ModifiedUnitedHealthcarePolicy IEXD0084.09

Reblozyl (Luspatercept-Aamt) — Coverage Criteria

Defines UnitedHealthcare Individual Exchange medical benefit drug policy coverage criteria for Reblozyl (luspatercept-aamt) for adults with beta thalassemia, myelodysplastic syndromes (MDS), MDS/MPN overlap, and myelofibrosis-associated anemia; applies to Individual Exchange plans except MA, NV, and NY.

Policy Summary

PayerUnitedHealthcare

PolicyReblozyl (Luspatercept-Aamt) — Coverage Criteria

Policy CodePolicy IEXD0084.09

Change TypeMaterial revisions to coverage criteria and prior authorization requirements

Effective DateSep 1, 2025

Next Review DateN/A

Key ActionObtain prior authorization with documentation of diagnosis, specialist involvement, required biomarkers (ring sideroblasts and EPO where applicable), and evidence of positive clinical response for reauthorization.

SourceLink

POLICY UPDATE CHANGES

UnitedHealthcare recognizes indications and uses of injectable oncology medications listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence and Consensus of 1, 2A, and 2B as proven and medically necessary, and Categories of Evidence and Consensus of 3 as unproven and not medically necessary.

Removed language indicating Reblozyl is proven and/or medically necessary for the treatment of symptomatic anemia in erythropoiesis stimulating agent-naïve (ESA-naïve) patients with myelodysplastic syndromes (MDS).

Replaced criterion requiring 'diagnosis of beta thalassemia...' with 'diagnosis of anemia due to beta thalassemia...'.

Added requirement for documentation of a positive clinical response to Reblozyl (e.g., reduction in transfusion burden, increase in hemoglobin from baseline) for continuation of therapy.

Added criterion requiring documentation of a positive clinical response to Reblozyl (e.g., reduction in transfusion burden, increase in hemoglobin from baseline).

Removed criterion requiring diagnosis of beta thalassemia including beta+ thalassemia, beta0 thalassemia, and hemoglobin E/beta thalassemia (and related transfusion-reduction requirement).

Revised language to indicate Reblozyl is proven and medically necessary for treatment of symptomatic anemia in patients with MDS who meet specified criteria.

Added prescribing and dosing requirements: prescribed by or in consultation with a hematologist/oncologist or other specialist; dosing per FDA label; initial authorization limited to no more than 12 months; reauthorization limited to no more than 12 months.

Clarified initial therapy population: symptomatic anemia due to MDS with lower-risk disease per IPSS-R (Very Low, Low, Intermediate) and absence of confirmed del(5q).

Added language to indicate Reblozyl is proven and medically necessary for the treatment of anemia in patients with myelodysplastic syndrome/myeloproliferative overlap neoplasm (MDS/MPN).

Documentation of a positive clinical response to Reblozyl (e.g., reduction in transfusion burden, increase in hemoglobin from baseline) is required.

Prescribed by, or in consultation with, a hematologist, oncologist, or other specialist with expertise in diagnosis and management of myelodysplastic syndromes.

Dosing is in accordance with the FDA approved labeling.

Reauthorization will be for no more than 12 months.

Summary of Changes = Ring sideroblasts < 15% (or ring sideroblasts < 5% with an SF3B1 mutation) Serum erythropoietin ≤ 500 mU/mL § Ring sideroblasts ≥ 15% (or ring sideroblasts ≥ 5% with an SF3B1 mutation) o Prescribed by, or in consultation with, a hematologist, oncologist, or other specialist with expertise in the diagnosis and management of myelodysplastic syndromes.

Ring sideroblasts < 15% (or ring sideroblasts < 5% with an SF3B1 mutation) and Serum erythropoietin ≤ 500 mU/mL were added to the criteria discussion.

Specification that ring sideroblasts ≥ 15% (or ≥ 5% with an SF3B1 mutation) and that therapy be prescribed by or in consultation with a hematologist/oncologist or specialist was clarified.

Ring sideroblasts < 15% (or ring sideroblasts < 5% with an SF3B1 mutation) and serum erythropoietin ≤ 500 mU/mL noted in Summary of Changes.

Ring sideroblasts ≥ 15% (or ring sideroblasts ≥ 5% with an SF3B1 mutation) appears as alternative criterion in Summary of Changes.

Prescribed by, or in consultation with, a hematologist, oncologist, or other specialist is specified.

12 monthsmax initial auth

≥6 units/24wtransfusion req

J0896HCPCS

≤500 mU/mLEPO threshold

38%MDS response (MEDALIST)

Coverage Criteria for Reblozyl (luspatercept-aamt)

Initial Therapy — Beta Thalassemia

Covered when ALL of the following are met for adult beta thalassemia (Initial Therapy):

Beta thalassemia initial therapy - all required: Diagnosis of anemia due to beta thalassemia (including beta+ thalassemia, beta0 thalassemia, and hemoglobin E/beta thalassemia); patient is ≥18 years of age; 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 in accordance with FDA‑approved labeling; initial authorization ≤ 12 months.

Continuation Therapy — Beta Thalassemia

Continuation of therapy for beta thalassemia:

Beta thalassemia continuation: Documentation of a positive clinical response to Reblozyl (examples: reduction in transfusion burden or increase in hemoglobin from baseline); prescribed by, or in consultation with, a hematologist or other specialist with expertise in beta thalassemia; dosing in accordance with FDA‑approved labeling; reauthorization ≤ 12 months.

Initial Therapy — Lower‑risk MDS

Covered when ALL of the following are met for symptomatic anemia due to lower-risk MDS (Initial Therapy):

MDS initial therapy - required elements

Ring sideroblast/EPO criteria: Either: (1) Ring sideroblasts < 15% (or < 5% with an SF3B1 mutation) AND serum erythropoietin ≤ 500 mU/mL; OR (2) Ring sideroblasts ≥ 15% (or ≥ 5% with an SF3B1 mutation).EPO ≤ 500 mU/mL

Continuation Therapy — MDS

Continuation of therapy for MDS:

MDS continuation: Documentation of a positive clinical response to Reblozyl (examples: reduction in transfusion burden or increase in hemoglobin from baseline); prescribed by, or in consultation with, a hematologist, oncologist, or other specialist with expertise in MDS; dosing in accordance with FDA‑approved labeling; reauthorization ≤ 12 months.

Initial Therapy — MDS/MPN Overlap

Covered when ALL of the following are met for anemia due to MDS/MPN overlap (Initial Therapy):

MDS/MPN initial therapy: Diagnosis of anemia due to myelodysplastic syndrome/myeloproliferative overlap 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 in accordance with FDA‑approved labeling; initial authorization ≤ 12 months.

Initial Therapy — Myelofibrosis-associated Anemia

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

Myelofibrosis initial therapy - symptom strata: Diagnosis of myelofibrosis‑associated anemia; and one of the following: (a) symptomatic splenomegaly and/or constitutional symptoms AND used in combination with a JAK inhibitor (examples: fedratinib, ruxolitinib, momelotinib, pacritinib), OR (b) no splenomegaly or constitutional symptoms; prescribed by, or in consultation with, a hematologist, oncologist, or other specialist with expertise in myelofibrosis; dosing in accordance with FDA‑approved labeling; initial authorization ≤ 12 months.

Continuation Therapy — Myelofibrosis

Continuation of therapy for myelofibrosis-associated anemia:

Myelofibrosis continuation: Documentation of a positive clinical response to Reblozyl (examples: reduction in transfusion burden or increase in hemoglobin from baseline); prescribed by, or in consultation with, a hematologist, oncologist, or other specialist with expertise in myelofibrosis; dosing in accordance with FDA‑approved labeling; reauthorization ≤ 12 months.

Revisions to Coverage Criteria (Initial and Continuation Therapy, MDS)

Policy revisions related to covered indications and continuation requirements (summary of changes present in this section):

Initial Therapy - Beta Thalassemia (revised phrasing): Replaced prior wording requiring 'diagnosis of beta thalassemia...' with 'diagnosis of anemia due to beta thalassemia (including beta+ thalassemia, beta0 thalassemia, hemoglobin E/beta thalassemia)'.

Revision reflected in Policy History/Summary of Changes.

Continuation of Therapy - new requirement: Added requirement for documentation of a positive clinical response to Reblozyl (e.g., reduction in transfusion burden, increase in hemoglobin from baseline) for continuation/reauthorization; earlier wording requiring specific unit reduction was removed.

Revision reflected in Policy History/Summary of Changes.

Symptomatic Anemia in MDS clarified: Revised language indicates Reblozyl is proven and medically necessary for treatment of symptomatic anemia in lower‑risk MDS (IPSS‑R Very Low/Low/Intermediate) who meet specified ring sideroblast and EPO criteria.

Revision reflected in Policy History/Summary of Changes.

Initial Therapy

Covered when ALL of the following are met for initial therapy:

Initial therapy eligibility

Ring sideroblast/EPO criteria: Either: (1) Ring sideroblasts < 15% (or <5% with SF3B1 mutation) AND serum erythropoietin ≤ 500 mU/mL; OR (2) Ring sideroblasts ≥ 15% (or ≥5% with SF3B1 mutation).EPO ≤ 500 mU/mL

Continuation of Therapy

Covered when ALL of the following are met for continuation/reauthorization:

Continuation therapy: Documentation of a positive clinical response to Reblozyl (examples: reduction in transfusion burden, increase in hemoglobin from baseline); prescribed by, or in consultation with, a hematologist/oncologist or MDS specialist; dosing consistent with FDA‑approved labeling; reauthorization limited to no more than 12 months.

Coverage for Reblozyl in MDS/MPN

Covered when ALL of the following are met (policy history indicates addition of this criteria set):

Coverage criteria for Reblozyl in MDS/MPN: Diagnosis of anemia due to MDS/MPN meeting documented criteria; prescribed by, or in consultation with, an appropriate specialist; dosing per FDA labeling; documentation of a positive clinical response (e.g., reduction in transfusion burden or increase in hemoglobin from baseline); reauthorization ≤ 12 months.

Initial therapy eligibility (biomarker + prescriber)

Covered when meeting biomarker and prescriber criteria

Core criteria: Either: (A) Ring sideroblasts < 15% (or <5% with an SF3B1 mutation) AND serum erythropoietin ≤ 500 mU/mL; OR (B) Ring sideroblasts ≥ 15% (or ≥5% with an SF3B1 mutation). AND prescribed by, or in consultation with, a hematologist, oncologist, or other specialist with expertise in MDS.EPO ≤ 500 mU/mL

Document presents alternate phrasings in policy history; verify lab/pathology documentation.

Continuation Therapy

Continuation of therapy covered when meeting treatment response criteria

Continuation criteria: Documentation of a positive clinical response to Reblozyl (examples include reduction in transfusion burden or increase in hemoglobin from baseline); reauthorization limited to no more than 12 months.

Prescriber specialty and dosing per FDA labeling required.

Eligibility groups referenced

Coverage groups referenced in policy history/summary of changes

Group A: Both of the following: Ring sideroblasts < 15% (or <5% with SF3B1 mutation) AND serum erythropoietin ≤ 500 mU/mL.EPO ≤ 500 mU/mL

From Summary of Changes.

Group B: Ring sideroblasts ≥ 15% (or ≥5% with SF3B1 mutation) AND prescribed by, or in consultation with, a hematologist/oncologist.

From Summary of Changes.

Coverage for luspatercept in MDS-related anemia

Covered when meeting morphologic and laboratory criteria and specialist prescribing requirement

Luspatercept coverage criteria - summary: All of the following must be met: (1) ring sideroblasts criterion met (either ≥15% OR ≥5% with SF3B1 mutation); (2) serum erythropoietin ≤ 500 mU/mL where applicable; (3) prescribed by, or in consultation with, a hematologist, oncologist, or other specialist with expertise in MDS; dosing per FDA labeling.EPO ≤ 500 mU/mL

Referenced in multiple revision summary lines.

Eligibility Criteria (as cited)

Coverage-related criteria referenced in the policy history

Eligibility: Patient meets ring sideroblast criteria (either ring sideroblasts ≥15% OR ≥5% with an SF3B1 mutation) AND serum erythropoietin ≤ 500 mU/mL AND therapy prescribed by, or in consultation with, a hematologist/oncologist or other specialist with expertise in MDS.EPO ≤ 500 mU/mL

Documented in policy history/revision information.

Eligibility-related criteria

Coverage references conditions related to ring sideroblast percentage, SF3B1 mutation, and serum erythropoietin:

Ring sideroblasts and SF3B1-dependent thresholds: Ring sideroblasts < 15% (or <5% with SF3B1 mutation) OR ring sideroblasts ≥ 15% (or ≥5% with SF3B1 mutation).

Document ring sideroblast percentage and SF3B1 mutation status must be reported.

Erythropoietin threshold: Serum erythropoietin ≤ 500 mU/mL.≤ 500 mU/mL

Measure and document serum EPO level.

Prescriber requirement: Prescribed by, or in consultation with, a hematologist, oncologist, or other specialist with expertise in diagnosis and management of MDS.

Include documentation of specialist involvement.

Initial therapy eligibility

Covered when ALL of the following are met

Main eligibility: Patient has MDS with ring sideroblasts meeting ring sideroblast percentage threshold (≥15% or ≥5% if SF3B1 mutation present); serum erythropoietin ≤ 500 mU/mL; and therapy is prescribed by, or in consultation with, a hematologist/oncologist or appropriate specialist.ring sideroblasts and EPO thresholds

Derived from Summary of Changes text.

Eligibility by ring sideroblasts and SF3B1

Coverage considerations described in Summary of Changes reference the following numeric and biomarker criteria:

Ring sideroblast criteria: Ring sideroblasts ≥ 15% OR ring sideroblasts ≥ 5% with an SF3B1 mutation.

Used to define eligible MDS with ring sideroblasts.

Erythropoietin threshold

Additional laboratory criterion noted:

Erythropoietin threshold: Serum erythropoietin ≤ 500 mU/mL.≤ 500 mU/mL

Required per Summary of Changes.

Specialist prescribing/consultation

Prescriber requirement:

Specialist involvement: Therapy is prescribed by, or in consultation with, a hematologist, oncologist, or other specialist with expertise in diagnosis and management of MDS.N/A

Operational requirement reiterated in policy history.

Initial coverage criteria

Covered when ALL of the following are met

Eligibility for luspatercept: Patient has ring sideroblasts ≥ 15% OR ring sideroblasts ≥ 5% with SF3B1 mutation; serum erythropoietin ≤ 500 mU/mL; and therapy prescribed by, or in consultation with, a hematologist, oncologist, or other specialist.EPO ≤ 500 mU/mL

Derived from policy history summary lines.

Initial therapy

Covered when ALL of the following are met

Initial therapy: Patient has MDS with ring sideroblasts AND documented serum erythropoietin ≤ 500 mU/mL AND therapy prescribed by, or in consultation with, a hematologist/oncologist or other specialist; ring sideroblasts defined as ≥15% or ≥5% with SF3B1 mutation.EPO ≤ 500 mU/mL

Ring sideroblasts definition per policy history.

Referenced eligibility criteria (partial)

Coverage references clinical thresholds that must be met (as reflected in Summary of Changes lines).

Eligibility criteria (fragmentary): Patient meets ALL of: serum erythropoietin ≤ 500 mU/mL; presence of ring sideroblasts ≥ 15% OR ring sideroblasts ≥ 5% with an SF3B1 mutation; and therapy prescribed by, or in consultation with, a hematologist/oncologist or other specialist.see node

Extracted from repeated 'Summary of Changes' lines; full policy may include additional criteria.

UnitedHealthcare specifies that Reblozyl (luspatercept‑aamt) is not proven or medically necessary for treatment of the following conditions: alpha thalassemia; beta thalassemia in pediatric patients; non‑transfusion dependent beta thalassemia; and sickle beta thalassemia (HbS/beta thalassemia).

The policy clarifies a limitation of use: Reblozyl is not indicated as a substitute for red blood cell (RBC) transfusions when immediate correction of anemia is required. Providers should not use Reblozyl in place of urgent transfusion support for patients needing prompt hemoglobin correction.

Policy history documents that a prior criterion requiring a diagnosis listing specific beta thalassemia variants (including beta+ thalassemia, beta0 thalassemia, and hemoglobin E/beta thalassemia) plus wording about demonstrated transfusion‑reduction from pretreatment was removed from the coverage criteria.

Coding and Key Numeric Criteria

Applicable HCPCSHCPCSCovered

J0896

Injection, luspatercept-aamt, 0.25 mg.

Relevant ICD-10 Diagnosis 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.

No codes present in this fragmentmixed

No codes listed

Transfusion dependence — beta thalassemia

Transfusion requirementAt least six units of packed red blood cells (PRBC) in the previous 24 weeks

Transfusion-free intervalNo transfusion‑free period greater than 35 days during the prior 24 weeks

Age requirementPatient is 18 years of age or older

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

Authorization periodInitial authorization limited to no more than 12 months

Serum erythropoietin threshold (MDS criteria)

Erythropoietin thresholdSerum erythropoietin ≤ 500 mU/mL

Context of useUsed as a laboratory eligibility criterion for lower‑risk MDS with ring sideroblasts when ring sideroblasts <15% (or <5% with SF3B1)

Documentation expectationSerum EPO level reported in mU/mL and included in prior authorization documentation

Thrombocytosis threshold — MDS/MPN

Platelet thresholdPlatelet count ≥ 450 x 10^9/L

Associated biomarkerPresence of SF3B1 mutation referenced for MDS/MPN with thrombocytosis

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

Serum erythropoietin — eligibility fragment

Erythropoietin cutoffSerum erythropoietin ≤ 500 mU/mL

Role in criteriaApplied in combinations with ring sideroblast thresholds to determine eligibility

Required documentationSerum EPO must be documented for prior authorization where applicable

Serum erythropoietin — alternate fragment

Erythropoietin numeric thresholdSerum erythropoietin ≤ 500 mU/mL

Policy repetitionThreshold repeatedly cited in policy history/Summary of Changes for MDS eligibility

Measure unitsSerum EPO reported in mU/mL

Ring sideroblasts — thresholds and SF3B1 modifier

Primary thresholdRing sideroblasts ≥ 15%

SF3B1‑modified thresholdRing sideroblasts ≥ 5% when an SF3B1 mutation is present

Alternate phrasing notedDocument also references ring sideroblasts <15% (or <5% with SF3B1) in other summary lines

Prior Authorization, Documentation, and Denial Triggers

Prior Authorization

Prior Authorization Required

Prior authorization is required for Reblozyl (luspatercept). Initial authorizations are limited to no more than 12 months; reauthorization (continuation) is also limited to no more than 12 months and requires documentation of a positive clinical response. Prescriptions must be by, or in consultation with, an appropriate specialist (hematologist, oncologist, or other specialist with expertise in the relevant disease area). Dosing must follow the FDA‑approved labeling. No specific step‑therapy sequence is defined in this section.

Initial authorization ≤ 12 months
Reauthorization (continuation) ≤ 12 months and requires documented clinical response
Prescriber: hematologist/oncologist or specialist consultation required
Dosing consistent with U.S. FDA labeling
No explicit step‑therapy requirements specified

Documentation Required

Clinical Thresholds and Specialist Prescriber Required

Providers must document that clinical eligibility thresholds are met before approval. For myelodysplastic syndromes (MDS)/MDS‑MPN and related indications this includes ring sideroblast percentage and serum erythropoietin (EPO) level (serum EPO ≤ 500 mU/mL when applicable). For MDS with lower‑risk disease, ring sideroblasts ≥ 15% (or ≥ 5% with an SF3B1 mutation) OR ring sideroblasts below those thresholds with serum EPO ≤ 500 mU/mL per NCCN criteria. For beta thalassemia, document diagnosis of anemia due to beta thalassemia and evidence of transfusion dependence (≥6 units PRBC in prior 24 weeks and no transfusion‑free period >35 days).

MDS ring sideroblast thresholds: ≥15% (or ≥5% with SF3B1) OR <15% (or <5% with SF3B1) with serum EPO ≤500 mU/mL
Document serum erythropoietin level (report value)
Beta thalassemia: diagnosis of anemia due to beta thalassemia and transfusion‑dependence criteria (≥6 units PRBC in prior 24 weeks; no transfusion‑free period >35 days)
Prescriber specialty documented (hematologist/oncologist or specialist consultation)

Denial Risk

Explicit Non‑Covered Uses

Reblozyl is not proven and/or medically necessary for the following uses and therefore is not covered for these indications: alpha thalassemia; beta thalassemia in pediatric patients; non‑transfusion dependent beta thalassemia; and sickle beta thalassemia (HbS/beta thalassemia).

Alpha thalassemia: not covered
Beta thalassemia in pediatric patients: not covered
Non‑transfusion dependent beta thalassemia: not covered
Sickle beta thalassemia (HbS/beta thalassemia): not covered

Denial Risk

Denial Risk for Removed ESA‑naïve MDS Language

Policy language was revised to remove the prior statement that Reblozyl is proven/medically necessary for ESA‑naïve patients with MDS. Claims asserting coverage based on the removed ESA‑naïve language may be denied. Providers should ensure documentation reflects current policy criteria (history of ESA therapy effectiveness or reasons for prior ESA discontinuation consistent with MEDALIST/NCCN guidance when applicable).

Removed coverage for ESA‑naïve MDS — assertions of ESA‑naïve proven coverage risk denial
Document prior ESA therapy status and rationale if applicable (ineffective or intolerance per MEDALIST)

Denial Risk

Denial Triggers

Denials or non‑approval may be triggered by failure to provide required documentation or meet clinical thresholds. Common denial triggers include: absence of documented ring sideroblast percentage or SF3B1 mutation status when applicable; serum erythropoietin level above the policy threshold (>500 mU/mL) when required; lack of documented transfusion dependence for beta thalassemia; absence of specialist prescriber or documented consultation; dosing not consistent with FDA labeling; and lack of documented positive clinical response for reauthorization.

Missing ring sideroblast % or SF3B1 status when required
Serum EPO > 500 mU/mL when threshold required
Insufficient documentation of transfusion dependence for beta thalassemia (≥6 units PRBC / 24 weeks; no >35‑day transfusion‑free period)
No specialist prescriber or consultation note
Dosing inconsistent with FDA‑approved labeling
Insufficient documentation of clinical response for continuation (reduction in transfusion burden or hemoglobin increase)

Documentation Required

Required Clinical Documentation

Required clinical documentation for initial authorization includes: diagnosis and relevant disease details (e.g., MDS risk category, presence/absence of del(5q), SF3B1 mutation status), ring sideroblast percentage or SF3B1 mutation report when applicable, serum erythropoietin level (report value and date), age, transfusion history (units and dates) for beta thalassemia, and a prescriber/consultation note from an appropriate specialist. For continuation/reauthorization, include evidence of a positive clinical response (examples: decreased transfusion requirement from baseline, transfusion‑independence periods, or increase in hemoglobin from baseline as defined by NCCN).

Diagnosis and disease specifics (MDS IPSS‑R risk, del(5q) status)
Ring sideroblast % or SF3B1 mutation report (when applicable)
Serum EPO level (≤500 mU/mL threshold when required)
Age and transfusion history (for beta thalassemia: ≥6 units PRBC in prior 24 weeks; no transfusion‑free period >35 days)
Specialist prescriber or consultation note (hematologist/oncologist)
For reauthorization: documentation of positive clinical response (reduced transfusion burden or Hb increase)

Documentation Required

Required Documentation for Continuation

Examples of acceptable documentation to support continuation/reauthorization: transfusion records showing reduced units transfused compared with pretreatment baseline, laboratory hemoglobin values demonstrating an increase from baseline (e.g., NCCN lack‑of‑response defined as failure to increase Hb by 1.5 g/dL by 6–8 weeks), or documentation of transfusion‑independence intervals. Reauthorization eligibility requires these response data in the medical record.

Transfusion records comparing pre‑ and on‑treatment periods
Serial hemoglobin values with dates showing change from baseline
Clinician note summarizing clinical benefit (reduced transfusion burden or improved Hb)

Documentation Required

Prescriber and Dosing Documentation

Include the specialist’s prescription or consultation note with the request. Clearly document that dosing follows the FDA‑approved labeling (include dose and schedule). Failure to document specialist involvement or FDA‑aligned dosing may result in non‑approval.

Specialist prescriber or consultation note (hematologist/oncologist or other qualified specialist)
Dose and schedule consistent with FDA label (document actual dose and interval)
Statement that dosing follows FDA labeling

Documentation Required

Clinical Response Documentation

For reauthorization, include objective clinical response data: examples are reduced PRBC units over a comparable prior period, achievement of transfusion‑independence for defined periods, or hemoglobin increases from baseline. Lack of documented response may lead to non‑approval. NCCN defines lack of response as <1.5 g/dL rise in hemoglobin or no decrease in RBC transfusion requirement by 6–8 weeks.

Quantified reduction in transfusion units versus baseline
Documented hemoglobin change from baseline with dates
Clinician assessment of treatment benefit

Note

Expectations Regarding Prior ESA Therapy

Per MEDALIST and policy expectations, for MDS patients luspatercept is intended for patients who are unlikely to respond to erythropoiesis‑stimulating agents (ESAs) or who had ESA therapy that was not effective or discontinued due to adverse events. Providers should document prior ESA therapy status and reasons for discontinuation or ineffectiveness when relevant.

Document prior ESA therapy and response or intolerance (if applicable)
MEDALIST population: MDS patients refractory or unlikely to respond to ESAs

Prior Authorization

Eligibility Gating

Eligibility gating: approvals will be gated by the diagnostic subcriteria and thresholds noted above (ring sideroblast percentage or SF3B1 mutation when applicable, serum EPO ≤500 mU/mL when required, transfusion‑dependence criteria for beta thalassemia, age ≥18 for beta thalassemia indication). Ensure each gating item is documented in the submitted records.

Age ≥18 years for beta thalassemia indication
Transfusion dependence documented for beta thalassemia
MDS diagnostic thresholds (ring sideroblasts/SF3B1 and serum EPO)
Specialist prescriber documented

Background and Clinical Context

Beta‑thalassemias are inherited disorders of decreased beta‑globin synthesis that produce variable anemia severity; more severe forms frequently require regular RBC transfusions leading to transfusion dependence and risk of iron overload. Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by ineffective erythropoiesis causing symptomatic anemia in some patients; luspatercept is an erythroid maturation agent intended to enhance late stage erythropoiesis in appropriate indications.

Definitions and Thresholds

Definition — Transfusion dependent (beta thalassemia)

Definition (transfusion dependent)Required regular transfusion of at least six units PRBC in the previous 24 weeks

Maximum transfusion‑free intervalNo transfusion‑free period greater than 35 days in the prior 24 weeks

Indication contextApplies to adult beta thalassemia initial therapy coverage criteria

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

Authorization limitInitial authorization will be for no more than 12 months

Lower‑risk MDS (IPSS‑R) — definition

IPSS‑R categoriesLower‑risk MDS defined as IPSS‑R: Very Low, Low, or Intermediate

ExclusionPatient does not have a confirmed del(5q)

Prescriber requirementPrescribed by, or in consultation with, a hematologist/oncologist or MDS specialist

Lower‑risk MDS (alternate fragment)

Lower‑risk definitionIPSS‑R categories Very Low, Low, or Intermediate are considered lower‑risk

ApplicationUsed to gate eligibility for luspatercept in symptomatic MDS-related anemia

DocumentationIPSS‑R risk category should be documented in prior authorization materials

Limitations of Use

Not a transfusion substituteReblozyl is not indicated as a substitute for RBC transfusions when immediate correction of anemia is required

FDA noteLimitation of Use stated in FDA labeling (informational)

Operational impactPatients requiring immediate RBC correction are not appropriate for luspatercept as an alternative to transfusion

Ring sideroblasts — conditional criteria (combined)

Ring sideroblast groupsEligibility may be expressed as either ring sideroblasts <15% (or <5% with SF3B1) plus EPO ≤500 mU/mL, OR ring sideroblasts ≥15% (or ≥5% with SF3B1)

EPO requirementSerum erythropoietin ≤ 500 mU/mL applies to the <15% ring sideroblast subgroup per policy history

Prescriber requirementPrescribed by, or in consultation with, a hematologist/oncologist or MDS specialist

MDS/MPN — overlap neoplasm

Overlap neoplasmMyelodysplastic syndrome/myeloproliferative overlap neoplasm (MDS/MPN) referenced as an eligible condition for anemia treatment

SF3B1 rolePresence of SF3B1 mutation required in MDS/MPN coverage node

ThrombocytosisThrombocytosis threshold (platelets ≥450 x10^9/L) referenced in MDS/MPN criteria

Specialist with expertise in MDS

Specialist definitionA hematologist, oncologist, or other specialist with demonstrated expertise in diagnosis and management of myelodysplastic syndromes

Documentation expectationRecord that therapy was prescribed by, or in consultation with, such a specialist for prior authorization

RelevanceSpecialist involvement is reiterated across initial and continuation authorization requirements

Ring sideroblasts criterion (alternate phrasing)

Ring sideroblasts ≥15%Ring sideroblasts ≥ 15% qualifies for eligibility

SF3B1 modifierWhen SF3B1 mutation is present, a lower threshold (≥5%) may be used

Alternate textDocument also contains '<15%' and '<5%' variants in revision-history—these appear as alternate phrasing in the policy text

Serum erythropoietin — policy citation

Serum EPO thresholdSerum erythropoietin ≤ 500 mU/mL

UsageUsed to define eligibility for certain ring sideroblast subgroups in MDS criteria

Measurement unitsReported in mU/mL and expected in documentation

Line of Therapy Designation

second-line

Line of therapy context (trial and label-informed statements):

MDS MEDALIST trial context: MEDALIST enrolled lower‑risk MDS patients who were ESA‑refractory or unlikely to respond; luspatercept dosing studied 1.0 mg/kg titratable to 1.75 mg/kg subcutaneously every 3 weeks. These trial contexts inform expectations regarding prior ESA therapy and response assessment.

first-line | subsequent per specific indication

Line of therapy per indication (NCCN/FDA context):

MDS - Indication per FDA/NCCN: NCCN and FDA contexts describe use as first‑line or subsequent depending on prior ESA exposure and specific MDS features (e.g., ESA‑naïve ESA indication, or anemia failing ESA therapy in ring sideroblast MDS).

Line varies by indication as described in professional society and FDA sections.

first-line

Line of therapy statement in policy history:

Initial therapy line: Indicated for symptomatic anemia in patients with lower‑risk MDS (IPSS‑R Very Low/Low/Intermediate) meeting the stated ring sideroblast/EPO criteria (initial therapy context).

not_specified

Line of therapy not specified in fragment:

Not specified: The provided document fragments do not consistently state a specific line of therapy for all covered indications; full policy may specify per indication.

unspecified

Line of therapy unspecified in provided summary lines:

Unspecified: Line of therapy is not stated in the extracted Summary of Changes fragments; refer to full policy for definitive line‑of‑therapy assignments.

Biomarker and Laboratory Requirements

SF3B1 — biomarker role

SF3B1 biomarkerSF3B1 mutation presence modifies ring sideroblast thresholds for eligibility

Clinical roleUsed to identify MDS subtypes (ring sideroblast‑positive) that may qualify for luspatercept

DocumentationSF3B1 mutation status should be recorded when used to apply the ≥5% ring sideroblast criterion

SF3B1 — NCCN ring sideroblast guidance

NCCN‑referenced thresholdNCCN supports ring sideroblasts ≥15% (or ≥5% with SF3B1) for Reblozyl use in lower‑risk MDS

Evidence categoryNCCN recommendations cited (2A) for ring sideroblast contexts

Clinical implicationSF3B1 mutation allows application of the lower (≥5%) ring sideroblast threshold per guidance

SF3B1 mutation — threshold modifier

SF3B1 presence effectWhen SF3B1 mutation present, ring sideroblast threshold may be lowered to ≥5% (or <5% noted in alternate text)

Applied contextsUsed both in MDS initial therapy and MDS/MPN coverage statements

Documentation requirementSF3B1 mutation status should be included in prior authorization where relevant

Ring sideroblasts / SF3B1 — combined statement

Combined criterionEligibility expressed as ring sideroblasts ≥15% OR ≥5% with SF3B1 mutation

Alternate phrasing presentDocument also includes '<15% / <5%' variants in summary lines representing other eligibility groupings

Prescriber requirementTherapy must be prescribed by or in consultation with an appropriate specialist

Serum erythropoietin — repeated citation

EPO threshold restatedSerum erythropoietin ≤ 500 mU/mL is repeatedly cited as an eligibility threshold

Role in prior authEPO ≤ 500 mU/mL expected to be documented for authorization where applicable

Unit consistencyValue expressed consistently in mU/mL across policy fragments

SF3B1 — references in policy

SF3B1 referencedPolicy fragments consistently reference presence of SF3B1 mutation as modifying ring sideroblast thresholds

Operational noteWhen SF3B1 present, documentation may support use of the ≥5% ring sideroblast criterion

Clinical documentationInclude SF3B1 testing result in prior authorization materials when used to qualify patient

Regimens and Dosing

Regimen	Indication	Coverage status
Luspatercept in combination with a JAK inhibitor (examples: fedratinib, ruxolitinib, momelotinib, pacritinib)
Myelofibrosis-associated anemia with symptomatic splenomegaly and/or constitutional symptoms (used in combination with a JAK inhibitor)
Per policy: prescribed by or in consultation with a hematologist/oncologist or other specialist; dosing per FDA labeling; initial authorization ≤ 12 months

Drug / Dose	Dosing details (studied regimen)	Coverage status
Luspatercept
1.0 mg/kg subcutaneously every 3 weeks, titratable to 1.75 mg/kg (studied regimen in MEDALIST and COMMANDS)
Dosing must follow FDA‑approved labeling; documented per prior authorization requirements

Agent	Indication / Eligibility (key thresholds)	Coverage status
Luspatercept (erythroid maturation agent)
Anemia associated with myelodysplastic syndromes with ring sideroblasts: ring sideroblasts ≥ 15% (or ≥ 5% with SF3B1 mutation) and serum erythropoietin ≤ 500 mU/mL (policy references these thresholds); prescribed by or in consultation with a hematologist/oncologist or specialist
Documentation of ring sideroblast percentage, SF3B1 status if applicable, and serum EPO level expected for prior authorization and continuation

Therapeutic class / example	Use case	Coverage status
Erythroid maturation agent (e.g., luspatercept)
Treatment of anemia in MDS with ring sideroblasts to reduce transfusion burden or increase hemoglobin when patients meet morphologic and laboratory criteria (ring sideroblast thresholds and serum EPO ≤ 500 mU/mL as cited); studied dosing: 1.0 mg/kg titratable to 1.75 mg/kg SC every 3 weeks
Coverage requires specialist prescribing/consultation and documentation of response for continuation (e.g., reduction in transfusions or hemoglobin increase)

Policy Update and Summary of Changes

(no date given)revised_criteria

Replaced criterion phrasing for initial beta thalassemia coverage to 'diagnosis of anemia due to beta thalassemia' (including beta+ thalassemia, beta0 thalassemia, and hemoglobin E/beta thalassemia).

(no date given)added_continuation_requirement

Added requirement for continuation of therapy documenting a positive clinical response to Reblozyl (e.g., reduction in transfusion burden or increase in hemoglobin from baseline).

(no date given)removed_criterion

Removed prior continuation criterion that required a ≥2‑unit PRBC transfusion reduction while receiving Reblozyl and removed redundant beta thalassemia diagnostic phrasing from continuation language.

Policy revision notes indicate deletion of earlier language that characterized Reblozyl as proven/medically necessary for ESA‑naïve MDS; claims or requests that rely on the removed ESA‑naïve wording may be at increased risk for denial under the updated coverage rationale.

Policy Summary

PayerUnitedHealthcare

PolicyReblozyl (Luspatercept-Aamt) — Coverage Criteria

Policy CodePolicy IEXD0084.09

Change TypeMaterial revisions to coverage criteria and prior authorization requirements

Effective DateSep 1, 2025

Next Review DateN/A

SourceLink

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