MEDICAL POLICY POLICY TITLE HIGH DOSE CHEMOTHERAPY AND HEMATOPOIETIC STEM CELL SUPPORT FOR NON HODGKIN S LYMPHOMAS MP-9.

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1 Original Issue Date (Created): August 23, 2002 Most Recent Review Date (Revised): Effective Date: April 15, 2008 July 1, RETIRED I. DESCRIPTION/BACKGROUND High dose chemotherapy (HDC) involves the administration of cytotoxic agents using doses several times greater than the standard therapeutic dose. In some cases, whole body or localized radiotherapy is also given and included in the term HDC when applicable. The most significant side effect of HDC is marrow ablation and thus HDC is accompanied by a reinfusion of stem cells to repopulate the bone marrow. There are three potential donor sources of stem cells. Autologous stem cells are collected from either the bone marrow or the peripheral blood of the patient. Stem cells may be harvested from the peripheral blood using a pheresis technique. To increase the number of stem cells in the peripheral circulation, autologous donors may be pretreated with a course of chemotherapy or hematopoeitic growth factors, or both. Also blood harvested from the umbilical cord and placenta shortly after delivery of an infant contains stem and progenitor cells. Although cord blood is an allogeneic source, stem cells are immunologically naïve and are associated with a lower incidence of rejection or graft versus host disease. Non-Hodgkin s Lymphomas (NHL) are neoplasms arising from lymphocytes of varying cellular origin and maturational stages. NHLs are categorized according to their histologic type, grade, and stage, on the basis of immunologic phenotyping or a combination of the above. Until recently the most commonly used was the International Working Formulation (IWF) summarized here. IWF Class Histologic Type Grade B Follicular, small cleaved cell Low C Follicular, mixed small cleaved and large cell Low D Follicular large cell Intermediate E Diffuse small cleaved cell Intermediate F Diffuse mixed small and large cell Intermediate G Diffuse large cell (histiocytic) Intermediate H Large cell immunoblastic High I Lymphoblastic High Page 1

2 J Small non-cleaved cell (Burkitt s lymphoma) High Follicular refers to a pattern in which the neoplastic cells are arranged in nodules, or follicles, within the lymph node. Follicular lymphomas arise from a B-lymphocyte. In diffuse lymphomas, the normal pattern of the lymph node is entirely effaced. Diffuse lymphomas may arise from B- or T-cells. High-grade disease is frequently referred to as aggressive NHL, while low-grade is often termed indolent. Immunophenotyping using cell-surface antigens has become increasingly important for classifying NHL. The Revised European and American Lymphoma (REAL) classification scheme was initially developed by the International Lymphoma Study Group and updated under the auspices of the World Health Organization (WHO). This scheme uses the morphology, immunophenotype, and genetic and clinical features to define separate entities. It is replacing the IWF to define more homogeneous patient populations for clinical trials and is the basis for treatment choice outside of trials. The REAL/WHO system first divides NHLs into those of B-cell and those of T-cell or NK-cell origins. Each of these is further subdivided into precursor-cell or mature-cell neoplasms, with from ten to fourteen subtypes in each group of mature-cell lymphomas. The REAL/WHO scheme includes several previously undefined NHL subtypes such as marginal zone lymphoma and lymphoplasmacytoid lymphoma, both categorized as indolent lymphoma, and mantle cell lymphoma, which may have either an indolent or aggressive clinical behavior. Some newly distinct clinical entities that were merged with indolent or low-grade lymphomas in the IWF scheme may be closer in biologic behavior and prognosis to intermediate/aggressive lymphoid malignancies. However, the WHO/REAL Clinical Advisory Committee recommended against grouping the B- and T-/NK lymphomas into categories (e.g., indolent, intermediate, aggressive), opting instead to focus on scoring systems that combine prognostic features for individual patients. However, the published data still lags behind the adoption of the REAL/WHO classification. Therefore most outcomes in the published literature are still reported according to the IWF scheme, and thus this scheme is still the basis of the policy statements. II. DEFINITIONS ABLATION is the removal of a part, pathway, or function by surgery, chemical destruction, electrocautery or radiofrequency. ANTIGENIC is the provoking of an immune response or acting with antibodies. ALLOGENEIC refers to having a different genetic constitution but belonging to the same species, i.e., involves a donor and a recipient. APHERESIS is a procedure in which blood is temporarily withdrawn, one or more components are selectively removed, and the rest of the blood is reinfused into the donor. Page 2

3 AUTOLOGOUS refers to originating within an individual, i.e., self-donation. BONE MARROW is the soft tissue in the marrow cavities of long bones (yellow marrow) and in the spaces between trabeculae of spongy bone in the sternum and other flat and irregular bones (red marrow). Yellow marrow is mostly fat and stored energy. Red marrow produces all types of blood cells. CYTOTOXIC AGENT is any pharmacologic compound that inhibits the proliferation of cells within the body. HISTOLOGIC pertains to the microscopic anatomic and physiologic characteristics of tissues and the cells found therein. SALVAGE THERAPY describes chemotherapy given to patients who have either: Failed to achieve complete remission after initial treatment for newly diagnosed lymphoma; or Relapsed after an initial complete remission. SYNGENEIC refers to stem cells harvested from an identical twin. TRANSFORMATION describes a lymphoma whose histologic pattern has evolved to a highergrade lymphoma. Transformed lymphomas typically evolve from a nodular pattern to a diffuse pattern. III. POLICY High dose chemotherapy with either autologous or allogeneic stem cell support may be considered medically necessary for patients with NHL subtypes that the IWF classifies as intermediate or aggressive (high), or a mantle cell lymphoma with aggressive clinical behavior: As salvage therapy for patients who do not achieve a complete remission (CR) after first-line treatment (induction) with a full course of standard-dose chemotherapy; To consolidate a first CR for patients with an age-adjusted IPI score that predicts a high- or high-intermediate risk of relapse; or To achieve or consolidate CR for those in a chemosensitive first or subsequent relapse. Page 3

4 High dose chemotherapy with either autologous or allogeneic stem cell support may be considered medically necessary for patients with NHL subtypes that the IWF classifies as indolent, for marginal zone lymphoma with indolent behavior or lymphoplasmacytoid lymphoma, and for new subtypes defined by the WHO/REAL scheme: As salvage therapy for patients who do not achieve a complete remission (CR) after first-line treatment (induction) with a full course of standard-dose chemotherapy; To achieve or consolidate CR for those in a chemosensitive first or subsequent relapse, whether or not their lymphoma has undergone transformation to a high grade. Cross-references MP Cord Blood as a Source for Stem Cells MP Organ and Tissue Transplantation Services IV. EXCLUSIONS High dose chemotherapy with either autologous or allogeneic stem cell support is considered investigational: As initial therapy (i.e., without a full course of standard-dose induction chemotherapy) of all non-hodgkin s lymphomas; To consolidate a first complete remission (CR) for patients with NHL subtypes that the IWF scheme classified as intermediate or aggressive (high) and IPI scores that predict a low- or low-intermediate risk of relapse; and To consolidate a first CR for patients with NHL subtypes that the IWF scheme classified as indolent (low) or new subtypes defined by the WHO/REAL scheme. Tandem transplants are considered investigational to treat patients with any stage, grade or sub-type of NHL. High-dose chemotherapy with allogeneic stem-cell support is considered investigational to treat NHL that progresses or relapses relatively soon after a prior course of high-dose chemotherapy with autologous stem-cell support. These indications are investigational, as there is insufficient evidence to support a conclusion concerning the health outcomes or benefits associated with these indications. Page 4

5 Benefits are not provided for the purchase price of stem cells that are sold, rather than donated, to the recipient. V. BENEFIT VARIATIONS The existence of this medical policy does not mean that this service is a covered benefit under the member's contract. Benefit determinations should be based in all cases on the applicable contract language. Medical policies do not constitute a description of benefits. A member s individual or group customer benefits govern which services are covered, which are excluded, and which are subject to benefit limits and which require preauthorization. Members and providers should consult the member s benefit information or contact Capital for benefit information. VI. DISCLAIMER Capital s medical policies are developed to assist in administering a member s benefits, do not constitute medical advice and are subject to change. Treating providers are solely responsible for medical advice and treatment of members. Members should discuss any medical policy related to their coverage or condition with their provider and consult their benefit information to determine if the service is covered. If there is a discrepancy between this medical policy and a member s benefit information, the benefit information will govern. Capital considers the information contained in this medical policy to be proprietary and it may only be disseminated as permitted by law. VII. REFERENCES Apostolidis J, Foran JM, Johnson PW, et al. Patterns of outcome following recurrence after myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma. J Clin Oncol 1999; 17(1): Ballestrero A, Clavio M, Ferrando F, et al. High-dose chemotherapy with tandem autologous transplantation as part of the initial therapy for aggressive non-hodgkin s lymphoma. Int J Oncol 2000; 17(5): BCBSA 1987 TEC Evaluations, p. 61. BCBSA 1990 TEC Evaluations, p BCBSA 1995 TEC Assessments, Tab 28. BCBSA TEC Assessment Salvage HDC/AlloSCS for Relapse or Incomplete Remission Following HDC/AuSCS for Hematologic Malignancies. Volume 15, No. 9. Page 5

6 Ballestrero A, Clavio M, Ferrando F, et al. High-dose chemotherapy with tandem autologous transplantation as part of the initial therapy for aggressive non-hodgkin s lymphoma. Int J Oncol 2000; 17(5): Berglund A, Enblad G, Carlson K, et al. Long-term follow-up of autologous stem-cell transplantation for follicular and transformed follicular lymphoma. Eur J Haematol 2000; 65(1): Bierman PJ, Sweetenham JW, Loberiza FR, et al. Syngeneic hematopoietic stem-cell transplantation for non-hodgkin s Lymphoma: A comparison with allogeneic and autologous transplantation The Lymphoma Working Committee of the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation. Journal of Clinical Oncology 2003; 15(20): Bierman PJ, Vose JM, Anderson JR, et al. High-dose therapy with autologous hematopoietic rescue for follicular low-grade non-hodgkin's lymphoma. J Clin Oncol 1997; 15(2): Blay JY, Philip TO. High-dose chemotherapy in non-hodgkin s lymphoma. Cancer Treat Res 1996; 85: Blystad AK, Enblad G, Kvaloy S, et al. High-dose therapy with autologous stem cell transplantation in patients with peripheral T-cell lymphomas. Bone Marrow Transplant 2001; 27(7): Bolwell B, Kalaycio M, Andresen S, et al. Autologous peripheral blood progenitor cell transplantation for transformed diffuse large-cell lymphoma. Clin Lymphoma 2000; 1(3):226-31; discussion Brandt L, Kimby E, Nygren P, et al. A systematic overview of chemotherapy effects in indolent non-hodgkin s lymphoma. Acta Oncol 2001; 40 (2-3): Centers for Medicare and Medicaid Services (CMS) National Coverage Determination (NCD) , Stem Cell Transplantation. CMS [Website]: cd%3a110%2e8%2e1%3a4%3astem+cell+transplantation. Accessed January 22, Chen CI, Crump M, Tsang R, et al. Autotransplants for histologically transformed follicular non-hodgkin s lymphoma. Br J Haematol 2001; 113 (1): Decaudin D, Brousse N, Brice, P et al. Efficacy of autologous stem cell transplantation in mantle cell lymphoma: a 3-year follow-up study. Bone Marrow Transplant 2000; 25(3): Deconinck E, Foussard C, Milpied N, et al. High dose therapy followed by autologous purged stem cell transplantation and doxorubicin based chemotherapy in patients with Page 6

7 advanced follicular lymphoma: a randomized multicenter study by GOELAMS. Blood 2005; 105: Dreyling M, Hoster E, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression free survival in mantle cell lymphoma: Results of a prospective randomized trial of the European MCL network. Blood 2005; 105: Fisher RI. Autologous bone marrow transplantation for aggressive non-hodgkin s lymphoma: lessons learned and challenges remaining. J Natl Cancer Inst 2001; 93 (1): 4-5. Fisher RI. Autologous stem-cell transplantation as a component of initial treatment for poor-risk patients with aggressive non-hodgkin s lymphoma: resolved issues versus remaining opportunity. J Clin Oncol 2002; 20 (22): Foran JM, Apostolidis J, Papamichael D, et al. High-dose therapy with autologous haematopoietic support in patients with transformed follicular lymphoma: a study of 27 patients from a single centre. Ann Oncol 1998; 9(8): FreedmanAS, Gribben JG, Nadler LM. High dose therapy and autologous stem cell transplantation in follicular non-hodgkin's lymphoma. Leuk Lymphoma 1998; 28(3-4): Friedberg JW, Neuberg D, Gribben JG, et al. Autologous bone marrow transplantation after histologic transformation of indolent B cell malignancies. Biol Blood Marrow Transplant 1999; 5(4): Hahn T, Wolff SN, Czuczman M, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of diffuse large cell B-cell non Hodgkin s lymphoma: an evidence-based review. Biol Blood Marrow Transplant 2001; 7 (6): Haioun C, Mounier N, Quesnel B, et al. Tandem autotransplants as first-line consolidative treatment in poor-risk aggressive lymphoma: a pilot study of 36 patients. Ann Oncol 2001; 12 (12): Haioun C, Lepage E, Gissilbrecht C, et al. Survival benefit of high-dose therapy in poorrisk aggressive non-hodgkin s Lymphoma: Final analysis of the prospective LHN87-2 Protocol A Groupe d Etude des Lymphomes de l Adulte Study. Journal of Clinical Oncology 2000; 18(16): Haioun C, Lepage E, Gisselbrecht C, et al. Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-hodgkin's lymphoma: updated results of the prospective study LNH87-2. Groupe d'etude des Lymphomes de l'adulte. J Clin Oncol 1997; 15(3): Page 7

8 Kaiser U, Uebelacker I, Abel U, et al. Randomized study to evaluate the use of high-dose therapy as part of primary treatment for aggressive lymphoma. Journal of Clinical Oncology 2002; 20(22): Kimby E, Brandt L, Nygren P, et al. A systematic overview of chemotherapy effects in aggressive non-hodgkin s lymphoma. Acta Oncol 2001; 40 (2-3): Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, et al. Standard chemotherapy with or without high-dose chemotherapy for aggressive non-hodgkin s lymphoma: randomized phase III EORTC study. J Natl Cancer Inst 2001; 93 (1): (also see comment, pp 4-5). Lenz G, Dreyling M, Schiegnitz R, et al. Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low Grade Lymphoma Study Group. Blood 2004; 104: Martinez C, Carreras E, Rovira M, et al. Patients with mantle-cell lymphoma relapsing after autologous stem cell transplantation may be rescued by allogeneic transplantation. Bone Marrow Transplant 2000; 26(6): Morrison VA, Peterson BA. High-dose therapy and transplantation in non-hodgkin's lymphoma. Semin Oncol 1999; 26(1): Mosby s Medical, Nursing, & Allied Health Dictionary, 6 th edition. Mounier N, Haioun C, Cole BF, et al. Quality of life-adjusted survival analysis of highdose therapy with autologous bone marrow transplantation versus sequential chemotherapy for patients with aggressive lymphoma in first complete remission. Groupe d'etude les Lymphomes de l'adulte (GELA). Blood 2000; 95(12): Nademanee A, Forman SJ. Role of hematopoietic stem cell transplantation for advancedstage diffuse large cell B-cell lymphoma-b. Semin Hematol 2006; 43(4): National Comprehensive Cancer Network. Non-Hodgkin s Lymphoma. V [Website]: Accessed January 22, Pan D, Qin J, Farber C, et al. CHOP with high dose cyclophosphamide consolidation versus CHOP alone as initial therapy for advanced stage, indolent non-hodgkin s lymphoma. Leuk Lymphoma 2003; 44 (6): Papadopoulos KP, Noguera-Irizarry W, Hesdorffer CS. Tandem transplantation in lymphoma. Bone Marrow Transplant 2001; 28 (6): Philip T, Biron P. High-dose chemotherapy and autologous bone marrow transplantation in diffuse intermediate- and high-grade non-hodgkin s lymphoma. Crit Rev Oncol Hematol 2002; 41 (2): Page 8

9 Rodriquez J, Munsell M, Yazji S, et al. Impact of high-dose chemotherapy on peripheral T- cell lymphomas. J Clin Oncol 2001; 19 (17): Sweetenham JW, Santini G, Qian W, et al. High-dose therapy and autologous stem-cell transplantation versus conventional-dose consolidation/maintenance therapy as postremission therapy for adult patients with lymphoblastic lymphoma: Results of a randomized trial of the European Group for Blood and Marrow Transplantation and the United Kingdom Lymphoma Group. Journal of Clinical Oncology 2001; 19(11): Sweetenham JW. Stem cell transplantation for mantle cell lymphoma: should it ever be used outside clinical trials? Bone Marrow Transplant 2001; 28 (9): Taber s Cyclopedic Medical Dictionary, 19 th edition. The Non-Hodgkin s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-hodgkin s lymphoma. Blood 1997; 89(11): Van Besien K. The evolving role of autologous and allogeneic stem cell transplantation in follicular lymphoma. Blood Rev 2006; 20(5): Villanueva ML, Vose JM. The role of hematopoietic stem cell transplantation in non- Hodgkin lymphoma. Clin Adv Hematol Oncol 2006; 4(7): Vose JM, Bierman PJ, Lynch JC, et al. Effect of follicularity on autologous transplantation for large-cell non-hodgkin's lymphoma. J Clin Oncol 1998; 16(3): Vose JM, Bierman PJ, Weisenberger DD, et al. Autologous hematopoietic stem cell transplantation for mantle cell lymphoma. Biol Blood Marrow Transplant 2000; 6(6): Weigert O, Dreyling M, Unterhalt M, et al. Investigational strategies in autologous stem cell transplantation for follicular lymphoma. Curr Oncol Rep 2006; 895): Williams CD, Taghipour G, Lister TA, et al. Chemosensitive transformed follicular non- Hodgkin s lymphoma (NHL) is a firm indication for high-dose therapy and autologous stem cell transplantation. Blood 1996; 87(suppl 1): 685a. Williams CD, Harrison CN, Lister TA, et al. High-dose therapy and autologous stem-cell support for chemosensitive transformed low-grade follicular non-hodgkin s lymphoma: a case-matched study from the European Bone Marrow Transplant Registry. J Clin Onco l2001; 19 (3): VIII. PRODUCT VARIATIONS [N] = No product variation, policy applies as stated [Y] = Standard product coverage varies from application of this policy, see below Page 9

10 [N] CHIP POS [N] PPO [N] HMO [N] CHIP HMO [Y] SeniorBlue* [Y] SeniorBlue PPO* [N] Indemnity [N] SpecialCare [N] POS [N] FEP HMO [N] FEP PPO *Refer to Centers for Medicare and Medicaid Services (CMS) National Coverage Determination (NCD) , Stem Cell Transplantation. IX. POLICY HISTORY MP CAC 1/27/04 CAC 5/31/05 CAC 3/28/06 CAC 4/24/07 Policy approved for retirement effective 7/1/2009. Information added into policy as of 7/1/2009. Effective 10/1/ was retired. Refer to new policy: Health care benefit programs issued or administered by Capital BlueCross and/or its subsidiaries, Capital Advantage Insurance Company and Keystone Health Plan Central. Independent licensees of the Blue Cross and Blue Shield Association. Communications issued by Capital BlueCross in its capacity as administrator of programs and provider relations for all companies. Page 10