**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](https://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](https://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 initialvrelease may be an abstract that meets the requirements of the International Committee of MedicalvJournal Editors ([http://www.icmje.org](https://www.icmje.org)). However a full report of the outcomes must be made public no latervthan 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, reducedintensity 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](https://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 studys 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](https://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.)

**