Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2017035
Category:	Pharmacy
Initiated:	November 2017
Last Review:	September 2024

Gemtuzumab Ozogamicin (e.g., Mylotarg™)

Description:

Gemtuzumab ozogamicin is a CD33-directed antibody-drug conjugate. The antibody portion (hP67.6) recognizes human CD33 antigen. The small molecule, N-acetyl gamma calicheamicin, is a cytotoxic agent that is covalently attached to the antibody via a linker. Nonclinical data suggest that the anticancer activity of gemtuzumab ozogamicin is due to the binding of the ADC to CD33-expressing tumor cells, followed by internalization of the ADC-CD33 complex, and the intracellular release of N-acetyl gamma calicheamicin dimethyl hydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl gamma calicheamicin dimethyl hydrazide induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death (Mylotarg, 2021).

Regulatory Status

Gemtuzumab ozogamicin (e.g., Mylotarg) was approved by the U.S. Food and Drug Administration (FDA) on September 1, 2017, for the treatment of newly diagnosed CD33-positive acute myeloid leukemia in adults and relapsed or refractory CD33-positive acute myeloid leukemia in adults and in pediatric individuals 2 years and older.

Gemtuzumab ozogamicin (e.g., Mylotarg) was approved by the U.S. Food and Drug Administration (FDA) on June 16, 2020, for the treatment of newly diagnosed CD33-positive acute myeloid leukemia (AML) to include pediatric individuals 1 month and older.

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.

Effective January 1, 2025

Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria

Gemtuzumab ozogamicin (e.g., Mylotarg) meets member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL of the following criteria are met:

For FDA labeled indications, all products must be dosed in accordance with the FDA label unless otherwise specified.

For off-label indications, authorizations will not exceed 6 milligrams per square meter of body surface area OR maximum recommended doses as outlined in dosage and administration section unless medical literature supports a higher dose.

ACUTE MYELOID LEUKEMIA

INITIAL APPROVAL STANDARD REVIEW for up to 12 months:

1. Individual is 1 month of age or older and has a newly diagnosed CD33-positive acute myeloid leukemia (Mylotarg, 2021, NCCN 2A); OR

2. Individual is 2 years of age or older and has relapsed or refractory CD33-positive acute myeloid leukemia (Mylotarg, 2021, NCCN 2A); AND

3. Gemtuzumab ozogamicin will be used for treatment induction in individuals who are candidates for intensive induction therapy with (NCCN 2A):

a. Favorable-risk AML by cytogenetics (CBF-AML) and CD33-positive, or favorable-risk AML by molecular mutation profile (NPM1-mutated/FLT3 wild-type AML, in-frame bZIP mutation in CEBPA) and CD33-positive, or intermediate-risk AML and CD33-positive; OR

b. Favorable-risk AML by cytogenetics (CBF-AML) and CD33-positive; or favorable-risk AML by molecular mutation profile (NPM1-mutated/FLT3 wild-type AML, in-frame bZIP mutation in CEBPA) and CD33-positive CSF); OR

c. Intermediate-risk AML and CD33-positive; OR

4. Gemtuzumab ozogamicin will be used for consolidation therapy for individuals with CD33-positive AML (only if gemtuzumab ozogamicin was given during induction, NCCN 2A):

a. In combination with cytarabine for individuals with favorable-risk AML (CBF-AML,NPM1-mutated/FLT3 wild-type AML, in-frame bZIP mutation in CEBPA); OR

b. In combination with cytarabine and daunorubicin for individuals with favorable-risk AML (CBF-AML, NPM1-mutated/FLT3 wild-type AML, in-frame bZIP mutation in CEBPA) or intermediate-risk AML; OR

c. In combination with fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor (G-CSF) for individuals with poor-risk AML with and without TP53-mutation or del17p abnormality, therapy-related AML other than CBF-AML, antecedent MDS/CMML, or cytogenetic changes consistent with MDS (AML-MRC); OR

d. As a single agent as continuation of lower-intensity regimen used for induction in individuals with poor-risk AML with and without TP53-mutation or del17pabnormality, therapy-related AML other than CBF-AML, antecedent MDS/CMML, or cytogenetic changes consistent with MDS (AML-MRC); OR

5. Gemtuzumab ozogamicin will be used for relapsed/refractory disease for individuals with CD33-positive AML (NCCN 2A):

a. As a component of repeating the initial successful induction regimen if ≥12months since induction regimen; OR

b. As a single agent.

CONTINUED APPROVAL for up to 12 months:

1. Individual continues to meet the initial approval criteria; AND

2. Individual experiences objective benefit form continued treatment as defined by stabilization of disease or decrease in size of tumor or tumor spread; AND

3. Individual does not have unacceptable toxicity resulting from the treatment (e.g., severe infusion-related reactions, severe immune-mediated adverse reactions such as pneumonitis, hepatitis, colitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions).

ACUTE PROMYELOCYTIC LEUKEMIA

INITIAL APPROVAL STANDARD REVIEW for up to 12 months:

1. Individual has a diagnosis of acute promyelocytic leukemia; AND

a. Gemtuzumab will be used in certain circumstances (if arsenic is not available or contraindicated) for treatment induction in low-risk disease (white blood cell count less than or equal to 10,000/mcL) in combination with tretinoin (ATRA, NCCN 2A); OR

b. Gemtuzumab will be used for treatment induction in high-risk disease (white blood cell count greater than 10,000/mcL) in individuals with no cardiac issues in combination with tretinoin (ATRA) and arsenic trioxide (NCCN 2A); OR

c. Gemtuzumab will be used for treatment induction in high-risk disease (white blood cell count greater than 10,000/mcL) in individuals with cardiac issues (NCCN 2A):

i. In combination with tretinoin (ATRA) and arsenic trioxide (if low ejection fraction); OR

ii. In combination with ATRA (if prolonged QTc); OR

d. Gemtuzumab will be used in certain circumstances (if arsenic is not available or contraindicated) for consolidation therapy in low-risk disease (white blood cell count ≤10 x 10^9/L) in combination with tretinoin (ATRA, NCCN 2A); OR

e. Gemtuzumab will be used for consolidation therapy in high-risk disease (white blood cell count greater than 10,000/mcL) in individuals with no cardiac issues (NCCN 2A):

i. In combination with tretinoin (ATRA) if arsenic trioxide was discontinued due to toxicity; OR

ii. In combination with arsenic trioxide if ATRA was discontinued due to toxicity; OR

f. Gemtuzumab will be used for consolidation therapy in high-risk disease (white blood cell count greater than 10,000/mcL) in individuals with cardiac issues (low ejection fraction [EF] or prolonged QTc) (NCCN 2A):

i. In combination with tretinoin (ATRA) if arsenic trioxide was discontinued due to toxicity (if low ejection fraction); OR

ii. In combination with arsenic trioxide if ATRA was discontinued due to toxicity (if low ejection fraction); OR

iii. In combination with ATRA (if prolonged QTc); OR

g. Gemtuzumab will be used as therapy for first relapse (morphologic or molecular) (NCCN 2A):

i. As a single agent for early relapse (less than 6 months) after ATA and arsenic trioxide; OR

ii. In combination with arsenic trioxide, with or without tretinoin (ATRA), in individuals with no prior exposure to arsenic trioxide or early relapse (less than 6 months) after ATRA + anthracycline-containing regimen; OR

iii. In combination with arsenic trioxide, with or without ATRA, in individuals with late relapse (greater than or equal to 6 months) after arsenic trioxide-containing regimen; OR

h. Gemtuzumab will be used as treatment of leukocytosis associated with differentiation syndrome in difficult-to-treat cases as a single agent (NCCN 2A).

CONTINUED APPROVAL for up to 12 months:

1. Individual continues to meet the initial approval criteria; AND

2. Individual experiences objective benefit form continued treatment as defined by stabilization of disease or decrease in size of tumor or tumor spread; AND

3. Individual does not have unacceptable toxicity resulting from the treatment (e.g., severe infusion-related reactions, severe immune-mediated adverse reactions such as pneumonitis, hepatitis, colitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions).

The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).

Dosing and Administration

Dosing per FDA Guidelines

Dosing must be within FDA dosage guidelines of:

Newly diagnosed, de novo AML (combination regimen):

Adults:

Induction: 3 mg/square meter of body surface area (up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine
Consolidation: 3 mg/square meter of body surface area on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.

Pediatric individuals 1 month and older:

Induction: 3 mg/square meter of body surface area for individuals with body surface area (BSA) 0.6 square meters or greater OR 0.1 mg/kg for individualss with BSA less than 0.6 square meters on day 6 in combination with daunorubicin and cytarabine
Consolidation: 3 mg/square meter of body surface area for individuals with BSA 0.6 m2 or greater OR 0.1 mg/kg for individuals with BSA less than 0.6 square meters on day 7.

Newly diagnosed AML (single-agent regimen):

Adults:

Induction: 6 mg/square meter of body surface area on Day 1 and 3 mg/square meters on Day 8
Continuation: For individuals without evidence of disease progression following induction, up to 8 continuation courses of gemtuzumab ozogamicin 2 mg/square meters on Day 1 every 4 weeks.

Relapsed or refractory AML(single-agent regimen):

Adults and pediatric individuals 2 years and older:

3 mg/square meter of body surface area on Days 1, 4, and 7

Gemtuzumab ozogamicin (e.g., Mylotarg) is available as 4.5 mg lyophilized cake or powder in a single-dose vial for reconstitution and dilution.

Gemtuzumab ozogamicin (e.g., Mylotarg) should be administered as an intravenous infusion by a healthcare professional.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Gemtuzumab ozogamicin (e.g., Mylotarg), for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without member benefit certificate primary coverage criteria, gemtuzumab ozogamicin (e.g., Mylotarg), for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective September 2023 to December 31, 2024

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Gemtuzumab ozogamicin meets member benefit certificate primary coverage criteria that there be scientific evidenceof effectiveness in improving health outcomes for the following indications:

Acute Myeloid Leukemia

a. Newly-diagnosed CD33-positive acute myeloid leukemia in adults and pediatric individuals 1 month and older (NCCN 2A)

b. Relapsed or refractory CD33-positive acute myeloid leukemia in adults and in pediatric individuals 2 years and older. (NCCN 2A)

2. Acute Promyelocytic Leukemia

a. Useful in certain circumstances (if arsenic is not available or contraindicated) for treatment induction in low-risk disease (white blood cell count less than or equal to 10,000/mcL) in combination with tretinoin (ATRA). (NCCN 2A)

b. Preferred for treatment induction in high-risk disease (white blood cell count greater than 10,000/mcL) in individuals with no cardiac issues in combination with tretinoin (ATRA) and arsenic trioxide. (NCCN 2A)

c. For treatment induction in high-risk disease (white blood cell count greater than 10,000/mcL) in individuals with cardiac issues (NCCN 2A)

i. In combination with tretinoin (ATRA) and arsenic trioxide (if low ejection fraction)

ii. In combination with ATRA (if prolonged QTc)

iii. Can be substituted for anthracycline for individuals who have prolonged QTc as their sole comorbidity

d. Preferred for consolidation therapy in high-risk disease (white blood cell count greater than 10,000/mcL) in individuals with no cardiac issues NCCN 2A)

i. In combination with tretinoin (ATRA) if arsenic trioxide was discontinued due to toxicity

ii. In combination with arsenic trioxide if ATRA was discontinued due to toxicity

e. For consolidation therapy in high-risk disease (white blood cell count greater than10,000/mcL) in individuals with cardiac issues (low ejection fraction [EF] or prolonged QTc) (NCCN 2A)

i. In combination with tretinoin (ATRA) if arsenic trioxide was discontinued due to toxicity (if low ejection fraction)

ii. In combination with arsenic trioxide if ATRA was discontinued due to toxicity (if low ejection fraction)

iii. In combination with ATRA (if prolonged QTc)

iv. Can be substituted for anthracycline for patients who have prolonged QTc as their sole comorbidity

f. Therapy for first relapse (morphologic or molecular) (NCCN 2A)

i. As a single agent for early relapse (less than 6 months) after ATA and arsenic trioxide.

ii. In combination with arsenic trioxide, with or without tretinoin (ATRA), in individuals with no prior exposure to arsenic trioxide or early relapse (less than 6 months) after ATRA + anthracycline-containing regimen

iii. In combination with arsenic trioxide, with or without ATRA, in individuals with late relapse (greater than or equal to 6 months) after arsenic trioxide-containing regimen

g. For treatment induction in individuals who are candidates for intensive induction with (NCCN 2A)

i. Favorable-risk AML (CBF-AML, NPM1-mutated/FLT3 wild-type AML, in-frame bZIP mutation in CEBPA) and CD33-positive or intermediate-risk AML and CD33-positive in combination with standard-dose cytarabine and daunorubicin (preferred regimen in individuals with favorable-risk AML)

h. For consolidation therapy for individuals with CD33-positive AML (NCCN 2A)

i. In combination with high-dose cytarabine for individuals age less than 60 years with NPM1-mutated and FLT3 negative in favorable-risk AML (CBF-AML, NPM1-mutated/FLT3 wild-type AML, in-frame bZIP mutation in CEBPA)

ii. In combination with intermediate-dose cytarabine and daunorubicin for individuals age less than 60 years with NPM1-mutated and FLT3 negative favorable-risk AML (CBF-AML, NPM1-mutated/FLT3 wild-type AML, in-frame bZIP mutation in CEBPA)

iii. In combination with intermediate-dose cytarabine and daunorubicin for individuals less than 60 years with AML with FLT3/ITD/TKD mutation or intermediate-risk AML

iv. In combination with intermediate-dose cytarabine and daunorubicin for individuals age greater than or equal to years with favorable risk AML (CBF-AML, NPM1-mutated/FLT3 wild-type AML, in-frame bZIP mutation in CEBPA)

v. As a single agent as continuation of low-intensity regimen used for induction in patients with poor-risk AML with and without TP53-mutation or del17p abnormality, therapy-related AML other than CBF-AML, antecedent MDS/CMML, or cytogenetic changes consistent with MDS (AML-MRC)

i. For relapsed/refractory disease for individuals with CD33-positive AML

i. As a component of repeating the initial successful induction regimen if late relapse (greater than or equal to 12 months since induction regimen)

ii. As a single agent

Dosing and Administration

Dosing per FDA Guidelines

Dosing must be within FDA dosage guidelines of:

Newly-diagnosed, de novo AML (combination regimen):

Adults:

Induction: 3 mg/square meters (up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine
Consolidation: 3 mg/square meters on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.

Pediatric individuals 1 month and older:

Induction: 3 mg/square meters for individuals with body surface area (BSA) 0.6 square meters or greater OR 0.1 mg/kg for individualss with BSA less than 0.6 square meters on day 6 in combination with daunorubicin and cytarabine
Consolidation: 3 mg/square meters for individuals with BSA 0.6 m2 or greater OR 0.1 mg/kg for individuals with BSA less than 0.6 square meters on day 7.

Newly-diagnosed AML (single-agent regimen):

Adults:

Induction: 6 mg/square meters on Day 1 and 3 mg/square meters on Day 8
Continuation: For individuals without evidence of disease progression following induction, up to 8 continuation courses of gemtuzumab ozogamicin 2 mg/square meters on Day 1 every 4 weeks.

Relapsed or refractory AML(single-agent regimen):

Adults and pediatric indivdiualss 2 years and older:

3 mg/square meters on Days 1, 4, and 7

Gemtuzumab ozogamicin is available as 4.5 mg lyophilized cake or powder in a single-dose vial for reconstitution and dilution.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Gemtuzumab ozogamicin, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without member benefit certificate primary coverage criteria, gemtuzumab ozogamicin, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective November 1, 2021 to August 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Gemtuzumab ozogamicin meets primary coverage criteria that there be scientific evidence for the following indications:

Acute Myeloid Leukemia

Newly-diagnosed CD33-positive acute myeloid leukemia in adults and pediatric patients 1 month and older (NCCN 2A)
Relapsed or refractory CD33-positive acute myeloid leukemia in adults and in pediatric patients 2 years and older. (NCCN 2A)

2. Acute Promyelocytic Leukemia

Useful in certain circumstances (if arsenic is not available or contraindicated) for treatment induction in low-risk disease (white blood cell count less than or equal to 10,000/mcL) in combination with tretinoin (ATRA). (NCCN 2A)
Preferred for treatment induction in high-risk disease (white blood cell count greater than 10,000/mcL) in patients with no cardiac issues in combination with tretinoin (ATRA) and arsenic trioxide. (NCCN 2A)
For treatment induction in high-risk disease (white blood cell count greater than 10,000/mcL) in patients with cardiac issues (NCCN 2A)

In combination with tretinoin (ATRA) and arsenic trioxide (if low ejection fraction)
In combination with ATRA (if prolonged QTc)
Can be substituted for anthracycline for patients who have prolonged QTc as their sole comorbidity

Preferred for consolidation therapy in high-risk disease (white blood cell count greater than 10,000/mcL) in patients with no cardiac issues NCCN 2A)

In combination with tretinoin (ATRA) if arsenic trioxide was discontinued due to toxicity
In combination with arsenic trioxide if ATRA was discontinued due to toxicity

For consolidation therapy in high-risk disease (white blood cell count greater than10,000/mcL) in patients with cardiac issues (low ejection fraction [EF] or prolonged QTc) (NCCN 2A)

in combination with tretinoin (ATRA) if arsenic trioxide was discontinued due to toxicity (if low ejection fraction)
in combination with arsenic trioxide if ATRA was discontinued due to toxicity (if low ejection fraction)
in combination with ATRA (if prolonged QTc)
can be substituted for anthracycline for patients who have prolonged QTc as their sole comorbidity

therapy for first relapse (morphologic or molecular) (NCCN 2A)

in combination with arsenic trioxide, with or without tretinoin (ATRA), in patients with no prior exposure to arsenic trioxide or early relapse (less than 6 months) after ATRA + anthracycline-containing regimen
in combination with arsenic trioxide, with or without ATRA, in patients with late relapse (greater than or equal to 6 months) after arsenic trioxide-containing regimen

For treatment induction for patients with CD33-positive AML (NCCN 2A)

in patients physiologic age less than 60 years with favorable-risk cytogenetics or intermediate-risk disease in combination with standard-dose cytarabine and daunorubicin (preferred regimen in patients with favorable-risk cytogenetics)
in patients physiologic age greater than or equal to 60 years in combination with standard-dose cytarabine and daunorubicin in candidates for intensive remission induction therapy with favorable-risk cytogenetics or intermediate-risk disease

For post-remission therapy for patients with CD33-positive AML (NCCN 2A)

in combination with high-dose cytarabine for patients physiologic age less than 60 years with core binding factor (CBF) cytogenetic translocations and MRD negative
in combination with intermediate-dose cytarabine and daunorubicin for patients physiologic age less than 60 years with core binding factor (CBF) cytogenetic translocations and MRD negative, or intermediate-risk cytogenetics and/or molecular abnormalities including MRD positive
in combination with intermediate-dose cytarabine and daunorubicin for patients physiologic age greater than or equal to 60 years with complete response to previous intensive therapy

For relapsed/refractory disease for patients with CD33-positive AML

as a component of repeating the initial successful induction regimen if late relapse (greater than or equal to 12 months since induction regimen)
as a single agent

Dosing

Dosing must be within FDA dosage guidelines of:

Newly-diagnosed, de novo AML (combination regimen):

Adults:

Induction: 3 mg/m2 (up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine
Consolidation: 3 mg/m2 on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.

Pediatric patients 1 month and older:

Induction: 3 mg/m2 for patients with body surface area (BSA) 0.6 m2 or greater OR 0.1 mg/kg for patients with BSA less than 0.6 m2 on day 6 in combination with daunorubicin and cytarabine
Consolidation: 3 mg/m2 for patients with BSA 0.6 m2 or greater OR 0.1 mg/kg for patients with BSA less than 0.6 m2 on day 7.

Newly-diagnosed AML (single-agent regimen):

Adults:

Induction: 6 mg/m2 on Day 1 and 3 mg/m2 on Day 8
Continuation: For patients without evidence of disease progression following induction, up to 8 continuation courses of gemtuzumab ozogamicin 2 mg/m2 on Day 1 every 4 weeks.

Relapsed or refractory AML(single-agent regimen):

Adults and pediatric patients 2 years and older:

3 mg/m2 on Days 1, 4, and 7

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of gemtuzumab ozogamicin for the treatment of any other indication does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For members with contracts without primary coverage criteria the use of gemtuzumab ozogamicin for the treatment of any other indication is considered investigational.

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective December 2020 to October 31, 2021

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Gemtuzumab ozogamicin meets primary coverage criteria that there be scientific evidence for the following indications:

1. Newly-diagnosed CD33-positive acute myeloid leukemia in adults and pediatric patients 1 month and older; OR

2. Relapsed or refractory CD33-positive acute myeloid leukemia in adults and in pediatric patients 2 years and older.

Off Label use

NCCN 1 and 2A recommendations in accordance with Coverage Policy #2000030.

Dosing

Dosing must be within FDA dosage guidelines of:

Newly-diagnosed, de novo AML (combination regimen):

Adults:

Induction: 3 mg/m2 (up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine
Consolidation: 3 mg/m2 on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.

Pediatric patients 1 month and older:

Induction: 3 mg/m2 for patients with body surface area (BSA) 0.6 m2 or greater OR 0.1 mg/kg for patients with BSA less than 0.6 m2 on day 6 in combination with daunorubicin and cytarabine
Consolidation: 3 mg/m2 for patients with BSA 0.6 m2 or greater OR 0.1 mg/kg for patients with BSA less than 0.6 m2 on day 7.

Newly-diagnosed AML (single-agent regimen):

Adults:

Induction: 6 mg/m2 on Day 1 and 3 mg/m2 on Day 8
Continuation: For patients without evidence of disease progression following induction, up to 8 continuation courses of gemtuzumab ozogamicin 2 mg/m2 on Day 1 every 4 weeks.

Relapsed or refractory AML(single-agent regimen):

Adults and pediatric patients 2 years and older:

3 mg/m2 on Days 1, 4, and 7

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of gemtuzumab ozogamicin for the treatment of any other indication does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For members with contracts without primary coverage criteria the use of gemtuzumab ozogamicin for the treatment of any other indication is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective December 2019 to November 2020

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Gemtuzumab ozogamicin meets primary coverage criteria for any of the following indications:

1. Newly-diagnosed CD33-positive acute myeloid leukemia in adults; OR

2. Relapsed or refractory CD33-positive acute myeloid leukemia in adults and in pediatric patients 2 years and older.

Off Label use

NCCN 1, 2A and 2B Recommendations in accordance with Coverage Policy #2000030.

Dosing

Dosing must be within FDA dosage guidelines of:

Newly-diagnosed, de novo AML (combination regimen):

Induction: 3 mg/m2 (up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine
Consolidation: 3 mg/m2 on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.

Newly-diagnosed AML (single-agent regimen):

Induction: 6 mg/m2 on Day 1 and 3 mg/m2 on Day 8
Continuation: For patients without evidence of disease progression following induction, up to 8 continuation courses of gemtuzumab ozogamicin 2 mg/m2 on Day 1 every 4 weeks

Relapsed or refractory AML(single-agent regimen): 3 mg/m2 on Days 1, 4, and 7

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of gemtuzumab ozogamicin for the treatment of any other indication does not meet member benefit certificate primary coverage criteria.

For members with contracts without primary coverage criteria the use of gemtuzumab ozogamicin for the treatment of any other indication is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective November 2017 to November 2019

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Gemtuzumab ozogamicin meets primary coverage criteria for any of the following indications:

1. Newly-diagnosed CD33-positive acute myeloid leukemia in adults; OR

2. Relapsed or refractory CD33-positive acute myeloid leukemia in adults and in pediatric patients 2 years and older.

Off Label use

NCCN 1, 2A and 2B Recommendations in accordance with Coverage Policy #2000030.

Dosing

Dosing must be within FDA dosage guidelines of:

Newly-diagnosed, de novo AML (combination regimen):

Induction: 3 mg/m2 (up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine
Consolidation: 3 mg/m2 on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.

Newly-diagnosed AML (single-agent regimen):

Induction: 6 mg/m2 on Day 1 and 3 mg/m2 on Day 8
Continuation: For patients without evidence of disease progression following induction, up to 8 continuation courses of gemtuzumab ozogamicin 2 mg/m2 on Day 1 every 4 weeks

Relapsed or refractory AML(single-agent regimen): 3 mg/m2 on Days 1, 4, and 7

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of gemtuzumab ozogamicin for the treatment of any other indication does not meet member benefit certificate primary coverage criteria.

Rationale:

The safety and efficacy of gemtuzumab ozogamicin in newly-diagnosed AML was investigated in 2 randomized, multicenter, open-label Phase 3 studies, one in which it was studied in combination with chemotherapy and one in which it was studied as single-agent therapy.

In the study that looked at gemtuzumab ozogamicin as combination therapy, 271 patients age 50 to 70 years old with newly-diagnosed AML were randomized to receive induction therapy of daunorubicin (60 mg/m2 on Days 1 to 3) and cytarabine (200 mg/m2 on Days 1 to 7) with (n=135) or without (n=136) gemtuzumab ozogamicin 3mg/m2 (up to a maximum of one vial) on Days 1, 4, and 7. Patients who did not achieve a response after first induction could receive a second induction with daunorubicin and cytarabine alone. Patients with response received consolidation therapy with 2 courses of treatment including daunorubicin (60 mg/m2 on Day 1 of consolidation course 1; 60 mg/m2 on Days 1 and 2 of consolidation course 2) and cytarabine (1 g/m2 every 12 hours on Days 1 to 4) with or without gemtuzumab ozogamicin 3 mg/m2 (up to a maximum of one vial) on Day 1 according to their initial randomization. Patients who experienced remission were also eligible for allogeneic transplantation. An interval of at least 2 months between the last dose of gemtuzumab ozogamicin and transplantation was recommended. The primary endpoint was event-free survival (EFS), measured from the date of randomization until induction failure, relapse, or death by any cause. Per protocol, induction failure was defined as failure to achieve CR or CRp in induction, and date of induction failure was defined as date of marrow evaluation after the last course of induction. Median EFS was 17.3 months in the gemtuzumab ozogamicin arm versus 9.5 months in the control arm; hazard ratio (HR) 0.56 (95% CI: 0.42-0.76). There was no statistically significant difference between treatment arms in overall survival (Castaigne, 2012).

The second study, which evaluated gemtuzumab ozogamicin as single-agent therapy, was a multicenter, randomized, open-label Phase 3 study comparing gemtuzumab ozogamicin (n=118) to best supportive care (n=119) for patients with newly-diagnosed AML who were a) greater than 75 years of age or b) 61 to 75 years of age with a World Health Organization performance status (WHO PS) greater than 2 or were unwilling to receive intensive chemotherapy. Basic supportive care included standard supportive care measures and hydroxyurea or other anti-metabolites for palliative purposes. Patients were randomized 1:1 and stratified by age (61-75 vs 76-80 years vs ≥ 81 years), CD33 positivity of bone marrow blasts (less than 20 % vs 20-80% vs greater than 80% vs unknown), initial white blood cell count (less than 30 vs greater than or equal to 30 x 109/L), WHO PS (0-1 vs 2 vs 3-4), and institution. During induction, gemtuzumab ozogamicin 6 mg/m2 was given on Day 1 and gemtuzumab ozogamicin 3 mg/m2 was given on Day 8. Patients with no evidence of disease progression or significant toxicities after gemtuzumab ozogamicin induction received continuation therapy as outpatients with up to 8 courses of treatment including gemtuzumab ozogamicin 2 mg/m2 on Day 1 every 4 weeks. Patients continued therapy if they did not experience significant toxicities, relapse, or disease progression. The primary endpoint was improvement of overall survival. Median OS was 4.9 months in the gemtuzumab ozogamicin arm versus 3.6 months in the control arm (HR for OS was 0.69 (95% CI: 0.53-0.90) (Amadori, 2016).

Gemtuzumab ozogamicin as a single-agent for relapsed or refractory AML was evaluated in a phase 2, single-arm, open-label study in adults with CD33-positive AML in first relapse. Patients with secondary leukemia or a prior autologous or allogeneic stem cell transplantation were excluded. Patients (n=57) received a single course of gemtuzumab ozogamicin 3 mg/m2 on Days 1, 4, and 7. Consolidation therapy consisted of cytarabine intravenously every 12 hours for 3 days. The cytarabine dose was 3 g/m2 for patients less than 55 years old and 1 g/m2 for patients 55 years or older and/or patients with a creatinine clearance below 50 mL/minute. The endpoints studied were complete remission rate and duration of remission. Fifteen (26%; 95% CI 16% - 40%) patients achieved CR following a single course of gemtuzumab ozogamicin. Median relapse-free survival, measured from the first documentation of CR to the date of relapse or death, was 11.6 months.

2018 Update

A literature search conducted through November 2018 did not reveal any new information that would prompt a change in the coverage statement.

2019 Update

Annual policy review completed with a literature search using the MEDLINE database through December 2019. No new literature was identified that would prompt a change in the coverage statement.

2020 Update

To improve survival rates in children with acute myeloid leukemia (AML), an evaluation of gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, was conducted as an alternative to further chemotherapy dose escalation. The primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. The secondary objectives examined outcomes by risk group and method of intensification.

Children, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children’s Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m2/dose) administered once in induction course 1 and once in intensification course 2 (two of three).

There were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v. 46.9%; hazard ratio [HzR], 0.83; 95% CI, 0.70 to 0.99; P.04) but not OS (3 years: 69.4% v. 65.4%; HzR, 0.91; 95% CI, 0.74 to 1.13; P = .39). Although remission was not improved (88% v. 85%; P = .15), posthoc analyses found relapse risk (RR) was significantly reduced among GO recipients overall (3 years: 32.8% v. 41.3%; HzR, 0.73; 95% CI, 0.58 to 0.91; P = .006). Despite an increased postremission toxic mortality (3 years: 6.6% v. 4.1%; HzR, 1.69; 95% CI, 0.93 to 3.08; P = .09), disease-free survival was better among GO recipients (3 years: 60.6% v. 54.7%; HzR, 0.82; 95% CI, 0.67 to 1.02; P = .07).

GO added to chemotherapy improved EFS through a reduction in RR for children and adolescents with AML. (Gamis AS, Alonzo TA, Meshinchi S, et. al., 2014)

2022 Update

Annual policy review completed with a literature search using the MEDLINE database through September 2022. No new literature was identified that would prompt a change in the coverage statement.

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through September 2023.

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2024. Coverage policy updated to the newest NCCN guideline compendium.

CPT/HCPCS:

References:

Amadori S, Suciu S, Selleslag D, et al.(2016) Gemtuzumab Ozogamicin Versus Best Supportive Care in Older Patients With Newly Diagnosed Acute Myeloid Leukemia Unsuitable for Intensive Chemotherapy: Results of the Randomized Phase III EORTC-GIMEMA AML-19 Trial. J Clin Oncol. 2016;34(9):972-9.

Castaigne S, Pautas C, Terré C, et al.(2012) Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012;379(9825):1508-16.

Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R.(2014) Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014 Sep 20;32(27):3021-32. doi: 10.1200/JCO.2014.55.3628. PMID: 25092781; PMCID: PMC4162498.

Gemtuzumab ozogamicin. Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. c2017- [cited 2017 September 17]. Available from: http://www.clinicalpharmacology.com

Mylotarg® [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals, Inc.; 2017

National Comprehensive Cancer Network (NCCN)(2021) National Comprehensive Cancer Network, Inc. 2021 Practice Guidelines in Oncology—Acute Myeloid Leukemia v.3.2021. Available at https://www.nccn.org/professionals/drug_compendium/content/. Accessed August 17,2021.

National Comprehensive Cancer Network (NCCN)(2023) National Comprehensive Cancer Network, Inc. 2023 Practice Guidelines in Oncology—Acute Myeloid Leukemia v.4.2023. Available at https://www.nccn.org. Accessed September 11, 2023.

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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