CurrentUnitedHealthcarePolicy CS2026D0084R

Reblozyl (luspatercept-aamt) Medical Benefit Drug Policy

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Defines UnitedHealthcare Community Plan medical benefit coverage criteria for Reblozyl (luspatercept-aamt) for treatment of anemia in beta thalassemia, myelodysplastic syndromes (MDS), MDS/MPN, and myelofibrosis-associated anemia in adults, including initial and continuation authorization and applicable coding. Applies nationally except where state-specific exceptions are listed.

Policy Summary

PayerUnitedHealthcare

PolicyReblozyl (luspatercept-aamt) Medical Benefit Drug Policy

Policy CodePolicy CS2026D0084R

Change TypeNo material changes

Effective DateAug 1, 2026

Last ReviewAug 1, 2026

Next Review DateN/A

Key ActionObtain prior authorization with documentation of diagnosis, specialist involvement, dosing per FDA label, and baseline clinical features to support approval.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

12 monthsmax initial/reauth period

≥6PRBC units required (24 wks)

≤35 daysmax transfusion-free period

J0896

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CurrentUnitedHealthcarePolicy CS2026D0084R

Reblozyl (luspatercept-aamt) Medical Benefit Drug Policy

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Policy Summary

PayerUnitedHealthcare

PolicyReblozyl (luspatercept-aamt) Medical Benefit Drug Policy

Policy CodePolicy CS2026D0084R

Change TypeNo material changes

Effective DateAug 1, 2026

Last ReviewAug 1, 2026

Next Review DateN/A

Key ActionObtain prior authorization with documentation of diagnosis, specialist involvement, dosing per FDA label, and baseline clinical features to support approval.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

12 monthsmax initial/reauth period

≥6PRBC units required (24 wks)

≤35 daysmax transfusion-free period

J0896

2FDA major indications

Coverage Criteria for Reblozyl (luspatercept-aamt)

Initial Therapy — Beta Thalassemia

Covered when ALL of the following are met for beta thalassemia (transfusion-dependent) initial therapy:

Beta thalassemia initial therapy requirements: Diagnosis of anemia due to beta thalassemia (including beta+ thalassemia, beta0 thalassemia, and hemoglobin E/beta thalassemia); patient is 18 years of age or older; patient is transfusion dependent as evidenced by BOTH: required regular transfusion of at least six units of packed red blood cells (PRBC) in the previous 24 weeks AND no transfusion-free period greater than 35 days; prescribed by, or in consultation with, a hematologist or other specialist with expertise in the diagnosis and management of beta thalassemia; dosing is in accordance with the U.S. Food and Drug Administration (FDA)–approved labeling; initial authorization will be for no more than 12 months.see documentation

Prescribing specialist and transfusion history required.

Continuation of Therapy

For continuation of therapy (beta thalassemia and other labeled indications):

Continuation: Documentation of a positive clinical response to Reblozyl (for example, reduction in transfusion burden or increase in hemoglobin from baseline); prescribed by, or in consultation with, an appropriate specialist (hematologist/oncologist or other specialist with expertise in the condition); dosing in accordance with FDA‑approved labeling; reauthorization will be for no more than 12 months.clinical response

Positive clinical response required for continuation (e.g., decreased transfusion requirement or hemoglobin improvement).

Initial Therapy — Myelodysplastic Syndromes (MDS)

Covered when ALL of the following are met for symptomatic anemia due to MDS (initial therapy):

MDS initial therapy requirements

Ring sideroblasts / EPO criteria (one of the following)
- Option A: Both of the following: ring sideroblasts < 15% (or < 5% with an SF3B1 mutation) AND serum erythropoietin ≤ 500 mU/mL.RS <15% (or <5% with SF3B1) AND EPO ≤500 mU/mL
- Option B: Ring sideroblasts ≥ 15% (or ≥ 5% with an SF3B1 mutation).RS ≥15% (or ≥5% with SF3B1)

Initial Therapy — MDS/MPN

Covered when ALL of the following are met for MDS/MPN with anemia (initial therapy):

MDS/MPN initial therapy: Diagnosis of anemia due to myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN); presence of an SF3B1 mutation; thrombocytosis defined as platelet count ≥ 450 x 10^9/L; prescribed by, or in consultation with, a hematologist/oncologist or other specialist with expertise in MDS/MPN; dosing is in accordance with FDA‑approved labeling; initial authorization will be for no more than 12 months.SF3B1 mutation positive; platelets ≥450 x10^9/L

Genetic requirement (SF3B1) is explicit.

Initial Therapy — Myelofibrosis-associated Anemia

Covered when ALL of the following are met for myelofibrosis-associated anemia (initial therapy):

Myelofibrosis-associated anemia initial therapy

Clinical scenario (one of)
- Scenario A: Ongoing symptomatic splenomegaly and/or constitutional symptoms AND used in combination with Jakafi (ruxolitinib).
  Combination with ruxolitinib required in this scenario.
- Scenario B: No splenomegaly or constitutional symptoms.
  Monotherapy acceptable in this scenario per policy wording.
- Scenario C: Splenomegaly and/or constitutional symptoms are well controlled on current JAK inhibitor and used in combination with a JAK inhibitor.
  Combination with a JAK inhibitor when symptoms controlled on therapy.

Beta-thalassemia — Initial coverage criteria

Covered when ALL of the following are met (per FDA label and pivotal trial populations):

Beta-thalassemia indication: Adult patient with beta thalassemia who require regular red blood cell (RBC) transfusions; prescribed by, or in consultation with, a hematologist or specialist with expertise in beta thalassemia; dosing per FDA‑approved labeling; initial authorization will be for no more than 12 months.per FDA: regular transfusions

BELIEVE trial population: 6-20 RBC units per 24 weeks with no transfusion-free period >35 days; exclusions in BELIEVE (e.g., HbS/β-thalassemia, alpha-thalassemia, major organ damage, recent DVT/stroke, recent ESA/immunosuppressant/hydroxyurea) may affect applicability.

MDS — Initial coverage criteria

Covered when ALL of the following are met (per FDA label and pivotal trials):

MDS ESA-naive indication: Adult patient with very low- to intermediate-risk myelodysplastic syndromes with anemia without previous erythropoiesis-stimulating agent (ESA) use (ESA‑naïve) who may require regular RBC transfusions; prescribed by, or in consultation with, a hematologist/oncologist; dosing per FDA‑approved labeling; initial authorization will be for no more than 12 months.FDA: ESA‑naive

Supported by COMMANDS (ESA‑naive) evidence.

MDS ESA-failure / ring sideroblast indication: Adult patient with very low- to intermediate-risk MDS with ring sideroblasts, or MDS/MPN‑RS‑T, with anemia failing an ESA and requiring ≥2 RBC units over 8 weeks; prescribed by, or in consultation with, a hematologist/oncologist; dosing per FDA‑approved labeling; initial authorization will be for no more than 12 months.FDA: failing ESA and ≥2 RBC units over 8 weeks

Supported by MEDALIST evidence and FDA indication.

Reblozyl (luspatercept-aamt) is considered not medically necessary for the following situations: non‑transfusion dependent beta thalassemia, beta thalassemia in pediatric patients, sickle beta thalassemia (hemoglobin S/HbS‑beta thalassemia), and alpha thalassemia.

Clinical trial eligibility in BELIEVE excluded certain hemoglobinopathies and patients with major organ dysfunction or recent thromboembolic events. Specifically, the trial excluded patients with hemoglobin S/β‑thalassemia and alpha‑thalassemia, patients with major organ damage (significant liver, heart, or lung disease or renal insufficiency), and patients with recent deep vein thrombosis or stroke. The trial also excluded patients with recent use of erythropoiesis‑stimulating agents (ESA), immunosuppressants, or hydroxyurea.

Reblozyl is not a substitute for urgent red blood cell (RBC) transfusion. The FDA labels Reblozyl with a limitation of use stating it is not indicated to replace RBC transfusions when immediate correction of anemia is required.

Specifically excluded uses include treatment of non‑transfusion dependent beta thalassemia, pediatric beta thalassemia, sickle beta thalassemia (HbS/β‑thalassemia), and alpha thalassemia. In addition, applicability to patients with major organ damage or recent thromboembolic events is limited based on pivotal trial exclusions, and use as an immediate alternative to RBC transfusion is outside the labeled indication.

Use of Reblozyl with the intent to immediately correct anemia in place of an RBC transfusion is outside the FDA‑labeled use. Requests that seek to substitute Reblozyl for urgent transfusion to rapidly restore hemoglobin should be considered non‑covered.

Coding and Transfusion History

Covered HCPCS CodesHCPCSCovered

J0896

Injection, luspatercept-aamt, 0.25 mg

Relevant ICD-10 CodesICD-10

D46.1	Refractory anemia with ring sideroblasts
D46.20	Refractory anemia with excess of blasts, unspecified
D46.21	Refractory anemia with excess of blasts 1
D46.22	Refractory anemia with excess of blasts 2
D46.B	Refractory cytopenia with multilineage dysplasia and ring sideroblasts
D56.1	Beta thalassemia
D56.5	Hemoglobin E-beta thalassemia

Transfusion history — requirement for transfusion‑dependent beta thalassemia

Transfusion dependence definitionAt least 6 units of PRBC transfused in the previous 24 weeks and no transfusion‑free period greater than 35 days.

Age requirement (beta thalassemia)Patient is 18 years of age or older.

Prescriber requirementPrescribed by, or in consultation with, a hematologist or other specialist with expertise in beta thalassemia.

Serum erythropoietin threshold (MDS criteria)

Serum erythropoietin thresholdSerum erythropoietin ≤ 500 mU/mL when required per MDS criteria.

Context of useApplied in MDS criteria that combine ring sideroblast percentage with EPO level to determine eligibility.

Provider Actions, Documentation, and Prior Authorization

Prior Authorization

Prior authorization required — specialist, FDA dosing, and baseline features

Prior authorization is required. Requests must document the diagnosis, that the drug is prescribed by or in consultation with an appropriate specialist (hematologist or other specialist with expertise in the condition), dosing consistent with FDA-approved labeling, and baseline clinical features as specified for the indication. Initial authorizations are limited to no more than 12 months.

Diagnosis must match the specific indication (e.g., transfusion-dependent beta thalassemia, symptomatic lower-risk MDS, MDS/MPN with SF3B1, myelofibrosis-associated anemia).
Prescriber must be a hematologist, oncologist, or other specialist with relevant expertise or consult with one.
Dosing must follow FDA-approved labeling.
Initial authorization duration: ≤ 12 months.

Prior Authorization

Prior authorization must document eligible population and transfusion/ESA status

Prior authorization must demonstrate the member meets the FDA-indicated population and trial-based transfusion burden or ESA status appropriate to the indication.

Dosing Regimens and Administration

Regimen	Route & Frequency	Starting Dose	Titration/Max Dose	Indication / Trial(s)
Luspatercept (Reblozyl)
Subcutaneous every 3 weeks
Start 1.0 mg/kg
Titrate as needed up to 1.75 mg/kg
ESA‑naïve lower‑risk MDS requiring transfusions (as used in the COMMANDS and MEDALIST trials)

Biomarker and Diagnostic Requirements

SF3B1 — biomarker requirement for certain MDS/MDS‑MPN indications

SF3B1 mutation requirementPresence of an SF3B1 mutation is required for the MDS/MPN‑RS‑T indication and is used to define ring sideroblast‑related eligibility.

Clinical roleSF3B1 status allows lower ring sideroblast percentage thresholds to qualify (e.g., ≥5% RS with SF3B1 mutation per NCCN guidance).

DocumentationMutation testing should be documented when asserting eligibility for SF3B1‑defined indications.

del(5q) — exclusion for MDS initial therapy

del(5q) exclusionPatient must NOT have a confirmed del(5q) mutation to meet MDS initial therapy criteria.

ContextAbsence of del(5q) is specified in the policy’s MDS initial therapy requirements and in NCCN‑aligned recommendations.

Line of Therapy Considerations

Informational — line-of-therapy note

Informational: line-of-therapy guidance — policy defines coverage by indication-specific criteria rather than by explicit line number.

Line of therapy guidance: Policy defines initial therapy coverage criteria by diagnosis-specific clinical features and does not explicitly enumerate lines of cancer therapy (first-line/second-line). Use is permitted when criteria for the specific indication are met and dosing follows FDA labeling.

first-line | second-line — designation guidance for use

Designation guidance for use in MDS populations (informational — mapping to trial populations):

First-line | Second-line designation: Used in lower‑risk MDS either as initial therapy for ESA‑naive patients (COMMANDS) or after ESA failure for MDS‑RS/MDS‑MPN‑RS‑T (MEDALIST). Clinical prerequisites such as IPSS‑R risk category, ring sideroblast percentage, SF3B1 mutation status, and serum erythropoietin should be documented to align the patient with the appropriate trial‑based indication.

Definitions and Background Terms

Transfusion dependent (beta thalassemia) — policy definition

Transfusion‑dependent (policy definition)Evidence of transfusion dependence: ≥6 units PRBC in prior 24 weeks and no transfusion‑free period >35 days.

Clinical implicationThis definition is used to identify adults with beta‑thalassemia who require regular RBC transfusions for coverage decisions.

Associated documentationTransfusion records should be submitted to support the stated transfusion burden.

Beta‑thalassemia — definitional statement

Beta‑thalassemia definitionInherited disorder caused by mutations or deletions in the beta globin gene leading to reduced (beta+) or absent (beta0) beta‑globin synthesis; severity ranges from asymptomatic to transfusion‑dependent.

Clinical features

Policy Revision History

2026-08-01policy_effectiveLatest

Policy published/updated with revised Background, Clinical Evidence, and References; archived previous version CS2025D0084Q.

Policy Summary

PayerUnitedHealthcare

PolicyReblozyl (luspatercept-aamt) Medical Benefit Drug Policy

Policy CodePolicy CS2026D0084R

Change TypeNo material changes

Effective DateAug 1, 2026

Last ReviewAug 1, 2026

Next Review DateN/A

Key ActionObtain prior authorization with documentation of diagnosis, specialist involvement, dosing per FDA label, and baseline clinical features to support approval.

SourceLink

On This Page

NCCN alignmentNCCN cites EPO ≤ 500 mU/mL as a consideration for certain lower‑risk MDS with lower ring sideroblast percentages.

Thrombocytosis — platelet count threshold

Thrombocytosis thresholdPlatelet count ≥ 450 × 10^9/L.

Indication contextRequired for MDS/MPN indication (MDS/MPN‑RS‑T) along with presence of SF3B1 mutation.

Prescriber requirementPrescribed by, or in consultation with, a hematologist/oncologist or specialist with expertise in MDS/MDS‑MPN.

BELIEVE trial transfusion requirement

BELIEVE transfusion eligibilityRequired regular RBC transfusions of 6–20 units per 24 weeks with no transfusion‑free period greater than 35 days (trial population).

Trial designBELIEVE was a randomized, double‑blind, placebo‑controlled trial in adults (n=336) with beta thalassemia requiring regular transfusions.

Exclusions notedBELIEVE excluded patients with hemoglobin S/β‑thalassemia, alpha‑thalassemia, major organ damage, recent DVT/stroke, or recent ESA/immunosuppressant/hydroxyurea use.

COMMANDS trial transfusion requirement

COMMANDS transfusion requirementRequired 2–6 packed RBC units per 8 weeks for ≥8 weeks immediately before randomization in ESA‑naïve patients.

PopulationESA‑naïve lower‑risk MDS patients randomized to luspatercept or epoetin alfa (n=356).

Dosing used in trialLuspatercept subcutaneously every 3 weeks starting at 1.0 mg/kg with possible titration to 1.75 mg/kg.

MEDALIST transfusion‑independence endpoint

MEDALIST primary endpoint (transfusion independence)Transfusion independence for ≥8 weeks during weeks 1–24 (primary end point).

Trial population and dosingMEDALIST randomized lower‑risk MDS patients (n=229) to luspatercept 1.0–1.75 mg/kg subcutaneously every 3 weeks versus placebo.

Primary outcome result38% of luspatercept patients achieved ≥8‑week transfusion independence vs 13% with placebo (p<0.001).

Beta thalassemia: evidence of regular RBC transfusions as per BELIEVE (6–20 RBC units per 24 weeks with no transfusion-free period >35 days).
MDS ESA‑naïve indication: documentation of no prior ESA use (per FDA/MEDALIST/COMMANDS).
MDS ESA‑failure/ring sideroblast indication: documentation of ESA failure and required transfusion burden (≥2 RBC units over 8 weeks for MEDALIST-type populations).

Step Therapy

MDS prerequisites — IPSS‑R, del(5q) exclusion, ring sideroblasts/EPO

For MDS indications, prior assessment must document lower‑risk disease by IPSS‑R (Very Low, Low, or Intermediate) and absence of a confirmed del(5q) mutation; ring sideroblast percentage and serum erythropoietin thresholds per policy must also be documented.

IPSS‑R risk category: Very Low, Low, or Intermediate required.
Confirmed del(5q) must be absent (exclusion).
Either: ring sideroblasts <15% (or <5% with SF3B1) AND serum erythropoietin ≤500 mU/mL, OR ring sideroblasts ≥15% (or ≥5% with SF3B1).

Step Therapy

Step therapy considerations — consider prior ESA (epoetin alfa) per trial/NCCN context

Clinical guidance and trial design support consideration of prior or alternative therapy in lower‑risk MDS; COMMANDS compared luspatercept to epoetin alfa in ESA‑naïve patients, so prior ESA considerations and response timelines may inform therapy sequencing.

COMMANDS trial enrolled ESA‑naïve patients and randomized luspatercept versus epoetin alfa (supports consideration of epoetin alfa as an alternative in ESA‑naïve patients).
NCCN defines response timelines and ESA considerations (e.g., lack of response defined by 6–8 weeks for decrease in RBC transfusion requirement or <1.5 g/dL hemoglobin rise).

Documentation Required

Required documentation — diagnosis, age, transfusion history, labs/mutations, specialist

Documentation must support the diagnosis, age when applicable, transfusion history, relevant laboratory or mutation data (ring sideroblast percentage, SF3B1 mutation status, serum erythropoietin), and prescriber specialty involvement.

Diagnosis specifics (e.g., transfusion‑dependent beta thalassemia, lower‑risk MDS, MDS/MPN with SF3B1, myelofibrosis‑associated anemia).
Age ≥18 years where required (beta thalassemia indication).
Prescribing clinician specialty or documentation of consultation with appropriate specialist.
Relevant labs/genetic tests: ring sideroblasts %, SF3B1 mutation status, serum erythropoietin level.

Documentation Required

Documentation to support transfusion burden and prior ESA use per trial definitions

Clinical documentation should explicitly support the diagnosis and the transfusion burden as defined in the pivotal trials or FDA labeling, and report prior ESA use and response status when relevant.

For beta thalassemia: record transfusion history consistent with BELIEVE (6–20 RBC units per 24 weeks; no transfusion‑free period >35 days).
For COMMANDS‑type patients: document 2–6 PRBC units per 8 weeks for ≥8 weeks prior to randomization when applicable.
For MEDALIST‑type patients: document ESA failure or lack of response and transfusion requirements per trial definitions.

Denial Risk

Not medically necessary indications — excluded uses that risk denial

Requests for Reblozyl for the listed excluded indications will be considered not medically necessary and may be denied.

Non‑transfusion dependent beta thalassemia.
Beta thalassemia in pediatric patients.
Sickle beta thalassemia (hemoglobin S/β‑thalassemia).
Alpha thalassemia.

Denial Risk

Do not substitute Reblozyl for urgent RBC transfusion — risk of noncoverage

Reblozyl is not indicated as a substitute for RBC transfusions when immediate correction of anemia is required; using it in lieu of urgent transfusion is outside the labeled use and may trigger non‑coverage or denial.

Do not use Reblozyl to immediately correct anemia instead of performing an urgent RBC transfusion.

ImplicationConfirmed del(5q) should be documented and would preclude Reblozyl eligibility under these criteria.

Ring sideroblasts (%) — combined criteria with SF3B1 status

Ring sideroblast thresholds (combined with SF3B1)Either: Ring sideroblasts <15% (or <5% with SF3B1 mutation) with serum EPO ≤500 mU/mL, OR ring sideroblasts ≥15% (or ≥5% with SF3B1 mutation).

UsageThese thresholds form the policy’s OR logic for defining eligible MDS populations.

Source alignmentThresholds are consistent with trial inclusion criteria and NCCN recommendations cited in the policy.

SF3B1 — use in defining ring sideroblast‑related indications

SF3B1 role in RS definitionsSF3B1 mutation status is used to lower the ring sideroblast percentage threshold (≥5% RS with SF3B1) for eligibility per cited guidance.

Policy applicationSF3B1 mutation is required for MDS/MPN‑RS‑T indication and influences RS‑based eligibility in MDS criteria.

Documentation requirementMutation testing results should be included in authorization documentation when applicable.

Ring sideroblast percentage thresholds (NCCN‑aligned)

Primary RS percentage thresholds (NCCN)Ring sideroblasts ≥15% qualifies, or ≥5% if an SF3B1 mutation is present (per NCCN recommendations).

Alternate lower thresholdRing sideroblasts <15% (or <5% with SF3B1) may still qualify when combined with serum EPO ≤500 mU/mL.

Clinical alignmentThese thresholds are explicitly cited by NCCN and incorporated into the policy’s eligibility logic.

Serum erythropoietin — NCCN‑referenced threshold

Erythropoietin threshold per NCCNSerum erythropoietin ≤ 500 mU/mL is used in NCCN guidance to support eligibility when ring sideroblasts are below the primary threshold.

Policy integrationPolicy applies the ≤500 mU/mL threshold as part of the combined ring sideroblast/EPO criteria for MDS initial therapy.

DocumentationEPO laboratory value should be provided when required to apply the lower RS eligibility branch.

Forms include thalassemia major, intermedia, and minor; thalassemia major typically presents in infancy and requires regular RBC transfusions.

ComplicationsRegular transfusion therapy can lead to iron overload and related organ complications, necessitating chelation and monitoring.

Luspatercept (Reblozyl) — mechanism and indicated adult populations

Luspatercept (Reblozyl) — mechanismRecombinant fusion protein that binds select TGF‑β superfamily ligands and enhances late‑stage erythropoiesis.

FDA‑approved adult indicationsAnemia in adult patients with beta thalassemia requiring regular RBC transfusions; anemia in very low‑ to intermediate‑risk MDS (ESA‑naïve) who may require regular RBC transfusions; anemia failing an ESA and requiring ≥2 RBC units over 8 weeks in very low‑ to intermediate‑risk MDS‑RS or MDS/MPN‑RS‑T.

Typical dosing regimen in trialsSubcutaneous administration every 3 weeks, starting at 1.0 mg/kg with possible titration to 1.75 mg/kg (as used in COMMANDS and MEDALIST).

Beta‑thalassemias are hereditary disorders of β‑globin synthesis with a clinical spectrum that ranges from asymptomatic carriers to severe, transfusion‑dependent anemia. Patients who require regular RBC transfusions are at risk of iron overload and related complications; these disorders are caused by mutations or deletions in the β‑globin gene that reduce (β+) or abolish (β0) β‑globin production. Disease severity and transfusion dependence determine clinical management and eligibility for therapies such as luspatercept.