MHN acalabrutinib (Calquence) Coverage Update

Coverage Criteria

Initial Therapy: Mantle Cell Lymphoma

Covered when ALL of the following are met

MCL initial: 1. Diagnosis of mantle cell lymphoma (MCL). 2. Prescribed by or in consultation with an oncologist or hematologist. 3. Age ≥ 18 years. 4. For Calquence requests, member must use generic acalabrutinib if available unless contraindicated or clinically significant adverse effects are experienced. 5. Member does not have Imbruvica-refractory MCL with BTK C481S mutations. 6. Member meets one of the following: (a) received ≥1 prior therapy; OR (b) meets one of: (i) prescribed in combination with bendamustine and rituximab and is ineligible for autologous HSCT; (ii) prescribed in combination with rituximab for less aggressive induction therapy; (iii) prescribed in combination with rituximab as pretreatment to limit cycles of aggressive induction therapy with RHyperCVAD. 7. Dose does not exceed 400 mg (4 capsules or 4 tablets) per day, or the dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).

Prescribed regimen must be FDA-approved or recommended by NCCN.

Initial Therapy: CLL/SLL

Covered when ALL of the following are met

CLL/SLL initial: 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 Calquence requests, member must use generic acalabrutinib if available unless contraindicated or clinically significant adverse effects are experienced. 5. Calquence is prescribed in one of the following ways: (a) first-line as a single agent; (b) first-line in combination with venetoclax (Venclexta), with or without obinutuzumab (Gazyva), only when the member does NOT have the del(17p)/TP53 mutation; (c) first-line in combination with obinutuzumab (Gazyva); (d) subsequent therapy (member has received ≥1 prior therapy) as single-agent for relapsed/refractory disease; (e) single-agent therapy for histologic transformation from CLL/SLL (Richter). 6. Member does not have Imbruvica-refractory CLL/SLL with BTK C481S mutations. 7. Request meets one of the following: (a) dose does not exceed 400 mg (4 capsules or 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).Total duration ≤14 cycles when used with venetoclax for first-line in patients without del(17p)/TP53

Prescribed regimen must be FDA-approved or recommended by NCCN; when combined with venetoclax/obinutuzumab follow specific cycle sequencing and durations per dosing guidance.

Initial Therapy: Waldenstrom Macroglobulinemia / LPL (off‑label)

Covered when ALL of the following are met

WM/LPL off-label: 1. Diagnosis of Waldenstrom macroglobulinemia (WM) or lymphoplasmacytic lymphoma (LPL). 2. Prescribed by or in consultation with an oncologist or hematologist. 3. Age ≥ 18 years. 4. For Calquence requests, member must use generic acalabrutinib if available unless contraindicated or clinically significant adverse effects are experienced. 5. Calquence is prescribed as a single agent as second-line or subsequent therapy. 6. Calquence is not prescribed concurrently with Imbruvica (ibrutinib) or Brukinsa (zanubrutinib). 7. Request meets one of the following: (a) dose does not exceed 400 mg (4 capsules or 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).

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

Initial Therapy: Marginal Zone Lymphoma (off‑label)

Covered when ALL of the following are met

MZL off‑label: 1. Diagnosis of marginal zone lymphoma (MZL): (a) nodal MZL for relapsed, refractory, or progressive disease; OR (b) splenic MZL; OR (c) extranodal MZL (noncutaneous) for relapsed, refractory, or progressive disease. 2. Prescribed by or in consultation with an oncologist or hematologist. 3. Age ≥ 18 years. 4. For Calquence requests, member must use generic acalabrutinib if available unless contraindicated or clinically significant adverse effects are experienced. 5. Member has received ≥1 prior therapy. 6. Calquence is not prescribed concurrently with Imbruvica (ibrutinib) or Brukinsa (zanubrutinib). 7. Request meets one of the following: (a) dose does not exceed 400 mg (4 capsules or 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).

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

Continuation Therapy

Covered when ALL of the following are met

Continuation: 1. Member is currently receiving medication via the Centene benefit, or documentation supports that member has received Calquence for at least 30 days. 2. Member is responding positively to therapy. 3. For combination use with venetoclax as first-line therapy for CLL/SLL in members without the del(17p)/TP53 mutation, total duration of therapy will not exceed 14 cycles. 4. For Calquence requests, member must use generic acalabrutinib if available unless contraindicated or clinically significant adverse effects are experienced. 5. If request is for a dose increase, the new dose does not exceed 400 mg (4 capsules or 4 tablets) per day, or the new dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).Approval duration: 12 months (or ≤14 total cycles for specified venetoclax combination)

Prescribed regimen must be FDA-approved or recommended by NCCN.

Coverage criteria (high-level)

Covered when aligned with FDA approval and NCCN-supported indications and when dosing/regimen matches prescribing information:

General dosing and formulation: Member will be prescribed acalabrutinib at recommended dosing (typically 100 mg PO twice daily) and not to exceed 400 mg/day; available 100 mg formulations (tablet or capsule) should be used as documented.

See disease-specific dosing and sequencing guidance in the dosing section.

CLL/SLL first-line combinations: Use as monotherapy or in combination per NCCN and FDA — includes combination with venetoclax (Venclexta) per 1Q2026 updates (only for patients without del(17p)/TP53) and combination with obinutuzumab (Gazyva) for previously untreated CLL/SLL; follow specific cycle sequencing when combined (e.g., start Calquence Cycle 1; start Gazyva Cycle 2; when used with venetoclax start Calquence Cycle 1 and venetoclax at Cycle 3).Total duration ≤14 cycles when used with venetoclax for first-line in patients without del(17p)/TP53

Refer to dosing table for exact cycle timing.

MCL indications:

Requests for non‑FDA approved indications that are not specifically addressed in this policy will be excluded unless the prescriber provides sufficient documentation of efficacy and safety in accordance with the payer's off‑label use policies (for example, CP.CPA.09 for Commercial, HIM.PA.154 for Health Insurance Marketplace, or CP.PMN.53 for Medicaid).

The policy includes an explicit exclusion for Imbruvica‑refractory mantle cell lymphoma (MCL) with a BTK C481S mutation; use in that setting may be denied. In addition, the policy states that Calquence should not be prescribed concurrently with other BTK inhibitors (for example, Imbruvica or Brukinsa) in certain B‑cell indications such as Waldenström macroglobulinemia, LPL, and marginal zone lymphoma.

Per the policy and supporting NCCN guidance, acalabrutinib (Calquence) lacks activity in ibrutinib‑refractory disease when a BTK C481S mutation is present; therefore use in ibrutinib‑refractory CLL/SLL or MCL with BTK C481S mutations is considered not appropriate.

The policy clarifies that, in line with NCCN guidance, Calquence is not appropriate for Imbruvica‑refractory CLL/SLL if a BTK C481S mutation is present. This position was incorporated into the policy during routine updates to align with guideline recommendations.

Coding

Codes referencedmixed

N/A	No explicit CPT/HCPCS/ICD-10/NDC codes listed in this part of the document

Coding referenced but not listedmixed

N/A	Document cites guideline and prescribing information updates but does not list specific CPT/HCPCS/NDC codes in this excerpt.

Maximum daily dose — ≤ 400 mg/day

Maximum daily dose≤ 400 mg/day (policy: dose does not exceed 400 mg per day or supported by guidelines)

Typical regimen referenceMCL dosing regimen is 100 mg PO BID (section V: Dosage and Administration)

FormulationsAvailable as 100 mg tablet or capsule (product availability)

Maximum daily dose — 400 mg/day

Maximum daily dose400 mg/day (policy: maximum dose specified for CLL/SLL and MCL)

Dose exampleStandard dosing is 100 mg PO BID (total 200 mg/day), not to exceed 400 mg/day

Provider Actions & Requirements

Prior Authorization

Prior Authorization Required

Prior authorization is required for Calquence (acalabrutinib) requests. Providers must submit documentation (office notes, labs, pathology, prior therapy details, mutation testing) that supports the member meets all applicable approval criteria, including diagnosis, prescriber specialty, age, prior therapies or specified combination regimens, and absence of excluded BTK C481S mutation where applicable. Requests for off‑label regimens must include supporting evidence (peer‑reviewed literature or guideline citations).

Affected indications: MCL, CLL/SLL, WM/LPL, MZL and other policy‑listed diagnoses
Authorization durations: initial approvals updated per policy (see policy header/criteria) — initial authorizations for Medicaid/HIM updated from 6 to 12 months where applicable
Off‑label use: prescriber must submit supporting evidence (guideline or literature)

Documentation Required

Dosing & Formulation Documentation

Prescribers must document dosing regimen and product formulation on the PA submission. For MCL and CLL/SLL the usual dosing is 100 mg PO twice daily (maximum 400 mg/day). For combination regimens (e.g., with obinutuzumab or venetoclax) specify cycle timing and sequence per product labeling/NCCN (for example: start acalabrutinib 100 mg PO BID at Cycle 1 and start obinutuzumab at Cycle 2 when indicated; when used with venetoclax in frontline CLL/SLL, acalabrutinib is started at Cycle 1 and venetoclax at Cycle 3 per regimen guidance). Indicate whether tablet or capsule (100 mg) formulation will be used and note if generic acalabrutinib will be used unless contraindicated.

Background

Acalabrutinib (Calquence) is a Bruton tyrosine kinase (BTK) inhibitor indicated for adult patients with mantle cell lymphoma (MCL) and for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) per the product labeling and updated approvals. The policy notes that Calquence can be used in approved and certain NCCN‑supported regimens (including updated first‑line combinations in CLL/SLL), but it also documents limited activity in ibrutinib‑refractory disease with BTK C481S mutations and therefore excludes use in that molecular context.

Definitions

BTK C481S — BTK C481S mutation

DefinitionBTK C481S — a mutation in Bruton tyrosine kinase (BTK) designated C481S

Clinical relevanceAssociated with lack of activity of some BTK inhibitors in ibrutinib-refractory disease

Reference sourceListed in policy appendices as abbreviation/key and discussed in Appendix D (general information)

Induction therapy (MCL) — For MCL, policy specifies induction or maintenance and clarifies induction use in combination with rituximab

Induction use (MCL)Policy permits acalabrutinib as induction therapy for MCL when prescribed in combination with rituximab for less aggressive induction therapy

Alternative MCL combinationsAlso allowed in combination with bendamustine + rituximab for certain untreated patients ineligible for autologous HSCT

Line of Therapy

first-line | second-line | subsequent

Lines: First-line (single agent or specified combinations), subsequent therapy (≥1 prior therapy), and specific second-line/subsequent uses for off-label indications

first-line

First-line CLL/SLL: Acalabrutinib used first-line as monotherapy or in combination with venetoclax or obinutuzumab per updated NCCN and FDA/PI guidance; when combined with obinutuzumab start Calquence at Cycle 1 and Gazyva at Cycle 2; when combined with venetoclax start Calquence at Cycle 1 and venetoclax at Cycle 3 for the specified durations; venetoclax combinations are restricted to patients without del(17p)/TP53 mutation.

AMPLIFY trial results added to the Calquence PI; policy aligned to allow these regimens.

second-line

Biomarker & Mutation Requirements

del(17p)/TP53 — must NOT have del(17p)/TP53 mutation for venetoclax combination in first‑line

Biomarker requirementdel(17p)/TP53 — member must NOT have del(17p)/TP53 mutation to receive acalabrutinib + venetoclax in first-line CLL/SLL

Regimen timingWhen used with venetoclax first-line, start acalabrutinib Cycle 1 and venetoclax at Cycle 3 per dosing guidance

Duration limitTotal duration when combined with venetoclax in first-line CLL/SLL without del(17p)/TP53 is limited (policy: ≤14 cycles)

BTK C481S — presence indicates ibrutinib‑refractory disease where acalabrutinib lacks activity

Clinical implicationPresence of BTK C481S indicates ibrutinib-refractory disease where acalabrutinib lacks activity

Policy action

Covered Regimens and Dosing

Regimen	Indication	Coverage status
Acalabrutinib 100 mg PO BID; monotherapy or in combination per FDA labeling
Mantle cell lymphoma (MCL): as monotherapy for patients who have received ≥1 prior therapy, or in combination with bendamustine + rituximab for previously untreated patients who are ineligible for autologous HSCT
Dose not to exceed 400 mg/day (4 capsules or 4 tablets) unless supported by guidelines or literature

Regimen	Patient selection / biomarker requirement	Duration / Coverage status
Acalabrutinib 100 mg PO BID in combination with venetoclax (with or without obinutuzumab)
Previously untreated CLL/SLL without del(17p)/TP53 mutation
Total duration when used with venetoclax in first-line (patients without del(17p)/TP53): not to exceed 14 cycles (Calquence up to 14 cycles; venetoclax total 12 cycles). Coverage: covered with criteria

Regimen	Restrictions	Coverage status
Acalabrutinib 100 mg PO BID as single agent
May be used off-label for Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) and marginal zone lymphoma (MZL) as second-line or subsequent therapy; must NOT be prescribed concurrently with ibrutinib (Imbruvica) or zanubrutinib (Brukinsa); prior authorization may be required
Off-label use covered when criteria met; coverage with criteria (restricted)

Regimen	Cycle timing	Coverage status
Calquence (acalabrutinib) 100 mg PO BID combined with obinutuzumab (Gazyva)
Start Calquence at Cycle 1 (28-day cycles); start Gazyva at Cycle 2 for a total of 6 cycles; administer Calquence prior to Gazyva when given the same day
Covered for previously untreated CLL/SLL per regimen and criteria

Regimen	Cycle timing / duration	Coverage status
Calquence (acalabrutinib) 100 mg PO BID in combination with venetoclax
Start Calquence at Cycle 1 (28-day cycles) for up to 14 cycles; start venetoclax at Cycle 3 for a total of 12 cycles
Covered for previously untreated CLL/SLL without del(17p)/TP53 when criteria met; total duration not to exceed 14 cycles for Calquence

Parameter	Value	Notes / Policy alignment
Typical dosing regimen
100 mg PO BID
MCL and CLL/SLL standard dosing per prescribing information and policy (see dosing section).

OpenPayer

Acalabrutinib (Calquence) coverage

Coverage Criteria

Coding

Provider Actions & Requirements

Background

Definitions

Line of Therapy

Biomarker & Mutation Requirements

Covered Regimens and Dosing