DESCRIPTION/BACKGROUND

Original Issue Date (Created): August 23, 2004 Most Recent Review Date (Revised): Effective Date: October 21, 2008 July 1, 2009- RETIRED I. DESCRIPTION/BACKGROUND Hematopoietic Stem-Cell Transplantation Hematopoietic stem-cell transplantation (SCT) refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone-marrow-toxic doses of cytotoxic drugs, with or without whole-body radiation therapy. Bone-marrow stem cells may be obtained from the transplant recipient (i.e., autologous SCT) or from a donor (i.e., allogeneic SCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood and placenta shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically naïve and thus are associated with a lower incidence of rejection or graftversus-host disease (GVHD). Immunologic incompatibility between infused stem cells and the recipient is not an issue in autologous SCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic SCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. Reduced-Intensity Conditioning for Allogeneic SCT Reduced-intensity conditioning (RIC) refers to chemotherapy regimens that seek to reduce adverse effects secondary to bone marrow toxicity, while retaining the beneficial graftversus-malignancy effect of allogeneic transplantation. These regimens do not eradicate the patient s hematopoietic ability, thereby allowing for relatively prompt hematopoietic recovery (e.g., 28 days or less) even without a transplant. Patients who undergo RIC with allogeneic SCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism, which may be supplemented with donor lymphocyte infusions to eradicate residual malignant cells. A number of different cytotoxic regimens, with or without radiotherapy, may be used for RIC Page 1

allotransplantation. They represent a continuum in their effects, from nearly totally myeloablative, to minimally myeloablative with lymphoablation. Acute Lymphocytic Leukemia (ALL) ALL occurs in multiple forms that vary with regard to cellular morphology, cytochemistry, immunophenotype, cytogenetic abnormalities, and other prognostic features. Although adult and childhood forms of ALL vary in the distribution of these prognostic features, there is considerable overlap, particularly among late adolescents and young adults. Consequently, no clear age demarcation divides the adult and childhood forms. However, in general, adult ALL is characterized by a predominance of immature and pleomorphic cells, more frequent co-expression of myeloid markers, a greater percentage of leukemias derived from T-cells rather than B-cells, and a higher incidence of cytogenetic abnormalities with negative prognostic implications (such as the Philadelphia chromosome). In contrast, childhood ALL cells usually have a more mature morphology, and infrequently are of T-cell origin or positive for myeloid markers or the Philadelphia chromosome. As a consequence of these differences, the adult and childhood forms of ALL respond differently to treatment and vary in their risk for relapse once remission is achieved. For example, childhood ALL is a highly curable disease, with long-term survival rates ranging from sixty to eighty-five percent (60-85%). Similar therapy regimens have had less favorable outcomes in adult ALL. Approximately sixty five to ninety percent (65-90%) of those with adult ALL achieve an initial complete remission, but only twenty to thirty percent (20-30%) are long-term survivors. II. DEFINITIONS ALLOGENEIC refers to having a different genetic constitution but belonging to the same species, i.e., involves a donor and a recipient. AUTOLOGOUS refers to originating within an individual, i.e., self-donation. CYTOTOXIC AGENT is any pharmacologic compound that inhibits the proliferation of cells within the body. GRAFT- VERSUS-HOST DISEASE refers to immunological injury suffered by an immunosuppressed recipient of a bone marrow transplant. The donated lymphoid cells (the graft ) attack the recipient (the host ), causing damage to the skin, liver, and gastrointestinal tract. Page 2

HEMATOPOIETIC pertains to or effecting the production and development of blood cells. PLEOMORPHIC refers to having many shapes. RADIOTHERAPY is the treatment of disease with ionizing or nonionizing radiation. III. POLICY Children Allogeneic or autologous hematopoietic stem- cell support (SCT) after ablative or subablative chemotherapy or radiation may be considered medically necessary to treat childhood ALL in first complete remission but at high risk of relapse. (For definition of high-risk factors, see below.) Autologous or allogeneic hematopoietic SCT after ablative or subablative chemotherapy or radiation may be considered medically necessary to treat childhood ALL in second or greater remission or refractory ALL. Adults Allogeneic or autologous hematopoietic SCT after ablative or subablative chemotherapy or radiation may be considered medically necessary to treat adult ALL in first complete remission but at high risk of relapse. (For definition of high-risk factors, see below.) Allogeneic hematopoietic stem cell support after ablative or subablative chemotherapy or radiation may be considered medically necessary to treat adult ALL in second or greater remissions, or in patients with relapsed or refractory ALL. Risk factors associated with a high risk of relapse following initial complete remission include: Age greater than 15 years Leukocyte count greater than 10 X 10 (9)/ L Extramedullary disease, particularly in the CNS Chromosomal abnormalities, including Philadelphia chromosome Failure to achieve a complete remission within 6 weeks after induction therapy begins IV. EXCLUSIONS Allogeneic hematopoietic SCT is considered investigational to treat relapsing ALL in adults and children after a prior autologous SCT Page 3

Autologous hematopoietic stem cell support is investigational to treat adult ALL in second or greater remission or those with refractory disease. Reduced-intensity conditioning (RIC) allogeneic SCT is considered investigational as a treatment of ALL in those who do not qualify for a myeloablative SCT. In all the above situations, these services are considered investigational, as there is insufficient evidence to support a conclusion concerning the health outcomes or benefits associated with this procedure. 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 American Society for Blood and Marrow Transplantation Executive Committee. ASBMT position statement: the role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of acute lymphoblastic leukemia in children. Biol Blood Marrow Transplant. 2006 Mar;12(3):370-1. American Society for Blood and Marrow Transplantation Executive Committee. ASBMT position statement: the role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of acute lymphoblastic leukemia in adults. Biol Blood Marrow Transplant. 2006 Mar; 12(3): 368-9. Page 4

Attal M, Blaise D, Marit G et al. Consolidation treatment of adult acute lymphoblastic leukemia: a prospective, randomized trial comparing allogeneic versus autologous bone marrow transplantation and testing the impact of recombinant interleukin- 2 after autologous bone marrow transplantation. BGMT Group. Blood 1995; 86(4): 1619-28. BCBSA 1990 TEC Assessments; page 254. BCBSA 1997 TEC Assessments; Tab 25. BCBSA 2000 TEC Assessments; Tab 9. Blaise D, Attal M, Reiffers J et al. Randomized study of recombinant interleukin-2 after autologous bone marrow transplantation for acute leukemia in first complete remission. Eur Cytokine Netw 2000; 11(1):91-8. Blaise D, Kuentz M, Fortanier C et al. Randomized trial of bone marrow versus lenograstim-primed blood cell allogeneic transplantation in patients with early stage leukemia: a report from the Société Française de Greffe de Moelle. J Clin Oncol 2000; 18(3): 537-46. Centers for Medicare and Medicaid Services (CMS) National Coverage Determination (NCD) 110.8.1 Stem Cell Transplantation. Effective 01/03/06. CMS [Website]: http://www.cms.hhs.gov/mcd/viewncd.asp?ncd_id=110.8.1&ncd_version=4&basket=n cd%3a110%2e8%2e1%3a4%3astem+cell+transplantation Accessed July 2, 2008. Champlin RE, Schmitz N, Horowitz MM et al. Blood stem cells compared to bone marrow as a source of hematopoietic cells for allogeneic transplantation. Blood 2000; 95(12): 3702-9. Dombret H, Gabert J, Boiron JM et al. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia-results of the prospective multicenter LALA-94 trial. Blood 2002; 100(7): 2357-66. Gaynon PS, Trigg ME, Heerema NA et al. Children s Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995. Leukemia 2000; 14(12): 2223-33. Goldstone AH, Lazarus HJ, Richards SM et al. The outcome of 551 1st CR transplants in adult ALL from the UKALL XII/ECOG 2993 study [abstract]. Blood 2004; 104:178a. Gutierrez-Aguirre CH, Gomez-Almaguer D, Cantu-Rodriguez OG et al. Nonmyeloablative stem cell transplantation in patients with relapsed acute lymphoblastic leukemia: results of a multicenter study. Bone Marrow Transplant 2007; 40(6): 535-9. Hahn T, Wall D, Camitta B, Davies S et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia Page 5

in adults: an evidence-based review. Biol Blood Marrow Transplant. 2006 Jan;12(1):1-30. Hahn T, Wall D, Camitta B, et al. The Role of Cytotoxic Therapy with Hematopoietic Stem Cell Transplantation in the Therapy of Acute Lymphoblastic Leukemia in Children: An Evidence-Based Review. Biol Blood Marrow Transplant. 2005 Nov; 11(11): 823-61. Hallbook H, Hagglund H, Stockelberg D et al. Swedish Adult ALL Group. Autologous and allogeneic stem cell transplantation in adult ALL: the Swedish Adult ALL Group experience. Bone Marrow Transplant. 2005 Jun; 35(12): 1141-8. Harrison G, Richards S, Lawson S et al. Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. Ann Oncol 2000; 11(8): 999-1006. Hunault M, Harousseau JL, Delain M et al. Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: a GOELAMS trial. Blood 2004; 104(10): 3028-37. Lawson SE, Harrison G, Richards S et al. The UK experience in treating relapsed childhood acute lymphoblastic leukaeima: a report on the Medical Research Council UK ALLR1 study. Br J Haematol 2000; 108(3): 531-43. Mohty M, Labopin M, Tabrizzi R et al. Reduced intensity conditioning allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation. Haematologica 2008; 93(2): 303-6. Mosby s Medical, Nursing, and Allied Health Dictionary, 6th edition. National Cancer Institute. Adult Acute Lymphoblastic Leukemia (PDQ ): Treatment.Updated05/16/08. [Website]: http://www.cancer.gov/cancertopics/pdq/treatment/adultall/healthprofessional/allpag es. Accessed July 2, 2008. National Cancer Institute. Childhood Acute Lymphoblastic Leukemia (PDQ ): Treatment. Last modified05/30/08. [Website]: http://www.cancer.gov/cancertopics/pdq/treatment/childall/healthprofessional/allpag es. Accessed July 2, 2008. Oyekunle AA, Kroger N, Zabelina T et al. Allogeneic stem-cell transplantation in patients with refractory acute leukemia: a long-term follow-up. Bone Marrow Transplant. 2006 Jan; 37(1): 45-50. Page 6

Ribera JM, Ortega JJ, Oriol A et al. Comparison of intensive chemotherapy, allogeneic, or autologous stem-cell transplantation as postremission treatment for children with very high risk acute lymphoblastic leukemia: PETHEMA ALL-93 trial. J Clin Oncol 2007; 25(1); 16-24. Ribera JM, Oriol A, Bethencourt C et al. Comparison of intensive chemotherapy, allogeneic or autologous stem cell transplantation as post-remission treatment for adult patients with high-risk acute lymphoblastic leukemia. Results of the PETHEMA ALL-93 trial. Haematologica 2005; 90(10): 1346-56. Taber s Cyclopedic Medical Dictionary, 19th edition. Uderzo C, Dini G, Locatelli F et al. Treatment of childhood acute lymphoblastic leukemia after the first relapse: curative strategies. Haematologica 2000; 85(11 suppl):47-53. Uderzo C. Indications and role of allogeneic bone marrow transplantation in childhood very high risk acute lymphoblastic leukemia in first complete remission. Haematologica 2000; 85(11 suppl):9-11. Vitale, Antonella; Guarini, Anna; Chiaretti, Sabina; Foa, Robin The changing scene of adult acute lymphoblastic leukemia. Current Opinion in Oncology. 18(6):652-659, November 2006. Wheeler KA, Richards SM, Bailey CC et al. Bone marrow transplantation versus chemotherapy in the treatment of very high-risk childhood acute lymphoblastic leukemia in first remission: results from Medical Research Council UKALL X and XI. Blood 2000; 96(7): 2412-8. Yanada M, Matsuo K, Suzuki T, Naoe T. Allogeneic hematopoietic stem cell transplantation as part of postremission therapy improves survival for adult patients with high-risk acute lymphoblastic leukemia: a metaanalysis. Cancer. 2006 Jun 15; 106(12): 2657-63. 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 7

VIII. PRODUCT VARIATIONS [N] = No product variation, policy applies as stated [Y] = Standard product coverage varies from application of this policy, see below [N] CHIP POS [N] PPO [N] HMO [N] CHIP HMO [Y] SeniorBlue* [Y] SeniorBlue PPO* [N] Indemnity [N] SpecialCare [N] POS [Y] FEP HMO** [Y] FEP PPO** * Refer to Centers for Medicare and Medicaid (CMS) National Coverage Determination (NCD) 110.8.1. Stem Cell Transplantation, ** The Federal Employee Program (FEP) may include specific conditions in which autologous bone marrow transplantation may be considered eligible for coverage. IX. CODING INFORMATION Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The identification of a code in this section does not denote coverage as coverage is determined by the terms of member benefit information. In addition, not all covered services are eligible for separate reimbursement. 38204 38205 38206 38207 38208 38209 38210 38211 38212 38213 38214 38215 38220 38221 38230 38240 38241 38242 86812 86813 86816 86817 86821 86822 G0265 G0266 G0267 Q0083 Q0084 Q0085 S2140 S2142 S2150 Page 8

X. POLICY HISTORY MP 9.034 CAC 3/25/03 CAC 7/27/04 CAC 7/26/05 CAC 6/27/06 CAC 11/28/06 CAC 11/27/07 CAC 9/30/08 Policy approved for retirement effective 7/1/2009. Information added into policy 9.037 as of 7/1/2009. Effective 10/1/14-9.037 was retired. Refer to new policy: 9.041. Page 9