Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes (MDS)

HCT/Ps that do not meet all of these criteria are regulated as drugs, devices, and/or biological products, and require FDA’s premarket review and approval. 21 CFR § 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." 1271.3(c) defines the term homologous use as "the repair, reconstruction, 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."

Per 21 CFR §1271.3(d) and (d)(4), “minimally manipulated bone marrow for homologous use and not combined with another article (except for water, crystalloids, or a sterilizing, preserving, or storage agent, if the addition of the agent does not raise new clinical safety concerns with respect to the bone marrow)”, is not considered an HCT/P.

Currently, the only stem cell products that are FDA-approved for use in the United States consist of blood-forming stem cells (also known as hematopoietic progenitor cells) that are derived from umbilical cord blood. These products are approved for limited use in patients with disorders that affect the body system that is involved in the production of blood (called the “hematopoietic” system). These FDA-approved stem cell products are listed on the following FDA website: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products.

VI. General Methodological Principles

When making NCDs, CMS generally 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 beneficiaries. 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.

Public comments sometimes cite 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. Public comments that contain personal health information will be redacted or will not be made available to the public on the CMS website. CMS responds in detail to the public comments on a proposed national coverage determination when issuing the final national coverage determination.

VII. Evidence

A.  Introduction

This section provides a summary of the evidence we considered during our review. The evidence reviewed to date includes the published medical literature on pertinent clinical trials of the use of allogeneic hematopoietic stem cell transplant in patients with MDS. Our assessment focuses on the three key evidence questions below in B.1.

The focus of this National Coverage Analysis (NCA) is to determine if there is sufficient evidence to support the use of allogeneic hematopoietic stem cell transplant in Medicare beneficiaries 65 and older with MDS.

B.  Discussion of Evidence

1.  Evidence Question(s)

Question 1: Prospectively, compared to Medicare beneficiaries with MDS who do not receive allogeneic hematopoietic stem cell transplantation, do Medicare beneficiaries with MDS who receive allogeneic hematopoietic stem cell transplantation have improved outcomes as indicated by:

• relapse free mortality,
• progression free survival,
• relapse, and
• overall survival?

Question 2: Prospectively, in Medicare beneficiaries with MDS who receive allogeneic 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?

Question 3: Prospectively, in Medicare beneficiaries with MDS who receive allogeneic 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?

2. External Technology Assessments

CMS did not request an external technology assessment (TA) on this issue. 

3.  Internal Technology Assessment

We searched PubMed/MEDLINE, Embase, and Web of Science for studies published between 2010 and 2023, using a combination of key words along with their synonyms, and Boolean operations to combine search terms. The following search criteria were used: “Myelodysplastic Syndromes” [MeSH] OR “MDS” AND “Hematopoietic Stem Cell Transplantation” [MeSH] AND “Allogeneic stem cell transplantation” [MeSH] “Aged” [MeSH] AND “Humans” [MeSH] AND “Clinical Trial” [MeSH] AND “Meta-Analysis” [MeSH] AND “Retrospective Analysis” [MeSH] AND “Randomized Controlled Trial” [MeSH] AND “English.” To ensure that we captured all the relevant articles, a search was conducted independently by the contractor International Consulting Associates (ICA), and the CMS Coverage and Analysis Group (CAG).

Nine full text articles, including two Coverage with Evidence (CED) studies by Atallah et al. and Nakamura et al., met the inclusion criteria and were included in the NCD analysis. Table 1 contains the inclusion and exclusion criteria.

Table 1

4.  Medicare Evidence Development & Coverage Advisory Committee (MEDCAC)

A MEDCAC meeting was not convened on this issue.

Below are four Evidence Tables.

Table 2 contains characteristics of included studies.

Table 3 contains study outcomes.

Table 4 contains study outcomes according to IPSS or IPSS-R Classifications.

Table 5 contains study outcomes relevant to Evidence Question 3.

The full citation for the publications can be found in the bibliography of this decision memorandum which will allow anyone to find the information reviewed by CMS.

Table 2. Characteristics of Included Studies

°The eligibility criteria for median age was modified in retrospect to identify studies close to the Medicare population of 65 years and older, due to few studies meeting the PICOTs criteria.
*Advanced MDS defined as refractory anemia excess blasts (in transformation), chronic myelomonocytic leukemia, or marrow blasts ≥5%
Abbreviations: AEs = adverse events, aGVHD = acute GVHD, AHSCT = allogeneic hematopoietic stem cell transplant, AML = acute myeloid leukemia, BM = bone marrow, cGVHD = chronic CVHD, CIBMTR = Center for International Blood and Marrow Transplant Research, CMML = chronic myelomonocytic leukemia, DFCI = Dana-Farber Cancer Institute, EFS = event free survival, FAB = French-American-British classification system, GVHD = graft versus host disease, HMA = hypomethylating agent, IPSS = International Prognostic Scoring System, IPSS-R = Revised IPSS, MAC = myeloablative conditioning, MassGen = Massachusetts General Hospital, MDS = myelodysplastic syndrome, NIH = National Institutes of Health, NMA = non-myeloablative conditioning, NR = not reported, NRM = non-relapse mortality, OS = overall survival, RA = refractory anemia, RAEB = RA with excess blasts, RAEB-T = RAEB in transition to AML, RARS = RA with ringed sideroblasts, RCMD = refractory cytopenia with multilineage dysplasia, RCMD/RS = RCMD with ringed sideroblasts, RFS = relapse free survival, RIC = reduced intensity conditioning, TBI = total body irradiation, TRM = treatment related mortality, WHO = World Health Organization classification system

Table 3. Study Outcomes

Table 4. Study Outcomes according to IPSS or IPSS-R Classifications

Table 5. Study Outcomes Relevant to Evidence Question 3

Quality and strength of evidence

To assess the methodological quality of each eligible study, we employed a components approach, assessing each study for specific aspects of design or conduct.

No RCTs were identified, therefore no risk of bias (RoB) for RCTs was assessed. Rather, we assessed RoB for nonrandomized comparative studies, using the Risk of bias in Nonrandomized Studies of Interventions (ROBINS-I) (Sterne, 2016). We assessed the following domains: bias due to confounding; (2) bias in selection of participants; (3) bias in classification of interventions; (4) bias due to deviations from intended interventions; (5) bias due to missing data; (6) bias in measurement of outcomes; and (7) bias in selection of the reported result. Risk of bias was judged as “Low”, “Moderate”, “Serious”, or “Critical”, and the overall RoB reflects the worse RoB for any domain. We also assessed the overall quality of each study as either good, fair, or poor regarding its adherence to well-accepted methodological standards. For single arm studies that had no comparative arm, we decided to slightly modify the RoB tool by downgrading the RoB domain for bias in classification of interventions by one level. Table 3 details our RoB assessments, and Appendix B details the RoB judgement comments.

A search for evidence-based guidelines identified the following guidelines:

American Society of Hematology (ASH)

• “Transplantation for myelodysplastic syndromes: who, when, and which conditioning regimens” https://doi.org/10.1182/asheducation-2016.1.478.
• “Timing of allogeneic stem cell transplantation for myelodysplastic syndromes and aplastic anemia” https://doi.org/10.1182/asheducation-2014.1.77.

American Society of Transplantation and Cellular Therapy (ASTCT; formerly known as American Society of Blood and Marrow Transplantation)

• “Hematopoietic Cell Transplantation in the Management of Myelodysplastic Syndrome: An Evidence-Based Review from the American Society for Transplantation and Cellular Therapy Committee on Practice Guidelines”
  https://www.astctjournal.org/article/S2666-6367(22)01782-1/pdf.

The National Comprehensive Cancer Network (NCCN)

• Guidelines for MDS
  www.NCCN.org
  Clinical practice guidelines for Hematopoietic Cell Transplantation
  https://education.nccn.org/node/92893

Other Professional Society Recommendations/Consensus Statements/Expert Opinion
European LeukemiaNet

• "Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet” https://doi.org/10.1182/blood-2013-03-492884

The Chinese Society of Hematology

• “The consensus from The Chinese Society of Hematology on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation: 2021 update” https://doi.org/10.1186/s13045-021-01159-2.

Additional relevant guidelines that were identified are listed below:

VIII. Public Comment

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.

CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum. All comments that are submitted without personal health information may be viewed in their entirety by using the following link https://www.cms.gov/medicare-coverage-database/view/ncacal-tracking-sheet.aspx?ncaid=312&doctype=all&timeframe=30&sortBy=updated&bc=20.

Initial Comment Period: 6/7/2023-7/7/2023

During the 30-day comment period following the release of the tracking sheet, CMS received 10 comments. All comments were published on the CMS website and considered for this proposed decision. All the comments were in support of Medicare coverage of allogeneic HSCT for beneficiaries with MDS absent a CED requirement. Commenters cited that HSCT was more effective than therapies for MDS and improved overall survival. Additionally, commenters highlighted the importance of removing CED to create equitable access to HSCT for older patients, racial/ethnic minority groups, and beneficiaries facing financial barriers to treatment.

Commenters included physicians, researchers, and a biotech company. Three comments were provided by national associations/professional organizations including the National Comprehensive Cancer Network (NCCN), a joint comment by the American Society of Hematology (ASH), the American Society for Transplantation and Cellular Therapy (ASTCT), the National Marrow Donor Program (NMDP), the Center for International Blood and Marrow Transplant Research (CIBMTR), the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), and the Aplastic Anemia and MDS International Foundation (AAMDSIF).

Numerous commenters provided references for our deliberation of this NCA. We very much appreciate this information. All such references were assessed for inclusion in our evidence review.

Second Comment Period: 12/7/2023-1/6/2024

During the second 30-day comment period, after the posting of the proposed NCD, CMS received 30 comments. Of these comments, one was not published on the CMS website due to excessive personal health information content; however, all comments were considered for this final decision. All but one commenter was supportive of coverage of allogeneic HSCT for beneficiaries with MDS absent a CED requirement. One commenter disagreed with any decision to restrict the physician’s ability to make the best choice of care for their patients with MDS. Commenters also requested that CMS include umbilical cord blood as a donor source and let the patient’s medical team determine the best donor source, expand the risk criteria to include intermediate-risk, and expressed concern for the risk stratification system. Several commenters stated that more patient groups should be considered such as those with secondary MDS, severe bone marrow failure, and those who fail to respond to treatment (e.g., patients with hypomethylation-treatment failure, or severe cytopenia). We also received a couple comments concerned about MAC discretion such as possible inconsistency and that CMS should require MACs to establish an informal but binding prior authorization process. All comments were considered for this final decision and are summarized in the comments and responses below.

We received 10 comments from physicians and other health professionals, 7 from academic institutions, 4 comments from professional societies/national associations, 3 from medical centers specializing in cancer or blood treatments, 2 from pharmacists, 1 from a women’s health company, 1 from a cell therapy company, and 2 comments did not specify. The four comments provided by professional societies/national associations, included the Aplastic Anemia and MDS International Foundation (AAMDSIF), the Cord Blood Association (CBA), the National Comprehensive Cancer Network® (NCCN®), and a joint comment letter by the American Society of Hematology (ASH), American Society for Transplantation and Cellular Therapy (ASTCT), the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), the Center for International Blood and Marrow Transplantation (NMDP).

Numerous commenters provided references for our deliberation of this NCA. We appreciate this information. All such references were assessed for inclusion in our evidence review.

Coverage with Evidence Development (CED) requirement

Comment: The majority of commenters commended CMS’ reconsideration of this NCD following the publication of two coverage with evidence (CED) studies and supported the expansion of national coverage absent the CED requirement.

Response: The two CED studies were particularly important because prior studies failed to include Medicare-aged participants in their studies. Additionally, the two CED studies were well-designed and executed. The studies demonstrated that older patients were at no greater risk of death due to the procedure when compared to younger patients. It also showed that older patients who received allo-HSCT were more likely to have improved health outcomes (e.g., improved overall survival and leukemia-free survival), than patients of the same age that did not get allo-HSCT. We will finalize removal of the CED requirement.

Stem Cell Donor Source

Comment: Many commenters expressed concern that umbilical cord blood was not included as a stem cell donor source along with peripheral blood and bone marrow. Commenters noted that excluding umbilical cord blood could potentially limit equitable access to transplantation for some Medicare patients, especially those from certain racial and ethnic populations for whom cord blood may be the only HSCT option if a matched allogeneic adult donor could not be identified. Other commenters note that advantages of umbilical cord blood include immediate availability, less stringent HLA matching requirements, and lower incidence of chronic graft-versus-host disease. Commenters also pointed out that the NCCN Guidelines include cord blood stem cell grafts as one of the standards of care for MDS, the American Society for Transplantation and Cellular Therapy Committee (ASTCT) cite the use of umbilical cord blood in the management of patients with MDS, and umbilical cord blood is included with bone marrow and peripheral blood as a stem cell source outlined in the Further Consolidated Appropriations Act of 2020.

The commenters also acknowledged and agreed with the proposed decision that placenta and amniotic fluid are not currently validated sources for stem cells capable of hematologic and immunologic reconstitution.

Response: We appreciate the comments and the supporting evidence to expand the stem cell source to include umbilical cord blood in addition to peripheral blood and bone marrow in treating MDS. After reviewing the evidence submitted by public commenters, which consisted of professional guidelines as well as numerous clinical studies, we agree there is sufficient evidentiary support for umbilical cord blood to be used a stem cell source in treating MDS under this NCD. Studies have indicated that umbilical cord blood as a source for stem cells has comparable outcomes for hematologic malignancies as compared to bone marrow or peripheral stem cells from a matched unrelated or a mismatched unrelated donor. In a registry performed by Applebaum it revealed that certain ethnic groups (e.g., African Americans) had less access to HLA matched donors and umbilical cord blood is an alternative source for stem cells (Applebaum et al. 2012). Cord blood may be the only viable donor source available for a patient based on the less stringent HLA matching requirements needed for cord blood as compared to adult donors. This issue is most prominent for patients of mixed and minority race and ethnicity who may only have cord blood as a potential donor source (Gutman et al. 2016; Gerds et al. 2017). We will finalize this decision to include coverage of allogeneic hematopoietic stem cell transplant using bone marrow, peripheral blood and umbilical cord blood stem cell products for Medicare patients with MDS.

We agree with the commenters who say there is insufficient evidence to demonstrate that placenta and amniotic fluid are viable sources of stem cells for use in allogeneic hematopoietic stem cell transplants.

Risk Stratification System

Comment: Some commenters noted that risk stratification systems for MDS have been rapidly evolving especially with the use of molecular profiles. They noted that International Prognostic Scoring System-Molecular (IPSS-M) is becoming the clinical standard because it incorporates important molecular mutations in the prognostic model, as well as changes in patients over time and across treatments. In addition to IPSS-M, it was noted there are other risk stratification models including personalized prediction models, such as the EuroMDS, but the commenters believe that IPSS-M is replacing IPSS-R as the clinical standard. Commenters noted that NCCN and the ASTCT mention the use of IPSS-M in their guidelines.

Response: We appreciate the comments and the supporting evidence regarding the IPSS-M risk stratification system. After reviewing the evidence, including evidence submitted by public commenters, we believe that the IPSS-M risk stratification system is an appropriate tool that can help determine which patients are appropriate for allo-HSCT. Some studies comparing IPSS-M to IPSS-R have even shown that based on the model and its stratification, its improved prognostic precision would result in improved health outcomes. The IPSS-M tool includes six risk categories (very low, low, moderately low, moderately high, high, and very high). When comparing IPSS-M to IPSS-R using retrospective data, there is some direct crossover from one tool to another, but also there is upgrading and downgrading. Most of the studies reveal that more of the intermediate IPSS-R patients are upgraded to high or very high in the IPSS-M stratification, than downshifted to moderate high, moderate low, or lower levels of risk (Baer et al. 2023; Zamanillo et al. 2023). Several studies have validated this prognostic tool in an external cohort, which consisted of retrospective data (Sabile et al. 2023; Garcia-Manerto et al. 2023; Aguirre et al. 2023). A number of studies have confirmed that the use of IPSS-M provides a better prognostication at patient level compared to IPSS-R (Maggioni et al. 2022; Wu et al. 2022; Lee et al. 2023).

Sauta and associates reported improved discrimination of IPSS-M compared to IPSS-R for overall survival (OS) and leukemia-free survival (LFS) and proved its applicability in post-allo stem cell transplantation settings (Sauta et al. 2023). These findings were noted across all clinical end points with respect to outcomes. Baer and associates validated the model, confirmed the results, and performed an exploratory analysis on the importance on individual genes for risk prediction, since some mutations included in the score, such as MLL-PTD, may not be routinely analyzed in all laboratories (Baer et al. 2023). Zamanillo used retrospective data to calculate IPSS-R and IPSS-M scores and compared OS, and LFS, then analyzed which patients would have been affected by the re-stratification in terms of clinical management (Zamanillo et al. 2023). Wu and associates were able to demonstrate that IPSS-M was a more reliable tool in survival prediction accuracy than IPSS-R (Wu et al. 2022). Others have also confirmed the validity and prognostic accuracy of IPSS-M compared to IPSS-R (Lee et al. 2023; Mangaonkar et al. 2023).

While we acknowledge there is not a perfect crosswalk between IPSS-R and IPSS-M, the IPSS-M model designates patients as high-risk with a score of 0.5 to 1.5 and designates patients as very high-risk with a score of 1.5 or higher. Since IPSS-M is the newest model and has demonstrated its’ prognostic precision, we believe it is appropriate to add to the national coverage criteria for allogeneic hematopoietic stem cell transplants for patients with MDS.

Comment: Many commenters requested we expand the risk criteria to include intermediate-risk. As proposed, coverage for intermediate-risk would be at MAC discretion. Several commenters noted that enrollment criteria for the BMT CTN 1102 (Cusatis et al. 2021) included patients characterized as Intermediate-2 or High according to the IPSS criteria available when the study was designed.

Response: The studies that supported coverage of intermediate-risk patients were based on the IPSS. In addition to the Cusatis study, the Nakamura study demonstrated that patients who were Intermediate-2 (IPSS) had improvement on overall survival, as well as leukemia-free survival. Greenberg et al. conducted a study using IPSS to determine the cut point demarcating patients with intermediate risk of transformation to AML. Their findings found that patients with a score of 1.5 to 2.0 indicated Intermediate-2 risk. The Abel study combined patients with Intermediate-2 and high-risk status and showed improved overall survival, compared to patients in a combined group of low and Intermediate-1 risk. Based on the totality these studies we believe it is reasonable to add patients with MDS designated as Intermediate-2 or high-risk with a score of ≥ 1.5 according to criteria specified by the IPSS.

Comment: Many commenters expressed concern with using the International Prognostic Scoring System-Revised (IPSS-R) as the exclusive risk stratification system to determine patient eligibility. Some commenters noted that risk stratification systems for MDS have been rapidly evolving and felt that the use of specific risk models could become outdated over time. They suggested that coverage should not be based on a specific risk model but rather based on current, validated scoring systems recognized and/or referenced by NCCN, the World Health Organization (WHO) or other authoritative clinical organizations.

Response: We agree that risk stratification systems will change over time and that some additional flexibility in policy is necessary. All nine studies reviewed in this analysis used a stratification system that identified study participants by their risk of AML transformation; five studies used IPSS and four studies used IPSS-R. While the risk stratification systems have evolved over time, IPSS-R was used in the two CED studies. In this final decision memo, we are expanding coverage for additional individuals based on IPPS and IPSS-M. In addition, future changes in coverage based on other risk stratification systems can be considered by MACs based on section 110.23.D of the Medicare National Coverage Determinations manual. (See Appendix B).

MAC Discretion

Comment: Two commenters were concerned about possibility of inconsistent coverage across geographic regions for those patients who do not meet the national coverage criteria. One of these commenters suggested that CMS should require the MACs to establish an informal but binding prior authorization process.

Response: We are allowing MACs to make reasonable and necessary determinations under section 1862(a)(1)(A) for any beneficiary who does not meet the national coverage criteria. See Appendix B. MACs are structured to be able to take into account individualized patient factors on a claim-by-claim basis or establish local coverage determinations. We acknowledge that there is a possibility that coverage could vary somewhat over various geographic areas. Questions about coverage outside the nationally covered indications may be directed to the appropriate MAC. https://www.cms.gov/Medicare/Medicare-Contracting/Medicare-Administrative-Contractors/Who-are-the-MACs.html. We are not requiring MACs to use a prior authorization process. Prior authorization is typically employed through CMS rulemaking in order to protect the Medicare Trust Fund from improper payments, therefore, prior authorization is not being considered.

Clinical Indications

Comment: One commenter disagreed with any policy to restrict the physician’s ability to make the best choice of care for their patients with MDS.

Response: We appreciate the comment and recognize that physicians are integral to the patients' care. Based on the current evidence, specifically the two Coverage with Evidence (CED) studies that were generated from the NCD established in 2010, we believe the evidence supports the expanded national Medicare coverage as described in this final decision. We have also expanded coverage by including umbilical cord blood as an additional stem cell source in this final decision for MDS, allowing the physician to determine the best donor source for the patient. CMS (or its contractors) must determine whether an item or service is covered under the Medicare Act pursuant to statutory criteria. Our NCD will help to ensure that similar claims are processed and paid in a similar manner nationally under Title XVIII.

Comment: Some commenters were concerned that the proposed risk criteria would disadvantage patients that are transfusion dependent and who are not high-risk by the proposed criteria. Additionally, commenters requested that this NCA include patients with Intermediate-1 or 2 disease who are needing frequent blood transfusion support.

Response: Based on the additional evidence submitted during the comment period, CMS will nationally cover MDS patients with Intermediate-2 disease with a score of ≥ 1.5 based on the IPSS risk assessment tool. This would include Intermediate-2 patients requiring frequent blood or platelet transfusions, but national coverage would be based on the scale and not specifically the need for frequent blood transfusions. However, for patients who do not meet the specific criteria necessary for coverage under the NCD, coverage determinations under section 1862(a)(1)(A) would be made by the MACs.

Comment: Some commenters recommend the inclusion of patients with secondary or treatment-related MDS. They note that this biologically distinct subset of MDS patients have a very poor prognosis with non-transplant treatment and are universally accepted as high-risk. They also note that allo-HSCT is the sole curative option for this group of patients.

Response: We appreciate the comment. The scope of this reconsideration is limited to the use of allo-HSCT in de novo MDS. The use of allo-HSCT in patients whose MDS is secondary, or treatment related is outside the scope of this NCD. Coverage of any claims for secondary or treatment-related MDS will be determined by the MACs.

Comment: Some commenters were concerned that the proposed risk criteria would disadvantage patients with high-risk molecular findings such as ASXL1 or TP53.

Response: We will finalize this decision to include a score of ≥ 0.5 according to the IPSS-M as a risk assessment tool for predicting AML. Included in this tool are several mutations which might predispose an MDS patient to AML, including the mutations ASXL1 and TP53. To address conditions not nationally covered, CMS has allowed MACs to make coverage determinations under section 1862(a)(1)(A).

Comment: Some commenters were concerned that CMS did not consider MDS patients who fail to respond to hypomethylating agents for treatment for their MDS or patients with severe neutropenia not responding to initial therapy with an HMA. They note that even though these patients are categorized with lower-risk MDS they have significantly lower survival and an increased risk of transformation to AML compared to those who respond to hypomethylating agents. They further note that this population is under rigorous study, both to identify treatments that may be of benefit, as well as to understand the unique biology of their disease.

Response: Based on the additional evidence submitted during the comment period, we are expanding coverage to include MDS patients with a score of ≥ 0.5 according to the IPSS-M risk assessment tool. The inclusion of this additional risk assessment tool may be able to address patients with hypomethylation failure, or patients with severe neutropenia not responding to initial therapy with an HMA if they meet the score. In addition, to provide additional flexibility to address conditions not nationally covered, MACs will be permitted to make coverage determinations under section 1862(a)(1)(A).

Comment: One commenter requested that age alone should not be an exclusionary factor for allogenic HCT.

Response: We are not establishing age as an exclusionary factor under the final NCD. As part of the NCA evidence review, we found that age was not a significant factor in determining outcomes. Many studies have shown that comorbidity status is more closely associated with outcomes (higher comorbidities are associated with worsening outcomes).

Key Outcomes

Comment: One commenter was concerned that this NCA did not include information about how the key outcomes were selected. While they support the key health outcomes in Appendix A, they recommended that CMS identify whether a relevant core outcome set (COS) exists, and also asked us to consider whether the core outcomes should inform the O in the PICO statement for an evidence review. The commenter sought greater transparency on how outcomes are chosen.

Response: We appreciate the comment. As noted in Appendix A, a study’s selected outcomes are an important consideration in generalizing available clinical evidence to Medicare coverage determinations. In general, as part of the National Coverage Analysis (NCA) process, we determine whether or not an item or service is reasonable and necessary, and whether clinically meaningful health outcomes are generalizable to the Medicare population. CMS reviews the medical literature to determine what health outcomes are appropriate for each topic. These health outcomes form the basis of the evidence questions. When CMS issues a proposed decision, we look forward to receiving comments on our evidence questions and selection of relevant health outcomes to be sure they represent outcomes of relevance and important to the population. CMS often uses the PICOTS process, as suggested by the Agency for Healthcare and Quality (AHRQ), as a means of not only identifying appropriate health outcomes, but also populations, interventions, comparators, as well as time frame and settings. Risk, benefits, decrease in mortality, improvement in longevity, and improvement in quality of life, are just a few of the health outcomes that CMS seeks when evaluating a medical intervention.

Early Referral

Comment: One commenter requested alignment with NCCN guidelines which state that early referral for transplant evaluation is recommended.

Response:  We appreciate the comment though we did not identify in the guidelines the appropriate timing for referring a patient to specialists for transplant evaluation. That issue was not specifically reviewed as part of this analysis.

Second allogeneic-HSCT Transplant

Comment: One commenter stated that for patients who experience a disease relapse after initial HCT or whose disease did not respond to treatment, NCCN Guidelines (Category 2A) recommend consideration of a second allogeneic HCT. They further state that NCCN Guidelines suggest the physician consider a second transplant or donor lymphocyte infusion immune-based therapy for appropriate patients who had a prolonged remission after first transplant.

Response: While we appreciate the reference to the NCCN Guidelines for second transplant and donor lymphocyte infusion immune-based therapy for patients who had a prolonged remission after first transplant, this is outside the scope of this NCA analysis. In our assessment of the literature, no studies were identified where a second allo-HSCT was performed. Though the NCCN Guidelines suggest that physicians consider a second transplant, and give it a category 2A level of evidence, there were no studies showing improved outcomes as part of a second transplant.

FDA Section

Comment: One commenter noted that the statement in Section V. Food and Drug Administration (FDA) Status, “[c]urrently, the only stem cell products that are FDA-approved for use in the United States consist of blood-forming stem cells (also known as hematopoietic progenitor cells) that are derived from umbilical cord blood. These products are approved for limited use in patients with disorders that affect the body system that is involved in the production of blood (called the “hematopoietic” system),” is inconsistent with the FDA-approved indications for umbilical cord blood stem cell products, such as the recently approved Omisirge® which is specific to patients undergoing an allogeneic stem cell transplant for hematologic malignancies, inclusive of MDS.

Response: The language included in Section V of this document is provided for convenience. Please contact the FDA’s Center for Biologics Evaluation and Research (CBER) if you have questions or concerns about this language.

Technical Correction

Comment: One commenter stated that the CED study BMT CTN 1102 was incorrectly noted in the evidence tables to be funded by industry (Helocyte, Miyarisan Pharmaceutical). This study was conducted by the BMT CTN which is an NIH-funded network supported by the National Heart, Lung and Blood Institute and the National Cancer Institute and this study was fully funded by NIH grants U10HL069294 and U24HL138660.

Response: The study has been updated in the evidence tables. Thank you for bringing this to our attention.

IX. CMS Analysis

Introduction

National coverage determinations are determinations by the Secretary with respect to whether or not a particular item or service is covered nationally by Medicare (§1869(f)(1)(B) of the Act). In order to be covered by Medicare, an item or service must fall within one or more benefit categories contained within Part A or Part B, and must not be otherwise excluded from coverage. Moreover, with limited exceptions, the expenses incurred for items or services must be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member (§1862(a)(1)(A) of the Act).

When making national coverage determinations, we evaluate the evidence related to our analytic questions based on the quality, strength and totality of evidence presented in the reviewed literature. As part of this evaluation, it is important to consider whether the evidence is relevant to the Medicare beneficiary population. In determining the generalizability of the results of the body of evidence to the Medicare population, we consider, at minimum, the age, race, and gender of the study participants.

For this NCD reconsideration, CMS focused on the following three questions:

1. Prospectively, compared to Medicare beneficiaries with MDS who do not receive allogeneic 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?

Based on the analysis below, MDS patients who received alloHSCT were more likely to benefit from the procedure than patients who did not receive alloHSCT. The use of alloHSCT in patients with MDS provides a benefit of improved overall survival and improved leukemia-free survival, with no decrease in quality of life compared to alternative treatments.

Within the nine studies included in this analysis a number of outcomes were identified. Overall Survival (OS) was the most common outcome reported. Progression-free survival (PFS) as well as references to relapse (e.g., relapse rate/progression, relapse-free survival (RFS), relapse incidence, non-relapsing mortality (NRM)) were also reported. None of the studies included information about relapse-free mortality. Other pertinent outcomes reported include leukemia-free survival (LFS), acute graft versus host disease (aGVHD), chronic graft versus host disease (cGVHD), transplantation-related mortality (TRM), event-free survival (EFS), and disease-free survival (DFS). Some of these terms may have been used interchangeably. Most of the studies had at least five of these parameters. We will discuss outcomes within the context of each study. Prospective studies will be listed first, followed by studies using a retrospective analysis approach.

Prospective studies

The Nakamura study (CED study, NCT02016781) included Overall Survival (OS), leukemia-free survival (LFS), disease-free survival (DFS), transplant-related mortality (TRM), cumulative incidence of relapse, and quality of life (QOL) as outcomes. Results of the study revealed that the adjusted OS rate at 3 years in the alloHSCT group was higher (47.9%) compared with 26.6% in the non-transplant group. The study found that the Leukemia-free survival at 3 years was greater in the transplant group (35.8%) compared with the non-transplant group (20.6%). The survival benefit was seen across all subgroups of MDS. Among the patients that received transplants OS was 55.7% and DFS was 49.7% at 27 months post-HCT. The estimated median DFS was 26.1 months. One hundred-day and 1-year TRM were 7.4% and 15.5%, respectively. Multivariable analysis revealed that higher IPSS risk score was a significant predictor of both OS and DFS. At 27 months post-HCT, the cumulative incidence of relapse following HCT was 29.6%, and the TRM was 20.6%. Also, a patient-reported QOL outcomes survey demonstrated no differences between the transplant group and the non-transplant group QOL scores at any time points evaluated (enrollment, 6, 12, 18, 24, and 36 months). This finding indicated that for patients who received the transplant, their QOL was maintained, and not altered by the procedure.

The Atallah study (CED study, NCT01166009) used overall survival (OS), non-relapse mortality (NRM), relapse-free survival (RFS), as well as acute graft versus host disease (aGVHD) and chronic graft versus host disease cGVHD) as outcomes. The study revealed that there was no difference in overall survival between patients in the older group (aged 65 years or older) and those in the younger group (patients aged 55 to 64 years). The 3-year OS was 37% versus 42% for the 65 years or older group versus the 55 to 64 years age group, respectively. After adjusting for excess risk of NRM in the older population, there was no statistically significant difference in NRM between the aged 65 years or older group and the aged 55 to 64 years group. The adjusted RFS at 3 years was 27% versus 35% for the group aged 65 years or older versus those aged 55 to 64 years (P = .005), but upon multivariable analysis, age group 65 years or older versus those 55 to 64 years had no significant association with RFS. When evaluating acute GVHD, there was no difference between groups in rates of grades II to IV acute GVHD (aGVHD). At 100 days, the incidence of grades II to IV aGVHD was 38% in both groups. On univariate analysis, there was no statistical difference in chronic GVHD (cGVHD) between the age groups. And at 1 year, the incidence of cGVHD was 44% and 47% in the aged 65 years or older and the 55 to 64 years groups, respectively.

The Abel study used overall survival (OS), non-relapse mortality (NRM), progression-free survival (PFS) and relapse as outcomes. For the entire cohort of MDS patients (those who received transplants and those who did not receive transplants) the median OS was 29 months, and the 3-year OS was 46%. Using multivariate analysis, the hazard ratio (HR) for death in the alloHSCT cohort compared to no-HCT was 0.75, indicating that patients who received alloHSCT were less likely to die compared to the non-allo group. For the alloHSCT cohort, the 3-year PFS was 53% and 3-year cumulative incidence of non-relapse mortality and relapse were 9.3% and 39%, respectively.

The Kröger study used overall survival (OS), transplant-related mortality (TRM), event-free survival (EFS), relapse, acute graft versus host disease (aGVHD), and chronic graft versus host disease (cGVHD) as outcomes. The 3-year OS for patients starting 5-aza induction and treatment allocation was 50% in the 5-aza arm for HSCT in comparison with 32% in the 5-aza continuous arm. The cumulative incidence of TRM after HSCT at 1 year was 19%. The event-free survival (EFS) and overall survival (OS) after 5-aza pretreatment and treatment allocation at 3 years were 34% and 50% after alloHSCT and 0% and 32% after continuous 5-aza treatment respectively. During the 5-aza induction phase, 16% of patients experienced relapse or progression. After allocation to continuous 5-aza or HSCT, 13.6% experienced relapse or progression in the alloHSCT arm, whereas 100% of patients in the 5-aza continuous arm relapsed or progressed during follow-up. For patients that received alloHSCT acute GVHD grade II-IV was found in 41%, and severe acute GVHD grade III or IV in 15%. Overall chronic GVHD was noted in 57% of the patients receiving transplants. This study again confirmed that MDS patients who received alloHSCT had superior outcomes compared to MDS patients who did not receive alloHSCT.

Retrospective Studies

The Platzbecker study used Overall Survival (OS), Event-free Survival (EFS), Non-relapse Mortality (NRM), relapse rate, and progression as outcome indicators. In the alloHSCT group the estimated 2-year OS and EFS were 39% and 37%, and relapse and NRM were 30% and 33%, respectively. The 5-year OS and EFS were 35% and 36%, respectively. At last follow-up, 39% were alive in remission after alloHSCT. In the AZA group the 2-year OS, EFS, relapse/progression incidence and NRM were 23%, 14%, 52% and 34%, respectively. At the time of last follow-up, 21% were alive in that group. This study confirmed that MDS patients who received alloHSCT had superior outcomes compared to MDS patients who received AZA.

In the Yucel study, they used Overall Survival (OS), transplant-related mortality (TRM), cumulative incidence of disease progression, acute graft versus host disease (aGVHD), and chronic graft versus host disease (cGVHD) as indicators of outcome. In this cohort of patients, they all received alloHSCT. The 3-year incidence of progression, transplant-related mortality (TRM), and overall survival (OS) were 26%, 35%, and 41%, respectively. The incidence of grade 2-4 and grade 3-4 acute GVHD at day 180 was 43% and 11%, respectively. The incidence of chronic GVHD at 3 years was 38%. The findings of this study were consistent with other studies in the medical literature that involved younger patients with this disease.

The McClune study used Overall Survival (OS), relapse, non-relapse Mortality (NRM), disease-free Survival (DFS), acute graft versus host disease (aGVHD), and chronic graft versus host disease (cGVHD) as indicators of outcome. In MDS patients age 40 to 54, 55 to 59, 60 to 64, and > 65 years, their 2-year survival rates were 42%, 35%, 45%, and 38%, respectively. Multivariate analysis revealed no significant impact of age on NRM, relapse, DFS, or OS. In patients with MDS, NRM at 1 year was 29% for the youngest cohort compared with 35% for the oldest cohort. The cumulative incidences of NRM did not differ between the age cohorts either at day 100 or 1 year. The most common primary causes of death in MDS patient groups were relapse (33%), infection (21%), GVHD (14%), and organ failure (14%). At day 100, the incidence of grade 2 to 4 acute GVHD was similar across all groups. Multivariate analysis showed age had no significant effect on the incidence of acute GVHD but was associated with a borderline higher risk of chronic GVHD, although only in the oldest age cohort.

In the registry study of alloHSCT patients performed by Heidenreich, outcomes in the analysis included OS, RFS, NRM, and relapse incidence. The authors reported that the cumulative incidence of non-relapse mortality at 1 year and relapse at 3 years was 32% and 28%, respectively, with a 3-year overall survival rate of 34%. RFS at 3 years was higher for patients with higher KPS scores and those who were CMV-negative. The estimated 3-year overall survival (OS) rate was 34% with a median follow-up of 29.8 months. The findings of this study were consistent with other studies in the medical literature that featured younger patients who had received alloHSCT for MDS.

Discussion of Outcomes

Question one addresses whether or not outcomes differ between patients who have received alloHSCT, compared to patients who have not received alloHSCT. Some of the studies compared the use of alloHSCT to other forms of therapy (e.g., HMA/AZA). Other studies only involved the use of alloHSCT as a form of treatment and compared differing age groups. For those studies that did a comparative analysis based on treatment, they all showed that patients who received alloHSCT had superior outcomes compared to patients who received alternative therapy. In all of these comparative studies, OS was superior in the alloHSCT group. In those studies that evaluated Disease-free survival/Leukemia-free survival/Event-free survival/Progression-free survival as an outcome, patients that received alloHSCT had better outcomes (longer disease-free intervals) than patients who received alternative treatments.

Other outcomes (e.g., RFS, NRM, relapse incidence, TRM, EFS) were also found to be more favorable in the alloHSCT group compared to patients who received alternative treatments.

Also, when considering overall survival, the studies that performed an analysis based on age revealed that older age patients (≥ 65 and older) were no more likely to die from the procedure than younger patients (no difference in overall survival between age groups). These studies also showed that there was no statistical difference between age groups in exploring other outcomes, including non-relapse mortality (NRM), transplant-related mortality (TRM) nor relapse-free survival (RFS). Some studies also found that there was no difference in rates of grades II to IV acute graft versus host disease (aGVHD) as well as chronic graft versus host disease (cGVHD) between the age groups. In studies were TRM and incidence of relapse were considered in patients who received alloHSCT, they were found to be relatively low.

The Nakamura study as well as the Cusatis study were the only studies that looked at quality of life (QoL) measures. The Nakamura study found that patients who received alloHSCT did not suffer a diminution in QoL compared to patients who received other forms of therapy. In the Cusatis study, alloHSCT patients were compared to non-alloHSCT patients. The Functional Assessment of Cancer Therapy-General (FACT-G), the SF-36, and the EQ-5D were used as measurement tools at enrollment, every 6 months until 24 months, and 36 months. Patient-reported outcome (PRO) scores were compared between both groups. The study involved 384 subjects. It found that baseline PRO scores were the most consistent independent predictor of subsequent QoL and survival. It also found that the survival advantage associated with donor availability and alloHCT did not come at the cost of worst QoL.

In terms of outcomes and results evaluated in this analysis, they are consistent with findings in the medical literature on younger populations with MDS (patients 64 and younger) who underwent the procedure. When comparing prospective studies to retrospective studies, the former group provides more strength of evidence. Most of the prospective studies included a comparator group that received alternative treatment. These analyses revealed that MDS patients who received alloHSCT were more likely to benefit from the procedure than patients who did not receive alloHSCT. Both CED studies (Atallah et al. and Nakamura et al.) developed considerable evidence that supported improved health outcomes. In summary, the use of alloHSCT in patients with MDS provides a benefit of improved survival as well as prolonged disease-free intervals, with no decrease in quality of life compared to alternative treatments. AlloHSCT provides other favorable outcomes to patients with MDS. The studies also revealed that age is not a contributing factor in these outcomes. In conclusion, based on the analysis of all of the above studies Medicare-aged patient with MDS had improved health outcomes after alloHSCT.

2. Prospectively, in Medicare beneficiaries with MDS who receive allogeneic 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?

Based on the analysis below, the following risk stratification systems are nationally covered:

• ≥ 1.5 (Intermediate-2 or high) using the International Prognostic Scoring System (IPSS), or
• ≥ 4.5 (high or very high) using the International Prognostic Scoring System - Revised (IPSS-R), or
• ≥ 0.5 (high or very high) using the Molecular International Prognostic Scoring System (IPSS-M).

MDS has two classification systems. The first system is a diagnostic classification and divides MDS into subgroups primarily based on morphology. The second classification system is based on risk of AML transformation (in general the lower the risk, the less likely AML will develop; the higher the risk, the more likely AML will occur). This information, which is quantifiable as a score, is helpful to clinicians managing patients with MDS because risk stratification helps in the timing and choice of therapy. In general, clinicians managing patients at low-risk of AML transformation tend to use less aggressive treatment strategies (e.g., supportive care, HMA therapy), than patients with high-risk disease. Those in the latter group tend to receive more aggressive treatment strategies (e.g., allogeneic stem cell transplants). Choice of treatment is largely dictated by disease classification and potential risk of AML (as determined by risk scores).

There are 3 risk stratification systems that have been used for treatment and management purposes in classifying risk of AML transformation: WPSS (WHO classification-based Prognostic Scoring System), IPSS (International Prognostic Scoring System), and IPSS-R (Revised International Prognostic Scoring System).

• The WPSS system is based on a time-dependent regression model and permits dynamic estimation of survival and risk of AML transformation at multiple time points during the natural course of MDS. The system uses three components: WHO diagnostic classification, karyotype, and transfusion needs. Based on these factors WPSS stratifies patients into five risk groups: Very Low, Low, Intermediate, High, and Very High.
• IPSS (International Prognostic Scoring System) The prognostic score is based upon the percent of blasts in bone, karyotype, and cytopenias. In the model it stratifies patients into four risk groups (Low, Intermediate-1, Intermediate-2, and High). Its current application is limited to the time of MDS diagnosis.
• IPSS-R (Revised IPSS) is similar to the original IPSS scoring system, but the revised model incorporates a larger number of cytogenetic abnormalities, it better accounts for the severity of cytopenias and establishes a lower cutoff for ANC and assigns greater weight to cytogenetic abnormalities than to blast percentage (Greenberg et al. 2012). This results in more accurate prognostic information. IPSS-R was derived from patients who primarily received supportive care and is intended for use only at the time of diagnosis. IPSS-R stratifies MDS patients into five categories: Very low, Low, Intermediate, High, and Very high-risk. Patients with IPSS-R score of <4.5 are said to have "low-risk" disease, while those with a score 4.5 or greater have "high-risk" disease (Greenberg et al. 2012) (See Tables 1 and 2 in Appendix D). The American Society of Clinical Oncology (ASCO) considers IPSS-R the gold standard in risk assessment tools for MDS (Haider et al. 2017). Other medical entities including the MDS Foundation (Mishra et al. 2013) and American Society for Hematology (ASH) (Bejar 2013) have identified advantages of IPSS-R over IPSS. Even NCCN guidelines for MDS does note that given its more accurate risk stratification, the IPSS-R categorization is preferred although the other systems also have good value.

All nine studies reviewed in this analysis used a stratification system that identified study participants by their risk of AML transformation. Five studies used IPSS (Abel, Platzbecker, Nakamura, Kröger, Cusatis), while four studies used IPSS-R (Nakamura used both IPSS and IPSS-R in their study), Atallah, Heidenreich, Yucel (though Heidenreich used the IPSS-R system, participants were designated as very good, good, intermediate, poor, and very poor; in the Yucel study they combined patients designated as very low and low together, just as they combined together patients with high and very high designations)). The study by McClune used neither risk stratification system, but instead, patients were classified as early or advanced disease. When evaluating risk, four of the studies provided information about MDS sub-groups (Kröger, Yucel, Heidenreich, Platzbecker). Some studies included patients who were designated as having a very-low, or low potential for AML transformation, included patients with early disease, or included patients with a very good or good status (15% of Abel participants were designated low; 43% of McClune participants were designated early; 17% of Atallah participants were designated very low or low; 25% of Yucel participants were designated very low/low; 51% of Heidenreich participants were designated as very good or good). By including patients at low-risk, the analysis could determine if this group with less severe disease also benefitted from alloHSCT.

In addition to risk stratification, some studies also included information about comorbidities, using Hematopoietic Cell Transplant Comorbidity Index (HCT-CI) scores (Atallah, Yucel). Other surrogate markers for comorbidities included Eastern Cooperative Oncology Group (ECOG) performance status (Abel, Nakamura, Kröger, and Platzbecker), or Karnofsky performance scores (KPS) (McClune, Nakamura, and Heidenreich) in helping to predict health outcomes. In answering research question two we will concentrate on predictors of overall survival because it is the most important outcome to patients, and because it was the outcome most consistently reported. Prospective studies will be reported first, followed by retrospective studies.

There was one study, Abel, that incorporated all four parameters mentioned in question 2 (patient’s age, risk scores, degree of cytopenia, and comorbidities) in determining OS health outcome. In the study, the authors looked at age (ranged from 59 to 74), risk status (IPSS ranging from low-risk to high-risk but defined adverse-risk disease as Intermediate-2 or high-risk), degree of cytopenia (severity as defined by WPSS), as well as comorbidity as measured by the Eastern Cooperative Oncology Group (ECOG) scores (ranged from 0 to 3). The study found that after adjusting for age, gender, ECOG performance status, cytogenetic risk, and IPSS risk group, death was lower in patients who were at higher risk of AML transformation and received alloHSCT, than patients who were at lower risk and had severe cytopenia. Also, when considering cytopenia, Abel found that survival was significantly improved if alloHSCT was performed early or for adverse risk disease, but not for standard disease with severe cytopenia. According to the same study, the population that seemed to have derived a survival benefit from alloHSCT included those with ECOG performance score of 1, those with poor-risk cytogenetics, those with Intermediate-2 or high IPSS scores, those with adverse-risk MDS, and those of the male gender. When considering levels of risk and outcomes the analysis demonstrated that patients in the Intermediate-2 and higher risk groups had better OS compared to those in the low-risk group (low-risk and Intermediate-1 risk group).

The Nakamura study used age (range 50 to 75), IPSS and IPSS-R as the risk tools (for IPSS Intermediate-2 or higher scores were used, but for the IPSS-R risk tool all five levels of risk were used), and ECOG performance status (0 and > 0) as well as KPS scores (<90 and 90 to 100) as comorbidity measures to determine health outcomes. The study concluded that patients that received RIC alloHCST from matched donors had a greater overall survival than patients who did not receive alloHSCT, and these same patients had a greater leukemia-free survival than non-transplant recipients. The multivariate model concluded that only high IPSS scores predicted relapse. Specifically looking at overall survival, the study found no evidence of interaction between treatment assignment, age group (older or younger than 65 years), HMA response type, or any other factors reviewed in the study. Using IPSS the study showed OS was higher in patients with Intermediate-2 status, but when using IPSS-R only patients with who were at high-risk or very high-risk had improved OS outcomes.

In the Kröger study, age (those who were aged 64 or less and those 65 and older), risk status (IPSS was used to assess risk; low-risk patients were not included in the study, only Intermediate-1 with high-risk cytology, Intermediate-2, and high-risk were evaluated), and ECOG status (categorized as either levels 0 and 1, or 2) were used as predictor variables. The study concluded that the event-free survival and overall survival were greater in patients who received 5-aza pretreatment and alloHSCT than those who received continuous 5-aza treatment alone. The authors also reported that a survival benefit was mainly seen in patients who were >65 years of age, in IPSS Intermediate-2 risk level, and in remission (partial response or complete response) at the time of transplant. When looking at levels of risk and outcomes (Intermediate-1 with high-risk cytology, Intermediate-2, and high-risk), for those patients who did receive a transplant, their 3-year survival was no better than patients that received 5-AZA.

In the Atallah study, age groups consisted of those 55 to 64 versus those aged 65 or older, and the IPSS-R system of risk were used in the model. KPS scores (≥80 prior to preparative regimen), along with HCT-CI status (0, 1 to 2, 3, 4 or greater) were also used in the model as comorbidity indexes in determining overall survival. After adjusting for excess risk of mortality in the older group, age group had no significant association with OS. Multivariate analysis revealed that IPSS-R high/very high, in vivo T-cell depletion, bBM greater than 11% prior to transplant, use of a conditioning regimen, not in complete remission before transplant, and HCT-CI status of 4 or greater were associated with worse relapse-free survival (RFS). The study found that patients with IPSS-R high/very high-risk levels had more favorable relapse-free survival, and there was no difference in OS, RFS, NRM, and acute/chronic graft versus host disease in patients older than 55 years of age compared to younger patients. Multivariate analysis for OS identified high/very high IPSS-R, blast in bone marrow (BBM) greater than 11% prior to transplant, non-age-adjusted HCT-CI status of 4 or greater, and GVHD prophylaxis were independently associated with inferior outcomes. It reiterated the fact that OS was more influenced by comorbidity than age. When looking specifically at risk levels, only patients in the very high-risk group had improved OS, and patients that were in the high and very high-risk group had improved Relapsed-free Survival.

The Platzbecker study used age (range 60 to 70), the IPSS system to identify risk (Intermediate-1, Intermediate-2, or high), cytogenetics (good versus intermediate versus poor) and ECOG scores (0, 1, 2), to find determinants of OS. The study found that the 2-year OS was higher in the alloHSCT patient group compared to the AZA patient group. The study noted that ECOG performance status and cytogenetics significantly contributed to the prediction of OS and Event-free survival (EFS), and that high-risk cytogenetics were associated with adverse outcome secondary to an increased incidence of relapse. In this study when considering risk, no comparison was made between patients who received transplants and those who received AZA.

In the McClune study, patient’s ages ranged from 40 to 78. The study failed to use the typical risk assessment tools (WPSS, IPSS, IPSS-R), but instead, used cytogenetic risk classification. Comorbidity measures included Karnofsky performance scores at transplantation (> 80). Also included in the study was a variable related to conditioning regiment (RIC versus non-ablative). The study ultimately revealed that age had no significant impact on NRM, relapse, DFS, or OS. It demonstrated that unfavorable cytogenetic status and KPS scores less than 80 adversely impacted relapse, DFS, and OS. No validation was provided showing that cytogenetic risk classification could be used as a substitute for the more typical risk assessment tools.

In determining OS, the Yucel study involved patients in two age groups (those less than 65 and those greater than 65), IPSS-R was used as a risk tool, and HCT-CI scores as a comorbidity index measure (0, 1 to 2, 3 to 4, greater than 4). Cytogenetic abnormalities were categorized according to IPSS-R system and monosomal karyotype (MK). The study found that progression was highest in the poor/very poor cytogenetic risk group compared with the good/very good risk group, and that patients with MKpos had a higher incidence of progression compared with good-risk cytogenetics. None of the other variables, including age >65 years and bone marrow blast count at the time of the alloHSCT, was found to have a prognostic impact on disease progression. A multivariate analysis confirmed that HCT-CI score of >3 was the only independent prognostic factor for TRM at 3 years, and poor risk cytogenetics and HCT-CI scores of >3 were associated with inferior OS. Patients aged > 65 were found not to be associated with worst OS, and using IPSS-R as a risk tool, patients who were at high or very high-risk of AML transformation had improvement in OS.

In the Heidenreich study, patient’s age ranged from 70 to 78. Cytogenetic data were available for a limited number of patients and allocated to cytogenetic risk according to the IPSS-R system (but the IPSS-R risk assessment tool was not used). KPS was used as a comorbidity measure (90 to 100 and 40 to 80), and conditioning regimen (myeloablative versus non-myeloablative versus RIC) was incorporated into the model to determine predictors of overall survival. The authors found that KPS scores > 90 had a strong protective effect against NRM, while CMV seropositivity of the recipient, and grafts from unrelated donors were associated with a higher NRM risk. OS was lower in patients with KPS scores ≤ 80%, and lower in CMV-seropositive recipients. Neither patient gender, choice of conditioning regimen, CMV status of the donor, nor use of T cell depletion had an impact on OS and other primary endpoints in the study. There was no direct assessment of risk using the IPSS or IPSS-R risk tools.

Molecular International Prognostic Scoring System (IPSS-M)

The predictive model that some professional societies are adopting is the Molecular International Prognostic Scoring System (IPSS-M). This model incorporates not only information about MDS classification, demographic information (e.g., hematologic and clinical features), and treatment, but also uses genomic data using somatic mutations found in the patients. Using IPSS-M, patients are divided into six categories that are distinct from one another (very low, low, moderately low, moderately high, high, very high), as opposed to the five categories found in IPSS-R (very low, low, intermediate, high, very high).

Analysis of the data reveals that, when comparing IPSS-R to IPSS-M there is some overlap between the two assessment tools, but by using IPSS-M, some patients are upgraded to a higher level of risk, while some other patients may be downgraded to a lower level of risk. Most of the studies reveal that more of the intermediate IPSS-R patients are upgraded to high or very high in the IPSS-M stratification, than downshifted to moderate high, moderate low, or lower levels of risk (Baer et al. 2023; Zamanillo et al. 2023). Though this model is based on retrospective data (Sabile et al. 2023; Garcia-Manerto et al. 2023; Aguirre et al. 2023), several studies have validated the precision of IPSS-M in external cohorts to identify high-risk patients and therefore, identify patients for whom allo-stem cell transplant would be appropriate. Allo-stem cell transplant is appropriate in this population given their risk of developing AML is at least equal (if not higher) than the risk levels and models we have proposed for national coverage.

Some studies comparing IPSS-M to IPSS-R have shown that based on the model and its stratification, its improved precision would result in improved health outcomes. Sauta and associates reported improved discrimination of IPSS-M compared to IPSS-R for overall survival (OS) and leukemia-free survival (LFS) and proved its applicability in post-allo stem cell transplantation setting (Sauta et al 2023). This retrospective study involved data from the GenoMed4All consortium. They found that with the addition of information about somatic gene mutations, IPSS-M improved prognostic discrimination across all clinical end points with respect to IPSS-R (concordance was 0.81 v 0.74 for overall survival and 0.89 v0.76 for leukemia-free survival, respectively). The study also found that, compared with the IPSS-R based stratification, the IPSS-M risk group changed in 46% of patients (23.6% and 22.4% of subjects were upstaged and down staged respectfully).

Zamanillo compared IPSS-R and IPSS-M using retrospective data and found that IPSS-M re-stratified 48.2% of the patients, of which 16.9% were downgraded and 31.3% were upgraded (Zamanillo et al. 2023). IPSS-M improved outcome prediction for overall survival (OS) and leukemia-free survival (LFS). In 22.2% of the cohort, the reclassification of the IPSS-M could potentially affect clinical management; 17.4% of the patients would be eligible for treatment intensification and 4.8% for treatment reduction. These findings may be important because they might result in a more effective selection of candidates to allo-HSCT and demonstrate improvement in overall survival, disease progression, and leukemia-free survival. Wu and associates were able to demonstrate that IPSS-M was a more reliable tool in survival prediction accuracy than IPSS-R (Wu et al. 2022). Baer used retrospective data and Harrell’s concordance index (c-index) as a statistic to assess the correlation between predictions according to the IPSS-R and IPSS-M with outcomes (Baer et al. 2023). The study showed that the c-index for the IPSS-R was 0.68 for overall survival (OS), 0.69 for leukemia-free survival (LFS) and 0.77 leukemic transformation (LT), and improved to 0.71 (OS), 0.73 (LFS) and 0.81 (LT) when using the IPSS-M model.

Discussion of age, comorbidity, risk status, and degree of cytopenia

When considering the variables; age, risk status, degree of cytopenia, and comorbidities as determinants of outcomes, a number of observations were found. First, in general, when considering MDS and the clinical benefits of alloHSCT, there is a paucity of Medicare-aged participants in the published medical literature. In the past, Medicare-aged patients may not have been considered for alloHSCT because of the belief that they were poor candidates for the procedure due to their age. But based on this assessment that is not true; these studies fail to show that age is a negative determinate of overall survival. Multiple studies in our analysis have confirmed this. In the nine studies reviewed in this NCA, patients ranged in age from 55 to 78. These studies refute the notion that age has a deleterious effect and indicate that Medicare-aged patients were no more likely to die from the procedure than patients who are 64 years of age and younger. The studies also found that they did not have lower leukemia-free survival compared to patients 64 and younger in age. Some studies included in this assessment found that other outcomes, such as NRM, relapse, and DFS were not affected by age. Other studies found that age group had no significant association with aGVHD or cGVHD, nor did it have a significant association with RFS. Clinicians have proposed that older patients with MDS be allowed alloHSCT, especially since safer conditioning agents (e.g., RIC) are available. These findings could result in elderly MDS patients getting access to alloHSCT. Based on our analysis we agree that age alone is not a significant predictor of health outcomes and should not be a barrier to alloHSCT. This would make the procedure more available to older patients with MDS.

The second observation noted is that, even though age is not a determinant of outcomes, comorbidity status is highly influential in outcome results. In the studies used in this analysis, a number of comorbidity indicators were used. HCT-CI status was the most common indicator used. It provides information with regard to the overall survival as well as non-relapse mortality risk that a patient is likely to experience after hematopoietic stem cell transplantation. Other comorbidity measures used included Karnofsky performance scores (KPS), as well as Eastern Cooperative Oncology Group (ECOG) status. Though these latter two are not specific to transplant patients, they do provide valuable information about a patient’s health status. Studies included in this analysis did reveal that the worst the health index (the worst the comorbidity scores), the worst were the outcomes-not only for overall survival, but for other outcome measures (e.g., relapse, DFS). Yucel found that for transplant-related mortality (TRM), HCT-CI>3 was associated with worse outcomes. Functional status was more predictive of outcome than age alone.

Risk status was also an important determinant of outcomes. Some believe that alloHSCT should be made available to all patients with MDS, no matter the extent of their disease. But based on the evidence, are some patients with certain characteristics more likely to benefit from the procedure than others? The answer to this question is very important to CMS. In answering this question some of the studies used in this review were of limited value because they used proxies to measure risk (e.g., “early/advanced” disease or cytology according to IPSS-R criteria when describing risk). Studies reviewed in this analysis used either IPSS, IPSS-R or both tools (Nakamura) when assessing risk levels (though McClune used “early” or “advanced” disease as a proxy, and Heidenreich used cytology according to IPSS-R criteria when describing risk). Our analysis revealed that some studies using IPSS as a risk indicator found that patients with Intermediate-2 and high-risk status had improved health outcomes (longer overall survival) secondary to alloHSCT, as opposed to patients with low or Intermediate-1 status (Abel, Nakamura). In studies where IPSS-R was used as a risk assessment tool, they found that patients with high or very high-risk status had improved health outcomes (overall survival, progression-free survival or relapse-free survival) after alloHSCT, as opposed to patients who had very low, low, or Intermediate risk of AML transformation. These findings are especially relevant and pertinent because in the Nakamura study, both IPSS and IPSS-R risk assessment tools were used in a comparable population. The study confirmed that when using IPSS, patients with Intermediate-2 achieved improved overall survival, but when evaluating IPSS-R patients, only those with high and very high-risk of AML transformation had improved overall survival.

Many national professional organizations consider IPSS-R the gold standard when assessing risk of AML transformation because it more accurately identifies patients who had high or very high-risk of AML transformation that could benefit from alloHSCT. Also, IPSS-R is universally used not only for risk stratification and therapeutic decision-making in the clinic but also in designing clinical trials; in turn, it is included in the approved indications (drug labels) of drug regulatory agencies (Cazzola, et al. 2022). We believe it is reasonable based on the published studies to use the IPSS-R as a mechanism to identify appropriate patients. CMS acknowledges that as medical technologies advance, there may also be changes in diagnostic and management tools to keep pace. Both of the CED studies that were the basis of this reconsideration used IPSS-R as a risk assessment tool (Atallah and Nakamura). Both confirmed that patients at high or very high-risk had improved outcomes (e.g., improvement in overall survival or relapse-free survival). The Nakamura study also found that when using IPSS, patients with Intermediate-2 and high-risk status had improvements in overall survival. Greenburg and associates, as well as some MDS medical entities (e.g., MDS Foundation) have designated patients with an IPSS-R score of 4.5 or greater to be at high-risk of AML transformation. None of these CED studies (or other studies that used IPSS-R) found that patients with very low, low, or Intermediate-1 risk scores had improved overall survival (or other outcomes) after undergoing alloHSCT. Nor did any of the studies using IPSS find that patients with low or Intermediate-1 had improved health outcomes after alloHSCT. These findings were confirmed in both prospective studies as well as retrospective studies. IPSS-R is the preferred risk assessment tool because it more accurately identified patients who had high or very high-risk of AML transformation. Therefore, based on review of the studies using IPSS-R, it is reasonable and necessary to finalize national coverage of allogeneic stem cell transplant in MDS patients who are at high or very high-risk based on IPSS-R criteria.

The final component of question two addressed the degree of cytopenia and how it affected outcomes. It was evaluated only in the study performed by Abel. The author noted that the degree of cytopenia (severity) was defined by WPSS. The study found that death was lower in patients who were at higher risk of AML transformation and received alloHSCT, than patients who were at lower risk and had severe cytopenia. It also found that survival was significantly improved if alloHSCT was performed early or for adverse risk disease, but not for standard disease with severe cytopenia. Based on these two findings it appears that the degree of cytopenia play a less important role in outcomes. But in the final analysis, Abel used IPSS as a risk assessment tool and it found that patients with Intermediate-2 and higher status had better overall survival than patients with low or Intermediate-1 status.

3. Prospectively, in Medicare beneficiaries with MDS who receive allogeneic 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?

In our review of the articles, only one study addressed the issue of facility characteristics. Atallah and associates reported that center characteristics such as volume of allogeneic transplants, total transplant volume, and years of operation had no effect on any of the outcomes reported (e.g., overall survival (OS), non-relapse mortality (NRM), relapse-free survival (RFS), acute graft versus host disease (aGVHD) and chronic graft vs host disease (cGVHD). For this reason, we did not establish requirements of volume of transplants, physician experience, or any other facility characteristics.

In all studies, alloHSCT took place at a transplant center. With the exception of three studies (Atallah, Nakamura, Kröger) the source of the donor stem cells for alloHSCT were either peripheral blood or bone marrow (the three studies did not list the source of stem cells). There was no mention of other sources of stem cells including amniotic fluid, umbilical cord, or placenta. Only one study provided information about facility characteristics and outcomes. Atallah reported in his study that center characteristics such as volume of allogeneic transplants, total transplant volume, and years of operation had no effect on any of the outcomes reported (e.g., overall survival (OS), non-relapse mortality (NRM), relapse-free survival (RFS), acute graft versus host disease (aGVHD) and chronic graft vs host disease (cGVHD).

Two other important issues must also be addressed when considering alloHSCT in patients with MDS: the effectiveness of the procedure at the subgroup level, and which conditioning agents are most effective in the cytoreductive process. Some of the studies in this review did included information about subgroups based on WHO classification (Nakamura, Kröger, Platzbecker, Yucel, Heidenreich), while other studies based subgroup classifications on cytology according to IPSS or IPSS-R criteria. Among the groups of studies that based subgroups on WHO criteria, Kröger found that alloHSCT was equally effective in all subgroups. Nakamura not only found that overall survival (OS) was equally effective in all subgroups of MDS patients who received alloHSCT, the study found the same for leukemia-free survival (LFS). Therefore, when looking at subgroup classifications of MDS patients, all groups benefit from alloHSCT.

Myeloablative Conditioning (MAC) and Reduced Intensity Condition (RIC), which is a form of Non-Myeloablative Conditioning (NMAC), are options for cytoreduction. Half of the studies used RIC alone in its conditioning regimen (Nakamura, Yucel, McClune, Kröger), so in these studies no comparisons can be made between MAC and RIC. In other studies, both MAC and RIC were used (Atallah, Platzbecker, Abel, Heidenreich), but Heidenreich was the only study that performed an analysis comparing the two regimens. The analysis found that there were no differences between the regimens when comparing OS, relapse-free survival (RFS), relapse incidence (RI), or non-relapse mortality (NRM). Though the study by McClune did not compare MAC to RIC, it did reveal that transplantation toxicity, relapse, and survival for older adults were not significantly different than those for younger adults undergoing a similar NMAC or RIC alloHSCT. Also, there were no significant differences on NRM, relapse, DFS, or OS between the two conditioning strategies. Based on these findings, MAC or RIC conditioning could be used as part of the alloHSCT treatment for Medicare patients with MDS.

Stem Cell Sources

Based on the analysis below, we are expanding Medicare coverage for allogeneic hematopoietic stem cell transplant using bone marrow, peripheral blood or umbilical cord blood stem cell products for Medicare patients with myelodysplastic syndromes who meet the designated prognostic risk scores.

In this national coverage analysis, we focused primarily on peripheral blood and bone marrow as sources for stem cells. That is because studies have shown that these two sources offer the best results in outcomes (e.g., overall survival). Allo-HSCT is the only curative therapeutic option for patients with MDS, however only one-in-four patients will have a sibling donor that is matched for human leukocyte antigens (HLA) (USCB, 2016). Since MDS most commonly occurs in the elderly, their siblings may not be suitable donors due to comorbid conditions. Also, registries have demonstrated that though HLA-matched donor can be identified for approximately 75% of Caucasian recipients, the numbers are quite lower for other ethnic groups (Appelbaum et al. 2021; Gragert et al. 2014). Umbilical cord blood (UCB) is an alternative source for stem cells, and it has two distinct advantages compared to other sources: one, is its relative tolerance of HLA disparity, and the other, as a cryopreserved stem cell source, its rapid availability with flexible timing of transplant (Barker et al. 2010; Barker et al. 2002). One drawback of using UCB as a donor source is the limited number of cells leading to a delayed time to engraftment and immune reconstitution. Recent retrospective analyses have revealed that disease-free survival after UCB for hematologic malignancies is comparable to that of matched-related or unrelated donors (Brunstein et al. 2012; Brunstein et al. 2010; Chen et al. 2010). Other studies have shown the benefit of UCB in patients. Some studies have shown that umbilical cord blood results in comparable outcomes across the spectrum of diseases (including MDS) for which HSCT is appropriate, and at expert centers when comparable patients are compared, cord blood may in fact be associated with better outcomes than other donor sources (Sharma et al. 2020); Brunstein et al. 2010; Gutman et al. 2016; Milano et al. 2016; Ponce et al. 2011; Milano et al. 2020).

The NCCN guidelines include cord blood stem cell grafts as one of the standards of care for MDS and gives it a category 2A level of evidence (Greenberg et al. 2023). The ASTCT does mention the use of umbilical cord blood in the management of patients with MDS (DeFlippo et al. 2023). They note that although HLA fully matched related or unrelated donors are preferrable to optimize post-transplantation outcomes, this is not always possible, especially among racial and ethnic minority groups. In their guideline they recommend the use of cord blood as an alternative donor option. The grade of the recommendation is C, and the highest level of evidence is 2+. Based on this information, the use of umbilical cord blood in patients with MDS is reasonable.

Currently, there is no evidence that using placenta or amniotic fluid as a source of stem cell in allogeneic stem cell transplantation is of benefit. For this reason, none of the professional societies endorse its use for this purpose.

Therefore, national coverage will be expanded to bone marrow, peripheral blood and umbilical cord blood stem cell products for Medicare patients with MDS. Other sources of stem cells will not be covered.

Based on this analysis, alloHSCT is a reasonable and necessary treatment for the patients identified with MDS under section 1862(a)(1)(A) of the Social Security Act.

Health Disparities
All of the studies in this analysis included information about gender, except for the study done by Yucel. Information about race/ethnicity was more limited. Only the studies by Nakamura, Atallah, and Abel provided information about race/ethnicity. None of the studies included information on sexual orientation, religion, and other demographic information. Based on the findings of these studies, there does not appear to be any discrepancies in services available to, or outcomes based on gender or race/ethnic background.

Poverty was an important barrier to accessing HSCT, as patients from areas with higher poverty rates diagnosed with myeloid neoplasia, including MDS, were less likely to receive AHSCT compared to patients from wealthier counties. Additionally, patients from a low socioeconomic status or those residing more than 75 miles from the transplant center were significantly more likely than the rest of the population to have higher 1-year non-relapse related mortality.

Future studies performed not only in the United States, but the rest of the world should provide evidence about benefits or harms related to other population classifiers that have been historically associated with healthcare access or outcome disparities.

Summary
Given the evidence provided in this analysis and submitted by public commenters, CMS will expand what was proposed to include umbilical cord stem cell products, add Intermediate-2 risk patients (IPSS) and include the IPSS-M scoring system.

Because MDS is a progressive condition, we will provide greater flexibility by enabling Medicare Administrative Contractor to make a coverage determination under section 1862(a)(1)(A) for allogeneic hematopoietic stem cell transplants for patients with MDS who do not meet the national coverage criteria. This will allow Medicare Administrative Contractors to assess additional information including information on mutations and individual patient characteristics when making coverage decisions.

IX.   Conclusion

CMS has reconsidered one aspect of the national coverage determination established at section 110.23 of the Medicare National Coverage Determinations Manual Pub. 100-03. We are expanding Medicare coverage for allogeneic hematopoietic stem cell transplant using bone marrow, peripheral blood or umbilical cord blood stem cell products for Medicare patients with myelodysplastic syndromes who have prognostic risk scores of:

• ≥ 1.5 (Intermediate-2 or high) using the International Prognostic Scoring System (IPSS), or
• ≥ 4.5 (high or very high) using the International Prognostic Scoring System - Revised (IPSS-R), or
• ≥ 0.5 (high or very high) using the Molecular International Prognostic Scoring System (IPSS-M).

For these patients, the evidence demonstrates that the treatment is reasonable and necessary under section 1862(a)(1)(A) of the Social Security Act.

In addition, coverage of all other indications for stem cell transplantation not otherwise specified will be made by local Medicare Administrative Contractors under section 1862(a)(1)(A) of the Act.

See Appendix B for the NCD manual language, specifically Section B.1.c for the expanded nationally covered indications and Section D recognizing that the Medicare Administrative Contractors may determine coverage under section 1862(a)(1)(A) for other beneficiaries with myelodysplastic syndromes.

APPENDIX A

General Methodological Principles of Study Design
(Section VI of the Decision Memorandum)

When making national coverage determinations, 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 is reasonable and necessary. The overall objective for the critical appraisal of the evidence is 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.

We divide the assessment of clinical evidence into three stages: 1) the quality of the individual studies; 2) the generalizability of findings from individual studies to the Medicare population; and 3) overarching conclusions that can be drawn from the body of the evidence on the direction and magnitude of the intervention’s potential risks and benefits.

The methodological principles described below represent a broad discussion of the issues we consider when reviewing clinical evidence. However, it should be noted that each coverage determination has its unique methodological aspects.

Assessing Individual Studies

Methodologists have developed criteria to determine weaknesses and strengths of clinical research. Strength of evidence generally refers to: 1) the scientific validity underlying study findings regarding causal relationships between health care interventions and health outcomes; and 2) the reduction of bias. In general, some of the methodological attributes associated with stronger evidence include those listed below:

• Use of randomization (allocation of patients to either intervention or control group) in order to minimize bias.
• Use of contemporaneous control groups (rather than historical controls) in order to ensure comparability between the intervention and control groups.
• Prospective (rather than retrospective) studies to ensure a more thorough and systematical assessment of factors related to outcomes.
• Larger sample sizes in studies to demonstrate both statistically significant as well as clinically significant outcomes that can be extrapolated to the Medicare population. Sample size should be large enough to make chance an unlikely explanation for what was found.
• Masking (blinding) to ensure patients and investigators do not know to that group patients were assigned (intervention or control). This is important especially in subjective outcomes, such as pain or quality of life, where enthusiasm and psychological factors may lead to an improved perceived outcome by either the patient or assessor.

Regardless of whether the design of a study is a randomized controlled trial, a non-randomized controlled trial, a cohort study or a case-control study, the primary criterion for methodological strength or quality is to the extent that differences between intervention and control groups can be attributed to the intervention studied. This is known as internal validity. Various types of bias can undermine internal validity. These include:

• Different characteristics between patients participating and those theoretically eligible for study but not participating (selection bias).
• Co-interventions or provision of care apart from the intervention under evaluation (performance bias).
• Differential assessment of outcome (detection bias).
• Occurrence and reporting of patients who do not complete the study (attrition bias).

In principle, rankings of research design have been based on the ability of each study design category to minimize these biases. A randomized controlled trial minimizes systematic bias (in theory) by selecting a sample of participants from a particular population and allocating them randomly to the intervention and control groups. Thus, in general, randomized controlled studies have been typically assigned the greatest strength, followed by non-randomized clinical trials and controlled observational studies. The design, conduct and analysis of trials are important factors as well. For example, a well-designed and conducted observational study with a large sample size may provide stronger evidence than a poorly designed and conducted randomized controlled trial with a small sample size. The following is a representative list of study designs (some of that have alternative names) ranked from most to least methodologically rigorous in their potential ability to minimize systematic bias:

Randomized controlled trials
Non-randomized controlled trials
Prospective cohort studies
Retrospective case control studies
Cross-sectional studies
Surveillance studies (e. g., using registries or surveys)
Consecutive case series
Single case reports

When there are merely associations but not causal relationships between a study’s variables and outcomes, it is important not to draw causal inferences. Confounding refers to independent variables that systematically vary with the causal variable. This distorts measurement of the outcome of interest because its effect size is mixed with the effects of other extraneous factors. For observational, and in some cases randomized controlled trials, the method in that confounding factors are handled (either through stratification or appropriate statistical modeling) are of particular concern. For example, in order to interpret and generalize conclusions to our population of Medicare patients, it may be necessary for studies to match or stratify their intervention and control groups by patient age or co-morbidities.

Methodological strength is, therefore, a multidimensional concept that relates to the design, implementation and analysis of a clinical study. In addition, thorough documentation of the conduct of the research, particularly study selection criteria, rate of attrition and process for data collection, is essential for CMS to adequately assess and consider the evidence.

Generalizability of Clinical Evidence to the Medicare Population

The applicability of the results of a study to other populations, settings, treatment regimens and outcomes assessed is known as external validity. Even well-designed and well-conducted trials may not supply the evidence needed if the results of a study are not applicable to the Medicare population. Evidence that provides accurate information about a population or setting not well represented in the Medicare program would be considered but would suffer from limited generalizability.

The extent to that the results of a trial are applicable to other circumstances is often a matter of judgment that depends on specific study characteristics, primarily the patient population studied (age, sex, severity of disease and presence of co-morbidities) and the care setting (primary to tertiary level of care, as well as the experience and specialization of the care provider). Additional relevant variables are treatment regimens (dosage, timing and route of administration), co-interventions or concomitant therapies, and type of outcome and length of follow-up.

The level of care and the experience of the providers in the study are other crucial elements in assessing a study’s external validity. Trial participants in an academic medical center may receive more or different attention than is typically available in non-tertiary settings. For example, an investigator’s lengthy and detailed explanations of the potential benefits of the intervention and/or the use of new equipment provided to the academic center by the study sponsor may raise doubts about the applicability of study findings to community practice.

Given the evidence available in the research literature, some degree of generalization about an intervention’s potential benefits and harms is invariably required in making coverage determinations for the Medicare population. Conditions that assist us in making reasonable generalizations are biologic plausibility, similarities between the populations studied and Medicare patients (age, sex, ethnicity and clinical presentation) and similarities of the intervention studied to those that would be routinely available in community practice.

A study’s selected outcomes are an important consideration in generalizing available clinical evidence to Medicare coverage determinations. One of the goals of our determination process is to assess health outcomes. These outcomes include resultant risks and benefits such as increased or decreased morbidity and mortality. In order to make this determination, it is often necessary to evaluate whether the strength of the evidence is adequate to draw conclusions about the direction and magnitude of each individual outcome relevant to the intervention under study. In addition, it is important that an intervention’s benefits are clinically significant and durable, rather than marginal or short-lived. Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits.

If key health outcomes have not been studied or the direction of clinical effect is inconclusive, we may also evaluate the strength and adequacy of indirect evidence linking intermediate or surrogate outcomes to our outcomes of interest.

Assessing the Relative Magnitude of Risks and Benefits

Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits. Health outcomes are one of several considerations in determining whether an item or service is reasonable and necessary. CMS places greater emphasis on health outcomes actually experienced by patients, such as quality of life, functional status, duration of disability, morbidity and mortality, and less emphasis on outcomes that patients do not directly experience, such as intermediate outcomes, surrogate outcomes, and laboratory or radiographic responses. The direction, magnitude, and consistency of the risks and benefits across studies are also important considerations. Based on the analysis of the strength of the evidence, CMS assesses the relative magnitude of an intervention or technology’s benefits and risk of harm to Medicare beneficiaries.

APPENDIX B
Medicare National Coverage Determinations Manual

Table of Contents
(Rev.)

110.23 - Stem Cell Transplantation (Formerly 110.8.1) (Various Effective Dates Below)

A. General

Stem cell transplantation is a process in which stem cells are harvested from either a patient’s (autologous) or donor’s (allogeneic) bone marrow or peripheral blood for intravenous infusion. Autologous stem cell transplantation (AuSCT) is a technique for restoring stem cells using the patient's own previously stored cells. AuSCT must be used to effect hematopoietic reconstitution following severely myelotoxic doses of chemotherapy (HDCT) and/or radiotherapy used to treat various malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) is a procedure in which a portion of a healthy donor's stem cell or bone marrow is obtained and prepared for intravenous infusion. Allogeneic HSCT may be used to restore function in recipients having an inherited or acquired deficiency or defect. Hematopoietic stem cells are multi-potent stem cells that give rise to all the blood cell types; these stem cells form blood and immune cells. A hematopoietic stem cell is a cell isolated from blood or bone marrow that can renew itself, differentiate to a variety of specialized cells, can mobilize out of the bone marrow into circulating blood, and can undergo programmed cell death, called apoptosis - a process by which cells that are unneeded or detrimental will self-destruct.

The Centers for Medicare & Medicaid Services (CMS) is clarifying that bone marrow and peripheral blood stem cell transplantation is a process which includes mobilization, harvesting, and transplant of bone marrow or peripheral blood stem cells and the administration of high dose chemotherapy or radiotherapy prior to the actual transplant. When bone marrow or peripheral blood stem cell transplantation is covered, all necessary steps are included in coverage. When bone marrow or peripheral blood stem cell transplantation is non-covered, none of the steps are covered.

B. Nationally Covered Indications

I. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

a) 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,

b) 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, and

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. The abnormal production of blood cells in the bone marrow leads to low blood cell counts, referred to as cytopenias, which are a hallmark feature of MDS along with a dysplastic and hypercellular-appearing bone marrow.

II. Autologous Stem Cell Transplantation (AuSCT)

a) Effective for services performed on or after April 28, 1989, AuSCT is considered reasonable and necessary under §l862(a)(1)(A) of the Act for the following conditions and is covered under Medicare for patients with:

1. Acute leukemia in remission who have a high probability of relapse and who have no human leucocyte antigens (HLA)-matched;

2. Resistant non-Hodgkin's lymphomas or those presenting with poor prognostic features following an initial response;

3. Recurrent or refractory neuroblastoma; or,

4. Advanced Hodgkin's disease who have failed conventional therapy and have no HLA-matched donor.

b) Effective October 1, 2000, single AuSCT is only covered for Durie-Salmon Stage II or III patients that fit the following requirements:

c) Effective for services performed on or after March 15, 2005, when recognized clinical risk factors are employed to select patients for transplantation, high dose melphalan (HDM) together with AuSCT is reasonable and necessary for Medicare beneficiaries of any age group with primary amyloid light chain (AL) amyloidosis who meet the following criteria:

C. Nationally Non-Covered Indications

I. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Effective for claims with dates of service on or after May 24, 1996, through January 26, 2016, allogeneic HSCT is not covered as treatment for multiple myeloma.

II. Autologous Stem Cell Transplantation (AuSCT)

Insufficient data exist to establish definite conclusions regarding the efficacy of AuSCT for the following conditions:

a) Acute leukemia not in remission;
b) Chronic granulocytic leukemia;
c) Solid tumors (other than neuroblastoma);
d) Up to October 1, 2000, multiple myeloma;
e) Tandem transplantation (multiple rounds of AuSCT) for patients with multiple  myeloma;
f) Effective October 1, 2000, non-primary AL amyloidosis; and,
g) Effective October 1, 2000, through March 14, 2005, primary AL amyloidosis for Medicare beneficiaries age 64 or older.

In these cases, AuSCT is not considered reasonable and necessary within the meaning of §l862(a)(1)(A) of the Act and is not covered under Medicare.

D. Other

(This NCD last reviewed March 2024.)

APPENDIX C
Current Medicare National Coverage Determinations Manual

110.23 - Stem Cell Transplantation (Formerly 110.8.1) (Various Effective Dates Below) (Rev. 193, Issued; 07-01-16, Effective: 01-27-16, Implementation: 10-03-16)

A. General

Stem cell transplantation is a process in which stem cells are harvested from either a patient’s (autologous) or donor’s (allogeneic) bone marrow or peripheral blood for intravenous infusion. Autologous stem cell transplantation (AuSCT) is a technique for restoring stem cells using the patient's own previously stored cells. AuSCT must be used to effect hematopoietic reconstitution following severely myelotoxic doses of chemotherapy (HDCT) and/or radiotherapy used to treat various malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) is a procedure in which a portion of a healthy donor's stem cell or bone marrow is obtained and prepared for intravenous infusion. Allogeneic HSCT may be used to restore function in recipients having an inherited or acquired deficiency or defect. Hematopoietic stem cells are multi-potent stem cells that give rise to all the blood cell types; these stem cells form blood and immune cells. A hematopoietic stem cell is a cell isolated from blood or bone marrow that can renew itself, differentiate to a variety of specialized cells, can mobilize out of the bone marrow into circulating blood, and can undergo programmed cell death, called apoptosis - a process by which cells that are unneeded or detrimental will self-destruct.

The Centers for Medicare & Medicaid Services (CMS) is clarifying that bone marrow and peripheral blood stem cell transplantation is a process which includes mobilization, harvesting, and transplant of bone marrow or peripheral blood stem cells and the administration of high dose chemotherapy or radiotherapy prior to the actual transplant. When bone marrow or peripheral blood stem cell transplantation is covered, all necessary steps are included in coverage. When bone marrow or peripheral blood stem cell transplantation is non-covered, none of the steps are covered.

B. Nationally Covered Indications

I. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

a) 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,

b) 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.

c) Effective for services performed on or after August 4, 2010, for the treatment of Myelodysplastic Syndromes (MDS) pursuant to Coverage with Evidence Development (CED) in the context of a Medicare-approved, prospective clinical study.

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. The abnormal production of blood cells in the bone marrow leads to low blood cell counts, referred to as cytopenias, which are a hallmark feature of MDS along with a dysplastic and hypercellular-appearing bone marrow.

Medicare payment for these beneficiaries will be restricted to patients enrolled in an approved clinical study. In accordance with the Stem Cell Therapeutic and Research Act of 2005 (US Public Law 109-129) a standard dataset is collected for all allogeneic transplant patients in the United States by the Center for International Blood and Marrow Transplant Research. The elements in this dataset, comprised of two mandatory forms plus one additional form, encompass the information we require for a study under CED.

A prospective clinical study seeking Medicare payment for treating a beneficiary with allogeneic HSCT for MDS pursuant to CED must meet one or more aspects of the following questions:

1.      Prospectively, compared to Medicare beneficiaries with MDS who do not receive HSCT, do Medicare beneficiaries with MDS who receive HSCT have improved outcomes as indicated by:

• Relapse-free mortality,
• progression free survival,
• relapse, and
• overall survival?

2.     Prospectively, in Medicare beneficiaries with MDS who receive HSCT, how do International Prognostic Scoring System (IPSS) scores, patient age, cytopenias, and comorbidities predict the following outcomes:

• Relapse-free mortality,
• progression free survival,
• relapse, and
• overall survival?

3.      Prospectively, in Medicare beneficiaries with MDS who receive HSCT, what treatment facility characteristics predict meaningful clinical improvement in the following outcomes:

• Relapse-free mortality,
• progression free survival,
• relapse, and
• overall survival?

 In addition, the clinical study must adhere to the following standards of scientific integrity and relevance to the Medicare population:

a. The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes.

b. 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.

c. The research study does not unjustifiably duplicate existing studies.

d. The research study design is appropriate to answer the research question being asked in the study.

e. The research study is sponsored by an organization or individual capable of executing the proposed study successfully.

f. 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.

g. All aspects of the research study are conducted according to appropriate standards of scientific integrity (see http://www.icmje.org).

 h. The research study has a written protocol that clearly addresses, or incorporates by reference, the standards listed here as Medicare requirements for CED coverage.

i. 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.

j. The clinical research study is registered on the ClinicalTrials.gov Web site by the principal sponsor/investigator prior to the enrollment of the first study subject.

k. The research study protocol specifies the method and timing of public release of all pre-specified 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 3 years after the end of data collection.

l. 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.

m. 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, the Agency for Health Research and Quality (AHRQ) supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions.

The clinical research study should also have the following features:

• It should be a prospective, longitudinal study with clinical information from the period before HSCT and short- and long-term follow-up information.
• Outcomes should be measured and compared among pre-specified subgroups within the cohort.
• The study should be powered to make inferences in subgroup analyses.
• Risk stratification methods should be used to control for selection bias. Data elements to be used in risk stratification models should include:

  Patient selection:

  - Patient Age at diagnosis of MDS and at transplantation

  - Date of onset of MDS

  - Disease classification (specific MDS subtype at diagnosis prior to preparative/conditioning regimen using World Health Organization (WHO) classifications). Include presence/absence of refractory cytopenias

  - Comorbid conditions

  - IPSS score (and WHO-adapted Prognostic Scoring System (WPSS) score, if applicable) at diagnosis and prior to transplantation

  - Score immediately prior to transplantation and one-year post-transplantation

  - Disease assessment at diagnosis at start of preparative regimen and last assessment prior to preparative regimen Subtype of MDS (refractory anemia with or without blasts, degree of blasts, etc.)

  - Type of preparative/conditioning regimen administered (myeloabalative, non-myeloablative, reduced-intensity conditioning)

  - Donor type

  - Cell Source

Facilities must submit the required transplant essential data to the Stem Cell Therapeutics Outcomes Database.

d) Effective for claims with dates of service on or after January 27, 2016, allogeneic HSCT for multiple myeloma is covered by Medicare only for beneficiaries with Durie-Salmon Stage II or III multiple myeloma, or International Staging System (ISS) Stage II or Stage III multiple myeloma, and participating in an approved prospective clinical study that meets the criteria below. There must be appropriate statistical techniques to control for selection bias and confounding by age, duration of diagnosis, disease classification, International Myeloma Working Group (IMWG) classification, ISS stage, comorbid conditions, type of preparative/conditioning regimen, graft vs. host disease (GVHD) prophylaxis, donor type and cell source.

A prospective clinical study seeking Medicare coverage for allogeneic HSCT for multiple myeloma pursuant to CED must address the following question:

Compared to patients who do not receive allogeneic HSCT, do Medicare beneficiaries with multiple myeloma who receive allogeneic HSCT have improved outcomes as indicated by:

• Graft vs. host disease (acute and chronic);
• Other transplant-related adverse events;
• Overall survival; and
• (optional) Quality of life?

All CMS-approved clinical studies and registries must adhere to the below listed standards of scientific integrity and relevance to the Medicare population as listed in section g.

e) Effective for claims with dates of service on or after January 27, 2016, allogeneic HSCT for myelofibrosis (MF) is covered by Medicare only for beneficiaries with Dynamic International Prognostic Scoring System (DIPSSplus) Intermediate-2 or High primary or secondary MF and participating in an approved prospective clinical study. All Medicare approved studies must use appropriate statistical techniques in the analysis to control for selection bias and potential confounding by age, duration of diagnosis, disease classification, DIPSSplus score, comorbid conditions, type of preparative/conditioning regimen, graft vs. host disease (GVHD) prophylaxis, donor type and cell source.

A prospective clinical study seeking Medicare coverage for allogeneic HSCT for myelofibrosis pursuant to Coverage with Evidence Development (CED) must address the following question:

Compared to patients who do not receive allogeneic HSCT, do Medicare beneficiaries with MF who receive allogeneic HSCT transplantation have improved outcomes as indicated by:

• Graft vs. host disease (acute and chronic);
• Other transplant-related adverse events;
• Overall survival; and
• (optional) Quality of life?

All CMS-approved clinical studies and registries must adhere to the below listed standards of scientific integrity and relevance to the Medicare population as listed in section g.

f) Effective for claims with dates of service on or after January 27, 2016, allogeneic HSCT for sickle cell disease (SCD) is covered by Medicare only for beneficiaries with severe, symptomatic SCD who participate in an approved prospective clinical study.

A prospective clinical study seeking Medicare coverage for allogeneic HSCT for sickle cell disease pursuant to Coverage with Evidence Development (CED) must address the following question:

Compared to patients who do not receive allogeneic HSCT, do Medicare beneficiaries with SCD who receive allogeneic HSCT have improved outcomes as indicated by:

• Graft vs. host disease (acute and chronic),
• Other transplant-related adverse events;
  
• Overall survival; and
• (optional) Quality of life?

All CMS-approved clinical studies and registries must adhere to the below listed standards of scientific integrity and relevance to the Medicare population listed in section g:

g) All CMS-approved clinical studies and registries in sections d, e and f must adhere to the below listed standards of scientific integrity and relevance to the Medicare population:

a. The principal purpose of the study is to test whether the item or service meaningfully improves health outcomes of affected beneficiaries who are represented by the enrolled subjects.

b. The rationale for the study is well supported by available scientific and medical evidence.

c. The study results are not anticipated to unjustifiably duplicate existing knowledge.

d. The study design is methodologically appropriate and the anticipated number of enrolled subjects is sufficient to answer the research question(s) being asked in the National Coverage Determination.

e. The study is sponsored by an organization or individual capable of completing it successfully.

f. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found in the Code of Federal Regulations (CFR) at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it is also in compliance with 21 CFR Parts 50 and 56. In addition, to further enhance the protection of human subjects in studies conducted under CED, the study must provide and obtain meaningful informed consent from patients regarding the risks associated with the study items and/or services, and the use and eventual disposition of the collected data.

g. All aspects of the study are conducted according to appropriate standards of scientific integrity.

h. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements.

i. The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Such studies may meet this requirement 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.

j. The clinical research studies and registries are registered on the www.ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. Registries are also registered in the Agency for Healthcare Quality (AHRQ) Registry of Patient Registries (RoPR).

k. 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 12 months of the study’s primary completion date, which is the date the final subject had final data collection for the primary endpoint, even if the trial does not achieve its primary aim. The results must include number started/completed, summary results for primary and secondary outcome measures, statistical analyses, and adverse events. Final results must be reported in a publicly accessibly manner; either in a peer-reviewed scientific journal (in print or on-line), in an on-line publicly accessible registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for studies with negative or incomplete results).

l. The study protocol must explicitly discuss beneficiary subpopulations affected by the item or service 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 in 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.

m. The study protocol explicitly discusses how the results are or are not expected to be generalizable to affected beneficiary subpopulations. 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 Act, the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions.

II. Autologous Stem Cell Transplantation (AuSCT)

a) Effective for services performed on or after April 28, 1989, AuSCT is considered reasonable and necessary under §l862(a)(1)(A) of the Act for the following conditions and is covered under Medicare for patients with:

1. Acute leukemia in remission who have a high probability of relapse and who have no human leucocyte antigens (HLA)-matched;

2. Resistant non-Hodgkin's lymphomas or those presenting with poor prognostic features following an initial response;

3. Recurrent or refractory neuroblastoma; or,

4. Advanced Hodgkin's disease who have failed conventional therapy and have no HLA-matched donor.

b) Effective October 1, 2000, single AuSCT is only covered for Durie-Salmon Stage II or III patients that fit the following requirements:

c) Effective for services performed on or after March 15, 2005, when recognized clinical risk factors are employed to select patients for transplantation, high dose melphalan (HDM) together with AuSCT is reasonable and necessary for Medicare beneficiaries of any age group with primary amyloid light chain (AL) amyloidosis who meet the following criteria:

C. Nationally Non-Covered Indications

I. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Effective for claims with dates of service on or after May 24, 1996, through January 26, 2016, allogeneic HSCT is not covered as treatment for multiple myeloma.

II. Autologous Stem Cell Transplantation (AuSCT)

Insufficient data exist to establish definite conclusions regarding the efficacy of AuSCT for the following conditions:

a) Acute leukemia not in remission;

b) Chronic granulocytic leukemia;

c) Solid tumors (other than neuroblastoma);

d) Up to October 1, 2000, multiple myeloma;

e) Tandem transplantation (multiple rounds of AuSCT) for patients with multiple myeloma;

f) Effective October 1, 2000, non-primary AL amyloidosis; and,

g) Effective October 1, 2000, through March 14, 2005, primary AL amyloidosis for Medicare beneficiaries age 64 or older.

In these cases, AuSCT is not considered reasonable and necessary within the meaning of §l862(a)(1)(A) of the Act and is not covered under Medicare.

D. Other

All other indications for stem cell transplantation not otherwise noted above as covered or non-covered remain at local Medicare Administrative Contractor discretion.

(This NCD last reviewed January 2016.)

APPENDIX D

Table 1. Revised International prognosis scoring system (IPSS-R) in myelodysplastic syndromes

Very good = del(11q), -Y
Good = normal karyotype, del(20q), del(5q), del(12p), double including del(5q)
Intermediate = +8, del(7q), i(17q), +19, any other single or double independent clone
Poor = -7, inv(3)/t(3q)/del(3q), double including -7/del(7q), complex: 3 abnormalities
Very poor = Complex >3 abnormalities

Table 2. IPSS-R prognostic risk categories and clinical outcomes