cCategory
1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention
is appropriate.8
NCCN makes no warranties of any kind whatsoever regarding their content, use or
application and disclaims any responsibility for their application or use in any way.
Study Design1,2
The Phase 3 study was a randomized, multicenter, open-label,
active-controlled superiority study of VYXEOS (N=153) versus cytarabine and daunorubicin
(7+3; N=156) in patients 60 to 75 years of age with newly-diagnosed t-AML or AML-MRC (N=309). Efficacy was established on the basis
of overall survival from the date of randomization to death from any cause.1
VYXEOS 44 mg/100 mg per m2
(daunorubicin/cytarabine) was given intravenously on Days 1, 3, and 5 for first induction
and on Days 1 and 3 for those needing a second induction. For consolidation, the VYXEOS dose
was 29 mg/65 mg per m2
(daunorubicin/cytarabine) on Days 1 and 3. In the
7+3 arm, first induction was cytarabine 100 mg/m2/day
on Days 1-7 by continuous infusion + daunorubicin 60
mg/m2/day
on Days 1-3. For second induction and consolidation, cytarabine was dosed on Days 1-5 and
daunorubicin on Days 1 and 2. Patients could receive up to 2 cycles of induction and 2
cycles of consolidation in each arm. Subsequent induction was highly recommended for
patients who did not achieve a response and was mandatory for patients achieving >50%
reduction in percent blasts.1
A prospectively planned overall survival analysis of the ITT
population was conducted based on the final 5-year follow-up results from the Phase 3 trial.
Exploratory post hoc subgroup analyses were also conducted.2
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IMPORTANT SAFETY INFORMATION, continued |
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Warnings and Precautions |
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Hemorrhage |
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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. |
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Cardiotoxicity |
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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. |
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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. |
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Hypersensitivity Reactions |
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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. |
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Copper Overload |
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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.
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Tissue Necrosis |
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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. |
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Embryo-Fetal Toxicity |
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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. |
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MOST COMMON ADVERSE REACTIONS |
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The most common adverse reactions (incidence ≥25%) were 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%). |
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Please see full
Prescribing Information, including BOXED Warning. |
AML=acute myeloid leukemia; AML-MRC=AML with
myelodysplasia-related changes; CI=confidence interval; CMML=chronic myelomonocytic
leukemia; CR=complete remission; CRi=complete remission with incomplete neutrophil or
platelet recovery; HR=hazard ratio; HSCT=hematopoietic stem cell transplant; ITT=intent to
treat; KM=Kaplan-Meier; MDS=myelodysplastic syndromes; NCCN=National Comprehensive Cancer
Network; NR=not reached; OS=overall survival; t-AML=therapy-related AML.
References: 1. VYXEOS [package insert]. Palo Alto, CA: Jazz Pharmaceuticals. 2. Lancet JE, Uy GL, Newell LF, et al.
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. Lancet Haematol. 2021;8(7):e481-e491. 3. 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. 4. Data on File (VYX-2021-045). Jazz
Pharmaceuticals, Inc. 5. Data on File
(VYX-2021-046). Jazz Pharmaceuticals, Inc. 6. Uy GL, Newell LF, Lin TL, et al.
Transplant outcomes after CPX-351 vs 7+3 in older adults with newly diagnosed high-risk
and/or secondary AML. Blood Adv. 2022. doi:10.1182/bloodadvances.2021006468. 7. Supplement to: Lancet JE, Uy GL, Newell
LF, et al. 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. Lancet Haematol.
2021;8(7):e481-e491. doi:10.1016/S2352-3026(21)00134-4. 8. Referenced with permission from the
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
for Acute Myeloid Leukemia V.1.2022. © National Comprehensive Cancer Network, Inc.
2021. All rights reserved. Accessed December 2, 2021. To view the most recent and complete
version of the guideline, go online to NCCN.org.
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