MHN venetoclax (Venclexta) Coverage Update

Coverage Criteria for Venetoclax (Venclexta)

Initial Therapy — CLL/SLL

Covered when ALL of the following are met for CLL/SLL (Initial approval):

CLL/SLL initial criteria: 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, b, or c): 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, only when the member does not have the del(17p)/TP53 mutation; b. Prescribed as subsequent therapy as a single agent or in combination with rituximab, Gazyva, or Imbruvica; c. Prescribed as initial therapy for histologic (Richter) transformation to diffuse large B-cell lymphoma as a component of an RCHOP regimen.

Prior authorization may be required; prescribed regimen must be FDA-approved or recommended by NCCN.

Initial Therapy — AML and BPDCN

Covered when ALL of the following are met for myeloid leukemias (Initial approval):

Myeloid leukemias initial criteria: 1. Diagnosis of acute myeloid leukemia (AML) or 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: a. Venclexta is prescribed for induction, post-induction, or consolidation therapy, and one of the following: i. Age ≥ 75 years and disease is newly diagnosed; ii. Member is not a candidate for or declines intensive induction chemotherapy; OR b. Disease is relapsed/refractory; 6. If BPDCN: a. Disease is systemic and request is for palliative treatment, or b. Disease is relapsed/refractory; 7. Prescribed in combination with azacitidine, decitabine, or low-dose (20 mg/m2) cytarabine.Dose limits apply: azacitidine/decitabine combinations ≤ 400 mg/day (4 tablets); low-dose cytarabine combination ≤ 600 mg/day (6 tablets).

Prescribed regimen must be FDA-approved or recommended by NCCN; prior authorization may be required. Approval duration typically 12 months.

Initial Therapy — Mantle Cell Lymphoma (off-label)

Covered when ALL of the following are met for mantle cell lymphoma (off-label):

Mantle cell lymphoma criteria: 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 (ibrutinib) as subsequent therapy; c. In combination with Gazyva and Imbruvica when both of the following are met: i. Disease is positive for TP53 mutation; ii. A clinical trial is not available (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 (prescriber must submit supporting evidence).

Prescribed regimen must be FDA-approved or recommended by NCCN; prior authorization may be required. Clinical trial is strongly recommended for TP53-mutant disease.

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

Covered when ALL of the following are met for multiple myeloma with t(11;14) (off-label):

Multiple myeloma t(11;14) criteria: 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; b. Member has received ≥ 1 prior therapy and venetoclax is prescribed in combination with dexamethasone; 6. 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).

Prescribed regimen must be FDA-approved or recommended by NCCN; prior authorization may be required. Approval duration typically 12 months.

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

Covered when ALL of the following are met for additional NCCN-recommended off-label uses:

Additional NCCN uses: 1. Diagnosis is one of the following: a. Chronic myelomonocytic leukemia (CMML)-2 with venetoclax prescribed in combination with a hypomethylating agent (e.g., azacitidine or decitabine); b. Higher-risk myelodysplastic syndrome (MDS) with venetoclax in combination with azacitidine or decitabine; c. Relapsed/refractory hairy cell leukemia; d. Myeloproliferative neoplasm with venetoclax in combination with hypomethylating agents; e. Acute lymphoblastic leukemia (ALL) subtypes: i. Pediatric relapsed/refractory ALL; ii. Relapsed/refractory T-cell ALL; iii. Philadelphia chromosome negative B-cell ALL with either substantial comorbidities (age ≥ 18) or age ≥ 65; f. Systemic light chain amyloidosis relapsed/refractory; g. Waldenström macroglobulinemia/lymphoplasmacytic lymphoma with venetoclax as 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 certain diagnoses (hairy cell leukemia, pediatric ALL, systemic light chain amyloidosis, Waldenström): member has received ≥ 1 prior therapy; 5. 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).

Prescribed regimen must be FDA-approved or recommended by NCCN; prior authorization may be required. Policy updates reflect alignment with NCCN for added indications and simplified justification language.

Continuation Therapy

Continuation of therapy (renewal) — Covered when ALL of the following are met:

Continuation criteria: 1. Member is currently receiving Venclexta via the Centene benefit or documentation supports at least 30 days prior use 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, therapy must remain in combination with azacitidine, decitabine, or low-dose (20 mg/m2) cytarabine; 5. If request is for a dose increase, new dose must meet one of the following: a. For CLL/SLL or AML in combination with azacitidine or decitabine: new dose ≤ 400 mg/day and ≤ 4 tablets/day; b. For AML in combination with low-dose cytarabine: new dose ≤ 600 mg/day and ≤ 6 tablets/day; c. New dose is supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence).

Approval duration typically 12 months; prior authorization may be required.

Indication-specific dosing and continuation

Coverage tied to indication-specific dosing, combinations, and alignment with NCCN/FDA-labeled uses per documented annual reviews

CLL/SLL therapy: Patient will follow a 5-week ramp-up schedule: 20 mg PO QD x1 week, then 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 PO QD as monotherapy until disease progression or per combination-specific durations.

Combination specifics: with Gazyva start Venclexta on Cycle 1 Day 22 and continue 400 mg PO QD from Cycle 3 Day 1 until last day of Cycle 12; with rituximab administer rituximab after ramp-up and continue Venclexta 400 mg PO QD for 24 months from Cycle 1 Day 1 of rituximab; with Calquence for previously untreated CLL/SLL without del(17p)/TP53 start Venclexta on Cycle 3 Day 1 and continue 400 mg PO QD until last day of Cycle 14.

AML therapy: When used in AML with azacitidine or decitabine: Day 1 = 100 mg PO QD, Day 2 = 200 mg PO QD, Day 3 = 400 mg PO QD, Day 4 and beyond continue 400 mg/day until disease progression or unacceptable toxicity. When used with low-dose cytarabine: escalate per Days 1-3 and continue at 600 mg/day thereafter.

Maximum dose 400 mg/day with azacitidine or decitabine; 600 mg/day with low-dose cytarabine; prior authorization may be required.

Requests for indications that are not FDA‑approved and not specifically addressed in this policy will be denied unless the provider supplies sufficient documentation supporting safety and efficacy per the applicable off‑label use policies: CP.CPA.09 (commercial), HIM.PA.154 (health insurance marketplace), or CP.PMN.53 (Medicaid).

Concomitant administration of Venclexta with strong CYP3A inhibitors at initiation and during the 5‑week ramp‑up period for patients with CLL/SLL is a listed contraindication and may result in denial of the request.

Off‑label uses of venetoclax must be supported by adequate evidence of efficacy and safety; requests for non‑FDA indications not described in this policy require documentation that meets the referenced off‑label use policies before coverage will be authorized.

Recent document updates removed some prior medical‑justification requirements (for example, the explicit requirement that a patient be unable to receive intensive induction chemotherapy for AML) and replaced them with language aligned to the NCCN guidance (e.g., permitting patients who decline or are ineligible for intensive induction). Providers should reference the NCCN‑aligned criteria in the policy and supporting references when submitting documentation.

Permitted Regimens and Scheduling

Regimen	Indication / population	Coverage status
Venetoclax in combination with azacitidine
Newly diagnosed acute myeloid leukemia (AML) in adults age ≥ 75 years or adults with comorbidities that preclude intensive induction chemotherapy; also for AML in relapsed/refractory disease when combined with a hypomethylating agent per criteria
Venetoclax in combination with decitabine
Newly diagnosed AML in adults age ≥ 75 years or adults with comorbidities that preclude intensive induction chemotherapy; also for AML in relapsed/refractory disease when combined with a hypomethylating agent per criteria
Venetoclax in combination with low-dose cytarabine
Newly diagnosed AML in adults age ≥ 75 years or adults with comorbidities that preclude intensive induction chemotherapy; also for AML in relapsed/refractory disease when combined with low-dose cytarabine per criteria

Regimen	Indication / population	Coverage status
Venetoclax as single agent (monotherapy)
Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after completion of 5-week ramp-up; continue 400 mg PO QD until disease progression or per combination-specific durations
Venetoclax in combination with Gazyva (obinutuzumab)
First-line CLL/SLL: start Venclexta per 5-week ramp-up; with Gazyva start Venclexta on Cycle 1 Day 22 and continue 400 mg PO QD from Cycle 3 Day 1 until last day of Cycle 12
Venetoclax in combination with rituximab
CLL/SLL: administer rituximab after the 5-week ramp-up; continue Venclexta 400 mg PO QD for 24 months from Cycle 1 Day 1 of rituximab
Venetoclax in combination with Calquence (acalabrutinib)
CLL/SLL previously untreated without del(17p)/TP53 mutation: start Venclexta on Cycle 3 Day 1 per 5-week ramp-up and continue 400 mg PO QD until last day of Cycle 14
Venetoclax in combination with listed BTK inhibitors (e.g., Imbruvica/ibrutinib)
CLL/SLL: combination options allowed per criteria as first-line or subsequent therapy when prescribed by/with oncologist or hematologist

Regimen	Indication / population	Coverage status
Venetoclax as single agent
Mantle cell lymphoma: prescribed as single-agent subsequent therapy per criteria (off-label); prescriber must provide supporting evidence and use generic if available
Venetoclax in combination with rituximab or ibrutinib (Imbruvica)
Mantle cell lymphoma: permitted as subsequent therapy in combination with rituximab or Imbruvica; dose must be within FDA maximum or supported by guidelines/literature
Venetoclax in combination with Gazyva and Imbruvica
Mantle cell lymphoma: permitted only when disease is TP53 mutation–positive AND a clinical trial is not available (clinical trial strongly recommended); prescriber must submit supporting evidence
Venetoclax in combination with dexamethasone
Multiple myeloma with t(11;14): member has CNS disease with no other options OR has received ≥1 prior therapy and venetoclax is prescribed with dexamethasone; dose must be supported by FDA limit or guidelines/literature

Topic	Detail	Coverage status
CLL/SLL 5-week ramp-up schedule
20 mg PO QD for 1 week → 50 mg PO QD for 1 week → 100 mg PO QD for 1 week → 200 mg PO QD for 1 week → 400 mg PO QD
Combination timing with Gazyva (obinutuzumab)
Start Venclexta according to 5-week ramp-up on Cycle 1 Day 22; continue Venclexta 400 mg PO QD from Cycle 3 Day 1 until last day of Cycle 12
Combination timing with rituximab
Administer rituximab after completion of the 5-week ramp-up; continue Venclexta 400 mg PO QD for 24 months from Cycle 1 Day 1 of rituximab
Combination timing with Calquence (acalabrutinib)
For previously untreated CLL/SLL without del(17p)/TP53 mutation: start Venclexta on Cycle 3 Day 1 per the 5-week ramp-up schedule; continue 400 mg PO QD until last day of Cycle 14

Step	AML dosing detail	Coverage status
Days 1–3 escalation
Day 1: 100 mg PO QD; Day 2: 200 mg PO QD; Day 3: 400 mg PO QD
Post-escalation maintenance with azacitidine or decitabine
Continue 400 mg PO QD from Day 4 and beyond until disease progression or unacceptable toxicity; maximum dose 400 mg/day when combined with azacitidine or decitabine
Post-escalation maintenance with low-dose cytarabine
Continue 600 mg PO QD from Day 4 and beyond when used with low-dose cytarabine; maximum dose 600 mg/day with cytarabine

Coding and Dose Limits

Therapeutic alternatives (examples listed, not billing codes)mixed

No codes listed

Affected codesmixed

affected codes

Placeholder in document for codes impacted by prior authorization; specific CPT/HCPCS/NDC codes not listed in these chunks

inv-14: Dose limits (per indication/combo)

CLL/SLL and AML (azacitidine/decitabine)Maximum 400 mg per day; limit to 4 tablets per day

AML with low‑dose cytarabineMaximum 600 mg per day; limit to 6 tablets per day

Dose increase requests — evidence pathwayNew or higher doses exceeding limits must be supported by practice guidelines or peer‑reviewed literature with prescriber documentation

inv-15: CLL/SLL ramp-up schedule

Week 120 mg PO once daily for 1 week

Week 250 mg PO once daily for 1 week

Prescriber Requirements and Operational Notes

Prior Authorization

Prior Authorization Required

Prior authorization required. Provider must submit documentation (office chart notes, lab results, or other clinical information) supporting that the member meets all approval criteria.

Affected products: Venclexta (venetoclax) — prior auth may be required for labeled and NCCN-recommended off-label uses.
Prescriber requirement: Prescribed by or in consultation with an oncologist or hematologist for most indications.

Step Therapy

Therapeutic Alternatives / Step Therapy (see Appendix B)

Therapeutic alternatives and step therapy information is provided in Appendix B. Providers should consider listed alternatives (for example: ibrutinib [Imbruvica], acalabrutinib [Calquence], zanubrutinib [Brukinsa], obinutuzumab [Gazyva], rituximab, duvelisib [Copiktra], lenalidomide [Revlimid], ofatumumab [Arzerra], chlorambucil [Leukeran], FCR regimen, HDMP + rituximab, and others) when applicable; note that listed alternatives may not be formulary for all lines of business and some may also require prior authorization.

Positioning in Treatment Sequence

first-line | second-line | salvage (general grouping)

lines noted: First-line (specific combinations for CLL), subsequent therapy (single agent or combinations), induction/post-induction/consolidation for AML in older/unfit patients, and relapsed/refractory disease for the multiple listed hematologic malignancies.

first-line | second-line (specific grouping)

CLL/SLL lines: Documented use in first-line and relapsed/refractory settings with specified combination options (e.g., Gazyva, rituximab); policy updates removed some prior restrictions when used in combination per NCCN. Specific line assignments depend on NCCN/FDA alignment and prior therapy history.

first-line | post-induction | consolidation

AML:

Biomarker and Diagnostic Requirements

inv-30: TP53 mutation requirement

RequirementTP53 mutation must be positive for the specific Mantle Cell Lymphoma indication when Venclexta is used in combination with Gazyva and Imbruvica

ContextA clinical trial is strongly recommended for TP53‑mutant disease if available

Supporting evidenceDose must be within FDA maximum or supported by practice guidelines/peer‑reviewed literature (prescriber submits evidence)

inv-31: t(11;14) requirement for multiple myeloma

RequirementPresence of t(11;14) translocation is required for multiple myeloma eligibility under this off‑label indication

Use conditionsVenclexta for t(11;14) multiple myeloma is allowed if member has CNS disease with no other options OR has received ≥1 prior therapy and venetoclax is prescribed with dexamethasone

Background and Drug Information

Venetoclax (Venclexta) is a BCL‑2 inhibitor used in hematologic malignancies. It is FDA‑approved for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and for newly diagnosed acute myeloid leukemia (AML) in older adults or patients unfit for intensive induction chemotherapy, and the policy also addresses selected NCCN‑recommended off‑label hematologic indications. Tablets are available in 10 mg, 50 mg, and 100 mg strengths. Dosing for CLL/SLL includes a 5‑week ramp‑up (20 mg → 50 mg → 100 mg → 200 mg → 400 mg PO QD), and AML regimens use short escalation to a maintenance dose (commonly up to 400 mg/day with azacitidine/decitabine or up to 600 mg/day when combined with low‑dose cytarabine).

inv-25: Venetoclax (Venclexta) — BCL-2 inhibitor

Drug classBCL‑2 inhibitor

Generic/BrandVenetoclax (Venclexta)

FDA‑approved indicationsCLL/SLL; in combination with azacitidine, decitabine, or low‑dose cytarabine for newly diagnosed AML in adults ≥75 or unfit for intensive induction chemotherapy

inv-26: Limited functional status definition (ECOG ≥ 2)

OpenPayer

Venetoclax (Venclexta) Coverage