Clinical Policy Title: Bone marrow transplants for cancer (other than breast cancer)

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1 Clinical Policy Title: Bone marrow transplants for cancer (other than breast cancer) Clinical Policy Number: Effective Date: January 1, 2016 Initial Review Date: November 18, 2015 Most Recent Review Date: February Next Review Date: February 2019 Related policies: CP# CP# Stem cell transplant for autoimmune disease Stem cell transplant for breast cancer Policy contains: Bone marrow transplant. Hematopoietic stem cell transplant. Autologous bone marrow transplant. Allogeneic bone marrow transplant. ABOUT THIS POLICY: Prestige Health Choice has developed clinical policies to assist with making coverage determinations. Prestige Health Choice s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by Prestige Health Choice when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Prestige Health Choice s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. Prestige Health Choice s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, Prestige Health Choice will update its clinical policies as necessary. Prestige Health Choice s clinical policies are not guarantees of payment. Coverage policy Prestige Health Choice considers the use of bone marrow transplants and stem cell transplants to be clinically proven and, therefore, medically necessary for the following cancers: 1. Autologous bone marrow transplants are considered necessary for the following diagnoses: a. Non-Hodgkin s lymphoma, stage III or IV. Hodgkin's disease (lymphoma), stage III or IV. b. Neuroblastoma, stage III or IV. c. Acute lymphocytic or non-lymphocytic leukemia and first or subsequent remission. 2. Allogeneic bone marrow transplants are considered necessary for the following diagnoses: a. Non-Hodgkin s lymphoma, stage III or IV. b. Hodgkin's disease (lymphoma), stage III or IV. 1

2 c. Neuroblastoma, stage III or IV. d. Chronic myelogenous leukemia in blast crisis or chronic phase. e. Acute lymphocytic or non-lymphocytic leukemia, acute myelocytic leukemia, in first or subsequent remission, but at high risk for relapse. f. Amylodoisis, stages I and II. g. Multiple myeloma. h. Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes syndrome. 3. Allogeneic bone marrow transplants for non-malignancies are considered necessary for the following diagnoses: a. Severe aplastic anemia. b. Homozygous beta-thalassanemia. c. Wiskott-Aldrich syndrome. d. Severe combined immunodeficiencies. e. Infantile malignant osteopetrosis. f. Mucopolysaccharidoses. g. Mucolipidoses. h. Myelodysplastic syndrome. i. Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes syndrome (NCCN, 2013). Limitations: Coverage determinations are subject to benefit limitations and exclusions as delineated by the state Medicaid authority. The Florida Medicaid website may be accessed at Prestige Health Choice considers all other uses of bone marrow and stem cell transplants to be investigational and, therefore, not medically necessary. 1. An autologous or allogeneic (ablative and non-myeloablative [mini-transplant]) hematopoietic stem cell transplantation, single or planned tandem, is considered investigational and not medically necessary as a treatment of autoimmune diseases, including, but not limited to: a. Juvenile idiopathic arthritis. b. Rheumatoid arthritis. c. Multiple sclerosis. d. Systemic lupus erythematosus. e. Systemic sclerosis (scleroderma). 2. An autologous or allogeneic (ablative and non-myeloablative [mini-transplant]) hematopoietic stem cell transplantation, single or planned tandem, is considered investigational and not medically necessary as a treatment for the following diseases and conditions: 2

3 a. Epithelial ovarian cancer. b. Breast cancer. c. Malignant astrocytomas and gliomas, including both glioblastoma multiforme, and oligodendroglioma. d. Adult miscellaneous solid tumors, including, but not limited to: Cancer of the bile duct. Cancer of the fallopian tubes. Cervical cancer. Colon cancer. Esophageal cancer. Gallbladder cancer. Lung cancer, any histology. Malignant melanoma. Nasopharyngeal cancer. Neuroendocrine tumors. Pancreas cancer. Paranasal sinus cancer. Prostate cancer. Rectal cancer. Renal cell cancer. Soft tissue sarcoma. Stomach cancer. Thyroid tumors. Tumors of the thymus. Uterine cancer. Undifferentiated tumors and tumors of unknown primary origin. 3. Required documentation for members: a. Medical records, physical exam, medical and family history. b. History of current medication. c. Active smoking, alcohol and drug abuse. d. Summary of the course of illness. e. Laboratory assessments, including serologies. f. Psychosocial concerns. g. All other information requested by the plan. Alternative covered services: Maximum medical management by treating physician to determine the best health decision for the member s individual needs. 3

4 Note: See Appendix A and B for National Comprehensive Cancer Network Categories of Evidence and Consensus for additional resources. Background Bone marrow and stem cell transplant Blood cells, along with skin cells, have the greatest powers of self-renewal of any adult tissue. They are responsible for the constant maintenance and immune protection of every cell type in the body. This relentless and brutal work requires that blood cells, along with skin cells, have the greatest powers of self-renewal of any adult tissue. The stem cells that form blood and immune cells are known as hematopoietic stem cells. They are ultimately responsible for the constant renewal of blood, which involves the production of billions of new blood cells each day. Physicians and basic researchers have known and capitalized on this fact for more than 50 years in treating many diseases. The first evidence and definition of blood-forming stem cells came from studies of people exposed to lethal doses of radiation in A bone marrow transplant, also called stem cell transplant, is a procedure that replaces damaged or destroyed bone marrow with healthy bone marrow stem cells. Bone marrow is the soft, fatty tissue inside the bones. Stem cells are immature cells in the bone marrow that give rise to all blood cells. There are three basic kinds of bone marrow transplants: Autologous bone marrow transplant: The term auto means self. Stem cells are removed from a patient before receiving high-dose chemotherapy or radiation treatment. The stem cells are stored in a freezer (cryopreservation). After high-dose chemotherapy or radiation treatments, stem cells are put back in the body to regenerate normal blood cells. This is called a rescue transplant. Allogeneic bone marrow transplant: The term allo means other. Stem cells are removed from another person, called a donor. Most times, the donor's genes must at least partly match the member s genes. Special blood tests are done to see if a donor is a good match for the member. A brother or sister is most likely to be a good match. Sometimes parents, children and other relatives are good matches. Donors who are not related to members may be found through national bone marrow registries. Syngeneic stem cell transplant: This is a special kind of allogenic transplant that can only be used when the recipient has an identical sibling (twin or triplet) who can donate someone who has the same tissue type. An advantage of syngeneic stem cell transplant is that graft-versus-host disease will not be a problem. No cancer cells should be in a transplant, either, as there would be no cancer cells in an autologous transplant. 4

5 Some people may have a stem cell transplant using stem cells from umbilical cord blood. There are cord blood banks that store blood taken from the umbilical cord. After the baby is born and the umbilical cord has been cut, a doctor takes blood from the umbilical cord and placenta. The blood bank may then give the donated stem cells to a person whose blood cells closely match the donated cells. These transplants are mostly used for children because of the lower volume of cells collected. It may be possible for adults to have a hematopoietic stem cell transplant from two different umbilical cords (double-cord transplant). Hematopoietic stem cell transplant 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 transplant) or from a donor (i.e., allogeneic transplant). 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 graft-versus-host disease. Sources of hematopoietic stem cellss Bone marrow: The classic source of hematopoietic stem cellss is bone marrow. For more than 40 years, doctors performed bone marrow transplants by anesthetizing the stem cell donor, puncturing a bone typically a hipbone and drawing out the bone marrow cells with a syringe. About one in every 100,000 cells in the marrow is a long-term, blood-forming stem cell; other cells present include stromal cells, stromal stem cells, blood progenitor cells and mature and maturing white and red blood cells. Peripheral blood: As a source of hematopoietic stem cells for medical treatments, bone marrow retrieval directly from bone is quickly fading into history. For clinical transplantation of human hematopoietic stem cells, doctors now prefer to harvest donor cells from peripheral, circulating blood. It has been known for decades that a small number of stem and progenitor cells circulate in the bloodstream, but in the last 10 years, researchers have found they can coax the cells to migrate from marrow to blood in greater numbers by injecting the donor with a cytokine, such as granulocyte colony-stimulating factor. Donor stem cells can be collected in two ways: Bone marrow harvest: This minor surgery is done under general anesthesia. This means the donor will be asleep and pain-free during the procedure. The bone marrow is removed from the back of both hip bones. The amount of marrow removed depends on the weight of the person who is receiving it. 5

6 Leukapheresis: First, the donor is given five days of shots to help stem cells move from the bone marrow into the blood. During leukapheresis, blood is removed from the donor through an intravenous line in a vein. The part of white blood cells that contains stem cells is then separated in a machine, removed, and later given to the recipient. The red blood cells are returned to the donor. Autoimmune diseases The use of high-dose chemotherapy with autologous stem cell transplantation has demonstrated improved outcomes for specific oncologic indications, such as leukemia and lymphoma. Based on the experiences in these historic applications, the use of autologous and allogeneic stem cell transplantations continues to be studied in other oncologic and non-oncologic indications, such as autoimmune diseases and miscellaneous solid tumors. However, in a position statement from an international workshop on the feasibility of allogeneic hematopoietic stem cell transplantation for autoimmune diseases, sponsored by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, the authors concluded, "Although safer allogeneic transplantation strategies have become available, experience is currently insufficient to allow reliable extrapolation of data on safety and risks from patients with malignancies to patients with autoimmune diseases" (Griffith, 2005). Hematopoietic stem cells collected from peripheral blood stem cells have been successfully used for transplantation. Originally, these cells, collected from patients with chronic myelogenous leukemia, were used to restore the chronic phase of the disease. More recently, peripheral blood stem cells have been used principally for autologous transplantation for non-hematologic malignancies, although there are a few recorded cases of allogeneic transplantation with peripheral blood stem cells. The process of obtaining peripheral blood stem cells is tedious compared to the process of harvesting bone marrow for transplantation, which requires multiple lengthy apheresis procedures to collect sufficient cells for transplant. Moreover, the risks associated with peripheral blood stem cell collection (anesthesia risk for catheter placement, risk of introducing infection during collection) are just as great as those associated with marrow harvesting. However, for the patient whose bone marrow is unharvestable due to hypocellularity or fibrosis, peripheral blood stem cell transplantation may reopen the option of treatment by high-dose cytotoxic therapy and autologous hematopoietic stem cell rescue. Peripheral blood stem cell transplantation may also afford the transplant option to the patient whose marrow has been infiltrated with disease. While it has not been demonstrated, it is hypothetically likely that the probability of tumor cell contamination of circulating blood is quite low due to the lack of adherence necessary for colonization. Recent reports have indicated that autologous transplantation with peripheral blood stem cells may result in more rapid engraftment, relative to autologous transplantation with bone marrow. This has only been reported in programs wherein peripheral blood stem cells are collected under mobilizing conditions. If it is the case that peripheral blood stem cells produce more rapid engraftment, however, then the additional effort and cost associated with peripheral blood stem cell collection might be outweighed by 6

7 the reduced morbidity, mortality and cost associated with the early return of granulocytes in the transplant patient. The biology of the early engraftment phenomenon should be studied because it might relate to the mobilizing conditions under which the cells are collected and not be due to an intrinsic quality of peripheral blood stem cells (Janssen, 1993). Stem cell transplant for multiple myeloma The patient receives high-dose chemotherapy sometimes with full-body radiation to the whole body to kill the cells in the bone marrow, including the myeloma cells. The patient then receives new, healthy blood-forming stem cells. When stem cell transplants were first developed, the new stem cells came from bone marrow. This procedure came to be known as a bone marrow transplant. Now, stem cells are more often gathered from the blood (a peripheral blood stem cell transplant). Stem cell transplants are commonly used to treat multiple myeloma. Before the transplant, drug treatment is used to reduce the number of myeloma cells in the patient s body (MedlinePlus, 2017). The National Comprehensive Cancer Network has issued detailed guidelines on which types of neoplasms are indicated for bone marrow transplants. Appendices A and B list whether the network considers such a procedure (NCCN, 2013). The categories for recommending whether procedures are necessary include S (standard of care), C (standard of care, clinical evaluation available), N (not generally recommended), D (developmental promising, best used in a clinical trial) and R (standard of care, intervention recommended). Numeorus other guidelines are available for bone marrow transplants, typically for specific types of cancer. Searches Prestige Health Choice searched PubMed and the databases of: UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality s National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). We conducted searches on December 11, Search terms were bone marrow transplant, bone marrow transplantation, HSCs, stem cell transplantation, and the free text term transplants. We included: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. 7

8 Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings Numerous articles on bone marrow transplants for malignancies, among them many systematic reviews and meta-analyses, have been published in the peer-reviewed medical literature. By far, the largest number of these publications address leukemia and multiple myeloma. Transplants have become the standard of care in patients younger than age 65, and estimated 10-year survival is 39 percent (Radocha, 2013). A substantial number of reviews address efficacy of various forms of chemotherapy that often follows transplantation. Below are summaries of large reviews for the two most-studied cancers, namely multiple myeloma and leukemia. Multiple myeloma: 1. In a study of 560 patients with high-dose therapy and autotransplant for non-hodgkin s lymphoma, Hodgkin s lymphoma, multiple myeloma, germ-cell tumors and acute leukemias, only two cases of graft failure occurred (Wannesson, 2007). 2. A systematic review of 11 studies of allogenic stem cell transplantation for patients with highrisk multiple myeloma who had relapsed after autologous transplantations showed a median progression-free survival from 5.2 to 36.8 months and an overall survival of 13.0 to 63.0 months (Oostvogels, 2017). 3. In carefully selected cases, outpatient autologous stem cell transplantation for multiple myeloma can be performed in the outpatient setting (Khouri, 2017). 4. A meta-analysis of three randomized controlled trials (n = 1,208) found that after autologous stem cell transplantation, maintenance with lenalidomide had a higher median progression-free survival than with placebo (52.8 versus 23.5 months). Median overall survival was 86.0 months for the placebo group but not yet reached for the lenalidomide group (McCarthy, 2017). 5. While autologous (possibly followed by allogenic) stem cell transplantation is the standard treatment for patients with multiple myeloma who are undergoing transplants, a tandem approach can be considered for all patients and studied in future clinical trials (Martino, 2016). 6. A meta-analysis of two studies (n = 691) of bortezomib after autologous stem cell transplantation, compared with placebo, for patients with multiple myeloma, found a significant increase in three-year progression-free survival (odds ratio = 1.52) for the drug group, but no difference in overall survival (0.91). More in the bortezomib arm experienced peripheral neuropathy (4.03, 4.26 for neuropathy over grade two) (Gao, 2015). This review followed a systematic review of 1,436 records four years earlier, cautioning that more studies of the use of post-transplant bortezomib and thalidomide were needed (Picot, 2011). 7. A meta-analysis of two randomized controlled studies (n = 1,074) compared lenalidomide with placebo after autologous stem cell transplants for multiple myeloma. The lenalidomide group 8

9 had higher progression-free survival (odds ratio = 2.5) and overall survival (1.21), but had significantly higher rates of neutropenia (4.88), infection (2.82), hematologic cancers (3.31) and solid tumors (2.24). Other types of adverse events were not significantly elevated (Gao, 2014). This study was part of an ongoing effort to improve on the performance of thalidomide, which improved survival but at the expense of higher rates of serious adverse events (Kumar, 2011). Leukemia: 1. A meta-analysis of nine studies (n = 6,762) compared safety and efficacy of unrelated hematopoietic stem cell transplants and umbilical cord blood transplants in patients with acute leukemia. Risk of relapse was similar between the stem cell and umbilical cord groups (odds ratio = 1.03), overall survival (1.417) and progression-free survival (1.165). Neutrophil and platelet recovery periods were both shorter after hematopoietic stem cell transplant, leading authors to support increased use of umbilical cord blood transplants for children with acute leukemia (Lou, 2017). 2. A similar comparsion of hematopoietic stem cell transplants and umbilical cord blood transplants in patients with leukemia (seven studies, n = 3,389), found leukemia-free survival and overall survival were significantly lower in the umbilical cord group, which differs from the 2017 Lou et al. study (Zhang, 2012). 3. A review of adults older than age 60 with acute myeloid leukemia asserts that assessing patient frailty and evaluating comorbid conditions are important in selecting patients for intense therapy. Moreover, patients treated with induction chemotherapy after transplant have superior outcomes, with many achieving complete remission (Finn, 2016). 4. A meta-analysis of nine articles (n = 1,950) studied patients with intermediate-risk acute myeloid leukemia with allogenic versus non-allogenic stem cell transplants. It documented that those with allogenic transplants had significantly better relapse-free survival (31.6 percent higher), overall survival (+24) and relative response (+42). Treatment-related mortality was similar between the two groups (Li, 2015). 5. A systematic review of four studies (n = 600) of patients with chronic lymphocytic leukemia found that offering front-line high-dose therapy did not improve overall survival (hazard ratio = 0.91) but it did improve event-free survival (0.46). High-dose therapy did not result in a higher rate of secondary malignancy. Despite these encouraging signs, authors recommend that highdose therapy be restricted to clinical trials (Rejlic, 2015). 6. A meta-analysis of 23 trials (n = 15,258) found no overall survival benefit of myeloablative conditioning transplants over reduced-intensity conditioning before transplants in patients with acute myeloid leukemia and acute lymphoblastic leukemia (Abdul Wahid, 2014). 7. A meta-analysis of 13 studies (n = 2,962) of adults with acute lymphoblastic leukemia with allogenic transplant determined a survival benefit for having a matched sibling donor for patients younger than age 35 (odds ratio = 0.79) but not for those older than age 35 (1.01) (Gupta, 2013). 8. A meta-analysis of 15 studies revealed that allogeneic stem cell transplantation may be more effective than chemotherapy in adult myeloid leukemia, along with children and adults after the 9

10 first complete remission (Ashfaq, 2010). 9. A review of 11 studies comparing allogenic hematopoietic stem cell transplantation with optimal drug therapy (tyrosine kinase inhibitors) found mixed results for survival, cytogenic response, hematologic response and molecular response, but generally better outcomes with transplants (Hayes, 2017). In addition, patients with Hodgkin s lymphoma are candidates for stem cell transplants. In a metaanalysis of 42 studies (n = 1,850), persons undergoing allogeneic transplantation had six-month, oneyear, two-year and three-year relapse-free survival percentages of 77, 50, 37 and 31, respectively. Overall survival numbers were 83 percent, 68 percent, 58 percent and 50 percent, respectively. Authors acknowledge that results have improved over time, but the need to continue improvement is clear (Rashidi, 2016). Policy updates: A total of four guidelines/otherand 17 peer-reviewed references were added and six guidelines/other and nine peer-reviewed references were removed from this policy in December Updated National Coverage Determinations (NCDs) and reference information, and deleted old information. Summary of clinical evidence: Citation McCarthy (2017) Outcomes of lenalidomide after autologous stem cell transplant in multiple myeloma. Lou (2017) Hematopoietic stem cell transplant vs. umbilical cord blood transplants in patients with acute leukemia. Gao (2015) Content, Methods, Recommendations Key points: Meta-analysis of three randomized controlled trials (n = 1,208); patients with multiple myeloma. Comparison of survival of lenalidomide versus placebo after autologous stem cell transplant. Maintenance with lenalidomide had a higher median progression-free survival than placebo (52.8 months versus 23.5 months). Median overall survival was 86.0 months with placebo less than the lenalidomide group, which is not yet reached and will be higher. Key points: Meta-analysis of nine studies (n=6,762); patients with acute leukemia. Safety and efficacy of unrelated hematopoietic stem cell transplants (n = 4,736) and umbilical cord blood transplants (n = 2, 026) were compared. The stem cell group had insignificantly superior risk of relapse (odds ratio = 1.03, P< 0.847), overall survival (odds ratio = 1.417, P < 0.100) and progression-free survival (odds ratio = 1.165, P < 0.056) versus the umbilical cord group. Neutrophil and platelet recovery periods were both shorter after hematopoietic stem cell transplant. Data support greater use of umbilical cord blood transplants for children with acute leukemia. Key points: Meta-analysis of two studies (n = 691); patients with multiple myeloma. 10

11 Citation Survival and adverse effects of bortezomib after autologous stem cell transplant for multiple myeloma. Li (2015) Survival of patients with leukemia with allogenic versus nonallogenic stem cell transplant. Content, Methods, Recommendations Comparison of bortezomib to placebo after autologous stem cell transplantation. Significant increase in three-year progression-free survival (odds ratio = 1.52) for drug group, but no difference in overall survival (0.91). Odds ratio = 1.73 for rate of complete or near-complete response. More in the bortezomib arm experienced peripheral neuropathy (odds ratio = 4.03, and 4.26 for neuropathy over grade two). Key points: Meta-analysis of nine articles (n = 1,950); patients with intermediate-risk acute myeloid leukemia. Patients randomized to those with allogenic versus non-allogenic stem cell transplants. Those with allogenic transplants had significantly better relapse-free survival (hazard ratio = 0.684), overall survival (0.76) and relative response (0.58). Treatment-related mortality for subgroups was similar between the two groups (0.99). References Professional society guidelines/other: Hayes, Inc. Comparative effectiveness of allogenic hematopoietic stem cell transplant versus drug-based strategies for treatment of chronic myelogenous leukemia. Lansdale PA: Hayes, Inc., last updated April 24, Lewis SL, Shaw CA. Genetics, Altered immune responses, and transplantation. In: Lewis S, Heitkemper MM, Dirksen SR, O'Brien PG, Bucher L, editors. Medical Surgical Nursing: Assessment and Management of Clinical Problems. 7th ed. St. Louis, MO: Mosby; 2007: Majhail NS, Farnia SH, Carpenter PA, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Trans. 2015;21(11): Medline Plus. Bone marrow transplant. Bethesda MD: National Library of Medicine, last updated December 5, Accessed December 11, NCCN Guidelines and Clinical Resources: NCCN categories of evidence and consensus. Available at Accessed December 11, National Marrow Donor Program. Be the Match, Accessed December 11, National Cancer Institute. Bone Marrow Transplantation and Peripheral Blood Stem Cell Transplantation: Questions and Answers. Reviewed August 12, Available at: 11

12 Accessed December 11, National Library of Medicine. Medline Plus. Bone Marrow Transplantation. Available at: Accessed December 11, Newton S. Management of clients with leukemia and lymphoma. In: Black JM, Hawks JH, editors. Medical-Surgical Nursing: Clinical Management for Positive Outcomes. 8th ed. St. Louis, MO: Saunders Elsevier; 2009: Princeton University, Office of Communications. Princeton Scientists describe genetics of blood stem cells. Press release, Princeton University, June 1, Accessed on December 11, Transfusion therapy and blood and marrow stem cell transplantation. In: Nettina SM, editor. Lippincott Manual of Nursing Practice. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006: Peer-reviewed references: Abdul Wahid SF, Ismail NA, Mohd-Idris MR, et al. Comparison of reduced-intensity and myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and acute lymphoblastic leukemia: a meta-analysis. Stem Cells Dev. 2014;23(21): Burt RK, Loh Y, Cohen B, et al. Autologous non-myeloablative hematopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study. Lancet Neurol. 2009;8(3): Chen XL, Su H, Zhong KL, DA Y, Xiao XB, et al. Autologous peripheral blood stem cell transplantation combined with autologous bone marrow transplantation for treating refractory lymphoma. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2009;17(1): Finn LE, Foran JM. Are we curing more older adults with acute myeloid leukemia with allogeneic transplantation in CR1? Curr Opin Hematol. 2016;23(2): Gao M, Gao L, Yang G, et al. Lenalidomide after stem-cell transplantation for multiple myeloma: a metaanalysis ofrandomized controlled trials. Int J Clin Exp Pathol. 2014;7(6): Gao M, Yang G, Han Y, et al. Single-agent bortezomib or bortezomib-based regimens as consolidation therapy after autologous hematopoietic stem cell transplantation in multiple myeloma: a meta-analysis of randomized controlled trials. Int J Clin Exp Med. 2015;8(8): Gupta V, Richards S, Rowe J, Acute Leukemia Stem Cell Transplantation Trialists Collaborative Group. 12

13 Allogenic, but not autologous, hematopoietic cell transplantation improves survival only among younger adults with acute lymphoblastic leukemia in first remission: an individual patient data meta-analysis. Blood. 2013;121(2): Janssen WE. Peripheral blood and bone marrow hematopoietic stem cells: are they the same? Semin Oncol. 1993;20(5 Suppl 6): Khouri J, Majhail NS. Advances in delivery of ambulatory autologous stem cell transplantation for multiple myeloma. Curr Opin Support Palliat Care. 2017;11(4): Kumar A, Galeb S, Djulbegovic B. Treatment of patients with multiple myeloma: an overview of systematic reviews. Acta Haematol. 2011;125(1-2):8 22. Li D, Wang L, Zhu H, et al. Efficacy of allogeneic hematopoietic stem cell transplantation in intermediaterisk acute myeloid leukemia adult patients in first complete remission: a meta-analysis of prospective studies. PLoS One. 2015;10(7):e Lou X, Zhao C, Chen H. Unrelated donor umbilical cord blood transplant versus unrelated hematopoietic stem cell transplant in patients with acute leukemia: A meta-analysis and systematic review. Blood Rev Nov. 15. Doi: j.blre [Epub ahead of print]. Martino M, Recchia AG, Fedele R, et al. The role of tandem stem cell transplantation for multiple myeloma patients. Expert Opin Biol Ther. 2016;16(4): McCarthy L, Holstein SA, Petrucci MT, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol. 2017;35(29): Oostvogels R, Uniken Venema SM, de Witte M, et al. In search of the optimal platform for Post- Allogeneic SCT immunotherapy in relapsed multiple myeloma: a systematic review. Bone Marrow Transplant. 2017;52(9): Picot J, Cooper K, Bryant J, Clegg AJ. The clinical effectiveness and cost-effectiveness of bortezomib and thalidomide in combination regimens with an alkylating agent and a corticosteroid for the first-line trtment of multiple myeloma: a systematic review and economic evaluation. Health Technol Assess. 2011;15(41): Radocha J, Maisnar V, Zavrelova A, et al. Fifteen years of a single center experience with stem cell transplantation for multiple myeloma: a retrospective analysis. Acta Medica (Hradec Kralove). 2013;56(1):9 13. Rashidi A, Ebadi M, Cashen AF. Allogeneic hematopoietic stem cell transplantation in Hodgkin 13

14 lymphoma: a systematic review and meta-analysis. Bone Marrow Transplant. 2016;51(4): Rejlic T, Kumar A, Djulbegovic B, Kharfan-Dabaja MA. High-dose therapy and autologous hematopoietic cell transplantation as front-line consolidation in chronic lymphocytic leukemia: a systematic review. Bone Marrow Transplant. 2015;50(8): Reston JT, Uhl S, Treadwell JR, et al. Autologous hematopoietic cell transplantation for multiple sclerosis: a systematic review. Mult Scler 2011;17(2): Wannesson L, Panzarella T, Mikhael J, Keating A. Feasibility and safety of autotransplants with noncryopreserved marrow or peripheral blood stem cells: a systematic review. Ann Oncol. 2007;18(4): Zhang H, Chen J, Que W. A meta-analysis of unrelated donor umbilical cord blood transplantation versus unrelated donor bone marrow transplantation in acute leukemia patients. Biol Blood Marrow Transplant. 2012;18(8): CMS National Coverage Determinations (NCDs): Histocompatibility Testing. CMS website. Effective August 1, Accessed December 11, Stem Cell Transplant (formerly ) EffectiveOctober 3, Accessed December 11, CMS. Manual System Pub NCD Transmittal 191 rescinded and replaced with transmittal 193. Effective January 27, Stem Cell Transplantation for Multiple Myeloma, Myelofibrosis, Sickle Cell Disease, and Myelodysplastic Syndromes. Guidance/Guidance/Transmittals/Downloads/R193NCD.pdf. Accessed December 11, Local Coverage Determinations (LCDs): No LCDs identified as of the writing of this policy. Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill accordingly. 14

15 CPT Code Description Comments Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor Hematopoietic progenitor cell (HPC); autologous transplantation ICD-10 Code Description Comments C74.10-C74.92 C82.00-C96.9 C81.00-C81.99 C82.00-C82.89 C83.00-C83.89 Malignant neoplasm of cortex of adrenal gland Malignant neoplasm of lymphoid, hematopoietic and related tissue [except Hodgkin's disease] Hodgkin s lymphoma Follicular lymphoma Non-follicular lymphoma C90.00 Multiple myeloma C C91.Z2 C C92.Z2 C C93.Z2 C94.00-C94.82 C95.00-C95.92 C96.9 C96.Z D46.0-D46.Z Lymphoid leukemia Myeloid leukemia Monocytic leukemia Other leukemias of specified cell type Leukemia of unspecified cell type Malignant neoplasm of lymphoid, hematopoietic and related tissue, unspecified Other specified malignant neoplasms of lymphoid, hematopoietic and related tissue Myelodysplastic syndromes D56.1 Beta thalassemia D61.01-D61.9 Other aplastic anemias and other bone marrow failure syndromes D82.0 Wiskott-Aldrich syndrome E76.01-E76.3 E77.0-E77.1 Mucopolysaccharidosis E85.9 Amyloidosis Disorders of glycoprotein metabolism (Mucolipidosis) E88.09 POEM s Syndrome Q78.2 Osteopetrosis HCPCS Level II Code N/A Description Comments Appendix A 15

16 National Comprehensive Cancer Network (NCCN) Guidelines and clinical resources NCCN Categories of Evidence and Consensus: Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. All recommendations are category 2A, unless otherwise noted. Definitions for classifying indications: The definitions for categorizing indications for transplantation are presented below. Standard of care (S): This category includes indications that are well defined and are generally supported by evidence in the form of high-quality clinical trials or observational studies, or both (e.g., through CIBMTR or EBMT). Standard of care, clinical evidence available (C): This category includes indications for which large clinical trials and observational studies are not available. However, hematopoietic cell transplantation has been shown to be an effective therapy with acceptable risk of morbidity and mortality in sufficiently large single- or multi-center cohort studies. Hematopoietic cell transplantation can be considered as a treatment option for individual patients after careful evaluation of risks and benefits. As more evidence becomes available, some indications may be reclassified as standard of care. Standard of care, rare indication (R): Indications included in this category are rare diseases for which clinical trials and observational studies with sufficient number of patients are not currently feasible because of their very low incidence. However, single- or multi-center or registry studies in relatively small cohorts of patients have shown 16

17 hematopoietic cell transplantation to be effective treatment, with acceptable risks of morbidity and mortality. For patients with diseases in this category, hematopoietic cell transplantation can be considered as a treatment option for individual patients after careful evaluation of risks and benefits. Developmental (D): Developmental indications include diseases where pre-clinical or early phase clinical studies, or both, show hematopoietic cell transplantation to be a promising treatment option. Hematopoietic cell transplantationis best pursued for these indications as part of a clinical trial. As more evidence becomes available, some indications may be reclassified as standard of care, clinical evidence available or standard of care. Not generally recommended (N): Transplantation is not currently recommended for these indications where evidence and clinical practice do not support the routine use of hematopoietic cell transplantation. The effectiveness of nontransplant therapies for an earlier phase of a disease does not justify the risks of hematopoietic cell transplantation. Alternatively, a meaningful benefit is not expected from the procedure in patients with an advanced phase of a disease. However, this recommendation does not preclude investigation of hematopoietic cell transplantation as a potential treatment, and transplantation may be pursued for these indications within the context of a clinical trial. Appendix B Table 1: Indications for hematopoietic stem cell transplantation in pediatric patients (generally younger than age 18). Acute myeloid leukemia Indication and disease status Allogeneic Autologous CR1, low risk N N CR1, intermediate risk C C CR1, high risk S N CR2+ S C Not in remission C N Acute lymphoblastic leukemia CR1, standard risk N N CR1, high risk S N CR2 S N CR3+ C N Not in remission C N 17

18 Indication and disease status Allogeneic Autologous Chronic myeloid leukemia Chronic phase C N Accelerated phase C N Blast phase C N Myelodysplastic syndromes Low risk C N High risk S N Juvenile myelomonocytic leukemia S N Therapy related S N T-cell Non-Hodgkin s lymphoma CR1, standard risk N N CR1, high risk S N CR2 S N CR3+ C N Not in remission C N Lymphoblastic B-cell Non-Hodgkin s lymphoma (non-burkitt) CR1, standard risk N N CR1, high risk S N CR2 S N CR3+ C N Not in remission C N Burkitt s lymphoma First remission R R First or greater relapse, sensitive R R First or greater relapse, resistant R N Hodgkin s lymphoma CR1 N N Primary refractory, sensitive C C Primary refractory, resistant C N First relapse, sensitive C C First relapse, resistant C N Second or greater relapse C C Anaplastic large cell lymphoma CR1 N N Primary refractory, sensitive C C 18

19 Indication and disease status Allogeneic Autologous Primary refractory, resistant C N First relapse, sensitive C C First relapse, resistant C N Second or greater relapse C C Solid tumors Germ cell tumor, relapse D C Germ cell tumor, refractory D C Ewing s sarcoma, high risk or relapse D S Soft tissue sarcoma, high risk or relapse D C Neuroblastoma, high risk or relapse D S Wilm s tumor, relapse N C Osteosarcoma, high risk N C Medulloblastoma, high risk N C Other malignant brain tumors N C Non-malignant diseases Severe aplastic anemia, new diagnosis S N Severe aplastic anemia, relapse/refractory S N Fanconi s anemia R N Dyskeratosis congenital R N Blackfan-Diamond anemia R N Sickle cell disease C N Thalassemia C N Severe combined immunodeficiency R N T-cell immunodeficiency, SCID variants R N Wiskott-Aldrich syndrome R N Hemophagocytic disorders R N Lymphoproliferative disorders R N Severe congenital neutropenia R N Chronic granulomatous disease R N Other phagocytic cell disorders R N IPEX syndrome R N Juvenile RA N D Systemic sclerosis N D Other autoimmune and immune dysregulation disorders R N Mucopolysaccharoidoses (MPS-I and MPS-VI) R N Other metabolic diseases R N Osteopetrosis R N Globoid cell leukodystrophy (Krabbe) R N Metachromatic leukodystrophy R N Cerebral X-linked adrenoleukodystrophy R N 19

20 = hematopoietic cell transplantation. Recommendation categories (see text for definition): S = standard of care; C = standard of care, clinical evidence available; R = standard of care, rare indication; D = developmental; N = not generally recommended. Table 2: Indications for hematopoietic stem cell transplantation in adults (generally age 18 or older). Indication and disease status Acute myeloid leukemia Allogeneic Autologous CR1, low risk N C CR1, intermediate risk S C CR1, high risk S C CR2 S C CR3+ C C Not in remission C N Acute promyelocytic leukemia CR1 N N CR2, molecular remission C S CR2, not in molecular remission S N CR3+ C N Not in remission C N Relapse after autologous transplant C N Acute lymphoblastic leukemia CR1, standard risk S C CR1, high risk S N CR2 S C CR3+ C N Not in remission C N Chronic myeloid leukemia Chronic phase 1, TKI intolerant C N Chronic phase 1, TKI refractory C N Chronic phase 2+ S N Accelerated phase S N Blast phase S N Myelodysplastic syndromes Low/intermeditate-1 risk C N Intermediate-2/high risk S N Therapy-related AML/MDS 20

21 Indication and disease status Allogeneic Autologous CR1 S N Myelofibrosis Primary, low risk C N Primary, intermediate/high risk C N Secondary C N Plasma cell disorders Myeloma, initial response D S Myeloma, sensitive relapse C S Myeloma, refractory C C Plasma cell leukemia C C Primary amyloidosis N C POEMS syndrome N R Relapse after autologous transplant C C Hodgkin lymphoma CR1 (PET negative) N N CR1 (PET positive) N C Primary refractory, sensitive C S Primary refractory, resistant C N First relapse, sensitive S S First relapse, resistant C N Second or greater relapse C S Relapse after autologous transplant C N Diffuse large B-cell lymphoma CR1 (PET negative) N N CR1 (PET positive) N C Primary refractory, sensitive C S Primary refractory, resistant C N First relapse, sensitive C S First relapse, resistant C N Second or greater relapse C S Relapse after autologous transplant C N Follicular lymphoma CR1 N C Primary refractory, sensitive S S Primary refractory, resistant S N First relapse, sensitive S S First relapse, resistant S N 21

22 Indication and disease status Allogeneic Autologous Second or greater relapse S S Transformation to high grade lymphoma C S Relapse after autologous transplant C N Mantle cell lymphoma CR1/PR1 C S Primary refractory, sensitive S S Primary refractory, resistant C N First relapse, sensitive S S First relapse, resistant C N Second or greater relapse C S Relapse after autologous transplant C N T-cell lymphoma CR1 C C Primary refractory, sensitive C S Primary refractory, resistant C N First relapse, sensitive C S First relapse, resistant C N Second or greater relapse C C Relapse after autologous transplant C N Lymphoplasmacytic lymphoma CR1 N N Primary refractory, sensitive N C Primary refractory, resistant R N First or greater relapse, sensitive R C First or greater relapse, resistant R N Relapse after autologous transplant C N Burkitt s lymphoma First remission R R First or greater relapse, sensitive R R First or greater relapse, resistant R N Relapse after autologous transplant R N Cutaneous T-cell lymphoma Relapse C C Relapse after autologous transplant C N Plasmablastic lymphoma CR1 R R 22

23 Indication and disease status Allogeneic Autologous Relapse R R Chronic lymphocytic leukemia High risk, first or greater remission C N T-cell prolymphocytic leukemia R R B-cell, prolymphocytic leukemia R R Transformation to high grade lymphoma C C Solid tumors Germ cell tumor, relapse N C Germ cell tumor, refractory N C Ewing s sarcoma, high risk N C Breast cancer, adjuvant high risk N D Breast cancer, metastatic D D Renal cancer, metastatic D N Non-malignant diseases Severe aplastic anemia, new diagnosis S N Severe aplastic anemia, relapse/refractory S N Fanconi s anemia R N Dyskeratosis congenita R N Sickle cell disease C N Thalassemia D N Hemophagocytic syndromes, refractory R N Mast cell diseases R N Common variable immunodeficiency R N Chronic granulomatous disease R N Multiple sclerosis N D Systemic sclerosis N D Rheumatoid arthritis N D Systemic lupus erythematosus N D Crohn s disease N D Polymyositis-dermatomyositis N D = hematopoietic stem cell transplantation; POEMS = polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes; PET = positron emission tomography. Recommendation categories (see text for definition): S = standard of care; C = standard of care, clinical evidence available; R = standard of care, rare indication; D = developmental; N = not generally recommended. 23