%]; OR = 1.69 [95% CI: 1.03–2.78]; 2‐sided P = 0.040).Aims:This exploratory analysis of the phase 3 study evaluated outcomes in the subgroup of patients (pts) who achieved CR+CRi following induction with CPX‐351 versus 7+3.Methods:A total of 309 pts were randomized 1:1 to receive up to 2 induction cycles of CPX‐351 (100 units/m2 [daunorubicin 44 mg/m2 + cytarabine 100 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (cytarabine 100 mg/m2/day continuously for 7 days [2nd induction: 5 days] + daunorubicin 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 [daunorubicin 29 mg/m2 + cytarabine 65 mg/m2] on Days 1 and 3) or 5+2 (as for 2nd induction). For this analysis, outcomes were evaluated in the subgroup of pts who achieved CR+CRi following induction.Results:Baseline characteristics of pts who achieved CR+CRi were generally balanced between arms. Median OS was longer with CPX‐351 versus 7+3 in pts who achieved CR+CRi (25.43 vs 10.41 months; HR = 0.49 [95% CI: 0.31–0.77]) or CR (25.43 vs 10.97 months; HR = 0.49 [95% CI: 0.29–0.83]; Figure 1). Of pts who achieved CR+CRi, 40/73 (55%) in the CPX‐351 arm and 24/52 (46%) in the 7+3 arm underwent transplantation (OR = 0.71 [95% CI: 0.35–1.44]; median OS landmarked from the date of transplant was not reached versus 11.65 months, respectively (HR = 0.42 [95% CI: 0.20–0.86]; Figure 2). Serious treatment‐emergent adverse events in ≥5% of pts who achieved CR+CRi were febrile neutropenia (CPX‐351: 15%; 7+3: 12%), acute respiratory failure (7%; 2%), ejection fraction decreased (5%; 4%), sepsis (5%; 4%), pneumonia (3%; 6%), and pulmonary edema (1%; 6%). Four pts with CR+CRi died during the treatment phase (sepsis [CPX‐351]; atrial fibrillation [7+3]; disease progression [7+3]; intracranial hemorrhage [7+3]); no patient experienced early mortality (within 60 days) in either arm. Median time for recovery to neutrophils ≥1,000/μL and platelets ≥100,000/μL, respectively, in pts who achieved CR+CRi was longer with CPX‐351 (37 and 42 days) versus 7+3 (29 and 32 days).Summary/Conclusion:Among pts who achieved CR+CRi in this study, those who received CPX‐351 had longer median OS, a higher rate of transplantation, and longer median OS landmarked from the date of transplant versus 7+3, suggesting potentially deeper responses may be achieved with CPX‐351. The safety profile of CPX‐351 in pts who achieved CR+CRi was consistent with the known profile of 7+3, as well as the overall study population.image

CPX-351 (Vyxeos®), a dual-drug liposomal encapsulation of cytarabine/daunorubicin at a synergistic ratio, is approved by the FDA and EMA for the treatment of adults with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes. In a phase 3 study, CPX-351 significantly improved median overall survival (OS; 9.56 vs 5.95 months; HR=0.69 [95% CI: 0.52-0.90]; 1-sided P=0.003) and remission rates (CR+CRi; 73/153 [48%] vs 52/156 [33%]; OR=1.77 [95% CI: 1.11-2.81]; 2-sided P=0.016) versus 7+3 chemotherapy.