Rituximab (Rituxan®) is a genetically engineered chimeric murine/human monoclonal antibody. It binds specifically to the antigen CD20 (human B-lymphocyte-restricted differentiation antigen, Bp35). This antigen is a hydrophobic transmembrane protein that is located on pre-B and mature B lymphocytes. It is also expressed on more than 90% of B-cell non-Hodgkin's lymphomas, but it is not expressed on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues.

Rituximab and hyaluronidase human (Rituxan Hycela™) is a combination of rituximab and hyaluronidase human in a subcutaneous formulation that is given by a healthcare professional after an initial administration of intravenous rituximab (Rituxan). These two products are different formulations and cannot be used interchangeably.

Rituximab-abbs (Truxima®), rituximab-arrx (Riabni™), and rituximab-pvvr (Ruxience™) are biosimilars of rituximab (Rituxan).

Preferred Products

Rituximab-arrx (Riabni) and rituximab-pvvr (Ruxience) are the preferred rituximab biosimilars for individuals initiating new therapy for oncologic indications when the clinical criteria within this policy are met. A non-preferred product will be considered when the individual has a documented therapy failure after an adequate therapeutic trial of a preferred product, or the preferred product has not been tolerated or is contraindicated.

Adequate therapeutic trial is defined as 180 days from first dose of therapy at Food and Drug Administration (FDA) or compendia based therapeutic doses of preferred product.

New therapy is defined as no previous utilization within the last 180 calendar days.

Rituximab (Rituxan)

Food and Drug Administration (FDA) Approved Indications

Rituximab (Rituxan) may be considered medically necessary for ANY of the following indications:

Antineutrophil Cytoplasmic Antibody‒Associated Vasculitides (Granulomatosis with Polyangiitis [Wegener Granulomatosis] and Microscopic Polyangiitis)

• Treatment of individuals with antineutrophil cytoplasmic antibody‒associated vasculitides (i.e., granulomatosis with polyangiitis (GPA) [Wegener granulomatosis] and microscopic polyangiitis), in combination with glucocorticoids; or

Chronic Lymphocytic Leukemia (CLL)

• Treatment of previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide (FC); or

Non-Hodgkin’s Lymphoma (NHL)

Treatment of NHL in any of the following:

• Relapsed or refractory, low grade or follicular, CD20-positive B-cell NHL as a single agent; or
• Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in individuals achieving a complete or partial response to rituximab (Rituxan) in combination with chemotherapy, as single-agent maintenance therapy; or
• Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy; or
• Previously untreated diffuse large B-cell, CD20-positive NHL in combination with (cyclophosphamide, doxorubicin, vincristine, and prednisone) (CHOP) or other anthracycline-based chemotherapy regimens; or

Pemphigus Vulgaris (PV)

• Treatment of moderate to severe treatment-refractory PV in individuals 18 years or older; or

Rheumatoid Arthritis (RA)

• Treatment of individuals 18 years of age or older with RA who meet the following criteria:
  • RA is moderately to severely active (e.g., greater than or equal to eight (8) swollen and tender joints); and
  • Rituximab (Rituxan) is administered in combination with methotrexate, or other conventional synthetic disease-modifying anti-rheumatic drug (DMARD) if methotrexate is contraindicated; and
    • Individual has had an inadequate response to one (1) or more tumor necrosis factor inhibitors, or is not suitable for treatment with tumor necrosis factor inhibitors; or
    • Combination therapy with methotrexate or other conventional synthetic DMARD not applicable to individuals who have had an inadequate response to methotrexate or other conventional synthetic DMARDs.

The use of rituximab (Rituxan) for all other indications not listed on this policy is considered experimental/investigational and therefore, not covered. Scientific evidence does not support the use for all other indications.

National Comprehensive Cancer Network (NCCN) Approved Recommendations

Rituximab (Rituxan) may be considered medically necessary for ANY of the following indications:

Acute Lymphoblastic Leukemia (ALL)

• Induction/consolidation therapy for Philadelphia chromosome-negative ALL in adolescent and young adult (AYA) and adult individuals less than 65 years of age as a component of:
  • GRAALL-2005 regimen (daunorubicin, vincristine, prednisone, pegaspargase, and cyclophosphamide) with rituximab for CD20-positive disease (individuals aged less than 60 years); or
  • HyperCVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with high-dose methotrexate and cytarabine), with or without rituximab for CD20-positive disease; or
• Induction therapy for Philadelphia chromosome-negative ALL in adults aged greater than or equal to 65 years as a component of GMALL (idarubicin, dexamethasone, vincristine, cyclophosphamide, and cytarabine, with or without rituximab for CD20-positive disease) (moderate intensity); or
• Therapy for relapsed/refractory Philadelphia chromosome-negative ALL or for relapsed/refractory Philadelphia chromosome-positive ALL refractory to TKIs as a component of MOpAD regimen (methotrexate, vincristine, pegaspargase, dexamethasone) with rituximab for CD20-positive disease; or
• Therapy for relapsed/refractory Philadelphia chromosome-positive ALL as a component of MOpAD regimen (methotrexate, vincristine, pegaspargase, dexamethasone) with rituximab for CD20-positive disease and TKI; or

B-Cell Lymphoma - AIDS-Related

• Treatment in combination with growth factor support for AIDS-related Burkitt lymphoma as a component of:
  • DA-EPOCH-R (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen; or
  • Modified CODOX-M (cyclophosphamide, doxorubicin, and vincristine, with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate) regimen alternating with IVAC (ifosfamide, cytarabine, etoposide, and intrathecal methotrexate) regimen with rituximab; or
• In combination with growth factor support for AIDS-related Burkitt lymphoma as a component of R-HyperCVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen; or
• Second-line therapy for relapse of AIDS-related Burkitt lymphoma as a component of:
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab (if not previously given as first-line therapy); or
  • RICE (rituximab, ifosfamide, carboplatin, and etoposide) regimen in combination with intrathecal methotrexate (if not previously given); or
  • RIVAC (rituximab, ifosfamide, cytarabine, etoposide) regimen in combination with intrathecal methotrexate (if not previously given); or
  • RGDP (rituximab, gemcitabine, dexamethasone, cisplatin) regimen; or
  • High-dose cytarabine and rituximab regimen; or
• Treatment In combination with growth factor support for CD20+ AIDS-related diffuse large B-cell lymphoma (DLBCL) primary effusion lymphoma, and HHV8-positive DLBCL, not otherwise specified (NOS) as a component of R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen; or
• In combination with growth factor support for CD20+ AIDS-related diffuse large B-cell lymphoma and HHV8-positive DLBCL, not otherwise specified (NOS) as a component of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen with rituximab; or
• Used for relapsed AIDS-related DLBCL, HHV8-positive DLBCL, not otherwise specified (NOS), and primary effusion lymphoma in combination with bortezomib-ICE (ifosfamide, carboplatin, and etoposide) regimen; or
• Second-line therapy or subsequent therapy for relapse of AIDS-related DLBCL, primary effusion lymphoma, and HHV8-positive DLBCL, not otherwise specified (NOS):
  • For individuals with intention to proceed to transplant as a component of DHAP (dexamethasone, cisplatin, and cytarabine), DHAX (dexamethasone, cytarabine, and oxaliplatin), ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin), GDP (gemcitabine, dexamethasone, and cisplatin or gemcitabine, dexamethasone, and carboplatin), GemOX (gemcitabine and oxaliplatin), ICE (ifosfamide, carboplatin, and etoposide), or MINE (mesna, ifosfamide, mitoxantrone, and etoposide) regimen with rituximab; or
  • In non-candidates for transplant as a single agent, in combination with polatuzumab vedotin-piiq with or without bendamustine (greater than or equal to two (2) prior therapies), with lenalidomide (for non-germinal center DLBCL) or bendamustine, with gemcitabine and vinorelbine, or as a component of CEPP (cyclophosphamide, etoposide, prednisone, and procarbazine), dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), CEOP (cyclophosphamide, etoposide, vincristine, and prednisone), GDP, or GemOX regimen with rituximab; or

B-Cell Lymphomas – Burkitt Lymphoma

• Induction therapy for low-risk disease for individuals less than 60 years of age as a component of:
  • CODOX-M (cyclophosphamide, doxorubicin, and vincristine, with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate) regimen (original or modified) regimen with rituximab; or
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab and intrathecal methotrexate; or
  • HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine regimen with rituximab (regimen includes intrathecal therapy); or
• Induction therapy for high-risk disease in individuals less than 60 years of age as a component of:
  • CODOX-M (cyclophosphamide, doxorubicin, and vincristine, with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate) regimen (original or modified) alternating with IVAC (ifosfamide, cytarabine, etoposide, and intrathecal methotrexate) regimen with rituximab; or
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab and intrathecal methotrexate for individuals not able to tolerate aggressive therapy; or
  • Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine regimen with rituximab (regimen includes intrathecal therapy); or
• Induction therapy for low-risk and high-risk disease in individuals 60 years of age or older as a component of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab and intrathecal methotrexate; or
• Used as a component of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab and intrathecal methotrexate, RICE (rituximab, ifosfamide, carboplatin, and etoposide) regimen with intrathecal methotrexate if not previously given, RIVAC (rituximab, ifosfamide, cytarabine, and etoposide) regimen with intrathecal methotrexate if not previously given:
  • As second-line therapy for relapse of Burkitt lymphoma greater than 6-18 months following appropriate first-line therapy; or
  • For individuals with partial response to second-line therapy as additional therapy (if not previously given) for relapse or refractory disease; or
• Second-line therapy for individuals with disease relapse greater than 6-18 months after appropriate first-line therapy or for individuals with partial response to second-line therapy as additional therapy (if not previously given) for relapsed or refractory disease:
  • As a component of RGDP (rituximab, gemcitabine, dexamethasone, and cisplatin) regimen; or
  • As a component of high-dose cytarabine with rituximab regimen; or

B-Cell Lymphomas – Castleman's Disease (CD)

• Used for unicentric CD with or without prednisone and/or cyclophosphamide:
  • For surgically unresectable disease; or
  • For symptomatic disease following incomplete resection; or
  • As second-line therapy for relapsed or refractory disease; or
• Therapy for active multicentric CD with no organ failure with or without prednisone for individuals who are human immunodeficiency virus-negative and human herpesvirus-8-negative:
  • As primary treatment; or
  • For relapsed disease; or
  • If no response to primary treatment; or
• Therapy for active multicentric CD with no organ failure with or without liposomal doxorubicin and/or prednisone for individuals who are human herpesvirus-8-positive:
  • As preferred** primary treatment; or
  • For relapsed disease; or
  • If no response to primary treatment; or
• Used with or without prednisone for active multicentric CD with no organ failure for progression greater than or equal to six (6) months following completion of rituximab; or
• Primary treatment for multicentric CD for individuals with fulminant human herpesvirus-8 with or without organ failure: 
  • In combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • In combination with CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) regimen; or
  • In combination with CVP (cyclophosphamide, vincristine, and prednisone) regimen; or
  • In combination with Liposomal doxorubicin; or
  • As a single agent if individual is not a candidate for combination therapy; or
• Treatment for refractory or progressive multicentric CD in combination with liposomal doxorubicin or with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), or CVP (cyclophosphamide, vincristine, and prednisone) regimen:
  • As initial treatment; or
  • If no response to initial treatment for refractory or progressive disease; or
• Subsequent therapy for multicentric CD that has progressed following treatment of relapsed/refractory or progressive disease in combination with:
  • Bortezomib; or
  • Lenalidomide; or
  • Thalidomide; or

B-Cell Lymphomas – Diffuse Large B-Cell Lymphoma (DLBCL)

• First-line therapy for stage I-II disease as a component of:
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
• First-line therapy for stage I-II disease for individuals with poor left ventricular function as a component of:
  • RCEPP (rituximab, cyclophosphamide, etoposide, prednisone, and procarbazine) regimen; or
  • RCDOP (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone) regimen; or 
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab; or
  • RCEOP (rituximab, cyclophosphamide, etoposide, vincristine, and prednisone) regimen; or
  • RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone) regimen; or
• First-line therapy for stage I-II disease for very frail individuals and individuals greater than 80 years of age with comorbidities as a component of:
  • RCEPP regimen; or
  • RCDOP regimen; or
  • R-mini-CHOP; or
  • RGCVP regimen; or
• First-line therapy for stage III-IV disease as a component of:
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab; or
• First-line therapy for stage III-IV disease in individuals with poor left ventricular function as a component of:
  • RCEPP (rituximab, cyclophosphamide, etoposide, prednisone, and procarbazine) regimen; or
  • RCDOP (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone) regimen; or
  • Dose-adjusted EPOCH regimen with rituximab; or
  • RCEOP (rituximab, cyclophosphamide, etoposide, vincristine, and prednisone) regimen; or
  • RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone) regimen; or
• First-line therapy for stage III-IV disease for very frail individuals and individuals greater than 80 years of age with comorbidities as a component of:
  • RCEPP regimen; or
  • RCDOP regimen; or
  • R-mini-CHOP; or
  • RGCVP regimen; or
• Second-line or subsequent therapy for partial response, no response, relapsed, progressive, or refractory disease in individuals with intention to proceed to transplant as a component of:
  • DHAP (dexamethasone, cisplatin, and cytarabine) regimen with rituximab; or
  • DHAX (dexamethasone, cytarabine, and oxaliplatin) regimen with rituximab,
  • ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) regimen with rituximab; or
  • GDP (gemcitabine, dexamethasone, and cisplatin or gemcitabine, dexamethasone, and carboplatin) regimen with rituximab; or
  • GemOX (gemcitabine and oxaliplatin) regimen with rituximab; or
  • ICE (ifosfamide, carboplatin, and etoposide) regimen with rituximab; or
  • MINE (mesna, ifosfamide, mitoxantrone, and etoposide) regimen with rituximab; or
• Second-line or subsequent therapy for partial response, no response, relapsed, progressive, or refractory disease in non-candidates for transplant:
  • As a single agent; or
  • In combination with lenalidomide (non-germinal center lymphoma); or
  • In combination with bendamustine; or
  • In combindation with Polatuzumab vendotin-piiq with or without bendamustine after greater than or equal to two (2) prior therapies; or
  • As a component of CEPP (cyclophosphamide, etoposide, prednisone, and procarbazine) with rituximab regimen; or
  • As a component of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) with rituximab regimen; or
  • As a component of CEOP (cyclophosphamide, etoposide, vincristine, and prednisone) with rituximab regimen; or
  • As a component of GDP with rituximab regimen; or
  • As a component of GemOX with rituximab regimen; or
  • As a component of gemcitabine and vinorelbine regimens with rituximab; or
• First-line therapy for primary mediastinal large B-cell lymphoma as a component of:
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab; or
  • Dose-dense RCHOP regimen followed by ICE (ifosfamide, carboplatin, and etoposide) regimen; or
• First-line therapy for grey zone lymphoma as a component of:
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab; or
• First-line therapy for grey zone lymphoma for individuals with poor left ventricular function as a component of:
  • RCEPP (rituximab, cyclophosphamide, etoposide, prednisone, and procarbazine) regimen; or  
  • RCDOP (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone) regimen; or
  • Dose-adjusted EPOCH regimen with rituximab; or
  • RCEOP (rituximab, cyclophosphamide, etoposide, vincristine, and prednisone) regimen; or
  • RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone) regimen; or
• First-line therapy for grey zone lymphoma for very frail individuals and individuals greater than 80 years of age with comorbidities as a component of:
  • RCEPP regimen; or
  • RCDOP regimen; or  
  • R-mini-CHOP; or
  • RGCVP regimen; or
• Treatment of primary cutaneous DLBCL, leg type as first-line with involved site radiation therapy or as second-line therapy (if not previously received) for solitary regional T 1-2 disease, or as firs-line therapy for generalized cutaneous, T3 disease:
  • As a component of RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
• Treatment of primary cutaneous DLBCL, leg type as first-line with involved site radiation therapy or as second-line therapy (if not previously received) for solitary regional T 1-2 disease, or as firs-line therapy for generalized cutaneous, T3 disease in individuals with poor left ventricular function as a component of:
  • RCEPP (rituximab, cyclophosphamide, etoposide, prednisone, and procarbazine) regimen; or
  • RCDOP (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone) regimen; or
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab; or  
  • RCEOP (rituximab, cyclophosphamide, etoposide, vincristine, and prednisone) regimen; or
  • RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone) regimen; or
• Treatment of primary cutaneous DLBCL, leg type as first-line with involved site radiation therapy or as second-line therapy (if not previously received) for solitary regional T 1-2 disease, or as firs-line therapy for generalized cutaneous, T3 disease for very frail individuals and individuals greater than 80 years of age with comorbidities as a component of:
  • RCEPP regimen; or
  • RCDOP regimen; or
  • R-mini-CHOP; or
  • RGCVP regimen; or
• First-line therapy for extracutaneous primary cutaneous DLBCL, leg type as a component of:
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab; or
• First-line therapy for extracutaneous primary cutaneous DLBCL, leg type for individuals with poor left ventricular function as a component of:
  • RCEPP (rituximab, cyclophosphamide, etoposide, prednisone, and procarbazine) regimen; or
  • RCDOP (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone) regimen; or
  • Dose-adjusted EPOCH regimen with rituximab; or
  • RCEOP (rituximab, cyclophosphamide, etoposide, vincristine, and prednisone) regimen; or
  • RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone) regimen; or
• First-line therapy for extracutaneous primary cutaneous DLBCL, leg type for very frail individuals and individuals greater than 80 years of age with comorbidities as a component of:
  • RCEPP regimen; or
  • RCDOP regimen; or
  • R-mini-CHOP; or
  • RGCVP regimen; or

B-Cell Lymphomas – Follicular Lymphoma (grade 1-2)

• First-line therapy for stage I, contiguous stage II, non-contiguous stage II disease, or for individuals with the indications for treatment with stage III or IV disease as:
  • A component of RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • A component of RCVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen; or
  • In combination with bendamustine or lenalidomide; or
• Used as a single agent in elderly or infirm individuals when tolerability of combination chemotherapy is a concern as:
  • First-line therapy for stage I, contiguous stage II, non-contiguous stage II disease, or for individuals with indications for treatment with stage III or IV disease; or
  • Second-line or subsequent therapy (if not previously given as first-line) for refractory or progressive disease in individuals with indications for treatment; or
• Used in elderly or infirm individuals with indications for treatment in combination with chlorambucil or in combination with cyclophosphamide as:
  • First-line therapy for stage I, contiguous stage II, non-contiguous stage II disease, or for individuals with indications for treatment with stage III or IV disease; or
  • Second-line or subsequent therapy (if not previously given as first-line) for refractory or progressive disease in individuals with indications for treatment; or
• First-line therapy for stage I, contiguous stage II non-contiguous stage II disease, or for individuals with indications for treatment with stage III or IV disease a single agent in individuals that were initially observed and have progressed with a low tumor burden; or
• First-line therapy for stage I, II pediatric-type follicular lymphoma in adults with extensive local disease who are not candidates for excision or involved site radiation therapy as a component of RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) regimen; or
• Second-line or subsequent therapy for refractory or progressive disease in individuals with indications for treatment as a single agent or in combination with:
  • Bendamustine (if not previously given as first-line); or
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen (if not previously given as first-line); or
  • RCVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen (if not previously given as first-line); or
  • Lenalidomide ( if not previously given as first line); or
  • DHAP (dexamethasone, cisplatin, and cytarabine) regimen; or
  • DHAX (dexamethasone, cytarabine, and oxaliplatin) regimen; or
  • ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) regimen; or
  • GDP (gemcitabine, dexamethasone, and cisplatin or gemcitabine, dexamethasone, and carboplatin) regimen; or
  • GemOX (gemcitabine and oxaliplatin) regimen; or
  • ICE (ifosfamide, carboplatin, and etoposide) regimen; or
  • MINE (mesna, ifosfamide, mitoxantrone, and etoposide) regimen; or
  • CEPP (cyclophosphamide, etoposide, prednisone, and procarbazine) regimen; or
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen; or
  • CEOP (cyclophosphamide, etoposide, vincristine, and prednisone) regimen; or
  • Gemcitabine and vinorelbine; or
  • Polatuzumab vendotin-piiq with or without bendamustine; or
• Treatment of histologic transformation to DLBCL without translocations of MYC and BCL2 and/or BCL6 in individuals who have received minimal or no prior chemotherapy as a component of:
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) and rituximab regimen; or  
• Treatment of histologic transformation to DLBCL without translocations of MYC and BCL2 and/or BCL6 in individuals who have received minimal or no prior chemotherapy and have poor left ventricular function as a component of:
  • RCEPP (rituximab, cyclophosphamide, etoposide, prednisone, and procarbazine) regimen; or
  • RCDOP (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone) regimen; or
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab; or
  • RCEOP (rituximab, cyclophosphamide, etoposide, vincristine, and prednisone) regimen; or
  • RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine and prednisolone) regimen; or  
• Treatment of histologic transformation to DLBCL without translocations of MYC and BCL2 and/or BCL6 in individuals who have received minimal or no prior chemotherapy and are very frail and for individuals greater than 80 years of age with comorbidities as a component of:
  • RCEPP regimen; or
  • RCDOP regimen; or
  • R-mini-CHOP regimen; or
  • RGCVP regimen; or
• Used in combination with polatuzumab vedotin-piiq with or without bendamustine as treatment of histologic transformation to DLBCL without translocations of MYC and BCL2 and/or BCL6 in individuals who have received minimal or no prior chemotherapy prior to histologic transformation and have no response or progressive disease after chemoimmunotherapy; or
• Treatment of histologic transformation to DLBCL with translocations of MYC and BCL2 and/or BCL6 in individuals who have received minimal or no prior chemotherapy as a component of;:
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab; or
  • HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine regimen with rituximab; or
  • R-CODOX-M (rituximab, cyclophosphamide, vincristine, and doxorubicin with methotrexate) regimen alternating with R-IVAC (rituximab, ifosfamide, etoposide, and cytarabine) regimen; or
• Treatment of histologic transformation to DLBCL in individuals who have received multiple lines of chemoimmunotherapy for indolent or transformed disease as a single agent or in combination with:
  • Bendamustine; or
  • DHAP (dexamethasone, cisplatin, and cytarabine) regimen; or
  • DHAX (dexamethasone, cytarabine, and oxaliplatin) regimen; or
  • ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) regimen; or
  • GDP (gemcitabine, dexamethasone, and cisplatin or gemcitabine, dexamethasone, and carboplatin) regimen; or
  • GemOX (gemcitabine and oxaliplatin) regimen; or
  • ICE (ifosfamide, carboplatin, and etoposide) regimen; or
  • MINE (mesna, ifosfamide, mitoxantrone, and etoposide) regimen; or
  • CEPP (cyclophosphamide, etoposide, prednisone, and procarbazine) regimen; or
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen; or
  • CEOP (cyclophosphamide, etoposide, vincristine, and prednisone) regimen; or
  • Lenalidomide; or
  • Gemcitabine and vinorelbine; or
  • Polatuzumab vendotin-piiq with or without bendamustine; or
• First-line consolidation therapy in individuals with indications for treatment if initially treated with single-agent rituximab; or
• Maintenance therapy:
  • As first-line consolidation or extended dosing in individuals initially presenting with high tumor burden (stage III, IV) who achieve a complete or partial response following treatment with RCHOP (rituximab, cyclophosphamide,doxorubicin, and prednisone) regimen or RCVP (rituximab, cyclophosphamide, vincristine and prednisone) regimen; or
  • Second-line consolidation or extended dosing; or
  • Can be considered for individuals with histologic transformation to DLBCL that is coexisting with extensive follicular lymphoma who achieve a complete response to chemoimmunotherapy; or

B-Cell Lymphomas – Gastric MALT Lymphoma

• Initial therapy (if involved site radiation therapy is contraindicated) as a single agent stage I1, or I2, or stage II1 disease in individuals who are H-pylori-positive and t(11;18) positive or who are H-pylori-negative; or
• Treatment for individuals with indications for treatment as a component of RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen, RCVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen, or in combination with bendamustine:
  • As first-line therapy for stage IIE, or II2, or stage IV disease (distant nodal, advanced stage); or
  • As additional therapy for stage I1, or I2, or stage II1 H. pylori positive disease if repeat endoscopy shows no response or recurrence after antibiotic therapy and involved site radiation therapy (ISRT); or
  • As additional therapy after ISRT or rituximab alone for stage I1, or I2, or stage II1 disease that is lymphoma positive after restaging with endoscopy; or
• Used as a single agent in individuals with indications for treatment as:
  • First-line therapy for stage IIE, or II2, or stage IV (distant nodal or advanced stage); or
  • Additional therapy for stage I1, or I2, or stage II1 H. pylori positive disease if repeat endoscopy shows no response or recurrence after antibiotic therapy and ISRT; or
  • Additional therapy after involved site radiation therapy ISRT alone for stage I1, or I2, or stage II1 disease that is lymphoma positive after restaging with endoscopy; or
  • Second-line or subsequent therapy for recurrent or progressive disease (if longer duration of remission); or
• Used in combination with lenalidomide for individuals with indications for treatment as:
  • First-line therapy for stage IIE, or II2, or stage IV disease (distant nodal or advanced stage); or
  • Additional therapy for stage I1, or I2, or stage II1 H. pylori positive disease if repeat endoscopy shows no response or recurrence after antibiotic therapy and ISRT; or
  • Additional therapy after ISRT or rituximab alone) for stage I1, or I2, or stage II1 disease that is lymphoma positive after restaging with endoscopy; or
• Used as a single agent or in combination with chlorambucil or cyclophosphamide in elderly or infirm individuals with indications for treatment when tolerability of combination chemotherapy is a concern as:
  • First-line therapy for stage IIE, or II2, or stage IV (distant nodal or advanced stage) disease; or
  • Additional therapy for stage I1, or I2, or stage II1 H. pylori positive disease if repeat endoscopy shows no response or recurrence after antibiotic therapy and ISRT; or
  • Additional therapy after ISRT or rituximab alone for stage I1, or I2, or stage II1 disease that is lymphoma positive after restaging with endoscopy; or
  • Second-line or subsequent therapy for recurrent or progressive disease; or
• Consolidation as optional first-line extended therapy in individuals initially treated with single agent rituximab; or
• Second-line therapy or subsequent therapy for recurrent or progressive disease in individuals with indications for treatment:  
  • In combination with Bendamustine (not recommended if previously treated with bendamustine**); or
  • As a component of RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • As a component of RCVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen; or
  • In combination with Lenalidomide (including for the elderly or infirm when tolerability of combination chemotherapy is a concern); or

B-Cell Lymphomas – High-Grade B-Cell Lymphomas

• Used as induction therapy for high-grade B-cell lymphomas with translocations of MYC and BCL2 and/or BCL6 (double/triple hit lymphoma) or high-grade B-cell lymphomas, not otherwise specified as a component of: 
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab; or
  • Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine regimen with rituximab; or
  • R-CODOX-M (rituximab, cyclophosphamide, vincristine, and doxorubicin with methotrexate) regimen alternating with R-IVAC (rituximab, ifosfamide, etoposide, and cytarabine) regimen; or
• Used as induction therapy for high-grade B-cell lymphomas, not otherwise specified* as a component of:
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab; or
  • Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine regimen with rituximab; or
  • R-CODOX-M (rituximab, cyclophosphamide, vincristine, and doxorubicin with methotrexate) regimen alternating with R-IVAC (rituximab, ifosfamide, etoposide, and cytarabine) regimen; or
• Second-line or subsequent therapy for partial response, no response, relapsed, progressive, or refractory high-grade B-cell lymphomas with translocations of MYC and BCL2 and/or BCL6 (Double/Triple Hit Lymphoma) in:
  • Individuals with intention to proceed to transplant as a component of DHAP (dexamethasone, cisplatin, and cytarabine), DHAX (dexamethasone, cytarabine, and oxaliplatin), ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin), GDP (gemcitabine, dexamethasone, and cisplatin or gemcitabine, dexamethasone, and carboplatin), GemOX (gemcitabine and oxaliplatin), ICE (ifosfamide, carboplatin, and etoposide), or MINE (mesna, ifosfamide, mitoxantrone, and etoposide) regimen with rituximab; or
  • Non-candidates for transplant as a single agent, in combination with lenalidomide (non-germinal center lymphoma) or bendamustine, or as a component of CEPP (cyclophosphamide, etoposide, prednisone, and procarbazine), dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), CEOP (cyclophosphamide, etoposide, vincristine, and prednisone), GDP, GemOX, or gemcitabine and vinorelbine regimen with rituximab; or
  • Non-candidates for transplant in combination with polatuzumab vendotin-piiq with or without bendamustine after greater than or equal to two (2) prior therapies; or
• Second-line and subsequent therapy for partial response, no response, relapsed, progressive, or refractory high-grade B-cell lymphoma, NOS, in:
  • Individuals with intention to proceed to transplant as component of DHAP, DHAX, ESHAP, GDP, gemcitabine, dexamethasone, and carboplatin, GemOx, ICE, or MINE, regimen with rituximab; or
  • Non-candidates for transplant as a single agent, in combination with lenalidomide (non-germinal center lymphoma) or bendamustine, or as a coponet of CEPP, dose-adjusted EPOCH, CEOP, GDP, gemcitabine, dexamethasone, and carboplatin, GemOx, or gemcitabine and vinorelbine regimen with rituximab
  • Non-candidates for transplant in combination with polatuzumab vevedotin-piiq with or without bendamustine; or

*RCHOP has been associated with inferior outcomes for individuals with highgrade B-cell lymphomas with translocations of MYC and BCL2 and/or BCL6 (double/triple hit lymphoma)

B-Cell Lymphomas – Nongastric MALT Lymphoma (Noncutaneous)

• First-line therapy for stage I-II disease in selected cases; or
• First-line therapy for stage IV disease or recurrent stage I-II disease in individuals with indications for treatment as a component of:
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • RCVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen; or
  • Bendamustine with rituximab; or
• First-line therapy as a single agent or in combination with lenalidomide for stage IV disease or recurrent stage I-II disease in individuals with indications for treatment; or
• Used as a single agent or in combination with chlorambucil or cyclophosphamide for stage IV disease or recurrent stage I-II disease in elderly or infirm individuals with indications for treatment when tolerability of combination chemotherapy is a concern as:
  • First-line therapy; or
  • Second-line or subsequent therapy for recurrent or progressive disease; or
• Second-line or subsequent therapy for recurrent or progressive disease in individuals with indications for treatment in:
  • Bendamustine with rituximab; or
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • RCVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen; or
  • Lenalidomide with rituximab (including for the elderly or infirm when tolerability of combination chemotherapy is a concern); or
• Consolidation as optional first-line extended therapy; or
• Second-line or subsequent therapy as a single agent for recurrent or progressive disease in individuals with indications for treatment (if longer duration of remission); or

B-Cell Lymphomas – Nodal Marginal Zone Lymphoma

• Used as a single agent or in combination with chlorambucil or cyclophosphamide for stage I, contiguous stage II, non-contiguous stage II, or stage III, IV disease in elderly or infirm individuals with indications for treatment when tolerability of combination chemotherapy is a concern as:                                              
  • First-line therapy; or
  • Second-line or subsequent therapy; or
• First-line therapy for stage I, contiguous stage II, non-contiguous stage II, or stage III, or IV disease in individuals with indications for treatment in combination with bendamustine or as a component of:
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • RCVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen; or
• First-line therapy as a single agent or in combination with lenalidomide for stage I, contiguous stage II, non-contiguous stage II, or stage III, IV disease in individuals with indications for treatment; or
• Second-line or subsequent therapy for refractory or progressive disease in individuals with indications for treatment:
  • In combination with bendamustine (not recommended if previously treated with bendamustine); or
  • In combination with lenalidomide including for the elderly or infirm when tolerability of combination chemotherapy is a concern; or
  • As a component of RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • As a component of RCVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen; or
• Consolidation as optional first-line extended therapy; or
• Second-line or subsequent therapy as a single agent for refractory or progressive disease in individuals with indications for treatment (if longer duration of remission); or

B-Cell Lymphomas – Histologic Transformation of Marginal Zone Lymphoma to Diffuse Large B-Cell Lymphoma (DLBCL)

• Treatment of individuals who have received minimal or no prior chemotherapy as a component of:
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) and rituximab regimen; or
• Treatment of individuals who have received minimal or no prior chemotherapy and have poor left ventricular function as a component of:
  • RCEPP (rituximab, cyclophosphamide, etoposide, prednisone, and procarbazine) regimen; or
  • RCDOP (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone) regimen; or
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab; or
  • RCEOP (rituximab, cyclophosphamide, etoposide, vincristine, and prednisone) regimen; or
  • RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine and prednisolone) regimen; or
• Treatment of individuals who have received minimal or no prior chemotherapy and are very frail and for individuals greater than 80 years of age with comorbidities as a component of:
  • RCEPP regimen; or
  • RCDOP regimen; or
  • R-mini-CHOP regimen; or
  • RGCVP regimen; or
• Subsequent therapy for individuals who have received multiple lines of chemoimmunotherapy for indolent or transformed disease as a single agent, in combination with bendamustine, or as a component of:
  • DHAP (dexamethasone, cisplatin, and cytarabine) regimen; or
  • DHAX (dexamethasone, cytarabine, and oxaliplatin) regimen; or
  • ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) regimen; or
  • GDP (gemcitabine, dexamethasone, and cisplatin or gemcitabine, dexamethasone, and carboplatin) regimen; or
  • GemOX (gemcitabine and oxaliplatin) regimen; or
  • ICE (ifosfamide, carboplatin, and etoposide) regimen; or
  • MINE (mesna, ifosfamide, mitoxantrone, and etoposide) regimen; or
  • CEPP (cyclophosphamide, etoposide, prednisone, and procarbazine) regimen; or
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen; or
  • CEOP (cyclophosphamide, etoposide, vincristine, and prednisone) regimen with rituximab; or
  • Lenalidomide: or
  • Gemcitabine and vinorelbine; or
• Used in combination with polatuzumab vedotin-piiq with or without bendamustine for individuals who have received multiple prior therapies including greater than or equal to two (2) lines of chemoimmunotherapy for indolent or transformed disease; or

B-Cell Lymphomas – Mantle Cell Lymphoma

• Aggressive induction therapy for stage I-II disease that had a partial response, progression, or relapse after initial treatment with involved site radiation therapy alone, or for aggressive stage II bulky, III, or IV disease, or symptomatic indolent stage II bulky, III, or IV TP53 mutation negative (Aggressive induction therapy followed by HDT/ASCR may not be appropriate for TP53 positive disease.) disease in individuals who are candidates for high-dose therapy/autologous stem cell rescue (HDT/ASCR) as a component of:
  • RDHA + platinum (rituximab, dexamethasone, cytarabine) + carboplatin, cisplatin, or oxaliplatin regimen; or
  • Alternating RCHOP/RDHAP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)/(rituximab, dexamethasone, cytarabine, and cisplatin) regimen; or
  • HyperCVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine regimen with rituximab; or
  • Bendamustine with rituximab followed by rituximab in combination with high-dose cytarabine; or
• Aggressive induction therapy in combination with bendamustine for stage I-II disease that had a partial response, progression, or relapse after initial treatment with involved site radiation therapy alone, or for aggressive stage II bulky, III, or IV disease, or symptomatic indolent stage II bulky, III, or IV TP53 mutation negative disease (Aggressive induction therapy followed by HDT/ASCR may not be appropriate for TP53 positive disease.); or
• Less aggressive induction therapy for stage I-II disease as initial therapy (localized presentation, extremely rare), or for partial response, progression, or relapse after initial treatment with involved site radiation therapy alone, or for aggressive stage II bulky, III, or IV disease, or symptomatic indolent stage II bulky, III, or IV TP53 mutation positive disease in individuals who are not candidates for high dose therapy/autologous stem cell rescue in combination with bendamustine or lenalidomide, or as a component of
  • VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) regimen; or
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen with rituximab; or
• Less aggressive induction therapy for stage I-II disease (localized presentation, extremely rare) as initial therapy, or for partial response, progression, or relapse after initial treatment with involved site radiation therapy alone, or for aggressive stage II bulky, III, or IV TP53 mutation positive disease, or symptomatic indolent stage II bulky, III, or IV disease in individuals who are not candidates for high-dose therapy/autologous stem cell rescue as a component of:
  • RBAC500 (rituximab, bendamustine, and cytarabine) regimen; or
  • Modified HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with rituximab regimen in individuals older than 65 years
• Single-agent maintenance therapy for aggressive stage II bulky, III, or IV disease, or symptomatic indolent stage II bulky, III, or IV disease following complete or very good partial response to less aggressive induction therapy or high-dose therapy with autologous stem cell rescue; or
• Second-line therapy for stage I-II disease or aggressive stage II bulky, III, or IV disease, or symptomatic indolent stage II bulky, III, or IV disease in individuals who have stable disease or partial response with substantial disease after induction therapy, or who have relapsed or progressed following prior treatment with chemoimmunotherapy:
  • In combination with bendamustine (if not previously given); or
  • As a component of RBAC500 (rituximab, bendamustine and cytarabine) regimen (f not previously given); or
  • In combination with bortezomib; or
  • as a component of DHAP (dexamethasone, cisplatin, and cytarabine) with rituximab regimen; or
  • As a component of DHAOx (dexamethasone, cytarabine, and oxaliplatin) with rituximab regimen; or
  • As a component of GemOx (gemcitabine, oxaliplatin) with rituximab regimen; or
  • In combination with ibrutinib and lenalidomide; or
  • In combination with venetoclax; or
• Second-line or subsequent therapy for stage I-II, aggressive stage II bulky, III, or IV, or symptomatic indolent stage II bulky, III, or IV disease in individuals who have stable disease or partial response with substantial disease after induction therapy, or who have relapsed or progressed following prior chemoimmunotherapy:
  • In combination with ibrutinib; or
  • In combination with lenalidomide; or

B-Cell Lymphomas – Pediatric Aggressive Mature B-Cell Lymphomas

• Induction therapy for individuals with greater than or equal to 20% reduction after COP reduction phase as a component of COG ANHL1131 regimen B/induction 1 and 2 with COPADM (cyclophosphamide, vincristine, prednisone, doxorubicin, methotrexate, and intrathecal therapy with methotrexate and hydrocortisone) with rituximab regimen:
  • For group B individuals with low-risk disease [stage I or II individuals who are not fully resected or any stage III individual with LDH ≤2 times the upper limit of normal (ULN)]; or
  • For group B individuals with high-risk disease (any stage III individual with LDH greater than two (2) times upper limit of normal (ULN), and all non-CNS stage IV individuals with less than 25% bone marrow involvement); or
• Consolidation therapy 1 for individuals with greater than or equal to 20% reduction after COP reduction phase as a component of COG ANHL1131 regimen B with CYM (cytarabine, methotrexate, and intrathecal therapy with methotrexate, cytarabine, and hydrocortisone) with rituximab regimen:
  • For group B individuals with low-risk disease [stage I or II individuals who are not fully resected or any stage III individual with LDH less than or equal to two (2) times the ULN]; or
  • For group B individuals with high-risk disease (any stage III individual with LDH greater than two (2) times ULN, and all non-CNS stage IV individuals with less than 25% bone marrow involvement); or
• Induction therapy as a component of COG ANHL1131 regimen C1/induction 1 and 2 with R-COPADM (cyclophosphamide, vincristine, prednisone, doxorubicin, methotrexate, and intrathecal therapy with methotrexate, cytarabine, and hydrocortisone) with rituximab regimen for:
  • Group B individuals with less than 20% size reduction after COP reduction phase; or
  • Group C individuals with CNS negative disease after initial treatment with COP reduction phase; or
  • Group C individuals with CNS positive and CSF negative or positive disease after initial treatment with COP reduction phase; or
• Alternative induction therapy as a component of COG ANHL1131 regimen C3*/induction 1 and 2 with R-COPADM (cyclophosphamide, vincristine, prednisone, doxorubicin, methotrexate, and intrathecal therapy with methotrexate, cytarabine, and hydrocortisone) with rituximab regimen for:
  • Group C indiviuals with CNS and CSF positive disease; or
  • Group C individuals on regimen C1 therapy with less than 20% size reduction after COP reduction phase; or
• Consolidation therapy 1 and 2 as a component of COG ANHL1131 regimen C1 with R-CYVE (cytarabine, etoposide and intrathecal therapy with methotrexate and hydrocortisone) with rituximab regimen:
  • For group B individuals with less than complete response after first cycle of consolidation with CYM (cytarabine, methotrexate, and intrathecal therapy with methotrexate, cytarabine, and hydrocortisone) regimen; or
  • For group C individuals with CNS negative disease; or
  • For group C individuals with CNS positive disease, plus high-dose methotrexate and additional intrathecal therapy with methotrexate, cytarabine, and hydrocortisone after R-CYVE 1 only; or
• Consolidation therapy 1 and 2 as a component of COG ANHL1131 regimen C3 with R-CYVE (cytarabine, etoposide and intrathecal therapy with methotrexate and hydrocortisone) with rituximab regimen for group C individuals with CNS and CSF positive disease, plus high-dose methotrexate and additional intrathecal therapy with methotrexate, cytarabine, and hydrocortisone after R-CYVE 1 only; or
• Preferred treatment for relapsed or refractory disease (if not previously received as a part of initial therapy) as a component of R-CYVE (cytarabine, etoposide, and intrathecal therapy with methotrexate and hydrocortisone) with rituximab regimen; or
• Preferred treatment for relapsed or refractory disease as a component of R-ICE (ifosfamide, carboplatin, and etoposide) with rituximab regimen; or

B-Cell Lymphomas – Post-transplant Lymphoproliferative Disorder (PTLD)

• Single-agent therapy as:
  • First-line therapy for monomorphic (B-cell type) or polymorphic (B-cell type) PTLD; or
  • Second-line therapy for partial response, persistent or progressive non-destructive lesions or for partial response, persistent or progressive monomorphic (B-cell type) PTLD if immunosuppressive was reduced in first-line therapy; or
  • Maintenance therapy for polymorphic (B-cell type) PTLD achieving complete response on first-line therapy; or
• Concurrent chemoimmunotherapy for CD20+ disease as a component of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen with rituximab or as a component of CVP (cyclophosphamide, vincristine, and prednisone), CEPP (cyclophosphamide, etoposide, prednisone, and procarbazine), or CEOP (cyclophosphamide, etoposide, vincristine, and prednisone) regimen with rituximab for frail individuals who cannot tolerate anthracyclines as:
  • First-line therapy for monomorphic (B-cell type) or systemic polymorphic (B-cell type) PTLD; or
  • Second-line therapy for partial response, persistent or progressive monomorphic (B-cell type) or polymorphic (B-cell type) PTLD; or
• Sequential chemoimmunotherapy as a single agent followed by CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen with or without rituximab as:
  • First-line therapy for monomorphic (B-cell type) or systemic polymorphic (B-cell type) PTLD; or
  • Second-line therapy for persistent or progressive monomorphic (B-cell type) or polymorphic (B-cell type) PTLD; or
• Used in combination with high-dose methotrexate for primary CNS PTLD (B-cell type); or
• Second-line and subsequent therapy for individuals with partial response, persistent or progressive disease after receiving chemoimmunotherapy as first-line treatment for monomorphic PTLD (B-cell type) as a single agent or in combination with:
  • Bendamustine; or 
  • DHAP (dexamethasone, cisplatin, and cytarabine) regimen; or 
  • DHAX (dexamethasone, cytarabine, and oxaliplatin) regimen; or
  • ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) regimen; or 
  • GDP (gemcitabine, dexamethasone, and cisplatin or gemcitabine, dexamethasone, and carboplatin) regimen; or 
  • GemOX (gemcitabine and oxaliplatin) regimen; or 
  • ICE (ifosfamide, carboplatin, and etoposide) regimen; or 
  • MINE (mesna, ifosfamide, mitoxantrone, and etoposide) regimen; or 
  • CEPP (cyclophosphamide, etoposide, prednisone, and procarbazine) regimen; or 
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen; or 
  • CEOP (cyclophosphamide, etoposide, vincristine, and prednisone) regimen with rituximab; or 
  • Lenalidomide; or
  • Gemcitabine and vinorelbine; or
  • Polatuzumab vedotin-piiq with or without bendamustine (after greater than or equal to two (2) prior therapies; or

B-Cell Lymphoma – Primary Cutaneous

• Therapy for primary cutaneous marginal zone or follicle center lymphomawith:
  • Solitary/regional, T1-2 disease that is refractory to initial therapy; or
  • Generalized disease (skin only), T3 disease; or

Central nervous system cancers – Leptomeningeal metastases

• Intra-cerebrospinal fluid (CSF) treatment for leptomeningeal metastases from lymphomas for:
  • Primary treatment in individuals with good risk status (KPS greater than or equal to 60, no major neurologic deficits, minimal systemic disease, and reasonable systemic treatment options if needed); or
  • Maintenance treatment in individuals with negative CSF cytology or in clinically stable individuals with persistently positive CSF cytology; or
  • Treatment in individuals with positive CSF cytology that have progressed after receiving prior treatment; or

Central Nervous System Cancers - Primary CNS Lymphoma:

• Induction therapy:
  • In combination with high-dose methotrexate; or
  • In combination with high-dose methotrexate and temozolomide; or
  • As a component of R-MPV (rituximab, methotrexate, procarbazine, and vincristine) regimen; or
  • In combination with high-dose methotrexate and temozolomide followed by post-RT temozolomide; or
  • As a single agent if individual is unsuitable for or intolerant to high-dose methotrexate; or
  • In combination with temozolomide if individual is unsuitable for or intolerant to high-dose methotrexate; or
  • In combination with lenalidomide if individual is unsuitable for or intolerant to high-dose methotrexate; or
• Consider as intra-CSF therapy if CSF positive or spinal MRI positive as:
  • Part of induction therapy; or
  • Treatment alone or in combination with systemic chemotherapy for relapsed or refractory disease in individuals with prior WBRT; or
• Consider for consolidation therapy as continuation of induction regimen in individuals with complete response or complete response unconfirmed (CRu) to induction therapy:
  • In combination with high-dose methotrexate; or
  • In combination with high-dose methotrexate and temozolomide; or
  • As a component of R-MPV (rituximab, methotrexate, procarbazine, and vincristine) regimen; or
  • In combination with high-dose methotrexate and temozolomide followed by post-RT temozolomide; or
• Treatment as a single agent or in combination with temozolomide or lenalidomide for relapsed or refractory disease:
  • May be considered in individuals who received prior whole brain radiation therapy (RT); or
  • In individuals who received a prior high-dose methotrexate-based regimen without prior RT; or
  • In combination with whole brain RT or involved field RT in individuals who received a prior high-dose methotrexate-based regimen without prior RT after no response or short response duration (less than 12 months) to prior regimen; or
  • In individuals who received prior high-dose chemotherapy with stem cell rescue; or
• Treatment in combination with high-dose methotrexate with or without ibrutinib for relapsed or refractory disease:
  • In individuals who received prior whole brain radiation; or
  • In individuals who received a prior high-dose methotrexate-based regimen without prior radiation therapy (RT) and a previous long response duration (greater than or equal to12 months) to prior regimen; or

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

• First-line therapy for disease without del(17p)/TP53 mutation in frail individuals with significant comorbidity (not able to tolerate purine analogs) or in individuals age greater than or equal 65 years and younger individuals with significant comorbidities (CrCl less than 70 ml/min) who have indications for treatment:
  • In combination with high-dose methylprednisolone; or
  • As a single agent; or
• First-line therapy in combination with bendamustine for disease without del(17p)/TP53 mutation in individuals greater than or equal to 65 years of age and younger individuals with or without significant comorbidities who have indications for treatment (not recommended for frail individuals) ; or
• First-line therapy for disease without del(17p)/TP53 mutation in individuals age less than 65 years without significant comorbidities who have indications for treatment:
  • In combination with ibrutinib; or
  • In combination with high-dose methylprednisolone; or
  • As a component of PCR (pentostatin, cyclophosphamide, and rituximab) regimen; or
• First-line therapy for disease with del(17p)/TP53 mutation in combination with alemtuzumab or high-dose methylprednisolone in individuals with indications for treatment; or
• First line therapy for disease without del(17p)/TP53 mutations in individuals less than 65 years of age without significant comorbidities who have indications for treatment as a component of:
  • FCR (fludarabine, cyclophosphamide, and rituximab) regimen (for individuals with IGHV mutated CLL); or
  • Fludarabine and rituximab (FR) regimen [not recommended for CLL with del(11q)]; or
• Second-line and subsequent therapy for CLL/SLL without del(17p)/TP53 mutation in frail individuals with significant comorbidity or age greater than or equal to 65 years and younger individuals with significant comorbidities (creatining clearance less than 70 mL/min) who have indications for retreatment:
  • In combination with idelalisib or venetoclax; or
  • As a single agent in a dose-dense regimen; or
  • In combination with alemtuzumab, chlorambucil. lenalidomide, or high-dose methylprednisolone; or
  • As a component of reduced-dose FCR (fludarabine, cyclophosphamide, and rituximab) or reduced-dose PCR (pentostatin, cyclophosphamide, and rituximab) regimen; or
• Second-line and subsequent therapy in combination with bendamustine and with or without ibrutinib or idelalisib for CLL/SLL without del(17p)/TP53 mutation in individuals greater than or equal to 65 years of age or younger individuals with significant comorbidities (CrCl less than 70 ml/min) who have indications for retreatment (not recommended for frail individuals); or
• Second-line and subsequent therapy for CLL/SLL without del(17p)/TP53 mutation in individuals less than 65 years without significant comorbidities who have indications for retreatment:
  • In combination with idelalisib or venetoclax ; or
  • In combination with alemtuzumab, bendamustine with or without ibrutinib or idelalisib, high-dose methylprednisolone, or lenalidomide; or
  • As a component of FCR (fludarabine, cyclophosphamide, and rituximab) or PCR (pentostatin, cyclophosphamide, and rituximab) regimen; or
• Second-line and subsequent therapy for CLL/SLL with del(17p)/TP53 in individuals with indications for retreatment in combination with:
  • Idelalisib or venetoclax; or
  • Alemtuzumab, lenalidomide, or high-dose methylprednisolone; or
• Initial therapy for histologic (Richter's) transformation to DLBCL (clonally related or unknown clonal status) as a component of:
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) with rituximab regimen; or
  • HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with rituximab regimen alternating with high-dose methotrexate and cytarabine regimen; or
  • OFAR (oxaliplatin, fludarabine, cytarabine, and rituximab) regimen; or

Hairy Cell Leukemia

• Used in individuals with indications for treatment in combination with:
  • Cladribine as initial therapy; or
  • Cladribine for less than complete response or relapse within two (2) years of complete response following initial treatment with pentostatin; or
  • Pentostatin for less than complete response or relapse within two (2) years of complete response following initial treatment with cladribine; or
  • Cladribine or pentostatin for relapse greater than or equal to two (2) years following initial treatment; or
  • Vemurafenib for progression after therapy for relapsed/refractory disease; or
• As a single agent in individuals with indications for treatment who are unable to receive purine analogs for:
  • Less than complete response following initial treatment with cladribine or pentostatin; or
  • Relapse; or

Hematopoietic Cell Transplantation

• For chronic graft-versus-host disease (GVHD) as additional therapy in conjunction with systemic corticosteroids following no response (steroid refractory disease) to first-line therapy options; or

Hodgkin Lymphoma – Nodular Lymphocyte-Predominant

• Primary treatment as a component of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) + rituximab, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + rituximab, or CVP (cyclophosphamide, vinblastine, prednisolone) + rituximab for individuals 18 years of age or older:
  • With involved site radiation therapy (ISRT) for stage IA or IIA disease (bulky or non-contiguous): or
  • With ISRT for stage IB or IIB disease; or
  • With or without ISRT for stage III-IV disease; or
• Primary treatment as a single agent for stage III or IV disease; or
• Second-line or subsequent systemic therapy (if not previously used) for progressive, relapsed, or refractory disease as a single agent, with or without ISRT; or
• May be considered as maintenance therapy for individuals treated with second-line systemic therapy with rituximab alone for progressive, relapsed, or refractory disease; or
• Second-line or subsequent systemic therapy (if not previously used) for progressive, relapsed, or refractory disease in combination with:
  • DHAP (dexamethasone, cisplatin, and high-dose cytarabine); or
  • ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin); or
  • ICE (ifosfamide, carboplatin, and etoposide); or
  • IGEV (ifosfamide, gemcitabine, and vinorelbine); or
  • Bendamustine; or
  • ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) + rituximab; or
  • CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + rituximab; or
  • CVP (cyclophosphamide, vinblastine, prednisolone) + rituximab; or

Immune Checkpoint Inhibitor-Related Toxicities

• Management of the following immunotherapy-related toxicities:
  • As additional therapy for moderate (G2), severe (G3) or life-threatening (G4) immunotherapy-related bullous dermatitis; or
  • Moderate, severe, or life-threatening steroid-refractory myalgias or myositis; or
  • For severe (G 3-4) myasthenia gravis in individuals refractory to plasmapheresis or intravenous immune globulin (IVIG)
  • Treatment of immunotherapy-related encephalitis after viral causes have been excluded in individuals positive for autoimmune encephalopathy antibody, or who have had limited or no improvement after 7-14 days on pulse-dose methylprednisolone with or without IVIG; or

Rosai-Dorfman Disease

·       First-line or subsequent therapy, irrespective of mutation for nodal and immune-cytopenia diseases, as a single agent for:

o   Symptomatic unresectable (bulky/site of disease) unifocal disease; or

o   Symptomatic multifocal disease; or

o   Relapsed/refractory disease; or

o   Immunoglobulin G4 (IgG4) disease; or

Splenic Marginal Zone Lymphoma

• Therapy as a single-agent for symptomatic individuals with splenomegaly who are:
  • Hepatitis C negative; or
  • Hepatitis C positive with contraindications for hepatitis treatment; or
  • Hepatitis C positive with no response to appropriate hepatitis treatment; or
• Used as a single agent or in combination with chlorambucil or cyclophosphamide for disease recurrence following initial management of splenomegaly in elderly or infirm individuals with indications for treatment when tolerability of combination chemotherapy is a concern as:
  • First-line therapy (if treatment naïve); or
  • Second-line or subsequent therapy; or
• First-line therapy for disease recurrence following initial management of splenomegaly in treatment naïve individuals with indications for treatment as a single agent, in combination with bendamustine, or as a component of:
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • RCVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen; or
• Used in combination with lenalidomide as first-line therapy for disease recurrence following initial treatment for splenomegaly in treatment naïve individuals with indications for treatment; or
• Consolidation as optional first-line extended therapy in individuals initially treated with single agent rituximab; or
• Second-line (if prior treatment with rituximab) or subsequent therapy for disease recurrence in individuals with indications for treatment in combination with bendamustine (not recommended if previously treated with bendamustine**), or as a component of:
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • RCVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen; or
• Second-line (if previously treated with rituximab) or subsequent therapy in combination with lenalidomide for disease recurrence in individuals with indications for treatment, including the elderly or infirm when tolerability of combination chemotherapy is a concern; or
• Second-line or subsequent therapy as a single agent for disease recurrence in individuals with indications for treatment (if previously treated with rituximab with a longer duration of remission); or

Waldenström's Macroglobulinemia/Lymphoplasmacytic Lymphoma

• Used as a component of CaRD (carfilzomib, rituximab, and dexamethasone) regimen or in combination with ixazomib and dexamethasone:
  • As primary therapy; or
  • For relapse if previously used as primary therapy that was well tolerated and elicited a prolonged response; or
• Used as primary therapy, for relapse if previously used as primary therapy that was well tolerated and elicited a prolonged response, or for progressive or relapsed disease:
  • In combination with bendamustine; or
  • In combination with bortezomib and dexamethasone; or
  • In combination with ibrutinib; or
  • In combination with cyclophosphamide and dexamethasone; or
  • As a single agent; or
  • In combination with bortezomib; or
  • In combination with cyclophosphamide and prednisone; or
  • As a component of CHOP-R (cyclophosphamide, doxorubicin,  vincristine, prednisone, and rituximab) regimen; or
  • In combination with cladribine or fludarabine in individuals who are not potential autologous stem cell transplant candidates; or
  • As a component of FCR (fludarabine, cyclophosphamide, and rituximab) regimen in individuals who are not potential autologous stem cell transplant candidates; or
• Consider for maintenance therapy following a complete, very good partial, partial, or minor response to primary therapy if regimen included rituximab.

The use of rituximab (Rituxan) for all other indications not listed on this policy is considered experimental/investigational and therefore, not covered. Scientific evidence does not support the use for all other indications.

Other clinically supported indications

Rituximab (Rituxan) may be considered medically necessary for ANY of the following 2b or higher off-label indications:

Autoimmune Hemolytic Anemia (AIHA)

• Warm AIHA in glucocorticoid-refractory or glucocorticoid-dependent individuals; or
• Cold agglutination syndrome; or

Churg-Strauss Syndrome (Eosinophilic Granulomatosis with Polyangiitis)

• First-line treatment in combination with glucocorticoids for individuals with severe (organ-threatening) disease; or
• Add-on therapy for treatment-refractory disease; or

Epstein-Barr virus disease; Prophylaxis - Hemopoietic stem cell transplant

• Prophylaxis for Epstein Barr virus infection in pediatric individuals undergoing hematopoietic stem cell transplant; or

Evans syndrome (Pediatric only)

• Treatment for Evans syndrome refractory to immunosuppressive therapy; or

Hemophilia

• Treatment of individuals 18 years of age or older for hemophilia with acquired inhibitors in individuals who are refractory to conventional first line treatments (i.e. immunosuppression with prednisone and cyclophosphamide); or

Hepatitis C Virus‒Associated Cryoglobulinemic Vasculitis

• As add-on therapy for individuals with hepatitis C virus‒associated cryoglobulinemic vasculitis who have:
  • Active disease resistant to antiviral drugs; or
  • Severe or life-threatening cryoglobulinemic vasculitis; or

Idiopathic Membranous Nephropathy

• As treatment for idiopathic membranous nephropathy; or

Immune thrombocytopenia, previously treated (Pediatric only)

• Treatment for pediatric individuals with previously treated primary and secondary immune thrombocytopenia; or

Inflammatory Myopathy (Idiopathic)

• Treatment for individuals 18 years of age or older who have failed to respond to, or are intolerant to, another immunosuppressant (e.g. methotrexate) with refractory idiopathic inflammatory myopathy; or

Lupus Nephritis

• As add-on therapy for lupus nephritis refractory to standard first-line treatment regimen; or

Microscopic polyarteritis nodosa (Adult only)

• treatment for microscopic polyarteritis nodosa in combination with glucocorticoids; or

Minimal change disease (Pediatric only)

• Treatment for remission induction and maintenance of remission in pediatric individuals who have refractory, steroid-dependent or steroid-resistant minimal change disease; or

Multiple Sclerosis (Primary Progressive)

• Treatment for individuals 18 years of age or older with primary progressive multiple sclerosis who have gadolinium brain lesions at baseline and have failed treatment with ocrelizumab; or

Multiple Sclerosis (Relapsing Remitting)

• Treatment of relapsing remitting multiple sclerosis when the individuals has experienced therapeutic failure, intolerance, or contraindication to two (2) alternative drug therapies indicated for the treatment of multiple sclerosis (e.g. Avonex, Aubagio, Gilenya, etc.); or   

Myasthenia Gravis

• Treatment for individuals 18 years of age or older with myasthenia gravis refractory to conventional therapy (e.g., azathioprine, corticosteroids, immunosuppressants, plasma exchange, IV immunoglobulin, thymectomy); or

Myopathy, Idiopathic Inflammatory

• Treatment for refractory idiopathic inflammatory myopathy in individuals who have failed to respond to, or are intolerant to, another immunosuppressant (e.g. methotrexate); or

Neuromyelitis Optica

• Rituximab (Rituxan) may be considered medically necessary as treatment for neuromyelitis optica for relapse prevention; or

Pemphigoid Diseases

• Treatment for ANY of the following pemphigoid diseases in treatment-refractory individuals:
  • Bullous pemphigoid; or
  • Mucous membrane pemphigoid, including ocular cicatricial pemphigoid; or
  • Epidermolysis bullosa acquisita; or

Pemphigus Diseases

• Treatment for pemphigus diseases (i.e., pemphigus vulgaris, paraneoplastic pemphigus); or

Pemphigus Foliaceus

• Treatment for individuals 18 years of age or older with pemphigus foliaceus in combination with a tapering course of corticosteroids; or

Sjögren’s Syndrome (Primary)

• Treatment for individuals 18 years of age or older with primary Sjögren’s syndrome as a one (1) time course of treatment over 15 days; or

Systemic Lupus Erythematosus

• Treatment as add-on therapy for systemic lupus erythematosus refractory to immunosuppressive therapy; or

Systemic Sclerosis (Scleroderma)

• Treatment for systemic sclerosis (scleroderma) in individuals refractory to first-line treatment; or

Thrombocytopenic purpura (Idiopathic)

• Treatment for individuals 18 years of age or older with idiopathic thrombocytopenic purpura refractory to first-line therapy (e.g., corticosteroids, IV immune globulin, splenectomy, etc.) who are at risk of bleeding (grade 2C); or

Thrombotic Thrombocytopenic Purpura

• Treatment in combination with steroids and plasma exchange in individuals 18 years of age or older with refractory thrombotic thrombocytopenic purpura (i.e., lack of response to plasma exchange therapy and glucocorticoids).

The use of rituximab for all other indications not listed on this policy is considered experimental/investigational and therefore, not covered. Scientific evidence does not support the use for all other indications.

Rituximab and hyaluronidase human (Rituxan Hycela^®) subcutaneous (SC) – healthcare administered

FDA Approved Indications

Rituximab and hyaluronidase human (Rituxan Hycela) may be considered medically necessary for adult individuals 18 years of age and older only after individual has received at least one full dose of a rituximab product by intravenous infusion for ANY of the following indications:

Chronic lymphoid leukemia (CLL)

• Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide (FC); or

Diffuse Large B-Cell Lymphoma (DLBCL)

• Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens; or

Follicular lymphoma (FL)

• Relapsed or refractory, follicular lymphoma as a single agent; or
• Previously untreated follicular lymphoma in combination with first line chemotherapy and, in individuals achieving a complete or partial response to rituximab (Rituxan) in combination with chemotherapy, as single-agent maintenance therapy; or
• Non-progressing (including stable disease), follicular lymphoma as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy; or

NCCN Approved Recommendations

As a substitute for rituximab (Rituxan) as a single agent or in combination with other systemic therapies (except ibritumomab tiuxetan where indicated for the disease) after individuals have received the first full dose of rituximab by intravenous infusion for the treatment of ANY of the following where rituximab (Rituxan) was recommended for individuals 18 years of age and older:

• Castleman's Disease; or
• DLBCL; or
• Follicular Lymphoma (grade 1-2); or
• Gastric MALT; or
• High-Grade B-Cell Lymphomas; or
• Histologic Transformation of Nodal Marginal Zone Lymphoma to DLBCL; or
• High-Grade B-Cell Lymphomas with Translocations of MYC and BCL2 and/or BCL6 (Double/Triple Hit Lymphoma); or
• Mantle Cell Lymphoma; or
• Nodal Marginal Zone Lymphoma; or
• Nongastric MALT Lymphoma (Noncutaneous); or
• Post-Transplant Lymphoproliferative Disorders; or
• Splenic Marginal Zone Lymphoma; or
• Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; or
• Hairy Cell Leukemia; or
• Primary Cutaneous B-Cell Lymphomas or follicle center lymphoma with:
  • Solitary/regional, T1-2 disease that is refractory to initial therapy; or
  • Generalized disease (skin only), T3; or
• Waldenström Macroglobulinemia / Lymphoplasmacytic Lymphoma.

Individuals receiving rituximab and hyaluronidase human (Rituxan Hycela) cannot have a live vaccination prior to or during treatment with rituximab and hyaluronidase human (Rituxan Hycela).

The use of rituximab and hyaluronidase human (Rituxan Hycela) for all other indications not listed on this policy is considered experimental/investigational and therefore, not covered. Scientific evidence does not support the use for all other indications.

Rituximab-abbs (Truxima) may be considered medically necessary for the treatment of individuals 18 years and older for ANY of the following indications: 

FDA Indications

Chronic Lymphocytic Leukemia (CLL)

• For previously untreated or previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide; or

Granulomatosis with Polyangitis, Wegener’s Granulomatosis, and Microscopic Polyangiitis

• As therapy in combination with glucocorticoids; or

Non-Hodgkin’s Lymphoma (NHL)

• Relapsed or refractory, low grade or follicular, CD20-positive B-cell NHL as a single agent; or
• Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in individuals achieving a complete or partial response to a rituximab product in combination with chemotherapy, as a single agent maintenance therapy; or
• Non-progressive (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy; or
• Previously untreated DLBCL, CD20-positive NHL in combination with CHOP or anthracycline-based chemotherapy regimens; or

Rheumatoid Arthritis (RA)

• As therapy in combination with methotrexate, or other conventional synthetic DMARD if methotrexate is contraindicated, for moderately-to-severely-active RA who have had an inadequate response to one or more TNF antagonist therapies:
  • Combination therapy with methotrexate or other conventional synthetic DMARD not applicable to individuals who have had an inadequate response to methotrexate or other conventional synthetic DMARDs; or

NCCN Recommendations

As a substitute for rituximab (Rituxan) for the treatment of ANY of the following where rituximab (Rituxan) was recommended:

• AIDS-related B-cell lymphoma; or
• Burkitt lymphoma; or
• Castleman’s disease; or
• Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL); or
• DLBCL; or
• Follicular lymphoma (grade 1-2); or
• Gastric MALT lymphoma; or
• Hairy cell leukemia; or
• Hematopoietic Cell Transplantation; or
• High-grade B-cell lymphomas; or
• High-grade-cell lymphomas with translocations of MYC and BCL2 and/or BCL6 (double/triple hit lymphoma); or
• Histologic transformation of nodal marginal zone lymphoma to DLBCL; or
• Mantle cell lymphoma; or
• Management of immunotherapy-related toxicities-immune checkpoint inhibitor-related toxicities; or
• Nodal marginal zone lymphoma; or
• Nongastric MALT lymphoma (noncutaneous); or
• Post-transplant lymphoproliferative disorders; or
• Primary cutaneous B-cell lymphoma; or
• Rosai-Dorfman disease; or
• Splenic marginal zone lymphoma.

The use of rituximab-abbs (Truxima) for all other indications not listed on this policy is considered experimental/investigational and therefore, not covered. Scientific evidence does not support the use for all other indications.

Rituximab-pvvr (Ruxience) or rituximab-arrx (Riabni)may be considered medically necessary for the treatment of individuals 18 years and older for ANY of the following indications: 

FDA Indications

Chronic Lymphocytic Leukemia (CLL)

• For previously untreated or previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide; or

Granulomatosis with Polyangitis, Wegener’s Granulomatosis, and Microscopic Polyangiitis

• As therapy in combination with glucocorticoids; or

Non-Hodgkin’s Lymphoma (NHL)

• Relapsed or refractory, low grade or follicular, CD20-positive B-cell NHL as a single agent; or
• Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in individuals achieving a complete or partial response to a rituximab product in combination with chemotherapy, as a single agent maintenance therapy; or
• Non-progressive (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy; or
• Previously untreated DLBCL, CD20-positive NHL in combination with CHOP or anthracycline-based chemotherapy regimens; or

NCCN Recommendations

As a substitute for rituximab (Rituxan) for the treatment of ANY of the following where rituximab (Rituxan) was recommended:

• AIDS-related B-cell lymphoma; or
• Burkitt lymphoma; or
• Castleman’s disease; or
• Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL); or
• DLBCL; or
• Follicular lymphoma (grade 1-2); or
• Gastric MALT lymphoma; or
• Hairy cell leukemia; or
• Hematopoietic Cell Transplantation; or
• High-grade B-cell lymphomas; or
• High-grade-cell lymphomas with translocations of MYC and BCL2 and/or BCL6 (double/triple hit lymphoma); or
• Histologic transformation of nodal marginal zone lymphoma to DLBCL; or
• Mantle cell lymphoma; or
• Management of immunotherapy-related toxicities-immune checkpoint inhibitor-related toxicities; or
• Nodal marginal zone lymphoma; or
• Nongastric MALT lymphoma (noncutaneous); or
• Post-transplant lymphoproliferative disorders; or
• Primary cutaneous B-cell lymphoma; or
• Rosai-Dorfman disease; or
• Splenic marginal zone lymphoma.

The use of rituximab-pvvr (Ruxience) or rituximab-arrx (Riabni) for all other indications not listed on this policy is considered experimental/investigational and therefore, not covered. Scientific evidence does not support the use for all other indications.

*Maintenance rituximab is not appropriate after bendamustine and rituximab therapy and has not been tested after VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) or RBAC (rituximab, bendamustine and cytarabine) therapy.

**Note: Language derived from National Comprehensive Cancer Network (NCCN) guidelines

NOTE: In addition to the above criteria, product specific dosage and/or frequency limits may apply in accordance with the U.S. Food and Drug Administration (FDA)-approved product prescribing information, national compendia, Centers for Medicare and Medicaid Services (CMS) and other peer reviewed resources or evidence-based guidelines. Highmark may deny, in full or in part, reimbursement for utilization that does not fall within the applicable dosage and/or frequency limits