Clinical UM Guideline

 

Subject: Azacitidine (Vidaza®)
Guideline #:  CG-DRUG-48 Publish Date:    06/27/2019
Status: Revised Last Review Date:    06/25/2019

Description

This document addresses azacitidine (Vidaza, Celgene Corporation, Summit, NJ), 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 venetoclax for individuals 75 years of age and older or individuals who cannot tolerate more aggressive regimens; or
    3. Used in combination with sorafenib for relapsed or refractory AML with FLT3-ITD mutations; or
    4. 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

C93.00-C93.02

Acute monoblastic/monocytic leukemia

C93.10-C93.12

Chronic myelomonocytic leukemia

C94.00-C94.02

Acute erythroid leukemia

C94.20-C94.22

Acute megakaryoblastic leukemia

C94.40-C94.42

Acute panmyelosis with myelofibrosis

C94.6

Myelodysplastic disease, not classified

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

D47.1

Chronic myeloproliferative disease

D47.4

Osteomyelofibrosis

D75.81

Myelofibrosis

Discussion/General Information

On May 19, 2004, Azacitidine (Vidaza) received FDA approval for the treatment of the following French American British (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 red blood cell (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.

In 2017, Chou and colleagues studied the safety and efficacy of azacitidine in Taiwanese subjects with high risk MDS in a multicenter, open-label, single arm, phase IV study. The primary endpoint was hematologic response and hematologic improvement (HI). Subjects received azacitidine 75 mg/m2/day for 7 days/28-day cycle for up to 6 cycles, and had baseline and cycle 6 marrow assessments. Out of 44 initially enrolled, 25 subjects (57%) completed the study. The authors found that 22 subjects (50%) achieved HI. Some limitations to this study include small sample size and 25% of subjects not evaluated for hematologic response (primary endpoint) due to no post-baseline bone marrow assessment.

Du and colleagues (2017) evaluated the safety, efficacy, and pharmacokinetics of azacitidine in Chinese subjects with high risk MDS in a multicenter, single-arm, open-label phase II study. The authors’ primary outcome was response rate, which included complete remission, partial remission, and stable disease. A total of 72 subjects enrolled in the study and 39 subjects (54%) completed more than 6 treatment cycles. Results showed an overall response rate of 96% with complete remission being 1%, partial remission being 0%, and stable disease being 94%. The authors conclude that azacitidine provides clinical benefit to Chinese subjects with high risk MDS.

A meta-analysis was performed by Komrokji and colleagues (2017) to evaluate azacitidine in subjects with RBC transfusion-dependent low risk MDS. The endpoints for the meta-analysis were RBC transfusion independence (TI) and Clinical Benefit (RBC-TI, erythroid response, and complete or partial remission). The search for publications between 2000 and 2015 yielded data for 233 subjects from 6 clinical studies and 1 registry study. The authors found that 90.3% of subjects had non-deletion (5q) low risk MDS. In addition, “pooled estimates from random-effects models of RBC-TI and Clinical Benefit were 38.9% and 81.1%, respectively; for the ESA-refractory subgroup, they were 40.5% and 77.3%; and for patients with isolated anemia, they were 41.9% and 82.5%” (Komrokji, 2017). Study limitations noted by the authors include an imbalance in subject numbers due to the majority of subject data coming from the registry study and some subject demographic characteristics and pretreatment data were not available.

Ram and colleagues (2017) studied treatment with azacitidine in elderly and infirm subjects with AML with either induction refractory or relapse disease. This retrospective study aimed to assess progression-free and overall survival in 34 subjects. The assessment showed “at 12 and 18 months after the first course of azacitidine, 33 and 10% of the patients were progression-free, respectively. Incidences of overall survival at 12 and 24 months were 54.5 and 16%, respectively” (Ram, 2017). Retrospective design and small sample size are noted as study limitations. The authors conclude that prospective studies are needed to validate the results.

In 2018, Maurillo and colleagues reported on an observational, retrospective study that compared the efficacy of azacitidine and intensive chemotherapy in individuals greater than or equal to age 60 years with untreated AML. Complete remission, OS, and disease-free survival (DFS) were assessed in the two groups [azacitidine group (n=74) treated between June 2005 and December 2013, and intensive chemotherapy control group (n=74) treated between May 2000 and December 2010] after adjustments were made using the propensity-score matching method to minimize treatment selection bias. The data showed the complete remission rate was 73% and 25% for the intensive chemotherapy control group and the azacitidine group, respectively (p<0.0001). There were no significant differences found between the 3-year OS rates and the median OS rates (21.6 versus 11% and 15.8 versus 13 months, respectively). Also, no significant difference was found in individuals who achieved DFS in the intensive chemotherapy control group (n=58) and the azacitidine group (n=31) (11.5 versus 9.8 months, respectively). Due to the retrospective study design, and potential selection and confounding biases, controlled, randomized trials are needed to validate these findings.

Also in 2018, Sanchez-Garcia and colleagues published a multicenter randomized open-label study with the aim to compare the efficacy of azacitidine (n=20) versus best supportive care (BSC) (n=20) in lower-risk myelodysplastic syndromes (LR-MDS) lacking del(5q). The primary endpoint was erythroid hematologic improvement (HI-E) after 9 months. The secondary endpoints were achievement of TI, neutrophils HI (HI-N), platelets HI (HI-P), progression to AML, OS, health-related quality of life (HRQoL) and safety. Of the 40 individuals included, 28 (70%) completed the study (azacitidine group: n=14; BSC group: n=14); however, the evaluators included those who completed at least one of the nine cycles of azacitidine (n=18) or BSC treatment (n=18) in the reported data. The primary endpoint of HI-E was confirmed in 8 individuals in the azacitidine group (44.4%) and 1 individual in the BSC group (5.5%) (p=0.018, 95% CI: 0.015-0.021). No significant differences were found in the secondary endpoints except achievement of TI, which was confirmed in 6 individuals in the azacitidine group (33.3%) and 1 individual in the BSC group (5.5%) (p=0.012). In regards to safety, manageable hematological toxicity was found in 52.2% of individuals and severe adverse events occurred in 7 individuals (38.8%) in the azacitidine group. In the BSC group, 8 individuals (44.4%) also experienced adverse events.

Huls and colleagues (2019) published a randomized phase III study that evaluated azacitidine as post remission therapy in older individuals (greater than 60 years of age) with AML or MDS-RAEB. Individuals were randomized into the azacitidine group (n=56) or the observation group (n=60). One individual had a relapse before the start of the azacitidine treatment. Those in the azacitidine group received up to 12 cycles unless there was relapse [55 individuals received at least 1 cycle of azacitidine (98%), 46 individuals received at least 4 cycles (82%), and 35 individuals at least 12 cycles (63%)]. Of the 60 individuals in the observation group, 23 (38%) completed the observation protocol treatment without relapse. The primary endpoint of DFS was found to be significantly better in the azacitidine group (64%) versus the observation group (42%) at 12 months (p=0.04). No significant improvement was found in OS (84% versus 70% at 12 months; p=0.69). There were several limitations to this study, which included a low randomization rate over 7.5 years and study protocol treatment limit of 1 year instead of given until progression.

Also in 2019, DiNardo and colleagues released the results of a multicenter, phase 1b dose-escalation and expansion study that aimed to assess the safety and efficacy of venetoclax with decitabine or azacitidine. The study included 145 individuals who were at least 65 years of age, did not have prior treatment for AML, and were ineligible for intensive chemotherapy. “Sixty patients received venetoclax 400 mg (29 with azacitidine, 31 with decitabine), 74 received venetoclax 800 mg (37 each azacitidine or decitabine), and 11 received venetoclax 1200 mg (6 azacitidine, 5 decitabine)” (DiNardo, 2019). The median time for the study was 8.9 months with a median follow-up of 15.1 months. Common adverse events included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. Infections were reported in 107 (74%) participants, 10 (7%) of which resulted in death. A total of 101 (70%) individuals discontinued the study. Of the individuals in the azacitidine cohorts, 16 (22%) discontinued the study. Overall response rate (complete remission [CR] and complete remission with incomplete blood count recovery [Cri] and partial remission [PR]) was achieved in 99 (68%) individuals (all doses) in the intent-to-treat population (n=145). Specifically for the individuals treated with azacitidine, the overall response rate was achieved in 22 (76%) individuals in the venetoclax 400 mg cohort, 22 (59%) individuals in the venetoclax 800 mg cohort, and 2 individuals (33%) in the venetoclax 1200 mg cohort. The median OS of all individuals was 17.5 months (95% CI, 12.3 months-NR). For azacitidine treated individuals, the median OS was not reported for the venetoclax 400 mg cohort, 15.2 months (95% CI, 9.1-NR) for the venetoclax 800 mg cohort, and 8.8 months (95% CI, 0.9-NR) for the venetoclax 1200 mg cohort. The results of this study show venetoclax in combination with azacitidine is an effective treatment option with a tolerable safety profile for older individuals who cannot tolerate intensive remission induction therapy.

Venetoclax has been approved by the FDA for treatment of AML in combination with azacitidine in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy (Venclexta Prescribing Information, 2019).

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (2019) 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 (2019) addresses using azacitidine for treatment of lower and higher risk MDS under specific circumstances. Most recently, the NCCN (2019) added the recommendation of azacitidine in combination with venetoclax as induction or post-remission therapy for individuals 60 years of age and older who are not candidates for intensive remission induction therapy.

Contraindications, Warnings, Precautions and Adverse Events (Vidaza Prescribing Information, 2018)

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, 2018)

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, 2018)

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, 2018)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. Chou WC, Yeh SP, Hsiao LT, et al. Efficacy, safety, and pharmacokinetics of subcutaneous azacitidine in Taiwanese patients with higher-risk myelodysplastic syndromes. Asia Pac J Clin Oncol. 2017; 13(5): e430-e439.
  3. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naïve, elderly patients with acute myeloid leukemia. Blood. 2019; 133(1):7-17.
  4. 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.
  5. Du X, Lai YY, Xiao Z, et al. Efficacy, safety and pharmacokinetics of subcutaneous azacitidine in Chinese patients with higher risk myelodysplastic syndromes: Results from a multicenter, single-arm, open-label phase 2 study. Asia Pac J Clin Oncol. 2018; 14(3):270-278.
  6. 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.
  7. 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.
  8. Greenberg P, Cox C, LeBeau M, et al. Erratum. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1998; 91:1100.
  9. Greenberg P, Cox C, LeBeau M, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89:2079-2088.
  10. Greenberg P, Heinz T, Schanz J, et al. Revised International Prognostic Scoring System for Myelodysplastic Syndromes. Blood. 2012; 20: 2454-2465.
  11. Huls G, Chitu DA, Havelange V, et al. Azacitidine maintenance after intensive chemotherapy improves DFS in older AML patients. Blood. 2019; 133(13):1457-1464.
  12. Komrokji R, Swern AS, Grinblatt D, et al. Azacitidine in lower-risk myelodysplastic syndromes: a meta-analysis of data from prospective studies. Oncologist. 2018; 23(2):159-170.
  13. 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.
  14. 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.
  15. Maurillo L, Buccisano F, Spagnoli A, et al. Comparative analysis of azacitidine and intensive chemotherapy as front-line treatment of elderly patients with acute myeloid leukemia. Ann Hematol. 2018; 97(10):1767-1774.
  16. Ram R, Gatt M, Merkel D, et al. Second line azacitidine for elderly or infirmed patients with acute myeloid leukemia (AML) not eligible for allogeneic hematopoietic cell transplantation-a retrospective national multicenter study. Ann Hematol. 2017; 96(4):575-579.
  17. Sanchez-Garcia J, Falantes J, Medina Perez A, et al. Prospective randomized trial of 5 days azacitidine versus supportive care in patients with lower-risk myelodysplastic syndromes without 5q deletion and transfusion-dependent anemia. Leuk Lymphoma. 2018; 59(5):1095-1104.
  18. 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.
  19. 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.
  20. 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 June 13, 2019.
  2. Azacitidine (systemic). In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated October 2, 2018. Available at: http://www.micromedexsolutions.com. Accessed on June 13, 2019.
  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. NCCN Clinical Practice Guidelines in Oncology™. © 2019 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on June, 2019.
    • Acute Myeloid Leukemia (V3.2019). Revised May 7, 2019.
    • Myelodysplastic Syndromes (V2.2019). Revised October 18, 2018.
  5. Venclexta® [Product Information]. North Chicago, IL. AbbVie Inc. May 2019. Available at: https://www.rxabbvie.com/pdf/venclexta.pdf. Accessed on June 13, 2019.
  6. Vidaza® [Product Information]. Summit, NJ. Celgene Corporation. September 2018. Available at: http://www.vidaza.com/pi.pdf. Accessed on June 13, 2019.
Websites for Additional Information
  1. National Cancer Institute. Available at: http://www.cancer.gov/. Accessed on June 13, 2019.
    • Acute Myeloid Leukemia Treatment (PDQ). Updated February 8, 2019.
    • Myelodysplastic Syndromes Treatment (PDQ). Updated February 1, 2019.
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

Revised

06/25/2019

Medical Policy & Technology Assessment Committee (MPTAC) review. Added Medically Necessary criteria for use in combination with venetoclax for older individuals with relapsed or refractory AML. Discussion, References, and Websites sections updated.

Reviewed

03/21/2019

MPTAC review.

Reviewed

03/20/2019

Hematology/Oncology Subcommittee review. Discussion, References, and Websites sections updated. Updated Coding section with additional AML and MDS diagnosis codes.

Reviewed

05/03/2018

MPTAC review.

Reviewed

05/02/2018

Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date.” Updated formatting in the Clinical Indications section. Description, Discussion, References, and Websites sections updated.

Reviewed

05/04/2017

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.