0963 Luspatercept-aamt (Reblozyl) · treatment for iron overload due to the transfusions. On...

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Luspatercept-aamt (Reblozyl)

Number: 0963

Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.

Note: REQUIRES PRECERTIFICATION

Precertification of Reblozyl is required of all Aetna participating

providers and members in applicable plan designs. For

precertification of luspatercept–aamt, call (866) 752-7021

(Commercial), (866) 503-0857 (Medicare), or fax (866) 267-

3277.

Aetna considers luspatercept–aamt (Reblozyl) medically

necessary for

I. The treatment of anemia with beta thalassemia when all

of the following criteria are met:

A. The member has symptomatic anemia evidenced by

a pretreatment or pretransfusion Hgb level less than

or equal to 11 grams per deciliter; and

B. The member has a diagnosis of beta thalassemia

(β-thalassemia) or hemoglobin E/β-thalassemia

(β-thalassemia with mutation and/or multiplication

of alpha globin is allowed) confirmed by hemoglobin Proprietary

Policy History

Last Review

06/09/2020

Effective: 02/13/2020

Next

Review: 10/25/2020

Review History

Definitions

Ad d i t ion al Information

Clinical Policy Bulletin

Notes

http://www.aetna.com/)


electrophoresis or high-performance liquid

chromatography (HPLC); and

C. The member required at least 6 red blood cell (RBC)

units transfused in the previous 24 weeks.

II. The treatment of very low- to intermediate-risk

myelodysplastic syndrome or

myelodysplastic/myeloproliferative neoplasm when all

of the following criteria are met:

A. The member has symptomatic anemia evidenced by

a pretreatment or pretransfusion Hgb level less than

or equal to 11 grams per deciliter; and

B. The member has been receiving regular RBC

transfusions; and

C. The member meets either of the following:

1. Ring sideroblasts are greater than or equal to

15%; or

2. Ring sideroblasts are greater than or equal to 5%

and less than 15% and the patient has an SF3B1

mutation; and

D. The member meets either of the following:

1. Pretreatment serum erythropoietin levels greater

than 500 mU/mL; or

2. Pretreatment serum erythropoietin levels less

than or equal to 500mU/mL following no

response to the combination of an

erythropoiesis-stimulating agent (ESA) and

granulocyte-colony stimulating factor (G-CSF).

Aetna considers continued treatment with luspatercept–aamt

(Reblozyl) medically necessary in members requesting

authorization for anemia with beta

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thalassemia, myelodysplastic syndrome or

myelodysplastic/myeloproliferative neoplasm when the all of

the following criteria are met:

I. Member must achieve or maintain red blood cell

transfusion burden reduction; and

II. Member must not experience an unacceptable toxicity

from Reblozyl; and

III. Member must have a pre-dose Hgb level less than or

equal to 11 grams per deciliter; if the Hgb level is

greater than 11 grams per deciliter, the prescriber

agrees to hold the dose until the level falls to 11 grams

per deciliter.

Note: For initial therapy and continuation of therapy, if a red

blood cell (RBC) transfusion occurred prior to dosing, the

pretransfusion hemoglobin (Hgb) level must be considered for

dosing purposes.

Aetna considers luspatercept–aamt (Reblozyl) experimental

and investigational for the following

I. Members with hemoglobin S/β-thalassemia or alpha-

thalassemia;

II. Members with recent deep vein thrombosis or stroke

(defined as less than or equal to 24 weeks prior to

initiation of Reblozyl therapy);

III. Members with platelet count greater than 1000 x 109 per

liter (i.e., greater than 1 million per microliter).

Dosing Recommendations

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The recommended starting dose is 1 mg/kg once every 3

weeks by subcutaneous injection. Review hemoglobin (Hgb)

results prior to each administration.

Source: Celgene 2020.

Background

Beta Thalassemia

Beta thalassemia, also called “Cooley’s anemia,” is an

inherited blood disorder that reduces the production of

hemoglobin, an iron-containing protein in red blood cells that

carries oxygen to cells throughout the body. In beta

thalassemia, low levels of hemoglobin lead to a lack of oxygen

in many parts of the body and anemia, causing pale skin,

weakness, fatigue and more serious complications. People

with beta thalassemia are also at an increased risk of

developing abnormal blood clots. Supportive treatment for

people with beta thalassemia often consists of lifelong

regimens of chronic blood transfusions for survival and

treatment for iron overload due to the transfusions.

On November 08, 2019, the U.S. Food and Drug

Administration approved Reblozyl (luspatercept–aamt) for the

treatment of anemia (lack of red blood cells) in adult patients

with beta thalassemia who require regular red blood cell (RBC)

transfusions. Reblozyl was approved by the FDA with both a

fast track and orphan drug designations. Reblozyl was

approved based on the results of a multicenter, randomized,

double-blind, placebo-controlled trial in which (n=336) patients

with beta thalassemia requiring regular red blood cell

transfusions (6-20 RBC units per 24 weeks) with no transfusion-

free period greater than 35 days during that period were

randomized 2:1 to Reblozyl (n=224) or placebo (n=112)

(BELIEVE Trial; NCT02604433). Reblozyl was administered

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subcutaneously once every 3 weeks as long as a reduction in

transfusion requirement was observed or until unacceptable

toxicity. All patients were eligible to receive best supportive

care, which included RBC transfusions; iron-chelating agents;

use of antibiotic, antiviral, and antifungal therapy; and/or

nutritional support, as needed. The trial excluded patients with

hemoglobin S/β-thalassemia or alpha-thalassemia, had major

organ damage (liver disease, heart disease, lung disease,

renal insufficiency), and patients with recent deep vein

thrombosis or stroke or recent use of ESA,

immunosuppressant, or hydroxyurea therapy. The median age

was 30 years (range: 18-66). The trial was comprised of

patients who were 42% male, 54.2% white, 34.8% Asian, and

0.3% Black or African American. The percent of patients

reporting their race as “other” was 7.7%, and race was not

collected or reported for 3% of patients (Reblozyl prescribing

information, 2019).

The primary efficacy endpoint of Reblozyl in adult patients with

beta thalassemia was the proportion of patients achieving

RBC transfusion burden reduction (≥33% reduction from

baseline) with a reduction of at least 2 units from Week 13 to

Week 24. Twenty-one percent of the patients who received

Reblozyl achieved at least a 33% reduction in transfusions

compared to 4.5% of the patients who received a placebo (risk

difference: 17; 95% CI: 10.4, 23.6); p < 0.0001) from Week 13

to Week 24. From Week 37 to Week 48, 19.6 percent of

patients who received Reblozyl achieved at least a 33%

reduction in transfusions compared to 3.6% of patients who

received placebo (risk difference: 16.1; 95% CI: 9.8, 22.4); p <

0.0001). The proportion of patients achieving RBC transfusion

burden reduction (≥50% reduction from baseline) with a

reduction of at least 2 units for 12 consecutive weeks was also

greater with Reblozyl (7.6%) compared to placebo (1.8%) from

Week 13 to Week 24 (risk difference: 5.8; 95% CI: 1.6, 10.1);

p = 0.0303) and from Week 37 to Week 48 (10.3% with

Reblozyl compared with 0.9% with placebo; risk difference:

9.4; 95% CI: 5, 13,7); p = 0.0017. The transfusion reduction

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meant that the patient needed fewer transfusions over 12

consecutive weeks while taking Reblozyl (Reblozyl prescribing

information, 2019).

In their open-label, nonrandomized, uncontrolled study, Piga et

al (2019; NCT01749540 and NCT02268409) aimed to

determine whether luspatercept could improve anemia and

disease complications in patients with β-thalassemia. This

study consisted of a 24-week dose-finding and expansion

stage (initial stage) and a 5-year extension stage, currently

ongoing. Sixty-four patients were enrolled; 33 were non-

transfusion dependent (mean hemoglobin,


Common side effects for patients taking Reblozyl were

headache, bone pain, arthralgia (joint pain), fatigue, cough,

abdominal pain, diarrhea and dizziness. Patients may

experience hypertension while using Reblozyl. Health care

professionals are advised to monitor a patient’s blood pressure

during treatment and to initiate anti-hypertensive treatment if

necessary. Patients who receive Reblozyl should be monitored

for thrombosis (blood clots). The FDA advises health care

professionals to tell females of reproductive age to use

effective contraception during treatment with Reblozyl. Women

who are pregnant or breastfeeding should not take Reblozyl

because it may cause harm to a developing fetus or newborn

baby (Reblozyl prescribing information, 2019).

Myelodysplastic Syndromes

On April 3, 2020, the Food and Drug Administration approved

luspatercept-aamt (Reblozyl, Celgene Corporation) for the

treatment of anemia failing an erythropoiesis stimulating agent

and requiring 2 or more red blood cell (RBC) units over 8

weeks in adult patients with very low- to intermediate-risk

myelodysplastic syndromes with ring sideroblasts (MDS-RS)

or with myelodysplastic/myeloproliferative neoplasm with ring

sideroblasts and thrombocytosis (MDS/MPN-RS-T). Efficacy

was demonstrated in the MEDALIST trial by Fenaux et al

(NCT02631070). Fenaux et al (2020; NCT02631070;) stated

patients with anemia and lower-risk myelodysplastic

syndromes in whom erythropoiesis-stimulating agent therapy

is not effective generally become dependent on red-cell

transfusions. Luspatercept, a recombinant fusion protein that

binds transforming growth factor β superfamily ligands to

reduce SMAD2 and SMAD3 signaling, showed promising

results in a phase 2 study. This double-blind, placebo-

controlled, phase 3 trial randomly assigned patients with very-

low-risk, low-risk, or intermediate-risk myelodysplastic

syndromes (defined according to the Revised International

Prognostic Scoring System) with ring sideroblasts who had

been receiving regular red-cell transfusions to receive

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either luspatercept (at a dose of 1.0 up to 1.75 mg per

kilogram of body weight) or placebo, administered

subcutaneously every 3 weeks. The primary end point was

transfusion independence for 8 weeks or longer during weeks

1 through 24, and the key secondary end point was

transfusion independence for 12 weeks or longer, assessed

during both weeks 1 through 24 and weeks 1 through 48. Of

the 229 patients enrolled, 153 were randomly assigned to

receive luspatercept and 76 to receive placebo; the baseline

characteristics of the patients were balanced. Transfusion

independence for 8 weeks or longer was observed in 38% of

the patients in the luspatercept group, as compared with 13%

of those in the placebo group (P

Treatment of lower risk* disease associated with symptomatic

anemia with ring sideroblasts ≥15% (or ring sideroblasts ≥5%

with an SF3B1 mutation) [2A]

▪ with serum erythropoietin >500 mU/mL

▪ with serum erythropoietin ≤500 mU/mL following no

response to the combination of an erythropoiesis-

stimulating agent (ESA) and granulocyte-colony

stimulating factor (G-CSF)

*Lower risk defined as IPSS-R (Very Low, Low, Intermediate),

IPSS (Low/Intermediate-1), WPSS (Very Low, Low,

Intermediate)

CPT Codes / HCPCS Codes / ICD-10 Codes

Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":

Code Code Description

Other CPT codes related to the CPB:

96372 Therapeutic, prophylactic, or diagnostic

injection (specify substance or drug);

subcutaneous or intramuscular

HCP CS codes covered if selection criteria are met:

Luspatercept-aamt (Reblozyl) - no specific code

ICD-10 codes covered if selection criteria are met:

D46.0 -

D46.Z

Myelodysplastic syndromes

D56.1 Beta thalassemia

D56.5 Hemoglobin E-beta thalassemia

ICD-10 codes not covered for indications listed in the CPB ( no t all-inclusive):


Proprietary

D56.0 Alpha thalassemia

D56.3 Thalassemia minor

D56.8 D56.8

I82.401 -

I82.91

Deep vein thromboses (DVT)

I63.00 -

I63.9

Cerebral infarction (Stroke)


Code Code Description

The above policy is based on the following references:

1. Benz EJ. Clinical manifestations and diagnosis of the

thalassemias. UpToDate [online serial]. Waltham, MA:

UpToDate; reviewed November 2019.

2. Celgene Corporation. Reblozyl (luspatercept-aamt) for

injection, for subcutaneous use. Prescribing

Information. Summit, NJ; revised November 2019.

3. Celgene Corporation. Reblozyl (luspatercept-aamt) for

injection, for subcutaneous use. Prescribing

Information. Summit, NJ; revised April 2020.

4. Fenaux P., Platzbecker U, Mufti GJ, et.al. Luspatercept

in Patients with Lower-Risk Myelodysplastic

Syndromes. N Engl J Med 2020;382:140-51

5. National Comprehensive Cancer Network (NCCN).

Reblozyl. NCCN Drugs and Biologics Compendium.

Fort Washington, PA: NCCN; 2019.

6. Piga A, Perrotta S, Gamberini MR, et al. Luspatercept

improves hemoglobin levels and blood transfusion

requirements in a study of patients with

β-thalassemia. Blood. 2019;133(12):1279-1289.

Proprietary


7. U.S. Food and Drug Administration (FDA). FDA

approves first therapy to treat patients with rare blood

disorder. FDA News Release. Silver Spring, MD: FDA;

November 08, 2019. Available at:

https://www.fda.gov/news-events/press-

announcements/fda-approves-first-therapy-treat-

patients-rare-blood-disorder. Accessed November 15,

2019.

8. U.S. National Library of Medicine. ClinicalTrials.gov. An

Efficacy and Safety Study of Luspatercept (ACE-536)

Versus Placebo in Adults Who Require Regular Red

Blood Cell Transfusions Due to Beta (β) Thalassemia

(BELIEVE).

https://clincialtrials.gov/ct2/show/NCT02604433.

Accessed 11/14/2019.

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http://www.fda.gov/news-events/press-https://clincialtrials.gov/ct2/show/NCT02604433http:ClinicalTrials.gov


Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan

benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,

general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care

services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors

in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely

responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is

subject to change.

Copyright © 2001-2020 Aetna Inc.

Proprietary

AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment to Aetna Clinical Policy Bulletin Number: 0963 Luspatercept

aamt (Reblozyl)

There are no amendments for Medicaid.

www.aetnabetterhealth.com/pennsylvania revised 06/09/2020

Proprietary

http://www.aetnabetterhealth.com/pennsylvania

Luspatercept-aamt (Reblozyl)Background The above policy is based on the following references: Back Cover

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