Centene ponatinib (Iclusig) Coverage Update

Coverage Criteria — Ponatinib (Iclusig)

Initial Therapy — Acute Lymphoblastic Leukemia

Covered when ALL of the following are met

ALL initial approval: 1. Diagnosis of Ph+ (BCR-ABL1-positive) acute lymphoblastic leukemia (ALL); 2. Prescribed by or in consultation with an oncologist or hematologist; 3. One of the following: (a) age ≤ 18 years and request is for (i) relapsed/refractory BCR-ABL1-positive B-cell ALL (off-label) or (ii) T-cell ALL with ABL-class translocation (off-label); (b) age ≥ 15 years and member meets one of: (i) member has BCR-ABL T315I mutation; (ii) no other TKI therapy is indicated; (iii) newly diagnosed ALL and request is for use in combination with chemotherapy (or corticosteroid per NCCN); 4. For brand Iclusig requests, member must use generic ponatinib, if available, unless contraindicated or clinically significant adverse effects are experienced; 5. Dose does not exceed one of the following: (a) newly diagnosed ALL in combination therapy: 30 mg per day; (b) all other requests: 45 mg per day; OR one tablet per day; OR dose is supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence); 6. Prescribed regimen must be FDA-approved or recommended by NCCN30 mg/day for newly diagnosed ALL in combination; 45 mg/day otherwise

Pediatric and off-label uses have age-specific criteria.

Initial Therapy — Myeloid/Lymphoid Neoplasms (Off‑label)

Covered when ALL of the following are met

Myeloid/Lymphoid neoplasms (off-label): 1. Diagnosis of lymphoid, myeloid, or mixed lineage neoplasms with eosinophilia and FGFR1 or ABL1 rearrangement in blast or chronic phase; 2. Prescribed by or in consultation with an oncologist or hematologist; 3. Age ≥ 18 years; 4. If disease is ABL1 rearrangement positive, one of the following: (a) member has contraindication, intolerance, or disease progression on imatinib; (b) request is for treatment in a State with regulations against step therapy in certain oncology settings (see Appendix E) — Illinois HIM requests: step therapy requirements do not apply as of 1/1/2026; 5. For brand Iclusig requests, member must use generic ponatinib, if available, unless contraindicated or clinically significant adverse effects are experienced; 6. Dose is within FDA maximum limit for any FDA-approved indication or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence); 7. Prescribed regimen must be FDA-approved or recommended by NCCNprior imatinib failure for ABL1 rearranged disease unless exception applies

State-specific step therapy exceptions (e.g., IL HB 5395) apply.

Initial Therapy — GIST (Off‑label)

Covered when ALL of the following are met

GIST (off-label): 1. Diagnosis of gastrointestinal stromal tumor (GIST); 2. Prescribed by or in consultation with an oncologist; 3. Age ≥ 18 years; 4. Failure of imatinib, ripretinib (Qinlock), sunitinib (Sutent), or regorafenib (Stivarga) unless clinically significant adverse effects are experienced or all are contraindicated; 5. Prescribed as a single agent; 6. For brand Iclusig requests, member must use generic ponatinib, if available, unless contraindicated or clinically significant adverse effects are experienced; 7. Dose is within FDA maximum limit for any FDA-approved indication or is supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence); 8. Prescribed regimen must be FDA-approved or recommended by NCCNprior failure of listed GIST therapies

Prior authorization may be required; quantity limit: one tablet per day (policy-level).

Indication-specific coverage

Coverage and dosing guidance summarized by indication and phase

Accelerated or blast phase CML and Ph+ ALL (monotherapy or T315I-positive): Starting dose 45 mg PO QD; maximum dose 45 mg/day; consider dose reduction for patients with accelerated phase CML who achieve a major cytogenetic response.

Supports use when T315I mutation positive or when no other TKI therapy is indicated per NCCN

Chronic phase CML: Starting dose 45 mg PO QD with reduction to 15 mg PO QD upon achievement of ≤10%? No, upon achievement of <=1% BCR-ABL1; patients with loss of response can re-escalate to previously tolerated 30 mg or 45 mg PO QD; maximum 45 mg/day.<=1% BCR-ABL1

2-TKI prior therapy requirement clarified to apply to chronic phase per NCCN

Newly diagnosed Ph+ ALL: Starting dose 30 mg PO QD in combination with chemotherapy; reduce to 15 mg PO QD upon achievement of MRD-negative (<=0.01% BCR::ABL1/ABL1) complete remission at end of induction; maximum 30 mg/day.

Non‑FDA approved indications that are not specifically addressed in this policy are not authorized unless the provider submits sufficient documentation of efficacy and safety consistent with applicable off‑label use policies (CP.CPA.09 for Commercial, HIM.PA.154 for Health Insurance Marketplace/ICHRA, and CP.PMN.53 for Medicaid) or the member’s evidence of coverage documents. Requests for off‑label use must include rationale and supporting clinical information per the referenced off‑label policy to be considered for authorization.

Ponatinib (Iclusig) carries boxed warnings for serious adverse events including arterial occlusion, venous thromboembolism (VTE), congestive heart failure, and hepatotoxicity. These risks should be weighed against expected benefit when considering therapy and documented in the medical record as part of the authorization request.

Although the appendix lists no formal contraindications, the presence of boxed‑warning events (arterial occlusion, VTE, heart failure, hepatotoxicity) may make ponatinib inappropriate for some patients. Providers seeking authorization for high‑risk patients or for off‑label uses must document how risks will be mitigated and provide supporting safety/efficacy evidence per the off‑label use policies referenced elsewhere in this document.

Dosing and Regimens

Regimen	Indication	Coverage
Ponatinib 30 mg per day in combination with chemotherapy (starting dose 30 mg PO QD; reduce to 15 mg PO QD upon MRD-negative (<=0.01% BCR::ABL1/ABL1) complete remission at end of induction)
Indication: Newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) when used in combination with chemotherapy
Approved under accelerated approval based on MRD‑negative complete remission at end of induction; coverage allowed per policy when criteria met

Regimen	Scope / Limits	Coverage
Ponatinib up to 45 mg per day (one tablet per day)
Applies to other CML/ALL indications and most requests not covered by the 30 mg combination ALL regimen; maximum routine adult dose cited as 45 mg/day unless an alternative dose is supported by practice guidelines or peer‑reviewed literature
Covered when policy clinical criteria are met and dose does not exceed 45 mg/day (or when alternative dosing is justified and documented)

Regimen	Response-based adjustment	Coverage
Start 45 mg PO QD; reduce to 15 mg PO QD upon achieving <=1% BCR-ABL1
Patients who lose response may be re-escalated to a previously tolerated dose of 30 mg or 45 mg PO QD
Covered for chronic phase CML per policy when criteria are met; maximum dose 45 mg/day

Regimen	Response-based adjustment	Coverage
Start 30 mg PO QD; reduce to 15 mg PO QD upon MRD-negative (<=0.01% BCR::ABL1/ABL1) complete remission
Continue per clinical response; maximum dose for this indication = 30 mg/day
Covered for newly diagnosed Ph+ ALL in combination with chemotherapy (accelerated approval) when policy criteria are met

Comparator TKI	Typical dosing / maximum dose (per appendices)	Use in step therapy/redirection
Imatinib (Gleevec)
ALL: Adult 600 mg/day PO for relapsed/refractory Ph+ ALL; CML: Adult 400–600 mg/day (chronic phase), 600–800 mg/day (accelerated/blast); Max 800 mg/day
Policy redirects to generic oral TKIs (e.g., imatinib) for ABL1-rearranged disease before ponatinib unless contraindication/intolerance, disease progression, or state regulations prohibit redirection

Line of Therapy Specifications

second-line

Second-line (chronic phase CML): For chronic phase CML, ponatinib is used after failure of two TKIs per chronic-phase requirement; dosing: start 45 mg PO QD with response‑based reduction to 15 mg PO QD when <=1% BCR-ABL1 achieved; re-escalation permitted for loss of response.

salvage

Salvage: Accelerated or blast phase CML and Ph+ ALL (monotherapy or T315I-positive) when no other TKI therapy is indicated; starting dose 45 mg PO QD, maximum 45 mg/day.

first-line

First-line (newly diagnosed Ph+ ALL): Newly diagnosed Ph+ ALL: permitted in combination with chemotherapy (and corticosteroid per NCCN) with starting dose 30 mg PO QD and reduction to 15 mg PO QD upon MRD-negative (<=0.01% BCR::ABL1/ABL1) complete remission at end of induction; maximum 30 mg/day.

Biomarker and Mutation Requirements

inv-27: BCR-ABL T315I — biomarker requirement (T315I mutation presence called out)

BiomarkerPresence of BCR-ABL T315I mutation (T315I-positive)

Required forIndication of ponatinib in CML and ALL when mutation present

Supporting sourceIclusig prescribing information lists T315I-positive CML and Ph+ ALL as FDA indications

inv-28: BCR-ABL (including T315I) — biomarker requirement

BiomarkerBCR-ABL (including T315I) documented by molecular testing

Use caseJustifies ponatinib for T315I-positive disease or when prior TKI therapy is limited or unsuitable

Provider Actions, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization required. Approval durations: Medicaid/HIM/ICHRA — 12 months; Commercial — 12 months or duration of request, whichever is shorter.

Prior authorization required
Approval duration — Medicaid/HIM/ICHRA: 12 months
Approval duration — Commercial: 12 months or duration of request, whichever is less

Documentation Required

Documentation Required to Avoid Denial

Provider must submit documentation (such as office chart notes, lab results, or other clinical information) demonstrating the member meets all approval criteria. Failure to provide required documentation may result in denial.

Office visit notes or chart documentation supporting diagnosis and disease phase

Background — Drug and Indications

Ponatinib (Iclusig) is an oral BCR‑ABL tyrosine kinase inhibitor (TKI) indicated for certain BCR‑ABL–positive leukemias and related disorders. It is specifically referenced for use in chronic myeloid leukemia (CML) including chronic, accelerated, and blast phases when resistant or when the BCR‑ABL T315I mutation is present, and for Philadelphia chromosome‑positive acute lymphoblastic leukemia (Ph+ ALL) including newly diagnosed use in combination with chemotherapy under accelerated approval. The prescribing and dosing guidance in this policy reflect approved indications and NCCN‑recommended off‑label uses, with maximum routine adult dosing cited as 45 mg/day (and 30 mg/day for newly diagnosed Ph+ ALL in combination therapy where indicated).

Definitions and Abbreviations

inv-19: Philadelphia chromosome-positive (Ph+) definition/key term

DefinitionPhiladelphia chromosome-positive (Ph+): presence of BCR-ABL1 fusion (BCR-ABL1-positive)

Clinical relevanceDesignates leukemias (e.g., CML, Ph+ ALL) eligible for BCR-ABL targeted TKIs such as ponatinib when criteria met

Policy contextPh+ diagnosis is a required criterion for CML and ALL initial approval sets

inv-20: tyrosine kinase inhibitor (TKI) definition/key term

DefinitionTyrosine kinase inhibitor (TKI): a class of targeted therapy that inhibits BCR-ABL and other kinases

ExamplesImatinib, dasatinib, nilotinib, bosutinib (listed in appendices) used as prior or alternative therapies

Coding, Quantity Limits, and Billing Notes

Billing Rule

Quantity limit: 1 tablet per day

Quantity limit: one tablet per day is enforced by the policy.

Dose limits in the policy: 30 mg/day for newly diagnosed Ph+ ALL in combination; 45 mg/day for other requests; and the policy specifies 'one tablet per day' as a dispensing constraint.

OpenPayer

Clinical Policy: Ponatinib (Iclusig)

Coverage Criteria — Ponatinib (Iclusig)

Dosing and Regimens

Line of Therapy Specifications

Biomarker and Mutation Requirements

Provider Actions, Prior Authorization, and Documentation

Background — Drug and Indications

Definitions and Abbreviations

Coding, Quantity Limits, and Billing Notes