ModifiedUnitedHealthcarePolicy IEXD0084.09

Reblozyl (luspatercept-aamt) — Coverage Criteria for Anemia

Defines UnitedHealthcare medical necessity criteria for coverage of Reblozyl (luspatercept-aamt) for adults with beta thalassemia, lower-risk myelodysplastic syndromes (MDS), MDS/MPN overlap, and myelofibrosis-associated anemia; specifies prescriber qualifications, dosing per FDA label, and authorization durations.

Policy Summary

PayerUnitedHealthcare

PolicyReblozyl (luspatercept-aamt) — Coverage Criteria for Anemia

Policy CodePolicy IEXD0084.09

Change TypeMaterial revisions to coverage criteria and authorization requirements

Effective Date09/01/2025

Next Review DateN/A

Key ActionSubmit prior authorization with diagnosis, required documentation (age ≥18, transfusion history or biomarker data, specialist involvement), and evidence of positive clinical response for continuation.

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 ESA-naïve patients with MDS.

Revised coverage criteria and other policy sections referencing anemia in adult patients with beta thalassemia and MDS.

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

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

Removed criterion requiring that patient has experienced a reduction in transfusion requirements from pretreatment baseline of at least 2 units PRBC while receiving Reblozyl.

Revised language to indicate Reblozyl is proven and medically necessary for symptomatic anemia in MDS patients who meet specific IPSS-R and ring sideroblasts/SF3B1 criteria.

Removed criterion requiring explicit listing of beta thalassemia subtypes (beta+ thalassemia, beta0 thalassemia, hemoglobin E/beta thalassemia) in some places.

Specified exclusion: patient does not have a confirmed deletion 5q [del(5q)].

Specified ring sideroblasts criterion: < 15% (or < 5% with an SF3B1 mutation) and specified serum erythropoietin ≤ 500 mU/mL.

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).

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09/01/2025policy effective date

59%COMMANDS primary endpoint (luspatercept)

38%MEDALIST transfusion independence

356patients in COMMANDS

12 moinitial auth max

≤500EPO threshold

Coverage Criteria for Reblozyl (luspatercept-aamt)

inv-01: Beta thalassemia — Initial Therapy — Covered when ALL of the following are met

Covered when ALL of the following are met

Beta thalassemia initial therapy criteria: Diagnosis of anemia due to beta thalassemia (including beta+ thalassemia, beta0 thalassemia, and hemoglobin E/beta thalassemia); and age ≥ 18 years; and transfusion dependent as evidenced by both: (1) required regular transfusion of at least six units of packed red blood cells (PRBC) in the previous 24 weeks; and (2) no transfusion-free period greater than 35 days; and prescribed by, or in consultation with, a hematologist or other specialist with expertise in the diagnosis and management of beta thalassemia; and dosing is in accordance with the United States Food and Drug Administration approved labeling; and initial authorization will be for no more than 12 months.

inv-02: Beta thalassemia — Continuation of Therapy — Covered when ALL of the following are met

Covered when ALL of the following are met

Beta thalassemia continuation criteria: Documentation of a positive clinical response to Reblozyl (e.g., reduction in transfusion burden, increase in hemoglobin from baseline); and prescribed by, or in consultation with, a hematologist or other specialist with expertise in the diagnosis and management of beta thalassemia; and dosing is in accordance with the United States Food and Drug Administration approved labeling; and reauthorization will be for no more than 12 months.

inv-03: Myelodysplastic syndromes (MDS) — Initial Therapy — Covered when ALL of the following are met

Covered when ALL of the following are met

MDS initial therapy criteria: Diagnosis of symptomatic anemia due to myelodysplastic syndrome (MDS); and patient has lower-risk disease defined as IPSS-R: Very Low, Low, or Intermediate; and patient does not have a confirmed deletion 5q [del(5q)]; and one of the following pathways: (A) both ring sideroblasts < 15% (or ring sideroblasts < 5% with an SF3B1 mutation) AND serum erythropoietin ≤ 500 mU/mL; OR (B) ring sideroblasts ≥ 15% (or ring sideroblasts ≥ 5% with an SF3B1 mutation); and prescribed by, or in consultation with, a hematologist, oncologist, or other specialist with expertise in the diagnosis and management of MDS; and dosing is in accordance with the United States Food and Drug Administration approved labeling; and initial authorization will be for no more than 12 months.EPO ≤ 500 mU/mL; ring sideroblast percent criteria

Logical OR nested within AND as specified

inv-04: MDS — Continuation of Therapy — Covered when ALL of the following are met

Covered when ALL of the following are met

MDS continuation criteria: Documentation of a positive clinical response to Reblozyl (e.g., reduction in transfusion burden, increase in hemoglobin from baseline); and prescribed by, or in consultation with, a hematologist, oncologist, or other specialist with expertise in the diagnosis and management of myelodysplastic syndromes; and dosing is in accordance with the United States Food and Drug Administration approved labeling; and reauthorization will be for no more than 12 months.

inv-05: MDS/MPN overlap — Initial Therapy — Covered when ALL of the following are met

Covered when ALL of the following are met

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

inv-06: MDS/MPN — Continuation of Therapy — Covered when ALL of the following are met

Covered when ALL of the following are met

MDS/MPN continuation criteria: Documentation of a positive clinical response to Reblozyl (e.g., reduction in transfusion burden, increase in hemoglobin from baseline); and Reblozyl is prescribed by, or in consultation with, a hematologist, oncologist, or other specialist with expertise in the diagnosis and management of MDS/MPN; and dosing is in accordance with the FDA approved labeling; and reauthorization will be for no more than 12 months.

inv-07: Myelofibrosis-associated anemia — Initial Therapy — Covered when ALL of the following are met

Covered when ALL of the following are met

Myelofibrosis initial criteria: 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; and prescribed by, or in consultation with, a hematologist, oncologist, or other specialist with expertise in the diagnosis and management of myelofibrosis; and dosing is in accordance with the FDA approved labeling; and initial authorization will be for no more than 12 months.

JAK inhibitor combination required if splenomegaly/constitutional symptoms present

inv-08: Myelofibrosis — Continuation of Therapy — Covered when ALL of the following are met

Covered when ALL of the following are met

Myelofibrosis continuation criteria: Documentation of a positive clinical response to Reblozyl (e.g., reduction in transfusion burden, increase in hemoglobin from baseline); and Reblozyl is prescribed by, or in consultation with, a hematologist, oncologist, or other specialist with expertise in the diagnosis and management of myelofibrosis; and dosing is in accordance with the FDA approved labeling; and reauthorization will be for no more than 12 months.

inv-09: Evidence and indication criteria — Coverage considerations reference FDA indications and NCCN Compendium recommendations; clinical evidence from COMMANDS trial informs effectiveness context

Coverage considerations reference FDA indications and NCCN Compendium recommendations; clinical evidence from COMMANDS trial informs effectiveness.

FDA indications: Reblozyl (luspatercept-aamt) FDA indications (informational): anemia in adults with beta thalassemia who require regular RBC transfusions; anemia without previous ESA use (ESA-naïve) in adults with very low‑ to intermediate‑risk MDS who may require regular RBC transfusions; and anemia failing an ESA and requiring ≥2 RBC units over 8 weeks in adults with very low‑ to intermediate‑risk MDS‑RS or MDS/MPN‑RS‑T.

From FDA label (informational).

NCCN recommendations: NCCN Drugs and Biologics Compendium recommends Reblozyl for lower‑risk MDS with symptomatic anemia without del(5q) with ring sideroblasts ≥15% (or ≥5% with SF3B1 mutation), and for selected patients with ring sideroblasts <15% with serum erythropoietin ≤500 mU/mL; NCCN defines lack of response criteria.

NCCN recommendations (informational).

COMMANDS trial evidence: In ESA‑naïve, transfusion‑dependent lower‑risk MDS (COMMANDS trial), luspatercept achieved the primary endpoint in 59% of patients vs 31% with epoetin alfa (p<0.0001); safety included grade 3–4 events and one AML-related death considered related to luspatercept.

inv-10: Initial Therapy — Beta Thalassemia — Covered when ALL of the following are met

Covered when ALL of the following are met

Initial therapy beta thalassemia: Diagnosis of anemia due to beta thalassemia (including beta+ thalassemia, beta0 thalassemia, hemoglobin E/beta thalassemia).

Replaced prior wording that required diagnosis of beta thalassemia

inv-11: Continuation of Therapy — Covered with continuation criteria when ALL of the following are met

Covered with continuation criteria when ALL of the following are met

Continuation: Documentation of a positive clinical response to Reblozyl (e.g., reduction in transfusion burden, increase in hemoglobin from baseline); and prescribed by, or in consultation with, a hematologist or specialist; and dosing is in accordance with FDA-approved labeling; and reauthorization will be for no more than 12 months.

Removed prior requirement of ≥2 unit PRBC reduction; added broader positive response requirement

inv-12: Initial Therapy — Symptomatic Anemia in MDS — Covered when ALL of the following are met

Covered when ALL of the following are met

MDS initial: Diagnosis of symptomatic anemia due to MDS; and patient has lower-risk disease per IPSS-R (Very Low, Low, Intermediate); and no confirmed del(5q); and one of: (a) ring sideroblasts <15% (or <5% with SF3B1 mutation) AND serum erythropoietin ≤ 500 mU/mL, or (b) ring sideroblasts ≥15% (or ≥5% with SF3B1 mutation); and prescribed by, or in consultation with, a hematologist/oncologist or specialist in MDS; and dosing per FDA labeling; and initial authorization ≤ 12 months.EPO ≤ 500 mU/mL where applicable

Prescribed by or in consultation with hematologist/oncologist and dosing per FDA labeling

inv-13: Initial and ongoing coverage criteria — Covered when ALL of the following are met

Covered when ALL of the following are met

Reblozyl coverage criteria for symptomatic anemia in MDS: Patient has lower-risk disease as defined by IPSS-R (Very Low, Low, or Intermediate); and patient does not have a confirmed deletion 5q [del(5q)]; and either ring sideroblasts <15% (or <5% with an SF3B1 mutation) OR ring sideroblasts <5% with SF3B1 mutation (pathway-specific assessment); and serum erythropoietin ≤ 500 mU/mL where applicable; and patient has experienced a reduction in transfusion requirements from pretreatment baseline of at least 2 units PRBC while receiving Reblozyl when continuation criteria require demonstration of response (policy history notes).≤ 500 mU/mL; ≥ 2 units PRBC reduction (historical continuation note)

Combines initial and ongoing coverage criteria as presented in policy history

inv-14: Initial Therapy Criteria — Covered when ALL of the following pathway-specific criteria are met

Covered when ALL of the following pathway-specific criteria are met:

Pathway A: Ring sideroblasts ≥ 15% OR ring sideroblasts ≥ 5% with an SF3B1 mutation.see node

Supports eligibility per policy text

Pathway B: Ring sideroblasts < 15% OR ring sideroblasts < 5% with an SF3B1 mutation AND serum erythropoietin ≤ 500 mU/mL.see node

Alternate eligibility pathway per policy text

inv-15: Continuation Therapy — Continuation of therapy requires ALL of the following

Continuation of therapy requires ALL of the following:

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

Supporting documentation required

Prescriber: 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 FDA-approved labeling.

inv-16: Coverage statement — Reblozyl for MDS/MPN anemia — Covered when a policy-level determination applies

Covered when a policy-level determination applies

Coverage statement: Reblozyl (luspatercept-aamt) is indicated as proven and medically necessary for treatment of anemia in patients with myelodysplastic syndrome/myeloproliferative overlap neoplasm (MDS/MPN).

No patient-level criteria present in this fragment.

Patients with a confirmed deletion 5q [del(5q)] are excluded from coverage under the MDS indication. The policy explicitly requires that the patient "does not have a confirmed mutation with deletion 5q [del(5q)]" as a condition for eligibility for Reblozyl in symptomatic anemia due to MDS.

Reblozyl is not indicated as a substitute for red blood cell (RBC) transfusions when a patient requires immediate correction of anemia. The FDA labeling states: Reblozyl is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia, and the policy requires documentation of this limitation when requesting coverage.

For the MDS initial therapy pathway, patients with a confirmed del(5q) mutation are explicitly excluded. The initial therapy criteria list as a requirement that the "patient does not have a confirmed mutation with deletion 5q [del(5q)]," and this exclusion is reiterated in the policy history and criteria language.

Previously listed beta thalassemia subtypes (for example, beta+ thalassemia, beta0 thalassemia, and hemoglobin E/beta thalassemia) were removed from eligibility language in the revised policy. In addition, the presence of a del(5q) cytogenetic abnormality excludes patients from the MDS-related coverage group.

As part of the MDS eligibility requirements, the policy requires documentation that the patient does not have a confirmed deletion 5q [del(5q)]. This absence of del(5q) is an explicit exclusionary finding for the relevant MDS coverage pathways.

Provider Actions, Prior Authorization & Documentation

Prior Authorization

Prior Authorization Required

Prior authorization is required. Requests must demonstrate all applicable criteria for the requested indication, including diagnosis, age (≥18 years where specified), transfusion history or relevant laboratory/mutation data (e.g., ring sideroblast percentage, SF3B1 mutation status, serum erythropoietin level), prescriber specialty (hematologist/oncologist or consultation documented), and dosing consistent with U.S. FDA–approved labeling. Initial authorizations will be for no more than 12 months; reauthorization/continuation is addressed under the continuation criteria and limited to no more than 12 months.

Include diagnosis and site-specific supporting documentation (labs, mutation testing, transfusion records).
Document prescriber specialty or consultation with a hematologist/oncologist/MDS specialist.
Confirm dosing aligns with U.S. FDA–approved labeling.
Initial authorization ≤ 12 months; reauthorization/continuation ≤ 12 months.

Note

Prior Authorization Requirements (Informational)

Key Thresholds and Coding-Adjacent Values

Transfusion requirement (beta thalassemia)

Transfusion requirementRequired regular transfusion of ≥ 6 units packed red blood cells (PRBC) in the previous 24 weeks with no transfusion‑free period greater than 35 days

Age requirementPatient is 18 years of age or older

Diagnosis requirementDiagnosis of anemia due to beta thalassemia (including beta+ thalassemia, beta0 thalassemia, hemoglobin E/beta thalassemia)

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

Authorization durationInitial authorization will be for no more than 12 months

Serum erythropoietin (MDS eligibility)

Biomarker and Diagnostic Requirements

SF3B1 — biomarker role

SF3B1 as gating biomarkerSF3B1 mutation is referenced as a gating biomarker to modify ring sideroblast thresholds for MDS eligibility

Clinical applicationSF3B1 presence allows using a 5% ring sideroblast threshold instead of 15% in specified pathways

DocumentationSF3B1 mutation status should be documented when applicable

SF3B1 — referenced

SF3B1 referenced in guidanceSF3B1 mutation is referenced by NCCN and policy as a determinant for ring sideroblast‑based eligibility

Impact on thresholdsPresence of SF3B1 reduces ring sideroblast threshold to 5% in specified criteria

Dosing, Trials, and Regimens

Regimen	Indication	Coverage status
Luspatercept subcutaneously every 3 weeks starting 1.0 mg/kg with possible titration to 1.75 mg/kg	ESA‑naïve, transfusion‑dependent lower‑risk MDS (COMMANDS trial population)

Regimen	Indication	Coverage status
Epoetin alfa subcutaneously once weekly starting 450 IU/kg with possible titration up to 1050 IU/kg (maximum total dose 80,000 IU)	Comparator arm in COMMANDS trial (ESA option for trial participants)

Regimen	Requirement / prescriber	Coverage status
Luspatercept dosing per U.S. FDA–approved labeling	Must be prescribed by, or in consultation with, a hematologist, oncologist, or other specialist with expertise in MDS; dosing per FDA labeling

Product	Indication (policy statement)	Coverage status
Reblozyl (luspatercept‑aamt)	Anemia in patients with myelodysplastic syndrome/myeloproliferative overlap neoplasm (MDS/MPN)

Definitions and Key Terms

Beta-thalassemias are inherited disorders of beta-globin synthesis that cause variable severity of anemia. Patients with severe disease may become transfusion dependent; chronic red blood cell transfusions can lead to iron overload and associated complications. Policy criteria reference transfusion dependence definitions and trial enrollment characteristics when considering Reblozyl for beta thalassemia-related anemia.

Transfusion dependent (beta thalassemia)

Definition — transfusion dependent (beta thalassemia)Required regular transfusion of at least six units of PRBC in the previous 24 weeks with no transfusion‑free period greater than 35 days

Clinical contextUsed to identify patients with beta thalassemia who require Reblozyl consideration

DocumentationTransfusion records should support the transfusion‑dependence definition

Lower‑risk MDS

Lower‑risk MDS definition

Line of Therapy

inv-98: first-line | second-line — 1 top-level node

Line of therapy per FDA/NCCN: Indications include ESA‑naïve anemia in very low‑ to intermediate‑risk MDS and anemia failing an ESA in similar risk MDS‑RS or MDS/MPN‑RS‑T; NCCN recommendations apply to lower‑risk MDS with ring sideroblast criteria and serum EPO thresholds.

Policy History and Material Changes

2025-09-01policy_effective_date_and_scopeLatest

Policy updated to recognize indications and uses listed in the NCCN Drugs & Biologics Compendium (Categories 1, 2A, 2B) as proven and medically necessary and Category 3 as not medically necessary; multiple coverage criteria and policy rationale revisions made including revisions specific to anemia indications.

revised_coverage_criteria

Revised coverage criteria and policy sections to focus on anemia due to beta thalassemia and to update MDS eligibility pathways (IPSS-R lower-risk specification, ring sideroblast/SF3B1 combinations, and serum EPO thresholds), and to align prescriber and dosing requirements with FDA labeling.

Policy Summary

PayerUnitedHealthcare

PolicyReblozyl (luspatercept-aamt) — Coverage Criteria for Anemia

Policy CodePolicy IEXD0084.09

Change TypeMaterial revisions to coverage criteria and authorization requirements

Effective Date09/01/2025

Next Review DateN/A

SourceLink

On This Page

Phase 3 interim analysis.

Informational: Policy references FDA labeling and the NCCN Drugs & Biologics Compendium recommendations. Prior authorization requests should include indication-specific context such as prior ESA use status (if relevant), transfusion burden, and trial- or guideline-relevant criteria (e.g., ESA‑naïve versus ESA‑exposed populations). FDA approval alone is informational and not by itself sufficient for coverage determination.

Document whether patient is ESA‑naïve or previously treated with ESAs as applicable (MEDALIST and COMMANDS trial contexts).
Reference NCCN criteria (ring sideroblast and EPO thresholds) when applicable.
FDA indications are: anemia in transfusion-dependent beta thalassemia; ESA‑naïve anemia in certain MDS patients; anemia failing an ESA in MDS with ring sideroblasts/MDS‑MPN-RS-T.

Note

Prior Authorization Requirements Updated

Updated prior authorization criteria: for beta thalassemia pathway, the required diagnostic language has been changed to 'anemia due to beta thalassemia' (rather than listing beta thalassemia subtypes alone); continuation criteria now require documentation of a positive clinical response to Reblozyl (for example, reduction in transfusion burden or increase in hemoglobin from baseline).

Ensure documentation specifies 'anemia due to beta thalassemia' when applying the beta thalassemia criteria.
For continuation requests, provide objective evidence of clinical response (see continuation documentation callout).
Removed prior criterion that a patient must have experienced ≥2 unit PRBC reduction while receiving Reblozyl for continuation eligibility — instead submit broader positive-response documentation.

Prior Authorization

Prior Authorization Required When Criteria Met / Coverage Statement

Reblozyl is considered proven and medically necessary for specified indications when all criteria are met. For beta thalassemia, MDS, MDS/MPN, and myelofibrosis-associated anemia pathways, prior authorization must document that the patient satisfies the listed clinical, laboratory, and prescriber requirements.

For beta thalassemia: diagnosis of anemia due to beta thalassemia, age ≥18, transfusion dependence (≥6 units PRBC in prior 24 weeks and no transfusion-free period >35 days), hematology prescriber involvement, dosing per FDA labeling.
For MDS (lower-risk IPSS‑R): document IPSS‑R category, absence of del(5q), ring sideroblast percentage and/or SF3B1 mutation status, and serum EPO where applicable.
For MDS/MPN: document SF3B1 mutation, thrombocytosis (platelets ≥450 x 10^9/L), prescriber specialty, and dosing per FDA labeling.

Documentation Required

Beta Thalassemia: Transfusion Dependence

Beta thalassemia — transfusion dependence documentation is required. Lack of documentation showing transfusion dependence (at least six units PRBC in the prior 24 weeks and no transfusion‑free period >35 days) may render the request ineligible.

Attach transfusion records covering the prior 24 weeks showing total PRBC units and dates to demonstrate no transfusion‑free period >35 days.
Age ≥18 must be documented.

Denial Risk

Denial Risk from Policy Revision

Denial risk from policy revisions — removal of prior language (e.g., ESA‑naïve MDS coverage statements or prior numeric transfusion‑reduction requirements) may lead to denials if requests rely on language that has been removed. Providers should ensure current documentation aligns with the revised criteria.

Do not submit requests relying on previously removed coverage statements (for example, ESA‑naïve MDS coverage that was removed).
Update supporting documentation to reflect the current required elements (diagnosis phrasing, response evidence, transfusion dependence thresholds).

Denial Risk

Failure to Document Required Diagnosis or Response

Failure to document required diagnosis or clinical elements may result in denial. Specifically, for beta thalassemia pathway requests, the diagnosis must be documented as 'anemia due to beta thalassemia' and continuation requests must include evidence of positive clinical response.

If the record lists only 'beta thalassemia' without stating 'anemia due to', supplement the chart with clinician rationale linking the diagnosis to the current anemia.
For continuation, include objective measures (transfusion logs, hemoglobin trends) showing improvement.

Documentation Required

Biomarker/Clinical Gating Requirements

Absence of documented ring sideroblast percentage or SF3B1 mutation status (when applicable) or missing serum erythropoietin level may trigger denial for MDS pathways that require these biomarkers. Provide laboratory/pathology reports showing ring sideroblast percentage and SF3B1 mutation testing results and recent serum EPO level (≤ 500 mU/mL when required).

Attach bone marrow pathology report with ring sideroblast percentage.
Attach molecular testing report for SF3B1 mutation when referenced.
Include a serum erythropoietin (EPO) level result when applying the EPO ≤ 500 mU/mL pathway.

Documentation Required

Continuation of Therapy / Reauthorization Documentation

Continuation documentation — Reauthorization requests must include objective evidence of a positive clinical response to Reblozyl, such as reduction in transfusion burden or increase in hemoglobin from baseline. Reauthorization will be for no more than 12 months.

Provide pre‑ and on‑treatment transfusion records quantifying units and dates and/or hemoglobin trend data.
Document ongoing prescribing specialist involvement and that dosing remains consistent with FDA labeling.
Reauthorization period limited to ≤ 12 months.

Documentation Required

MDS Initial Therapy Documentation

MDS initial therapy documentation — For initial MDS pathway requests, include IPSS‑R risk category (Very Low, Low, or Intermediate), absence of confirmed del(5q), ring sideroblast percentage and/or SF3B1 mutation status as applicable, and serum erythropoietin level when using the EPO‑restricted pathway.

Attach pathology and cytogenetics reports documenting del(5q) status and ring sideroblast percentage.
Include IPSS‑R scoring documentation or clinician note stating the risk category.
Include serum EPO result when applying the EPO ≤ 500 mU/mL criterion.

Documentation Required

Transfusion Reduction Documentation

Transfusion reduction documentation — When referenced, demonstrate reduction in transfusion requirements from pretreatment baseline if required by the pathway or for clinical response documentation. Provide quantified comparisons (units PRBC) from baseline and during treatment.

Baseline transfusion burden (units per defined baseline interval) and on‑treatment transfusion totals with dates.
If prior policy language required a ≥2 unit PRBC reduction, note that criterion was removed — continuation now requires broader evidence of positive clinical response.

Documentation Required

Erythropoietin Level Documentation

Erythropoietin level — When applying the EPO‑limited MDS pathway, include a documented serum erythropoietin level. The policy uses a threshold of ≤ 500 mU/mL where applicable.

Attach the lab result specifying serum EPO value and date.
If EPO > 500 mU/mL, indicate alternate pathway criteria (e.g., ring sideroblasts ≥15% or SF3B1 mutation) if applicable.

Documentation Required

Disease Characterization Requirements

Disease characterization — Document IPSS‑R lower‑risk categorization (Very Low, Low, or Intermediate), ring sideroblast percentage, and SF3B1 mutation status when applicable for MDS pathways.

Include IPSS‑R scoring or clinical note documenting risk category.
Provide bone marrow pathology and molecular testing reports for ring sideroblasts and SF3B1.

Documentation Required

Prescriber and Dosing Requirements

Dosing and prescriber requirements — Dosing must be in accordance with U.S. FDA–approved labeling. Treatment should be prescribed by, or in consultation with, a hematologist, oncologist, or other specialist with expertise in the relevant disease state (beta thalassemia, MDS, MDS/MPN, myelofibrosis).

Document prescribed dose, dose adjustments, and schedule consistent with FDA label.
Document specialist involvement or consultation in the medical record.

Documentation Required

Criteria Reference: Alternative Pathways

Alternative pathway documentation — Where the policy outlines alternate eligibility pathways (for example, ring sideroblast thresholds vs. SF3B1 mutation, or EPO‑restricted vs. non‑EPO pathways), clearly document which pathway the patient meets and include the supporting lab/pathology evidence.

State explicitly in the request which eligibility pathway is being used and attach corresponding evidence (e.g., ring sideroblast % OR SF3B1 mutation result OR serum EPO).
Do not mix pathway criteria without documentation proving each required element.

Step Therapy

ESA / Step Therapy Context (No Mandatory Step Therapy Specified)

No step therapy requirement specified — The policy excerpts do not impose explicit sequential drug‑step requirements. ESA considerations are referenced for clinical context (trial populations), but no formal step therapy (mandatory trial of an ESA before Reblozyl) is specified in these policy fragments.

Document ESA history when relevant (ESA‑naïve vs prior ESA use) to support the chosen indication, but note that the policy does not specify an ESA trial as a universal requirement in these excerpts.

Serum erythropoietin thresholdSerum erythropoietin ≤ 500 mU/mL

ContextApplies to MDS initial therapy pathway when ring sideroblasts <15% (or <5% with SF3B1 mutation)

DocumentationEPO level must be documented for eligibility assessment

Thrombocytosis (MDS/MPN)

Thrombocytosis thresholdPlatelet count ≥ 450 x 10^9/L

Associated biomarkerPresence of SF3B1 mutation required for MDS/MPN overlap indication

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

Serum erythropoietin

Serum erythropoietin thresholdSerum erythropoietin ≤ 500 mU/mL

Applies toMDS initial therapy pathway when ring sideroblasts <15% (or <5% with SF3B1 mutation)

Documentation noteEPO level should be included in authorization documentation

Transfusion reduction

Transfusion reduction requirementReduction of at least 2 units PRBC from pretreatment baseline while receiving Reblozyl

PurposeExample of a positive clinical response used historically for continuation documentation

Continuation contextDocumentation of positive clinical response may be required for reauthorization

Ring sideroblasts (lower pathway)

Ring sideroblasts threshold (lower pathway)Ring sideroblasts < 15% (or < 5% with SF3B1 mutation)

Alternate requirementWhen <15%, serum erythropoietin ≤ 500 mU/mL is also required (per pathway rules)

DocumentationRing sideroblast percentage and SF3B1 status must be documented

Ring sideroblasts (pathway-specific)

Ring sideroblasts — pathway optionsEligibility may require either: (A) ≥ 15% (or ≥ 5% with SF3B1 mutation) OR (B) < 15% (or < 5% with SF3B1 mutation) depending on the pathway

SF3B1 effectPresence of SF3B1 mutation lowers the ring sideroblast threshold to 5% in relevant pathways

Authorization noteDocument which pathway applies when submitting prior authorization

Serum erythropoietin (EPO)

Serum erythropoietin thresholdSerum erythropoietin ≤ 500 mU/mL

RoleUsed as an eligibility gate in MDS pathway when ring sideroblasts are below threshold

DocumentationEPO level must be included in MDS initial therapy documentation

Documentation requirementInclude SF3B1 mutation testing results in authorization materials

Ring sideroblast percentage

Ring sideroblast percentage threshold>= 15% OR >= 5% with SF3B1 mutation

SourceNCCN Drugs and Biologics Compendium recommendations referenced in policy

UseApplied to determine eligibility for Reblozyl in lower‑risk MDS with symptomatic anemia

SF3B1 conditional thresholds

Conditional SF3B1 thresholdsCriteria reference <5% ring sideroblasts with SF3B1 mutation (conditional) or ≥5% with SF3B1 mutation depending on pathway

Policy contextUsed when defining alternative eligibility pathways for MDS patients

DocumentationSpecify which conditional threshold applies in the patient record

del(5q) — exclusion

del(5q) exclusionPresence of a confirmed deletion 5q [del(5q)] excludes the patient from the MDS initial therapy criteria

DocumentationAbsence of del(5q) should be documented for MDS eligibility

SourcePolicy initial therapy criteria for MDS

SF3B1 mutation — <5% RS implication

SF3B1 and low RSSF3B1 mutation allows consideration of eligibility when ring sideroblasts are <5% in specific pathways

Clinical implicationSF3B1 presence lowers the numeric RS threshold required for eligibility

DocumentationSF3B1 mutation testing should be provided when RS <15%

Serum erythropoietin (EPO)

EPO thresholdSerum erythropoietin (EPO) ≤ 500 mU/mL

Applies toMDS eligibility when ring sideroblasts are below pathway threshold

Documentation requirementEPO level must be included in clinical documentation for eligibility

SF3B1 — threshold adjustment

SF3B1 lowers RS thresholdPresence of SF3B1 mutation is used to lower the ring sideroblast threshold to 5% for eligibility in referenced pathways

ReferencePolicy and NCCN guidance articulate this adjustment

RequirementDocument SF3B1 mutation status to apply the lowered threshold

MDS classified as Very Low, Low, or Intermediate per IPSS‑R

Use in policyRequired for eligibility for Reblozyl in symptomatic MDS initial therapy

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

Lower risk MDS (definition)

Lower‑risk MDS definedDefined as IPSS‑R categories Very Low, Low, or Intermediate

Policy applicationUsed to gate eligibility for Reblozyl in MDS initial therapy

Documentation noteProvide IPSS‑R categorization with the request

Lack of response to luspatercept (NCCN)

NCCN definition of lack of response to luspaterceptLack of response defined as lack of 1.5 g/dL rise in hemoglobin or lack of decrease in RBC transfusion requirement by six to eight weeks of treatment

ContextUsed by NCCN and referenced for assessing response in clinical pathways

ImplicationMay inform continuation or switch decisions in practice

Positive clinical response

Positive clinical response (examples)Positive clinical response to Reblozyl may include reduction in transfusion burden or increase in hemoglobin from baseline

Use for continuationDocumentation of such a response is required for continuation/re‑authorization

DocumentationProvide objective measures (transfusion records, hemoglobin values) to support response

IPSS‑R lower‑risk definition

IPSS‑R categories as lower‑riskIPSS‑R Very Low/Low/Intermediate are defined as lower‑risk disease for Reblozyl eligibility

Policy useRequired for symptomatic MDS initial therapy pathway

Documentation noteInclude IPSS‑R categorization in authorization documentation

Ring sideroblasts — threshold

Ring sideroblast threshold (policy)Ring sideroblasts <15% (or <5% if SF3B1 mutation present)

ApplicationSpecifies one pathway for MDS eligibility when combined with EPO ≤ 500 mU/mL

DocumentationReport ring sideroblast percentage and SF3B1 status

Ring sideroblasts — criteria

Ring sideroblasts criteria (policy)Ring sideroblasts criteria referenced: either ≥15% (or ≥5% with SF3B1) or <15% (or <5% with SF3B1) as pathway‑specific options

Clinical notePolicy requires documenting which pathway (≥15% vs <15%) applies

SF3B1 effectSF3B1 mutation reduces numeric RS threshold to 5% in both pathway types

Serum erythropoietin — threshold

Erythropoietin threshold referencedSerum erythropoietin ≤ 500 mU/mL

ContextUsed in MDS eligibility when ring sideroblasts are below threshold per policy and NCCN guidance

DocumentationEPO result should be provided with prior authorization request

MDS/MPN overlap — indication

MDS/MPN overlap indicationAnemia in patients with myelodysplastic syndrome/myeloproliferative overlap neoplasm (MDS/MPN) referenced as an indicated clinical population

Policy additionPolicy history adds coverage statement for Reblozyl in MDS/MPN anemia

DocumentationInclude diagnosis of MDS/MPN and relevant biomarkers (SF3B1, platelets) in request

Anemia in MDS/MPN (term)

MDS/MPN termAnemia in Patients With Myelodysplastic Syndrome/Myeloproliferative Overlap Neoplasm (MDS/MPN)

Policy useReferenced in coverage statement additions in policy history

Documentation noteProvide clinical and biomarker data when applicable

Expertise in MDS management

Expertise recommendationExpertise in the diagnosis and management of myelodysplastic syndromes is recommended for prescribing or consulting clinicians

Prescriber requirementPrescribed by, or in consultation with, a hematologist, oncologist, or MDS specialist as specified in criteria

DocumentationInclude specialist consultation or attestation in authorization materials when required

changed_continuation_requirements

Continuation criteria revised to require documentation of a positive clinical response for continued therapy and removed the single numeric requirement of ≥2 units PRBC reduction in some places.

removed_beta_thalassemia_subtypes

Removed explicit listing of beta thalassemia subtypes from some sections as part of simplification to 'anemia due to beta thalassemia'.

2025-09-01added_coverage_statement_MDS_MPN

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

2025-09-01policy_effective_dateLatest

Policy effective date set to 09/01/2025 reflecting multiple updates including recognition of NCCN compendia indications and coverage rationale changes.

removed_statement_for_ESA_naive_MDS

Removed prior language indicating Reblozyl was proven and/or medically necessary for symptomatic anemia in ESA‑naïve patients with MDS; coverage now reflects specified clinical criteria and NCCN/FDA-aligned considerations.

clarified_MDS_initial_criteria

Clarified MDS initial therapy criteria to require lower‑risk disease per IPSS‑R, absence of del(5q), and ring sideroblasts/SF3B1 and serum erythropoietin-based pathway requirements; prescriber specialty and FDA dosing alignment added.

Policy history shows removal of prior language that stated Reblozyl was proven and/or medically necessary for ESA‑naïve MDS. The revision entries explicitly note that the earlier statement claiming medical necessity for ESA‑naïve symptomatic MDS patients was removed from the policy language.

Multiple policy history entries document revisions across coverage criteria and documentation requirements. Changes include removal of explicit beta thalassemia subtype listings, addition of specific MDS biomarker and EPO thresholds, explicit exclusion of del(5q), and updates to continuation documentation requirements (for example, specifying a broader requirement for documentation of a positive clinical response rather than relying solely on a fixed ≥2 unit PRBC reduction).