CurrentAnthemPolicy CC-0156

Reblozyl (luspatercept) — Clinical coverage criteria

Clinical coverage criteria for use of Reblozyl (luspatercept) for adults with beta thalassemia, myelodysplastic syndromes (MDS) and related MDS/MPN diagnoses, and myelofibrosis-associated anemia, including initial and continuation requirements and quantity limits. Applies to Anthem medical benefit reviews and prior authorization.

Policy Summary

PayerAnthem

PolicyReblozyl (luspatercept) — Clinical coverage criteria

Policy CodePolicy CC-0156

Change TypeMaterial clinical updates and clarifications

Effective DateOct 1, 2025

Next Review Date

Key ActionSubmit prior authorization (J0896) with documentation of diagnosis, transfusion history, baseline hemoglobin, relevant labs (including serum EPO and SF3B1 when applicable), and response for continuation requests.

SourceLink

POLICY UPDATE CHANGES

Updated myelofibrosis-associated anemia indication and added combination use with JAK inhibitors (JAKi).

Added ESA refractory or relapse language to MDS coverage criteria.

Clarified documentation requirements for transfusion dependence definitions and baseline hemoglobin thresholds.

Consolidated and updated ICD-10 code ranges and descriptions.

6-20β-thalassemia RBC units (24 wks)

>=2MDS RBC units (8 wks)

≤11 g/dLBaseline Hgb threshold

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6 moInitial approval duration

12 moContinuation approval duration

1.75 mg/kgMax dose per 3 wks

Coverage Criteria for Reblozyl (luspatercept)

inv-01: β-thalassemia — Initial Therapy — Covered when ALL criteria are met

Covered when ALL of the following are met

ALL of the following

Age: Individual is 18 years of age or older
Diagnosis of beta thalassemia or hemoglobin E beta (E/β)-thalassemia
Transfusion dependence: Documentation is provided that individual required regular red blood cell transfusions at initiation6-20 RBC units in last 24 weeks AND no transfusion-free period >35 days in last 24 weeks
(NCT02604433)
Baseline Hgb: Baseline hemoglobin ≤ 11 g/dL≤ 11 g/dL

inv-02: β-thalassemia — Continuation Therapy — Covered when ALL criteria are met

Covered when ALL of the following are met

ALL of the following

Demonstrated benefit: Documentation of continued need for treatment and confirmation of response evidenced by a decrease in transfusion burden from baseline
Hemoglobin ≤ 11 g/dL≤ 11 g/dL

inv-03: β-thalassemia — Not approvable conditions — 1 top-level node

ANY of the following

Sickle beta thalassemia: Diagnosis of sickle beta thalassemia (S/β-thalassemia)
Alpha thalassemia: Diagnosis of alpha (α)-thalassemia
High platelet count: Platelet count greater than 1000 x10^9/L>1000 x10^9/L
Recent thrombotic event: History of deep vein thrombosis (DVT) or stroke within the last 24 weeks

inv-04: Myelofibrosis-associated anemia — Initial Therapy — Covered when ALL criteria are met (NCCN 2A supportive language)

Covered when ALL of the following are met (NCCN 2A supportive language)

ANY of the following

With symptoms on ruxolitinib: Diagnosis of myelofibrosis-associated anemia AND symptomatic splenomegaly and/or constitutional symptoms AND using in combination with ruxolitinib
NCCN 2A
No splenomegaly or constitutional symptoms: Diagnosis of myelofibrosis-associated anemia with no splenomegaly or constitutional symptoms
Controlled on JAKi: Patient with splenomegaly and constitutional symptoms well controlled on a JAK inhibitor and will use in combination with a JAK inhibitor

inv-05: Myelofibrosis-associated anemia — Continuation Therapy — Covered when ALL criteria are met

Covered when ALL of the following are met

ALL of the following

Demonstrated benefit: Documentation of continued need for treatment and confirmation of response evidenced by a decrease in transfusion burden from baseline

inv-06: MDS / MDS‑MPN (including MDS-RS, MDS/MPN-RS-T, MDS/MPN-T-SF3B1) — Initial Therapy — Covered when ALL criteria are met

Covered when ALL of the following are met

ALL of the following

Age: Individual is 18 years of age or older
Eligible diagnoses: One of: MDS-RS, MDS/MPN-RS-T, MDS, or MDS/MPN-T-SF3B1 (see subcriteria)
Transfusion dependence: Documentation is provided that individual required regular red blood cell transfusions≥2 units over 8 weeks in last 16 weeks
Baseline Hgb:

inv-07: MDS / MDS‑MPN — Not approvable conditions — 1 top-level node

ANY of the following

Inadequate ESA response or unresolved iron deficiency: Inadequate response to ESAs or unresolved iron deficiency (defined as serum ferritin ≤15 µg/L or transferrin saturation ≤20%) when applicable
(NCT02631070)
No response limit: Use beyond 9 weeks (administration of 3 consecutive doses) without response at maximum dose (1.75 mg/kg every 3 weeks)
Non-approvable
ESA-naïve exclusions: If ESA‑naïve: unresolved iron deficiency (serum ferritin <100 µg/L) or uncontrolled hypertension
Platzbecker et al.

Use of Reblozyl beyond 9 weeks (three consecutive doses) without evidence of response at the specified maximum labeled dose is not approved. For β‑thalassemia the nonresponse rule applies at a maximum dose of 1.25 mg/kg every 3 weeks. For MDS / MDS‑MPN (including MDS‑RS, MDS/MPN‑RS‑T, MDS/MPN‑T‑SF3B1) the nonresponse rule applies at a maximum dose of 1.75 mg/kg every 3 weeks. Specific diagnoses that are excluded from approval in β‑thalassemia include sickle beta thalassemia (S/β‑thalassemia) and alpha (α)-thalassemia, and other exclusions include platelet count > 1000 x10^9/L and recent thrombotic events (history of DVT or stroke within the last 24 weeks).

Therapy with Reblozyl is not medically necessary when the patient does not meet the documented diagnostic, transfusion, laboratory, or response criteria specified in this policy. Examples include inadequate transfusion history for the indicated diagnosis (e.g., not meeting the 6–20 RBC units in the last 24 weeks with no transfusion‑free period >35 days requirement for β‑thalassemia or ≥2 RBC units over 8 weeks in the last 16 weeks for MDS/MDS‑MPN), baseline hemoglobin above 11 g/dL, unresolved iron deficiency where defined, or lack of response after the required trial period (use beyond 9 weeks without response at the applicable maximum dose).

Drug / Strength	Quantity limit	Notes
Reblozyl (luspatercept) 25 mg vial; Reblozyl (luspatercept) 75 mg vial	Limit = 1.75 mg/kg per 3 weeks	Maximum dosing reference used in nonresponse rules: β‑thalassemia — 1.25 mg/kg every 3 weeks; MDS (as applicable) — 1.75 mg/kg every 3 weeks. Use beyond 9 weeks (three consecutive doses) without response at the specified maximum dose is non‑approvable.

Billing and Diagnosis Codes

HCPCSHCPCS

J0896

Injection, luspatercept-aamt, 0.25 mg [Reblozyl]

ICD-10 DiagnosisICD-10

C93.10	Chronic myelomonocytic leukemia, not having achieved remission
C94.40-C94.42	Acute panmyelosis with myelofibrosis
C94.6	Myelodysplastic disease, not elsewhere classified
D46.0-D46.9	Myelodysplastic syndromes
D47.1	Chronic myeloproliferative disease
D47.4	Osteomyelofibrosis
D56.1	Beta Thalassemia
D56.5	Hemoglobin E-Beta thalassemia
D75.81	Myelofibrosis

inv-12: Baseline Hemoglobin — ≤ 11 g/dL

Baseline hemoglobin thresholdBaseline hemoglobin (Hgb) level ≤ 11 g/dL

Measurement timingHgb assessed at baseline and for continuation requests (continuation requires Hgb ≤ 11 g/dL)

ApplicabilityRequired for β-thalassemia, MDS/MDS‑MPN, and myelofibrosis-associated anemia coverage criteria

inv-13: β‑thalassemia transfusion requirement — 6–20 RBC units in prior 24 weeks; no transfusion‑free period >35 days in prior 24 weeks

Transfusion count requirementReceived 6–20 RBC units in the last 24 weeks

Transfusion-free interval requirementNo transfusion‑free period greater than 35 days in the last 24 weeks

Provider Actions, Documentation, and Prior Authorization

Prior Authorization

Prior Authorization Required

Prior authorization is required for Reblozyl billed as HCPCS J0896 (luspatercept 0.25 mg). Requests must meet clinical criteria for approval and include required documentation to support medical necessity.

HCPCS: J0896 (Injection, luspatercept-aamt, 0.25 mg)

Documentation Required

Required Documentation

Provide documentation of diagnosis, transfusion history, treatment response, and relevant lab/ESA information. Include specific subtype for MDS/MDS‑MPN or confirmation of β‑thalassemia/hemoglobin E β‑thalassemia, baseline hemoglobin, and transfusion units and timing.

Diagnosis: specify MDS subtype (e.g., MDS‑RS, MDS/MPN‑RS‑T, MDS/MPN‑T‑SF3B1) or β‑thalassemia / hemoglobin E β‑thalassemia
Transfusion history: number of RBC units and dates (e.g., 6–20 units in last 24 weeks for β‑thalassemia; ≥2 units over 8 weeks in the last 16 weeks for MDS/MDS‑MPN)

Background

Reblozyl (luspatercept) is an erythroid maturation agent indicated for treatment of anemia in adults with transfusion‑dependent beta thalassemia and for selected lower‑risk myelodysplastic syndromes and related MDS/MPN diagnoses. It is administered by subcutaneous injection in the outpatient setting and reduces transfusion burden but does not eliminate the need for transfusions in all patients. This policy applies to adults (≥18 years) and defines specific transfusion dependence, baseline hemoglobin, and response criteria required for medical necessity and prior authorization review.

Definitions

inv-22: Transfusion dependence (β‑thalassemia) — Defined as receiving 6–20 RBC units in the last 24 weeks and having no transfusion‑free period greater than 35 days in the last 24 weeks.

DefinitionReceiving 6–20 RBC units in the last 24 weeks and having no transfusion‑free period greater than 35 days in the last 24 weeks

Use in criteriaDefines transfusion dependence for β‑thalassemia initial therapy eligibility

Supporting trial referenceDefinition referenced to NCT02604433 in policy text

inv-23: Transfusion dependence (MDS/MDS‑MPN) — Defined as requiring two or more RBC units over eight weeks within the last 16 weeks.

DefinitionRequiring two or more RBC units over eight weeks within the last 16 weeks

Use in criteriaDefines transfusion dependence for MDS/MDS‑MPN initial therapy eligibility

Line of Therapy

inv-25: first-line — 1 top-level node

ANY of the following

FDA indications: Indication consistent with FDA-approved labeling: anemia in adult patients with beta thalassemia requiring regular RBC transfusions; anemia in selected MDS patients including ESA‑naïve and ESA‑refractory lower‑risk MDS with ring sideroblasts
FDA labeling

Biomarker and Laboratory Requirements

inv-26: SF3B1 — Mutation positive when used to qualify lower ring sideroblast percentages or MDS/MPN-T-SF3B1

Role of SF3B1SF3B1 mutation must be documented and is required when qualifying lower ring sideroblast percentages (5–14%) or for MDS/MPN‑T‑SF3B1

When applicableUsed to qualify MDS‑RS with 5–14% ring sideroblasts and to define MDS/MPN‑T‑SF3B1 subtype eligibility

DocumentationProvide molecular testing result showing SF3B1 mutation positive when used for eligibility

inv-27: Serum EPO — ≤ 500 U/L (with different ESA‑naïve and post‑ESA response implications)

ThresholdSerum erythropoietin (EPO) level ≤ 500 U/L

ContextRequired for MDS indications: applicable for ESA‑naïve status or to document lack of ESA response per MDS criteria

Revision History

2025-08-15Annual review — material updateLatest

Updated myelofibrosis-associated anemia indication and added combination use with JAK inhibitors; added ESA refractory or relapse language to MDS coverage criteria; administrative documentation updates recorded.

2024-08-16Annual review — content expansion

Added MDS-RS criteria updates (including del(5q) wording), added MDS to continuation therapy, added myelofibrosis-associated anemia and MDS/MPN-T-SF3B1 to indications, and updated ICD-10 code list.

2023-09-11

Policy Summary

PayerAnthem

PolicyReblozyl (luspatercept) — Clinical coverage criteria

Policy CodePolicy CC-0156

Change TypeMaterial clinical updates and clarifications

Effective DateOct 1, 2025

Next Review Date

SourceLink

On This Page

No response limit: Use beyond 9 weeks (administration of 3 consecutive doses) without response at maximum dose (1.25 mg/kg every 3 weeks)

Baseline hemoglobin ≤ 11 g/dL

MDS-RS specifics: If MDS-RS: very low to intermediate risk with ring sideroblasts ≥15% (or 5–14% with SF3B1 mutation) and serum EPO criteria as applicable

Label, NCCN

MDS/MPN-RS-T specifics: Ring sideroblasts ≥15% and thrombocytosis (platelets ≥450 x10^9/L)ring sideroblasts ≥15%; platelets ≥450 x10^9/L

WHO 2017

MDS/MPN-T-SF3B1 specifics: Thrombocytosis (platelets ≥450 x10^9/L) and documentation of SF3B1 mutationplatelets ≥450 x10^9/L; SF3B1 mutation positive

NCCN 2A

MDS with EPO criteria: For MDS: documentation of serum EPO ≤500 U/L AND either ESA‑naïve or no response/relapse after ESA despite adequate iron storesEPO ≤500 U/L

NCCN 2A

DocumentationTransfusion history must be provided at initiation (number of RBC units and transfusion-free intervals)

inv-14: MDS transfusion requirement — ≥ 2 RBC units over 8 weeks in the last 16 weeks

Transfusion count requirementRequired regular red blood cell transfusions of ≥ 2 RBC units over 8 weeks measured within the last 16 weeks

Timing for assessmentTransfusion requirement is assessed using the most recent 16-week period (counts over any 8-week interval)

DocumentationProvide transfusion history demonstrating ≥2 units over an 8-week period within the last 16 weeks

Baseline Hgb: ≤ 11 g/dL

Evidence of response for continuation: decrease in transfusion burden from baseline

Relevant labs: serum ferritin and transferrin saturation when assessing iron deficiency, serum EPO level if applicable

ESA history: documentation of prior ESA use or ESA‑naïve status

Denial Risk

Denial Triggers — β‑Thalassemia

For β‑thalassemia, requests may be denied if patient does not meet transfusion‑dependence criteria or other baseline requirements. Ensure documentation shows regular RBC transfusions (6–20 units in the last 24 weeks and no transfusion‑free interval >35 days) and baseline Hgb ≤ 11 g/dL.

Denial triggers: not meeting transfusion dependence (e.g., fewer than 6 RBC units in the last 24 weeks)
No documentation of transfusion frequency or transfusion‑free period >35 days in the last 24 weeks
Baseline Hgb > 11 g/dL
Diagnosis exclusions: sickle beta thalassemia (S/β‑thalassemia) or alpha (α)‑thalassemia

Denial Risk

Denial Triggers — MDS / MDS‑MPN

For MDS / MDS‑MPN indications, requests may be denied if transfusion requirements, iron status, ESA response/history, or other exclusions are not met. Document at least 2 RBC units over 8 weeks in the last 16 weeks, baseline Hgb ≤ 11 g/dL, and address iron deficiency and ESA response.

Denial triggers: fewer than 2 RBC units over 8 weeks in the last 16 weeks
Unresolved iron deficiency (serum ferritin ≤ 15 µg/L or TSAT ≤ 20% for certain contexts; ferritin <100 µg/L in ESA‑naïve patients)
Inadequate response to ESAs when required by indication
Uncontrolled hypertension in ESA‑naïve patients where specified
Use beyond 9 weeks (three consecutive doses) without response at maximum labeled dose

Documentation Required

ESA Considerations

Assess ESA use and document prior ESA therapy or ESA‑naïve status as applicable. For certain MDS indications, either prior inadequate response to ESAs must be shown or, for ESA‑naïve patients, document ESA‑naïve status plus absence of contraindications (e.g., unresolved iron deficiency or uncontrolled hypertension).

Document prior ESA therapy and response (inadequate response required for some MDS indications)
If ESA‑naïve, document serum ferritin and TSAT to rule out iron deficiency and document blood pressure control
Consider reporting serum EPO level where relevant to support ESA considerations

DocumentationProvide transfusion record showing ≥2 units over an 8-week interval within the last 16 weeks

inv-24: Unresolved iron deficiency — For some criteria defined as serum ferritin ≤15 µg/L or transferrin saturation ≤20%; for ESA‑naïve MDS defined as serum ferritin <100 µg/L.

General definitionUnresolved iron deficiency defined as serum ferritin ≤ 15 µg/L or transferrin saturation (TSAT) ≤ 20% for some criteria

ESA‑naïve MDS specificFor ESA‑naïve MDS, unresolved iron deficiency defined as serum ferritin < 100 µg/L

ImplicationUnresolved iron deficiency is an exclusion for approval when specified (e.g., ESA‑naïve patients) and must be documented

DocumentationProvide serum EPO level result with the prior authorization request to support MDS eligibility

Select review — criteria addition

Added criteria for MDS in ESA-naïve patients with wording and formatting updates; added ICD-10-CM D46.C to coding.

2023-08-18Annual review — no material change

Annual review with no clinical changes documented.

2022-08-19Annual review — editorial updates

Wording and formatting changes; ICD-10-CM formatting updates noted.

2021-08-20Annual review — added continuation criteria

Updated criteria to add continuation therapy and made wording/formatting changes.

2021-08-01Administrative update

Administrative update to add documentation requirements.

2021-02-19Annual review — references updated

Updated references during annual review; coding reviewed with no changes.