Clinical UM Guideline



Subject: Azacitidine (Vidaza®)
Guideline #:  CG-DRUG-48 Current Effective Date:    06/28/2017
Status: Reviewed Last Review Date:    05/04/2017

Description

This document addresses azacitidine (Vidaza), a nucleoside metabolic inhibitor used for the treatment of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) under specific conditions.

Clinical Indications

Medically Necessary:

Azacitidine is considered medically necessary for the following conditions:

  1. Myelodysplastic syndrome (MDS); or
  2. Acute myelogenous leukemia (AML) if the following criteria are met:
    1. Used as a single agent for individuals 60 years of age and older or individuals who cannot tolerate more aggressive regimens; or
    2. Used in combination with sorafenib for relapsed or refractory AML with FLT3-ITD mutations; or
    3. AML arising from MDS.

Not Medically Necessary:

  Azacitidine (Vidaza) is considered not medically necessary if the above criteria are not met.

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS  
J9025 Injection, azacitidine, 1 mg [Vidaza]
   
ICD-10 Diagnosis  
C92.00-C92.02 Acute myeloblastic leukemia
C92.40-C92.42 Acute promyelocytic leukemia
C92.50-C92.52 Acute myelomonocytic leukemia
C92.60-C92.62 Acute myeloid leukemia with 11q23-abnormality
C92.A0-C92.A2 Acute myeloid leukemia with multilineage dysplasia
C93.10-C93.12 Chronic myelomonocytic leukemia
D46.0 Refractory anemia without ring sideroblasts, so stated
D46.1 Refractory anemia with ring sideroblasts (RARS)
D46.20-D46.22 Refractory anemia with excess of blasts (RAEB)
D46.A Refractory cytopenia with multilineage dysplasia
D46.B Refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD RS)
D46.C Myelodysplastic syndrome with isolated del(5q) chromosomal abnormality
D46.4 Refractory anemia, unspecified
D46.Z Other myelodysplastic syndromes
D46.9 Myelodysplastic syndrome, unspecified
   
Discussion/General Information

On May 19, 2004, Azacitidine (Vidaza) received FDA approval for the treatment of the following FAB myelodysplastic syndrome (MDS) subtypes:

The safety and efficacy of azacitidine were demonstrated in one multi-center, randomized trial consisting of 191 subjects with all five FAB subtypes of MDS, and in two multi-center single-arm azacitidine trials consisting of 120 subjects. Silverman and colleagues (2002) reported on the randomized trial in which treatment consisted of either subcutaneous azacitidine plus supportive care (n=99) or supportive care alone (n=92). Subjects in the supportive care arm were free to cross over to the azacitidine arm if their symptoms worsened during the trial. Azacitidine was administered by subcutaneous injection at 75 mg/m2 daily for 7 days every 4 weeks. The dose was increased to 100 mg/m2 if there were no beneficial effects after two treatment cycles. Responses occurred in 60% of subjects on the azacitidine arm (7% complete response, 16% partial response, 37% improved) compared with 5% on the supportive care arm (P<0.001). Median time to leukemic transformation or death was 21 months for azacitidine versus 13 months for supportive care (P=0.007). Transformation to AML occurred as the first event in 15% of those in the azacitidine arm and in 38% receiving supportive care (P=0.001). Eliminating the confounding effect of early cross-over to azacitidine, a 6-month analysis showed median survival of an additional 18 months for azacitidine and 11 months for supportive care (P=0.03). Similar response rates were observed in the two single arm studies (as reported by the FDA approval summary). During response, subjects became independent of red cell or platelet transfusions. Median duration of response was at least 9 months. An additional 19% of those treated with azacitidine had less than partial responses with most becoming transfusion independent. Common adverse events attributed to azacitidine were hematologic, gastrointestinal, local injection site, and constitutional. No deaths were attributed to azacitidine in these studies.

A quality-of-life assessment was performed by Kornblith and colleagues (2002) on the 191 subjects from the Silverman trial. Quality of life measures were assessed by telephone interviews at baseline and days 50, 106, and 182.The authors found significant advantages in physical function, symptoms, and psychological state for those in the azacitidine treatment group. Significant differences between the two groups in quality of life were maintained even after controlling for the number of RBC transfusions. The authors concluded that improved quality of life for subjects treated with azacitidine along with significantly greater treatment response and delayed time to transformation to AML or death compared with those on supportive care (P < 0.001) establishes azacitidine as an important treatment option for MDS.

Since the initial clinical trials of azacitidine for MDS, new classification systems, such as World Health Organization (WHO) diagnostic criteria and the International Prognostic Scoring System and response criteria guidelines have been developed and revised. In 2006, Silverman and colleagues analyzed previous trials of azacitidine treatment for MDS and reported results using newer classification systems. The authors noted that overall, complete remissions occurred in 10-17% of subjects treated with azacitidine, partial remissions were rare, and 23%-36% of subjects demonstrated hematologic improvement (HI). Using WHO criteria, 103 subjects had AML at baseline and 35%-48% had responses of HI or better. Of the 27 subjects with AML randomly assigned to azacitidine, the median survival time was 19.3 months as compared to the 25 subjects assigned to the observation groups who had a median survival time of 12.9 months.

Azacitidine has been used in the treatment of previously untreated AML in elderly individuals not eligible to receive standard induction therapy with an anthracycline-cytarabine regimen, and also in the treatment of elderly with relapsed or refractory AML (AHFS, 2011). A retrospective review by Sudan and colleagues (2006) included 12 subjects with bone marrow blast counts up to 29% (mean age of 66 years [range, 44–80]), that had been previously assigned by the FAB classification as having refractory anemia with excess blasts in transformation (RAEB-t). Under the newer WHO classification, these individuals met criteria for AML. An additional 8 subjects (mean age of 71 years [range, 58–79]) with more than 29% blasts in the marrow were deemed to be poor candidates for standard induction therapy. All individuals were treated with azacitidine for 7 consecutive days via subcutaneous injection. This cycle was repeated every 28 days for as long as therapy was tolerated and a response was maintained. The overall response rate was 60% (12/20): complete response (CR; n= 4; 20%); partial response (PR; n=5; 25%); hematologic improvement (HI; n=3; 15%). The median survival of responders was 15+ months compared with 2.5 months for non-responders. During treatment, responders had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The most common adverse event was infection.

A phase III randomized controlled trial (Fenaux, 2009) demonstrated prolonged overall survival (OS) of subjects with higher-risk MDS syndromes treated with azacitidine compared with conventional care regimens (CCR). A total of 358 persons were randomized to receive azacitidine (n=179) or CCR (n=179). Approximately one-third of these individuals could be classified as having AML under WHO criteria. After a median follow-up of 20.1 months, median OS was 24.5 months for the azacitidine group versus 15 months for the CCR group. The 2 year overall survival rates were 50.8% and 26.2%, respectively. The most common grade 3-4 adverse events were peripheral cytopenias.

In 2010, Fenaux and colleagues performed further analysis of 113 elderly subjects (median age of 70 years) from their primary study who met WHO criteria for AML. These individuals had been randomized to azacitidine (n=55) or CCR (n=58). A total of 86% were deemed "unfit" to receive intensive chemotherapy. After a median follow-up period of 20.1 months, median OS for those treated with azacitidine was 24.5 months as compared to 16 months for those treated with CCR considered unfit for intensive chemotherapy. The 2 year OS rates were 50% and 16%, respectively. The most common grade 3 or 4 hematologic adverse events were thrombocytopenia, neutropenia and anemia.

Dombret and colleagues (2015) performed a multi-center, randomized, open-label, phase III trial that evaluated azacitidine safety and efficacy versus CCR in 488 individuals 65 years or older with newly diagnosed AML with greater than 30% bone marrow blasts. Prior to randomization, a CCR consisting of standard induction chemotherapy, low-dose ara-c, or supportive care only was preselected for each person. Participants were then assigned 1:1 to azacitidine (n=241) or CCR (n=247). Median OS was increased with azacitidine versus CCR: 10.4 months (95% confidence interval [CI], 8.0-12.7 months) vs 6.5 months (95% CI, 5.0-8.6months), respectively. Survival rates at 1 year with azacitidine and CCR were 46.5% and 34.2%, respectively. A prespecified analysis of subjects who received AML treatment after discontinuing study drug showed median OS with azacitidine versus CCR was 12.1 months (95% CI, 9.2-14.2 months) versus 6.9 months (95% CI, 5.1-9.6 months). Univariate analysis showed favorable trends for azacitidine compared with CCR across all subgroups defined by baseline demographic and disease features. Adverse events were consistent with the established safety profile of azacitidine. The authors concluded that study results were encouraging and suggested that azacitidine may provide an additional treatment option for elderly individuals with newly diagnosed AML.

The NCCN Drugs and Biologics compendium (2017) addresses the use of azacitidine (2A recommendations) for AML, including single agent use for low intensity therapy in individuals 60 years of age and older as induction therapy or post remission therapy, and for use as therapy for relapsed or refractory disease in individuals who cannot tolerate more aggressive regimens as a single agent; or in combination with sorafenib (FLT3-ITD mutation positive). Additionally, the NCCN Drugs and Biologics compendium (2017) addresses using azacitidine for treatment of lower and higher risk MDS under specific circumstances.

Contraindications, Warnings, Precautions and Adverse Events (Vidaza Prescribing Information, 2016)

  Contraindications:

Warnings and Precautions:

Adverse Reactions:
Most common adverse reactions (>30%) by SC route are: nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia and ecchymosis. Most common adverse reactions by IV route also included petechiae, rigors, weakness and hypokalemia.

Definitions

French American British (FAB) myelodysplastic syndrome subtypes: A classification of myelodysplastic syndrome subtypes based on bone marrow appearance and blood cell counts. The FAB system consists of 5 subtypes of MDS:

International Prognostic Scoring System (IPSS)a,b :

Survival and AML evolution
  Score value
Prognostic variable 0 0.5 1.0 1.5 2.0
Marrow blasts (%)c < 5 5-10 --- 11-20 21-30
Karyotyped Good Intermediate Poor

 

 

Cytopeniae 0/1 2/3

 

 

 

 

IPSS Risk category Overall Risk Score
Low

0

INT-1

0.5-1.0

INT-2

1.5-2.0

High

≥2.5

a Greenberg P, Cox C, LeBeau M, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89:2079-2088.
b Greenberg P, Cox C, LeBeau M, et al. Erratum. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1998; 91:1100.
c Patients with 20-30 % blasts may be considered as MDS or AML.
d Cytogenetics: Good = normal, -Y alone, del(5q) alone, del(20q) alone; Poor = complex (³ 3 abnormalities) or chromosome 7 anomalies; Intermediate = other abnormalities. [This excludes karyotypes t(8;21), inv16, and t(15;17), which are considered to be AML not MDS.]
e Cytopenias: neutrophil count <1,800/mcL, platelets < 100,000/mcL, Hb < 10g/dL

International Prognostic Scoring System-Revised (IPSS-R) F

  Score value
Prognostic variable

0

0.5

1.0

1.5

2

3

4

Cytogenetics

Very good

n/a

Good

n/a

Intermediate

Poor

Very poor
Bone marrow blasts %

≤ 2

n/a

> 2% to < 5%

n/a

5-10

>10

n/a

Hemoglobin

≥ 10

n/a

8 to < 10

< 8

n/a

n/a

n/a

Platelets

≥ 100

50 to < 100

< 50

n/a

n/a

n/a

n/a

ANC

≥ 0.8

< 0.8

n/a

n/a

n/a

n/a

n/a

ANC – Absolute neutrophil count
n/a – not applicable

IPSS-R Risk category Overall Risk
Score
Very low

≤ 1.5

Low

> 1.5 to 3

Intermediate

> 3.0 to 4.5

High

> 4.5 to 6

Very high

> 6

f Greenberg P, Heinz T, Schanz J, et al. Revised International Prognostic Scoring System for Myelodysplastic Syndromes. Blood. 2012;120: 2454-2465.

Myelodysplastic syndrome (MDS): A condition that occurs when the blood-forming cells in the bone marrow are damaged.

World Health Organization (WHO) Classification Systems:

WHO 2016 Classification for MDS (NCCN, 2017)

Subtype Blood Bone marrow
MDS with single lineage dysplasia (MDS-SLD) Single or bicytopenia Dysplasia in greater than or equal to 10% of one cell line, less than 5% blasts
MDS with ring sideroblasts (MDS-RS) Anemia, no blasts Greater than or equal to 15% of erythroid precursors with ring sideroblasts, or greater than or equal to 5% ring sideroblasts if SF3B1 mutation present.
MDS with multilineage dysplasia (MDS-MLD) Cytopenia(s), less than 1 x 109 /L monocytes Dysplasia in greater than or equal to 10% of cells in greater than or equal to 2 hematopoietic lineages, ± 15% ring sideroblasts, less than 5% blasts
MDS with excess blasts–1 (MDS-EB-1) Cytopenia(s), less than or equal to 2-4% blasts, less than 1 x 109 /L monocytes Unilineage or multilineage dysplasia, 5% to 9% blasts, no Auer rods
MDS with excess blasts–2 (MDS-EB-2) Cytopenia(s) 5-19% blasts, less than 1 x 109 /L monocytes Unilineage or multilineage dysplasia, 10% to 19% blasts, ± Auer rods
MDS, unclassifiable (MDS-U) Cytopenias, ±1% blasts on at least 2 occasions Unilineage dysplasia or no dysplasia but characteristic MDS cytogenetics, less than 5% blasts
MDS associated with isolated del(5q) Anemia, platelets normal or increased Unilineage erythroid dysplasia, isolated del 5(q), less than 5% blasts
Refractory cytopenia of childhood Cytopenias, less than 2% blasts Dysplasia in 1-3 lineages, less than 5% blasts
MDS with excess blasts in transformation (MDS-EB-T) Cytopenias, 5%-19% blasts Multilineage dysplasia, 20%-29% blasts, ± Auer rods

WHO Classification Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) (NCCN, 2017)

Subtype Blood Bone Marrow
Chronic myelomonocytic leukemia (CMML)-0 Greater than 1 x 109 /L monocytes, less than 2% blasts Dysplasia in greater than or equal to 1 hematopoietic line, less than 5% blasts
Chronic myelomonocytic leukemia (CMML)-1 Greater than 1 x 109 /L monocytes, 2-4% blasts Dysplasia in greater than or equal to 1 hematopoietic line, 5-9% blasts
CMML-2 Greater than 1 x 109 /L monocytes, 5-19% blasts or Auer rods Dysplasia in greater than or equal to 1 hematopoietic line, 10-19% blasts or Auer rods
Atypical chronic myeloid leukemia (CML), BCR-ABL 1 negative WBC greater than 13 x 109 /L, neutrophil precursors greater than 10%, less than 20% blasts, dysgranulopoiesis Hypercellular, less than 20% blasts

Chronic neutrophilic leukemia (CNL)

 

WBC greater than or equal to 25,000 with PMN/bands greater than or equal to 80%, no dysplasia Mature myeloid hyperplasia, less than 5% blasts, no dysplasia
Juvenile myelomonocytic leukemia (JMML) Greater than 1 x 109 /L monocytes, less than 20% blasts Greater than 1 x 109 /L monocytes, less than 20% blasts
MDS/MPN, unclassifiable (overlap syndrome) Dysplasia + myeloproliferative features, no prior MDS or MPN Dysplasia + myeloproliferative features
MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) Dysplasia + myeloproliferative features, platelets greater than or equal to 450 x 109 /L, greater than or equal to 15% ring sideroblasts Dysplasia + myeloproliferative features

WHO-Based Prognostic Scoring System (WPSS) (NCCN, 2017)g :

Variable

Variable scores

0

1

2

3

WHO category

RCUD, RARS, MDS with isolated deletion (5q)

RCMD

RAEB-1

RAEB-2

Karyotype

Good

Intermediate

Poor

n/a

Severe anemia (hemoglobin < 9 g/dl in males or < 8g/dl in females)

Absent

Present

n/a

n/a

 

WPSS Risk

Sum of individual variable scores

Median survival (y) from diagnosis

Median time (y) to AML progression from diagnosis

Very low

0

11.6

Not recorded

Low

1

9.3

14.7

Intermediate

2

5.7

7.8

High

3-4

1.8

1.8

Very high

5-6

1.1

1.0

g Malcovati L, Della Porta MG, Strupp C, et al. Impact of the degree of anemia on the outcome of patients with myelodysplastic syndrome and its integration into the WHO classification-based Prognostic Scoring System (WPSS). Haematologica. 2011; 96(10):1433-1440.

References

Peer Reviewed Publications:

  1. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016; 127(20):2391-2405.
  2. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015; 126(3):291-299.
  3. Fenaux P, Mufti GJ, Hellström-Lindberg E, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010; 28(4):562-569.
  4. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al; International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009; 10(3):223-232.
  5. Greenberg P, Cox C, LeBeau M, et al. Erratum. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1998; 91:1100.
  6. Greenberg P, Cox C, LeBeau M, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89:2079-2088.
  7. Greenberg P, Heinz T, Schanz J, et al. Revised International Prognostic Scoring System for Myelodysplastic Syndromes. Blood. 2012; 20: 2454-2465.
  8. Kornblith AB, Herndon JE 2nd, Silverman LR, et al. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol. 2002; 20(10):2441-2452.
  9. Malcovati L, Della Porta MG, Strupp C, et al. Impact of the degree of anemia on the outcome of patients with myelodysplastic syndrome and its integration into the WHO classification-based Prognostic Scoring System (WPSS). Haematologica. 2011; 96(10):1433-1440.
  10. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002; 20(10):2429-2440.
  11. Silverman LR, McKenzie DR, Peterson BL, et al; Cancer and Leukemia Group B. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol. 2006; 24(24):3895-3903.
  12. Sudan N, Rossetti JM, Shadduck RK, et al. Treatment of acute myelogenous leukemia with outpatient azacitidine. Cancer. 2006; 107(8):1839-1843.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Azacitidine Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS® ) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised May 11, 2011. Accessed on February 13, 2017.
  2. Azacitidine (systemic). In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated December 19, 2016. Available at: http://www.micromedexsolutions.com. Accessed on February 13, 2017.
  3. Kaminskas E, Farrell A, Abraham S, et al; FDA. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res. 2005; 11(10):3604-3608.
  4. National Comprehensive Cancer Network® . NCCN Drugs & Biologic Compendium™ (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on February 13, 2017.
  5. NCCN Clinical Practice Guidelines in Oncology™. © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on February 13, 2017.
    • Acute Myeloid Leukemia (V.2.2016). Revised June 29, 2016.
    • Myelodysplastic Syndromes (V.2.2017). Revised November 10, 2016.
  6. Vidaza® [Product Information]. Summit, NJ. Celgene Corporation. August 2016. Available at: http://www.vidaza.com/pi.pdf. Accessed on February 13, 2017.
Websites for Additional Information
  1. National Cancer Institute. Available at: http://www.cancer.gov/. Accessed on February 13, 2017.
    • Acute Myeloid Leukemia Treatment (PDQ). Last modified January 20, 2017.
    • Myelodysplastic Syndromes Treatment (PDQ). Last modified April 2, 2015.
Index

Aza C

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

Reviewed 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review.
Reviewed 05/03/2017 Hematology/Oncology Subcommittee review. Description, Discussion, Definitions and References sections updated.
New 05/05/2016 MPTAC review.
New 05/04/2016 Hematology/Oncology Subcommittee review. Initial document development.