Articles

CPX-351 versus 7+3 cytarabine and daunorubicin

chemotherapy in older adults with newly diagnosed
high-risk or secondary acute myeloid leukaemia: 5-year
results of a randomised, open-label, multicentre, phase 3 trial
Jeffrey E Lancet, Geoffrey L Uy, Laura F Newell, Tara L Lin, Ellen K Ritchie, Robert K Stuart, Stephen A Strickland, Donna Hogge, Scott R Solomon,
Dale L Bixby, Jonathan E Kolitz, Gary J Schiller, Matthew J Wieduwilt, Daniel H Ryan, Stefan Faderl, Jorge E Cortes

Summary
Background Daunorubicin and cytarabine are used as standard induction chemotherapy for patients with acute Lancet Haematol 2021;
myeloid leukaemia. CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 8: e481–91

1:5 molar ratio. Primary analysis of the phase 3 trial in adults aged 60–75 years with newly diagnosed high-risk or See Comment page e468
secondary acute myeloid leukaemia provided support for approval of CPX-351 by the US Food and Drug Administration H Lee Moffitt Cancer Center &
and European Medicines Agency. We describe the prospectively planned final 5-year follow-up results. Research Institute, Tampa, FL,
USA (Prof J E Lancet MD);
Washington University School
Methods This randomised, open-label, multicentre, phase 3 trial was done across 39 academic and regional cancer centres of Medicine, St Louis, MO, USA
in the USA and Canada. Eligible patients were aged 60–75 years and had a pathological diagnosis of acute myeloid (Prof G L Uy MD); Knight Cancer
leukaemia according to WHO 2008 criteria, no previous induction therapy for acute myeloid leukaemia, and an Institute, Hematology and
Medical Oncology, Oregon
Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned 1:1 (stratified by
Health & Science University,
age and acute myeloid leukaemia subtype) to receive up to two induction cycles of CPX-351 (100 units/m² administered Portland, OR, USA
as a 90-min intravenous infusion on days 1, 3, and 5; on days 1 and 3 for the second induction) or standard (L F Newell MD); University of
chemotherapy (cytarabine 100 mg/m² per day continuous intravenous infusion for 7 days plus intravenous Kansas Medical Center, Kansas
City, KS, USA (T L Lin MD); Weill
daunorubicin 60 mg/m² on days 1, 2, and 3 [7+3]; cytarabine for 5 days and daunorubicin on days 1 and 2 for the Cornell Medical College of
second induction [5+2]). Patients with complete remission or complete remission with incomplete neutrophil or Cornell University, New York,
platelet recovery could receive up to tw cycles of consolidation therapy with CPX-351 (65 units/m² 90-min infusion on NY, USA (E K Ritchie MD);
days 1 and 3) or chemotherapy (5+2, same dosage as in the second induction cycle). The primary outcome was overall Hollings Cancer Center, Medical
University of South Carolina,
survival analysed in all randomly assigned patients. No additional adverse events were collected with long-term Charleston, SC, USA
follow-up, except data for deaths. This trial is registered with ClinicalTrials.gov, NCT01696084, and is complete. (Prof R K Stuart MD);
Vanderbilt-Ingram Cancer
Findings Between Dec 20, 2012, and Nov 11, 2014, 309 patients with newly diagnosed high-risk or secondary acute Center, Nashville, TN, USA
(S A Strickland MD); Leukemia/
myeloid leukaemia were enrolled and randomly assigned to receive CPX-351 (153 patients) or 7+3 (156 patients). At a Bone Marrow Transplant
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 Program of British Columbia,
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) Vancouver, BC, Canada
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 (D Hogge MD); Leukemia
Program, Northside Hospital
8% (4–13%) in the 7+3 group. The most common cause of death in both groups was progressive leukaemia (70 [56%] Cancer Center Institute,
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 Atlanta, GA, USA
CPX-351 group and seven (5%) of 140 deaths in the 7+3 group were considered related to study treatment. (S R Solomon MD);
Comprehensive Cancer Center,
University of Michigan, Grass
Interpretation After 5 years of follow-up, the improved overall survival with CPX-351 versus 7+3 was maintained, Lake, MI, USA (D L Bixby MD);
which supports the previous evidence that CPX-351 can contribute to long-term remission and improved overall Monter Cancer Institute,
survival in patients aged 60–75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia. Northwell Health System, Lake
Success, NY, USA
(Prof J E Kolitz MD); David
Funding Jazz Pharmaceuticals. Geffen School of Medicine at
UCLA, Los Angeles, CA, USA
Copyright © 2021 Elsevier Ltd. All rights reserved. (Prof G J Schiller MD);
Stephenson Cancer Center,
University of Oklahoma,
Introduction leukaemia (acute myeloid leukaemia following previous Oklahoma City, OK, USA
Although patients aged 60 years or older with acute myeloid malignancy or as a late complication of chemo­ (M J Wieduwilt MD); University
myeloid leukaemia are often given less intense therapies therapy or ionising radiation [therapy-related acute of Rochester, Rochester, NY,
USA (Prof D H Ryan MD); Jazz
than are younger patients, several studies1–3 have shown myeloid leukaemia]) have poorer outcomes than do those
Pharmaceuticals, Palo Alto, CA,
that many of these older patients could be treated with with de novo acute myeloid leukaemia, especially in USA (S Faderl MD); University of
and benefit from standard induction chemotherapy (eg, a patients aged 60 years or older.4–7 Poorer performance Texas MD Anderson Cancer
regimen of cytarabine for 7 days and daunorubicin for status and higher incidences of comorbid conditions, Center, Houston, TX, USA
(Prof J E Cortes MD);
3 days [7+3]). Patients with secondary acute myeloid adverse cytogenetic abnormalities, and multidrug

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Georgia Cancer Center, Augusta
University, Augusta, GA, USA
(Prof J E Cortes)
Correspondence to:
Prof Jeffrey E Lancet,
H Lee Moffitt Cancer Center &
Research Institute, Tampa,
FL 33612, USA
jeffrey.lancet@moffitt.org
See Online for appendix
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Research in context
Evidence before this study
We searched PubMed for studies investigating the long-term
results of the treatment of patients with secondary acute
myeloid leukaemia, especially in patients aged 60 years or older,
published between Jan 1, 2000, and Jan 31, 2021. Search terms
used were “secondary acute myeloid leukaemia”, “secondary
AML”, “chemotherapy”, and “intensive chemotherapy”. We also
searched for related abstracts from international meetings
published in the same timeframe. Our search results showed
that data on long-term outcomes in this field are scarce, and
reports indicate that only 6–17% of patients aged 60 years or
older who are diagnosed with secondary acute myeloid
leukaemia are still alive 5 years after diagnosis.
Added value of this study
After 5 years of follow-up, CPX-351 continued to provide
survival and remission benefit versus conventional
resistance associated with increasing age might
contribute to poor outcomes in patients with secondary
acute myeloid leukaemia.5,8 Additionally, patients with
secondary acute myeloid leukaemia might have previously
received hypomethylating agent (HMA) therapy for a
haemato­logical malignancy, which could also contribute
to poor outcomes.9,10 Only 6–17% of patients aged 60 years
or older who are diagnosed with secondary acute myeloid
leukaemia are still alive 5 years after diagnosis, with
few reporting long-term remission.1,4,11 Therefore, more
effective therapies are needed to offer long-term
remission and improved overall survival in this population
at high risk.
CPX-351 is a liposomal encapsulation of daunorubicin
and cytarabine at a synergistic 1:5 molar ratio.12 The
CPX-351 liposome, which contains bilayers of distearoyl­
phosphatidylcholine, distearoylphos­pha­tidylglycerol, and
cholesterol at a 7:2:1 molar ratio, remains in a gel phase
at body temperature and provides stability without the
inclusion of polyethylene glycol; this composition
facilitates the controlled release of daunorubicin and
cytarabine with little systemic drug distribution.13 In
preclinical studies,12,14,15 the CPX-351 liposome showed
better therapeutic efficacy than free drugs when
administered at the same drug ratios; the therapeutic
advantage of CPX-351 was associated with long
maintenance of the synergistic drug ratio and more
uptake in leukaemia cells than in healthy cells in the
bone marrow. In human plasma, the synergistic drug
ratio was maintained within the CPX-351 liposomes for
up to 24 h after infusion, with detectable drug present
more than 7 days after administration.16,17 CPX-351 is
approved for the treatment of newly diagnosed therapy-
related acute myeloid leukaemia or acute myeloid
leukaemia with myelodysplasia-related changes in adults
and children aged 1 year and older in the USA, and in
adults aged 18 years or older in the EU.18,19 These approvals
7+3 chemotherapy in patients aged 60–75 years with newly
diagnosed secondary acute myeloid leukaemia.
Implications of all the available evidence
CPX-351 provides overall survival and remission benefit
versus 7+3 in older patients with newly diagnosed high-risk
or secondary acute myeloid leukaemia. Although we did not
evaluate depth of remission via measurable residual disease
assessments, the longer median overall survival observed
with CPX-351 versus 7+3 in patients who had remission and
in those who proceeded to haematopoietic stem-cell
transplantation suggests potentially deeper responses might
be possible with CPX-351 treatment; however, this
observation needs to be substantiated in a future study.
These results further support the use of CPX-351 in patients
aged 60 years or older with newly diagnosed high-risk or
secondary acute myeloid leukaemia.
were based on the primary endpoint analysis of this
randomised, phase 3 study,20 which evaluated CPX-351
versus the conventional 7+3 chemo­therapy in 309 patients
aged 60–75 years with newly diagnosed high-risk or
secondary acute myeloid leukaemia. After a median
follow-up of 20·99 months (IQR 16·56–27·37), the study
met its primary endpoint of significantly improved
median overall survival with CPX-351 (9·56 months,
95% CI 6·60–11·86) versus 7+3 (5·95 months, 4·99–7·75;
hazard ratio [HR] 0·69; 95% CI 0·52–0·90, one-sided
p=0·003). CPX-351 treatment also resulted in a
significantly improved remission rate (48%, 95% CI
40–56) than 7+3 (33%, 26–41; odds ratio 1·77, 95% CI
1·11–2·81; two-sided p=0·016).20 The safety profile of
CPX-351 in this study was consistent with the known
safety profile of 7+3, but the median time to neutrophil
and platelet recovery in patients with remission was
longer following treatment with CPX-351 than with 7+3.20
We report results of the final analysis of this phase 3
study, with all patients followed up until death or up to
5 years after random assignment. The objective of this
analysis was to provide insights into the long-term
efficacy and tolerability of CPX-351 treatment in adults
aged 60 years or older with newly diagnosed high-risk or
secondary acute myeloid leukaemia.
Methods
Study design and participants
This randomised, open-label, multicentre, phase 3 study
was done in 39 academic and regional cancer centres in
the USA and Canada (appendix pp 2–3). This study was
done in accordance with the principles of the Declaration
of Helsinki and the International Conference on
Harmonisation Good Clinical Practice guidelines. The
study protocol (appendix p 16) and all amendments were
approved by the institutional review board or independent
ethics committee at each study site.
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Study eligibility criteria have been described pre­
viously.20 Briefly, eligible patients were aged 60–75 years
with a pathological diagnosis of acute myeloid leukaemia
according to WHO 2008 criteria (≥20% blasts in
peripheral blood or bone marrow), including therapy-
related acute myeloid leukaemia (based on previous
cytotoxic treatment) or acute myeloid leukaemia with
myelodysplasia-related changes (history of myelodys­
plastic syndrome [with or without previous HMAs],
chronic myelomonocytic leukaemia, or de novo acute
myeloid leukaemia with myelodysplasia-related cyto­
genetic abnormalities). Patients were also required to
have an Eastern Cooperative Oncology Group (ECOG)
performance status of 0–2 and be considered by the
investigator able to tolerate standard chemotherapy.
Eligible patients had serum creatinine less than 2 mg/dL,
serum total bilirubin less than 2 mg/dL, serum alanine
aminotransferase or aspartate amino­ transferase less
than 3 times the upper limit of normal, and cardiac
ejection fraction 50% or higher. Key exclusion criteria
included acute promyelocytic leukaemia t(15;17) or
other favourable cytogenetics known at the time of
random assignment, previous induction therapy for
acute myeloid leukaemia (except hydroxyurea), or an
active secondary malignancy or CNS leukaemia. Patients
with previous HMA exposure for the treatment of
myelodysplastic syndrome or chronic myelomonocytic
leukaemia were eligible. All patients provided written
informed consent before study participation.
Randomisation
Patients were stratified by age (60–69 years and
70–75 years) and acute myeloid leukaemia subtype, and
randomly assigned (1:1) using a dynamic balancing
randomisation algorithm to receive CPX-351 or 7+3
(cytarabine for 7 days and daunorubicin for 3 days).20 The
dynamic balancing randomisation algorithm balanced
the marginal distribution of the stratification factors
between the treatment regimens. Randomisation was
done via a telephonic or internet-based interactive
randomisation system to avoid bias. Allocation to the
treatment groups was not masked due to logistical
constraints.
Procedures
Patients could receive up to two cycles of induction
treatment followed by up to two cycles of consolidation
therapy. Patients assigned to receive CPX-351 were given
intravenous CPX-351 100 units per m² (daunorubicin
44 mg/m² plus cytarabine 100 mg/m²) as a 90-min
infusion on days 1, 3, and 5. Patients assigned to 7+3 were
given intravenous cytarabine 100 mg/m² per day
continuous infusion for 7 days, plus intravenous
daunorubicin 60 mg/m² on days 1, 2, and 3 in the first
induction cycle and days 1 and 2 in the second induction
cycle. Bone marrow assessment for antileukaemic effect
and the need for second induction was required on day 14
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Articles
after each induction. Patients who did not have
hypoplastic marrow on day 14 received a second induction
cycle at the same dose of CPX-351 on days 1 and 3, or
cytarabine continuous infusion for 5 days plus
daunorubicin on days 1 and 2. If bone marrow was non-
evaluable for a patient, a repeat evaluation could be done
5–14 days later at the discretion of the investigator.
Patients with complete remission or complete remission
with incomplete neutrophil or platelet recovery could
receive up to two cycles of consolidation with CPX-351
65 units per m² (daunorubicin 29 mg/m² plus cytarabine
65 mg/m²) administered as a 90-min infusion on days 1
and 3, or cytarabine 100 mg/m² per day continuous
infusion for 5 days plus daunorubicin 60 mg/m² on
days 1 and 2. The setting of induction and consolidation
administration was left to the discretion of the investi­
gators. Patients could undergo haematopoietic stem-
cell transplantation (HSCT) at the discretion of the
investigators.
Patients were discontinued from the treatment phase
due to persistent disease or no response to treatment,
relapsed disease following complete remission, relapsed
disease following complete remission with incomplete
neutrophil or platelet recovery, unacceptable toxic effects,
concurrent disease that affected assessment of clinical
status, or non-compliance with the protocol. Doses could
be delayed due to toxic effects, and any dose missed or
delayed due to toxic effects was administered as soon as
the patient recovered.
Biochemical laboratory assessments were done
monthly only if abnormalities persisted at the end of the
treatment phase and were continued until abnormality
returned to baseline, 1 year from random assignment,
relapse, or the initiation of a new therapy.
No additional data for adverse events were collected
since the primary endpoint analysis, except for deaths.
Outcomes
The primary outcome was overall survival. In this
prespecified final analysis, patients were followed up for
overall survival until death or up to 5 years following
random assignment. Secondary endpoints were response
rates (complete remission and complete remission with
incomplete neutrophil or platelet recovery, assessed
according to the Revised International Working Group
Criteria for acute myeloid leukaemia),21 response
duration, event-free survival, safety, pharmaco­kinetics,
and pharmacoeconomics (all previously reported).20
Statistical analysis
Statistical methods have been described previously.20
Based on accrual within 2 years, a minimum follow-up
of 1·2 years, and an estimated median overall survival
of 0·526 years in the 7+3 group, a sample size of
270 patients was expected to result in 236 deaths, for a
power of 93·7% and 1-sided α=0·025 to detect HR
of 0·635 between treatment groups. 30 additional
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CPX-351 group 7+3 group

458 patients assessed for eligibility
(n=153) (n=156)
Age
149 excluded Median (IQR), years 68 (64–71) 68 (64–71)
82 did not meet disease criteria
20 previous drug exposure 60 to 69 years 96 (63%) 102 (65%)
6 unable to provide informed consent 70 to 75 years 57 (37%) 54 (35%)
5 unable to adhere to study protocol
4 did not meet laboratory criteria* Sex
32 other reasons† Female 59 (39%) 60 (38%)
Male 94 (61%) 96 (62%)
ECOG performance status
309 enrolled and randomly assigned
0 37 (24%) 45 (29%)
1 101 (66%) 89 (57%)
2 15 (10%) 22 (14%)
153 assigned to CPX-351 group 156 assigned to 7+3 group AML subtype
Therapy-related AML 30 (20%) 33 (21%)
AML with antecedent MDS
5 withdrew consent before
study treatment With previous HMAs 50 (33%) 55 (35%)
Without previous HMAs 21 (14%) 19 (12%)
AML with antecedent CMML 11 (7%) 12 (8%)
153 included in efficacy analyses 156 included in efficacy analyses
153 received at least one cycle of CPX-351 151 received at least one cycle of 7+3 and were De novo AML with MDS 41 (27%) 37 (24%)
and were included in the safety analysis included in the safety analysis karyotype
Previous HMA therapy* 62 (41%) 70 (45%)
Figure 1: Trial profile Cytogenetic risk by NCCN
Figure adapted with permission from Jeffrey E Lancet and colleagues.20 CPX-351 (cytarabine and daunorubicin) Total available (n) 143 146
liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed
secondary acute myeloid leukemia. Journal of Clinical Oncology 2018; 36: 2684–92. © 2018 by American Society Favourable 7 (5%) 5 (3%)
of Clinical Oncology. *Patients without serum creatinine <2 mg/dL, serum total bilirubin <2 mg/dL, and serum Intermediate 64 (45%) 58 (40%)
alanine aminotransferase or aspartate aminotransferase <3 times the upper limit of normal. †Including patients Poor 72 (50%) 83 (57%)
with myocardial impairment of any cause that resulted in heart failure by New York Heart Association criteria
Bone marrow blasts, median 35% (5–93%) 35% (3–97%)
(n=3); active (uncontrolled, metastatic) second malignancies (n=1); active fungal infection, hepatitis B or C, or HIV
(range)
(n=1); cardiac ejection fraction <50% (n=1); incorrect age (n=1); secondary malignancy in remission (n=1); and
unspecified (n=24). 7+3=cytarabine and daunorubicin. White blood cell count 131 (86%) 131 (85%)†
<20 × 109 cells per L
Platelet count ≤50 × 10⁹ cells 95 (62%) 91 (59%)‡
patients were accrued to account for any patients who per L
were deemed ineligible or withdrew consent, for an FLT3 mutation 22 (16%)§ 21 (15%)¶
overall study population of 300. Ethnicity
The efficacy analyses were done in the intention-to- Hispanic or Latino 7 (5%) 7 (4%)
treat population (all randomly assigned patients), and Not Hispanic or Latino 146 (95%) 149 (96%)
safety was evaluated in all patients who received at least
Data are n (%) unless otherwise specified. 7+3=cytarabine and daunorubicin
1 dose of study treatment. Time-to-event endpoints were chemotherapy. AML=acute myeloid leukaemia. CMML=chronic myelomonocytic
calculated using a log-rank test (stratified by age and leukaemia. ECOG=Eastern Cooperative Oncology Group. HMA=hypomethylating
acute myeloid leukaemia subtype) to compare treatment agent. MDS=myelodysplastic syndrome. NCCN=National Comprehensive Cancer
groups. Distribution of endpoints over time were Network. *Includes patients in the prespecified randomisation strata of
antecedent MDS with previous HMA exposure as well as patients in other strata
estimated using Kaplan-Meier. HRs and 95% CIs were (eg, therapy-related AML, antecedent CMML) who had previously received HMAs.
estimated using a Cox proportional hazards regression †Of 155 patients. ‡Of 154 patients. §Of 138 patients. ¶Of 141 patients.
model, stratified by age and acute myeloid leukaemia
Table: Baseline characteristics
subtype. All statistical analyses were done using SAS
version 9.2 or higher.
Analysis of survival outcomes after 5 years of follow-up Role of the funding source
was prospectively planned. Post hoc exploratory analyses The funder of the study had a role in the study design,
of the 5-year final data were done to evaluate differences data collection, data analysis, interpretation of the data,
in overall survival in patients with complete remission and writing of the report (SF is employed by Jazz
or complete remission with incomplete neutrophil Pharmaceuticals).
or platelet recovery, and in subgroups by baseline
characteristics. An independent data and safety Results
monitoring committee oversaw the trial for safety and Between Dec 20, 2012, and Nov 11, 2014, we assessed
efficacy. This trial is registered at www.ClinicalTrials. 458 patients for eligibility. 149 patients were excluded
gov, NCT01696084. (82 did not meet disease criteria, 20 had previous drug

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exposure, six were unable to provide informed consent, 100 Median overall survival Hazard ratio
five were unable to adhere to the study protocol, four did (95% CI) (95% CI)
not meet laboratory criteria, and 32 met other exclusion 80 CPX-351 group 9·33 (6·37–11·86)
0·70 (0·55–0·91)
7+3 group

Overall survival (%)

criteria (figure 1). We randomly assigned 309 patients 5·95 (4·99–7·75)
60
with newly diagnosed high-risk or secondary acute
myeloid leukaemia (CPX-351 n=153, 7+3 n=156). 40
304 patients received at least one dose of study treatment 18% (12–25)
21% (15–28)
and were included in the safety analyses (153 patients in 20
9% (5–14) 8% (4–13)
the CPX-351 group, 151 patients in the 7+3 group
0
[five patients in the 7+3 group withdrew consent 0 6 12 18 24 30 36 42 48 54 60 66 72
immediately after random assignment]). Nine major Time from randomisation (months)
Number at risk
protocol deviations were reported during the study: delay (number censored)
of 1 week after random assignment before treatment CPX-351 group 153 92 62 49 40 33 30 29 29 28 22 2 0
administration (CPX-351 group, two patients), site delay (0) (0) (1) (2) (2) (2) (3) (3) (3) (3) (7) (27) (29)
7+3 group 156 77 43 28 20 17 14 13 12 12 5 0 0
in reporting a serious adverse event (CPX-351 group, one (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (7) (11) (11)
patient), administration of CPX-351 100 units per m² for
consolidation (CPX-351 group, one patient), incorrect Figure 2: Overall survival
3-year and 5-year Kaplan-Meier-estimated survival rates are shown with 95% CI. 7+3=cytarabine and daunorubicin.
assignment of acute myeloid leukaemia subtype
(7+3 group, two patients), administration of idarubicin
instead of daunorubicin for 1 treatment course analysis, factors associated with longer overall survival
(7+3 group, one patient), delay in administration of included better ECOG performance status, favourable or
daunorubicin (7+3 group, one patient), and failure to intermediate-risk karyotype, lower white blood cell count,
sign the informed consent form for the protocol higher platelet count, and treatment with CPX-351
amendment on Sept 17, 2013 (7+3 group, one patient). (appendix p 5).
These protocol deviations did not affect the safety of the To further evaluate the overall survival benefit of CPX-351
patients or the integrity of the study. versus 7+3, we did post hoc subgroup analyses by baseline
Baseline characteristics are shown in the table. characteristics. Overall survival was con­sistently better in
Importantly, the proportion of patients with any previous patients treated with CPX-351 than in patients given 7+3
HMA exposure was similar in patients given CPX-351 across most subgroups (figure 3, appendix pp 9–11);
and 7+3, and included patients in the prespecified however, the number of patients in some subgroups was
randomisation strata of previous myelodysplastic small. When analysed by age subgroup, median overall
syndrome with previous HMA exposure, and patients in survival was better in the CPX-351 group than in the
other strata (eg, therapy-related acute myeloid leukaemia, 7+3 group, both in patients aged 60–69 years (9·59 months
previous chronic myelomonocytic leukaemia) who had [95% CI 6·01–12·62] in patients given CPX-351 vs
previously received HMAs. 6·87 months [4·63–8·84] in patients given 7+3, HR 0·73;
At a median follow-up of 60·91 months 95% CI 0·54–0·99) and in those aged 70–75 years
(IQR 60·06–62·98) in the CPX-351 group and (8·87 months [4·73–12·19] in patients given CPX-351 vs
59·93 months (59·73–60·50) in the 7+3 group, the 5·62 months [3·29–7·52] in patients given 7+3, 0·52;
favourable difference in median overall survival in favour 0·34–0·77, appendix p 12). Overall survival at 3 years was
of CPX-351 versus 7+3 was maintained (9·33 months higher for CPX-351 versus 7+3 both in patients aged
[95% CI 6·37–11·86] in the CPX-351 group vs 5·95 60–69 years (23% [95% CI 15–32] in patients given CPX-
months [4·99–7·75] in the 7+3 group, HR=0·70; 95% CI 351 vs 14% [8–21] in patients given 7+3) and in those aged
0·55–0·91), with an HR that was stable and consistent 70–75 years (18% [9–28] in patients given CPX-351 vs
with the primary endpoint analysis (figure 2). Overall 0% [0–0] in patients given 7+3; appendix p 12). Similarly,
survival estimates were higher for CPX-351 versus 7+3 at overall survival at 5 years was higher for CPX-351
3 years (21% [95% CI 15–28%] for CPX-351 and versus 7+3 both in patients aged 60–69 years (20% [12–28]
9% [5–14%] for 7+3) and 5 years (18% [12–25%] for in patients given CPX-351 vs 12% [6–19] in patients
CPX-351 and 8% [4–13%] for 7+3). given 7+3) and in patients aged 70–75 years (16% [8–26] in
Univariable analysis stratified by age and acute myeloid patients given CPX-351 vs 0% [0–0] in patients
leukaemia subtype identified ECOG performance status, given 7+3; appendix p 12).
cytogenetic risk, white blood cell count, platelet count, and 53 (35%) of 153 patients in the CPX-351 group and
treatment group as having a significant association with 39 (25%) of 156 patients in the 7+3 group received an
overall survival (appendix p 4). Covariates not associated HSCT. Median time from random assignment to HSCT
with overall survival in the univariable analysis included was 114 days (IQR 89–153) in the CPX-351 group and
sex, haemoglobin concentration, percentage of bone 114 days (92–155) in the 7+3 group; median follow-up after
marrow blast, and presence of an FLT3 internal HSCT was 58·05 months (54·18–59·79) in the CPX-351
tandem duplication (FLT3-ITD) mutation. In multivariable group and 56·11 months (55·03–56·94) in the 7+3 group.

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CPX-351 group 7+3 group Hazard ratio

n/N Median overall
survival, (95% CI)
months
Age
60–69 years 76/96 9·59 (6·01–12·62)
70–75 years 48/57 8·87 (4·73–12·19)
AML subtype
Therapy-related AML 23/30 12·17 (7·43–27·37)
AML with antecedent CMML 9/11 9·33 (1·94–23·98)
AML with antecedent MDS
With previous HMA 43/50 5·65 (3·55–7·75)
Without previous HMA 16/21 15·74 (5·55–26·32)
De novo AML with MDS karyotype 33/41 9·66 (5·32–25·23)
ECOG PS
0 26/37 14·72 (7·00–33·58)
1 84/101 9·33 (6·37–11·60)
2 14/15 3·98 (1·61–6·24)
Karyotype
Favourable or intermediate 52/71 14· 72 (9·07–20·96)
Poor 63/72 6·42 (4·96–9·66)
White blood cells
<20 × 109 cells per L 103/131 10·61 (7·69–13·01)
≥20 × 109 cells per L 21/22 3·60 (1·48–7·49)
Platelets
≤50 × 109 cells per L 85/95 7·43 (4·96–9·66)
>50 × 109 cells per L 39/58 14·72 (9·33–26·71)
FLT3 mutation status
FLT3 wild type 92/115 8·87 (5·65–12·35)
FLT3 mutation 18/22 10·25 (5·62–14·95)
Previous HMA treatment
Yes 53/62 5·65 (3·55–7·75)
No 71/91 11·33 (9·17–18·69)
Overall study population 124/153 9·33 (6·37–11·86)
(95% CI) for death
n/N Median overall
survival, (95% CI)
months
91/102 6·87 (4·63–8·84) 0·73 (0·54–0·99)
54/54 5·62 (3·29–7·52) 0·52 (0·34–0·77)
30/33 5·95 (2·92–8·48) 0·54 (0·31–0·94)
11/12 2·28 (0·72–3·98) 0·40 (0·16–1·01)
52/55 7·43 (5·55–9·40) 0·96 (0·64–1·45)
19/19 5·13 (1·74–11·07) 0·45 (0·23–0·88)
33/37 7·36 (2·89–13·77) 0·72 (0·44–1·17)
41/45 8·41 (5·13–11·07) 0·55 (0·33–0·90)
82/89 5·55 (3·58–7·36) 0·67 (0·49–0·91)
22/22 5·13 (2·53–9·40) 1·09 (0·55–2·13)
55/63 8·41 (5·13–11·07) 0·65 (0·45–0·96)
81/83 5·16 (3·19–7·33) 0·66 (0·47–0·92)
120/131 6·64 (5·13–8·18) 0·64 (0·49–0·83)
24/24 3·42 (1·41–7·26) 0·83 (0·46–1·52)
85/91 5·55 (3·35–7·33) 0·77 (0·57–1·04)
58/63 7·43 (4·99–10·87) 0·49 (0·33–0·75)
109/118 5·82 (4·04–7·82) 0·65 (0·49–0·87)
21/21 4·60 (1·61–10·32) 0·51 (0·27–0·96)
67/70 5·98 (4·63– 7·75) 0·82 (0·57–1·18)
78/86 5·62 (3·88–8·80) 0·60 (0·43–0·83)
145/156 5·95 (4·99–7·75) 0·70 (0·55–0·91)

0·1 1·0 10·0

Favours CPX-351 Favours 7+3

Figure 3: Forest plot of overall survival by baseline patient characteristics

Hazard ratios and their 95% CIs are based on univariable Cox regression models stratified by age and acute myeloid leukaemia subtype. 7+3=cytarabine and
daunorubicin. AML=acute myeloid leukaemia. CMML=chronic myelomonocytic leukaemia. ECOG PS=Eastern Cooperative Oncology Group performance status.
HMA=hypomethylating agents. MDS=myelodysplastic syndrome. n=number of events. N=total number of patients.

Most patients who underwent HSCT were in complete
remission or complete remission with incomplete neutro­
phil or platelet recovery in both the CPX-351 group
(40 [75%] of 53 patients) and the 7+3 group (24 [62%] of
39 patients); one additional patient who had remission in
the CPX-351 group relapsed before HSCT. 13 (25%) of
53 patients who received HCT in the CPX-351 group and
18 (46%) of 39 patients who received HSCT in the
7+3 group received additional treatment (second line or
later) after completion of study treatment and before
HSCT. In patients who underwent HSCT, median overall
survival from the date of HSCT was not reached (95% CI
16·23–not estimable) for CPX-351 versus 10·25 months
(6·21–16·69) for 7+3 (HR 0·51, 95% CI 0·28–0·90;
figure 4). At 3 years, overall survival rate landmarked from
the date of HSCT was 56% (95% CI 42–68) for CPX-351
and 23% (11–37) for 7+3. In responders who did not
subsequently undergo HSCT, one patient in the CPX-351
group and two patients in the 7+3 group were alive after
5 years of follow-up.
Complete remission or complete remission with
incomplete neutrophil or platelet recovery was reported
in 73 (48%) of 153 patients in the CPX-351 group and
52 (33%) of 156 patients in the 7+3 group. 49 patients
received CPX-351 consolidation, including one patient
who did not have complete remission or complete
remission with incomplete neutrophil or platelet recovery
during induction (ie, protocol violation), and 32 patients
who had remission in the 7+3 group received
5+2 consolidation. 23 patients in the CPX-351 group and
12 patients in the 7+3 group received two cycles of
consolidation. All patients who received two cycles of

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consolidation had complete remission or complete 100 Median overall survival Hazard ratio
remission with incomplete neutrophil or platelet recovery (95% CI) (95% CI)
during induction. In patients who received consolidation, 80 CPX-351 group Not reached (16·23–NE)
0·51 (0·28–0·90)
7+3 group

Overall survival (%)

median overall survival was 21·72 months (95% CI 10·25 (6·21–16·69)
60
12·35–30·88) in the CPX-351 group and 8·53 months
(5·68–15·21) in the 7+3 group (HR 0·48, 95% CI 40
56% (42–68)
0·29–0·79; appendix p 13).
Median overall survival in patients with complete 20 23% (11–37)
remission or complete remission with incomplete
0
neutrophil or platelet recovery was 21·72 months (95% CI 0 6 12 18 24 30 36 42 48 54 60 66 72
13·01–29·70) in patients assigned to receive CPX-351 and Time from HSCT (months)
Number at risk
10·41 months (7·82–15·21) in patients who received 7+3 (number censored)
(HR 0·59, 95% CI 0·39–0·88), and overall survival was CPX-351 group 53 42 35 32 31 28 28 27 24 21 6 0 0
higher for patients assigned to CPX-351 than for patients (0) (0) (1) (1) (1) (2) (2) (3) (4) (7) (22) (28) (28)
7+3 group 39 27 18 12 12 9 9 9 9 8 0 0 0
assigned to 7+3 at 3 years (36% [95% CI 25–47] in patients (0) (0) (0) (0) (0) (0) (0) (0) (0) (1) (9) (9) (9)
assigned to CPX-351; 23% [13–35] in patients assigned
to 7+3) and 5 years (30% [20–41] in patients assigned Figure 4: Overall survival from date of HSCT
3-year Kaplan-Meier-estimated survival rates are shown with 95% CI. 5-year estimates were not available as the
to CPX-351; 19% [10–31] in patients assigned to 7+3;
follow-up time from the date of HSCT is less than 5 years. 7+3=cytarabine and daunorubicin.
appendix p 14). Univariable analysis identified karyotype, HSCT=haematopoietic stem-cell transplantation. NE=not estimable.
platelet count, and treatment group as having a statistically
significant association with overall survival in patients In patients with previous HMA exposure who had
with complete remission or complete remission with complete remission or complete remission with
incomplete neutrophil or platelet recovery (appendix p 6). incomplete neutrophil or platelet recovery (23 patients in
Covariates not associated with overall survival in the the CPX-351 group and 20 patients in the 7+3 group),
univariable analysis included sex, ECOG performance median overall survival was 14·72 months (95% CI
status, white blood cell count, haemoglobin concentration, 7·75–55·56) in the CPX-351 group versus 10·17 months
bone marrow blast %, and presence of an FLT3-ITD (4·86–17·91) in the 7+3 group. In the further subset of
mutation (appendix p 6). In multivariable analysis, factors these patients who proceeded to HSCT (13 patients in the
that were associated with longer overall survival in patients CPX-351 group and seven patients in the 7+3 group),
with complete remission or complete remission with median overall survival landmarked from the date of
incomplete neutrophil or platelet recovery included HSCT was not reached (95% CI 4·30–not estimable) in
favourable or intermediate-risk karyotype, higher platelet the CPX-351 group and 14·09 months (95% CI 2·14–not
count, and treatment with CPX-351 (appendix p 7). estimable) in the 7+3 group.
In patients with complete remission or complete In patients who had complete remission or complete
remission with incomplete neutrophil or platelet recovery, remission with incomplete neutrophil or platelet
41 (56%) of 73 patients in the CPX-351 group and 24 (46%) recovery and were censored at the date of HSCT, median
of 52 patients in the 7+3 group subsequently underwent event-free survival was 7·36 months (95% CI
HSCT. In these patients, median overall survival 6·01–10·87) in the CPX-351 group and 7·00 months
landmarked from the date of HSCT was not reached (3·45–16·49) in the 7+3 group (HR 0·99, 95% CI
(95% CI 15·64–not estimable) in the CPX-351 group versus 0·58–1·69). 37 patients with complete remission or
11·65 months (4·57–24·28) in the 7+3 group (HR 0·50, complete remission with incomplete neutrophil or
95% CI 0·26–0·97; appendix p 14), and the 3-year overall platelet recovery subsequently relapsed during the study
survival landmarked from the date of HSCT was higher for (22 [30%] of 73 patients in the CPX-351 group; 15 [29%]
CPX-351 (58%, 95% CI 41–71) than for 7+3 (29%, 13–48). of 52 patients in the 7+3 group), of whom one (5%)
Median overall survival landmarked from the date of best patient in the CPX-351 group and two (13%) patients in
response was not reached (95% CI 17·08–not estimable) the 7+3 group had a late relapse (ie, after more than
for CPX-351 versus 14·03 months (7·56–29·44) for 7+3 1 year). Only one patient who had remission with
(HR 0·52, 95% CI 0·27–1·00; appendix p 15), and 3-year CPX-351 and subsequently relapsed was censored at the
overall survival landmarked from the date of HSCT was last follow-up. In all responders who relapsed, median
higher for CPX-351 (58%, 95% CI 41–71) than for 7+3 overall survival was longer with CPX-351 (13·16 months,
(29%, 13–48). In patients who did not have complete 95% CI 9·33–16·82) versus 7+3 (7·82 months,
remission or complete remission with incomplete 4·86–13·40; HR 0·44, 95% CI 0·22–0·90). Of the
neutrophil or platelet recovery (12 patients assigned to patients who relapsed, 20 (91%) of 22 patients in the
CPX-351 and 15 patients assigned to 7+3), median overall CPX-351 group and 11 (73%) of 15 patients in the
survival landmarked from the date of HSCT was not 7+3 group received subsequent antileukaemic therapy
reached for CPX-351 (95% CI 3·98–not estimable) versus during follow-up, and median overall survival for these
7·13 months (95% CI 3·48–17·68) for 7+3. patients was longer with CPX-351 (13·16 months,

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95% CI 8·77–17·58) versus 7+3 (10·87 months,
5·49–16·66; HR 0·56, 95% CI 0·26–1·22).
Data on adverse events were reported with the primary
endpoint analysis,20 with no additional adverse event data
collected during the continued follow-up, except data for
deaths. Among the 264 patients who died, the most
common primary cause of death in both treatment
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; appendix p 8). Death was due to adverse
events in 17 (14%) of 124 deaths in the CPX-351 group and
19 (14%) of 140 deaths in the 7+3 group. Of the patients
who died due to causes other than progressive leukaemia
(54 [44%] of 124 deaths in the CPX-351 group and 66 [47%]
of 140 deaths in the 7+3 group), the most common causes
of death (irrespective of categorisation as an adverse
event or other event) were sepsis or septic shock
(six [5%] patients in the CPX-351 group and six [4%]
patients in the 7+3 group), haemorrhage or haematoma
(six [5%] patients in the CPX-351 group and four [3%]
patients in the 7+3 group), HSCT complications
(eg, graft-versus-host disease; five [4%] patients in each
group), pneumonia (four [3%] patients in the CPX-351
group and five [4%] patients in the 7+3 group), and
multiorgan failure (two [2%] deaths in the CPX-351 group
and nine [6%] patients in the 7+3 group). Causes of death
were mostly not considered related to study treatment
(118 [95%] of 124 deaths in the CPX-351 group and
133 [95%] of 140 deaths in the 7+3 group). Causes of
death that were considered at least possibly related to
study treatment were sepsis (n=2), cerebral haemorrhage
(n=2), multiorgan failure (n=1), and pneumonia (n=1) in
the CPX-351 group and respiratory failure (n=2), sepsis
(n=1), pulmonary haemorrhage (n=1), brain haemorrhage
(n=1), cardiac arrest (n=1), and multiorgan failure (n=1)
in the 7+3 group.
Discussion
CPX-351, a novel liposomal encapsulation of daunorubicin
and cytarabine, improved long-term overall survival and
remission versus conventional 7+3 chemo­therapy in a
population of adults aged 60–75 years with high-risk or
secondary acute myeloid leukaemia. With extended
follow-up, improved median overall survival with CPX-
351 versus 7+3 was durable, stable, and consistent with
the primary endpoint analysis.20 Median overall survival
for the CPX-351 group in this extended follow-up analysis
was slightly different from that reported in the primary
endpoint analysis (9·33 vs 9·56 months) because of
one patient death, reported after the cutoff date, with
shorter survival than the previous median. In subgroup
analyses, overall survival rates were higher for CPX-351
than for 7+3 at both 3 and 5 years, and improved median
overall survival was observed regardless of patient age
and across most acute myeloid leukaemia subtypes
(patients without previous HMA exposure, and patients
with therapy-related acute myeloid leukaemia, acute
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myeloid leukaemia with previous chronic myelomono­
cytic leukaemia, acute myeloid leukaemia with previous
myelodysplastic syndrome without previous HMA
exposure, and de novo acute myeloid leukaemia with
myelodysplastic syndrome karyotype), and in patients
who had complete remission or complete remission with
incomplete neutrophil or platelet recovery. Median overall
survival was similar with CPX-351 and 7+3 in patients
with previous myelodysplastic syndrome and previous
HMA exposure, although patients with previous HMA
exposure who had complete remission or complete
remission with incomplete neutrophil or platelet recovery,
and the subset of these patients who underwent HSCT,
had better median overall survival with CPX-351 than
with 7+3. Although post hoc analyses evaluated the
effect of CPX-351 treatment on overall survival in multiple
subgroups, the number of patients in some subgroups
was small, limiting the ability to make conclusions on the
basis of these data.
Consolidation therapy is crucial to prevent relapse in
patients with acute myeloid leukaemia, and usually
consists of multiple cycles of high-dose cytarabine or
lower-dose cytarabine combined with an anthracycline.22
In our study, consolidation therapy with a combination
of cytarabine (100 mg/m² per day continuous infusion
for 5 days) and daunorubicin (60 mg/m² on days 1 and 2)
was used for patients randomly assigned to induction
with 7+3. High-dose or intermediate-dose cytarabine is
an alternative approach frequently used as consolidation
therapy.23 The value of the addition of an anthracycline in
consolidation for patients with acute myeloid leukaemia
is uncertain. However, we found that median overall
survival was longer in patients who received consolidation
with CPX-351 than in those who received consolidation
with conventional chemotherapy; these results were
consistent with results from the primary analysis.24
Whether using high-dose cytarabine as consolidation
affected long-term outcomes is unclear, but the higher
complete remission rate after induction might have had
a more significant effect than choice of consolidation in
explaining the overall benefit of CPX-351. Future studies
are needed to optimise consolidation therapies to
maintain remission and prevent relapse.
Guidelines from the American Society of Hematology25
recommend the use of intensive therapy over less-
intensive therapy for the treatment of adults aged 60 years
or older with newly diagnosed acute myeloid leukaemia.
In our study, these patients given CPX-351 were more
likely to proceed to HSCT than were those treated with
conventional chemotherapy. With the extended follow-up,
this HSCT rate for the CPX-351 group differed slightly
from the primary endpoint analysis because of one
additional patient who proceeded to HSCT after data
cutoff. In previous studies,1,4,11 only 6–17% of patients older
than 60 years with secondary acute myeloid leukaemia
were still alive 5 years after diagnosis, with few reporting
long-term remission; however, the patient populations
www.thelancet.com/haematology Vol 8 July 2021

included in these studies varied in charac­teristics such as
previous HMA exposure, cytogenetic risk, and ECOG
performance status. In a real-life population of patients
with secondary acute myeloid leukaemia who were
included in the multinational PETHEMA registry,26 the
5-year survival rate was 8% (95% CI 7–10).
In a study in de novo or secondary acute myeloid
leukaemia patients who underwent allogeneic HSCT,27
the estimated survival rate at 5 years from the time of
HSCT was 33%. In our study, the overall survival at
3 years was over 50% in patients who received CPX-351
and proceeded to HSCT. The improved overall survival
after HSCT observed in patients given CPX-351 versus 7+3
might have been due to a more favourable general
wellbeing of patients following CPX-351 treatment, or an
increased proportion of patients with complete remission
or complete remission with incomplete neutrophil or
platelet recovery with undetectable measurable residual
disease in the CPX-351 group. We did not assess
measurable residual disease in this study, and this
hypothesis should be tested in subsequent studies. Other
factors, such as physical function at the time of HSCT
status or HSCT-related variables, might have also
contributed to this difference. HSCT-related outcomes
from this study and potential factors influencing these
outcomes are being investigated to better understand the
role of HSCT following initial treatment with CPX-351.28
Although this study did not assess measurable residual
disease, median overall survival was longer with CPX-351
than with 7+3 in patients who had complete remission or
complete remission with incomplete neutrophil or
platelet recovery, and in patients who proceeded to HSCT.
Although molecular response is not always a predictor of
overall survival, these data suggest deeper responses
might be possible with CPX-351 treatment, and this
hypothesis should be substantiated with measurable
residual disease analyses in a future clinical trial.
Our study has several limitations. The open-label design
of this study could have introduced bias into the results;
however, the construction of a purple liposomal placebo
was considered impractical, and the administration of
conventional 7+3 chemotherapy (including a continuous
7-day infusion of cytarabine) is notably different from that
of CPX-351 (90-min infusion on days 1, 3, and 5). Another
limitation of this analysis is the absence of long-term
adverse event data, as no adverse event data were collected
beyond that reported in the primary endpoint analysis
(except for data on deaths). Without additional long-term
safety data, we were unable to assess the long-term toxicity
profile of CPX-351, particularly the potential for long-term
effects on cardiac function, as anthracyclines are
associated with a risk of cardiotoxicity in patients with
acute myeloid leukaemia, especially patients aged 60 years
or older.29 However, the rate of all-cause mortality was
lower with CPX-351 than with 7+3 in this extended
analysis (81% vs 93%). In the previous primary endpoint
analysis,20 the safety profile of CPX-351 was consistent
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Articles
with that of the 7+3 regimen, except for longer time to
recovery of neutrophil and platelet counts and lower rates
of 30-day and 60-day early mortality in patients who
received CPX-351.20 Analysis of quality-adjusted time
without symptoms of disease progression or toxic effects
(Q-TWiST) using data from the phase 3 study was done to
compare survival quality between patients receiving
CPX-351 versus 7+3 after 5 years of follow-up.30 In this
analysis, the relative Q-TWiST gain with CPX-351
versus 7+3 was 53·6%, which was well above what is
considered a clinically important difference (15%)31 and
suggests the survival benefit observed with CPX-351 is
mostly from time without relapse or grade 3 or 4 toxic
effects in this patient population.
Our study excluded patients with acute promyelocytic
leukaemia t(15;17) or other favourable cytogenetics
known at the time of random assignment, but at the time
of enrolment this information was not available for some
patients. The number of patients with favourable
cytogenetics included in the study was small (seven
patients in the CPX-351 group and five patients in the
7+3 group) and similarly distributed between the
two groups. Therefore, although these patients could
affect the results, we believe this is unlikely and any
effect would probably be minimal.
In conclusion, the results from this final 5-year
follow-up analysis showed that CPX-351 continued to
provide overall survival and remission benefit versus 7+3
in patients with newly diagnosed high-risk or secondary
acute myeloid leukaemia. Improved overall survival in
patients given CPX-351 was observed regardless of
patient age and across most acute myeloid leukaemia
subtypes. Improved overall survival observed with
CPX-351 in patients who had remission and in those who
underwent HSCT suggests potentially deeper responses
might be possible with this treatment, although this
hypothesis needs to be substantiated with measurable
residual disease analyses in a future clinical trial.
Together, these results support the previous evidence
that CPX-351 has the ability to contribute to long-term
remission and survival in patients aged 60–75 years with
newly diagnosed high-risk or secondary acute myeloid
leukaemia, and further support the use of CPX-351 in
this patient population.
Contributors
JEL, RKS, DHR, SF, and JEC participated in conception and design of
the study. JEL, GLU, LFN, TLL, EKR, RKS, SAS, DH, SRS, DLB, JEK,
GJS, MJW, DHR, and JEC treated patients and participated in the
clinical data collection and assembly. All authors verified the underlying
data, participated in data analysis and interpretation, participated in
manuscript development, and provided final approval of the submitted
version. All authors had full access to all the data in the study and had
final responsibility for the decision to submit for publication.
Declaration of interests
JEL has received consulting fees from AbbVie, BerGenBio/DAVA
Oncology, Celgene/Bristol Myers Squibb, Daiichi Sankyo, ElevateBio
Management, Millennium Pharma/Takeda, and Novartis. GLU has
received consulting fees from AbbVie, Agios, GlaxoSmithKline, Jazz
Pharmaceuticals, and Novartis, and received honoraria from Astellas
e489
 Articles
Pharma. TLL has received institutional research funding from AbbVie,
Aptevo, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad,
Genentech/Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Mateon
Therapeutics, Ono Pharmaceutical, Pfizer, Prescient Therapeutics,
Seattle Genetics, Tolero Pharmaceuticals, and Trovagene. EKR has served
as a consultant for Celgene, Incyte, Novartis, and Pfizer; served on
speakers bureaus for Ariad Pharmaceuticals, Celgene, Incyte, and
Novartis; received research funding from Astellas Pharma, Bristol Myers
Squibb, Novartis, NS Pharma, and Pfizer; and received travel support
from Celgene and Novartis. RKS has served as a consultant for Sunesis
Pharmaceuticals; received honoraria from Sunesis Pharmaceuticals;
received research funding from Agios, Astellas Pharma, Bayer AG,
Incyte, Jazz Pharmaceuticals, Ono Pharmaceuticals, and Sunesis
Pharmaceuticals; and received travel support from Sunesis
Pharmaceuticals. SAS has served as a consultant for AbbVie, ArcherDx,
Astellas Pharma, Genentech, Incyte, Jazz Pharmaceuticals, Kite Pharma,
Kura Oncology, and Novartis; and received research funding from
Sunesis Pharmaceuticals. JEK participated in advisory boards for Amgen,
Magellan, and Pfizer, and has served on the editorial board for UpToDate.
GJS has received research funding from AbbVie, Agios, Actinium,
Amgen, Ariad Pharmaceuticals, Astellas Pharma, Bristol Myers Squibb,
Constellation, Cyclacel, Daiichi Sankyo, Deciphera, Delta-Fly, Forma,
Fujifilm, Gamida, Genentech/Roche, Geron, Incyte, Jazz
Pharmaceuticals, Karyopharm, Kite Pharma, Mateon, MedImmune,
Novartis, Onconova, Pfizer, Regimmune, Samus, Sangamo, Tolero, and
Trovagene; received consulting fees from Agios, Amgen,
AstraZeneca, Incyte, Novartis, and Ono Pharma; served on speakers
bureaus for Agios, Amgen, Celgene, Gilead Sciences, Incyte, Sanofi, and
Stemline; provided expert testimony for Kaiser Permanente; and holds
stock ownership and options in Amgen, Bristol Myers Squibb, Johnson &
Johnson, and Pfizer. MJW has received research funding from Amgen,
Leadiant, Merck, and Shire; participated in advisory committees for
Daiichi Sankyo; and holds stock ownership in Reata Pharmaceuticals.
DHR holds stock ownership in AbbVie and patents and royalties with the
University of Rochester. SF is an employee of and holds stock ownership
and options in Jazz Pharmaceuticals. JEC has received consulting fees
from Astellas Pharma, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis,
and Pfizer; and research funding (to his institution) from Arog, Astellas
Pharma, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, and Pfizer.
All other authors declare no competing interests.
Data sharing
All relevant data are provided within the manuscript and supporting
files, or in the files for the primary publication of this study.20
Acknowledgments
This study was supported by Jazz Pharmaceuticals. The authors thank
the patients who participated in the study and their families, and the
investigators, nurses, coordinators, and other research staff at each study
site. Medical writing and editorial assistance were provided by Senem
Kurtoglu Lubin, of Cello Health Communications/SciFluent, under the
direction of the authors, and were financially supported by Jazz
Pharmaceuticals.
References
1 Bertoli S, Tavitian S, Bories P, et al. Outcome of patients aged
60–75 years with newly diagnosed secondary acute myeloid leukemia:
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2 Medeiros BC, Satram-Hoang S, Hurst D, Hoang KQ, Momin F,
Reyes C. Big data analysis of treatment patterns and outcomes
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