Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndrome

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CMS has determined that the evidence does not demonstrate that the use of allogeneic hematopoietic stem cell transplantation (HSCT) improves health outcomes in Medicare beneficiaries with myelodysplastic syndrome (MDS). Therefore, we determine that allogeneic HSCT for MDS is not reasonable and necessary under §1862(a)(1)(A) of the Social Security Act (the Act). However, we believe the available evidence shows that allogeneic HSCT for MDS is reasonable and necessary under §1862(a)(1)(E) of the Act through Coverage with Evidence Development (CED). Therefore, we are making the following decision. Allogeneic HSCT for MDS is covered by Medicare only for beneficiaries with MDS participating in an approved clinical study that meets the criteria below. A clinical study seeking Medicare payment for allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome pursuant to Coverage with Evidence Development (CED) must address one or more aspects of the following questions. Prospectively, compared to Medicare beneficiaries with MDS who do not receive hematopoietic stem cell transplantation, do Medicare beneficiaries with MDS who receive hematopoietic stem cell transplantation have improved outcomes as indicated by: relapse free mortality, progression free survival, relapse, and overall survival? Prospectively, in Medicare beneficiaries with MDS who receive hematopoietic stem cell transplantation, how do International Prognostic Scoring System (IPSS) score, patient age, cytopenias and comorbidities predict the following outcomes: relapse free mortality, progression free survival, relapse, and overall survival? Prospectively, in Medicare beneficiaries with MDS who receive hematopoietic stem cell transplantation, what treatment facility characteristics predict meaningful clinical improvement in the following outcomes: relapse free mortality, progression free survival, relapse, and overall survival? The clinical study must adhere to the following standards of scientific integrity and relevance to the Medicare population: The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes. The research study is well supported by available scientific and medical information or it is intended to clarify or establish the health outcomes of interventions already in common clinical use. The research study does not unjustifiably duplicate existing studies. The research study design is appropriate to answer the research question being asked in the study. The research study is sponsored by an organization or individual capable of executing the proposed study successfully. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it must be in compliance with 21 CFR parts 50 and 56. All aspects of the research study are conducted according to appropriate standards of scientific integrity (see http://www.icmje.org). The research study has a written protocol that clearly addresses, or incorporates by reference, the standards listed here as Medicare requirements for CED coverage. The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Trials of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life threatening as defined in 21 CFR § 312.81(a) and the patient has no other viable treatment options. The clinical research study is registered on the ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. The research study protocol specifies the method and timing of public release of all prespecified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors (http://www.icmje.org). However a full report of the outcomes must be made public no later than three (3) years after the end of data collection. The research study protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary. The research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility. Consistent with section 1142 of the Social Security Act, AHRQ supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions. Revisions to sections 110.8.1 of the NCD Manual are available in Appendix C.

Decision Memo: To: Administrative File: (CAG-00415N) Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome From: Louis B. Jacques, MD Director, Coverage and Analysis Group Tamara Syrek Jensen, JD Deputy Director, Coverage and Analysis Group Marcel E. Salive, MD, MPH Director, Division of Medical and Surgical Services Roya Lotfi Lead Analyst Leslye Fitterman, PhD Epidemiologist Rosemarie Hakim, PhD Epidemiologist Lori Paserchia, MD Lead Medical Officer Subject: Decision Memorandum for Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome Date: August 4, 2010 I. Decision CMS has determined that the evidence does not demonstrate that the use of allogeneic hematopoietic stem cell transplantation (HSCT) improves health outcomes in Medicare beneficiaries with myelodysplastic syndrome (MDS). Therefore, we determine that allogeneic HSCT for MDS is not reasonable and necessary under §1862(a)(1)(A) of the Social Security Act (the Act). However, we believe the available evidence shows that allogeneic HSCT for MDS is reasonable and necessary under §1862(a)(1)(E) of the Act through Coverage with Evidence Development (CED). Therefore, we are making the following decision. Allogeneic HSCT for MDS is covered by Medicare only for beneficiaries with MDS participating in an approved clinical study that meets the criteria below. A clinical study seeking Medicare payment for allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome pursuant to Coverage with Evidence Development (CED) must address one or more aspects of the following questions. Prospectively, compared to Medicare beneficiaries with MDS who do not receive hematopoietic stem cell transplantation, do Medicare beneficiaries with MDS who receive hematopoietic stem cell transplantation have improved outcomes as indicated by: relapse free mortality, progression free survival, relapse, and overall survival? Prospectively, in Medicare beneficiaries with MDS who receive hematopoietic stem cell transplantation, how do International Prognostic Scoring System (IPSS) score, patient age, cytopenias and comorbidities predict the following outcomes: relapse free mortality, progression free survival, relapse, and overall survival? Prospectively, in Medicare beneficiaries with MDS who receive hematopoietic stem cell transplantation, what treatment facility characteristics predict meaningful clinical improvement in the following outcomes: relapse free mortality, progression free survival, relapse, and overall survival? The clinical study must adhere to the following standards of scientific integrity and relevance to the Medicare population: The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes. The research study is well supported by available scientific and medical information or it is intended to clarify or establish the health outcomes of interventions already in common clinical use. The research study does not unjustifiably duplicate existing studies. The research study design is appropriate to answer the research question being asked in the study. The research study is sponsored by an organization or individual capable of executing the proposed study successfully. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it must be in compliance with 21 CFR parts 50 and 56. All aspects of the research study are conducted according to appropriate standards of scientific integrity (see http://www.icmje.org). The research study has a written protocol that clearly addresses, or incorporates by reference, the standards listed here as Medicare requirements for CED coverage. The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Trials of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life threatening as defined in 21 CFR § 312.81(a) and the patient has no other viable treatment options. The clinical research study is registered on the ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. The research study protocol specifies the method and timing of public release of all prespecified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors (http://www.icmje.org). However a full report of the outcomes must be made public no later than three (3) years after the end of data collection. The research study protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary. The research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility. Consistent with section 1142 of the Social Security Act, AHRQ supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions. Revisions to sections 110.8.1 of the NCD Manual are available in Appendix C. II. Background Myelodysplastic Syndrome (MDS) refers to a group of diverse blood disorders in which the bone marrow does not produce enough healthy, functioning blood cells. These disorders are varied with regard to clinical characteristics, cytologic and pathologic features, and cytogenetics. Clinical Background and Burden of Disease There are three "families" of cells commonly found in the blood: red cells, white cells, and platelets. The abnormal production of blood cells in the bone marrow leads to low blood cell counts, referred to as cytopenia, which are a hallmark feature of MDS along with a dysplastic and hypercellular-appearing bone marrow. Most patients present with signs or symptoms of anemia (due to abnormally lowered red cell counts), which can be accompanied by infection (due to abnormally low white cell counts) and/or bleeding (due to abnormally low platelet counts). A persistently low blood cell count can necessitate the administration of frequent transfusions that over time may also have a decreasing positive impact for the patient, which is referred to as refractory cytopenia with transfusion dependency. Although some patients may not have any symptoms, most patients with MDS ultimately die from their low blood counts according to Nimer (2008). Failure of the bone marrow to produce mature healthy cells is typically a gradual process; therefore MDS is not necessarily a rapidly terminal disease. Life expectancy may be measured in months to years and will vary considerably depending on the severity of the specific disorder, the patient’s ability to withstand treatment and the patient’s responsiveness to treatment. The worst case scenario is the transformation of MDS to acute myeloid leukemia (AML), which occurs in approximately thirty percent of patients with MDS (MDS Foundation Handbook, 2008). AML is an aggressive type of cancer that often fails to respond to treatment and has a high mortality rate. In addition, AML that is secondary to MDS is generally more resistant to treatment than AML that arises without a prior association with MDS (National Comprehensive Cancer Network [NCCN] guideline, 2009). MDS becomes increasingly common with advanced age with an overall incidence of 3.3 per 100,000 and an incidence of between 15 and 50 per 100,000 in patients over age 70. The median age at presentation is 76 years. Eighty percent of the total population receiving an MDS diagnosis is 65 years of age or older. Classification of MDS Because the disease course of MDS varies greatly from patient to patient, a number of diagnostic classification systems for grouping MDS "subtypes" have been developed over the years. The initial system, the French-American-British (FAB) classification, was developed in the early 1980s. The key criterion for diagnosis centered on the percentage of abnormal blast (i.e., precursor) cells in the bone marrow with a higher blast count signifying more aggressive disease. A blast count greater than 30 percent signifies a diagnosis of AML. Diagnostic classification is based on examination of a bone marrow biopsy and, more recently, cytogenetics. Five subtypes of MDS were identified. Table 1 presents the FAB Classification of MDS as presented in the NCCN guideline, version 2, 2010. TABLE 1: FAB f classification of MDS g (from the NCCN® Clinical Practice Guidelines in Oncology, Myelodysplastic Syndromes – v.2.2010, used with permission) FAB subtype % Peripheral blasts % Bone marrow blasts Refractory anemia (RA) < 1 < 5 Refractory anemia with ringed sideroblasts (RARS) < 1 < 5 Refractory anemia with excess blasts (RAEB) < 5 5-20 Refractory anemia with excess blasts in transformation (RAEB-t) ≥ 5 21-30 Chronic myelomonocytic leukemia (CMML) ( > 1,000 monocytes/mcL blood) < 5 5-20 f FAB = French-American-British g Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982; 51:189-199. h WHO = World Health Organization In 2001, the World Health Organization (WHO) expanded upon the FAB system by taking into account the number of types of abnormal "families" of blood cells, the presence or absence of certain cytogenetics abnormalities as well as by lowering the maximum allowable percentage of blast cells in the blood (Nimer, 2008). The WHO classification system was further updated in 2008 in order to incorporate new scientific and clinical information and to add new diseases (NCCN guideline, 2009). The maximum blast count required for AML was reduced to twenty percent. Table 2 presents the 2008 WHO Classification of MDS as presented in the NCCN guidelines. TABLE 2: Classification Systems for de novo MDS: 2008 WHO h Classification of MDS i (from the NCCN® Clinical Practice Guidelines in Oncology, Myelodysplastic Syndromes – v.2.2010, used with permission) Subtype Blood Bone marrow Refractory cytopenia with unilineage dysplasia (RCUD) j Single or bicytopenia Dysplasia in ≥ 10 % of one cell line, < 5% blasts Refractory anemia with ring sideroblasts (RARS) Anemia, no blasts ≥ 15 % of erythroid precursors w/ring sideroblasts, erythroid dysplasia only, < 5 % blasts Refractory cytopenia with multilineage dysplasia (RCMD) Cytopenia(s): < 1 x 10 9/L monocytes Dysplasia in ≥ 10 % of cells in ≥ 2 hematopoietic lineages, ± 15 % ring sideroblasts, < 5 % blasts; Refractory anemia with excess blasts-1 (RAEB-1) Cytopenia(s): ≤ 2-4 % blasts, < 1 x 10 9/L monocytes Unilineage or multilineage dysplasia, No Auer rods, 5 % to 9 % blasts Refractory anemia with excess blasts-2 (RAEB-2) Cytopenia(s): 5-19 % blasts, < 1 x 10 9/L monocytes Unilineage or multilineage dysplasia Auer rods ±, 10 % to 19 % blasts Myelodysplastic syndrome, unclassified (MDS-U) Cytopenias Unilineage dysplasia or no dysplasia but characteristic MDS cytogenetics, < 5% blasts MDS associated with isolated del(5q) Anemia, platelets normal or increased Unilineage erythroid dysplasia, isolated del 5(q), < 5 % blasts i Brunning R, Orazi A, Germing U, et al. Myelodysplastic Syndromes, Chapter 5, in Swerdlow S, Campo E, Harris NL, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissue, 4th edition. IARC Press, 2008, p88-103. j This category encompasses refractory anemia (RA), Refractory Neutropenia (RN) and Refractory thrombocytopenia (RT). Cases of RN and RT were previously classified as MDS Unclassified. TABLE 3: Classification Systems for de novo MDS: Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) WHO Classification k (from the NCCN® Clinical Practice Guidelines in Oncology, Myelodysplastic Syndromes – v.2.2010, used with permission) Subtype Blood Marrow Chronic myelomonocytic leukemia-1 (CMML-1) > 1x109/L monocytes, < 5% blasts Dysplasia in 1 hematopoietic line, < 10% blasts CMML-2 > 1x109/L monocytes, 5-19% blasts or Auer rods Dysplasia in 1 hematopoietic line, 10-19% blasts or Auer rods Atypical chronic myeloid leukemia (CML), Bcr-Abl 1 negative WBC 13x109/L, neutrophil precursors > 10%, < 20% blasts Hypercellular, < 20% blasts Juvenile myelomonocytic leukemia (JMML) > 1x109/L monocytes, < 20% blasts l >1x10 9 /L monocytes, < 20% blastsl MDS/MPN, unclassifiable ('Overlap syndrome') Dysplasia + myeloproliferative featuresm , No prior MDS or MPN Dysplasia + myeloproliferative features Acute myeloid leukemia with myelodysplasia-related changes n WHO Classification o AML post MDS or MDS/MPN AML with an MDS-related cytogenetic abnormality AML with multilineage dysplasia k Orazi A, Bennet JM, Germing U, et al, Myelodysplastic/Myeloproliferative Neoplasms, Chapter 4, in Swerdlow S, Campo E, Harris NL, et al. (Eds.). World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. IARC Press, 2008, pp 76-86. l Ph negative plus 2 features: Hb F, PB immature myeloid cells, WBC > 10x109/L, clonal chromosomal abnormality, GM-CSF hypersensitivity in vitro, for example, thrombocytosis, leukocytosis, splenomegaly. n Greater than 20% blasts in PB or marrow. Some cases with 20-29% blasts, especially if arising from MDS, may be slowly progressive and may behave more similar to MDS (RAEB-t by FAB classification) than to overt AML. o Arber DA, Brunning RD, Orazi A, et al. Acute myeloid leukaemia with myelodysplasia-related changes, In Chapter 6, Acute Myeloid Leukemia and Related Precursor Neoplasms, in Swerdlow S, Campo E, Harris NL, et al. (Eds.). World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. IARC Press, 2008, pp 124-126. Although the revisions to the FAB system and hence the resultant WHO diagnostic classification system are considered to be an improvement, the 2009 NCCN guideline states that "the NCCN MDS panel members currently endorse reporting and using both the FAB and the WHO classification systems" in clinical practice. Similarly, when evaluating clinical studies and comparing results across those studies it is important to note whether patients were diagnosed with the FAB or WHO classification system. Due to the highly variable nature of the patient population with regards to MDS subtype, severity of disease and baseline medical condition, the clinical management of a patient with MDS is highly individualized and can range from solely supportive care with periodic transfusions and antibiotics to intensive chemotherapy with or without transplantation. The International Prognostic Scoring System (IPSS) is the classification scheme widely recognized and used in determining the most suitable treatment regimen. The IPSS scheme, as first described in Greenberg, et al. (1998), is the worldwide system used for risk-based grading of the severity and progression of MDS and for ascertaining the patient’s prognosis. The goal of the IPSS is to determine, for a given MDS subtype, the patient’s chance for survival and the risk for MDS to transform (i.e., progress) to AML (NCCN guideline, 2009). The authors found that three major variables (marrow blast percentage, number of cytopenias and cytogenetics subgroup) could determine the outcome; a risk score was assigned to each. Four risk groups with regards to survival and progression to AML were then created by combining the risk scores for the three major variables. Table 4 presents the IPSS Classification system as presented in the 2009 NCCN guideline. TABLE 4: IPSS (IPSS p,q ) Classification System (from the NCCN® Clinical Practice Guidelines in Oncology, Myelodysplastic Syndromes – v.2.2010, used with permission). Survival and AML evolution Score value Prognostic variable 0 0.5 1.0 1.5 2.0 Marrow blasts (%)r < 5 5-10 - 11-20 21-30 Karyotype s Good Intermediate Poor Cytopenia t 0/1 2/3 Risk category (% IPSS pop.) Overall score Median survival (y) in the absence of therapy 25% AML progression (y) in the absence of therapy LOW (33) 0 5.7 9.4 INT-1 (38) 0.5-1.0 3.5 3.3 INT-2 (22) 1.5-2.0 1.1 1.1 HIGH (7) >  2.5 0.4 0.2 p IPSS = International Prognostic Scoring System. q This research was originally published in Blood. Greenberg P, Cox C, LeBeau M, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:2079-2088; Erratum. Blood 1998;91:1100. © The American Society of Hematology. r Patients with 20-30 % blasts may be considered as MDS or AML. s Cytogenetics: Good = normal, -Y alone, del (5q) alone, del (20q) alone; Poor = complex (3 abnormalities) or chromosome 7 anomalies; Intermediate = other abnormalities. [This excludes karyotypes t (8; 21), inv16, and t (15; 17), which are considered to be AML not MDS.] t Cytopenias: neutrophil count < 1,800/mcL, platelets < 100,000/mcL, Hb < 10g/dL. Tables 1-4 are reproduced with permission from the NCCN 2.2010 Myelodysplastic Syndromes Clinical Practice Guidelines in Oncology, ©National Comprehensive Cancer Network, 2010. Available at: http://www.nccn.org (accessed February 23, 2010). Overall, the Low and Intermediate-1 categories are associated with a longer median survival and a lower chance for progression to AML; these 2 categories comprise the low risk group. The Intermediate-2 and High categories are associated with a shorter median survival and a higher chance for progression to AML and comprise the high risk group. Much like the diagnostic classification system, the IPSS prognostic system continues to evolve. The original IPPS was created using study data from patients who were diagnosed with the FAB classification. To acknowledge the introduction of the WHO classification, Malcovati, et al. performed analyses to determine the prognostic potential when using study data from patients diagnosed with the WHO classification (Malcovati et al., 2005). The impact of red blood cell transfusion dependency on overall survival and survival free of leukemia (i.e., progression to AML) was also examined although a definition of transfusion dependency was not provided. The resultant system is referred to as the WHO Prognostic Scoring System (WPSS). The authors found that the overall survival of patients who are dependent on red blood cell transfusions was statistically significantly shorter than for non-transfusion dependent patients. Survival free of AML was also statistically significantly shorter for patients with transfusion dependency than for patients without red blood cell transfusion dependency. Hence, the authors found that the persistent requirement for red blood cell transfusions is a negative prognostic factor for patients with MDS (Malcovati et al., 2005). In 2008, Kao et al. expanded on this finding by examining the impact of the severity of a low red cell count on overall survival and time to evolution to AML. The authors found that the overall survival worsened and time to AML shortened as the blood count worsened (defined as a hemoglobin level of less than 10 grams /deciliter). After multivariate analysis, the red blood cell count was determined to add useful prognostic value with regards to overall survival but not with regards to time to progression to AML. Typically a physician applies the FAB or WHO classification and the IPSS category as part of recommending a treatment plan. The type of plan will be based on the patient’s overall health but also on the extent to which symptoms can be relieved, blood abnormalities reduced and AML progression minimized (MDS Foundation Handbook, 2008). Hematopoietic Stem Cell Transplantation (HSCT) HSCT is a procedure in which stem cells are taken from a person’s bone marrow or blood and then administered to the patient by intravenous infusion. When the stem cells come from a donor, the procedure is called an allogeneic HSCT. Allogeneic HSCT is believed by some to be the only potential cure for patients with MDS. HSCT has traditionally been limited to patients younger than 55 or even fifty years of age. This is because of the increase in medical problems (a.k.a., comorbidities) and the general decline in overall health status that commonly occur as a person ages. For example, older patients have greater difficulty tolerating intensive (a.k.a., myeloablative) chemotherapy either with or without subsequent transplantation. The advent of nonmyeloablative chemotherapy and reduced–intensity chemotherapy (RIC) regimens prior to transplantation has significantly increased the potential for patients with MDS who are older than 55 years to receive HSCT (Alyea, et al., 2005). The attractiveness of RIC prior to transplant is "the lower incidence of side effects, which means the treatment will be better tolerated by the older patient, and the patient may have greater chance of a successful transplant." (Myelodysplastic Foundation Handbook, 2008) III. History of Medicare Coverage CMS does not have a national policy that specifically addresses coverage of allogeneic HSCT for MDS. Section 110.8.1 of the National Coverage Determination (NCD) Manual (http://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/103_cov_determ/ncd103c1_Part2.pdf) governs national coverage and noncoverage of Stem Cell Transplants, as described below. Indications and Limitations of Coverage Allogeneic Stem Cell Transplantation Allogeneic stem cell transplantation is a procedure in which a portion of a healthy donor's stem cell or bone marrow is obtained and prepared for intravenous infusion. Covered Indications The following uses of allogeneic bone marrow transplantation are covered under Medicare: Effective for services performed on or after August 1, 1978, for the treatment of leukemia, leukemia in remission, or aplastic anemia when it is reasonable and necessary; and Effective for services performed on or after June 3, 1985, for the treatment of severe combined immunodeficiency disease (SCID), and for the treatment of Wiskott-Aldrich syndrome. Noncovered Indications Effective for services performed on or after May 24, 1996, allogeneic stem cell transplantation is not covered as treatment for multiple myeloma. In the absence of a national coverage determination, contractors have the discretion to determine coverage for allogeneic HSCT for all other indications through the local coverage determination (LCD) process or by individual claim by claim adjudication. Current request CMS opened this NCA based on a request from the following groups: The National Marrow Donor Program, American Society for Blood and Marrow Transplantation, American Cancer Society, American Cancer Society Cancer Action Network, AABB, American Society of Hematology, American Society of Clinical Oncology, Aplastic Anemia and MDS International Foundation, Blood and Marrow Transplant Information Network, National Bone Marrow Transplant Link, The Bone Marrow Foundation and The Leukemia and Lymphoma Society. In their formal letter, the requestors asked for national coverage of allogeneic HSCT for Medicare beneficiaries "who would either be at high risk for progression to leukemia or be at risk for MDS complications that place them at high risk for death or prevent the future possibility of a transplant." On November 10, 2009, CMS accepted this formal request from several bone marrow and cancer organizations and societies and the first public comment period opened. A list of articles submitted by the requestor is included in Appendix B. Benefit Category Medicare is a defined benefit program. A prerequisite for Medicare coverage is that an item or service must meet one of the statutorily defined benefit categories in the Social Security Act and not otherwise be excluded from coverage.§1812 (Scope of Part A); §1832; (Scope of Part B); §1861 (s) (Definition of Medical and Other Health Services). CMS has determined that autologous and allogeneic stem cell transplantation fall within the benefit categories of inpatient hospital services under Part A and physicians’ services under Part B. See §1812 (a) (1) (inpatient hospital services); §1832 (outpatient hospital services incident to a physician’s service); §1861(s) (2) (incident to physician’s services); §1861(b) (inpatient hospital services). IV. Timeline of Recent Activities Date Action November 10, 2009 CMS accepts formal NCD request for coverage of the allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome. The tracking sheet is posted and the initial 30-day comment period begins. December 10, 2009 Initial 30 day public comment period closes. Comments are posted on the website. May 6, 2010 CMS posts the proposed decision memorandum for 30 days of public comment period. June 5, 2010 The public comment period on the proposed decision memo closes with 14 public comments received. V. FDA Status Hematopoietic stem/progenitor cells (HPC) for transplantation are regulated as human cells, tissues, and cellular-and tissue based products (HCT/Ps) by FDA under 21 CFR. §1271. Section 1271.3(d) defines human cells, tissues, or cellular or tissue-based products (HCT/Ps) as "articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion or transfer into a human recipient. Examples of HCT/Ps include, but are not limited to, bone, ligament, skin, dura mater, heart valve, cornea, hematopoietic stem cells derived from peripheral and cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix, and semen or other reproductive tissue." The regulatory approach to HCT/Ps, including HPC, distinguishes among autologous products, allogeneic products from first- or second-degree relatives, and allogeneic products form unrelated donors. HCT/Ps that meet all of the criteria set forth in 21 CFR §1271.10(a) are regulated solely under section 361 of the PHS Act and the regulations in Part 1271, and no FDA premarket review is required. To satisfy these criteria, a HCT/P must: be minimally manipulated; be intended for homologous use only; not be combined with another article (with some limited exceptions); and not have a systemic or metabolic effect; or if it does, it must be intended for autologous use or use by a first- or second-degree blood relative. NHCT/Ps that do not meet all of these criteria are also regulated as drugs, devices, and/or biological products, and require FDA premarket review. Section 1271.3(a) defines the term autologous use as "the implantation, transportation, infusion, or transfer of human cells or tissue back into the individual from whom the cells or tissue were recovered." Section 1271.3(c) defines the term homologous use as "the replacement or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor." VI. General Methodological Principles When making national coverage decisions under section 1862(a)(1)(A) of the Social Security Act, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for patients. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary. A detailed account of the methodological principles of study design that the agency utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A. In general, features of clinical studies that improve quality and decrease bias include the selection of a clinically relevant cohort, the consistent use of a single good reference standard, and the blinding of readers of the index test, and reference test results. Public comments sometimes cite the published clinical evidence and give CMS useful information. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. VII. Evidence A. Introduction The purpose of this national coverage analysis (NCA) is to determine if the evidence is sufficient to conclude that beneficiaries with MDS experience improved health outcomes with HSCT compared to beneficiaries with MDS whose management does not include HSCT. This NCA does not focus on any particular subtype of MDS. As noted in the Background section of this NCA, MDS refers to a group of blood disorders. Each subtype of MDS has a distinct presentation and prognosis. The underlying cause for the disease, the types and severity of abnormal blood counts and the potential for progression to AML are different for each subtype. Similarly, HSCT is a procedure that involves numerous steps and medical interventions that in sum lead to a complex set of medical decisions and procedures over a span of months. Some examples of these numerous and complex aspects include the use of: related versus unrelated matched donor; allogeneic versus autologous donor; bone marrow versus peripheral blood-sourced cells; one type of chemotherapeutic agent versus another type; standard myeloablative versus non-myeloablative versus reduced-intensity conditioning; the use of induction chemotherapy versus not; and the specific types and doses of agents used for graft versus host disease (GVHD) prophylaxis. CMS recognizes that each certified transplantation center in the U.S. develops a clinical treatment protocol that can vary to some degree from other centers but which adheres to standards of excellence set by clinical experts in the field of transplantation medicine, surgery, nursing and pharmacy. The Joint Accreditation Committee of the International Society for Cellular Therapy and the European Group for Blood and Marrow Transplantation (JACIE) was established in 1999. Both the National Marrow Donor Program (NMDP) and the Foundation for the Accreditation of Cellular Therapy (FACT) and the JACIE (jointly referred to as the FACT-JACIE ) which have established provider and facility standards for conducting HSCT, serve to bolster, support and oversee these standards of excellence. In addition, Congressionally-mandated data collection of the results of HSCT, which is conducted by the Center for International Blood and Marrow Transplant Research (CIBMTR), further serves to strengthen and improve the processes involved with performing HSCT. CMS generally focuses its review on evidence that includes patients who are 65 years of age or older. The typical Medicare beneficiary is 65 years of age or older; however, a relatively small percentage of beneficiaries may be younger than 65 year old due to Medicare entitlement based on other factors such as end stage renal disease or disability. However, CMS acknowledges that traditionally HSCT was routinely contraindicated in patients with MDS who were older than 55 or even 50 years of age due to the patient’s inability to tolerate the standard myeloablative conditioning regimen. The literature, therefore, is still dominated by evidence generated in patients younger than 65 years of age. This is slowly changing with the relatively recent introduction of non-myeloablative conditioning (NMA) and reduced-intensity conditioning (RIC) regimens for patients with MDS who are older than 65 years or who have other contra-indications to HSCT. There is considerable morbidity and mortality associated with some subtypes of MDS as well as with HSCT. The greater chance for non relapse mortality (NRM) or transplant-related mortality (TRM) with the use of standard myeloablative conditioning prior to transplantation has traditionally limited transplantation to nonelderly and nondebilitated patients (Martino, et al., 2006). Thus, the primary outcomes of interest in this NCA are overall survival (OS), progression-free survival (PFS) and TRM or NRM. Literature Search On February 4, 2010, CMS performed a PubMed search of the clinical literature using the following search terms: "myelodysplastic syndrome" or "MDS" and "transplant." The limitations used were: Human, English, Aged (65+ years), Publication Date (2000 to present) and Article type (Clinical Trial, Randomized Clinical Trial, Meta-analysis). B. Discussion of evidence reviewed 1. Question Is the evidence adequate to conclude that beneficiaries with a diagnosis of MDS would experience improved health outcomes with a HSCT compared to beneficiaries whose management does not include HSCT? 2. External technology assessment CMS did not commission an external technology assessment on this topic. 3. Internal technology assessment Results from the CMS literature search as well as the literature articles submitted by the requestors and the literature references provided by public commenters were considered for the internal technology assessment (TA). The CIBMTR Progress Report for calendar year 2008 was reviewed to find a listing of published articles based on research performed on the CIBMTR database. In addition, an Internet search was performed to identify any available evidence-based guidelines and professional society position statements. From the above evidence sources, CMS looked for published, peer-reviewed full articles (i.e., not abstracts) of controlled clinical trials that provided results on the use of HSCT versus other therapies in the clinical management of patients with MDS of any subtype. Emphasis was placed on articles that presented evidence in the Medicare population (i.e., 65 years of age or older). Articles that provided background information on MDS (e.g., epidemiology), a study that did not investigate HSCT (e.g., a study that examined the safety and/or efficacy of a chemotherapeutic agent) or a non-clinical study (i.e., animal research) were not included in this internal technology assessment 4. Evidence Summary Cutler CS, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: Delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 2004; 104:579-585. The authors performed a decision analysis to investigate the optimal timing for bone marrow transplantation for patients with MDS. There were two MDS data sources for the analysis: the International MDS Risk Analysis Workshop (IMRAW) database was the source for the nontransplantation cohort (n= 184); the International Bone Marrow Transplant Registry (IBMTR; n = 193)) and the Fred Hutchinson Cancer Research Center (n = 67) databases were the sources for the MDS transplantation cohort. IBMTR was the one AML data source (n = 230). All patients had received myeloablative conditioning. Three possible transplantation strategies were tested using a Markov decision model: 1) transplantation at time of MDS diagnosis; 2) transplantation at time of progression to AML; 3) transplantation at a fixed time interval after diagnosis. Analyses were performed for all four IPSS risk groups. A base case was used consisting of a 35 year old man with newly diagnosed MDS and an available HLA-matched sibling donor. All patients were sixty years old or younger. The median age in the nontransplantation cohort was 49.8 years while the median age in the various transplant groups was 39.4 to 45.6 years. In the nontransplantation group, the majority (73.9%) had an IPSS Low or Intermediate-1 risk profile. In the transplantation group, the majority (75%) had an IPSS Intermediate-1 or Intermediate-2 profile. The outcomes results are reported in tables 5-8 below. TABLE 5: Median survival in months according to transplantation status (from Cutler, et al., 2004). Nontransplantation Cohort Transplantation Cohort Median Survival (months) 62.9 14 Significance not stated TABLE 6: Median survival in months and 25% AML transformation time by IPSS risk group for the nontransplantation cohort (from Cutler, et al., 2004). IPSS Low Intermediate-1 Intermediate-2 High Median Survival (months) 141.1 62.9 22.5 4.9 25 % AML transformation time 84.6 19.2 2.7 All differences P < 0.001 TABLE 7: Median survival in months according to IPSS risk group for the transplantation cohort (from Cutler, et al., 2004). IPSS Low Intermediate-1 Intermediate-2 High Median Survival (months) 40.2 20.5 14.8 6.1 All differences P = 0.04 TABLE 8: Discounted life expectancy, in years, for alternative transplantation strategies (from Cutler, et al., 2004). Discounted life expectancy (yrs) IPSS Transplantation at diagnosis Transplantation at a fixed time point Transplantation at AML progression 2 yr 4 yr 6 yr 8 yr Low 6.51 6.86 7.47 7.46 7.49* 7.21 Intermediate-1 4.61 4.74 4.72 5.02 5.20* 5.16 Intermediate-2 4.93* 3.21 2.94 2.85 2.84 2.84 High 3.20* 2.75 2.75 2.75 2.75 2.75 * Dominant strategies The authors concluded that "delayed transplantation for IPSS Low and Intermediate-1 risk groups is associated with maximum discounted life years" while for the IPSS Intermediate-2 and High risk groups "transplantation at the time of diagnosis is associated with maximization of discounted life years." They also hypothesized that for the IPSS Low and Intermediate-1 risk groups the optimal timing of transplantation "is at the time of the development of a new cytogenetics abnormality, the appearance of a clinically important cytopenia, or the progression from one IPSS group to a higher risk group." Martino R, et al. Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood 2006; 108:836-846. A retrospective, multicenter study was performed to evaluate myeloablative conditioning versus reduced-intensity conditioning (RIC) prior to HSCT in patients with MDS or AML. Disease relapse, progression-free survival, overall survival and nonrelapse mortality were among the outcomes studied. Myeloablative conditioning was administered to 621 patients with MDS while 215 patients with MDS received RIC. Sixty-three percent of the patients who received myeloablative conditioning had MDS while 59% of the patients who received RIC had MDS. Of the fifty percent of patients for whom the authors could collect IPSS-related information, 66% who received myeloablative conditioning had high risk MDS and 69% who received RIC had high risk MDS. Twenty-seven percent of patients who received myeloablative conditioning were older than 50 years and 73% of the patients who received RIC were older than 50 years. The outcomes results are reported in tables 9-12. After each table is a report of the results of a multivariate analysis for that outcome. TABLE 9: Incidence of nonrelapse mortality (from Martino, et al., 2006). Myeloablative RIC % Nonrelapse mortality (95% CI) 3-month 0.20 (0.17-0.23) 0.15 (0.11-0.21) 1-year 0.28 (0.25-0.32) 0.20 (0.15-0.26) 3-year 0.32 (0.28-0.36) 0.22 (0.17-0.28) P = 0.04 Multivariate analysis of 3-year nonrelapse mortality showed that the use of RIC reduced nonrelapse mortality (HR, 0.61, 95%CI, 0.41-0.91; p = 0.015) compared to myeloablative conditioning and that patient age older than fifty years increased the nonrelapse mortality compared to patient age fifty and younger (HR, 1.4 , 95%CI, 1.1-1.8; p = 0.04). TABLE 10: Incidence of disease progression/relapse (from Martino, et al., 2006). Myeloablative RIC % Disease progression/relapse (95% CI) 3-month 0.08 (0.06-0.10) 0.14 (0.11-0.20) 1-year 0.22 (0.19-0.25) 0.35 (0.30-0.43) 3-year 0.27 (0.24-0.31) 0.45 (0.38-0.53) P < 0.01 Multivariate analysis of 3-year disease progression/relapse showed that the use of RIC increased disease progression/relapse (HR, 1.64, 95% CI, 1.2-2.2; p = 0.001) compared to myeloablative conditioning; and that an advanced stage of disease increased disease progression/relapse compared to an early stage of disease (HR, 2.2, 95% CI, 1.2-4.1; P = 0.01). TABLE 11: Incidence of progression-free survival (from Martino, et al., 2006). Myeloablative RIC % Progression-free survival (95% CI) 3-month 0.72 (0.74-0.80) 0.76 (0.69-0.81) 1-year 0.50 (0.46-0.54) 0.45 (0.38-0.52) 3-year 0.41 (0.37-0.45) 0.33 (0.27-0.40) P = 0.1 Multivariate analysis of 3-year progression-free survival showed that the use of RIC did not impact the progression-free survival compared to myeloablative conditioning; and that a diagnosis of MDS increased the progression-free survival compared to a diagnosis of secondary AML (HR, 0.78, 95% CI, 0.6-0.98; p = 0.03). There was a trend toward a decrease in progression-free survival in patients older than fifty years compared to patients fifty years or younger. TABLE 12: Overall survival (from Martino, et al., 2006). Myeloablative RIC % Overall survival (95% CI) 3-month 0.82 (0.79-0.85) 0.84 (0.79-0.89) 1-year 0.58 (0.54-0.62) 0.57 (0.49-0.63) 3-year 0.45 (0.41-0.49) 0.41 (0.35-0.47) P = 0.7 Multivariate analysis of 3-year overall survival showed that the use of RIC did not impact overall survival compared to myeloablative conditioning; that patient age older than fifty years decreased the overall survival compared to patient age fifty and younger (HR, 1.3, 95% CI, 1.05-1.6); p = 0.02); and that a diagnosis of MDS increased overall survival compared to a diagnosis of secondary AML (HR, 0.72, 95% CI, 0.57-0.92; p = 0.007). The authors concluded that "the reduction in 3-year NRM after a heterogeneous group of RIC indicates that the goal of reducing early NRM with RICs has been accomplished, but at the cost of a significantly higher risk of relapse." The authors continue to state that RIC needs further study, especially that "different RIC approaches should be compared in detail, since the alkylating agent dose intensity and the use of monoclonal antibodies may have an impact on transplantation outcome." Laport GG, et al. Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders. Biology of Blood and Marrow Transplantation 2008; 14:246-255. This was a prospective, multi-center study of 148 patients with MDS, AML, CMML or myeloproliferative disease who received allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. All patients were considered to be at high risk to receive myeloablative conditioning due to age, co-morbidities or prior history of transplantation. Given the multi-center nature of the study, various transplantation protocols were used. The protocols primarily differed in the use of HLA-matched versus unrelated donors, duration and intensity of graft versus host disease treatment and the specific type of agents used for conditioning. Patients had to be less than 75 years old. Outcomes studied were nonrelapse mortality, relapse/progression, relapse-free survival and overall survival. Patients with MDS were stratified by IPSS risk group: Low/Intermediate-1 and Intermediate-2/High. Forty patients had de novo MDS. Median age was sixty years with a range of 42 to 72. Twenty of these patients were sixty years of age or older. Twenty-two patients (56%) were in the Low/Intermediate-1 risk group. These forty patients with de novo MDS had no significant differences in relapse-free survival or non-relapse mortality between the Low/Intermediate-1 and Intermediate-2/High groups. The Intermediate-2/High group had a significantly higher incidence of relapse/progression compared to the Low/Intermediate-2 group (HR, 2.92, 95%CI, 1.0-8.6; p=0.04). In multivariate analysis, a significantly decreased relapse risk was associated with complete remission at the time of transplantation. The results in these forty patients were not reported by age. The authors’ conclude that, "Allogeneic HCT remains the only curative modality for MDS and MPD, with non-myeloablative conditioning or RIC regimens clearly benefiting this older population by reducing toxicity. However, further investigation is warranted to determine the optimal regimen with adequate dose intensity and low toxicity." Oliansky DM, et al. The role of cytoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic syndromes: An evidence-based review. Biology Blood Marrow Transplant 2009; 15:137-172. The American Society for Blood and Marrow Transplantation (ASBMT) sponsored a systematic review of the medical literature for the use of allogeneic HSCT in patients with MDS. A steering committee was convened to invite and oversee an independent panel of disease experts to conduct the systematic review and make treatment recommendations based on the evidence. The review article was published in Biology of Blood and Marrow Transplantation , which is the journal of the ASBMT (Oliansky, et al., 2009). Of note, ASBMT was one of the requestors for this NCD. The authors performed a PubMed and Medline search on January 17, 2007 using the search terms "myelodysplastic syndrome" or "MDS" plus "transplant." The search was limited to "human trials," "English language" and publication date of 1990 or later. There were two subsequent updated searches with the last update performed on April 15, 2008. Only articles that were peer-reviewed and presented the results of Phase two or three studies with 25 or more patients with MDS who were fifteen years of age or older were included in the systematic review. If the study evaluated patients with AML as well as de novo MDS, then at least sixty percent of the patients had to have had de novo MDS or the study results had to have been stratified by disease category. The authors graded the quality of the study design used in as well as the strength of the evidence from each article (Table 13). The authors also graded the strength of the treatment recommendation presented in each article (Table 14). TABLE 13: Grading the Quality of Study Design and the Strength of the Evidence (from Oliansky, et al., 2009). 1++ High-quality meta-analyses, systematic reviews of RCTs, or RCT with very low risk of bias 1+ Well conducted meta-analyses, systematic reviews of RCTs or RCTs with a low risk of bias 1- Meta-analyses, systematic reviews of RCTs or RCTs with a high risk of bias 2++ High-quality systematic reviews of case-control or cohort studies. High quality case-control or cohort studies with a very low risk of confounding, bias or chance, and a high probability that the relationship is causal. 2+ Well-conducted case-control or cohort studies with a low risk of confounding, bias or chance, and a moderate probability that the relationship is causal. 2- Case-control or cohort studies case-control or cohort studies with a high risk of confounding, bias or chance, and a significant risk that the relationship is not causal. 3 Non-analytic studies (e.g., case reports, case series) 4 Expert opinion RCT= randomized controlled trial TABLE 14: Grading the Strength of the Treatment Recommendation (from Oliansky, et al., 2009). A At least one meta-analysis, systematic review or RCT rated as 1++ and directly applicable to the target population; or a systematic review of RCTs or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population and demonstrating overall consistency of results B A body of evidence including studies rated as 2++ directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 1++ or 1+ C A body of evidence including studies rated as 2+ directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 2++ D Evidence level 3 or 4; or extrapolated evidence from studies rated as 2+ RCT= randomized controlled trial The authors assessed 46 articles that each typically focused on only one of a variety of clinical aspects of performing HSCT including: timing of transplantation, pre-HSCT induction chemotherapy, donor selection and transplantation techniques including reduced-intensity conditioning versus high dose conditioning. Three tables were presented that supplied the study design/methodology and results for each of the 46 articles. These tables are not reproduced in this NCA but can be found in the publication by Oliansky, et al, (2009). To briefly summarize: across all studies the study design/methodology ranged from single site to multi-center, from retrospective to prospective and from uncontrolled to controlled. Various combinations of therapies (pharmaceutical agents, biologicals, radiation therapy) were used for