CREST-UK: CPX-351 Real-World Effectiveness and Safety Study for the Treatment of Newly Diagnosed Therapy-Related AML and AML with Myelodysplasia-Related Changes in the UK

Background: In the UK, CPX-351 (Vyxeos® liposomal) has been licensed since August 2018 for adults with newly diagnosed, therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC), primarily based on favorable outcomes for CPX-351 versus 7+3 chemotherapy in a phase 3 trial in adults aged 60 to 75 y with newly diagnosed, high-risk/secondary AML. However, the phase 3 trial population did not reflect the full CPX-351 licensed population. As a complement to the phase 3 trial and to address important data gaps, CREST-UK was performed to assess the effectiveness and safety of CPX-351 in routine clinical practice in the UK and observe the impact of COVID-19 infection in these patients (pts).

Methods: CREST-UK is a retrospective, noninterventional, multicenter, single-arm, observational study (NCT05169307) that collected pseudonymized pt data abstracted from the medical records of adults aged ≥18 y with newly diagnosed t-AML or AML-MRC (per WHO 2016 criteria) who received ≥1 infusion of CPX-351 in routine practice; pts who received CPX-351 in a clinical trial were excluded. The primary objective was to describe complete remission (CR or CRi) and overall survival (OS). Key secondary objectives described pt and disease characteristics, frequency of hematopoietic cell transplantation (HCT), OS landmarked from the HCT date, and the CPX-351 safety profile. Median follow-up for OS was 10.6 mo (interquartile range [IQR]: 4.5, 18.4).

Results: A total of 147 pts who received their first CPX-351 induction from November 2018 to March 2022 were included from 15 centers. Median age was 64 y (range: 18, 83), with 17 (12%) pts aged <45 y, 39 (27%) aged 45-59 y, 64 (44%) aged 60-69 y, and 27 (18%) aged ≥70 y. Overall, 35 (24%) pts had t-AML and 112 (76%) had AML-MRC (n=43 with prior MDS, n=9 with prior CMML, n=41 with MDS-related cytogenetics, and n=19 with multilineage dysplasia alone); 13 (9%) had received prior azacitidine. The majority (90%) of pts had an ECOG performance status ≤1. Disease risk by European LeukemiaNet 2017 criteria was favorable for 13 (9%) pts, intermediate for 39 (27%), adverse for 66 (45%), and unknown for 29 (20%) due to limited mutational data. Complex karyotype, monosomal karyotype, and/or abn(17p) were reported for 37 (25%) pts. TP53 mutations were reported for 15/66 (23%) pts with evaluable data.

A best response of CR+CRi was achieved by 73/138 (53%) evaluable pts, and overall response (CR+CRi+MLFS+PR) was achieved by 88/138 (64%) pts. Post induction, 19/37 (51%) pts in CR or CRi with a known measurable residual disease (MRD) status achieved MRD negativity; 3 additional pts achieved MRD negativity at a later time point. Kaplan-Meier median OS was 12.85 mo (95% CI: 9.2, 15.4; Fig 1), with 2- and 3-y OS estimates of 36% and 34%, respectively. Fifty (34%) pts proceeded to HCT; median OS landmarked from the HCT date was not reached (Fig 2), with a 2-y OS estimate of 71%.

Among pts in CR or CRi, median recovery (IQR) to neutrophils ≥500/μL was 33 d (28, 43) and to platelets ≥50,000/μL was 34 d (27, 48) during the first induction. Grade ≥3 treatment-related adverse events (TRAEs) of interest included febrile neutropenia (36%; n=1 grade 5), infections (29%; n=6 grade 5), bleeding (4%; n=1 grade 5), and gastrointestinal events (3%). Cardiac TRAEs of any grade were reported for 5% of pts, with grade ≥3 events in 3% (n=1 grade 5). No extravasation was reported. Estimated all-cause mortality was 7% at 30 d and 14% at 60 d.

This study included pts who were diagnosed and treated for AML during the COVID-19 pandemic. A total of 26 COVID-19 infections happened at variable time intervals pre- or post-AML treatment. In this cohort, 2 deaths were directly linked to COVID-19; both were assessed by the site investigator as unrelated to CPX-351 treatment.

Conclusion: CREST-UK, a real-world study in the context of the COVID-19 pandemic, confirmed the efficacy and safety of CPX-351 in a broad population that included substantial proportions who were aged <60 y or ≥70 y and/or had adverse-risk disease. CR or CRi with MRD negativity and/or proceeding to HCT was achieved in proportions consistent with clinical trials and other real-world studies. Survival outcomes were also consistent with other real-world studies. No new safety concerns with CPX-351 were identified. These data provide new insights into the use of CPX-351 in routine clinical practice in the UK and support its continued use in adults with newly diagnosed t-AML and AML-MRC.

Mehta:Pfizer: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Khan:Abbvie: Honoraria; Astellas: Speakers Bureau; TC BioPharm: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maddox:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses and conference fees; Novartis: Other: Travel expenses and conference fees. Whitmill:Jazz: Other: Conference Cost for ASH and After Ash Meeting, Speakers Bureau. Cuadras:IQVIA Real World Solutions, which was contracted by Jazz Pharmaceuticals for the conduct of this study: Current Employment. Pedros:Employee of IQVIA Real World Solutions, which was contracted by Jazz Pharmaceuticals for the conduct of this study: Current Employment. Park:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Medalla:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Legg:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Campbell:Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, and Novartis: Consultancy, Speakers Bureau; Kite/Gilead: Research Funding.