VYXEOS® LIPOSOMAL IN AML-MRC AND t-AML PATIENTS:

RESULTS FROM EVERYDAY PRACTICE IN FOUR EUROPEAN COHORTS WERE SIMILAR TO THOSE IN STUDY 3011–5

Vyxeos Liposomal delivers quadruple endpoint superiority vs DA 3+7
improving: mOS, post-HSCT mOS, CR/CRi and EFS.5,6

Four European RWE studies complement these findings.1–4

The English experience

172 patients with a median age of 62.8 (SD=10.1) were diagnosed with AML-MRC, t-AML, or de novo AML and treated with Vyxeos Liposomal. Median follow-up was 11.2 months.1

England RWE - Patient Baseline Characteristics (N=172)1

n%
Cohort SizeN172100.00%
Age at diagnosis
(index date) (Years)		Mean (SD)62.78 (10.10)
Median (Q1-Q3)66.00 (58.00-70.00)
Percentile 5th-95th44.00-73.00
Age categories at diagnosis
(index date), binary (Years)		<604928.49%
≥6012371.51%
GenderFemale5934.30%
Male11365.70%
EthnicityWhite15087.21%
Mixed00.00%
Asian95.23%
Black**
Other**
Missing/Unknown00.00%
Diagnosis typet-AML3721.51%
AML-MRC5733.14%
Non-specific de novo AML7845.35%
ECOG at SACT initiation06537.79%
15230.23%
2105.81%
321.16%
400.00%
Missing/Unknown4325.00%
Azacitidine treatment for prior malignancy
(prior to index date)		Present63.49%
Absent16696.51%
HSCT status after
SACT initiation (All patients)		Present4325.00%
Absent12975.00%
HSCT status after SACT initiation
(patients with ≥3 months HES follow-up
time post SACT initiation)		Present4344.33%
Absent5455.67%
Available follow-up time
from diagnosis (days)		Mean (SD)338.70 (217.91)
Median (Q1-Q3)342.00 (111.00-514.00)
Percentile 5th-95th28.00 - 667.45

Adapted from Legg et al. 2021

* <6 patients (suppressed to protect patient confidentiality)

Vyxeos Liposomal efficacy in the English cohort:

In all patients1

  • 2-year OS was 39%
    (95% CI 0.30, 0.50; n at risk: 6*)
  • Patients were censored at the time of HSCT or on the last day of disease assessment or haematology assessment

Stratified by patient age: <60 and ≥601

  • 2-year OS was 56% in patients <60 years
    (95% CI 0.43, 0.74; n at risk: 0)
  • 2-year OS was 34% in patients ≥60 years
    (95% CI 0.24, 0.46; n at risk: 6*)
  • Patients were censored at the time of HSCT or on the last day of disease assessment or haematology assessment

Landmarked from the HSCT date1

  • 1-year OS was 74%
    (95% CI 0.62, 0.89; n at risk: 24)
  • 25% (43/172) of patients underwent HSCT1
  • Patients were censored at the time of HSCT or on the last day of disease assessment or haematology assessment

The French experience

103 patients with a median age of 67 (20–83) from 12 centres were diagnosed with AML-MRC or t-AML and treated with Vyxeos Liposomal. Median follow-up was 8.6 months.2

France RWE - Patient Baseline Characteristics (N=103)2

n (%)
Age, years
Median (range)67 (20-83)
18-6021 (20)
>6082 (80)
Sex
Male54 (52)
Female49 (48)
AML subtype
AML-MRC74 (72)
MDS-AML35 (47)
CMML-AML9 (12)
t-AML27 (26)
Other*2 (2)
WBCs, median (range), x109/L3 (0–156)
Hyperleukocytosis9 (9)
Cytopenia97 (94)
125 (24)
241 (40)
331 (30)
Karyotype
Complex35 (34)
Monosomal28 (27)
Prior HMA18 (18)
2017 ELN genetic risk stratification (n=102)
Favourable2 (2)
Intermediate38 (37)
Adverse62 (61)
Lindsley's classifier (n=80)
de novo/pan-AML21 (26)
Secondary-type mutations AML37 (46)
TP53-mutated AML22 (28)

Adapted from Chiche et al. 2021

Values present n (%) of patients unless otherwise indicated

* Two patients were treated after myeloproliferative neoplasm AML (one with prior essential thrombocythemia and one with myelofibrosis secondary to essential thrombocythemia)

Vyxeos Liposomal efficacy in the French cohort:

Induction results2

59% ORR(61/103)

MRD negativity2

57%

of patients were MRD negative (16/28)

  • MRD <10-3 was evaluable in 28 of the 61 patients who achieved CR/CRi

16 months mOS2

  • 35% (36/103) of patients had an ASCT2
  • The majority of patients who were eligible and received Vyxeos Liposomal did not proceed to ASCT2

Vyxeos Liposomal overcame the poor response rate associated with the ASXL1 and RUNX1 mutations2

The Italian experience

71 patients with a median age of 66 (52-79) from 31 centres were diagnosed with s-AML and treated with Vyxeos Liposomal. Median follow-up was 11 months.3

Italy RWE - Patient Baseline Characteristics (N=71)3

n (%)
Age, years
<7051 (71.8)
>7020 (28.2)
Sex
Male39 (54.9)
Female32 (45.1)
WBC
<30 × 109/L60 (84.5)
>30 × 109/L11 (15.5)
Marrow blasts
<30%22 (31.0)
>30%49 (69.0)
Previous HMA
No54 (76.1)
Yes17 (23.9)
NPM1 (evaluated in 68/71, 96%)
Wild type63 (92.7)
Mutated5 (7.3)
FLT3-ITD (evaluated in 69/71, 97%)
Negative64 (92.8)
Positive5 (7.2)
TP53 (evaluated in 37/71, 52%)
Wild type24 (64.9)
Mutated13 (35.1)
Karyotype
Favourable3 (4.7)
Intermediate36 (50.2)
Poor32 (45.1)
Vyxeos Liposomal indication
s-AML36 (50.2)
t-AML22 (31.0)
MDS-related changes13 (18.8)
ELN 2017
Low/intermediate8 (11.3)
Intermediate24 (33.8)
High39 (54.9)

Adapted from Guolo et al. 2020

Vyxeos Liposomal efficacy in the Italian cohort:

Induction results3

73% ORR(52/71)

MRD negativity3

~50%

of analysed patients achieved MRD negativity

  • Depth of response was evaluated after the first induction†
  • MRD was evaluated through flow cytometry in 40 patients and WT1-MRD analysis in 38 patients

69% OS at 12 months3

  • 71% OS for non-HSCT patients at 12 months3
  • 100% OS for HSCT patients at 12 months3
    • 40% (20/50) of the patients who achieved CR received an HSCT3

The presence of TP53 mutation in the context of a complex karyotype did not impact the survival rate3

The German experience

188 patients with a median age of 65 (range 26–80) across 25 centres were diagnosed with AML-MRC or t-AML and treated with Vyxeos Liposomal. Median follow-up was 9.3 months.4

Germany RWE - Patient Baseline Characteristics (N=188)4

Characteristicsn%
Age, years (median,range)65 (26-80)
Gender
Female7037
Male11863
Karnofsky (n=165)
≥8013582
<803018
HCT-CI (n=155)
Low2918
Intermediate5535
High7447
AML subtype (n=186)
AML-MRC13170
t-AML5329
Other*21
2017 ELN genetic risk (n=179)
Favourable127
Intermediate5933
Adverse10860
Karyotype (n=179)
Normal6335
Abnormal11665
Complex4425
Non-complex7240
Molecular genetics
NPM1/n.d.18/1110/6
FLT3-ITD/n.d.13/137/7
ASXL1/n.d.31/2416/13
TP53/n.d.14/267/14
RUNX1/n.d.24/2013/11
BM blast count at diagnosis (median, range)38 (7-99)
PB blast count at diagnosis (median, range)10 (0-92)
WBC at diagnosis, ×103/μl (median, range)3.8 (0.6/330)
Pretreatment with HMA1910

Adapted from Rautenberg et al. 2021

* Secondary AML evolving from systemic mastocytosis (n=1) and blastic plasmacytoid dendric cell neoplasm with antecedent history of chronic myelomonocytic leukaemia

Vyxeos Liposomal efficacy in the German cohort:

Induction results4

67% ORRpost induction(120/179)

MRD negativity4

64%

of patients achieved MRD negativity <10-3 (23/36) via flow cytometry analysis

  • MRD status was available for 36 of the 85 patients (42%) who achieved CR/CRi

21 months mOS4

  • 62% (116/188) patients underwent HSCT4
  • An estimated 73% of all HSCT patients reached 2-year survival4
  • 82  patients went on to receive allo-HSCT without further therapy4
    • 34 patients underwent bridging therapy consisting of Vyxeos Liposomal and/or cytarabine consolidation, HMA or salvage therapy before receiving allo-HSCT4

54% (14/26) of patients with TP53mut achieved CR/CRi with Vyxeos Liposomal4,7

See the efficacy of Vyxeos Liposomal from Study 301
and the European RWE studies

Vyxeos Liposomal Efficacy at a Glance

Study 3015,6England1 (N=172)France2 (N=103)Italy3
(N=71)		Germany4 (N=188)
Vyxeos Liposomal (N=153)DA 3+7 (N=156)
Median OS, months9.66.016.616.1NR (68.6% at 12 months)21
(p=0.009)
Median OS post-HSCT, monthsNR10.25NR (74% at 12 months)NRNR (100% at 12 months)NR (73% at 12 months)
(p=0.009)
CR, n/N (%)37%26%NA57/103 (55)38/71 (54)NA
(p=0.04)
CR+CRi, n/N (%)*48%33%NA61/103 (59)46/71 (65)85/179 (47)
(p=0.016)
CR+CRi+PR, n/N (%)*NANANA52/71 (73)NA
MRD negativity, n/N (%)*NANA16/28 (57)~50%†23/36 (64)

* Following induction
† Flow cytometry-based MRD assessment data were available from 17/31 centres (54.8%) for 40/71 patients (56.3%) and the MRD negativity rate was 37.5% (15/40 patients). WT1-based MRD was available for 15/31 (48.4%) centres for 38/71 patients (53.5%) and the MRD negativity rate was 53.8% (21/38 patients)

Safety results were not reported for the English cohort as the NCRAS database did not contain the relevant information
The French cohort study confirmed the acceptable safety profile reported in Study 3012
  • Median time to neutrophil recovery after the first induction was 29 days
  • Median time to platelet recovery after the first induction was 28 days

France RWE – AEs Occurring During Vyxeos Liposomal Therapy Regardless of Causality Tolerability profile2

All gradesGrade ≥3
Sepsis*-101 (98)
Febrile neutropenia94 (91)94 (91)
Pneumonia37 (36)30 (30)
Bacteraemia-25 (24)
Invasive pulmonary aspergillosis-10 (10)
Bleeding12 (12)6 (6)
Epistaxis4 (4)0
Oral haemorrhage2 (2)1 (1)
Gastrointestinal haemorrhage1 (1)1 (1)
Intra-alveolar haemorrhage1 (1)1 (1)
Intracranial haemorrhage2 (2)0
Haematuria1 (1)1 (1)
Ocular haemorrhage1 (1)0
Hypertensive crisis10 (10)2 (2)
Heart failure9 (9)7 (7)
Gastrointestinal toxicity52 (50)4 (4)
Nausea37 (36)0
Vomiting13 (13)1 (1)
Diarrhoea7 (7)0
Mucositis23 (22)3 (3)
Rash26 (25)2 (2)
Alopecia11 (11)0

* Sepsis was defined by either the CTCAE criteria (Grade >3 sepsis is a positive blood culture with signs and symptoms indicating treatment initiation) or the SIRS criteria (>2 of the following - temperature <36°C or >38°C; heart rate >90 beats/minute; respiratory rate >20 breaths/minute or ppCO2 <32 mmHg; WBC >12,000/mm3 or the presence of >10% immature neutrophils).

Values represent n (%) of patients.

Adapted from Chiche et al. 2021

Most AEs were easily manageable and resolved completely within the Italian cohort3
  • Median time to neutrophil recovery after the first induction was 38 days
  • Median time to platelet recovery after the first induction was 28 days

Italy RWE – Grade ≥1 AEs Occurring During Therapy3

Induction, n/71 (%)Second cycle, n/39 (%)
All grade AEs57 (80.3)25 (64.1)
Fever of unknown origin20 (28)9 (23.7)
Sepsis20 (28)3 (7.7)
Pneumonia8 (11.3)3 (7.7)
Pneumocystis jirovecii-related pneumonia2 (2.8)1 (2.6)
Invasive fungal infections3 (4.2)-
Mucositis5 (7)2 (5.2)
Skin- rash (self-resolving)18 (25.4)8 (20.5)
Alopecia4 (5.6)-

Adapted from Guolo et al. 2020

The German RWE study demonstrated a similar safety profile to the French and Italian studies4
  • Median time to neutrophil recovery after the first induction was 33 days
  • Median time to platelet recovery after the first induction was 30 days

Germany RWE – Grade ≥3 treatment toxicities4

Characteristicsn%
Grade III/IV non-hemarologic tocicities (n = 188)
Infection4122
GI (mucositis, nausea, vomiting)74
Bleeding74
Renal failure53
Febrile neutropenia2815
Pneumonia4222
Mortality on Day 30 after Vyxeos Liposomal unduction (n = 176)*
Alive16292
Dead148

Adapted from Rautenberg et al. 2021

* Patients proceeding to allo-HSCT before Day 30 following induction with Vyxeos Liposomal have been excluded

See the safety of Vyxeos Liposomal from Study 301
and the European RWE studies

Vyxeos Liposomal Safety at a Glance

Study 3015England1
(N=172)		France2
(N=103)		Italy3
(N=71)		Germany4
(N=188)
Vyxeos Liposomal
(N=153)		DA 3+7
(N=156)
Neutrophil recovery, days3529NA293833
Platelet recovery, days3729NA282830

Vyxeos Liposomal Study 301 results are now complemented by four European RWE studies in over 500 patients1–4,6,7

Peer-reviewed evidence has so far demonstrated that:1-7

  • Vyxeos Liposomal can deliver efficacy, even in those with poor prognostic factors (eg, a complex karyotype)
  • Vyxeos Liposomal can lay the foundation towards long-term survival for patients that receive transplant

Of note, the authors of the German study concluded:

A combined approach applying an effective induction with Vyxeos Liposomal and inducing an MRD-negative CR followed by the subsequent allo-HSCT without further delay may constitute the treatment approach with the highest probability of cure for patients with AML-MRC or t-AML.4
Visit the Resource Centre for exclusive access to reprints of the RWE and 5-year analysis papers
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In AML-MRC and t-AML, consider Vyxeos Liposomal first.

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FOOTNOTES

* To protect patient confidentiality, the NCRAS suppresses specific numbers <6

† MRD assessment was not a mandatory endpoint of the study. It was performed according to internal clinical practice, following ELN suggestions. WT1-MRD assessment was performed as recommended by ELN. Flow cytometry-based MRD assessment data were available from 17/31 centres (54.8%) for 40/71 patients (56.3%) and the MRD negativity rate was 37.5% (15/40 patients). WT1-based MRD was available for 15/31 (48.4%) centres for 38/71 patients (53.5%) and the MRD-negativity rate was 53.8% (21/38 patients)

‡ MLFS is defined as <5% blasts in the bone marrow with no blasts with Auer rods and no extramedullary disease, does not require count recovery

ABBREVIATIONS

AE, adverse event; allo-HSCT, allogeneic haematopoietic stem cell transplant; AML, acute myeloid leukaemia; AML-MRC, acute myeloid leukaemia with myelodysplasia-related changes; ASCT, allogeneic stem cell transplant; ASXL1, additional sex comb-like 1; BM, bone marrow; CI, confidence interval; CMML, chronic myelomonocytic leukaemia; CR, complete remission; CRi, complete remission with incomplete platelet and neutrophil recovery; DA, daunorubicin + cytarabine; ECOG, Eastern Cooperative Oncology Group; ELN, European LeukemiaNet; FLT3-ITD, FMS-like tyrosine kinase 3 internal tandem duplication; GI, gastrointestinal; HES, hypereosinophilic syndrome; HMA, hypomethylating agent; HSCT, haematopoietic stem cell transplant; MDS, myelodysplastic syndrome; MLFS, morphologic leukaemia-free state; mOS, median overall survival; MRD, minimal residual disease; NA, not applicable; NCRAS, National Cancer Registration and Analysis Service; n.d., not done; NE, not estimable; NR, not reached; ORR, overall response rate; OS, overall survival; PB, peripheral blood; PR, partial response; Q1, first quartile; Q3, third quartile; RCT, randomised control trial; RWE, real-world evidence; SACT, systemic anti-cancer therapy; s-AML, secondary acute myeloid leukaemia; SD, standard deviation; t-AML, therapy-related acute myeloid leukaemia; WBC, white blood cell; WT1-MRD, Wilms' tumour 1 minimal residual disease

REFERENCES
  1. Legg A, et al. Poster 2310. ASH Annual Meeting 2021
  2. Chiche E, et al. Blood Adv 2021;5(1):176–184
  3. Guolo F, et al. Blood Cancer J 2020;10(10):96
  4. Rautenberg C, et al. Blood Cancer J 2021;11:164
  5. Lancet JE, et al. J Clin Oncol 2018;36(26):2684–2692
  6. Lancet JE, et al. Lancet Haematol 2021;8(7):e481–e491
  7. Rautenberg C, et al. Blood Cancer J 2021;11:164 (Supplementary material)
  8. Kolitz JE, et al. Leuk Lymphoma 2020;61(3):631–640

ADVERSE EVENTS REPORTING

Adverse events should be reported. Reporting forms and information for the UK can be found at https://yellowcard.mhra.gov.uk/

For Ireland, reporting forms and information can be found at: www.hpra.ie

Adverse events should also be reported to Jazz Pharmaceuticals at AEreporting@jazzpharma.com

UK-VYX-2100242 | January 2022