mhn venetoclax (Venclexta) Coverage Update

Coverage Criteria for Venetoclax (Venclexta)

Initial Approval — Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Covered when ALL of the following are met

CLL/SLL initial approval: 1. Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). 2. Prescribed by or in consultation with an oncologist or hematologist. 3. Age ≥ 18 years. 4. For brand Venclexta requests, member must use generic venetoclax if available unless contraindicated or clinically significant adverse effects are experienced. 5. Request meets one of the following: (a) Prescribed as first-line therapy in one of the following ways: (i) in combination with Gazyva; (ii) in combination with Imbruvica; (iii) in combination with Calquence, with or without Gazyva; (b) Prescribed as subsequent therapy as a single agent or in combination with rituximab, Gazyva, or Imbruvica (see Appendix B for examples of prior therapy); (c) Prescribed as initial therapy for histologic (Richter) transformation to diffuse large B-cell lymphoma as a component of an R-CHOP regimen. 6. Dose meets one of the following: (a) Does not exceed both 400 mg per day and 4 tablets per day; or (b) Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).

Initial Approval — Myeloid Leukemias (AML and BPDCN)

Covered when ALL of the following are met

Myeloid leukemias initial approval: 1. Diagnosis of one of the following myeloid leukemias: (a) acute myeloid leukemia (AML), or (b) blastic plasmacytoid dendritic cell neoplasm (BPDCN). 2. Prescribed by or in consultation with an oncologist or hematologist. 3. Age ≥ 18 years. 4. For brand Venclexta requests, member must use generic venetoclax if available unless contraindicated or clinically significant adverse effects are experienced. 5. If AML, one of the following: (a) Venclexta is prescribed for induction, post-induction, or consolidation therapy, and one of: (i) age ≥ 75 years and disease is newly diagnosed; or (ii) member is not a candidate for or declines intensive induction chemotherapy (see Appendix B for examples); OR (b) disease is relapsed/refractory (see Appendix B for examples). 6. If BPDCN, one of: (a) disease is systemic and request is for palliative treatment (e.g., low performance/nutritional status, not candidate for intensive remission therapy or tagraxofusp-erzs); or (b) disease is relapsed/refractory. 7. Prescribed in combination with azacitidine, decitabine, or low-dose (20 mg/m2) cytarabine. 8. Dose meets one of the following: (a) In combination with azacitidine or decitabine: does not exceed both 400 mg per day and 4 tablets per day; (b) In combination with low-dose cytarabine: does not exceed both 600 mg per day and 6 tablets per day; (c) Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).

Initial Approval — Mantle Cell Lymphoma (off-label)

Covered when ALL of the following are met

Mantle cell lymphoma initial approval: 1. Diagnosis of mantle cell lymphoma. 2. Prescribed by or in consultation with an oncologist or hematologist. 3. Age ≥ 18 years. 4. For brand Venclexta requests, member must use generic venetoclax if available unless contraindicated or clinically significant adverse effects are experienced. 5. Venclexta is prescribed as one of the following: (a) single agent as subsequent therapy; (b) in combination with rituximab or Imbruvica as subsequent therapy; (c) in combination with Gazyva and Imbruvica when both of the following are met: (i) disease is positive for TP53 mutation; and (ii) a clinical trial is not available (a clinical trial is strongly recommended). 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).

Initial Approval — Multiple Myeloma (off-label, t(11;14))

Covered when ALL of the following are met

Multiple myeloma initial approval: 1. Diagnosis of multiple myeloma with t(11;14) translocation. 2. Prescribed by or in consultation with an oncologist or hematologist. 3. Age ≥ 18 years. 4. For brand Venclexta requests, member must use generic venetoclax if available unless contraindicated or clinically significant adverse effects are experienced. 5. One of the following: (a) member has central nervous system (CNS) disease with no other options available; or (b) member has received ≥ 1 prior therapy and Venclexta is prescribed in combination with dexamethasone (see Appendix B for examples). 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).

Initial Approval — Additional NCCN Recommended Uses (off-label)

Covered when ALL of the following are met

NCCN-recommended off-label uses: 1. Diagnosis is one of the following: (a) chronic myelomonocytic leukemia (CMML)-2 with Venclexta + hypomethylating agent (e.g., azacitidine or decitabine); (b) higher-risk myelodysplastic syndrome (MDS) with Venclexta + azacitidine or decitabine; (c) relapsed/refractory hairy cell leukemia; (d) myeloproliferative neoplasm with Venclexta + hypomethylating agent; (e) acute lymphoblastic leukemia (ALL) of selected types: (i) pediatric relapsed/refractory ALL; (ii) T-cell ALL relapsed/refractory; (iii) Philadelphia chromosome negative B-cell ALL with either (1) age ≥ 18 years and substantial comorbidities or (2) age ≥ 65 years; (f) systemic light chain amyloidosis relapsed/refractory; (g) Waldenström macroglobulinemia/lymphoplasmacytic lymphoma with Venclexta as a single agent. 2. Prescribed by or in consultation with an oncologist or hematologist. 3. For all indications except pediatric ALL: age ≥ 18 years. 4. For brand Venclexta requests, member must use generic venetoclax if available unless contraindicated or clinically significant adverse effects are experienced. 5. For hairy cell leukemia, pediatric ALL, systemic light chain amyloidosis, and Waldenström macroglobulinemia/lymphoplasmacytic lymphoma: member has received ≥ 1 prior therapy (see Appendix B for examples). 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).

Continued Therapy — All Indications

Continued coverage requires ALL of the following

Continued therapy: 1. Member is currently receiving Venclexta via the Centene benefit, or documentation supports the member has received Venclexta for at least 30 days for a covered indication. 2. Member is responding positively to therapy. 3. For brand Venclexta requests, member must use generic venetoclax if available unless contraindicated or clinically significant adverse effects are experienced. 4. For AML, Venclexta must be prescribed in combination with azacitidine, decitabine, or low-dose (20 mg/m2) cytarabine. 5. If request is for a dose increase, one of the following must be met: (a) For CLL, SLL, or AML in combination with azacitidine or decitabine: new dose does not exceed both 400 mg per day and 4 tablets per day; (b) For AML in combination with low-dose cytarabine: new dose does not exceed both 600 mg per day and 6 tablets per day; (c) New dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).

Covered indications and dosing

Coverage and dosing criteria by indication (high-level items and dosing described in V and appendices):

Indications: CLL/SLL; AML (in combination with azacitidine, decitabine, or low‑dose cytarabine); and NCCN‑supported off‑label hematologic malignancies (examples: BPDCN, systemic light chain amyloidosis, Waldenström macroglobulinemia, mantle cell lymphoma, CMML‑2, hairy cell leukemia, pediatric ALL, myeloproliferative neoplasm, MDS, multiple myeloma).

See appendices and references for full list and supporting NCCN citations.

CLL/SLL dosing: Patient must undergo a 5‑week venetoclax ramp‑up: 20 mg PO QD x1 week, 50 mg PO QD x1 week, 100 mg PO QD x1 week, 200 mg PO QD x1 week, then 400 mg PO QD. Continue 400 mg QD as monotherapy until progression or unacceptable toxicity or per specified combination regimens.Maximum 400 mg/day

When combined with Gazyva start venetoclax on Cycle 1 Day 22 per regimen; when combined with rituximab, continue venetoclax 400 mg QD for 24 months from Cycle 1 Day 1 of rituximab.

AML dosing: When used in AML in combination with azacitidine or decitabine: Day 1 100 mg, Day 2 200 mg, Day 3 400 mg, then 400 mg daily thereafter until progression or unacceptable toxicity. In combination with low‑dose cytarabine escalate to 600 mg/day and continue as tolerated.

If venetoclax has had a recent label change within the last 6 months that is not yet reflected in this policy, providers must follow the direction in the plan-level formulary/non‑formulary or related policies. For indications or dosing now on the formulary/PDL, refer to the applicable no coverage criteria policy (e.g., CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, CP.PMN.255 for Medicaid). For uses not on the formulary/PDL, refer to the applicable non‑formulary policy (e.g., CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, CP.PMN.16 for Medicaid).

Non‑FDA approved indications that are not explicitly addressed by this clinical policy are excluded from coverage unless the provider submits sufficient documentation of efficacy and safety in accordance with the applicable off‑label use policy for the member's line of business: CP.CPA.09 (commercial), HIM.PA.154 (health insurance marketplace), or CP.PMN.53 (Medicaid), or unless coverage is otherwise supported by evidence of coverage documents.

When state Medicaid coverage provisions conflict with the coverage provisions in this clinical policy, state Medicaid coverage provisions take precedence. Refer to the applicable state Medicaid manual for any specific coverage rules that apply to Medicaid members.

Patients with limited functional status or significant comorbidity may be poor candidates for intensive induction regimens. Examples include an Eastern Cooperative Oncology Group performance status of ≥2 or severe cardiac, pulmonary, or renal disease; these characteristics should be considered when determining medical necessity for intensive induction therapy.

Regimens and Dosing

Indication	Regimen	Coverage status
AML newly diagnosed in adults ≥75 years or adults unfit for intensive induction chemotherapy	Venetoclax in combination with azacitidine, decitabine, or low‑dose (20 mg/m2) cytarabine	Covered

Indication	Regimen / Use cases	Coverage status
Chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL)	Venetoclax used per criteria: first‑line in combination with Gazyva, Imbruvica, or Calquence (with/without Gazyva); subsequent therapy as single agent or in combination with rituximab, Gazyva, or Imbruvica; also as component of R‑CHOP for Richter transformation	Covered

Indication	Regimen	Coverage status
Multiple myeloma with t(11;14) translocation	Venetoclax in combination with dexamethasone, or venetoclax for CNS disease when no other options are available	Covered (off‑label, NCCN/criteria supported)

Regimen	Ramp / Maintenance schedule	Coverage status
CLL/SLL dosing and combination schedules	5‑week venetoclax ramp‑up: 20 mg QD x1 week → 50 mg QD x1 week → 100 mg QD x1 week → 200 mg QD x1 week → 400 mg QD; continue 400 mg QD as monotherapy until progression or unacceptable toxicity. With Gazyva: start venetoclax on Cycle 1 Day 22 per the 5‑week ramp; with rituximab: administer rituximab after ramp‑up and continue venetoclax 400 mg QD for 24 months from Cycle 1 Day 1 of rituximab.	Covered

Regimen	Ramp / Dose escalation	Coverage status
AML dosing with hypomethylating agents or low‑dose cytarabine	When used with azacitidine or decitabine: Day 1 100 mg → Day 2 200 mg → Day 3 400 mg, then 400 mg daily thereafter. When used with low‑dose cytarabine: escalate to 600 mg/day and continue as tolerated.	Covered

Prior Authorization, Documentation, and Administrative Guidance

Prior Authorization

Prior Authorization Required

Prior authorization may be required for Venclexta (venetoclax). Providers must demonstrate that indication-specific criteria are met as described in the Initial Approval Criteria (Section I) and any applicable continuation criteria. Prior authorization requirements are governed by the member’s plan-level rules; follow the Health Plan’s authorization processes and forms when submitting requests.

Prior authorization approval durations: Medicaid/HIM — 12 months; Commercial — 12 months or duration of request, whichever is less.
If the drug label has changed within the last 6 months and that change is not yet reflected in this policy, follow the formulary/non‑formulary or off‑label referral guidance (see related policy references).
Requests for non‑FDA approved indications not addressed in this policy will be denied unless sufficient documentation is provided per applicable off‑label policies.

Documentation Required

Providers must submit supporting clinical documentation with the prior authorization request. Acceptable documentation includes office/consult notes, relevant laboratory results, pathology reports, imaging, and prior therapy records that demonstrate the member meets all approval criteria. Failure to submit adequate documentation may result in denial of the request.

Dosing and Coding Highlights

Maximum daily dose

Maximum daily dose (most indications)400 mg per day (also limited to 4 tablets/day for these indications)

Maximum daily dose (AML with low‑dose cytarabine)600 mg per day (limited to 6 tablets/day)

Dose support exceptionDose above limits allowed if supported by practice guidelines or peer‑reviewed literature with prescriber supporting evidence

Continued therapy dose limitsDose increases must not exceed 400 mg/day (4 tablets) for CLL/SLL or AML with azacitidine/decitabine, or 600 mg/day (6 tablets) with low‑dose cytarabine unless supported by literature

Line of Therapy Definitions and Rules

first-line | second-line | salvage

Line of therapy specifics: CLL/SLL: first‑line when used in specified combinations (e.g., with Gazyva, Imbruvica, or Calquence); subsequent therapy allowed as single agent or in combination per Appendix B. Mantle cell lymphoma: generally used as subsequent therapy. Additional NCCN-supported off-label uses often require prior therapy (≥1) for specific diagnoses.

first-line | second-line | salvage

CLL/SLL lines: First‑line, second‑line, and subsequent therapies examples are provided in Appendix B (e.g., FCR; HDMP + rituximab; single-agent BTK inhibitors such as Imbruvica; Calquence ± Gazyva; Gazyva; rituximab-containing regimens). Venetoclax can be used as monotherapy or in combination (e.g., with rituximab or Gazyva) per NCCN and the policy's specified regimens; Gazyva combination options updated per NCCN guidance.

Diagnostic and Biomarker Requirements

TP53 mutation

BiomarkerTP53 mutation

Required forMantle cell lymphoma regimen combining Gazyva and Imbruvica (disease must be positive for TP53 mutation)

Clinical trial preferenceUse in TP53‑positive disease requires clinical trial not available as condition; trial strongly recommended

t(11;14) translocation

Biomarkert(11;14) translocation

Required forEligibility for venetoclax in multiple myeloma (policy requires diagnosis of multiple myeloma with t(11;14))

Background and Drug Information

Venetoclax (Venclexta) is an oral BCL‑2 inhibitor used in multiple hematologic malignancies including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and in combination regimens for acute myeloid leukemia. The policy addresses both FDA‑approved uses and selected NCCN‑supported off‑label hematologic indications, and it requires that prescribing be by or in consultation with an oncologist or hematologist and that dosing and administration follow the indication‑specific limits and guideline‑supported schedules.

Definitions and Abbreviations

Venetoclax (Venclexta)

DrugVenetoclax (Venclexta)

MechanismBCL-2 (B-cell lymphoma 2 protein) inhibitor

Formulary noteFor brand requests, policy prefers generic venetoclax if available unless contraindicated or adverse effects

CLL/SLL

TermCLL/SLL

DefinitionChronic lymphocytic leukemia / small lymphocytic lymphoma

ReferenceAbbreviations listed in Appendix A of the policy

Policy Revision History

08.25.25revisedLatest

Revised Medicaid and HIM initial approval durations to 12 months for all indications; modified CLL/SLL combination use with Gazyva by removing the 'relapse if previously used as first-line' requirement and other relapsed/subsequent therapy clarifications; simplified AML criteria (removed age ≥60 pathway, added FDA‑labeled option for age ≥75, and broadened 'newly diagnosed' to 'induction, post‑induction, or consolidation'); added CNS option for multiple myeloma and expanded additional NCCN recommended uses (adult ALL, MDS) and other combination options per NCCN.

07.17.24annual_review

For CLL/SLL, added Gazyva as combination therapy option for relapsed/refractory disease; for AML, removed requirement that member be unable to receive intensive induction chemotherapy and clarified eligibility; for mantle cell lymphoma, added option for combination with Gazyva and Imbruvica; added CMML‑2, hairy cell leukemia, myeloproliferative neoplasm, and pediatric ALL as off‑label recommended indications per NCCN.

OpenPayer

Venetoclax (Venclexta) coverage

Coverage Criteria for Venetoclax (Venclexta)

Regimens and Dosing

Prior Authorization, Documentation, and Administrative Guidance

Dosing and Coding Highlights

Line of Therapy Definitions and Rules

Diagnostic and Biomarker Requirements

Background and Drug Information

Definitions and Abbreviations

Policy Revision History