ModifiedmhnPolicy CP.PHAR.112

Clinical Policy: Ponatinib (Iclusig)

Defines medical necessity criteria, prior authorization requirements, and coverage limits for ponatinib (Iclusig) for commercial, HIM, and Medicaid members under Centene-affiliated health plans.

Policy Summary

Payermhn

PolicyClinical Policy: Ponatinib (Iclusig)

Policy CodePolicy CP.PHAR.112

Change TypeMaterial updates — added indications, dosing, quantity limit, and state-level step therapy changes

Effective Date06.01.13

Next Review Date

Key ActionSubmit prior authorization with documentation of diagnosis, specialist involvement, required prior TKI history or mutation status, and proposed dose within policy limits.

SourceLink

POLICY UPDATE CHANGES

Added criteria set for off-label use in gastrointestinal stromal tumor per NCCN Compendium.

Added new indication and dosing for newly diagnosed Ph+ ALL per updated prescribing information; revised appendices regarding recommended cycles for combination therapy in newly diagnosed ALL.

Added quantity limit of one tablet per day.

For ALL per NCCN Compendium added option for combination use with corticosteroid for newly diagnosed disease and pediatric option for relapsed/refractory BCR-ABL1-positive B- or T-cell ALL with ABL-class translocation.

Added step therapy bypass for IL HIM per IL HB 5395 and updated state-level Appendix E entries (added OK, MS; updated OH).

≥18Minimum age

45 mg/dayMax dose (routine)

30 mg/dayDose for new Ph+ ALL combo

12 months

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Approval duration (Commercial)

6 monthsApproval duration (Medicaid/HIM)

Coverage Criteria

COVERAGE CRITERIA — Chronic Myeloid Leukemia criteria set

Covered when ALL of the following are met for Chronic Myeloid Leukemia:

CML Initial Approval

Diagnosis of Ph+ (BCR-ABL1-positive) CML
Provider: Prescribed by or in consultation with an oncologist or hematologist
Age ≥ 18 years
Indication specifics: One of: (a) chronic phase with resistance, toxicity, or intolerance to ≥ 2 prior TKIs (e.g., imatinib, bosutinib, dasatinib, nilotinib); (b) accelerated or blast phase when no other TKI therapy is indicated; (c) presence of BCR-ABL T315I mutation
Examples of prior TKIs listed in policy
Generic use: For brand Iclusig requests, member must use generic ponatinib if available unless contraindicated or clinically significant adverse effects are experienced
Dose limits: Dose does not exceed 45 mg per day (one tablet per day) OR dose is supported by practice guidelines or peer-reviewed literature for relevant off-label use (prescriber must submit supporting evidence)<=45 mg/day or guideline-supported
Prescribed regimen must be FDA-approved or recommended by NCCN

Coverage criteria (summarized sets) — multiple distinct criteria sets referenced

Policy includes multiple distinct criteria sets: chronic phase CML, accelerated/blast phase CML, Ph+ ALL (newly diagnosed and relapsed/refractory), and off-label indications (e.g., GIST, MLNE).

Chronic phase CML: Covered when member has chronic phase CML and has experienced resistance, toxicity, or intolerance to two or more prior TKIs (2 prior TKIs required)2 prior TKIs required

Chunk support: 26,27

Accelerated or blast phase CML: Covered when accelerated or blast phase CML and either no other TKI therapy is indicated or member has failed prior therapies; 2-TKI requirement may be waived in these phasesno prior TKI required if no other TKI indicated

Chunk support: 26,23

Ph+ ALL - Newly diagnosed: Newly diagnosed Ph+ ALL: coverage includes combination use with chemotherapy per updated prescribing information (Iclusig starting 30 mg PO QD with reduction to 15 mg upon MRD-negative complete remission) and NCCN-based option to add corticosteroid

Non‑FDA approved (off‑label) indications that are not specifically addressed in this policy are excluded from coverage unless the provider submits sufficient documentation demonstrating efficacy and safety in accordance with the plan's off‑label use policies (see CP.CPA.09 for Commercial, HIM.PA.154 for Marketplace, and CP.PMN.53 for Medicaid).

Ponatinib carries multiple boxed warnings. Serious risks included in the boxed warnings are arterial occlusion, venous thromboembolism (VTE), heart failure, and hepatotoxicity. These safety concerns should be considered when evaluating medical necessity and prior authorization requests.

Off‑label use may be considered when the request is supported by adequate evidence and documentation. Providers must submit clinical records (office notes, labs, imaging, pathology, or other relevant information) that justify the requested off‑label indication and demonstrate adherence to the referenced off‑label use policies. Requests lacking sufficient supporting evidence per the off‑label policies are subject to denial.

Historically the policy has required prior tyrosine kinase inhibitor (TKI) therapy for certain CML indications. For chronic‑phase CML, coverage generally requires documented resistance, toxicity, or intolerance to two or more prior TKIs. The policy also preserves an exception allowing members with the BCR‑ABL T315I mutation to bypass prior‑TKI requirements in CML per established policy language.

Covered Regimens and Dosing

Regimen	Indication	Coverage status
Ponatinib 30 mg/day in combination with multi-agent chemotherapy (starting dose 30 mg PO QD; reduce to 15 mg PO QD upon MRD‑negative [≤0.01% BCR‑ABL1] complete remission)
Newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) when used in combination with chemotherapy (accelerated approval; continued approval contingent on confirmatory trial)
Per policy: starting dose 30 mg/day for newly diagnosed ALL combo therapy; dose reduction to 15 mg/day upon MRD‑negative CR; prescriber must document intended combination with chemotherapy

Regimen / Dosing	Indications (approved and guideline-supported off-label)	Coverage status
Ponatinib up to 45 mg per day (or dosing supported by practice guidelines or peer‑reviewed literature); one tablet per day unless guideline-supported alternative dosing provided
Chronic myeloid leukemia (CML) including chronic, accelerated, and blast phase; Ph+ ALL (other than newly diagnosed combo described separately); off‑label uses supported by NCCN or literature (e.g., MLNE with ABL1 rearrangement, GIST when criteria met)
Dose must not exceed 45 mg/day for most requests unless prescriber submits guideline/literature support for alternate dosing; prior‑TKI requirements apply for chronic phase CML (resistance/intolerance to ≥2 TKIs) but may be waived for accelerated/blast phase or T315I mutation per policy

Regimen	Dosing details / formulation	Coverage status
Iclusig (ponatinib) starting 30 mg PO once daily with planned reduction to 15 mg PO once daily upon achievement of MRD‑negative (≤0.01% BCR‑ABL1) complete remission
Applicable to newly diagnosed Ph+ ALL when given in combination with chemotherapy per prescribing information; tablets available in 10 mg, 15 mg, 30 mg, and 45 mg strengths
Prescribing clinician should document MRD status and planned dose reduction; product strengths: 10 mg, 15 mg, 30 mg, 45 mg

Regimen / Starting dose	Indication(s)	Coverage status / notes
Iclusig (ponatinib) starting dose 45 mg PO once daily; consider dose reductions per prescribing information
Accelerated‑phase or blast‑phase CML and other Ph+ indications (including certain T315I‑positive cases); also used for other indications where 45 mg/day is the referenced maximum
Policy notes: starting dose typically 45 mg/day for accelerated/blast phase CML; dose reductions should follow the prescribing information and policy limits (maximum 45 mg/day for most requests; exceptions supported by guidelines require documentation)

Provider Actions, Authorization & Documentation

Prior Authorization

Prior Authorization Required

Prior authorization is required. Provider must submit documentation demonstrating the member meets all applicable approval criteria, including diagnosis, specialist involvement, age criteria, prior TKI use or other indication-specific evidence. Requests should include office chart notes, laboratory results, pathology reports, mutation testing (e.g., BCR-ABL T315I), prior therapy history, and any documentation supporting intolerance or resistance to prior therapies. For brand Iclusig requests, generic ponatinib must be used if available unless contraindicated or clinically significant adverse effects are experienced.

Submit office notes, labs, pathology, mutation testing (e.g., T315I), and prior TKI treatment records
For CML chronic phase: documentation of resistance, toxicity, or intolerance to ≥2 TKIs OR other allowed options per criteria
T315I mutation allows bypass of prior-TKI requirement for CML
For ABL1 rearrangement positive myeloid/lymphoid neoplasms: step therapy with imatinib required unless contraindicated/intolerant or state regulation prohibits
State-specific prohibitions on step therapy/redirection (see Appendix E) override step therapy requirements where applicable

Dose Limits & Coding Summary

Maximum daily dose

Maximum daily dose (standard)45 mg per day (one tablet per day)

Maximum daily dose (newly diagnosed Ph+ ALL in combination)30 mg per day

Quantity limitOne tablet per day

Line of Therapy Definitions

inv-25: second-line | later — criteria node (1 top-level node)

Second-line | later: For chronic phase CML: member has experienced resistance, toxicity, or intolerance to prior therapy with two or more TKIs>=2 prior TKIs

Applies to chronic phase CML per initial approval criteria

inv-26: first-line | later — criteria node (1 top-level node)

First-line | later: Newly diagnosed Ph+ ALL: use in combination with chemotherapy is allowed (starting dose 30 mg PO QD with reduction per response); also applicable for other ALL settings when no other TKI is indicated or T315I mutation presentsee dosing guidance

Reflects first-line combination approval for newly diagnosed Ph+ ALL

Biomarker Requirements

BCR-ABL T315I — biomarker requirement

BiomarkerBCR-ABL T315I mutation

Permissive effectPresence of T315I allows use of ponatinib even when prior TKI requirements would otherwise apply (e.g., bypass 2‑TKI requirement for CML)

Applicable indicationsCML (chronic, accelerated, blast) and Ph+ ALL — T315I‑positive patients included in FDA indications

BCR-ABL T315I — biomarker requirement (alternate reference)

BiomarkerBCR-ABL T315I mutation

Policy effectT315I mutation noted in policy history as allowing bypass of prior‑TKI requirements for CML

Definitions and Background

Ponatinib (Iclusig) is a BCR‑ABL tyrosine kinase inhibitor approved for adult patients with Philadelphia chromosome‑positive (Ph+) chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL), including disease with the BCR‑ABL T315I mutation. The agent is approved as monotherapy for certain CML phases and Ph+ ALL, and it has an accelerated approval pathway for use in newly diagnosed Ph+ ALL in combination with chemotherapy (starting dose 30 mg PO once daily with recommended reduction to 15 mg PO once daily upon MRD‑negative complete remission). For accelerated or blast‑phase CML and other Ph+ indications, typical starting doses referenced in the prescribing information are up to 45 mg PO once daily; tablets are available in 10, 15, 30, and 45 mg strengths.

Ph+ definition (Philadelphia chromosome-positive)

DefinitionPh+: Philadelphia chromosome‑positive

Usage in criteriaRequired diagnosis statement for CML and ALL initial approval criteria (e.g., 'Diagnosis of Ph+ (BCR‑ABL1‑positive) CML/ALL')

Abbreviation expansionPh+ = Philadelphia chromosome‑positive (BCR‑ABL1‑positive)

Policy Summary

Payermhn

PolicyClinical Policy: Ponatinib (Iclusig)

Policy CodePolicy CP.PHAR.112

Change TypeMaterial updates — added indications, dosing, quantity limit, and state-level step therapy changes

Effective Date06.01.13

Next Review Date

Key ActionSubmit prior authorization with documentation of diagnosis, specialist involvement, required prior TKI history or mutation status, and proposed dose within policy limits.

SourceLink

On This Page

age and dosing specifics referenced in dosing section

Chunk support: 23,28

Ph+ ALL - Relapsed/Refractory: Relapsed/refractory BCR-ABL1-positive B-cell- or T-cell-ALL with ABL-class translocation: coverage expanded to pediatric patients (≤ 18 years) per 2Q2025 reviewpediatric eligibility added

Chunk support: 28

T315I mutation: Members with BCR-ABL T315I mutation allowed option to bypass prior TKIs for CMLpresence of T315I mutation

Chunk support: 26

Off-label GIST and MLNE: Off-label use criteria sets added for gastrointestinal stromal tumor and for lymphoid/myeloid/mixed lineage neoplasms with ABL1 rearrangement (with redirection to imatinib for ABL1 rearrangement positive unless prohibited by state regulation)per NCCN compendium

Chunk support: 27,28,26

Step Therapy

Step Therapy for ABL1 Rearrangement

Step therapy applies for ABL1 rearrangement-positive myeloid/lymphoid neoplasms: the member must have contraindication, intolerance, or disease progression on imatinib before approval of ponatinib, unless the request meets an exception. Exceptions include states with regulations prohibiting oncology step therapy/redirection for the setting in question (see Appendix E) or documented contraindication/intolerance to imatinib.

Imatinib required first-line for ABL1 rearrangement positive disease unless documented intolerance, contraindication, or progression
Illinois HIM requests are exempt from step therapy per IL HB 5395 (effective 1/1/2026)
If state law prohibits redirection/step therapy in the specific oncology setting, step therapy requirement is waived

Denial Risk

Non‑Covered Off‑Label Uses

Non‑covered off‑label uses may be denied unless sufficient supporting documentation is provided. Off‑label requests must be supported by FDA approval or recommendations in NCCN or by evidence per the plan's off‑label use policies (CP.CPA.09, HIM.PA.154, CP.PMN.53).

Prescriber must submit peer‑reviewed literature or guideline support when dosing or indication is off‑label
Coverage is allowed for specified off‑label indications in this policy only when all listed criteria are met
Requests lacking sufficient evidence or documentation for off‑label use may be denied

Documentation Required

Supporting Documentation & Denial Triggers

Supporting documentation required. Provider must submit clinical documentation (office notes, labs, prior therapy history, mutation testing, and rationale for deviation from step therapy where applicable) to demonstrate the member meets approval criteria and to justify exceptions (e.g., intolerance, contraindication, state-regulatory exemption). Lack of required documentation or failure to demonstrate prior‑TKI failure/intolerance may result in denial.

Documentation must support diagnosis, prior TKI therapy and reasons for failure or intolerance where applicable
Include mutation testing results (e.g., T315I) when used to justify bypassing prior TKI requirements
Provide evidence for contraindications or intolerances if requesting to bypass imatinib step therapy

inv-27: second-line — criteria node (1 top-level node)

Second-line: Member has experienced resistance, toxicity, or intolerance to prior therapy with two or more TKIs (policy clarifies 2-TKI requirement for chronic phase CML)2 prior TKIs required

Policy history: 2Q2021 and 2Q2023 clarifications

inv-28: salvage — criteria node (1 top-level node)

Salvage: Accelerated or blast phase CML: use allowed when no other TKI therapy is indicated (2-TKI requirement may be waived); suitable as salvage therapyno prior TKI required if no other TKI indicated

Dosing for accelerated/blast phase referenced in dosing section

inv-29: first-line — criteria node (1 top-level node)

First-line: Newly diagnosed Ph+ ALL: coverage for use in combination with chemotherapy per updated prescribing information; starting dose 30 mg PO QD with reduction to 15 mg PO QD upon MRD-negative (≤ 0.01% BCR::ABL1) complete remissionstart 30 mg/day, reduce to 15 mg/day upon MRD-negative CR

Continued approval contingent on confirmatory trial; see Appendix for cycle guidance

Clinical contextIncluded among criteria for ALL when age ≥15 (one of the qualifying conditions) and in CML initial criteria

Ponatinib (Iclusig) — product identification

Product name (brand)Iclusig (ponatinib)

Drug classBCR‑ABL tyrosine kinase inhibitor (TKI)

Tablet strengthsAvailable in 10 mg, 15 mg, 30 mg, and 45 mg tablets

TKI definition — Tyrosine kinase inhibitor

TermTyrosine kinase inhibitor (TKI)

ExamplesExamples listed in policy include imatinib, bosutinib, dasatinib, nilotinib

RoleClass of agents referenced throughout policy as prior therapies that may require failure/intolerance before ponatinib use

Ph+ duplicate definition entry (source chunk)

Definition (duplicate)Ph+: Philadelphia chromosome‑positive

Location in documentAppears in Appendices/General Information as definition and in dosing tables

RelevanceUsed as diagnostic qualifier for CML and ALL coverage criteria