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

The Centers for Medicare & Medicaid Services (CMS) is reconsidering one aspect of the national coverage determination established at section 110.23 of the Medicare National Coverage Determinations Manual Pub. 100-03.  We propose to expand Medicare coverage for allogeneic hematopoietic stem cell transplant using only bone marrow or peripheral blood stem cell products for Medicare patients with myelodysplastic syndromes designated as high-risk or very high-risk with a score of ≥ 4.5 points according to criteria specified by the International Prognostic Scoring System - Revised (IPSS-R). For these particular patients the evidence supports a national coverage determination under section 1862(a)(1)(A) of the Social Security Act.

In addition, CMS proposes that coverage of allogeneic hematopoietic stem cell transplant using bone marrow or peripheral blood stem cell products for Medicare patients with myelodysplastic syndromes who are not specified above will be determined by Medicare Administrative Contractors under section 1862(a)(1)(A) of the Act.

See Appendix B for the proposed 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.

CMS is seeking comments on our proposed decision pursuant to § 1862(l)(3)(B) of the Social Security Act. 

TO: 	Administrative File:  CAG-00415R

SUBJECT: Reconsideration- Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes (MDS) Proposed National Coverage Determination

DATE: 	December 7, 2023

I. Proposed Decision

The Centers for Medicare & Medicaid Services (CMS) is reconsidering one aspect of the national coverage determination established at section 110.23 of the Medicare National Coverage Determinations Manual Pub. 100-03.  We propose to expand Medicare coverage for allogeneic hematopoietic stem cell transplant using only bone marrow or peripheral blood stem cell products for Medicare patients with myelodysplastic syndromes designated as high-risk or very high-risk with a score of ≥ 4.5 points according to criteria specified by the International Prognostic Scoring System - Revised (IPSS-R). For these particular patients the evidence supports a national coverage determination under section 1862(a)(1)(A) of the Social Security Act.

In addition, CMS proposes that coverage of allogeneic hematopoietic stem cell transplant using bone marrow or peripheral blood stem cell products for Medicare patients with myelodysplastic syndromes who are not specified above will be determined by Medicare Administrative Contractors under section 1862(a)(1)(A) of the Act.

See Appendix B for the proposed 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.

CMS is seeking comments on our proposed decision pursuant to § 1862(l)(3)(B) of the Social Security Act. 

II. Background

Throughout this document we use numerous acronyms, some of which are not defined as they are presented in direct quotations.  Please find below a list of these acronyms and corresponding full terminology:

AEs - Adverse Events
aGVHD - acute Graft Versus Host Disease
AHRQ - Agency for Healthcare Research and Quality
AHSCT - Allogeneic Hematopoietic Stem Cell Transplantation
AlloHSCT - Allogeneic Hematopoietic Stem Cell Transplantation
AML - Acute Myelogenous Leukemia
ANC - Neutrophil Count
ASXL1 - ASXL Transcriptional Regulator 1mutation
ATG - Antithymocyte Globulin
AuSCT - Autologous Stem Cell Transplantation
BBM - Bone Marrow Blast
BMT - Bone Marrow Transplantation
CED - Coverage with Evidence Development
CFR - Code of Federal Regulations
cGVHD - chronic Graft Versus Host Disease
CI - Confidence Interval
CIBMTR - Center for International Blood and Marrow Transplant Research
CMML - Chronic myelomonocytic leukemia
CMS - Centers for Medicare & Medicaid Services
CR - Complete Remission
DFS - Disease-free Survival
DIPSS - Dynamic International Prognostic Scoring System
EBMT - European (Society for) Blood and Marrow Transplantation
EFS - Event-free Survival
EPO/ESA - Epoetin alfa/Erythropoiesis-Stimulating Agents
EZH2 - Enhancer of zeste homolog 2 mutation
FAB - French-American-British classification system
FDA - Food and Drug Administration
GvHD/GVHD - Graft Versus Host Disease
HLA - Human Leukocyte Antigen
HMA - hypomethylating agent
HPC - Hematopoietic stem/progenitor cells
HR - Hazard Ratio
HSCT - Hematopoietic Stem Cell Transplantation
IDH2 - Isocitrate dehydrogenase 1 mutation
IPSS - International Prognostic Scoring System
IPSS-R - International Prognostic Scoring System Revised
IRIC - Intensive Remission Induction Chemotherapy
ISS - International Staging System
MAC - Myeloablative Conditioning
MDS - Myelodysplastic Syndromes
MDS-del(5q)- Myelodysplastic Syndromes with isolated del(5q)
MDS-EB1 - Myelodysplastic Syndromes with excess blast, subgroup 1
MDS-EB2 - Myelodysplastic Syndromes with excess blast, subgroup 2
MDS-MLD - Myelodysplastic Syndromes with Multilineage Dysplasia
MDS-SLD - Myelodysplastic Syndromes with Single lineage Dysplasia
MDS-RS-MLD - Myelodysplastic Syndromes with Ring Sideroblast, Multilineage Dysplasia
MDS-RS-SLD - Myelodysplastic Syndromes with Ring Sideroblast, Single lineage Dysplasia
MDS/MPN - Myelodysplastic/myeloproliferative neoplasms
NCA - National Coverage Analysis
NCD - National Coverage Determination
NIH - National Institutes of Health
NMA - Non-Myeloablative conditioning
NMDP - National Marrow Donor Program
NRM - Non-relapsing Mortality
OS - Overall Survival
PFS - Progression-free Survival
QALE - Quality-Adjusted Life Expectancy
QoL - Quality of Life
RA - Refractory Anemia
RAEB - RA with Excess Blasts
RAEB-T - RAEB in transition to AML
RARS - RA with Ringed Sideroblasts
RBC - Red Blood Cell
RCUD - Refractory cytopenias with unilineage dysplasia
RCMD - Refractory Cytopenia with Multilineage Dysplasia
RCMD/RS - RCMD with ringed sideroblasts
RFS - Relapse Free Survival
RIC - Reduced-intensity Conditioning
RUNX1 - Runt-related transcription factor 1 mutation
SCT - Stem Cell Transplantation
SF3B1 - SF3B1 mutation
TP53 - Tumor protein P53 mutation
TRM - Transplantation-related Mortality
WHO - World Health Organization
WPSS - WHO Prognostic Scoring System

Myelodysplastic Syndromes

Myelodysplastic Syndromes (MDS) are a heterogeneous group of hematologic disorders characterized by (1) cytopenia (decreased number of red blood cells, white blood cells and platelets) due to bone marrow failure and (2) the potential development of acute myeloid leukemia (AML). In MDS, groups of clonal stem cell disorders are observed, characterized by low blood cell counts, abnormal blood cell development, genetic markers, hypercellular bone marrow, cytopenias, and dysplastic cells. Anemia, often with thrombocytopenia and neutropenia, occurs with dysmorphic (abnormal appearing) hematologic cells and usually abnormal cellular bone marrow, which results in ineffective blood cell production. Because of bone marrow failure, MDS patients are at risk for symptomatic anemia, infection, and bleeding.

For treatment purposes, patients with MDS are often stratified into risk groups based on the potential development of AML, which varies widely across MDS subtypes. Most patients with MDS have “low risk” status, and bone marrow failure is part of their clinical course. Other patients designated as “high-risk” are more likely to have leukemic progression. In this “high-risk” group, patients often present with myeloblasts at the time of diagnosis, as well as chromosomal abnormalities and genetic mutations. MDS shares clinical and pathologic features with AML, but MDS has a lower percentage of blasts in peripheral blood and bone marrow (by definition, <20 percent). MDS often results in fatality due, most often, to complications of cytopenia, or to progression to leukemia, but a large proportion of MDS patients will die of concurrent disease, and the comorbidities typical in an elderly population.

MDS are a disease of the elderly; the mean age at onset is older than 70 years (Harrison’s Principles of Medicine, 20^th edition, Jameson, Fauci, Kasper et al. 2018). Approximately 6% of cases of MDS are diagnosed in people under 50 years of age (Ma 2012). MDS is a relatively common form of bone marrow failure, with reported incidence rates of 35 to >100 per million persons in the general population and 120 to >500 per million in older adults. Estimates of incidence in the United States range from 30,000 to 40,000 new cases annually and a prevalence of 60,000–120,000 in the population. MDS is rare in children, in whom it often has an identifiable genetic basis (Kuendgen, et al. 2006). Secondary or therapy-related MDS is not age related. Rates of MDS have increased over time due to better recognition of the syndrome by physicians, and an aging population. MDS has been associated with long-term exposure to certain environmental chemicals, including benzene and chemicals used in the rubber and petroleum industry. It also has been found in patients who have received radiation, radiomimetic alkylating agents, as well as other forms of treatment for cancer. Genomics plays a major role in this disease, and the types and number of cytogenetic mutations strongly correlate with the probability of leukemic transformation and survival. Over 100 genes, including some recurrent somatic mutations have been associated with MDS. Many of these same genes are also mutated in AML without MDS, whereas others are distinctive in subtypes of MDS. Some mutations correlate with prognosis (e.g., spliceosome defects are associated with favorable outcomes), while mutations in EZH2, TP53, RUNX1, and ASXL1 are associated with poor outcomes.

Classification of MDS

As noted above, MDS is a heterogeneous group of hematologic disorders. The disease course varies greatly from patient to patient. Because of the various clinical and biological presentations, an accurate means of making a definitive diagnosis is needed. Proper diagnosis is crucial so that patients receive the most-effective treatment for MDS. A high-quality morphologic analysis, which includes a review of a peripheral blood smear, a representative bone marrow aspirate, and an adequate bone marrow biopsy is required in making the diagnosis and staging of the disease. Diagnosis is established by the presence of unexplained cytopenia and dysplasia. Bone marrow karyotype, peripheral blood counts and relevant molecular genetic testing may also be required. A number of diagnostic classification systems, which primarily look at morphology and percentage of blasts, have been developed over the years. The French, American, British Group system was first developed in 1982, but was later replaced by the WHO diagnostic classification. This schema divides MDS into subtypes depending on the percentage of myeloblasts, the presence or absence of ringed sideroblasts, the number of dysplastic lineages in the bone marrow, and the genetic profile of the bone marrow cells (cytogenetic abnormalities (e.g., the isolated 5q deletion) as well as mutations (e.g., SF3B1)). Another classification system used is the International Consensus Classification (ICC). Both the WHO and ICC classification systems are similar because they recognize the significance of bone marrow blast count, extent of dysplasia, and cytogenetic and molecular abnormalities for categorizing MDS. For diagnostic purposes the WHO system now recognizes 6 types of MDS: 

1. MDS with multilineage dysplasia (MDS-MLD) - This is the most common type of MDS and it has a higher occurrence in men. The clinical course is variable and is influenced by karyotype and the degree of cytopenias and dysplasia (Greenberg, et al. 2012; Malcovati, et al. 2005; Della Porta, et al. 2015). There is no definitive evidence that specific mutations influence prognosis within this category of MDS. Median overall survival (OS) was 36 months and evolution to AML was approximately 15 percent at two years and 28 percent at five years according to a database of 1,010 MDS-MLD patients (Reuss-Borst, et al. 1993). Patients with complex karyotypes have outcomes similar to those with MDS with excess blasts (Maassen, et al. 2013).


2. MDS with single lineage dysplasia (MDS-SLD) - This form of MDS is not common and it seldom, if ever, progresses to AML. Patients with this type of MDS can often live a long time, even without treatment. MDS-SLD accounts for 7 to 20 percent of all cases of MDS (Reuss-Borst, et al. 1993). Median overall survival (OS) is approximately 66 months, and the rate of progression to AML at five years is 10 percent (Greenberg, et al. 2012; Germing, et al. 2006).


3. MDS ring sideroblasts (MDS-RS)— This form of MDS is divided into 2 types based on how many of the cell types in the bone marrow are affected by dysplasia:
   1. MDS-RS with single lineage dysplasia (MDS-RS-SLD)
   2. MDS-RS with multilineage dysplasia (MDS-RS-MLD)

      MDS-RS accounts for 3 to 11 percent of all cases of MDS, with MDS-RS-MLD the more common subtype (Reuss-Borst, et al. 1993). For MDS-RS-SLD, approximately 1 to 2 percent of cases evolve to AML and the median OS is 69 to 108 months (Germing, et al. 2000). For MDS-RS-MLD, median OS is 28 months and approximately 8 percent progress to AML (Breccia, et al. 2006; Germing, et al. 2000; Ghesquieres, et al. 2015). RUNX1 mutation is associated with shorter survival (Malcovati, et al. 2015).

   3. MDS with excess blasts (MDS-EB)—This form of MDS can be further characterized as MDS-EB-1 or MDS-EB-2 based on the percentage of bone marrow and peripheral blood blasts, as well as the absence or presence of Auer rods. MDS-EB2 is characterized as having Auer rods. MDS-EB, accounts for 1 in 4 cases of MDS. Approximately 25 percent of MDS-EB-1 and 33 percent of MDS-EB-2 progress to AML (Reuss-Borst, et al. 1993). The median OS is approximately 16 months for MDS-EB-1, and 9 months for MDS-EB-2. Clonal cytogenetic findings are present in 30 to 50 percent of cases of MDS-EB (Reuss-Borst, et al. 1993). The most common findings are gain of chromosome 8, del(5q) or t(5q), loss of chromosome 7 or del(7q), and del(20q). Also, complex karyotypes may be seen in this form of MDS (Maassen et al. 2013). Mutations, including TP53, IDH1/IDH2, those involving the RAS pathway, and cohesion complex genes are commonly found in these MDS subgroups (Malcovati et al. 2014).
   
   
   4. MDS with isolated del(5q) primarily occurs in older women, and the female-to-male ratio is approximately 7:3 (Ingram et al. 2006). Because platelets and white blood cells are reasonably normal, there is a low incidence of bleeding and infection in these patients. Those with this form of MDS tend to have a good prognosis. They usually have a relatively benign course that extends over several years and have a low incidence of transformation into acute leukemia (Vardiman et al. 2008; Boultwood et al. 1994).
   
   
   5. MDS, unclassifiable (MDS-U)-This type of MDS has no distinguishing morphologic features and occurs infrequently. MDS-U subtypes exist as the following:
      1. MDS-U with 1 percent blood blasts
      2. MDS-U with SLD and pancytopenia
      3. MDS-U based on a defining cytogenetic abnormality

      For MDS-U patients the median survival and five-year cumulative risk of progression to AML is approximately 35 months and 14 percent, respectively.

In addition to the diagnostic classification of MDS, a second classification system was developed for the purpose of treatment and management. Though the WHO also has a system to address/estimate prognosis (WPSS), the IPSS and IPSS-R systems are more commonly used for this purpose. These classifications of MDS will be reviewed in the analysis section of this document.

Treatment of MDS

Currently, there are a number of medical and surgical treatments in the management of patients with MDS. For patients with low risk of AML transformation supportive care is available (e.g., transfusion therapy, erythropoietin, immunosuppressants), as well as treatment that is directed toward the specific cause of MDS (e.g., hypomethylating agents (HMA therapy)). Though these treatments may offer some temporary benefit, they do not alter the course of the disease. For patients at high-risk of AML transformation, more aggressive treatments such as chemotherapy that is used in the treatment of AML (intensive remission induction chemotherapy-IRIC), as well as hematopoietic allogeneic stem cell transplants (HSCT) are often part of the treatment regimen. Selection of treatment is influenced by the severity of symptoms and cytopenias, MDS classification, prognostic category, medical fitness, and patient preferences. Goals of therapy are different in patients at lower-risk (e.g., decrease need for transfusions and transformation to higher risk disease or AML) as opposed to patients at higher risk as well as in those with failure along the course of treatment (e.g., improve survival). These treatments not only improve blood counts but also delay onset of leukemia and improve survival. This NCD does not address the treatment and management of AML, which is a possible sequela of MDS. It is beyond the scope of this NCD. As mentioned before, treatment and management are often based on MDS classification strata as well as prognostic status.

Hematopoietic Stem Cell Transplantation (HSCT)

Hematopoietic stem cells are multi-potent cells that give rise to all the blood cell types. Sources of stem cells include bone marrow, umbilical cord, placenta, amniotic fluid, as well as peripheral blood. Stem cell transplantation (SCT) is a process that includes mobilization, harvesting, and transplant of stem cells and the administration of high dose chemotherapy and/or radiotherapy prior to the transplant. This pre-treatment cytoreduction process can take place in the form of Myeloablative Conditioning (MAC), which is generally reserved for patients ≤65 years of age, Non-myeloablative Conditioning (NMA), which usually uses much lower and less toxic doses of chemotherapy and radiation than MAC, or Reduced Intensity Conditioning (RIC), a form of NMA conditioning, which is generally preferred for patients >65 years of age.

Hematopoietic Stem Cell Transplantations (HSCT) have been around since the 1970s. During the process, stem cells are harvested from either the patient (autologous) or a donor (allogeneic) and subsequently administered by intravenous infusion to the recipient. For allogeneic transplants, the stem cell source may be a related or unrelated donor. In addition, the transplant can be HLA-identical (matched), unmatched or half-matched (also known as haplo-identical). The degree of matching is important because if the HLA match is not close, the donor’s immune cells, which are transplanted along with the donor’s stem cells, will attack the patient’s tissues; this is called graft versus host disease (GVHD). Allogeneic stem cell transplants (alloHSCT) may be used to restore function in recipients having an inherited condition (such as Sickle Cell disease) or an acquired condition (such as occurs after severely myelotoxic doses of chemotherapy and/or radiotherapy, which are used to treat various malignancies). AlloHSCT might also be used in conditions of deficiencies or even a defect if they are amiable to transplants. Autologous stem cell transplants (AuSCT) are used to effect hematopoietic reconstitution following severely myelotoxic doses of chemotherapy and/or radiotherapy.

Allogeneic Stem Cell Transplants in Patients with MDS

Studies have shown that allogeneic hematopoietic stem cell transplantation provides the highest likelihood of long-term survival for patients with high/very high risk MDS (Chang et al. 2007; Kröger et al. 2012; de Witt et al, 2017; Heidenreich et al. 2017), but participants included in those studies were younger than Medicare-aged patients. The lack of studies involving patients 65 and older is due to the high toxicity associated with myeloablative conditioning, and the inability of older patients with concomitant morbidities to tolerate these pre-transplant chemotherapy-related toxicities (Murillo, et al. 2018). The use of RIC is an attempt to ameliorate symptoms associated with the toxic effect of cytoreduction. Results from selected studies have reported prolonged disease-free survival in about 30 to 50% of patients who receive the transplant (Chang et al. 2007). It is the only approach that offers a substantial possibility of cure (Passweg, et al. 2011), and some believe that the earlier the transplantation is carried out in the disease course, the better are the long-term results.

Because of the findings of these studies, some have advocated the use of allogeneic HSCT in patients with high-risk disease, even in patients of Medicare-aged population. Studies done in the past on younger patients (64 years and younger) have revealed that allogeneic HSCT has resulted in 30 to 52 percent overall survival (OS), 16 to 50 percent disease-free survival (DFS), and 10 to 50 percent treatment reduction mortality (TRM) at three years in patients with MDS (Saber et al. 2013; de Witte et al. 2000; Kindwall et al. 2009; Scott et al. 2006). Up until recently, there have been no studies that have demonstrated a clear association between age and clinical outcome following the use of allogeneic HSCT in patients with high/very high risk MDS (Lim et al. 2010; Sorror et al. 2011; Kröger et al. 2012; Bokhari et al. 2012; Wallen et al. 2005). Also, there are no randomized clinical trials that have directly compared allogeneic HCT versus intensive remission induction therapy or other intensive approaches for patients with high/very high risk MDS. Some have also recommended the use of alloSCT in patients with low to intermediate risk disease, especially if they possess certain mutations as well as cytogenic features (Robin et al. 2017; Platzbecker 2019; Jabbour, et al. 2015), but other studies have shown no benefit of using alloHSCT in patients with low risk disease (Cutler, et al. 2004; Koreth, et al. 2013).

Some believe that the current advances in transplant technology are sufficient to allow the use of alternative donors to be the source of allogeneic stem cell transplants in older patients with MDS (Garcia-Manero et al. 2020; Zhang, et al. 2017; Abel, et al. 2021), though others believe that patients, including those Medicare-aged with less advanced disease (e.g., low risk) even when perfectly matched should not be exposed to the substantial risk of mortality from this procedure because of the favorable prognosis with standard treatment alone (de Witte, et al. 2017).

III. History of Medicare Coverage

CMS determined, on August 4, 2010, that the evidence did not demonstrate that the use of allogeneic hematopoietic stem cell transplantation (HSCT) improved health outcomes in Medicare beneficiaries with myelodysplastic syndrome (MDS). Therefore, the agency determined that allogeneic HSCT for MDS was not reasonable and necessary under §1862(a)(1)(A) of the Social Security Act (the Act). However, CMS believed the available evidence shows that allogeneic HSCT for MDS was reasonable and necessary under §1862(a)(1)(E) of the Act and could be covered through Coverage with Evidence Development (CED). Therefore, Allogeneic HSCT for MDS was covered by Medicare only for beneficiaries with MDS participating in an approved clinical study that met specific criteria. Two CED studies were conducted and are included in the evidence review. See Appendix C for the complete NCD 110.23.

A.  Current Request

CMS received a complete, formal joint request to reconsider NCD 110.23 from the American Society of Hematology (ASH), the American Society for Transplantation and Cellular Therapy (ASTCT), the National Marrow Donor Program (NMDP), and the Center for International Blood and Marrow Transplant Research (CIBMTR). The  request seeks  full coverage of allogeneic hematopoietic stem cell transplantation (HSCT) for individuals with myelodysplastic syndromes (MDS) and the removal of the Coverage with Evidence Development (CED) requirement currently tied to coverage for HSCT for Medicare beneficiaries with MDS.

B. Benefit Category

Medicare is a defined benefit program. For an item or service to be covered by the Medicare program, it must fall within one of the statutorily defined benefit categories outlined in the Social Security Act.

CMS has determined that autologous and allogeneic stem cell transplantation fall within the benefit categories of inpatient hospital services under Part A and physicians’ services under Part B. §1861(b) (inpatient hospital services); §1861(s) (2) (incident to physician’s services).

Please Note: This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service.

IV. Timeline of Recent Activities 

V.  Food and Drug Administration (FDA) Status

Hematopoietic stem/progenitor cells (HPC) for transplantation are considered human cells, tissues, and cellular- and tissue-based products (HCT/Ps) under 21 CFR 1271.3(d) defines human cells, tissues, or cellular or tissue-based products (HCT/Ps) as "articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. Examples of HCT/Ps include, but are not limited to, bone, ligament, skin, dura mater, heart valve, cornea, hematopoietic stem/progenitor cells derived from peripheral and cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix, and semen or other reproductive tissue…"

FDA has a tiered, risk-based approach to the regulation of HCT/Ps. HCT/Ps that meet all of the criteria set forth in 21 CFR §1271.10(a) are regulated solely under section 361 of the Public Health Act (PHS) Act and the regulations in 21 CFR §  1271, and FDA’s premarket review and approval are not required. To satisfy these criteria, an HCT/P must:

• be minimally manipulated;
• be intended for homologous use only;
• not be combined with another article (with some limited exceptions); and not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function;
• or if it does, it must be intended for autologous use or allogeneic use in a first- or second-degree blood relative.

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. 42 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." Section 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 42 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 national coverage determinations, 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 proposed 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. For each study, one investigator assigned a summary quality rating, which was then reviewed by a second investigator; disagreements were resolved by consensus or by a third investigator if agreement could not be reached.

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.

Evidence-Based Guidelines

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”
https://doi.org/10.1016/j.jtct.2022.11.014.

The National Comprehensive Cancer Network (NCCN)

• Guidelines for MDS
  https://jnccn.org/view/journals/jnccn/20/2/article-p106.xml
• 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.

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?

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 (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?

As mentioned in the background section, 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 very 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 classification 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 Intermediate-2 and higher risk groups had better OS compared to those in the low 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.

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 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 propose 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 ematopoietic 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 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

In this national coverage analysis, the sources of stem cells included bone marrow as well as peripheral blood. As mentioned in the background section, other sources of stem cells may include the placenta, amniotic fluid, as well as cord blood. None of the included studies used these other sources for stem cells. There is no study evidence that other sources for stem cell transplantation in Medicare patients with MDS have similar benefits and harms treatment profiles. Therefore, we propose that national coverage will be restricted to the sources of stem cells used in the studies reviewed as part of this analysis (bone marrow and peripheral blood).   

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, allogeneic hematopoietic stem cell transplants improve health outcomes for MDS patients with high, or very-high-risk of AML transformation designated as high-risk or very high-risk with a score of ≥ 4.5 points according to criteria specified by the revised International Prognostic Scoring System (IPSS-R), therefore, CMS proposes this expansion of coverage and removal of the CED requirement.

CMS appreciates the studies conducted under CED and the important evidence that has been developed through the CED studies and other studies since the initial NCD.

Because MDS is a progressive condition, we propose to provide greater flexibility by enabling  Medicare Administrative Contractor  to make the coverage determination under section 1862(a)(1)(A) for allogeneic hematopoietic stem cell transplants for patients with MDS who do not fall into the high or very-high-risk groups based on IPSS-R classification.  This will allow Medicare Administrative Contractors to assess additional information including information on mutations and individual patient characteristics when making coverage decisions.

IX.   Conclusion

The Centers for Medicare & Medicaid Services (CMS) is reconsidering one aspect of the national coverage determination established at section 110.23 of the Medicare National Coverage Determinations Manual Pub. 100-03. We propose to expand Medicare coverage for allogeneic hematopoietic stem cell transplant using only bone marrow or peripheral blood stem cell products for Medicare patients with myelodysplastic syndromes designated as high-risk or very high-risk with a score of  ≥ 4.5 points according to criteria specified by the International Prognostic Scoring System-Revised (IPSS-R). For these particular patients the evidence supports a national coverage determination under section 1862(a)(1)(A) of the Social Security Act (the Act).

In addition, CMS proposes that coverage of allogeneic hematopoietic stem cell transplant using bone marrow or peripheral blood stem cell products for Medicare patients with myelodysplastic syndromes who are not specified above will be determined by Medicare Administrative Contractors  under section 1862(a)(1)(A) of the Act.

See Appendix B for the proposed manual language, specifically Section B.1.c for 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.

CMS is seeking comments on our proposed decision pursuant to § 1862(l)(3)(B) of the Social Security Act.

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

Draft

We are seeking public comments on the proposed changes identified in red that we would include in the Medicare National Coverage Determinations Manual. This proposed language does not reflect public comments that will be received on the proposed decision memorandum, and which may be revised in response to those comments.

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

c) Effective for services performed on or after xx/xx/xx, allogeneic HSCT using only bone marrow or peripheral blood stem cell products for Medicare patients with myelodysplastic syndromes (MDS) designated as high-risk or very high-risk with a score of  ≥ 4.5 points according to criteria specified by the International Prognostic Scoring System-Revised (IPSS-R).

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 December 2023.)

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:

1. The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes.
2. 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.
3. The research study does not unjustifiably duplicate existing studies.
4. The research study design is appropriate to answer the research question being asked in the study.
5. The research study is sponsored by an organization or individual capable of executing the proposed study successfully.
6. 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.
7. All aspects of the research study are conducted according to appropriate standards of scientific integrity (see http://www.icmje.org).
8. The research study has a written protocol that clearly addresses, or incorporates by reference, the standards listed here as Medicare requirements for CED coverage.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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:

1. 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.
2. The rationale for the study is well supported by available scientific and medical evidence.
3. The study results are not anticipated to unjustifiably duplicate existing knowledge.
4. 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.
5. The study is sponsored by an organization or individual capable of completing it successfully.
6. 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.
7. All aspects of the study are conducted according to appropriate standards of scientific integrity.
8. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements.
9. 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.
10. 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).
11. 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).
12. 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.
13. 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:

• Newly diagnosed or responsive multiple myeloma. This includes those patients with previously untreated disease, those with at least a partial response to prior chemotherapy (defined as a 50% decrease either in measurable paraprotein [serum and/or urine] or in bone marrow infiltration, sustained for at least 1 month), and those in responsive relapse; and
• Adequate cardiac, renal, pulmonary, and hepatic function.

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:

• Amyloid deposition in 2 or fewer organs; and,
• Cardiac left ventricular ejection fraction (EF) greater than 45%.

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.)

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

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

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