RITUXAN (rituximab) RATIONALE FOR INCLUSION IN PA PROGRAM

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1 RATIONALE FOR INCLUSION IN PA PROGRAM Background Rituxan is a monoclonal antibody that is manufactured through biotechnology methods rather than by the human body s own immune system. The drug works by greatly reducing the number of specific immune cells in the blood, known as B-cells. The drug binds to a particular protein, the CD20 antigen, on the surface of normal and malignant B-cells, making it easier for the patient s immune system to attack the cancer cell as if it were a foreign pathogen. With the targeted mechanism of action of Rituxan to B-cells, it is used in the treatment of chronic lymphocytic leukemia (CLL), a slowly progressing blood and bone marrow cancer, that arises from a group of white blood cells known as B-cells, in the treatment of CD20 positive, Non-Hodgkin s Lymphoma (NHL), which is a type of cancer that occurs in B-cells, and in the treatment of rheumatoid arthritis (RA) which B-cells are believed to play an important role in RA (1,2,4). Rituxan, in combination with glucocorticoids (steroids), is used to treat patients with Wegener s granulomatosis (WG) and microscopic polyangiitis (MPA), two rare disorders that cause blood vessel inflammation (vasculitis). Vasculitis in patients with WG and MPA can lead to tissue damage. WG mostly affects the respiratory tract (sinuses, nose, trachea, and lungs) and kidneys, while MPA commonly affects the kidneys, lungs, nerves, skin, and joints (3). Regulatory Status FDA approved indications include: (2) Non-Hodgkin s Lymphoma (NHL) Rituxan is indicated for the treatment of patients with: Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent Previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy and, in patients achieving a complete or partial response to Rituxan in combination with chemotherapy, as single-agent maintenance therapy Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after first-line CVP chemotherapy Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens Chronic lymphocytic leukemia (CLL) Rituxan is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously

2 treated CD20-positive CLL. Rheumatoid arthritis (RA) Rituxan in combination with methotrexate is indicated for the treatment of adult patients with moderately- to severely-active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies. Granulomatosis with Polyangiitis (GPA) (Wegener s Granulomatosis) and Microscopic Polyangiitis (MPA) Rituxan in combination with glucocorticoids, is indicated for the treatment of adult patients with Granulomatosis with Polyangiitis (GPA) (Wegener s Granulomatosis) and Microscopic Polyangiitis (MPA). Limitations of use: Rituxan is not recommended for use in patients with severe, active infections (2). Rituxan has several boxed warnings regarding fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy (PML) resulting in death (2). Rituxan can cause severe, including fatal, infusion reactions.. Carefully monitor patients during infusions. Discontinue Rituxan infusion in patients who develop severe (grade 3 or 4) infusion reactions and administer medical treatment (2). Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, some fatal, can occur within hours after the first infusion of Rituxan in patients with non-hodgkin lymphoma (NHL). Patients at high risk for tumor lysis syndrome should be administered aggressive intravenous hydration, anti-hyperuricemic agents, and their renal function should be monitored (2). Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. Rituxan should be discontinued in patients who experience a severe mucocutaneous reaction (2). Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of Rituxan-based therapy. Discontinue Rituxan for serious infections and institute appropriate anti-infective therapy (2).

3 Rituxan infusions should be discontinued in patients that develop serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina (2). The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live virus vaccines is not recommended (2). In patients with lymphoid malignancies, during treatment with Rituxan monotherapy, obtain complete blood counts (CBC) and platelet counts prior to each Rituxan course. During treatment with Rituxan and chemotherapy, obtain CBC and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias. In patients with rheumatoid arthritis, granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA), obtain CBC and platelet counts at two to four month intervals during Rituxan therapy. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period (2). Off Label Uses: There are a number of important off-label uses for the use of Rituxan that are supported by the medical literature. The inclusion of the following conditions is based on the studies cited. Other Non-Hodgkin s Lymphomas (5) 1. Burkitt lymphoma 2. Gastric MALT lymphoma 3. Non-gastric MALT lymphoma 4. Nodal Marginal Zone lymphoma 5. Mantle cell lymphoma 6. AIDS-Related B-cell lymphomas 7. Post-transplant lymphoproliferative disorder 8. Primary cutaneous B-cell lymphoma 9. Splenic marginal zone lymphoma 10. Hairy Cell Leukemia Other Conditions 1. Waldenstrom s macroglobulinemia (6)

4 2. Steroid refractory chronic graft vs. host disease (7) 3. Immune thrombocytopenic purpura (8) 4. Thrombotic thrombocytopenic purpura (10) 5. Refractory autoimmune hemolytic anemia (9) Rituxan as monotherapy or in conjunction with various chemotherapy agents as well as other monoclonal antibodies is supported by clinical trial data and NCCN guideline recommendations (5). The following chemoimmunotherapy regimens are used for either first-line therapy or relapsed/refractory therapy depending on the results of genetic testing and comorbidities in affected patients: (5) 1. Alemtuzumab + Rituxan 2. Bendamustine, Rituxan (BR) 3. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + Rituxan 4. HyperCVAD (cyclophosphamide,vincristine,doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) + Rituxan 5. Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + Rituxan 6. HDMP (high-dose methylpredisolone) + Rituxan 7. Pentostatin, cyclophosphamide, Rituxan) (PCR) 8. CFAR (cyclophosphamide, fludarabine, alemtuzumab, Rituxan) 9. OFAR (oxaliplatin, fludarabine, cytarabine, Rituxan) 10. Lenalidomide + Rituxan Summary Rituxan is a monoclonal antibody that is manufactured through biotechnology methods rather than by the human body s own immune system. The drug works by greatly reducing the number of specific immune cells in the blood, known as B-cells. The drug binds to a particular protein, the CD20 antigen, on the surface of normal and malignant B-cells, making it easier for the patient s immune system to attack the cancer cell as if it were a foreign pathogen. Rituxan is therefore used to treat diseases which are characterized by excessive numbers of B cells, overactive B cells, or dysfunctional B cells. This includes non-hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), microscopic polyangiitis (MPA), and granulomatosis with polyangiitis (1-4).

5 Rituxan may be considered medically necessary for the treatment of Non-Hodgkin s Lymphoma, B-Cell, CD20-Positive, which include Chronic Lymphocytic Leukemia, follicular lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma, gastric MALT lymphoma, non-gastric MALT lymphoma, nodal marginal zone lymphoma, mantle cell lymphoma, AIDS-Related B-cell lymphomas, posttransplant lymphoproliferative disorder, primary cutaneous B-cell lymphoma, splenic marginal zone lymphoma, and hairy cell leukemia; in patients 18 years of age or older with moderately-to-severely active Rheumatoid Arthritis (previously inadequate response, intolerance, or contraindication to one or more tumor necrosis factor (TNF) antagonist therapies), granulomatosis with polyangiitis (formerly Wegener's granulomatosis) (concurrent with glucocorticoid) or Microscopic Polyangiitis (MPA) (concurrent with glucocorticoid). Rituxan may also be considered medically necessary in Waldenstrom s macroglobulinemia, steroid refractory chronic graft vs. host disease, immune thrombocytopenic purpura, thrombotic thrombocytopenic purpura, and refractory autoimmune hemolytic anemia. Rituxan should not be used with a Tumor Necrosis Factor (TNF) antagonist, not used with a live vaccine(s) (non-live vaccines should be administered at four weeks prior to a course of Rituxan), patient should not have severe or active infections, and will not be used with the following: Orencia (abatacept), Actemra (tocilizumab), Kineret (anakinra), and Xeljanz (tofacitinib). Rituxan may be considered investigational in patients who do not meet the criteria for medical necessity. Prior authorization is required to ensure the safe, clinically appropriate and cost effective use of Rituxan while maintaining optimal therapeutic outcomes. References 1. FDA Resource Pages. Food Drug Administration Website. FDA Approves Rituxan to Treat Chronic Lymphocytic Leukemia Rituxan [package insert]. South San Francisco, CA: Genentech Inc; August FDA Resource Pages. Food Drug Administration Website. FDA approves Rituxan to treat two rare disorders.

6 4. Rituxan Website. About NHL NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin s Lymphomas, version I. 2015; August NCCN Guidelines (NCCN Guidelines Waldenström s Macroglobulinemia / Lymphoplasmacytic Lymphoma, page WMPLP-2) 7. Zaja F, Bacigalupo A, Patriarca F, Stanzani M, Van Lint MT, Fili C, Scime R, Milone G, Falda M, Vener C, Laszlo D, Alessandrino PE, Narni F, Sica S, Olivieri A, Sperotto A, Bosi A, Bonifazi F, Fanin R; GITMO (Gruppo Italiano Trapianto Midollo Osseo). Treatment of refractory chronic GVHD with rituximab: a GITMO study. 8. Bone Marrow Transplant Aug; 40(3):273-7). Medeot M, Zaja F, Vianelli N,Battista M, Baccarani M, Patriarca F, Soldano F, Isola M, De Luca S, Fanin R. Rituximab therapy in adult patients with relapsed or refractory ITP: long term follow-up results. Eur J Haematol May Bader-Meunier B, Aladjidi N, Bellmann F, Monpoux F, Nelken B, Robert A, Armari-Alla C, Picard C, Ledeist F, Munzer M, Yacouben K, Bertrand Y, Pariente A, Chaussé A, Perel Y, Leverger G. Rituximab therapy for childhood Evans syndrome. Haematologica Dec;92(12):1691-4) 10. Rituximab for refractory and or relapsing thrombotic thrombocytopenic purpura. Elliott, et al; Eur j Haematol Oct; 83(4):