Policy #: 663 Effective Date: September 25, 2017 Category: Pharmacology Latest Review Date: August 2017

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1 Name of Policy: Rituxan (rituximab) Oncologic Uses Policy #: 663 Effective Date: September 25, 2017 Category: Pharmacology Latest Review Date: August 2017 Background/Definitions: As a general rule, benefits are payable under Blue Cross and Blue Shield of Alabama health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage. The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage: 1. The technology must have final approval from the appropriate government regulatory bodies; 2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes; 3. The technology must improve the net health outcome; 4. The technology must be as beneficial as any established alternatives; 5. The improvement must be attainable outside the investigational setting. Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are: 1. In accordance with generally accepted standards of medical practice; and 2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient s illness, injury or disease; and 3. Not primarily for the convenience of the patient, physician or other health care provider; and 4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient s illness, injury or disease. Page 1 of 13

2 Description of Procedure or Service: Rituximab is a monoclonal antibody that targets the CD20 antigen located on the cell surface of malignant and normal B-lymphocytes. It binds to the antigen CD20 on pre-b and mature B lymphocytes. This antigen is expressed on over 90% of B-cell non-hodgkin s lymphoma (NHL). This antigen is not found on other normal tissues. Rituximab rapidly depletes circulating and tissue based B-cells, and demonstrates a prolonged effect on cell depletion. Rituximab acts by mediating B-cell lysis. It is thought that cell lysis is caused by complement-dependent cytotoxicity and antibody dependent cell mediated cytotoxicity. Hyaluronan is a polysaccharide found in the extra cellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Hyaluronidase human increases permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan. It is used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. Rituximab was originally approved in 1997 by the U.S. Food and Drug Administration for the treatment of relapsed, refractory, low-grade, or follicular, B-cell non-hodgkin lymphoma. Rituxan Hycela is a combination of rituximab and hyaluronidase human, FDA approved for the treatment of follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia. Policy: Effective for dates of service on or after September 25, 2017 Rituxan Hycela (rituximab and hyaluronidase human) meets Blue Cross Blue Shield s medical criteria for coverage for the following indications: Follicular Lymphoma for one of the following: o as a single agent for relapsed or refractory disease, or o in combination with first line chemotherapy for previously untreated disease, or o as single agent maintenance therapy for individuals that achieve a complete or partial response to rituximab in combination with chemotherapy, or o as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy for non-progressing disease (including stable disease) Diffuse Large B-cell Lymphoma: o In combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimen for previously untreated disease Chronic Lymphocytic Leukemia o In combination with fludarabine and cyclophosphamide (FC) for previously untreated and treated disease. Note: Rituxan Hycela is only administered as a subcutaneous injection after at least one full dose of intravenous rituximab has been given. Page 2 of 13

3 Rituxan (rituximab) for oncologic use meets Blue Cross and Blue Shield s medical criteria for coverage when ALL of the following are met: The patient has a diagnosis of ONE of the following: o CD20-positive, B-cell Non-Hodgkin s Lymphoma (NHL) OR o Chronic lymphocytic leukemia (CLL) OR o One of the following: Acute lymphoblastic leukemia/lymphoma (ALL) AIDS related B-cell lymphoma Burkitt s lymphoma Castleman s Disease (CD) Diffuse large B-cell lymphoma Follicular Lymphoma Gastric MALT lymphoma Hairy cell leukemia Lymphoblastic Lymphoma Lymphoma related CNS Cancers (e.g. leptomeningeal metastases, primary CNS lymphoma) Mantle cell lymphoma Nodular lymphocyte predominate Hodgkin lymphoma (NLPHL) Non-gastric MALT lymphoma Posttransplant lymphoproliferative disorder Primary cutaneous B-cell lymphoma Splenic marginal zone lymphoma Waldenström s macroglobulinemia AND One of the following: The dose is within the program quantity limit and FDA labeled or compendia supported dose for labeled indications or is supported in literature for additional indications OR The quantity (dose) requested is greater than the maximum recommended dose and the prescriber has submitted documentation in support of therapy with a higher dose for the intended diagnosis which has been reviewed and approved Effective for dates of service September 1, 2015 through September 24, 2017 Rituxan (rituximab) for oncologic use meets Blue Cross and Blue Shield s medical criteria for coverage when ALL of the following are met: The patient has a diagnosis of ONE of the following: o CD20-positive, B-cell Non-Hodgkin s Lymphoma (NHL) OR o Chronic lymphocytic leukemia (CLL) OR o One of the following: Page 3 of 13

4 Acute lymphoblastic leukemia/lymphoma (ALL) AIDS related B-cell lymphoma Burkitt s lymphoma Castleman s Disease (CD) Diffuse large B-cell lymphoma Follicular Lymphoma Gastric MALT lymphoma Hairy cell leukemia Lymphoblastic Lymphoma Lymphoma related CNS Cancers (e.g. leptomeningeal metastases, primary CNS lymphoma) Mantle cell lymphoma Nodular lymphocyte predominate Hodgkin lymphoma (NLPHL) Non-gastric MALT lymphoma Posttransplant lymphoproliferative disorder Primary cutaneous B-cell lymphoma Splenic marginal zone lymphoma Waldenström s macroglobulinemia AND One of the following: The dose is within the program quantity limit and FDA labeled or compendia supported dose for labeled indications or is supported in literature for additional indications OR The quantity (dose) requested is greater than the maximum recommended dose and the prescriber has submitted documentation in support of therapy with a higher dose for the intended diagnosis which has been reviewed and approved Blue Cross and Blue Shield of Alabama does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. Blue Cross and Blue Shield of Alabama administers benefits based on the member's contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination. Key Points: Non-Hodgkin s Lymphoma (NHL) NHL is a cancers of the immune system, the lymphocytes specifically. B lymphocytes are responsible for generating proteins (antibodies) that attach to bacteria and viruses and mark them for elimination by the immune system. B-cell lymphomas make up about 85% of NHL lymphomas in the United States. Types of NHL include diffuse large B-cell, follicular, chronic lymphocytic leukemia, mantle cell, and marginal zone B-cell lymphoma. Diffuse large B-cell is Page 4 of 13

5 the most common type of NHL in the U.S. It accounts for 1 out of every 3 cases. Overall, with current treatment options patients with NHL have an overall survival rate at 5 years of approximately 50-60% with 30% of patients with aggressive disease being able to be cured. In 2017, an estimated 72,240 people will be diagnosed with NHL and there will be approximately 20,140 deaths due to the disease; cases of chronic lymphocytic leukemia (CLL) are estimated separately. NHL is the seventh leading site of new cancer cases and 3% of cancerrelated deaths. Rituxan Hycela Trial information was gathered from four controlled trials with exposure to Rituxan Hycela in 892 patients with exposures ranging from a single injection up to 27 months of treatment. The trial population included 382 patients with follicular lymphoma (FL), 369 patients with diffuse large B-cell lymphoma (DLBCL), and 141 patients with chronic lymphocytic leukemia (CLL). The population was aged years (with median age of 60 years), 53% male and 47% female. Most of the patients were Caucasians (84%). In the SABRINA study, patients with FL received a full dose of a rituximab product for intravenous infusion, followed by Rituxan Hycela (1,400 mg rituximab/ 23,400 units hyaluronidase human), in combination with chemotherapy for up to 7 doses, or as monotherapy for up to 12 doses (maintenance treatment). In the MabEASE study patients with DLBCL received a full dose of rituximab product by intravenous infusion, followed by Rituxan Hycela (1,400 mg rituximab/ 23,400 units hyaluronidase human), given in combination with chemotherapy for up to 7 dose. In the SAWYER study patients with CLL on part 2 received a full dose of a rituximab product by intravenous infusion, followed by Rituxan Hycela (1,600 mg rituximab/ 26,800 units hyaluronidase human) for up to 5 doses, in combination with fludarabine and cyclophosphamide. The SABRINA study, a two-stage randomized, controlled study in patients with previously untreated FL. The study compared patients receiving Rituxan Hycela with patients receiving a rituximab produce by intravenous infusion, both in combination with CHOP or CVP followed by maintenance treatment with Rituxan Hycela or a rituximab product by intravenous infusion. The majority of patients completed all 8 cycles of combination treatment with chemotherapy (91% Rituxan Hycela vs. 90% rituximab). In addition, 69% of patients in each of the treatment groups completed all 20 cycles of combination plus maintenance treatment. In both Rituxan Hycela and rituximab groups, patients experienced similar median duration of exposure (27.1 months for each arm). The MabEASE study, a comparative, randomized, parallel-group, multicenter study to investigate the efficacy of Rituxan Hycela versus a rituximab product by intravenous infusion, both in combination with CHOP (R-CHOP) in previously untreated patients with CD20-positive DLBCL. Eighty-two percent of patients receiving Rituxan Hycela or rituximab completed all 8 cycles of study treatment. In both Rituxan Hycela and rituximab treatment groups, patients experienced 4.9 months medical duration of rituximab exposure in each arm. Page 5 of 13

6 The SAWYER study, a two-part, comparative, randomized, parallel-group, multicenter study of Rituxan Hycela versus a rituximab product by intravenous infusion in combination with fludarabine and cyclophosphamide (FC) chemotherapy in patients with patients with previously untreated CLL. The safety analysis population in part 2 of the study included 85 patients receiving Rituxan Hycela and 89 patients receiving rituximab. In both Rituxan Hycela and rituximab groups, patients had similar median duration of rituximab exposure (4.9 vs 4.7 months). The majority of patients received all 6 cycles if study treatment (86 % Rituxan Hycela vs. 81% rituximab). A Cochrane report described results from a meta-analysis of seven randomized controlled trials involving 1943 individuals with follicular lymphoma, mantle cell lymphoma, or other indolent lymphomas. Better overall survival (OS) rates were observed in individuals treated with combination rituximab and other chemotherapy agents (R-chemo) (hazard ratio [HR] for mortality, 0.65; 95% confidence interval [CI], 0.54 to 0.78). An OR (relative risk of tumor response 1.21; 95% CI, 1.16 to 1.27), and disease control (HR of disease event 0.62; 95% CI, 0.55 to 0.71) were noted in individuals treated with R-chemo versus those treated with chemotherapy alone. R-chemo improved OS in individuals with follicular lymphoma (HR for mortality 0.63; 95% CI, 0.51 to 0.79) and in individuals with mantle cell lymphoma (HR for mortality 0.60; 95% CI, 0.37 to 0.98). The authors concluded "Concomitant treatment with rituximab and standard chemotherapy regimens should be considered the standard of care for individuals with indolent and mantle cell lymphomas who require therapy and for individuals with follicular lymphoma." Follicular Lymphoma Vidal and colleagues performed a systematic review and meta-analysis of randomized controlled trials that studied the use of rituximab as maintenance therapy in individuals with follicular lymphoma. Induction therapy consisted of chemotherapy alone, chemotherapy with or without rituximab, and rituximab alone. The meta-analysis included 1143 individuals in five trials that compared observation or treatment upon relapse, versus rituximab as maintenance therapy. Meta-analysis of OS data was available for 985 individuals. OS was statistically significant and better in individuals treated with maintenance rituximab, versus those in the observation cohort or treated at the time of relapse (HR of death, 0.60; 95% CI, 0.45 to 0.79). With further analysis, the authors noted individuals with refractory or relapsed follicular lymphoma treated with maintenance rituximab therapy had a survival benefit (HR for death, 0.58; 95% CI, 0.42 to 0.79) compared to that (HR for death, 0.68; 95% CI, 0.37 to 1.25) of previously untreated individuals. However, infection-related adverse events were higher (HR, 1.99; 95% CI, 1.21 to 3.27) in the maintenance treatment group. Despite the higher rates of adverse events, the data from one trial did not show a negative impact on OS. The authors concluded maintenance rituximab therapy should be included as treatment for individuals with relapsed or refractory follicular lymphoma who responded to induction therapy. The risk and management of infections should be included in treatment decisions when utilizing rituximab. A randomized controlled, phase III PRIMA trial of two years of rituximab maintenance after first-line treatment of individuals with follicular lymphoma demonstrated significant progression-free survival (PFS). This multicenter trial included an induction and a maintenance phase. After induction, 513 individuals were randomized to the observation group and 505 Page 6 of 13

7 participants were assigned to the rituximab treatment group. The rituximab maintenance regimen included a total of 12 infusions of 375 mg/m 2 infused every 8 weeks. At a median follow-up of 36 months in both groups, 3-year PFS was significantly prolonged at 74.9% (95% CI, ) in the treatment group compared to 57.6% ( ) in the observation cohort (p<0.0001). Chronic Lymphocytic Leukemia In February 2010, the FDA approved the combined use of rituximab with fludarabine and cyclophosphamide for the treatment of previously untreated, and previously treated CD20 + chronic lymphocytic leukemia. Chronic lymphocytic leukemia is an indolent form of non-hodgkin lymphoma marked by immunologically less mature lymphocytes and manifested by progressive accumulation of these cells in the blood, bone marrow, and lymphatic tissues. The lymphocytes are characterized by immunophenotype (CD5- and CD23-positive B cells). Additionally, B-cell antigens CD19 and CD20 are also co-expressed on CLL lymphocytes. Chronic lymphocytic leukemia may progress to a generally enlarged lymphatic system as well as complications resulting from pancytopenia. According to the NCI, "treatment with conventional doses of chemotherapy is not curative" for individuals with progressing chronic lymphocytic leukemia; therefore, treatments to prolong disease-free survival for indolent and active disease continue to be studied. Hairy Cell Leukemia Hairy cell leukemia is a mature B-cell, chronic lymphoproliferative disorder for which 10% of the individuals will not require any type of therapy. Characteristics include the presence of a leukemic cell with "hairy" cytoplasmic projections, pancytopenia and bone marrow involvement, including fibrosis. Treatment includes nucleoside analogs (for example, cladribine, pentostatin), interferon-alpha, or splenectomy, with reported 5-year survival rates of more than 85%. The NCI notes rituximab can induce durable complete remissions in individuals with multiple relapsing or refractory disease after purine analog therapy or after interferon. The use of rituximab in relapsed or refractory hairy cell leukemia is limited to case reports and uncontrolled, retrospective case series. However, the American Hospital Formulary Service notes that rituximab is used offlabel in the treatment of hairy cell leukemia. In addition, specialty consensus opinion suggests rituximab is indicated for treatment of hairy cell leukemia. Nonimmunosuppressed Primary Central Nervous System Lymphoma Lymphoma that is limited to the cranial-spinal region without systemic disease is defined as primary central nervous system lymphoma. According to the NCI, diffuse large B-cell neoplasms comprise almost all primary central nervous system lymphomas. Treatment includes radiation therapy alone or with chemotherapeutic agents. Retrospective, uncontrolled case series have investigated the off-label use of rituximab for the treatment of primary central nervous system lymphoma. Wong reported 5 individuals with complete radiographic responses and 2 partial responses in a retrospective review of 7 individuals who received rituximab induction prior to temozolomide treatments. Median duration of response was 6 months and the median survival was 8 months. The authors noted the sequential dosing of rituximab prior to temozolomide appears to sensitize the CD20 + B-cells. Larger trials are needed to confirm the findings. The offlabel use of rituximab for refractory or relapsed primary central nervous system lymphoma is Page 7 of 13

8 reported by the NCI (2016) and is a NCCN level 2A category of evidence and uniform consensus recommendation (NCCN, 2017). Waldenström's Macroglobulinemia Lymphoplasmacytic lymphoma is an indolent lymphoproliferative disease also known as Waldenström's macroglobulinemia. Waldenström's macroglobulinemia usually includes involvement of the bone marrow, lymph nodes, spleen, and may develop into hyperviscosity syndrome. The monoclonal serum paraprotein immunoglobulin M gammopathy is typically associated with Waldenström's. Treatment of acute symptoms usually includes plasmapheresis; long-term management of individuals with serum viscosity of 4 centipoise or less is typically managed with chemotherapeutic agents. Dimopoulos and colleagues reported on a series of 72 symptomatic individuals with Waldenström's macroglobulinemia (WM) in a phase II study. The enrolled individuals were treated with dexamethasone, rituximab and cyclophosphamide over a period of 5 days. The regimen was repeated every 21 days for a period of 6 months. Responses were evaluated on an intention-to-treat analysis. The OR rate (ORR) was 84% (95% CI, 73-91) which included 7% complete responses (CRs), 67% partial responses (PRs), and 9% minimal responses (MR). The 2-year PFS rate for all participants was 67% and for individuals who responded to treatment, 80%. Grade 3 or 4 neutropenia occurred in 7 individuals. A total of 20 infectious episodes with 1 death were recorded. The Fourth International Workshop on Waldenström's macroglobulinemia updated treatment recommendations include rituximab-based therapies, which may be the preferred first-line of therapy as a single agent or in combination regimens for most individuals with Waldenström's macroglobulinemia. The authors noted "reuse of a first-line single agent or combination is reasonable if an individual achieved an unmaintained response that lasted for at least 12 months." Additional considerations when determining the choice of salvage therapy include first-line therapy used, quality and duration of response and specific variables such as age, performance status, and side effects. The NCCN CPG (2017) recommends the off-label use of rituximab as a single agent along with plasmapheresis for treatment of symptomatic hyperviscosity for Waldenström's macroglobulinemia. Single agent use in individuals with an M-protein greater than 5 g/dl is discouraged. These recommendations are based on 2A category of evidence and uniform consensus. The peer-reviewed literature consists of case series and nonrandomized trials. Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia is an aggressive type of leukemia that involves an overabundance of lymphoblasts or lymphocytes in the bone marrow and the peripheral blood. This condition is also called acute lymphocytic leukemia. According to the NCI (2016): Successful treatment of acute lymphoblastic leukemia (ALL) consists of the control of bone marrow and systemic disease and the treatment (or prevention) of sanctuary-site disease, particularly the central nervous system (CNS). The cornerstone of this strategy includes systemically administered combination chemotherapy with CNS preventive Page 8 of 13

9 therapy. CNS prophylaxis is achieved with chemotherapy (intrathecal and/or high-dose systemic therapy) and, in some cases, cranial radiation therapy. The NCCN CPG (2017) includes rituximab as a treatment option with the Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with high-dose methotrexate and cytarabine) regimen for individuals aged 40 years and older with CD20 +, Philadelphia chromosome-negative acute lymphoblastic leukemia. This 2A off-label recommendation was based on improved CR duration rate and OS rates from phase II trials. Multicentric Castleman Disease, CD20 + Multicentric Castleman disease is an uncommon lymphoproliferative disorder, which has been associated with human herpes virus 8 (HHV-8) and Kaposi's sarcoma, and may evolve towards HHV-8-associated non-hodgkin lymphoma. An increased prevalence of multicentric Castleman disease is noted in human immunodeficiency virus infection. A systematic review of the published literature on multicentric Castleman disease conducted by Mylona and colleagues identified 84 individuals in 25 studies which met criteria for analysis. Chemotherapy treatment data was available for 75 out of the 84 individuals. Rituximab was utilized as first- or secondline therapy in 7 of the 75 individuals. Five cases have led to complete responses. The authors highlighted there were 3 cases of responders with worsening of existing Kaposi's sarcoma. In a prospective, open-label phase II trial, 4 weekly rituximab infusions were given to 24 individuals with human immunodeficiency virus-associated multicentric Castleman disease. One individual died as a result of progressive disease before completing the infusions and 1 individual died at day 112 from infection-related respiratory failure. The primary endpoint was a sustained remission (SR) at day 60 while remaining off of other chemotherapeutic agents. A total of 17 out of 22 individuals achieved SR at day 60 and remained off of chemotherapy at day 365. The authors concluded the estimated OS rate was 92% (95% CI, 71-98), event free survival (EFS) was 71% (95% CI, 48-85) and disease free survival (DFS) was 77% (95% CI, 54-90). Adverse events included exacerbation of Kaposi's sarcoma lesions in 8 of the 12 individuals who had pre-existing disease. In a single-group, open-label, phase II trial, 21 individuals with human immunodeficiency virusassociated multicentric Castleman disease were treated with rituximab as first-line treatment. The median follow-up was 12 months (range, 1-49 months). One individual died before completion of the therapy regimen. A total of 14 participants (67%) achieved radiologic response, and 20 individuals achieved remission of symptoms. At two years, the OS rate was 95% (95% CI, ) and the DFS rate was 79% (95% CI, ). NCCN CPG (2017) recommends the off-label use of rituximab in combination regimens to treat CD20 + acquired immune deficiency syndrome-related diffuse large B-cell lymphoma and lymphoma associated with multicentric Castleman disease. These recommendations were based on level 2A category of evidence and uniform consensus. Posttransplant Lymphoproliferative Disorder Posttransplant lymphoproliferative disorder is a rare and life-threatening complication after organ transplantation. Posttransplant lymphoproliferative disorder presents as a heterogeneous Page 9 of 13

10 group of lymphoproliferative disorders resulting from immune suppression, and the prognosis is dependent on additional risk factors such as the presence of Epstein-Barr virus. The primary treatment of posttransplant lymphoproliferative disorder has been a reduction in immunosuppression. However, many individuals fail to respond to reduction and modifications of the immunosuppression therapy. Lee and colleagues performed a systematic review of six studies of posttransplant lymphoproliferative disorder treatment with rituximab as a single agent or in combination with chemotherapy. A majority of the individuals involved in the studies were CD20 +. There have been case reports and phase II trials reported, but there is a lack of randomized, prospective, head-to-head comparisons of treatment regimens. The authors noted results from the limited trials, in combination with some long-term retrospective follow-up data, demonstrated rituximab therapy as a single agent or in combination, produced an ORR of % and a 5-year OS of 60%. Prospective, randomized controlled trials are needed to identify the optimal timing and treatment regimens for individuals with posttransplant lymphoproliferative disorder that have failed immunosuppressive therapy. In a retrospective, multicenter analysis of 80 solid organ transplant recipients, Evens noted individuals treated with first-line rituximab, with or without chemotherapy, had significantly improved PFS and OS. Of the 80 solid organ transplant recipients with posttransplant lymphoproliferative disorder, 59 individuals had early treatment with rituximab. With a median 40-month follow-up, significant differences in the rituximab treated cohort were noted with PFS 70% versus 21% (p<0.0001) and OS 73% versus 33% (p=0.0001). Key Words: B-cell Non-Hodgkin s Lymphoma (NHL), Chronic lymphocytic leukemia (CLL), AIDS related B-cell lymphoma, Burkitt s lymphoma, Hairy cell leukemia, Nodular lymphocyte predominate Hodgkin lymphoma (NLPHL), Acute lymphoblastic leukemia/lymphoma (ALL), Gastric MALT, Mantle cell lymphoma, Non-gastric MALT lymphoma, Posttransplant lymphoproliferative disorder, Primary cutaneous B-cell lymphoma, Splenic marginal zone lymphoma, Waldenström s macroglobulinemia, Diffuse large cell lymphoma, Rituxan, rituximab, Follicular lymphoma (FL), Castleman s Disease (CD), Rituxan Hycela, hyaluronidase. Approved By Governing Bodies Rituximab (Rituxan, Pfzier) was initially approved by the U.S. Food and Drug Administration on November 26, 1997, for the treatment of relapsed or refractory low-grade or follicular, CD20- positive, B cell NHL. Since 1997, rituximab has gained additional oncologic and nononcologic indications. Current FDA-approved oncologic indications of rituximab include follicular NHL, diffuse large B-cell lymphoma (DLBCL), and CLL. Page 10 of 13

11 Rituximab and hyaluronidase human (Rituxan Hycela, Genentech Inc.) was granted regular approval on June 22, 2017 by the U.S. Food and Drug Administration, for the treatment of adults with follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia. Benefit Application: Coverage is subject to member s specific benefits. Group specific policy will supersede this policy when applicable. ITS: Home Policy provisions apply. FEP: Special benefit consideration may apply. Refer to member s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity. Current Coding: CPT Codes: J9310 J9999 Injection, rituximab, 100 mg Not otherwise classified, antineoplastic drugs [when specified as rituximab and hyaluronidase human] References: 1. American Cancer Society. Non-Hodgkin s Lymphoma. Available at: 2. Bauer K, Rancea M, Roloff V, et al. Rituximab, ofatumumab and other monoclonal anti- CD20 antibodies for chronic lymphocytic leukaemia. Cochrane Database Syst Rev. 2012;(11):CD Byrd JC, Rai K, Peterson BL, et al. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB Blood. 2005; 105: Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, et al. Primary treatment of Waldenström macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol. 2007; 25(22): Dimopoulos MA, Gertz MA, Kastritis, et al. Update on treatment recommendations from the Fourth International Workshop on Waldenström's Macroglobulinemia. J Clin Oncol. 2009; 27(1): Evens AM, David KA, Helenowski I, et al. Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era. J Clin Oncol. 2010; 28(6): Garja, Ajeet. B-Cell Lymphoma. Medscape. Available at: //emedicine.medscape.com/article/ overview. 8. Gerard L, Berezne A, Galicier L, et al. Prospective study of rituximab in chemotherapydependent human immunodeficiency virus-associated multicentric Castleman's Disease: ANRS 117 CastlemaB Trial. J Clin Oncol. 2007; 25: Page 11 of 13

12 9. Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005; 23(18): Lee JJ, Lam MSH, Rosenberg A. Role of chemotherapy and rituximab for treatment of posttransplant lymphoproliferative disorder in solid organ transplantation. Annals of Pharmacotherapy. 2007; 41: Mylona E, Baraboutis IG, Lekakis LJ, et al. Multicentric Castleman's Disease in HIV infection: a systematic review of the literature. AIDS Rev. 2008; 10: National Cancer Institute (NCI). Available at: National Cancer Institute. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets: Non-Hodgkin Lymphoma. Available online at: seer.cancer.gov/statfacts/html/nhl.html. 14. National Comprehensive Cancer Network Compendia. Rituximab. Available at: National Comprehensive Cancer Network Guidelines. B-Cell Lymphomas. Version Available at: NICE Technology Appraisal Guidance TA243. Rituximab for the first-line treatment of stage III-IV follicular lymphoma: (review of NICE technology appraisal guidance 110). Available at: //publications.nice.org.uk/rituximab-for-the-first-line-treatment-of-stage-iii-ivfollicular-lymphoma-ta Quinn JP, Mohamedbhai, Chipperfield, et al. Efficacy of rituximab in combination with steroids in refractory chronic lymphocytic leukemia. Leukemia and Lymphoma. 2008; 49(10): Rituxan Hycela. Highlights of prescribing information. Revised: 6/2017. Available at: Rituxan Hycela. Rituxan Hycela (rituximab and hyaluronidase human) injection. Available at: Rituximab prescribing information. Available at: //dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b172773b a1c-ad95- bab4b #nlm Rituximab Monograph. Lexicomp Online, American Hospital Formulary Service (AHFS ) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised September 10, Rummel MJ, Niederle N, Maschmeyer G, et al.; on behalf of the Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicenter, randomised, phase 3 non-inferiority trial. Lancet. 2013; 381(9873): Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomized controlled trial. Lancet. 2011; 377: Schulz H, Bohlius J, Skoetz N, et al. Chemotherapy plus rituximab versus chemotherapy alone for B-cell non-hodgkin's lymphoma. Cochrane Database Syst Rev. 2007;(4):CD Thomas DA, O'Brien S, Faderl S, et al. Chemoimmunotherapy with a modified hyper-cvad and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol. 2010; 28(24): Page 12 of 13

13 26. Vidal L, Gafter-Gvili, Leibovici L, et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2009; 101: Wong ET, Tishler R, Barron L, Wu JK. Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. Cancer. 2004; 1010(1): Zent CS, Call TG, Shanafelt TD, et al. Early treatment of high-risk chronic lymphocytic leukemia with alemtuzumab and rituximab. Cancer. 2008; 113(8): Policy History Medical Policy Group: policy transferred to pharmacy with effective date September 1, 2015 Medical Policy Group, August 2016 (2): Updates to Description, Key Points, Approved by Governing Bodies, and References; Policy section updated to include additional oncologic indications per NCCN guidelines (Castleman s disease, Follicular lymphoma, Lymphoblastic lymphoma); no change in intent; added reference # 2-6, 8-13, 17, Medical Policy Group. August 2017 (2): Updates to Description, Key Points, Approved by Governing Bodies, and References; Policy section updated to include criteria for Rituxan Hycela. Available for comment August 10, 2017 through September 24, This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a caseby-case basis according to the terms of the member s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment. This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield s administration of plan contracts. Page 13 of 13