Medicare Advantage Preferred Provider Organization (MA PPO)

Applicable to enrollees from other Blue Cross Blue Shield Medicare Advantage Plans who obtain health care services within the 5-county Philadelphia service area.

Notification

Rituximab (Rituxan®) Infusion and Related Biosimilars, and Rituximab/Hyaluronidase Human for Subcutaneous Injection (Rituxan Hycela®)

Notification Issue Date:

This policy has been identified for the HCPCS code update, effective 07/01/2020.

The following NOC codes have been removed from this policy and are replaced by the following HCPCS code:
REMOVED:
C9399 Unclassified drugs or biologicals
J3590 Unclassified biologics

REPLACED WITH:
Q5119 Injection, rituximab-pvvr, biosimilar, (ruxience), 10 mg

Title:

Rituximab (Rituxan®) Infusion and Related Biosimilars, and Rituximab/Hyaluronidase Human for Subcutaneous Injection (Rituxan Hycela®)

Policy #:

MA08.022q

Policy

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

INDEX OF MEDICALLY NECESSARY INDICATIONS

This policy addresses numerous medically necessary indications for the use of rituximab and related biosimilars (listed in order of appearance within the Policy section). Please see below for the specific medical necessity criteria. (NOTE: The following sections must also be reviewed: Company-Designated Preferred Products, Not Medically Necessary, AND Experimental/Investigational).

RITUXIMAB AND RELATED BIOSIMILARS

Antineutrophil cytoplasmic antibodies (ANCA)–associated vasculitides (granulomatosis with polyangiitis, microscopic polyangiitis [MPA], eosinophilic granulomatosis with polyangiitis [EGPA] [formerly Churg-Strauss syndrome], pauci-immune glomerulonephritis)
Anemia, autoimmune hemolytic (AIHA)
Castleman disease (CD), multicentric and uncentric
Central nervous system cancers
Hematopoietic cell transplantation
Idiopathic membranous nephropathy
Immunoglobulin G4 (IgG4)–related disease
Toxicities related to immune checkpoint inhibitors
Leukemia, mature B-cell acute leukemia (B-AL)
Leukemia, Philadelphia chromosome–negative acute lymphoblastic (ALL)
Lupus nephritis
Lymphoma, Hodgkin
Lymphoma, non-Hodgkin (NHL)

High-grade B-cell lymphomas
Aquired immunodeficiency syndrome (AIDS)–related B-cell lymphoma
Burkitt lymphoma
Burkitt-like lymphoma
Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
Diffuse large B-cell lymphoma
Follicular lymphoma
Gastric mucosa-associated lymphoid tissue (MALT) lymphoma
Hairy cell leukemia
Histiocytic neoplasms (Rosai-Dorfman disease)
Histologic transformation of indolent lymphomas to diffuse large B-cell lymphoma
Mantle cell lymphoma
Nodal marginal zone lymphoma
Nongastric MALT lymphoma (noncutaneous)
Pediatric aggressive mature B-cell lymphomas (age 6 months and older)
Post-transplantation lymphoproliferative disorder (PTLD)
Primary cutaneous B-cell lymphoma
Splenic marginal zone lymphoma

Multiple sclerosis, relapsing-remitting
Myasthenia gravis
Nephrotic syndrome, including minimal change disease, in pediatric individuals
Neuromyelitis optica (NMO)
Pemphigoid diseases
Pemphigus diseases (i.e., pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus)
Pure red cell aplasia
Rheumatoid arthritis, active
Scleroderma
Sjögren syndrome, primary
Systemic lupus erythematosus (SLE)
Thrombocytopenic purpura, immune or idiopathic (ITP)
Thrombocytopenic purpura, thrombotic (TTP)
Transplantation, prophylaxis
Transplantation, antibody-mediated rejection (AMR)
Waldenström macroglobulinemia/lymphoplasmacytic lymphoma

RITUXIMAB AND HYALURONIDASE HUMAN (RITUXAN HYCELA)

Castleman disease (CD)
Lymphoma, non-Hodgkin (NHL)

Chronic lymphocytic leukemia (CLL)
Diffuse large B-cell lymphoma (DLBCL)
Follicular lymphoma
Gastric MALT lymphoma
Hairy cell leukemia
High-grade B-cell lymphomas
Histologic transformation of marginal zone lymphoma to diffuse large B-cell lymphoma
Mantle cell lymphoma
Nodal marginal zone lymphoma
Nongastric MALT lymphoma (noncutaneous)
Post-transplantation lymphoproliferative disorder (PTLD)
Primary cutaneous B-cell lymphomas
Splenic marginal zone lymphoma

Waldenström macroglobulinemia/lymphoplasmacytic lymphoma

COMMON CHEMOTHERAPY REGIMEN ABBREVIATIONS USED THROUGHOUT THE POLICY:

RCHOP^a (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)
DHAP^b (dexamethasone, cisplatin, and cytarabine)
ESHAP^c(etoposide, methylprednisolone, cytarabine, and cisplatin)
ICE^d (ifosfamide, carboplatin, and etoposide)
Dose-adjusted EPOCH^e(etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin)
RCVP^f (rituximab, cyclophosphamide, vincristine, and prednisone)
GDP^g (gemcitabine, dexamethasone, and cisplatin)
MINE^h (mesna, ifosfamide, mitoxantrone, and etoposide)
CEOPⁱ (cyclophosphamide, etoposide, vincristine, and prednisone)

MEDICALLY NECESSARY

COMPANY-DESIGNATED PREFERRED PRODUCTS
Although there are many rituximab products on the market (e.g., rituximab [Rituxan], rituximab-abbs [Truxima], rituximab-arrx [Riabni], rituximab-pvvr [Ruxience]), there is no reliable evidence of the superiority of any one product of rituximab compared with other products. The Company has designated the following rituximab biosimilar products as its preferred products: rituximab-pvvr (Ruxience) and rituximab-abbs (Truxima).

These products are less costly and at least as likely to produce equivalent therapeutic results as the nonpreferred products, which include, but are not limited to, rituximab (Rituxan), rituximab-arrx
(Riabni), and any other nonpreferred rituximab biosimilars.

According to the US Food and Drug Administration (FDA), “a biosimilar is a biological product that has no clinically meaningful differences from the existing FDA-approved reference product. All biosimilar products meet the FDA’s rigorous standards for approval for the indications described in the product labeling. Once a biosimilar has been approved by the FDA, the safety and effectiveness of these products have been established, just as they have been for the reference product.” Coverage of a biosimilar product as an alternate to a reference product is not considered a form of step therapy by the Company.

NONPREFERRED PRODUCTS
Use of the nonpreferred rituximab products that include but are not limited to rituximab (Rituxan), rituximab-arrx (Riabni), or any other nonpreferred biosimilars is considered medically necessary and, therefore, covered only for individuals who are currently receiving or have previously received a nonpreferred product for the specified rituximab indication.

If the individual has not previously received rituximab (Rituxan), rituximab-arrx (Riabni),or any other nonpreferred biosimilar to treat the specified indication, these nonpreferred products are eligible for coverage when the individual has contraindication(s) or intolerance(s) to the Company-designated preferred products (e.g., as documented per the FDA labeling).

RITUXIMAB AND RELATED BIOSIMILARS
Rituximab infusion and related biosimilars are considered medically necessary and, therefore, covered for the following indications when the requirements listed in the sections above (COMPANY-DESIGNATED PREFERRED PRODUCTS and NONPREFERRED PRODUCTS) are met:

Antineutrophil cytoplasmic antibodies (ANCA)–associated vasculitides (granulomatosis with polyangiitis, microscopic polyangiitis [MPA], eosinophilic granulomatosis with polyangiitis [EGPA] [formerly Churg-Strauss syndrome], pauci-immune glomerulonephritis)
- In adult and pediatric individuals 2 years of age and older, in combination with glucocorticoids

Anemia, autoimmune hemolytic (AIHA)
- For refractory autoimmune hemolytic anemia

Castleman disease (CD), multicentric
- Active multicentric CD with no organ failure with or without prednisone for individuals who are human immunodeficiency virus (HIV)–negative and human herpesvirus-8 (HHV-8)–negative, in one of the following regimens:
  - As primary treatment
  - As alternate treatment for relapsed disease
  - If no response to alternate primary treatment
- Active multicentric CD with no organ failure with or without liposomal doxorubicin and/or prednisone for individuals who are HHV-8–positive, in one of the following regimens:
  - As preferred primary treatment
  - As alternate treatment for relapsed disease
  - If no response to alternate primary treatment
- Active multicentric CD with or without prednisone for individuals with no organ failure who have disease progression ≥6 months following completion of rituximab
- Primary treatment for multicentric CD for individuals with fulminant HHV-8 with or without organ failure in combination with:
  - CHOP^a
  - CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone)
  - CVPf
  - Liposomal doxorubicin
  - As a single agent if individual is not a candidate for combination therapy
- Refractory or progressive multicentric CD in combination with liposomal doxorubicin or with CHOP^a, CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), or CVP^f regimen:
  - As initial treatment
  - 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
  - Lenalidomide
  - Thalidomide

Castleman Disease (CD), unicentric
- Unicentric CD with or without prednisone and/or cyclophosphamide for one of the following conditions:
  - For surgically unresectable disease
  - For symptomatic disease following partial resection
  - As second-line therapy for relapsed or refractory disease

Central nervous system cancers
- For leptomeningeal metastases
  - Intracerebrospinal fluid (CSF) treatment for leptomeningeal metastases from lymphoma by intrathecal administration
    - As primary treatment in individuals with good risk status (Karnofsky Performance Status [KPS] 60 or greater, no major neurologic deficits, minimal systemic disease, and reasonable systemic treatment options if needed)
    - As maintenance therapy for individuals with negative CSF cytology or for clinically stable individuals with persistently positive CSF cytology
    - Treatment of individuals with positive CSF cytology that has progressed after receiving prior treatment
- For primary central nervous system lymphoma
  - Induction therapy as a single agent (if individual is unsuitable for or intolerant to high-dose methotrexate) or in combination with one of the following regimens:
    - As a component of R-MPV (rituximab, methotrexate, procarbazine, and vincristine) (National Comprehensive Cancer Network [NCCN] preferred)
    - High-dose methotrexate (NCCN preferred)
    - High-dose methotrexate and temozolomide (NCCN preferred)
    - High-dose methotrexate and temozolomide followed by post–radiation therapy (RT) temozolomide (NCCN preferred)
    - Methotrexate, cytarabine, and thiotepa
    - Temozolomide (if individual is unsuitable for or intolerant to high-dose methotrexate)
    - Lenalidomide (if individual is unsuitable for or intolerant to high-dose methotrexate)
  - Consolidation therapy in individuals with complete response or complete response unconfirmed (CRu) to induction therapy in combination with one of the following regimens:
    - As a component of R-MPV (rituximab, methotrexate, procarbazine, and vincristine)
    - High-dose methotrexate
    - High-dose methotrexate and temozolomide
    - High-dose methotrexate and temozolomide followed by post-RT temozolomide
    - Cytarabine, methotrexate, and thiotepa
  - 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 RT
    - In individuals who received a prior high-dose methotrexate-based regimen without prior RT
    - 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 (<12 months) to prior regimen
    - In individuals who received prior high-dose chemotherapy with stem cell rescue
  - Treatment in combination with high-dose methotrexate with or without ibrutinib for relapsed or refractory disease for one of the following:

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
Conditioning for allogeneic transplant as part of a nonmyeloablative regimen in combination with cyclophosphamide and fludarabine

Idiopathic membranous nephropathy, resistant to at least one of the following conventional therapies:
- Conventional nonimmunosuppressive therapies (e.g, angiotensin-converting enzyme [ACE] inhibitor, angiotensin 2 receptor blocker [ARB])
- Immunosuppressive therapies (e.g., cyclophosphamide, cyclosporine, chlorambucil, corticosteroids, mycophenolate mofetil)

Immunoglobulin G4 (IgG4)-related disease, refractory to corticosteroids

Toxicities related to immune checkpoint inhibitors (e.g., ipilimumab [Yervoy], nivolumab [Opdivo], pembrolizumab [Keytruda])

As additional therapy for moderate grade 2 (G2), severe (G3), or life-threatening (G4) immunotherapy-related bullous dermatitis
Moderate or severe steroid-refractory myalgias or myositis (muscle weakness), or life-threatening steroid-refractory myositis
As additional therapy for severe (G3 to G4) myasthenia gravis in individuals refractory to plasmapheresis or intravenous immune globulin (IVIG)
For encephalitis in individuals positive for autoimmune encephalopathy antibody, or who have had limited or no improvement after 7 to 14 days on pulse-dose methylprednisolone with or without IVIG

Leukemia, mature B-cell acute leukemia (B-AL)

Pediatric individuals, aged 6 months and older with previously untreated, advanced stage, CD20-positive disease, in combination with chemotherapy

Leukemia, Philadelphia chromosome–negative acute lymphoblastic (ALL)
- As induction/consolidation therapy in individuals aged <65 years (adolescents, young adults, and adults) without substantial comorbidities as a component of one of the following:
  - GRAALL-2005 regimen (daunorubicin, vincristine, prednisone, pegaspargase, and cyclophosphamide) with rituximab for CD20-positive disease for individuals aged <60 years (adolescents, young adults, and adults)
  - HyperCVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) regimen, alternating with high-dose methotrexate and cytarabine; with rituximab for CD20-positive disease in adolescents, young adults, and adults
  - Linker four-drug regimen: daunorubicin, vincristine, pegaspargase, and prednisone; with rituximab for CD20-positive disease (individuals aged <60 years)
- As induction therapy as a component of GMALL (idarubicin, dexamethasone, vincristine, cyclophosphamide, and cytarabine); with rituximab for CD20-positive disease (moderate intensity) in adults aged ≥65 years or with substantial comorbidities
- Relapsed/refractory disease, as a component of MOpAD regimen (methotrexate, vincristine, pegaspargase, dexamethasone); with rituximab for CD20-positive disease

Lupus nephritis refractory to corticosteroids and other immunosuppressive therapies (e.g., cyclophosphamide, mycophenolate, hydroxychloroquine, azathioprine, cyclosporine)

Lymphoma, Hodgkin
- For nodular lymphocyte-predominant Hodgkin lymphoma (age 18 or greater years)
  - Primary treatment with involved site radiation therapy (ISRT) for stage IB or IIB disease, or stage IA (bulky) or IIA (bulky or noncontiguous) disease, or with or without ISRT for stage III-IV disease (based on clinical judgement), in combination with one of the following regimens:
    - ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)
    - RCHOP^a
    - RCVP^f
  - Primary treatment as a single agent for stage III to IV disease (based on clinical judgement)
  - Second-line or subsequent treatment (if not previously used) for refractory, relapsed, or progressive disease
    - As a single agent
    - In combination with one of the following regimens:
      1. DHAP^b
      2. ESHAP(etoposide, methylprednisolone, high-dose cytarabine, and cisplatin)
      3. ICE^d
      4. IGEV (ifosfamide, gemcitabine, and vinorelbine) regimen
      5. Bendamustine
      6. ABVD
      7. RCHOP^a
      8. RCVP^f
  - May be considered as maintenance therapy for individuals treated with second-line systemic therapy with rituximab alone for refractory, relapsed, or progressive disease

Lymphoma, Hodgkin (Pediatric)

Nodular lymphocyte-predominant Hodgkin lymphoma: primary treatment for stage IA or IIA (incomplete resection and nonbulky disease) as a component of CVbP (cyclophosphamide, vinblastine, prednisolone) regimen with rituximab (NCCN-preferred)

Lymphoma, non-Hodgkin (NHL)

High-grade B-cell lymphomas

Induction therapy as a component of one of the following:

RCHOP^a(Note: may be associated with a suboptimal outcome in those with high-grade B-cell lymphomas with translocations of MYC and BCL2 and/or BCL6 [double-hit/triple-hit lymphomas]; consider for low-risk individuals, per International Prognostic Index)
R-CODOX-M (rituximab, cyclophosphamide, vincristine, and doxorubicin with methotrexate) regimen alternating with R-IVAC (rituximab, ifosfamide, etoposide, and cytarabine) regimen
Dose-adjusted EPOCH^e regimen with rituximab
HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine regimen with rituximab

Induction therapy in frail or elderly individuals as a component of R-mini-CHOP
Second-line and subsequent therapy with rituximab in individuals with intention to proceed to transplant when they meet both of the following criteria:

One of the following conditions:

Relapsed disease >12 months after completion of first-line therapy
Primary refractory disease (partial response, no response, or progression) or relapsed disease <12 months after completion of first-line therapy on noncandidates for CAR T-cell therapy
Alternative systemic therapy (if not previously used) for relapsed/refractory disease in noncandidates for CAR T-cell therapy

As a component of one of the following regimens:

DHA (dexamethasone and cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin) (NCCN-preferred)
GDP (gemcitabine, dexamethasone, cisplatin) (NCCN-preferred)
Gemcitabine, dexamethasone, and carboplatin (NCCN-preferred)
ICE^d (NCCN-preferred)
ESHAP^c
GemOx (gemcitabine, oxaliplatin)
MINE^h

Second-line and subsequent therapy with rituximab in noncandidates for transplant when they meet both of the following criteria:

One of the following conditions:

Relapsed disease >12 months after completion of first-line therapy
Primary refractory disease (partial response, no response, or progression) or relapsed disease <12 months after completion of first-line therapy on noncandidates for CAR T-cell therapy
Alternative systemic therapy (if not previously used) for relapsed/refractory disease in noncandidates for CAR T-cell therapy

As a component of one of the following regimens:

Polatuzumab vedotin-piiq with or without bendamustine
As a single agent, in combination with lenalidomide (nongerminal center diffuse large B-cell lymphoma), or bendamustine
Dose-adjusted EPOCH^e regimen
CEOPⁱ
GDP^g
GemOx
Gemcitabine, dexamethasone, carboplatin
In combination with gemcitabine and vinorelbine regimen

Used as clinically indicated as a bridging option until CAR T-cell product is available, when the individual meets both of the following criteria:

One of the following conditions:

Individuals with intention to proceed to CAR T-cell therapy with axicabtagene ciloleucel who have primary refractory disease or relapsed disease <12 months after completion of first-line therapy
Individuals with primary refractory disease or relapsed disease <12 months after completion of first-line therapy with intention to proceed to CAR T-cell therapy with axicabtagene ciloleucel

As a component of one of the following:

DHA + platinum (carboplatin, cisplatin, or oxaliplatin)
Polatuzumab vedotin-piiq with or without bendamustine (consider/add bendamustine only after leukopheresis)
GDP^g
Gemcitabine, dexamethasone, carboplatin
GemOx
ICE

AIDS-related B-cell lymphoma
- NCCN-preferred therapy in combination with growth factor support as first-line therapy for AIDS-related Burkitt lymphoma as a component of one of the following:
  - DA-EPOCH-R (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin)
  - 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
- First-line therapy for AIDS-related Burkitt lymphoma, in combination with growth factor support, as a component of R-HyperCVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen
- First-line therapy, in combination with growth factor support, for CD20+ AIDS-related diffuse large B-cell lymphoma, primary effusion lymphoma, and HHV-8–positive diffuse large B-cell lymphoma not otherwise specified (NOS) as a component of R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen (NCCN-preferred regimen)
- First-line therapy, in combination with growth factor support, for CD20+ AIDS-related diffuse large B-cell lymphoma, primary effusion lymphoma, and HHV-8–positive diffuse large B-cell lymphoma NOS, as a component of RCHOP^aregimen
- Relapsed AIDS-related diffuse large B-cell lymphoma, HHV-8–positive diffuse large B-cell lymphoma NOS and primary effusion lymphoma, as a component of bortezomib-ICE (ifosfamide, carboplatin, and etoposide) regimen with or without rituximab
- Second-line and subsequent therapy for AIDS-related diffuse large B-cell lymphoma, primary effusion lymphoma, and HHV-8–positive diffuse large B-cell lymphoma NOS in individuals with intention to proceed to transplant when they meet both of the following criteria:
- Second-line and subsequent therapy for AIDS-related diffuse large B-cell lymphoma, primary effusion lymphoma, and HHV-8–positive diffuse large B-cell lymphoma NOS in noncandidates for transplant when they meet both of the following criteria:
- Used as clinically indicated as a bridging option until CAR T-cell product is available for individuals with primary refractory disease or relapsed disease <12 months after completion of first-line therapy with intention to proceed to CAR T-cell therapy with axicabtagene ciloleucel as a component of one of the following:
- Second-line therapy for relapse of AIDS-related Burkitt lymphoma as a component of:
Burkitt lymphoma
- Pediatric individuals, aged 6 months and older with previously untreated, advanced stage, CD20-positive disease, in combination with chemotherapy.
- Induction therapy for low-risk disease in individuals <60 years of age as a component of one of the following NCCN-preferred regimens:
  - CODOX-M (cyclophosphamide, doxorubicin, and vincristine, with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate) regimen (original or modified) with rituximab
  - Dose-adjusted EPOCH^e regimen with rituximab and intrathecal methotrexate
  - HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine regimen with rituximab (regimen includes intrathecal therapy)
- Induction therapy for high-risk disease in individuals <60 years of age, as a component of one of the following NCCN-preferred regimens. (Note: high-risk individuals presenting with symptomatic central nervous system [CNS] disease should be started with the portion of the systemic therapy that contains CNS-penetrating drugs.)
  - CODOX-M regimen (original or modified) alternating with IVAC (ifosfamide, cytarabine, etoposide, and intrathecal methotrexate) regimen with rituximab
  - HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine regimen with rituximab (regimen includes intrathecal therapy)
- Induction therapy for high-risk disease in individuals <60 years of age, as a component of dose-adjusted EPOCH^e regimen with rituximab and intrathecal methotrexate (for high-risk individuals with baseline CNS disease who are not able to tolerate aggressive treatments)
- Induction therapy (NCCN-preferred) for low-risk and high-risk disease in individuals 60 years of age or older, as a component of dose-adjusted EPOCH^e regimen with rituximab and intrathecal methotrexate. (Note: for high-risk individuals presenting with symptomatic CNS disease, the management of the CNS disease should be addressed with the initial regimen.)
- Second-line therapy for relapse of Burkitt lymphoma >6-18 months following appropriate first-line 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 as a component of one of the following:
  - Dose-adjusted EPOCH^e regimen with rituximab and intrathecal methotrexate
  - ICE^d regimen with rituximab, and 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
  - HDAC (high-dose cytarabine) with rituximab regimen
Burkitt-like lymphoma (BLL)

Pediatric individuals, aged 6 months and older with previously untreated, advanced stage, CD20-positive disease, in combination with chemotherapy

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
- First-line therapy
  - FCR (fludarabine, cyclophosphamide, and rituximab) for individuals with previously untreated CD20-positive CLL
  - In combination with chlorambucil for disease without del(17p)/TP53 mutation in frail individuals with significant comorbidity who are unable to tolerate purine analogues (NCCN-preferred regimen)
  - In combination with chlorambucil or bendamustine (NCCN-preferred regimens) for disease without del(17p)/TP53 mutation in individuals age 65 years or greater and younger individuals with or without significant comorbidities who have indications for treatment⁺ (not recommended for frail individuals)
  - As a component of FCR (fludarabine, cyclophosphamide, and rituximab) regimen with rituximab (NCCN-preferred regimen for individuals with immunoglobulin heavy-chain variable-region [IGHV]-mutated CLL) or in combination with bendamustine (NCCN-preferred regimen) for disease without del(17p)/TP53 mutation in individuals age <65 years without significant comorbidities who have indications for treatment⁺
  - In combination with fludarabine for disease without del(17p)/TP53 and del(11q) mutations in individuals age <65 years without significant comorbidities who have indications for treatment⁺
  - In combination with alemtuzumab (Campath) or high-dose methylprednisolone for CLL with del(17p)/TP53 mutation for individuals who have indications for treatment⁺
- Therapy for relapsed or refractory CLL
  - As a component of FCR (fludarabine, cyclophosphamide, and rituximab) for individuals with previously treated CD20-positive CLL
  - Without del(17p)/TP53 mutation in individuals age 65 years or greater, and younger individuals with significant comorbidities (creatinine clearance <70 mL/min) who have indications for retreatment⁺
    1. In combination with idelalisib (Zydelig), chlorambucil, or lenalidomide
    2. In combination with venetoclax (Venclexta) (NCCN-preferred regimen)
  - Without del(17p)/TP53 mutation in individuals <65 years without significant comorbidities who have indications for retreatment⁺
    1. In combination with venetoclax (Venclexta) (NCCN-preferred regimen)
    2. In combination with idelalisib (Zydelig), bendamustine, or lenalidomide
    3. As a component of FCR (fludarabine, cyclophosphamide, and rituximab) regimen
- Therapy for relapsed or refractory CLL with del(17p)/TP53 in individuals who have indications for retreatment⁺
  - In combination with venetoclax (Venclexta) (NCCN-preferred regimen)
  - In combination with alemtuzumab (Campath), lenalidomide, idelalisib (Zydelig), 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 one of the following regimens:
  - RCHOP^a
  - Dose-adjusted EPOCH^e
  - HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with rituximab regimen alternating with high-dose methotrexate and cytarabine with rituximab regimen
  - OFAR (oxaliplatin, fludarabine, cytarabine, and rituximab) regimen

⁺Indications for treatment/retreatment: eligible for clinical trial, significant disease-related symptoms (fatigue [severe], drenching night sweats, unintentional weight loss [10% or greater in previous 6 months], fever without infection), threatened end-organ function, progressive bulky disease (spleen >6 cm below costal margin, lymph nodes >10 cm), progressive anemia, progressive thrombocytopenia, steroid-refractory autoimmune cytopenias

Diffuse large B-cell lymphoma
- Pediatric individuals, aged 6 months and older with previously untreated, advanced stage, CD20-positive disease, in combination with chemotherapy
- First-line therapy for stage III-IV disease as a component of one of the following:
- First-line therapy for stage I-IV disease in individuals with poor left ventricular function as a component of one of the following regimens:
  - RCDOP (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone) regimen
  - Dose-adjusted EPOCH^e regimen with rituximab
  - RCEOP (rituximab, cyclophosphamide, etoposide, vincristine, and prednisone) regimen
  - RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone)
- First-line therapy for stage I-IV disease in very frail individuals and individuals >80 years of age with comorbidities as a component of one of the following regimens:
  - RCDOP
  - R-mini-CHOP
  - RGCVP
- First-line therapy for gray zone lymphoma as a component of one of the following:
- First-line therapy for gray zone lymphoma in individuals with poor left ventricular function as a component of one of the following regimens:
- First-line therapy for gray zone lymphoma in very frail individuals and individuals >80 years of age with comorbidities as a component of one of the following regimens:
  - RCDOP
  - R-mini-CHOP
  - RGCVP
- Second-line or subsequent therapy for relapsed or refractory disease in individuals with intention to proceed to transplant, when they meet both of the following criteria:
- First-line treatment of primary mediastinal large B-cell lymphoma as a component of one of the following regimens:
  - RCHOP^a
  - Dose-adjusted EPOCH^e
- First-line therapy for extracutaneous primary cutaneous diffuse large B-cell lymphoma, leg type
  - As a component of one of the following regimens:
    1. Dose-adjusted EPOCH^e with rituximab
    2. RCHOP^a (NCCN-preferred)
  - Individuals with poor left ventricular function as a component of one of the following regimens:
    1. RCDOP (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone) regimen
    2. Dose-adjusted EPOCH^e regimen with rituximab
    3. RCEOP (rituximab, cyclophosphamide, etoposide, vincristine, and prednisone) regimen
    4. RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone)
  - For very frail individuals and individuals >80 years of age with comorbidities as a component of one of the following regimens:
    1. RCDOP (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone) regimen
    2. R-mini-CHOP
    3. RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone)
- First-line therapy with ISRT or as second-line therapy (if not previously received) for solitary regional, T1-2 disease, or as first-line therapy for generalized cutaneous, T3 primary cutaneous diffuse large B-cell lymphoma, leg type as a component of RCHOP^a
- First-line therapy with ISRT or as second-line therapy (if not previously received) for solitary regional, T1-2 disease, or as first-line therapy for generalized cutaneous, T3 primary cutaneous diffuse large B-cell lymphoma, leg type in individuals with poor left ventricular function as a component of one of the following regimens:
  1. RCDOP
  2. Dose-adjusted EPOCH^e regimen with rituximab
  3. RCEOPⁱregimen with rituximab
  4. RGCVP
- First-line therapy with ISRT or as second-line therapy (if not previously received) for solitary regional, T1-2 disease, or as first-line therapy for generalized cutaneous, T3 primary cutaneous diffuse large B-cell lymphoma, leg type in very frail individuals and individuals >80 years of age with comorbidities as a component of one of the following regimens:
  1. RCDOP
  2. R-mini-CHOP
  3. RGCVP
- Second-line and subsequent therapy with rituximab in noncandidates for transplant, when they meet both of the following criteria:
- Used as clinically indicated as a bridging option until CAR T-cell product is available for individuals with primary refractory disease or relapsed disease <12 months after completion of first-line therapy with intention to proceed to CAR-T-cell therapy with axicabtagene ciloleucel as a component of one of the following:
  - DHA (dexamethasone and cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin) regimen
  - Polatuzumab vedotin-piiq without bendamustine
  - GDP regimen
  - Gemcitabine, dexamethasone, and carboplatin regimen
  - GemOx regimen
  - ICE^d regimen
Follicular lymphoma (grade 1-2)
- NCCN-preferred first-line therapy for stage I, contiguous stage II, noncontiguous stage II disease, or for individuals with indications for treatment* with stage III or IV disease
- First-line therapy for stage I, contiguous stage II, noncontiguous stage II disease, or for individuals with indications for treatment* with stage III or IV disease, as a single agent (consider in individuals who were initially observed and have progressed with a low tumor burden)
- Elderly or infirm individuals, as a single agent (NCCN-preferred), when tolerability of combination chemotherapy is a concern as:
- Elderly or infirm individuals with indications for treatment* in combination with chlorambucil or in combination with cyclophosphamide as:
- First-line therapy for stage I, II pediatric-type follicular lymphoma in adults with extensive local disease who are not candidates for excision or ISRT, as a component RCHOP^a regimen
- Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
- Second-line or subsequent therapy (if not previously given) for no response, relapsed, or progressive disease in individuals with the indications for treatment* in one of the following regimens:
  - As a single agent
  - Bendamustine with rituximab (NCCN-preferred)
  - RCHOP^a
  - RCVP^f
  - Lenalidomide with rituximab (NCCN-preferred)
  - DHA (dexamethasone and cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin) regimen
  - ESHAP^c regimen with rituximab
  - GDP^g regimen with rituximab
  - Gemcitabine, dexamethasone, and carboplatin regimen
  - GemOX (gemcitabine and oxaliplatin) regimen with rituximab
  - ICE^d regimen with rituximab
  - MINE^h regimen with rituximab
  - Dose-adjusted EPOCH^e regimen with rituximab
  - CEOPⁱ regimen with rituximab
  - Gemcitabine and vinorelbine with rituximab
  - Polatuzumab vedotin-piiq with or without bendamustine
- First-line consolidation therapy in individuals with the indications for treatment* if initially treated with single-agent rituximab
- Maintenance therapy
  - NCCN-preferred as first-line consolidation or extended dosing for 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
  - NCCN-preferred second-line consolidation or extended dosing

*Indications for treatment of follicular lymphoma are as follows: candidate for clinical trial, symptoms, threatened end-organ function, clinically significant or progressive cytopenia secondary to lymphoma, clinically significant bulky disease, steady or rapid progression.

Gastric MALT lymphoma
- Initial therapy (if irradiation is contraindicated) as a single agent for individuals with stage I1, or I2, or stage II1 disease in individuals who are Helicobacter pylori (H. pylori)–positive and t(11;18) positive or who are H. pylori–negative
- As a single agent in individuals with indications for treatment** as:
- As a single agent (NCCN-preferred) or in combination with chlorambucil or cyclophosphamide in elderly or infirm individuals with indications for treatment** where tolerability of combination chemotherapy is a concern as:
- Individuals with indications for treatment** as a NCCN-preferred component of RCHOP^a, RCVP^f , or in combination with bendamustine
  - As first-line therapy for stage IIE, or II2, or stage IV disease (distant nodal, advanced stage)
  - 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 ISRT
  - 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
- NCCN-preferred second-line or subsequent therapy for relapsed, refractory, or progressive disease in individuals with the indications for treatment** in one of the following regimens:
  - Bendamustine with rituximab (if bendamustine not previously used)
  - RCHOP^a
  - RCVP^f
  - Lenalidomide with rituximab, including for the elderly or infirm when tolerability of combination therapy is a concern
- Consolidation as optional first-line extended therapy

**Indications for treatment of gastric MALT lymphoma are as follows: candidate for clinical trial, symptoms, gastrointestinal bleeding, threatened end-organ function, clinically significant bulky disease, steady or rapid progression.

Hairy cell leukemia
- Used in combination with cladribine in individuals with the indication for treatment*** for initial therapy
- Used in combination with cladribine in individuals with the indication for treatment*** for less than complete response or relapse within 2 years of complete response if pentostatin was used as initial therapy
- Used in combination with pentostatin in individuals with the indication for treatment*** for less than complete response or relapse within 2 years of complete response if cladribine was used as initial therapy
- Used in combination with vemurafenib in individuals with the indication for treatment*** for progression after therapy for relapsed/refractory disease
- Used in combination with vemurafenib in individuals with the indication for treatment*** for less than complete response or relapse within 2 years of complete response if cladribine or pentostatin was used as initial therapy
- Used in combination with cladribine or pentostatin in individuals with the indication for treatment*** for relapse 2 years or greater following initial treatment
- As a single agent in individuals with the indication for treatment*** for individuals who are unable to receive purine analogues for one of the following:
  - Less than complete response following initial treatment with cladribine or pentostatin
  - Relapsed disease

***Indications for treatment of hairy cell leukemia are as follows: systemic symptoms (unexplained weight loss [>10% within prior 6 months], excessive fatigue), recurrent infection, hemoglobin <11 g/dL, platelets <100,000/mcL, absolute neutrophil count (ANC) <1000/mcL, symptomatic organomegaly, progressive lymphocytosis or lymphadenopathy.

Histiocytic neoplasms (Rosai-Dorfman disease)

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

Symptomatic unresectable (bulky/site of disease) unifocal disease
Symptomatic multifocal disease
Relapsed/refractory disease

Histologic transformation of indolent lymphomas to diffuse large B-cell lymphoma

Second-line therapy for partial response, no response, or progressive disease following chemoimmunotherapy in individuals with histologic transformation to diffuse large B-cell lymphoma after minimal or no prior treatment

NCCN-preferred without regard to transplant, if not previously given as a component of RCHOP^a regimen

Individuals who have received multiple lines of chemoimmunotherapy for indolent or transformed disease

NCCN-preferred without regard to transplant, if not previously given as a component of RCHOP^a regimen

NCCN-preferred in individuals with intention to proceed to transplant if previously treated with an anthracycline-based regimen as a component of one of the following:

RDHA (rituximab, dexamethasone, and cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin) regimen
GDP^g with rituximab regimen
Gemcitabine, dexamethasone, and carboplatin with rituximab regimen
ICE^d with rituximab regimen

NCCN-preferred in noncandidates for transplant if previously treated with anthracycline-based regimen as a component of one of the following:

GemOX (gemcitabine and oxaliplatin) with rituximab regimen
Polatuzumab vedotin-piiq with or without bendamustine and with rituximab

Used in noncandidates for transplant as a component of one of the following:

CEOPⁱ with rituximab regimen
GDP^g with rituximab regimen
Gemcitabine, dexamethasone, and carboplatin with rituximab regimen

Individuals without translocations of MYC and BCL2 and/or BCL6 who have received minimal or no prior chemotherapy, as a component of:

RCHOP^a
Dose-adjusted EPOCH^e

Individuals without translocations of MYC and BCL2 and/or BCL6 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
RCDOP (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone) regimen
Dose-adjusted EPOCH^e regimen with rituximab
RCEOPⁱ regimen with rituximab
RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone)

Individuals without translocations of MYC and BCL2 and/or BCL6 who have received minimal or no prior chemotherapy, and are very frail and/or >80 years of age with comorbidities, as a component of:

RCEPP
RCDOP
R-mini-CHOP regimen
RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone)

Mantle cell lymphoma
- NCCN-preferred aggressive induction therapy in individuals who are candidates for high-dose therapy/autologous stem cell rescue (HDT/ASCR) when they meet both of the following criteria:
- NCCN-preferred less-aggressive induction therapy, when they meet both of the following criteria:
- NCCN-preferred less-aggressive induction therapy classical or symptomatic indolent TP53 mutated stage II bulky, III, or IV disease (in absence of clinical trial) with the following:
- Less-aggressive induction therapy, when they meet both of the following criteria:
- Less-aggressive induction therapy for classical or symptomatic indolent TP53 mutated stage II bulky, III, or IV for HDT/ASCR (in absence of clinical trial), as a component of one of the following:
  - RBAC500
  - Modified HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) regimen with rituximab in individuals older than 65 years
- Maintenance therapy as a single agent for classical TP53 wildtype or symptomatic indolent TP53 wildtype or mutated stage II bulky, III, or IV disease following complete response or very good partial response to less-aggressive induction therapy or following high-dose therapy with autologous stem cell rescue. (Note: prospective trial data suggest no benefit of maintenance therapy following induction therapy with bendamustine + rituximab, and maintenance therapy following VR-CAP [bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone] or RBAC500 (rituximab, bendamustine and cytarabine) therapy has not been evaluated
- Second-line therapy (NCCN-preferred) for stage I-II disease with partial response, relapse, or progression after prior treatment with chemoimmunotherapy; or for classical or symptomatic indolent stage II bulky, III, or IV disease in those with stable or progressive disease or partial response with substantial disease after induction therapy; or for relapsed or progressive disease (if not previously given) in one of the following regimens:
- Second-line therapy or subsequent therapy (in certain circumstances outlined in NCCN guidelines) for stage I-II disease with partial response, relapse, or progression after prior treatment with chemoimmunotherapy; or for classical or symptomatic indolent stage II bulky, III, or IV disease in those with stable or progressive disease or partial response with substantial disease after induction therapy; or for relapsed or refractory disease (if not previously given) in one of the following regimens:
Nodal Marginal Zone Lymphoma
- First-line, second-line, or subsequent therapy for relapsed, refractory, or progressive disease, as a single agent (NCCN-preferred) or in combination with chlorambucil or cyclophosphamide for stage I (≥7 cm), contiguous stage II (≥7 cm), noncontiguous stage II, or stage III, IV disease in elderly or infirm individuals with indications for treatment^‡ where tolerability of combination chemotherapy is a concern
- NCCN-preferred first-line therapy for stage I (≥7 cm), contiguous stage II (≥7 cm) noncontiguous stage II, or stage III, IV disease in individuals with indications for treatment^‡ in one of the following regimens:
  - RCHOP^a
  - RCVP^f
  - Bendamustine with rituximab
- NCCN-preferred second-line or subsequent therapy for relapsed, refractory, or progressive disease in individuals with indications for treatment^‡ in one of the following regimens:
  - Bendamustine with rituximab (if not previously treated with bendamustine)
  - RCHOP^a
  - RCVP^f
  - Lenalidomide with rituximab including for the elderly or infirm when tolerability of combination therapy is a concern
- Consolidation as optional first-line extended therapy
- Second-line or subsequent therapy as a single agent for relapsed, refractory or progressive disease in individuals with the indications for treatment^‡ (if longer duration of remission)

^‡Indications for nodal marginal zone lymphoma include: candidate for clinical trial, symptoms, threatened end-organ function, clinically significant or progressive cytopenia secondary to the lymphoma, clinically significant bulky disease, steady or rapid progression

Nongastric MALT lymphoma (noncutaneous)
- First-line therapy for stage I or contiguous II disease in selected cases
- First-line, second-line, or subsequent therapy for relapsed, refractory, or progressive disease as a single agent (NCCN-preferred) or in combination with chlorambucil or cyclophosphamide for stage IV disease or in recurrent stage I or contiguous stage II disease in elderly or infirm individuals with the indications for treatment**** where tolerability of combination chemotherapy is a concern
- First-line therapy (NCCN-preferred) for stage IV disease or recurrent stage I or contiguous stage II disease in individuals with the indications for treatment**** in one of the following regimens:
  - RCHOP^a
  - RCVP^f
  - Bendamustine with rituximab
- First-line therapy as a single agent for stage IV disease or recurrent stage I or contiguous stage II disease in individuals with the indications for treatment****
- Consolidation as optional first-line extended therapy
- NCCN-preferred second-line or subsequent therapy for relapsed, refractory, or for progressive disease in individuals with the indications for treatment**** in one of the following regimens:
  - Bendamustine with rituximab (if not previously given)
  - RCHOP^a
  - RCVP^f
  - In combination with lenalidomide, including for the elderly or infirm when tolerability of combination chemotherapy is a concern
- Second-line or subsequent therapy as a single agent for relapsed, refractory, or progressive disease in individuals with the indications for treatment**** (if longer duration of remission)

****Indications for treatment of nongastric MALT lymphoma include: candidate for clinical trial, symptoms, gastrointestinal bleeding, threatened end-organ function, clinically significant bulky disease, steady or rapid progression.

Pediatric aggressive mature B-cell lymphomas (age 6 months and older)

Induction therapy for individuals with 20% or greater size reduction after COP (cyclophosphamide, vincristine, prednisone) reduction phase as a component of Children's Oncology Group (COG) Adolescent Non-Hodgkin's Lymphoma (ANHL)1131 regimen B/induction 1 and 2 with COPADM (cyclophosphamide, vincristine, prednisone, doxorubicin, methotrexate, and intrathecal therapy with methotrexate and hydrocortisone) with rituximab regimen (NCCN preferred) for:

Group B individuals with low-risk disease (unresected stage I or nonabdominal stage II individuals or any stage III individual with lactate dehydrogenase [LDH] 2 or less times the upper limit of normal [ULN])
Group B individuals with high-risk disease (any stage III individual with LDH >2 times ULN, and all non-CNS stage IV individuals with <25% bone marrow involvement)

Consolidation therapy 1 for individuals with 20% or greater size 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 (NCCN preferred) for:

Group B individuals with low-risk disease (unresected stage I or nonabdominal stage II individuals or any stage III individual with LDH 2 or less times the ULN)
Group B individuals with high-risk disease (any stage III individual with LDH >2 times ULN, and all non-CNS stage IV individuals with <25% bone marrow involvement)

Induction therapy as a component of COG ANHL1131 regimen C1/induction 1 and 2 with R-COPADM with rituximab regimen (NCCN preferred) for:

Group B individuals with <20% size reduction after COP reduction phase
Group C individuals with CNS-negative disease after initial treatment with COP reduction phase
Group C individuals with CNS-positive and CSF-negative or -positive disease after initial treatment with COP reduction phase

Alternative induction therapy as a component of COG ANHL1131 regimen C3/induction 1 and 2 with R-COPADM with rituximab regimen (NCCN preferred) for:

Group C individuals with CNS- and CSF-positive disease
Group C individuals on regimen C1 therapy with <20% size reduction after COP reduction phase

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 (NCCN preferred) for:

Group B individuals with less than complete response after first cycle of consolidation with CYM regimen
Group C individuals with CNS-negative disease
Group C individuals with CNS-positive disease, plus high-dose methotrexate and additional intrathecal therapy with methotrexate, cytarbine, and hydrocortisone after R-CYVE 1 only

Consolidation therapy 1 and 2 as a component of COG ANHL1131 regimen C3 with R-CYVE with rituximab regimen (NCCN preferred) 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
As a component of R-CYVE with rituximab regimen as treatment for relapsed/refractory disease if not previously received as a part of initial therapy (NCCN preferred)
As a component of R-ICE (ifosfamide, carboplatin, and etoposide) with rituximab regimen as treatment for relapsed/refractory disease (NCCN preferred)

Post-transplantation lymphoproliferative disorder (PTLD)

Used as clinically indicated as a bridging option until CAR T-cell product is available for individuals with primary refractory disease or relapsed disease <12 months after completion of first-line therapy with intention to proceed to CAR T-cell therapy with axicabtagene ciloleucel as a component of one of the following:

DHA (dexamethasone and cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin) regimen
Polatuzumab vedotin-piiq with or without bendamustine (consider/add bendamustine only after leukapheresis)
GDP^g regimen
Gemcitabine, dexamethasone, and carboplatin regimen
GemOx regimen
ICE^d regimen

Single-agent therapy as:

First-line therapy for monomorphic (B-cell type) or polymorphic (B-cell type) PTLD
Second-line therapy for partial response, persistent or progressive nondestructive lesions or for partial response, persistent or progressive monomorphic (B-cell type) PTLD if immunosuppressive was reduced in first-line therapy
Maintenance therapy for polymorphic (B-cell type) PTLD achieving complete response on first-line therapy

Concurrent chemoimmunotherapy for CD20+ disease as a component of RCHOP^a, RCVP^f, RCEPP (rituximab, cyclophosphamide, etoposide, prednisone, and procarbazine), or RCEOPⁱ 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
Second-line therapy for persistent or progressive monomorphic (B-cell type) or polymorphic (B-cell type) PTLD

Sequential chemoimmunotherapy as a single agent followed by CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen as:

First-line therapy for monomorphic (B-cell type) or systemic polymorphic (B-cell type) PTLD
Second-line therapy for partial response, persistent or progressive monomorphic (B-cell type) or polymorphic (B-cell type) PTLD

In combination with high-dose methotrexate for primary CNS PTLD (B-cell type)
Second-line and subsequent therapy for individuals with monomorphic PTLD (B-cell type) for one of the following:

Relapsed disease >12 months after completion of initial treatment with chemoimmunotherapy
Primary refractory disease (partial response, no response, or progression) or relapsed disease <12 months after completion of initial treatment with chemoimmunotherapy in noncandidates for CAR T-cell therapy
Alternative systemic therapy (if not previously used) for relapsed/refractory disease in noncandidates for CAR T-cell therapy

Second-line and subsequent therapy for individuals with monomorphic PTLD (B-cell type) with intention to proceed to transplant, as a component of:

DHA (dexamethasone and cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin) regimen
ESHAP^c
GDP^g regimen
GemOX (gemcitabine and oxaliplatin) regimen
ICE^d
MINE^h

Second-line and subsequent therapy for individuals with monomorphic PTLD (B-cell type) when they meet both of the following criteria:

One of the following conditions:

Relapsed disease >12 months after completion of initial treatment with chemoimmunotherapy
Primary refractory disease (partial response, no response, or progression) or relapsed disease <12 months after completion of initial treatment with chemoimmunotherapy in noncandidates for CAR T-cell therapy
Alternative systemic therapy (if not previously used) for relapsed/refractory disease in noncandidates for CAR T-cell therapy

As a component of one of the following regimens:

Polatuzumab vedotin-piiq with or without bendamustine
As a single agent, in combination with lenalidomide (nongerminal center diffuse large B-cell lymphoma), or bendamustine
Dose-adjusted EPOCH^e regimen (if not previously given)
CEOPⁱ
GDP^g
GemOx
Gemcitabine, dexamethasone, carboplatin
In combination with gemcitabine and vinorelbine regimen

Primary cutaneous B-cell lymphoma
- Therapy for primary cutaneous marginal zone or follicle center lymphoma with:
Splenic marginal zone lymphoma
- Single-agent therapy (NCCN-preferred) for symptomatic individuals with splenomegaly who have one of the following features:
  - Hepatitis C negative
  - Hepatitis C positive with contraindications for hepatitis treatment
  - Hepatitis C positive with no response to appropriate hepatitis treatment
- First-line (if treatment naive), second-line or subsequent therapy therapy as a single agent (NCCN-preferred) or in combination with chlorambucil or cyclophosphamide in elderly or infirm individuals with the indications for treatment^† upon disease recurrence following initial treatment for splenomegaly where tolerability of combination chemotherapy is a concern
- First-line therapy (NCCN-preferred) in treatment-naive individuals with the indications for treatment^† for disease recurrence following initial treatment for splenomegaly in one of the following regimens:
  - As a single agent
  - RCHOP^a
  - RCVP^f
  - Bendamustine with rituximab
- Consolidation as optional first-line extended therapy in individuals
- NCCN-preferred second-line (if previously treated with rituximab) and subsequent therapy for disease recurrence in combination with lenalidomide for disease recurrence in those with indications for treatment^†, including elderly or infirm when tolerability of combination chemotherapy is a concern
- Second-line and subsequent therapy as a single agent for disease recurrence in those with indications for treatment^† (if previously treated with rituximab with a longer duration of remission)
- NCCN-preferred second-line (if prior treatment with rituximab) or subsequent therapy for disease recurrence in individuals with the indications for treatment^† in one of the following regimens:
  - Bendamustine with rituximab (if not previously given)
  - RCHOP^a
  - RCVP^f
- NCCN-preferred second-line (if prior treatment with rituximab) or subsequent therapy for disease recurrence in combination with lenalidomide for disease recurrence in individuals with the indications for treatment^†, including elderly or infirm when tolerability of combination chemotherapy is a concern
- Second-line or subsequent therapy as a single agent for disease recurrence in individuals with the indications for treatment^†, if previously treated with rituximab with a longer duration of remission

^†Indications for treatment of splenic marginal cell lymphoma include: symptoms or cytopenias secondary to the lymphoma.

Multiple sclerosis, relapsing-remitting, after documented failure, contraindication or intolerance to at least two other disease-modifying treatments (DMTs)

Myasthenia gravis
- Refractory to previous treatments (e.g., corticosteroids, immunosuppressants, plasma exchange, IVIG, thymectomy) as demonstrated through baseline and periodic evaluation of disease status through 1.) the Myasthenia Gravis Foundation of America (MGFA) clinical classification; or 2.) the Myasthenia Gravis Activities of Daily Living (MG-ADL) score

Nephrotic syndrome, including Minimal Change Disease, in pediatric individuals when disease is refractory to corticosteroids or other immunosuppressive therapies (e.g., cyclophosphamide, cyclosporine, mycophenolate mofetil)

Neuromyelitis optica (NMO)

Pemphigoid diseases refractory to corticosteroids or other immunosuppressive therapies
- Bullous pemphigoid
- Mucous membrane pemphigoid, including ocular cicatricial pemphigoid
- Epidermolysis bullosa acquisita

Pemphigus diseases (i.e., pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus) as first-line or subsequent-line of treatment

Pure red cell aplasia, refractory to other standard therapies (e.g., corticosteroids, cyclophosphamide, cyclosporine)

Rheumatoid arthritis, active
- In combination with methotrexate, unless documented failure, contraindication or intolerance exists, in adults with moderate-to-severe active rheumatoid arthritis who have had an inadequate response to at least a 3-month trial of one or more tumor necrosis factor (TNF)–antagonist therapies

Scleroderma refractory to at least 3 months of corticosteroids or other immunosuppressive therapies (e.g., methotrexate, cyclophosphamide, azathioprine, mycophenolate mofetil)

Sjögren syndrome, primary, refractory to corticosteroids and other immunosuppressive therapies (e.g., methotrexate, cyclophosphamide, azathioprine)

Systemic lupus erythematosus (SLE), refractory to other immunosuppressive therapies (e.g., azathioprine, cyclophosphamide, mycophenolate mofetil)

Thrombocytopenic purpura, immune or idiopathic (ITP) when the individual has a documented platelet count < 30 × 10⁹/L

Thrombocytopenic purpura, thrombotic (TTP)

In combination with corticosteroids and therapeutic plasma exchange (TPE), unless documented failure, contraindication, or intolerance exists.

Transplantation, prophylaxis
- For prophylaxis, to reduce cardiac or renal transplantation rejection (pre- and post-) by reducing HLA antibodies in previously sensitized individuals
  - In combination with IVIG alone, or in combination with IVIG and TPE

Transplantation, antibody-mediated rejection (AMR)

For refractory cardiac, lung, pancreas, or renal transplantation AMR
- In combination or after failure of either IVIG alone, or IVIG in combination with TPE

Waldenström macroglobulinemia/lymphoplasmacytic lymphoma

RITUXIMAB AND HYALURONIDASE HUMAN (RITUXAN HYCELA)
Rituximab and hyaluronidase human (Rituxan Hycela) for subcutaneous injection is considered medically necessary and, therefore, covered as a substitute for rituximab and related biosimilars after at least one full dose of rituximab infusion or related biosimilars is administered, and when the following criteria are met:

Castleman Disease (CD)
- As a single agent or in combination with other systemic therapies

Lymphoma, non-Hodgkin (NHL)

Chronic lymphocytic leukemia (CLL)

With fludarabine, cyclophosphamide (FCR), for the treatment of previously untreated and previously treated CLL
As a single agent or in combination with other systemic therapies

Diffuse large B-cell lymphoma (DLBCL)
- Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens
- As a single agent or in combination with other systemic therapies (except ibritumomab tiuxetan)
Follicular lymphoma
- Relapsed or refractory, follicular lymphoma as a single agent
- Previously untreated follicular lymphoma in combination with first-line chemotherapy and, in individuals achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy
- Nonprogressing (including stable disease) follicular lymphoma as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy
- Follicular lymphoma grade 1-2, as a single agent or in combination with other systemic therapies (except ibritumomab tiuxetan)
Gastric MALT lymphoma
- As a single agent or in combination with other systemic therapies (except ibritumomab tiuxetan)
Hairy cell leukemia

As a single agent or in combination with other systemic therapies

High-grade B-cell lymphomas
- As a single agent or in combination with other systemic therapies
Histologic transformation of marginal zone lymphoma to diffuse large B-cell lymphoma
- As a single agent or in combination with other systemic therapies (except ibritumomab tiuxetan)
Mantle cell lymphoma
- As a single agent or in combination with other systemic therapies
Nodal marginal zone lymphoma
- As a single agent or in combination with other systemic therapies (except ibritumomab tiuxetan)
Nongastric MALT lymphoma (noncutaneous)
- As a single agent or in combination with other systemic therapies (except ibritumomab tiuxetan)
Post-transplantation lymphoproliferative disorder (PTLD)
- As a single agent or in combination with other systemic therapies (except ibritumomab tiuxetan)
Primary cutaneous B-cell lymphomas

Primary cutaneous marginal zone or follicle center lymphoma with one of the following: solitary/regional, T1-2 disease that is refractory to initial therapy or generalized disease (skin only), T3

Splenic marginal zone lymphoma
- As a single agent or in combination with other systemic therapies (except ibritumomab tiuxetan)
Waldenström macroglobulinemia/lymphoplasmacytic lymphoma

As a single agent

NOT MEDICALLY NECESSARY

For individuals receiving their first course of rituximab, use of the nonpreferred reference product rituximab (Rituxan) or any nonpreferred biosimilar, is considered not medically necessary and, therefore, not covered since they are more costly than the preferred products that are at least as likely to produce equivalent therapeutic results for that individual's illness.

EXPERIMENTAL/INVESTIGATIONAL

All other uses of rituximab infusion and related biosimilars, including the list below, are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the medical policy on off-label coverage for prescription drugs and biologics.

Anti-myelin–associated glycoprotein (anti-MAG) antibody demyelinating neuropathy
Autoimmune encephalitis
Chronic inflammatory demyelinating polyneuropathy (CIDP)
Dermatomyositis and polymyositis
Focal and segmental glomerulosclerosis (FSGS)
Minimal change disease in adults
Multiple sclerosis (MS) subtypes, other than relapsing-remitting
Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome

All other uses of rituximab and hyaluronidase human (Rituxan Hycela) for subcutaneous injection are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the medical policy on off-label coverage for prescription drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

Guidelines

There is no Medicare coverage determination addressing rituximab infusion or related biosimilars, or rituximab/hyaluronidase human for subcutaneous injection (Rituxan Hycela®); therefore, the Company policy is applicable.

DRUG ADMINISTRATION

Rituximab infusion and related biosimilars are administered by intravenous infusion; they should not be given as a push or bolus.

Rituximab and hyaluronidase human (Rituxan Hycela) is administered by subcutaneous injection over 5 to 7 minutes. Initial dose of rituximab infusion (i.e., administered as Cycle 1) is required to be administered before treatment with rituximab and hyaluronidase human (Rituxan Hycela) for subcutaneous injection.

BLACK BOX WARNINGS

Refer to the specific manufacturer's prescribing information for any applicable Black Box Warnings.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable Evidence of Coverage, rituximab infusion or related biosimilars, or rituximab/hyaluronidase human for subcutaneous injection (Rituxan Hycela®) is covered under the medical benefits of the Company’s Medicare Advantage products when the medical necessity criteria and dosing and frequency requirements listed in this medical policy are met.

However, services that are identified in this policy as experimental/investigational or not medically necessary are not eligible for coverage or reimbursement by the Company.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Rituximab (Rituxan) infusion was approved by the FDA on November 26, 1997, for the treatment of relapsed or refractory low-grade or follicular, CD20 positive, B-cell non-Hodgkin lymphoma. Supplemental approvals have since been issued. The safety and effectiveness in the pediatric population have been established for granulomatosis with polyangiitis (GPA) (Wegener’s granulomatosis) and microscopic polyangiitis (MPA); they have not been established in the pediatric population with non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), pemphigus vulgaris, and rheumatoid arthritis. The FDA has issued subsequent approvals for biosimilar products.

PEDIATRIC USE

According to FDA prescribing information, rituximab (Rituxan) is indicated for the treatment of GPA and MPA in pediatric individuals 2 years of age and older; it is not indicated in individuals less than 2 years of age with GPA or MPA. Rituximab (Rituxan) is also safe and effective in combination with chemotherapy for the treatment of previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma (DLBCL)/Burkitt lymphoma/Burkitt-like lymphoma/mature B-cell acute leukemia in pediatric individuals aged 6 months and older; it is not indicated in individuals less than 6 months of age.

Rituximab and hyaluronidase human (Rituxan Hycela) for subcutaneous injection was approved by the FDA on June 22, 2017 (only after administration with at least one full dose of rituximab [Rituxan] infusion) for the treatment of adults with follicular lymphoma, DLBCL, and CLL. The safety and effectiveness in the pediatric population have not been established.

Description

Rituximab and related biosimilars are antineoplastic agents that can be used as an alternative or adjunct to conventional chemotherapy. In 1997, the US Food and Drug Administration (FDA) approved the use of rituximab infusion for the treatment of relapsed or refractory low-grade or follicular, CD20-positive, B-cell non-Hodgkin lymphoma. Supplemental approvals have since been issued, including the use of rituximab for the treatment of multiple types of non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), pemphigus vulgaris, rheumatoid arthritis, Wegener's granulomatosis, and microscopic polyangiitis (MPA).

Rituximab and related biosimilars are genetically engineered, chimeric, murine/human monoclonal antibodies that bind specifically to the CD20 antigen (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 lymphomas, but it is not expressed on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues. Rituximab and related biosimilars exert a cytotoxic effect on B-cells by mediating B-cell lysis. Treatment with rituximab and related biosimilars results in quick, sustained depletion of circulating and tissue-based B-cells. B-lymphocyte levels return to normal approximately 12 months after treatment is completed.

Rituximab and related biosimilars are typically administered by intravenous infusion. However, intrathecal administration of rituximab infusion can be performed for certain conditions, including treatment of central nervous system tumors.

In 2017, rituximab and hyaluronidase human (Rituxan Hycela) for subcutaneous injection was approved by the FDA for the treatment of adults with follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia. Hyaluronidase human was combined with the rituximab product to increase the permeability of the subcutaneous tissue and increase the absorption rate of a rituximab product into the systemic circulation. The FDA notes at least one full dose of rituximab infusion or related biosimilar (i.e., administered as Cycle 1) is required to be administered before treatment with rituximab and hyaluronidase human (Rituxan Hycela) for subcutaneous injection. The FDA also states the limitation that rituximab and hyaluronidase human (Rituxan Hycela) is not indicated for the treatment of nonmalignant conditions.

OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

References

REFERENCES FOR MEDICALLY NECESSARY INDICATIONS OF RITUXIMAB AND RELATED BIOSIMILARS INFUSION

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Dello Strologo L, Guzzo I, Laurenzi C, et al. Use of rituximab in focal glomerulosclerosis relapses after renal transplantation. Transplantation. 2009, 88(3):417-420.

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Díaz-Manera J, Martínez-Hernández E, Querol L, et al. Long-lasting treatment effect of rituximab in MuSK myasthenia. Neurology. 2012;78(3):189-193.

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Ingen-Housz-Oro S, Valeyrie-Allanore L, Cosnes A, et al. First-line treatment of pemphigus vulgaris with a combination of rituximab and high-potency topical corticosteroids. JAMA Dermatol. 2015;151(2):200-203.

Iorio R, Damato V, Alboini PE, Evoli A. Efficacy and safety of rituximab for myasthenia gravis: a systematic review and meta-analysis. J Neurol. 2015;262(5):1115-1119.

Jellouli M, Charfi R, Maalej B, et al. Rituximab in the management of rediatric steroid-resistant nephrotic syndrome: a systematic review. J Pediatr. 2018;197:191-197.

Joly P, Maho-Vaillant M, Prost-Squarcioni C, et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet. 2017;389(10083):2031-2040.

Jones RB, Tervaert JW, Hauser T, et al.; European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010;363(3):211-220.

Jordan S, Distler JH, Maurer B, et al. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis. 2015;74(6):1188-1194.

Kaegi C, Wuest B, Schreiner J, et al. Systematic review of safety and efficacy of rituximab in treating immune-mediated disorders. Front Immunol. 2019;10:1990

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REFERENCES FOR EXPERIMENTAL/INVESTIGATIONAL INDICATIONS OF RITUXIMAB AND RELATED BIOSIMILARS INFUSION

Anti-Myelin-Associated Glycoprotein (Anti-MAG) Antibody Demyelinating Neuropathy

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Gastaldi M, Thouin A, Vincent A. Antibody-mediated autoimmune encephalopathies and immunotherapies. Neurotherapeutics. 2016;13(1):147-162.

Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.

Irani SR, Gelfand JM, Bettcher BM, et al. Effect of rituximab in patients with leucine-rich, glioma-inactivated 1 antibody–associated encephalopathy. JAMA Neurol. 2014;71(7):896-900.

Jones KC, Benseler SM, Moharir M. Anti-NMDA Receptor Encephalitis. Neuroimaging Clin N Am. 2013;23(2):309-320.

Lancaster E. The diagnosis and treatment of autoimmune encephalitis. J Clin Neurol. 2016;12(1):1-13.

Markovic I, Basic S, Devedjija S. Aggressive anti-LGI1 encephalitis defeated by one cycle of intravenous rituximab-a case report. Neurol Sci. 2020;41(7):1949-1950.

Nepal G, Shing YK, Yadav JK, et al. Efficacy and safety of rituximab in autoimmune encephalitis: a meta-analysis. Acta Neurol Scand. 2020;142(5):449-459.

Nosadini M, Mohammad SS, Ramanathan S, Brilot F, Dale RC. Immune therapy in autoimmune encephalitis: a systematic review. Expert Rev Neurother. 2015;15(12):1391-1419.

Stingl C, Cardinale K, Van Mater H. An update on the treatment of pediatric autoimmune encephalitis. Curr Treatm Opt Rheumatol. 2018;4(1):14-28.

Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157-165.

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Bailly L, Mongin M, Delorme C, et al. Tremor associated with chronic inflammatory demyelinating polyneuropathy and anti-Neurofascin-155 antibodies. Tremor Other Hyperkinet Mov (N Y). 2018;8:606.

Benedetti L, Briani C, Franciotta D, et al. Rituximab in patients with chronic inflammatory demyelinating polyradiculoneuropathy: a report of 13 cases and review of the literature. J Neurol Neurosurg Psychiatry. 2011;82(3):306-308.

Briani C, Salvalaggio A, Ruiz M, et al. Tongue tremor in neurofascin-155 IgG4 seropositive chronic inflammatory polyradiculoneuropathy. J Neuroimmunol. 2019;330:178-180.

Bright RJ, Wilkinson J, Coventry BJ. Therapeutic options for chronic inflammatory demyelinating polyradiculoneuropathy: a systematic review. BMC Neurol. 2014;14:26.

Fisse AL, Motte J, Grüter T, et al. Comprehensive approaches for diagnosis, monitoring and treatment of chronic inflammatory demyelinating polyneuropathy. Neurol Res Pract. 2020;2:42.

Godil J, Barrett MJ, Ensrud E, et al. Refractory CIDP: Clinical characteristics, antibodies and response to alternative treatment. J Neurol Sci. 2020;418:117098.

Ibrahim H, Dimachkie MM, Shaibani A. A review: the use of rituximab in neuromuscular diseases. J Clin Neuromuscul Dis. 2010;12(2):91-102.

Lehmann HC, Burke D, Kuwabara S. Chronic inflammatory demyelinating polyneuropathy: update on diagnosis, immunopathogenesis and treatment. J Neurol Neurosurg Psychiatry. 2019;90(9):981-987.

Knecht H, Baumberger M, Tobòn A, Steck A. Sustained remission of CIDP associated with Evans syndrome. Neurology. 2004;63(4):730-732.

Mahdi-Rogers M, Brassington R, Gunn AA, et al. Immunomodulatory treatment other than corticosteroids, immunoglobulin and plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. 2017;5:CD003280.

Sadnicka A, Reilly MM, Mummery C, et al. Rituximab in the treatment of three coexistent neurological autoimmune diseases: chronic inflammatory demyelinating polyradiculoneuropathy, Morvan syndrome and myasthenia gravis. J Neurol Neurosurg Psychiatry. 2011;82(2):230-232.

Dermatomyositis and Polymyositis

Ashton C, Paramalingam S, Stevenson B, et al. Idiopathic inflammatory myopathies: a review. Intern Med J. 2021; 51(6):845-852.

Dellaripa PF, Danoff SK. Interstitial lung disease in dermatomyositis and polymyositis: Treatment. UpToDate. Last Updated 10/07/2020. Available at: http://www.uptodate.com/contents/interstitial-lung-disease-in-dermatomyositis-and-polymyositis-treatment?source=search_result&search=polymyositis&selectedTitle=9~150. Accessed March 31, 2022.

Ernste FC, Reed AM. Idiopathic inflammatory myopathies: current trends in pathogenesis, clinical features, and up-to-date treatment recommendations. Mayo Clin Proc. 2013;88(1):83-105.

Fasano S, Gordon P, Hajji R, et al. Rituximab in the treatment of inflammatory myopathies: a review. Rheumatology (Oxford). 2017;56(1):26-36.

Fujisawa T. Management of myositis-associated interstitial lung disease. Medicina (Kaunas). 2021;57(4):347.

Hak AE, de Paepe B, de Bleecker JL, et al. Dermatomyositis and polymyositis: new treatment targets on the horizon. Neth J Med. 2011;69(10):410-421.

Hinze C. Juvenile dermatomyositis-what's new? Z Rheumatol. 2019;78(7):627-635.

Hinze CH, Speth F, Oommen PT, Haas JP. Current management of juvenile dermatomyositis in Germany and Austria: an online survey of pediatric rheumatologists and pediatric neurologists. Pediatr Rheumatol Online J. 2018;16(1):38.

Huber AM. Update on the clinical management of juvenile dermatomyositis. Expert Rev Clin Immunol. 2018;14(12):1021-8.

Ibrahim H, Dimachkie MM, Shaibani A. A review: the use of rituximab in neuromuscular diseases. J Clin Neuromuscul Dis. 2010;12(2):91-102.

Kuye IO, Smith GP. The use of rituximab in the management of refractory dermatomyositis. J Drugs Dermatol. 2017;16(2):162-166.

Lazarou IN, Guerne PA. Classification, diagnosis, and management of idiopathic inflammatory myopathies. J Rheumatol. 2013;40(5):550-564.

Lexi-Drugs Compendium. Rituximab. 04/14/2022. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed April 19, 2022.

Marie I, Mouthon L. Therapy of polymyositis and dermatomyositis. Autoimmun Rev. 2011;11(1):6-13.

Mastaglia FL. Inflammatory muscle diseases. Neurol India. 2008;56(3):263-270.

Mok CC. Current role of rituximab in systemic lupus erythematosus. Int J Rheum Dis. 2015;18(2):154-163.

Mok CC, Ho LY, To CH. Rituximab for refractory polymyositis: an open-label prospective study. J Rheumatol. 2007;34(9):1864-1868.

Noss EH, Hausner-Sypek DL, Weinblatt ME. Rituximab as therapy for refractory polymyositis and dermatomyositis. J Rheumatol. 2006;33(5):1021-6. Epub 2006 Mar 15.

Oddis CV, Reed AM, Aggarwal R, et al; Rituximab in Myositis (RIM) Study Group. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: A randomized, placebo-phase trial. Arthritis Rheum. 2013 Feb;65(2):314-324.

Orandi AB, Dharnidharka VR, Al-Hammadi N, et al. Clinical phenotypes and biologic treatment use in juvenile dermatomyositis-associated calcinosis. Pediatr Rheumatol Online J. 2018;16(1):84.

Rider LG, Aggarwal R, Pistorio A, et al; International Myositis Assessment and Clinical Studies Group and the Paediatric Rheumatology International Trials Organisation. 2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Juvenile Dermatomyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Ann Rheum Dis. 2017;76(5):782-791.

Fernandez RR, Callejas Rubio JL, Sánchez Cano D, et al. Rituximab in the treatment of dermatomyositis and other inflammatory myopathies. A report of 4 cases and review of the literature. Clin Exp Rheumatol. 2009;27(6):1009-1016.

Sasaki H, Kohsaka H. Current diagnosis and treatment of polymyositis and dermatomyositis. Mod Rheumatol. 2018;28(6):913-921.

Spencer CH, Rouster-Stevens K, Gewanter H, et al; Pediatric Rheumatologist Collaborators. Biologic therapies for refractory juvenile dermatomyositis: five years of experience of the Childhood Arthritis and Rheumatology Research Alliance in North America. Pediatr Rheumatol Online J. 2017;15(1):50.

Targoff IN. Treatment of recurrent and resistant dermatomyositis and polymyositis in adults. UpToDate. Last Updated 10/21/2021. Available at: http://www.uptodate.com/contents/treatment-of-recurrent-and-resistant-dermatomyositis-and-polymyositis-in-adults?source=search_result&search=rituximab+polymyositis&selectedTitle=1~150. Accessed March 31, 2022.

Traineau H, Aggarwal R, Monfort JB, et al. Treatment of calcinosis cutis in systemic sclerosis and dermatomyositis: a review of the literature. J Am Acad Dermatol. 2020;82(2):317-325.

Truven Health Analytics Inc. Micromedex® 2.0 Healthcare Series. DrugDex®. Rituximab. [Micromedex Web site]. 03/14/2022. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed April 19, 2022.

Unger L, Kampf S, Lüthke K, Aringer M. Rituximab therapy in patients with refractory dermatomyositis or polymyositis: differential effects in a real-life population. Rheumatology (Oxford). 2014;53(9):1630-1638.

Van den Hoogen LL, van Laar JM. Targeted therapies in systemic sclerosis, myositis, antiphospholipid syndrome, and Sjögren's syndrome. Best Pract Res Clin Rheumatol. 2020;34(1):101485.

Varnier GC, Consolaro A, Maillard S, et al. Comparison of treatments and outcomes of children with juvenile dermatomyositis followed at two European tertiary care referral centers. Rheumatology (Oxford). 2021;60(11):5419-23.

Varnier GC, Pilkington CA, Wedderburn LR. Juvenile dermatomyositis: novel treatment approaches and outcomes. Curr Opin Rheumatol. 2018;30(6):650-654.

Vermaak E, Tansley SL, McHugh NJ. The evidence for immunotherapy in dermatomyositis and polymyositis: a systematic review. Clin Rheumatol. 2015;34(12):2089-2095.

Zeng R, Glaubitz S, Schmidt J. Inflammatory myopathies: shedding light on promising agents and combination therapies in clinical trials. Expert Opin Investig Drugs. 2021;30(11):1125-1140.

Focal and segmental glomerulosclerosis (FSGS)

Araya CE, Dharnidharka VR. The factors that may predict response to rituximab therapy in recurrent focal segmental glomerulosclerosis: a systematic review. J Transplant. 2011;2011:374213.

Audard V, Kamar N, Sahali D, et al. Rituximab therapy prevents focal and segmental glomerulosclerosis recurrence after a second renal transplantation. Transpl Int. 2012;25(5):e62-e66.

Cattran DC, Appel GB. Focal segmental glomerulosclerosis: treatment and prognosis. [UpToDate]. Updated 10/28/2021. Available at: https://www.uptodate.com/contents/treatment-of-primary-focal-segmental-glomerulosclerosis?source=search_result&search=FSGS&selectedTitle=2~133. Accessed March 31, 2022.

Fernandez-Fresnedo G, Segarra A, González E, et al. Rituximab treatment of adult patients with steroid-resistant focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2009;4:1317.

Gauckler P, Shin JI, Alberici F, et al; RITERM study group. Rituximab in adult minimal change disease and focal segmental glomerulosclerosis - What is known and what is still unknown? Autoimmun Rev. 2020;19(11):102671.

Hansrivijit P, Cheungpasitporn W, Thongprayoon C, Ghahramani N. Rituximab therapy for focal segmental glomerulosclerosis and minimal change disease in adults: a systematic review and meta-analysis. BMC Nephrol. 2020;21(1):134.

Kronbichler A, Kerschbaum J, Fernandez-Fresnedo G, et al. Rituximab treatment for relapsing minimal change disease and focal segmental glomerulosclerosis: a systematic review. Am J Nephrol. 2014;39:322-330.

Kronbichler A, König P, Busch M, et al. Rituximab in adult patients with multi-relapsing/steroid-dependent minimal change disease and focal segmental glomerulosclerosis: a report of 5 cases. Wien Klin Wochenschr. 2013;125:328.

Meyer TN, Thaiss F, Stahl RA. Immunoadsorbtion and rituximab therapy in a second living-related kidney transplant patient with recurrent focal segmental glomerulosclerosis. Transpl Int. 2007;20(12):1066-71.

Ochi A, Takei T, Nakayama K, et al. Rituximab treatment for adult patients with focal segmental glomerulosclerosis. Intern Med. 2012;51:759.

Peters HP, van de Kar NC, Wetzels JF. Rituximab in minimal change nephropathy and focal segmental glomerulosclerosis: Report of four cases and review of the literature. Neth J Med. 2008;66(10):408-415.

Trachtman R, Sran SS, Trachtman H. Recurrent focal segmental glomerulosclerosis after kidney transplantation. Pediatr Nephrol. 2015;30(10):1793-1802.

Tsagalis G, Psimenou E, Nakopoulou L, Laggouranis A. Combination treatment with plasmapheresis and rituximab for recurrent focal segmental glomerulosclerosis after renal transplantation. Artif Organs. 2011;35(4):420-425.

Xue C, Yang B, Xu J, et al. Efficacy and safety of rituximab in adult frequent-relapsing or steroid-dependent minimal change disease or focal segmental glomerulosclerosis: a systematic review and meta-analysis. Clin Kidney J. 2020;14(4):1042-1054.

Minimal Change Disease in Adults

Bruchfeld A, Benedek S, Hilderman M, et al. Rituximab for minimal change disease in adults: long-term follow-up. Nephrol Dial Transplant. 2014;29(4):851-856.

Gauckler P, Shin JI, Alberici F, et al.; RITERM study group. Rituximab in adult minimal change disease and focal segmental glomerulosclerosis - What is known and what is still unknown? Autoimmun Rev. 2020 Nov;19(11):102671.

Guitard J, Hebral A, Fakhouri F, et al. Rituximab for minimal-change nephrotic syndrome in adulthood: predictive factors for response, long-term outcomes and tolerance. Nephrol Dial Transplant. 2014;29(11):2084-2091.

Hansrivijit P, Cheungpasitporn W, Thongprayoon C, Ghahramani N. Rituximab therapy for focal segmental glomerulosclerosis and minimal change disease in adults: a systematic review and meta-analysis. BMC Nephrol. 2020;21(1):134.

Iwabuchi Y, Takei T, Moriyama T, et al. Long-term prognosis of adult patients with steroid-dependent minimal change nephrotic syndrome following rituximab treatment. Medicine (Baltimore). 2014; 93:e300.

Hoxha E, Stahl RA, Harendza S. Rituximab in adult patients with immunosuppressive-dependent minimal change disease. Clin Nephrol 2011;76:151.

Kronbichler A, Kerschbaum J, Fernandez-Fresnedo G, et al. Rituximab treatment for relapsing minimal change disease and focal segmental glomerulosclerosis: a systematic review. Am J Nephrol. 2014;39:322-330.

Madanchi N, Bitzan M, Takano T. Rituximab in minimal change disease: mechanisms of action and hypotheses for future studies. Can J Kidney Health Dis. 2017;4:2054358117698667.

Meyrier AY. Treatment of focal segmental glomerulosclerosis with immunophilin modulation: When did we stop thinking about pathogenesis? Kidney Int. 2009;76(5):487-491.

Munyentwali H, Bouachi K, Audard V, et al. Rituximab is an efficient and safe treatment in adults with steroid-dependent minimal change disease. Kidney Int. 2013;83:511.

Palmer SC, Nand K, Strippoli GF. Interventions for minimal change disease in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2008;(1):CD001537.

Papakrivopoulou E, Shendi AM, Salama AD, et al. Effective treatment with rituximab for the maintenance of remission in frequently relapsing minimal change disease. Nephrology (Carlton). 2016;21(10):893-900.

Ruggenenti P, Ruggiero B, Cravedi P, et al. Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome. J Am Soc Nephrol. 2014;25(4):850-863.

Sinha A, Bagga A. Rituximab therapy in nephrotic syndrome: implications for patients' management. Nat Rev Nephrol. 2013;9:154.

Multiple sclerosis (MS) subtypes, other than relapsing-remitting (in addition to references in the Medical Necessity Section)

Bellinvia A, Prestipino E, Portaccio E, et al. Experience with rituximab therapy in a real-life sample of multiple sclerosis patients. Neurol Sci. 2020;41(10):2939-2945.

Castillo-Trivino T, Braithwaite D, Bacchetti P, et al. Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. PLoS One. Jul 2013;8(7):e66308.

Cheshmavar M, Mirmosayyeb O, Badihian N, et al. Rituximab and glatiramer acetate in secondary progressive multiple sclerosis: A randomized clinical trial. Acta Neurol Scand. 2021;143(2):178-187.

Hawker K, O'Connor P, Freedman MS, et al; OLYMPUS trial group. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009;66(4):460-471.

Ineichen BV, Moridi T, Granberg T, Piehl F. Rituximab treatment for multiple sclerosis. Mult Scler. 2020;26(2):137-152.

Naegelin Y, Naegelin P, von Felten S, et al. Association of rituximab treatment with disability progression among patients with secondary progressive multiple sclerosis. JAMA Neurol. 2019;76(3):274-281.

Olek MJ, Mowry E. Treatment of primary progressive multiple sclerosis in adults. [UpToDate]. Updated 05/2022. Available at: https://www.uptodate.com/contents/treatment-of-primary-progressive-multiple-sclerosis-in-adults?search=primary progressive multiple sclerosis&source=search_result&selectedTitle=1~29&usage_type=default&display_rank=1. Accessed June 17, 2022.

Olek MJ, Mowry E. Treatment of secondary progressive multiple sclerosis in adults. [UpToDate]. Updated 05/2022. Available at: https://www.uptodate.com/contents/treatment-of-secondary-progressive-multiple-sclerosis-in-adults?search=relapsing multiple sclerosis&topicRef=1687&source=related_link. Accessed June 17, 2022.

Yamout BI, El-Ayoubi NK, Nicolas J, et al. Safety and efficacy of rituximab in multiple sclerosis: a retrospective observational study. J Immunol Res. 2018;9084759.

Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes (POEMS) Syndrome

Allam JS, Kennedy CC, Aksamit TR, Dispenzieri A. Pulmonary manifestations in patients with POEMS syndrome: a retrospective review of 137 patients. Chest. 2008;133(4):969-974.

Dispenzieri A. POEMS syndrome: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol. 2011;86(7):591-601.

Dispenzieri A. POEMS syndrome: update on diagnosis, risk-stratification, and management. Am J Hematol. 2015;90(10):951-962.

Jaccard A. POEMS syndrome: therapeutic options. Hematol Oncol Clin North Am. 2018;32(1):141-151.

Keddie S, D'Sa S, Foldes D, et al. POEMS neuropathy: optimising diagnosis and management. Pract Neurol. 2018;18(4):278-290.

Kuwabara S, Dispenzieri A, Arimura K, et al. Treatment for POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome. Cochrane Database Syst Rev. 2012(6):CD006828. doi: 10.1002/14651858.CD006828.pub3.2012;(6). 02/23/12.

National Organization of Rare Diseases (NORD). POEMS Syndrome. 2021. Available at: http://www.rarediseases.org/rare-disease-information/rare-diseases/byID/789/viewAbstract. Accessed March 31, 2022.

REFERENCES FOR MEDICALLY NECESSARY INDICATIONS OF RITUXIMAB AND HYALURONIDASE HUMAN (RITUXAN HYCELA) FOR SUBCUTANEOUS INJECTION

Elsevier’s Clinical Pharmacology Compendium. Rituximab;Hyaluronidase. 06/29/17. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed November 11, 2021.

Lexi-Drugs Compendium. Rituximab and Hyaluronidase. 11/06/2021. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed November 11, 2021.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium™. Rituxan Hycela. [NCCN Web site]. Available at: https://www.nccn.org/professionals/drug_compendium/default.aspx [via subscription only]. Accessed April 20, 2022.

Rituxan Hycela. [prescribing information] South San Francisco, CA: Genentech Inc. 06/2021. Available at: https://www.gene.com/medical-professionals/medicines/rituxan-hycela. Accessed April 20, 2022.

Truven Health Analytics Inc. Micromedex® 2.0 Healthcare Series. DrugDex®. Rituximab/Hyaluronidase Human, Recombinant. [Micromedex Web site]. 11/06/2021. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed November 10, 2021.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Rituximab and hyaluronidase human (Rituxan Hycela™) for subcutaneous injection drug label [FDA Web site]. 06/10/2021. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed November 8, 2021.

Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

See Attachment A.

HCPCS Level II Code Number(s)

J9311 Injection, rituximab 10 mg and hyaluronidase

J9312 Injection, rituximab, 10 mg

Q5115 Injection, rituximab-abbs, biosimilar, 10 mg

Q5119 Injection, rituximab-pvvr, biosimilar, (ruxience), 10 mg

Q5123 Injection, rituximab-arrx, biosimilar, (riabni), 10 mg

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

BILLING REQUIREMENTS

If there is no specific HCPCS code available for the drug administered, then the drug must be reported with the most appropriate unlisted code along with the corresponding National Drug Code (NDC).

Cross Reference

Policy History

Revisions From MA08.022q:

01/01/2024

This version of the policy will become effective 01/01/2024.

This policy has been updated to communicate the changes in the Company's preferred product designation. Rituximab-arrx (Riabni) is no longer considered a preferred therapy, and has been replaced by Rituximab-abbs (Truxima). The other preferred product did not change (rituximab-pvvr [Ruxience]).

The following ICD-10 CM codes have been removed from this policy, due to specificity/laterality:

M05.00, M05.019, M05.029, M05.039, M05.049, M05.059, M05.069, M05.079, M05.10, M05.119, M05.129, M05.139, M05.149, M05.159, M05.169, M05.179, M05.20, M05.219, M05.229, M05.239, M05.249, M05.259, M05.269, M05.279, M05.30, M05.319, M05.329, M05.339, M05.349, M05.359, M05.369, M05.379, M05.40, M05.419, M05.429, M05.439, M05.449, M05.459, M05.469, M05.479, M05.50, M05.519, M05.529, M05.539, M05.549, M05.559, M05.569, M05.579, M05.60, M05.619, M05.629, M05.639, M05.649, M05.659, M05.669, M05.679, M05.70, M05.719, M05.729, M05.739, M05.749, M05.759, M05.769, M05.779, M05.80, M05.819, M05.829, M05.839, M05.849, M05.859, M05.869, M05.879, M06.00, M06.019, M06.029, M06.039, M06.049, M06.059, M06.069, M06.079, M06.80, M06.819, M06.829, M06.839, M06.849, M06.859, M06.869, M06.879

Revisions From MA08.022p:

01/01/2024

Effective 01/01/2024 this policy applies to New Jersey Medicare Advantage (MA) lines of business.

10/01/2023

This version of the policy will become effective 10/01/2023.

The following ICD-10 CM codes have been added to this policy for Rituxan and biosimilars:

D89.84 IgG4-related disease

N04.20 Nephrotic syndrome with diffuse membranous glomerulonephritis, unspecified

N04.21 Primary membranous nephropathy with nephrotic syndrome

N04.22 Secondary membranous nephropathy with nephrotic syndrome

N04.29 Other nephrotic syndrome with diffuse membranous glomerulonephritis

Z29.89 Encounter for other specified prophylactic measures

The following ICD-10 CM codes have been termed (no longer valid codes) and removed from this policy for Rituxan and biosimilars:
N04.2 Nephrotic syndrome with diffuse membranous glomerulonephritis

Z29.8 Encounter for other specified prophylactic measures

Revisions From MA08.022o:

10/01/2022

This version of the policy will become effective 10/01/2022.

This policy has been updated to communicate the Company's coverage position for rituximab/Rituxan Hycela, for the following indications, in alignment with US Food and Drug Administration (FDA) labeling, and National Comprehensive Cancer Network (NCCN).

The following policy criteria have been revised for rituximab:

Castleman’s disease, multicentric

Central nervous system cancers

Toxicities related to Immune Checkpoint Inhibitors

Leukemia, acute lymphoblastic (ALL)

Lymphoma, Hodgkin

Lymphoma, Hodgkin (Pediatric) Nodular Lymphocyte-Predominant Hodgkin Lymphoma

Lymphoma, non-Hodgkin (NHL) (all subtypes)

Thrombocytopenic purpura, immune or idiopathic (ITP)

Transplantation AMR: included lung and pancreas

Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma

The following policy criteria have been revised for Rituxan Hycela:

CLL

Primary cutaneous B-cell lymphomas

The following criteria have been added to this policy for rituximab:

Leukemia, mature B-cell acute leukemia (B-AL) in pediatrics

Hematopoietic Cell Transplantation

Immunoglobulin G4 (IgG4)-related disease, refractory to corticosteroids

NHL: Burkitt-like lymphoma (BLL) in pediatrics

NHL: Histiocytic Neoplasms (Rosai-Dorfman disease)

NHL: Pediatric Aggressive Mature B-Cell Lymphomas

The following criteria have been added to this policy for Rituxan Hycela:

Hairy Cell Leukemia

Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma

The following indication was changed from Medically Necessary to Experimental/Investigational for rituximab:

Systemic lupus erythematosus (SLE), refractory to other immunosuppressive therapies (e.g., azathioprine, cyclophosphamide, mycophenolate mofetil)

The following criteria have been deleted from this policy for rituximab:

Leukemia, Philadelphia chromosome--positive acute lymphoblastic (ALL)

The following criteria have been deleted from this policy for Rituxan Hycela:

AIDS-related B-cell lymphoma (NCCN)

Burkitt lymphoma (NCCN)

Guidelines Section was revised: Added Pediatric use, per FDA labeling.

Coding: Attachment A: ICD-10 CODES AND NARRATIVES

The following ICD-10 codes have been removed from this policy for Rituximab (Rituxan®) Infusion and Related Biosimilars:

Follicular lymphoma grade III unspecified, IIIa, & IIIb, codes:

C82.20, C82.21, C82.22, C82.23, C82.24, C82.25, C82.26, C82.27, C82.28, C82.29,

C82.30, C82.31, C82.32, C82.33, C82.34, C82.35, C82.36, C82.37, C82.38, C82.39,

C82.40, C82.41, C82.42, C82.43, C82.44, C82.45, C82.46, C82.48, C82.49

The following ICD-10 CM codes have been removed from this policy for Rituximab/Hyaluronidase Human for Subcutaneous Injection (Rituxan Hycela®):

Nodular lymphocyte predominant Hodgkin lymphoma codes: C81.00, C81.01, C81.02,

C81.03, C81.04, C81.05, C81.06, C81.07, C81.08, C81.09

Other Hodgkin lymphoma codes: C81.70, C81.71, C81.72, C81.73, C81.74, C81.75,
C81.76, C81.77, C81.78, C81.79

Follicular lymphoma grade III unspecified, IIIa, & IIIb, codes:

C82.20, C82.21, C82.22, C82.23, C82.24, C82.25, C82.26, C82.27, C82.28, C82.29,

C82.30, C82.31, C82.32, C82.33, C82.34, C82.35, C82.36, C82.37, C82.38, C82.39,

C82.40, C82.41, C82.42, C82.43, C82.44, C82.45, C82.46, C82.48, C82.49

Burkitt lymphoma codes: C83.70, C83.71, C83.72, C83.73, C83.74, C83.75, C83.76,

C83.77, C83.78, C83.79

The following ICD-10 CM codes have been added to this policy for Rituximab (Rituxan®) Infusion and Related Biosimilars:

Other specified types of non-Hodgkin lymphoma: C85.80, C85.81, C85.82, C85.83,

C85.84, C85.85, C85.86, C85.87, C85.88, C85.89

C91.A0 Mature B-cell leukemia Burkitt-type not having achieved remission

C91.A2 Mature B-cell leukemia Burkitt-type, in relapse

D76.3 Other histiocytosis syndromes

D89.89 Other specified disorders involving the immune mechanism, not elsewhere classified

D89.9 Disorder involving the immune mechanism, unspecified
D89.811 Chronic graft-versus-host disease

D89.812 Acute on chronic graft-versus-host disease

I77.82 Antineutrophilic cytoplasmic antibody [ANCA] vasculitis

M34.0 Progressive systemic sclerosis

M34.1 CR(E)ST syndrome

Systemic sclerosis codes: M34.2, M34.81, M34.82, M34.83, M34.89

M35.5 Multifocal fibrosclerosis

M35.9 Systemic involvement of connective tissue, unspecified

T86.810 Lung transplant rejection

T86.99 Other complications of unspecified transplanted organ and tissue

Z29.8 Encounter for other specified prophylactic measures

The following ICD-10 CM codes have been added to this policy for Rituximab/Hyaluronidase Human for Subcutaneous Injection (Rituxan Hycela®):

C88.0 Waldenstrom macroglobulinemia

C91.40 Hairy cell leukemia not having achieved remission
C91.42 Hairy cell leukemia, in relapse

Dosing and Frequency (Attachment) has been archived.

Revisions From MA08.022n:

04/01/2022

This version of the policy will become effective 04/01/2022.

This policy has been updated to communicate the changes in the Company's preferred product designation. Rituximab-abbs (Truxima) is no longer considered a preferred therapy, and has been replaced by rituximab-arrx (Riabni). The other preferred product did not change (rituximab-pvvr [Ruxience]).

Revisions From MA08.022m:

10/01/2021

This version of the policy will become effective 10/01/2021.

This policy was updated to communicate the Company's coverage position for rituximab/Rituxan Hycela, in accordance with US Food and Drug Administration (FDA).

Pediatric indication, dosing & frequency were added for Antineutrophil cytoplasmic antibodies (ANCA)--associated vasculitides.
Maintenance dosing for ANCA --associated vasculitides were updated for adults.

This policy has been identified for the ICD-10 CM code update, effective 10/01/2021.

The following ICD-10 CM codes have been added to this policy:

G92.00 Immune effector cell-associated neurotoxicity syndrome, grade unspecified

G92.01 Immune effector cell-associated neurotoxicity syndrome, grade 1

G92.02 Immune effector cell-associated neurotoxicity syndrome, grade 2

G92.03 Immune effector cell-associated neurotoxicity syndrome, grade 3

G92.04 Immune effector cell-associated neurotoxicity syndrome, grade 4

G92.05 Immune effector cell-associated neurotoxicity syndrome, grade 5

M31.10 Thrombotic microangiopathy, unspecified

M31.11 Hematopoietic stem cell transplantation-associated thrombotic microangiopathy [HSCT-TMA]

M31.19 Other thrombotic microangiopathy

M35.05 Sjogren syndrome with inflammatory arthritis

M35.06 Sjogren syndrome with peripheral nervous system involvement

M35.07 Sjogren syndrome with central nervous system involvement

M35.08 Sjogren syndrome with gastrointestinal involvement

M35.0A Sjogren syndrome with glomerular disease

M35.0B Sjogren syndrome with vasculitis

M35.0C Sjogren syndrome with dental involvement

The following ICD-10 CM codes have been termed (no longer valid code) from this policy:

G92 Toxic encephalopathy

M31.1 Thrombotic microangiopathy

The following ICD-10 CM narrative has narratives have been revised in this policy:

FROM: M35.00 Sicca syndrome, unspecified

TO: M35.00 Sjogren syndrome, unspecified

FROM: M35.01 Sicca syndrome with keratoconjunctivitis

TO: M35.01 Sjogren syndrome with keratoconjunctivitis

FROM: M35.02 Sicca syndrome with lung involvement

TO: M35.02 Sjogren syndrome with lung involvement

FROM: M35.03 Sicca syndrome with myopathy

TO: M35.03 Sjogren syndrome with myopathy

FROM: M35.04 Sicca syndrome with tubulo-interstitial nephropathy

TO: M35.04 Sjogren syndrome with tubulo-interstitial nephropathy

FROM: M35.09 Sicca syndrome with other organ involvement

TO: M35.09 Sjogren syndrome with other organ involvement

Revisions From MA08.022l:

07/01/2021

This policy has been identified for the HCPCS code update, effective 07/01/2021.

The following HCPCS code has been added to this policy:
Q5123 Injection, rituximab-arrx, biosimilar, (riabni), 10 mg

Revisions From MA08.022k:

10/01/2020

This policy has been identified for the HCPCS code update, effective 10/01/2020.

The following ICD-10 CM code has been deleted from this policy:

D59.1 Other autoimmune hemolytic anemias

The following ICD-10 CM codes have been added to this policy:

D59.10 Autoimmune hemolytic anemia, unspecified

D59.11 Warm autoimmune hemolytic anemia

D59.12 Cold autoimmune hemolytic anemia

D59.13 Mixed type autoimmune hemolytic anemia

D59.19 Other autoimmune hemolytic anemia

M05.7A Rheumatoid arthritis with rheumatoid factor of other specified site without organ or systems involvement

M05.8A Other rheumatoid arthritis with rheumatoid factor of other specified site

M06.0A Rheumatoid arthritis without rheumatoid factor, other specified site

M06.8A Other specified rheumatoid arthritis, other specified site

Revisions From MA08.022j:

07/01/2020

This policy has been identified for the HCPCS code update, effective 07/01/2020.

The following NOC codes have been removed from this policy and are replaced by the following HCPCS code:
REMOVED:
C9399 Unclassified drugs or biologicals
J3590 Unclassified biologics

REPLACED WITH:
Q5119 Injection,
rituximab-pvvr, biosimilar, (ruxience), 10 mg

Revisions From MA08.022i:

05/15/2020

This policy has been updated to communicate the Company's designation of two biosimilars as its preferred products: rituximab-pvvr (RuxienceTM) and rituximab-abbs (Truxima®).

Revisions From MA08.022h:

07/01/2019

This policy has been identified for the HCPCS code update, effective 07/01/2019.

The following HCPCS code has been added to this policy:

Q5115 Injection, rituximab-abbs, biosimilar, 10 mg

The following HCPCS codes have been removed from this policy:

C9399 Unclassified drugs or biologicals

J3590 Unclassified biologics

Revisions From MA08.022g:

06/17/2019

This Policy was revised with the following changes:

Added coverage of a new biosimilar, rituximab-abbs (Truxima®).

Extensive oncology changes for Rituxan and Rituxan Hycela to Policy criteria and Dosing and Frequency (Attachment A), per National Comprehensive Cancer Network (NCCN).

New Indications include: Leukemia, Philadelphia chromosome--positive acute lymphoblastic (ALL), High Grade B-Cell Lymphomas, Histologic transformation of Marginal Zone Lymphoma to Diffuse Large B-cell Lymphoma, Nodal Marginal Zone Lymphoma
Indication removed: Lymphoblastic lymphoma

Other criteria changes:

Pemphigus vulgaris: removed trial of steroids.
Pure red cell aplasia: added criteria for “refractory to other standard therapies (e.g. corticosteroids, cyclophosphamide, cyclosporine”
Rheumatoid arthritis: added criteria for “at least a 3-month trial” of TNF agonists.

Indications changed from Experimental/Investigational to Medically Necessary with criteria:

Castleman's disease, unicentric
Multiple sclerosis, relapsing-remitting
Myasthenia Gravis
Nephrotic Syndrome, including Minimal Change Disease, in pediatric individuals
Scleroderma
Sjogren’s syndrome

Indications added to Policy as Medically Necessary with criteria:

Idiopathic Membranous Nephropathy
Immune Checkpoint Inhibitor-Related Toxicities
Lupus Nephritis
Neuromyelitis optica (NMO)
Pemphigoid and Pemphigus diseases

IIndications added to Policy as Experimental/Investigational:

Autoimmune Encephalitis
Dermatomyositis
Multiple sclerosis (MS) subtypes, other than relapsing-remitting

Experimental/Investigational Indications further clarified:

Nephrotic syndrome as Experimental/Investigational was further defined as:
- Focal and segmental glomerulosclerosis (FSGS)
- Minimal Change Disease in adults

Coding Table:

THE FOLLOWING CODES ARE USED TO REPRESENT
RELATED BIOSIMILARS (E.G., RITUXIMAB-ABBS
[Truxima®]):

C9399 Unclassified drugs or biologicals
J3590 Unclassified biologics

Attachment A:

Extensive Dosing and Frequency changes based on FDA, NCCN, drug compendia, and other peer-reviewed literature.

Attachment B: ICD-10 Codes

The following codes were added to this policy for Rituxan and biosimilars:
C79.49 Secondary malignant neoplasm of other parts of nervous system
C85.10 - C85.19 Unspecified B-cell lymphoma
C91.00 Acute lymphoblastic leukemia not having achieved remission
G35 Multiple sclerosis
G36.0 Neuromyelitis optica [Devic]
G70.00 Myasthenia gravis without (acute) exacerbation
G92 Toxic encephalopathy
L10.2 Pemphigus foliaceous
L10.81 Paraneoplastic pemphigus
L12.0 Bullous pemphigoid
L12.1 Cicatricial pemphigoid
L12.30 Acquired epidermolysis bullosa, unspecified
L94.0 Localized scleroderma [morphea]
L94.1 Linear scleroderma
M32.14 Glomerular disease in systemic lupus erythematosus
M34.9 Systemic sclerosis, unspecified
M35.00 - M35.09 Sicca syndrome
N04.2 - N04.9 Nephrotic syndrome
N05.0- N05.9 Unspecified nephritic syndrome

The following codes were removed from this policy for Rituxan and biosimilars:
B20 Human immunodeficiency virus [HIV] disease
C83.50 - C83.59 Lymphoblastic (diffuse) lymphoma
N01.1 Rapidly progressive nephritic syndrome with focal and segmental glomerular lesions
Z94.0 Kidney transplant status
Z94.1 Heart transplant status
Z94.3 Heart and lungs transplant status

The following codes were added to this policy for Rituxan Hycela:
B20 Human immunodeficiency virus [HIV] disease
C81.00 - C81.09 Nodular lymphocyte predominant Hodgkin lymphoma
C81.70 - C81.79 Other Hodgkin lymphoma
C83.00 - C83.09 Small cell B-cell lymphoma
C83.10 - C83.19 Mantle cell lymphoma
C83.70 - C83.79 Burkitt lymphoma
C85.10 - C85.19 Unspecified B-cell lymphoma
C85.20 - C85.29 Mediastinal (thymic) large B-cell lymphoma
C88.4 - Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma]
D47.Z1 Post-transplant lymphoproliferative disorder (PTLD)
D47.Z2 Castleman disease

Revisions From MA08.022f:

01/01/2019

This policy has been identified for the HCPCS code update, effective 01/01/2019.

The following HCPCS codes have been added to this policy:
J9311 Injection, rituximab 10 mg and hyaluronidase
J9312 Injection, rituximab, 10 mg

The following HCPCS codes have been removed from this policy:
J9310 Injection, rituximab, 100 mg
C9467 Injection, rituximab and hyaluronidase, 10 mg
J9999 Not otherwise classified, antineoplastic drugs

Revisions From MA08.022e:

04/01/2018

This policy has been identified for the HCPCS code update, effective 04/01/2018.

The following HCPCS code has been added to this policy:

C9467 Injection, rituximab and hyaluronidase, 10 mg

Revisions From MA08.022d:

10/18/2017

This policy was updated to communicate the Company's coverage of rituximab and hyaluronidase human (Rituxan Hycela™) for subcutaneous injection.

Revisions From MA08.022c:

10/01/2016

This policy has been identified for the ICD-10 code update, effective 10/01/2016.

The following ICD-10 code has been added to this policy:

D47.Z2 Castleman disease

The following ICD-10 codes have been deleted from this policy:

R59.1 Generalized enlarged lymph nodes

R59.9 Enlarged lymph nodes, unspecified

Revisions From MA08.022b:

06/03/2015

This policy has been updated to revise the coverage criteria for the indication of Thrombocytopenic purpura, immune or idiopathic (ITP). A new indication and dosing criteria have been added for the treatment of Thrombocytopenic purpura, thrombotic (TTP).

Revisions From MA08.022a:

03/11/2015

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) and The National Comprehensive Cancer Network (NCCN), including the new indications of Hairy Cell leukemia and Lymphoblastic lymphoma.

Revisions From MA08.022:

01/01/2015

This is a new policy.

Version Effective Date:

1/1/2024

Version Issued Date:

1/2/2024

Version Reissued Date: