This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.

Rituximab (Rituxan) Intravenous (IV)

FDA Approved Indications

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

Rheumatoid Arthritis (RA)

Rituximab for the treatment of adults with RA may be considered medically necessary for the following conditions:

• RA is moderately to severely active (e.g,, greater than or equal to 8 swollen and greater than or equal to eight (8) tender joints); and
• Rituximab is administered in combination with methotrexate; and
• Individual has had an inadequate response to one (1) or more tumor necrosis factor inhibitors; or
• Individual has had an inadequate response to methotrexate or other conventional synthetic disease-modifying anti-rheumatic drug and is not suitable for treatment with tumor necrosis factor inhibitors (e.g., due to a recent [e.g., within five (5) years] history of lymphoma or other malignancy; latent tuberculosis and contraindications to chemoprophylaxis; or previous demyelinating disease).

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

Rituximab (Rituxan), in combination with glucocorticoids, may be considered medically necessary for the treatment of individuals with antineutrophil cytoplasmic antibody‒associated vasculitides (i.e., granulomatosis with polyangiitis (GPA) [Wegener granulomatosis] and microscopic polyangiitis).

Non-Hodgkin’s Lymphoma (NHL)

Rituximab (Rituxan) may be considered medically necessary for the treatment of NHL.

Chronic Lymphocytic Leukemia (CLL)

Rituximab (Rituxan) may be considered medically necessary for the treatment of CLL.

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.

Other clinically supported indications

Rituximab (Rituxan) may be considered medically necessary for the following off-label indications:

Autoimmune Hemolytic Anemia (AIHA)

Rituximab (Rituxan) may be considered medically necessary for the treatment of EITHER of the following AIHA:

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

Thrombotic Thrombocytopenic Purpura

Rituximab (Rituxan) may be considered medically necessary for the treatment of thrombotic thrombocytopenic purpura in individuals with refractory disease or relapse (i.e., lack of response to plasma exchange therapy and glucocorticoids).

Churg-Strauss Syndrome (Eosinophilic Granulomatosis with Polyangiitis)

Rituximab (Rituxan) may be considered medically necessary as treatment for 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.

Hemophilia

Rituximab (Rituxan) may be considered medically necessary for the treatment of hemophilia with acquired inhibitors who are refractory to conventional first line treatments (i.e. immunosuppression with prednisone and cyclophosphamide).

Hepatitis C Virus‒Associated Cryoglobulinemic Vasculitis

Rituximab (Rituxan) may be considered medically necessary 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.

Multicentric Castleman Disease Associated with Human Herpesvirus 8 (HHV-8) in HIV-Infected Individuals

Rituximab (Rituxan) may be considered medically necessary as treatment for multicentric Castleman disease (first- or second-line therapy).

Neuromyelitis Optica

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

Pemphigoid Diseases

Rituximab (Rituxan) may be considered medically necessary as 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.

Pemphigus Diseases

Rituximab (Rituxan) may be considered medically necessary as treatment for pemphigus diseases (i.e., pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus).

Primary Sjögren Syndrome

Rituximab (Rituxan) may be considered medically necessary as treatment for primary Sjögren syndrome that is refractory to glucocorticoids and at least two other immunosuppressive agents (e.g. cyclosporine, methotrexate, azathioprine, corticosteroids, etc.).

Systemic Lupus Erythematosus

Rituximab (Rituxan) may be considered medically necessary as add-on therapy for systemic lupus erythematosus refractory to standard first-line treatment.

Lupus Nephritis

Rituximab (Rituxan) may be considered medically necessary as add-on therapy for lupus nephritis refractory to standard first-line treatment regimen.

Systemic Sclerosis (Scleroderma)

Rituximab (Rituxan) may be considered medically necessary as treatment for systemic sclerosis (scleroderma) in individuals refractory to first-line treatment.

Glucocorticoid-Refractory Chronic Graft-Versus-Host Disease

Rituximab (Rituxan) may be considered medically necessary as treatment for glucocorticoid-refractory chronic graft-versus-host disease.

Desensitization of Human Leukocyte Antigen‒Sensitized Renal Transplant Candidates

Rituximab (Rituxan) may be considered medically necessary for desensitization of human leukocyte antigen‒sensitized renal transplant candidates before transplantation.

Idiopathic Membranous Nephropathy

Rituximab (Rituxan) may be considered medically necessary as treatment for idiopathic membranous nephropathy.

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

Rituximab (Rituxan) may be considered medically necessary for the prevention of Epstein Barr virus infection in hematopoietic stem cell transplant individuals.

Evans syndrome (Pediatric only)

Rituximab (Rituxan) may be considered medically necessary as treatment for Evans syndrome refractory to immunosuppressive therapy.

Idiopathic Thrombocytopenic purpura (Adult only)

Rituximab (Rituxan) may be considered medically necessary as treatment for idiopathic thrombocytopenic purpura.

Immune thrombocytopenia, previously treated (Pediatric only)

Rituximab (Rituxan) may be considered medically necessary as treatment for previously treated immune thrombocytopenia.

Microscopic polyarteritis nodosa (Adult only)

Rituximab (Rituxan) may be considered medically necessary as treatment for microscopic polyarteritis nodosa in combination with glucocorticoids.

Minimal change disease (Pediatric only)

Rituximab (Rituxan) may be considered medically necessary as treatment for refractory, steroid-dependent or steroid-resistant minimal change disease when:

• Remission induction and maintenance of remission of refractory steroid-resistant or steroid-dependent nephrotic syndrome.

Relapsing-Remitting Multiple Sclerosis

Rituximab (Rituxan) may be considered medically necessary as treatment for relapsing-remitting multiple sclerosis when:

• The member has experienced therapeutic failure, intolerance, or contraindication to two alternative drug therapies indicated for the treatment of multiple sclerosis (e.g. Avonex, Aubagio, Gilenya, etc.).   

Myasthenia Gravis

Rituximab (Rituxan) may be considered medically necessary as treatment for relapsed or refractory myasthenia gravis in individuals who have failed to respond to, or are intolerant to, conventional therapy, including azathioprine.

Idiopathic Inflammatory Myopathy

Rituximab (Rituxan) may be considered medically necessary as treatment for refractory idiopathic inflammatory myopathy in individuals who have failed to respond to, or are intolerant to, another immunosuppressant (e.g. methotrexate).

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.

NCCN Approved Indications

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

Central nervous system cancers

• Leptomeningeal Metastases:
  • Primary treatment in individuals with normal CSF flow or no clinical evidence of abnormal flow; 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.
• Intra-cerebrospinal fluid (intra-CSF) treatment for leptomeningeal metastases from lymphomas for:

• Primary CNS Lymphoma:
  • Primary treatment in patients with normal CSF flow or no clinical evidence of abnormal flow; 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.
• Induction therapy in combination with:
  • High-dose methotrexate, vincristine, procarbazine, and cytarabine; or
  • High-dose methotrexate with or without 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.
• Consider as intra-CSF therapy if CSF positive or spinal MRI positive.
• Consider for consolidation therapy in individuals with complete response or complete response unconfirmed (CRu) to induction therapy:
  • In combination with high-dose methotrexate, cytarabine, procarbazine, and vincristine; or
  • In combination with high-dose methotrexate with or without 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.
• Treatment as a single agent or in combination with temozolomide, lenalidomide, or high-dose methotrexate 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 after previous response with long duration (greater than or equal to 12 months) to prior regimen; or
  • In combination with whole brain RT or involved field RT in patients 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 patients who received prior high-dose chemotherapy with stem cell rescue after previous response with long duration (greater than or equal to 12 months).
• Intra-CSF treatment for leptomeningeal metastases from lymphoma for:

Hodgkin Lymphoma

• For Nodular Lymphocyte-Predominant Hodgkin Lymphoma  (Age greater than or equal to 18 years)
  • With ISRT for stage IA or IIA disease (bulky): or
  • With ISRT for stage IB or IIB disease; or
  • With or without involved site radiation therapy (ISRT) for stage III-IV disease; or
  • DHAP (dexamethasone, cisplatin, and high-dose cytarabine), with or without ISRT; or
  • ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), with or without ISRT; or
  • Gemcitabine/bendamustine/vinorelbine, with or without ISRT; or
  • GVD (gemcitabine, vinorelbine, and liposomal doxorubicin), with or without ISRT; or
  • ICE (ifosfamide, carboplatin, and etoposide), with or without ISRT; or
  • IGEV (ifosfamide, gemcitabine, and vinorelbine), with or without ISRT.
• Primary treatment in combination with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) + rituximab, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + rituximab, or CVP (cyclophosphamide, vinblastine, prednisolone) + rituximab:
• Primary treatment as a single agent for stage IIIA or IVA disease; or
• Second-line systemic therapy 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.
• Second-line therapy for progressive, relapsed, or refractory disease in combination with:

Non-Hodgkin Lymphomas

• AIDS-Related, B-Cell Lymphoma
  • Preferred** treatment in combination with growth factor support for AIDS-related Burkitt lymphoma as a component of:
    • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab; 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 or without rituximab.
  • In combination with growth factor support for AIDS-related Burkitt lymphoma as a component of HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine regimen with rituximab.
  • 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.
  • Preferred** treatment In combination with growth factor support for CD20+ AIDS-related diffuse large B-cell lymphoma and HHV8-positive diffuse large B-cell lymphoma, not otherwise specified (NOS) as a component of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab.
  • In combination with growth factor support for CD20+ AIDS-related diffuse large B-cell lymphoma and HHV8-positive diffuse large B-cell lymphoma, not otherwise specified (NOS) as a component of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen with rituximab.
  • Second-line therapy or subsequent therapy for relapse of AIDS-related diffuse large B-cell lymphoma, primary effusion lymphoma, and HHV8-positive diffuse large B-cell lymphoma, not otherwise specified (NOS):
    • For individuals with intention to proceed to high-dose therapy as a component of DHAP (dexamethasone, cisplatin, and cytarabine), 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
    • Noncandidates for high-dose therapy as a single agent, in combination with lenalidomide (for non-germinal center diffuse large B-cell 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, or GemOX regimen with rituximab.

• Burkitt Lymphoma
  • Induction therapy for low-risk disease 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; or
    • HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine regimen with rituximab.
• Induction therapy for high-risk disease 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; 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, RGDP (rituximab, gemcitabine, dexamethasone, and cisplatin) regimen, or HDAC (high-dose cytarabine) with rituximab regimen:
• As second-line therapy for relapse of Burkitt lymphoma following complete response to induction therapy; or
• As second-line therapy for less than complete response following induction therapy; or
• For individuals with partial response to second-line therapy as additional second-line therapy (if not previously given) for relapse or refractory disease.

• 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/partial resection; or
    • As second-line therapy for relapsed or refractory disease.
  • 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.
  • 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.
  • 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.
  • 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 patient is not a candidate for combination therapy.
  • 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.
  • Subsequent therapy for multicentric CD that has progressed following treatment of relapsed/refractory or progressive disease in combination with:
    • Bortezomib; or
    • Lenalidomide; or
    • Thalidomide.

• Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
  • First-line therapy for disease without del(17p)/TP53 mutation in frail individuals with significant comorbidity who are not able to tolerate purine analogs:
    • In combination with chlorambucil (preferred regimen**); or  
    • In combination with high-dose methylprednisolone.
  • First-line therapy for disease without del(17p)/TP53 mutation in individuals age greater than or equal 65 years and younger individuals with significant comorbidities:
    • In combination with chlorambucil, or bendamustine (preferred regimens**).
  • First-line therapy for disease without del(17p)/TP53 mutation in individuals age less than 65 years without significant comorbidities:
    • As a component of FCR (fludarabine, cyclophosphamide) with rituximab (preferred regimen**); or
    • In combination with bendamustine (preferred regimen**); or
    • In combination with high-dose methylprednisolone.
  • First-line therapy for disease with del(17p)/TP53 mutation in combination with alemtuzumab or high-dose methylprednisolone.
  • First line therapy in combination with fludarabine for disease without del(17p)/TP53 and del(11q) mutations in individuals age less than 65 years without significant comorbidities.
  • Therapy for relapsed or refractory disease 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:
    • In combination with idelalisib or venetoclax (preferred regimens**); or
    • As a single agent in a dose-dense regimen; or
    • In combination with alemtuzumab, bendamustine with or without ibrutinib, 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.
  • Therapy for relapsed or refractory disease without del(17p)/TP53 mutation in individuals less than 65 years without significant comorbidities:
    • In combination with idelalisib or venetoclax (preferred regimens**); 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.
  • Therapy for relapsed or refractory disease with del(17p)/TP53 in combination with:
  • IIelalisib or venetoclax (preferred regimens**); or
  • Alemtuzumab, lenalidomide, or high-dose methylprednisolone.
  • Initial therapy for histologic (Richter's) transformation to diffuse large B-cell lymphoma (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.

• Diffuse Large B-Cell Lymphoma
• First-line therapy for stage I-II disease as a component of:
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • Dose-dense RCHOP-14 Regimen.
• First-line therapy for patients 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.
• First-line therapy 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.
• 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.
• First-line therapy 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.
• First-line therapy 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.
• Second-line or subsequent  therapy for relapsed or refractory disease in:
  • Individuals with intention to proceed to high-dose therapy as a component of DHAP (dexamethasone, cisplatin, and cytarabine), 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
  • Noncandidates for high-dose therapy 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.
• Used to treat 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
  • RCHOP regimen followed by ICE (ifosfamide, carboplatin, and etoposide) regimen.
• Used to treat 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.
• 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.
• 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.
• Used to treat high-grade B-Cell lymphomas with translocations of MYC and BCL2 and/or BCL6 (double/triple hit lymphoma)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.
• First-line therapy for solitary regional, T1-2 or generalized cutaneous, T3 primary cutaneous diffuse large B-cell lymphoma, leg type as a component of:
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen.
• First-line therapy 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.
• First-line therapy 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.
• First-line therapy for extracutaneous primary cutaneous diffuse large B-cell lymphoma, 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.
• First-line therapy in individuals with poor left ventricular function as a component of:
• First-line therapy for very frail individuals and individuals greater than 80 years of age with comorbidities as a component of;
• Second-line or subsequent therapy for relapsed or refractory primary cutaneous diffuse large B-cell lymphoma, leg type:
  • As a component of DHAP (dexamethasone, cisplatin, and cytarabine), 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 in individuals with intention to proceed to high-dose therapy; or
  • 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 in noncandidates for high-dose therapy.

• Follicular Lymphoma (grade 1-2)
  • First-line therapy (or second-line and subsequent therapy (if not previously use as first-line)) in combination with chlorambucil or cyclophosphamide in elderly or infirm individuals in the setting of comorbidities where tolerability of combination chemotherapy is a concern for:
    • Stage I (greater than or equal to seven (7) cm),or II (greater than or equal to seven (7) cm), or non-contiguous stage II disease; or
    • Individuals with indications for treatment with stage III or IV disease.
  • Preferred** first-line or second-line and subsequent therapy as a single agent in elderly or infirm individuals in the setting of comorbidities where tolerability of combination chemotherapy is a concern.
  • Preferred** first-line therapy for stage I (greater than or equal to seven (7) cm), or contiguous stage II (greater than or equal to seven (7) cm), 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
    • In RCVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen; or
    • Bendamustine with rituximab.
  • First-line therapy for stage I (greater than or equal to seven (7) cm) (bulky), contiguous stage II (greater than or equal to seven (7) cm) (bulky), non-contiguous stage II disease, or for individuals with indications for treatment with stage III or IV disease as a single agent (consider for low tumor burden) or in combination with lenalidomide.
  • 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.
  • First-line consolidation therapy in individuals with indications for treatment if initially treated with single-agent rituximab.
  • 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 (preferred**, if not previously given as first-line); or
    • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen (preferred**, if not previously given as first-line); or
    • RCVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen (preferred**, if not previously given as first-line); or
    • DHAP (dexamethasone, cisplatin, and cytarabine) 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.
  • Treatment of histologic transformation to diffuse large B-cell lymphoma (DLBCL) 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.  
  • Treatment of histologic transformation to DLBCL 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.
  • Treatment of histologic transformation to DLBCL 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.
  • Subsequent therapy for histologic transformation to diffuse large B-cell lymphoma 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
    • 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.
  • First-line consolidation therapy in individuals with indications for treatment if initially treated with single-agent rituximab.
  • Maintenance therapy:
    • As first-line or second-line extended dosing in individuals with indications for treatment: or
    • Can be considered for individuals with histologic transformation to diffuse large B-cell lymphoma that is coexisting with extensive follicular lymphoma who achieve a complete response to chemoimmunotherapy.

• Gastric MALT Lymphoma
  • Initial therapy (if radiation is contraindicated) as a single agent for individuals with H. pylori-negative stage I₁, or I₂, or stage II₁ disease or for H. pylori-positive individuals with t(11;18) who, following antibiotic treatment, are lymphoma positive after endoscopy for restaging; or
  • Preferred regimens** as first-line therapy for stage IIE, or II₂, or stage IV (distant nodal or advanced stage) disease in individuals with the 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.
  • Preferred regimens** as additional therapy (after involved site radiation therapy or rituximab alone) for stage I₁, or I₂, or stage II₁ disease in patients with indications for treatment or in:
    • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
    • RCVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen; or
    • Bendamustine with rituximab.
  • First-line therapy as a single agent for stage IIE, or II₂, or stage IV (distant nodal or advanced stage) disease in patients with indications for treatment.
  • Used in combination with lenalidomide for patients 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 (after involved site radiation therapy or rituximab alone) for stage I₁, or I₂, or stage II₁ disease.
  • Used as a single agent or in combination with chlorambucil or cyclophosphamide in elderly or infirm individuals with indications for treatment in the setting of comorbidities where 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 (after involved site radiation therapy or rituximab alone) for stage I₁, or I₂, or stage II₁ disease; or
    • Second-line or subsequent therapy.
  • Consolidation as optional first-line extended therapy in patients initially treated with single agent rituximab.
  • Second-line therapy or subsequent therapy for recurrent or progressive disease in patients with indications for treatment as a single agent or 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.

• Nongastric MALT Lymphoma
  • First-line therapy for stage I-II disease in selected cases.
  • Preferred** 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.
  • First-line therapy as a single agent or in combination with lenalidomide for stage IV disease or recurrent stage I-II disease in patients with indications for treatment.
  • 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 in the setting of comorbidities where tolerability of combination chemotherapy is a concern as:
    • First-line therapy; or
    • Second-line or subsequent therapy.
  • Second-line or subsequent therapy for refractory or progressive disease in patients with indications for treatment as a single agent or 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.
  • Consolidation as optional first-line extended therapy in individuals initially treated with single agent rituximab.

• Nodal Marginal Zone Lymphoma
  • Used as a single agent or in combination with chlorambucil or cyclophosphamide for stage I (greater than or equal to seven (7) cm), contiguous stage II (greater than or equal to seven (7) cm), non-contiguous stage II, or stage III, IV disease in elderly or infirm individuals with indications for treatment in the setting of comorbidities where tolerability of combination chemotherapy is a concern as:                                              
    • First-line therapy; or
    • Second-line or subsequent therapy.
  • Preferred** first-line therapy for stage I (greater than or equal to seven (7) cm), contiguous stage II (greater than or equal to seven (7) cm), non-contiguous stage II, or stage III, or IV 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.
  • First-line therapy as a single agent or in combination with lenalidomide for stage I (greater than or equal to seven (7) cm), contiguous stage II (greater than or equal to seven (7) cm), non-contiguous stage II, or stage III, IV disease in patients with indications for treatment.
  • Second-line or subsequent therapy for refractory or progressive disease in patients with indications for treatment as a single agent or 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.
  • Consolidation as optional first-line extended therapy in patients initially treated with single agent rituximab.

• Histologic Transformation of Marginal Zone Lymphoma to Diffuse Large B-Cell Lymphoma
  • Treatment of histologic transformation to diffuse large B-cell lymphoma (DLBCL) 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.
  • Treatment of histologic transformation to DLBCL 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.
    • RGCVP regimen.
  • Treatment of histologic transformation to DLBCL in individuals who have received minimal or no prior chemotherapy and are very frail and for patients greater than 80 years of age with comorbidities as a component of:
    • RCEPP regimen; or
    • RCDOP regimen; or
    • R-mini-CHOP regimen; or
  • Subsequent therapy for histologic transformation to diffuse large B-cell lymphoma 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
    • 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.

• Hairy Cell Leukemia
  • Used in combination with cladribine or pentostatin for relapse or refractory disease; or
  • Used in combination with vemurafenib for progression if non-responsive to purine analog therapy; or
  • As a single agent in individuals with the indication for treatment for refractory disease or for relapse within two (2) years of complete response.

• Mantle Cell Lymphoma
• Preferred** induction therapy for stage I-II disease following partial response, progression, or relapse after 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 disease in individuals who are candidates for high-dose therapy/autologous stem cell rescue as a component of aggressive therapy with:
  • HyperCVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine regimen with rituximab; or
  • NORDIC (dose-intensified induction immunochemotherapy with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone [maxi-CHOP] alternating with rituximab and high-dose cytarabine) regimen; or
  • Alternating RCHOP/RDHAP (rituximab, dexamethasone, cisplatin, and cytarabine) regimen; or
  • RDHAP (rituximab, dexamethasone, cytarabine and cisplatin) regimen; or
  • RDHAX (rituximab, dexamethasone, cytarabine and oxaliplatin) regimen.
• Induction therapy for stage I-II disease following partial response or progression after 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 disease as a component of less aggressive therapy with bendamustine.
• Preferred** induction therapy for stage I-II disease as initial therapy (localized presentation, extremely rare), or for partial response, progression, or relapse after 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 disease in individuals who are not candidates for high dose therapy/autologous stem cell rescue as a component of less aggressive therapy with:
  • Bendamustine; or
  • VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) regimen; or
  • CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen with rituximab; or
  • Lenalidomide; or
  • Modified HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) regimen with rituximab in patients older than 65 years.
• Induction therapy for stage I-II disease (localized presentation, extremely rare) as initial therapy, or for partial response, progression, or relapse after 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 disease in individuals who are not candidates for high-dose therapy/autologous stem cell rescue as a component of less aggressive therapy with RBAC (rituximab, bendamustine, and cytarabine) regimen.
• Consider single-agent maintenance therapy for aggressive stage II bulky, III, or IV disease following complete or partial response to less aggressive induction therapy* or high-dose therapy with autologous stem cell rescue.
• 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 to achieve a complete response following partial response to induction therapy, for relapsed or progressive disease.
  • In combination with ibrutinib or lenalidomide (preferred regimens**) following a short response duration to prior chemoimmunotherapy; or
  • In combination with ibrutinib and lenalidomide.
• Second-line therapy for stage I-II disease, aggressive stage II bulky, III, or IV disease, or symptomatic indolent stage II bulky, III, or IV disease to achieve a complete response following partial response to induction therapy or for relapsed or progressive disease following an extended response duration to prior chemoimmunotherapy (greater than expected median progression free survival) as a single agent, in combination with bendamustine or bortezomib, or as a component of:
  • Bendamustine, bortezomib, and rituximab regimen; or  
  • Gemcitabine, vinorelbine and rituximab regimen; or
  • DHAP (dexamethasone, cisplatin, and cytarabine) regimen with rituximab; or
  • 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
  • CEPP (cyclophosphamide, etoposide, prednisone, and procarbazine) regimen with rituximab; or
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with rituximab; or
  • CEOP (cyclophosphamide, etoposide, vincristine, and prednisone) regimen with rituximab; or
  • CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen with rituximab (preferred regimen**, if not previously given); or
  • VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) regimen (preferred regimen**, if not previously given).

• Post-transplant Lymphoproliferative Disorder (PTLD)
  • Single-agent therapy as:
    • First-line therapy for monomorphic or polymorphic PTLD; or
    • Second-line therapy for partial response, persistent or progressive early 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 PTLD achieving complete response on first-line therapy.
  • 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), or CEOP (cyclophosphamide, etoposide, vincristine, and prednisone) regimen with rituximab for frail patients who cannot tolerate anthracyclines as:
    • First-line therapy for monomorphic (B-cell type) or systemic polymorphic PTLD; or
    • Second-line therapy for partial response, persistent or progressive monomorphic (B-cell type) or polymorphic PTLD.
  • 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 PTLD; or
    • Second-line therapy for persistent or progressive monomorphic (B-cell type) or polymorphic PTLD.
  • 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 
    • 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.

• Primary Cutaneous B-Cell Lymphoma
  • Therapy for generalized (skin only), T3 cutaneous primary cutaneous marginal zone or follicle center lymphoma

• Immune Checkpoint Inhibitor-Related Toxicities
• Treatment of immunotherapy-related encephalitis after viral causes have been excluded in individuals positive for autoimmune encephalopathy antibody, and who have had limited or no improvement on methylprednisolone with or without intravenous immune globulin.

• Splenic Marginal Zone Lymphoma
  • Hepatitis C negative; or
  • Hepatitis C positive with contraindications for hepatitis treatment; or
  • Hepatitis C positive with no response to appropriate hepatitis treatment.
• Preferred** therapy as a single-agent therapy for symptomatic patients with splenomegaly who have ONE of the following features:
• Used as a single agent (preferred**) or in combination with chlorambucil or cyclophosphamide in elderly or infirm patients with indications for treatment for disease progression following initial treatment for splenomegaly in the setting of comorbidities where tolerability of combination chemotherapy is a concern as:
  • First-line therapy; or
  • Second-line or subsequent therapy.
• Preferred** first-line therapy for progressive disease following initial treatment for splenomegaly in individuals with indications for treatment as a single agent or in:
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; or
  • RCVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen; or
  • Bendamustine with rituximab.
• Used in combination with lenalidomide as first-line therapy for progressive disease following initial treatment for splenomegaly in individuals with indications for treatment.
• Consolidation as optional first-line extended therapy in individuals initially treated with single agent rituximab; or
• Second-line therapy or subsequent therapy for refractory or progressive disease in individuals with indications for treatment as a single agent or 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.
• Maintenance therapy in individuals with indications for treatment as first-line or second-line extended dosing.

• Waldenström's Macroglobulinemia/Lymphoplasmacytic Lymphoma
  • Used as a component of CaRD (carfilzomib, rituximab, and dexamethasone) regimen:
  • As primary therapy; or
  • For relapse greater than or equal to 24 months if used as primary therapy.
  • Used as primary therapy, as therapy for previously treated disease that does not respond to primary therapy, or for progressive or relapsed disease:
    • In combination with bendamustine (preferred regimen**); or
    • In combination with bortezomib and dexamethasone (preferred regimen**); or
    • In combination with cyclophosphamide and  dexamethasone (preferred regimen**); 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.
  • Consider for maintenance therapy following a complete, very good partial, partial, or minor response to primary therapy if regimen included rituximab.

• Acute Lymphoblastic Leukemia
  • Induction/consolidation therapy for Philadelphia chromosome-negative ALL in AYA and adult individuals 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.
  • 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).
  • 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.
  • 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.

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.

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 ANY of the following indications:

• Chronic lymphoid leukemia (CLL)
• Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide (FC).
• Diffuse large B-cell lymphoma (DLBCL)
• Previously untreated diffuse large B-cell lymphoma in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens.
• 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 patients achieving a complete or partial response to rituximab 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.

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

NCCN Approved Indications

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

• Primary Cutaneous B-Cell Lymphomas
  • May be substituted for rituximab after individuals have received the first full dose of rituximab by intravenous infusion as therapy for generalized disease (skin only), T3 primary cutaneous marginal zone or follicle center lymphoma.
• Follicular Lymphoma (grade 1-2)
  • May be substituted for rituximab as a single agent or in combination with other systemic therapies (except ibritumomab tiuxetan) after individuals have received the first full dose of rituximab by intravenous infusion.
• Gastric MALT Lymphoma
  • May be substituted for rituximab as a single agent or in combination with other systemic therapies after individuals have received the first full dose of rituximab by intravenous infusion.
• Nongastric MALT Lymphoma
  • May be substituted for rituximab as a single agent or in combination with other systemic therapies after individuals have received the first full dose of rituximab by intravenous infusion.
• Nodal Marginal Zone Lymphoma
  • May be substituted for rituximab as a single agent or in combination with other systemic therapies after individuals have received the first full dose of rituximab by intravenous infusion.
• Splenic Marginal Zone Lymphoma
  • May be substituted for rituximab as a single agent or in combination with other systemic therapies after individuals have received the first full dose of rituximab by intravenous infusion.
• Histologic Transformation of Marginal Zone Lymphoma to Diffuse Large B-Cell Lymphoma
  • May be substituted for rituximab as a single agent or in combination with other systemic therapies (except for ibritumomab tiuxetan) after individuals have received the first full dose of rituximab by intravenous infusion.
• Mantle Cell Lymphoma
  • May be substituted for rituximab as a single agent or in combination with other systemic therapies after individuals have received the first full dose of rituximab by intravenous infusion.
• Diffuse Large B-Cell Lymphoma
  • May be substituted for rituximab as a single agent or in combination with other systemic therapies after patients have received the first full dose of rituximab by intravenous infusion.
• AIDS-Related B-Cell Lymphomas
  • May be substituted for rituximab as a single agent or in combination with other systemic therapies after patients have received the first full dose of rituximab by intravenous infusion.
• Burkitt Lymphoma
  • May be substituted for rituximab in combination with other systemic therapies after patients have received the first full dose of rituximab by intravenous infusion.
• Post-Transplant Lymphoproliferative Disorders
  • May be substituted for rituximab as a single agent or in combination with other systemic therapies after patients have received the first full dose of rituximab by intravenous infusion.
• Castleman's Disease (CD)
  • May be substituted for rituximab as a single agent or in combination with other systemic therapies after patients have received the first full dose of rituximab by intravenous infusion for:
    • Unicentric CD; or
    • Multicentric CD; or
    • Refractory or progressive disease.
• Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
  • First line therapy in combination with fludarabine and cyclophosphamide (FCR) regimen (preferred regimen**) for disease without del(17p)/TP53 mutation after individuals have received at least one full dose of a rituximab product by intravenous route for patients less than 65 years without significant comorbidities.
• Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
• Therapy for relapsed or refractory disease without del(17p)/TP53 mutation after individuals have received at least one full dose of a rituximab product by intravenous route in combination with:
• Fludarabine and cyclophosphamide (FCR) regimen in individuals age less than 65 years without significant comorbidities; or
• Reduced-dose fludarabine and cyclophosphamide (FCR) regimen in individuals greater than or equal to 65 years and younger patients with significant comorbidities.

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.

Experimental/Investigational (E/I) services are not covered regardless of place of service.

The administration of Rituximab (Rituxan®) is typically an outpatient procedure which is only eligible for coverage as an inpatient procedure in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.

Services that do not meet the criteria of this policy will be considered experimental/investigational (E/I). A network provider can bill the member for the experimental/investigational service. The provider must give advance written notice informing the member that the service has been deemed E/I. The member must be provided with an estimate of the cost and the member must agree in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.

• Link to Provider Resource Center for the Medical Policy Update

05/2018, Coverage Criteria Revised for Rituximab (Rituxan), Coverage Criteria Established for Rituximab and Hyaluronidase Human (Rituxan Hycela)

• Link to Diagnosis Codes

• Link to References