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Efficacy Safety Real-World Evidence

Safety profile

Comparable safety to 7+3

The safety profile of VYXEOS in the Phase 3 study was found to be comparable to 7+3. The types of adverse reactions, proportions of patients who experienced them, and severity of events were similar between treatment arms.1

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Adverse reactions

VYXEOS safety profile in the Phase 3 study2

Common adverse reactions (≥20% incidence in the VYXEOS arm) during the induction phase

All Gradesa
Grades 3 to 5a
Adverse Reaction All Gradesa Grades 3 to 5a
VYXEOS
(n=153)
n (%) 		7+3
(n=151)
n (%) 		VYXEOS
(n=153)
n (%) 		7+3
(n=151)
n (%)
Hemorrhage 107 (70) 74 (49) 15 (10) 9 (6)
Febrile neutropenia 104 (68) 103 (68) 101 (66) 102 (68)
Rash 82 (54) 55 (36) 8 (5) 2 (1)
Edema 78 (51) 90 (60) 2 (2) 5 (3)
Nausea 72 (47) 79 (52) 1 (1) 1 (1)
Diarrhea/colitis 69 (45) 100 (66) 4 (3) 10 (7)
Mucositis 67 (44) 69 (46) 2 (1) 7 (5)
Constipation 61 (40) 57 (38) 0 0
Musculoskeletal pain 58 (38) 52 (34) 5 (3) 4 (3)
Abdominal pain 51 (33) 45 (30) 3 (2) 3 (2)
Cough 51 (33) 34 (23) 0 1 (1)
Headache 51 (33) 36 (24) 2 (1) 1 (1)
Dyspnea 49 (32) 51 (34) 17 (11) 15 (10)
Fatigue 49 (32) 58 (38) 8 (5) 8 (5)
Arrhythmia 46 (30) 41 (27) 10 (7) 7 (5)
Decreased appetite 44 (29) 57 (38) 2 (1) 5 (3)
Pneumonia (excluding fungal) 39 (26) 35 (23) 30 (20) 26 (17)
Sleep disorders 38 (25) 42 (28) 2 (1) 1 (1)
Bacteremia (excluding sepsis) 37 (24) 37 (25) 35 (23) 31 (21)
Vomiting 37 (24) 33 (22) 0 0
Chills 35 (23) 38 (25) 0 0
Hypotension 30 (20) 32 (21) 7 (5) 1 (1)
Non-conduction cardiotoxicity 31 (20) 27 (18) 13 (9) 15 (10)
Adverse
Reaction		 All Gradesa
VYXEOS
(n=153)
n (%) 		7+3
(n=151)
n (%)
Hemorrhage 107 (70) 74 (49)
Febrile neutropenia 104 (68) 103 (68)
Rash 82 (54) 55 (36)
Edema 78 (51) 90 (60)
Nausea 72 (47) 79 (52)
Diarrhea/colitis 69 (45) 100 (66)
Mucositis 67 (44) 69 (46)
Constipation 61 (40) 57 (38)
Musculoskeletal pain 58 (38) 52 (34)
Abdominal pain 51 (33) 45 (30)
Cough 51 (33) 34 (23)
Headache 51 (33) 36 (24)
Dyspnea 49 (32) 51 (34)
Fatigue 49 (32) 58 (38)
Arrhythmia 46 (30) 41 (27)
Decreased appetite 44 (29) 57 (38)
Pneumonia (excluding fungal) 39 (26) 35 (23)
Sleep disorders 38 (25) 42 (28)
Bacteremia (excluding sepsis) 37 (24) 37 (25)
Vomiting 37 (24) 33 (22)
Chills 35 (23) 38 (25)
Hypotension 30 (20) 32 (21)
Non-conduction cardiotoxicity 31 (20) 27 (18)

Fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in 2% of patients in the VYXEOS arm and 0.7% in the control arm (7+3).

Other adverse reactions that occurred in ≥10% of patients in the VYXEOS arm included dizziness, fungal infection, hypertension, hypoxia, upper respiratory infections (excluding fungal), chest pain, pyrexia, catheter/device/injection site reaction, delirium, pleural effusion, anxiety, pruritus, sepsis (excluding fungal), hemorrhoids, petechiae, renal insufficiency, transfusion reactions, and visual impairment (except bleeding).

The safety population included all patients in the VYXEOS cohort and 151 patients from the 7+3 cohort (5 patients withdrew consent before the receipt of treatment).1

aAdverse reactions were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

Time to recovery of absolute neutrophil count and platelets may be prolonged with VYXEOS and require additional monitoring2

  • Incidences of Grade 3 thrombocytopeniab were prolonged in the absence of active leukemia in 28% (16/58) of patients in the VYXEOS arm and 12% (4/34) of patients in the 7+3 arm during Induction 1 and in 25% (12/48) of patients in the VYXEOS arm and 16% (5/32) of patients in the 5+2 arm during Consolidation 1
  • Incidences of Grade 4 neutropeniab were prolonged in the absence of active leukemia in 17% (10/58) of patients in the VYXEOS arm and 3% (1/34) of patients in the 7+3 arm during Induction 1 and in 10% (5/48) of patients in the VYXEOS arm and 3% (1/32) of patients in the 5+2 arm during Consolidation 1
  • bPlatelets <50 Gi/L or neutrophils <0.5 Gi/L lasting past cycle Day 42 in the absence of active leukemia.2

Mortality Rates

VYXEOS was associated with lower 30- and 60-day mortality rates compared with 7+32

30- and 60-day overall all-cause mortality in patients with sAML aged 60-75 years (safety population)

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  • 9 patients each in the VYXEOS arm (6%) and control arm (6%) had a fatal adverse reaction on treatment or within 30 days of treatment that was not in the setting of progressive disease
  • 8 patients in the control arm (5%) died within 30 days of treatment due to progressive leukemia
  • Fatal adverse reactions in the VYXEOS arm included infection, CNS hemorrhage, and respiratory failure

POSt hoc analysis

Lower cardiotoxicity rates with VYXEOS vs 7+33,4

A post hoc analysis was conducted to assess the impact of VYXEOS vs 7+3 on cardiac impairment in a subset of patients from the Phase 3 study.

Percentage of patients with clinically
significantc,d
change in LVEF or GLS3

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chart chart
chart

Patients from the Phase 3 study (VYXEOS [n=57]; 7+3 [n=45]) with normal baseline LVEF and at least one postbaseline echocardiogram measure were evaluated. Patients with prior cumulative anthracycline exposure of
>368 mg/m2 daunorubicin (or equivalent) were excluded from the study.3

Cardiac function was assessed at3:

  • Baseline (treatment initiation)
  • Follow-up 1: 30-45 days from last induction or prior to consolidation or salvage therapy, and/or
  • Follow-up 2: Day 150 or 45 days from last treatment (whichever was later)

Median baseline LVEFc and GLSd in the VYXEOS and 7+3 arms were3:

  • LVEF: VYXEOS, 63.3; 7+3, 62.0
  • GLS: VYXEOS, -21.3; 7+3, -21.1

Limitations of subanalysis3

The limitations of this analysis include its post hoc design, the restricted patient population, and limited follow-up time points. No conclusions should be drawn. Analysis was not powered to determine statistical significance.

VYXEOS treatment is not recommended in patients with LVEF that is less than normal. Discontinue VYXEOS in patients with impaired cardiac function unless the benefit of initiating or continuing treatment outweighs the risk.2

Safety Data
  • CNS=central nervous system; GLS=global longitudinal strain; LVEF=left ventricular ejection fraction.
  • cLVEF normal baseline defined as >53% and clinically significant change defined as >10% absolute decrease from baseline and LVEF <53%.3
  • dGLS normal baseline defined as ≥18% and clinically significant change defined as >12% relative decrease from baseline and GLS <18%.3

Outpatient Strategies

Some patients may be appropriate for outpatient administration of VYXEOS, giving you more options when planning their treatment. Read how some institutions are approaching outpatient use of VYXEOS.

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About sAML

Secondary AML is a broad category of high-risk AML that includes multiple subtypes of leukemias with different characteristics but similar poor prognosis and significant challenge to reach a cure.5,6 Learn more about which patients may be appropriate for intensive chemotherapy with VYXEOS.

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INDICATION Close

VYXEOS is indicated for the treatment of newly-diagnosed therapy-related acute myeloid leukemia (t‑AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older.

Important Safety Information Open Close

WARNING: DO NOT INTERCHANGE WITH OTHER DAUNORUBICIN AND/OR CYTARABINE-CONTAINING PRODUCTS

VYXEOS has different dosage recommendations than daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection. Verify drug name and dose prior to preparation and administration to avoid dosing errors.

Contraindications

VYXEOS is contraindicated in patients with a history of serious hypersensitivity reactions to cytarabine, daunorubicin, or any component of the formulation.

Warnings and Precautions
Hemorrhage

Serious or fatal hemorrhage events, including fatal CNS hemorrhages, associated with prolonged thrombocytopenia, have occurred with VYXEOS. The overall incidence (grade 1-5) of hemorrhagic events was 74% in the VYXEOS arm and 56% in the control arm. The most frequently reported hemorrhagic event was epistaxis (36% in VYXEOS arm and 18% in control arm). Grade 3 or greater events occurred in 12% of VYXEOS-treated patients and in 8% of patients in the control arm. Fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in 2% of patients in the VYXEOS arm and in 0.7% of patients in the control arm. Monitor blood counts regularly and administer platelet transfusion support as required.

Cardiotoxicity

VYXEOS contains daunorubicin, which has a known risk of cardiotoxicity. This risk may be increased in patients with prior anthracycline therapy, preexisting cardiac disease, previous radiotherapy to the mediastinum, or concomitant use of cardiotoxic drugs. Assess cardiac function prior to VYXEOS treatment and repeat prior to consolidation and as clinically required. Discontinue VYXEOS in patients with impaired cardiac function unless the benefit of initiating or continuing treatment outweighs the risk. VYXEOS is not recommended in patients with cardiac function that is less than normal.

Total cumulative doses of non-liposomal daunorubicin greater than 550 mg/m2 have been associated with an increased incidence of drug-induced congestive heart failure. The tolerable limit appears lower
(400 mg/m2) in patients who received radiation therapy to the mediastinum. Calculate the lifetime cumulative anthracycline exposure prior to each cycle of VYXEOS. VYXEOS is not recommended in patients whose lifetime anthracycline exposure has reached the maximum cumulative limit.

Hypersensitivity Reactions

Serious or fatal hypersensitivity reactions, including anaphylactic reactions, have been reported with daunorubicin and cytarabine. Monitor patients for hypersensitivity reactions. If a mild or moderate hypersensitivity reaction occurs, interrupt or slow the rate of infusion with VYXEOS and manage symptoms. If a severe or life-threatening hypersensitivity reaction occurs, discontinue VYXEOS permanently, treat the symptoms, and monitor until symptoms resolve.

Copper Overload

VYXEOS contains copper. Consult with a hepatologist and nephrologist with expertise in managing acute copper toxicity in patients with Wilson’s disease treated with VYXEOS. Monitor total serum copper, serum non-ceruloplasmin-bound copper, 24-hour urine copper levels, and serial neuropsychological examinations during VYXEOS treatment in patients with Wilson’s disease or other copper-related metabolic disorders. Use only if the benefits outweigh the risks. Discontinue in patients with signs or symptoms of acute copper toxicity.

Tissue Necrosis

Daunorubicin has been associated with severe local tissue necrosis at the site of drug extravasation. Administer VYXEOS by the intravenous route only. Confirm patency of intravenous access before administration. Do not administer by intramuscular or subcutaneous route.

Embryo-Fetal Toxicity

VYXEOS can cause embryo-fetal harm when administered to a pregnant woman. Patients should avoid becoming pregnant while taking VYXEOS. If VYXEOS is used during pregnancy or if the patient becomes pregnant while taking VYXEOS, apprise the patient of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of VYXEOS.

MOST COMMON ADVERSE REACTIONS

The most common adverse reactions (incidence ≥25%) are hemorrhagic events (74%), febrile neutropenia (70%), rash (56%), edema (55%), nausea (49%), mucositis (48%), diarrhea (48%), constipation (42%), musculoskeletal pain (43%), fatigue (39%), abdominal pain (36%), dyspnea (36%), headache (35%), cough (35%), decreased appetite (33%), arrhythmia (31%), pneumonia (31%), bacteremia (29%), chills (27%), sleep disorders (26%), and vomiting (25%).

Please see full Prescribing Information, including BOXED Warning.

References: 1. Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36(26):2684-2692. 2. VYXEOS [package insert]. Palo Alto, CA: Jazz Pharmaceuticals. 3. Mitchell JD, Pfeiffer M, Boehmer J, et al. P516: Cardiotoxicity of CPX-351 vs 7+3 in patients with untreated high-risk acute myeloid leukemia. Poster presented at: EHA2023 (European Hematology Association) Hybrid Congress; June 8–11, 2023; Frankfurt, Germany. 4. Mitchell JD, Pfeiffer M, Boehmer J, et al. P516: Cardiotoxivity of CPX-351 vs 7+3 in patients with untreated high-risk acute myeloid leukemia. Hemasphere. 2023;7(Suppl):e178806c. 5. Lalayanni C, Gavriilaki E, Athanasiadou A, et al. Secondary acute myeloid leukemia (sAML): similarly dismal outcomes of AML after an antecedent hematologic disorder and therapy related AML. Clin Lymphoma Myeloma Leuk. 2022;22(4):e233-e240.
6. Capelli D, Menotti D, Florentini A, Sarcani F, Olivieri A. Chapter 7: Secondary acute myeloid leukemia: pathogenesis and treatment. Accessed March 21, 2024. https://www.ncbi.nlm.nih.gov /books /NBK586211 /?report=printable

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Frequency of cardiac adverse events1

Cardiac adverse event (≥5%, any grade)
VYXEOS
n=57
n (%)
7+3
n=45
n (%)
Atrial fibrillation/flutter
4 (7.0)
5 (11.0)
Pericardial effusion
3 (5.3)
1 (2.2)
Supraventricular arrhythmias
0
3 (6.7)
Tachycardia
12 (21.0)
4 (8.9)
No grade 3-4 cardiac adverse events occurred in >5% of patients.

Cardiac adverse events (all grades) which occurred at a frequency of <5% in either treatment arm: acute coronary syndrome, aortic valve incompetence, atrioventricular block first degree, bradycardia, bundle branch block right, cardiomegaly, cardiomyopathy, congestive cardiac failure, cyanosis, diastolic dysfunction, ventricular dilatation, extrasystoles, left ventricular dysfunction, myocardial infarction, nodal arrhythmia, palpitations, pericarditis, sinus bradycardia, sinus tachycardia, ventricular extrasystoles, ventricular tachycardia

Reference: 1. Mitchell JD, Pfeiffer M, Boehmer J, et al. P516: Cardiotoxicity of CPX-351 vs 7+3 in patients with untreated high-risk acute myeloid leukemia. Poster presented at: EHA2023 (European Hematology Association) Hybrid Congress; June 8–11, 2023; Frankfurt, Germany.