CMS Pub. 100-03, ch. 1, § 110.23

A. General

Stem cell transplantation is a process in which stem cells are harvested from either a patient’s (autologous)

or donor’s (allogeneic) bone marrow or peripheral blood for intravenous infusion. Autologous stem cell

transplantation (AuSCT) is a technique for restoring stem cells using the patient's own previously stored

cells. AuSCT must be used to effect hematopoietic reconstitution following severely myelotoxic doses of

chemotherapy (HDCT) and/or radiotherapy used to treat various malignancies. Allogeneic hematopoietic

stem cell transplantation (HSCT) is a procedure in which a portion of a healthy donor's stem cell or bone

marrow is obtained and prepared for intravenous infusion. Allogeneic HSCT may be used to restore

function in recipients having an inherited or acquired deficiency or defect. Hematopoietic stem cells are

multi-potent stem cells that give rise to all the blood cell types; these stem cells form blood and immune

cells. A hematopoietic stem cell is a cell isolated from blood or bone marrow that can renew itself,

differentiate to a variety of specialized cells, can mobilize out of the bone marrow into circulating blood, and

can undergo programmed cell death, called apoptosis - a process by which cells that are unneeded or

detrimental will self-destruct.

The Centers for Medicare & Medicaid Services (CMS) is clarifying that bone marrow and peripheral blood

stem cell transplantation is a process which includes mobilization, harvesting, and transplant of bone

marrow or peripheral blood stem cells and the administration of high dose chemotherapy or radiotherapy

prior to the actual transplant. When bone marrow or peripheral blood stem cell transplantation is covered,

all necessary steps are included in coverage. When bone marrow or peripheral blood stem cell

transplantation is non-covered, none of the steps are covered.

B. Nationally Covered Indications

I. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

a) Effective for services performed on or after August 1, 1978, for the treatment of leukemia, leukemia

in remission, or aplastic anemia when it is reasonable and necessary,

b) Effective for services performed on or after June 3, 1985, for the treatment of severe combined

immunodeficiency disease (SCID) and for the treatment of Wiskott-Aldrich syndrome.

c) Effective for services performed on or after August 4, 2010, for the treatment of Myelodysplastic

Syndromes (MDS) pursuant to Coverage with Evidence Development (CED) in the context of a

Medicare-approved, prospective clinical study.

MDS refers to a group of diverse blood disorders in which the bone marrow does not produce

enough healthy, functioning blood cells. These disorders are varied with regard to clinical

characteristics, cytologic and pathologic features, and cytogenetics. The abnormal production of

blood cells in the bone marrow leads to low blood cell counts, referred to as cytopenias, which are a

hallmark feature of MDS along with a dysplastic and hypercellular-appearing bone marrow

Medicare payment for these beneficiaries will be restricted to patients enrolled in an approved

clinical study. In accordance with the Stem Cell Therapeutic and Research Act of 2005 (US Public

Law 109-129) a standard dataset is collected for all allogeneic transplant patients in the United States

by the Center for International Blood and Marrow Transplant Research. The elements in this dataset,

comprised of two mandatory forms plus one additional form, encompass the information we require

for a study under CED.

A prospective clinical study seeking Medicare payment for treating a beneficiary with allogeneic

HSCT for MDS pursuant to CED must meet one or more aspects of the following questions:

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

Medicare beneficiaries with MDS who receive HSCT have improved outcomes as indicated by:

• Relapse-free mortality,

• progression free survival,

• relapse, and

• overall survival?

2. Prospectively, in Medicare beneficiaries with MDS who receive HSCT, how do International

Prognostic Scoring System (IPSS) scores, patient age, cytopenias, and comorbidities predict the

following outcomes:

• Relapse-free mortality,

• progression free survival,

• relapse, and

• overall survival?

3. Prospectively, in Medicare beneficiaries with MDS who receive HSCT, what treatment facility

characteristics predict meaningful clinical improvement in the following outcomes:

• Relapse-free mortality,

• progression free survival,

• relapse, and

• overall survival?

In addition, the clinical study must adhere to the following standards of scientific integrity and

relevance to the Medicare population:

a. The principal purpose of the research study is to test whether a particular intervention potentially

improves the participants’ health outcomes.

b. The research study is well supported by available scientific and medical information or it is

intended to clarify or establish the health outcomes of interventions already in common clinical

use.

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

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

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

proposed study successfully.

f. The research study is in compliance with all applicable Federal regulations concerning the

protection of human subjects found at 45 CFR Part 46. If a study is regulated by the Food and

Drug Administration (FDA), it must be in compliance with 21 CFR parts 50 and 56.

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

integrity (see http://www.icmje.org).

h. The research study has a written protocol that clearly addresses, or incorporates by reference, the

standards listed here as Medicare requirements for CED coverage.

i. The clinical research study is not designed to exclusively test toxicity or disease pathophysiology

in healthy individuals. Trials of all medical technologies measuring therapeutic outcomes as one

of the objectives meet this standard only if the disease or condition being studied is life

threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment

options.

j. The clinical research study is registered on the ClinicalTrials.gov Web site by the principal

sponsor/investigator prior to the enrollment of the first study subject.

k. The research study protocol specifies the method and timing of public release of all pre-specified

outcomes to be measured including release of outcomes if outcomes are negative or study is

terminated early. The results must be made public within 24 months of the end of data

collection. If a report is planned to be published in a peer-reviewed journal, then that initial

release may be an abstract that meets the requirements of the International Committee of Medical

Journal Editors (http://www.icmje.org). However a full report of the outcomes must be made

public no later than 3 years after the end of data collection.

l. The research study protocol must explicitly discuss subpopulations affected by the treatment

under investigation, particularly traditionally underrepresented groups in clinical studies, how the

inclusion and exclusion criteria effect enrollment of these populations, and a plan for the

retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are

expected to have a negative effect on the recruitment or retention of underrepresented

populations, the protocol must discuss why these criteria are necessary.

m. The research study protocol explicitly discusses how the results are or are not expected to be

generalizable to the Medicare population to infer whether Medicare patients may benefit from the

intervention. Separate discussions in the protocol may be necessary for populations eligible for

Medicare due to age, disability or Medicaid eligibility.

Consistent with section 1142 of the Social Security Act, the Agency for Health Research and Quality

(AHRQ) supports clinical research studies that CMS determines meet the above-listed standards and

address the above-listed research questions.

The clinical research study should also have the following features:

• It should be a prospective, longitudinal study with clinical information from the period before

HSCT and short- and long-term follow-up information.

• Outcomes should be measured and compared among pre-specified subgroups within the cohort.

• The study should be powered to make inferences in subgroup analyses.

• Risk stratification methods should be used to control for selection bias. Data elements to be used

in risk stratification models should include:

Patient selection:

- Patient Age at diagnosis of MDS and at transplantation

- Date of onset of MDS

- Disease classification (specific MDS subtype at diagnosis prior to preparative/conditioning

regimen using World Health Organization (WHO) classifications). Include presence/absence

of refractory cytopenias

- Comorbid conditions

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

diagnosis and prior to transplantation

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

- Disease assessment at diagnosis at start of preparative regimen and last assessment prior to

preparative regimen Subtype of MDS (refractory anemia with or without blasts, degree of

blasts, etc.)

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

reduced–intensity conditioning)

- Donor type

- Cell Source

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

Database.

d) Effective for claims with dates of service on or after January 27, 2016, allogeneic HSCT for multiple

myeloma is covered by Medicare only for beneficiaries with Durie-Salmon Stage II or III multiple

myeloma, or International Staging System (ISS) Stage II or Stage III multiple myeloma, and

participating in an approved prospective clinical study that meets the criteria below. There must be

appropriate statistical techniques to control for selection bias and confounding by age, duration of

diagnosis, disease classification, International Myeloma Working Group (IMWG) classification, ISS

stage, comorbid conditions, type of preparative/conditioning regimen, graft vs. host disease (GVHD)

prophylaxis, donor type and cell source.

A prospective clinical study seeking Medicare coverage for allogeneic HSCT for multiple myeloma

pursuant to CED must address the following question:

Compared to patients who do not receive allogeneic HSCT, do Medicare beneficiaries with multiple

myeloma who receive allogeneic HSCT have improved outcomes as indicated by:

o Graft vs. host disease (acute and chronic);

o Other transplant-related adverse events;

o Overall survival; and

o (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:

o Graft vs. host disease (acute and chronic);

o Other transplant-related adverse events;

o Overall survival; and

o (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:

o Graft vs. host disease (acute and chronic),

o Other transplant-related adverse events;

o Overall survival; and

o (optional) Quality of life?

All CMS-approved clinical studies and registries must adhere to the below listed standards of

scientific integrity and relevance to the Medicare population listed in section g:

g) All CMS-approved clinical studies and registries in sections d, e and f must adhere to the below

listed standards of scientific integrity and relevance to the Medicare population:

a. The principal purpose of the study is to test whether the item or service meaningfully improves

health outcomes of affected beneficiaries who are represented by the enrolled subjects.

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

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

d. The study design is methodologically appropriate and the anticipated number of enrolled subjects

is sufficient to answer the research question(s) being asked in the National Coverage

Determination.

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

f. The research study is in compliance with all applicable Federal regulations concerning the

protection of human subjects found in the Code of Federal Regulations (CFR) at 45 CFR Part 46.

If a study is regulated by the Food and Drug Administration (FDA), it is also in compliance with

21 CFR Parts 50 and 56. In addition, to further enhance the protection of human subjects in

studies conducted under CED, the study must provide and obtain meaningful informed consent

from patients regarding the risks associated with the study items and/or services, and the use and

eventual disposition of the collected data.

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

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

as Medicare requirements.

i. The study is not designed to exclusively test toxicity or disease pathophysiology in healthy

individuals. Such studies may meet this requirement only if the disease or condition being

studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable

treatment options.

j. The clinical research studies and registries are registered on the www.ClinicalTrials.gov website

by the principal sponsor/investigator prior to the enrollment of the first study subject. Registries

are also registered in the Agency for Healthcare Quality (AHRQ) Registry of Patient Registries

(RoPR).

k. The research study protocol specifies the method and timing of public release of all prespecified

outcomes to be measured including release of outcomes if outcomes are negative or study is

terminated early. The results must be made public within 12 months of the study’s primary

completion date, which is the date the final subject had final data collection for the primary

endpoint, even if the trial does not achieve its primary aim. The results must include number

started/completed, summary results for primary and secondary outcome measures, statistical

analyses, and adverse events. Final results must be reported in a publicly accessibly manner;

either in a peer-reviewed scientific journal (in print or on-line), in an on-line publicly accessible

registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov, or

in journals willing to publish in abbreviated format (e.g., for studies with negative or incomplete

results).

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

service under investigation, particularly traditionally underrepresented groups in clinical studies,

how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the

retention and reporting of said populations in the trial. If the inclusion and exclusion criteria are

expected to have a negative effect on the recruitment or retention of underrepresented

populations, the protocol must discuss why these criteria are necessary.

m. The study protocol explicitly discusses how the results are or are not expected to be generalizable

to affected beneficiary subpopulations. Separate discussions in the protocol may be necessary for

populations eligible for Medicare due to age, disability or Medicaid eligibility.

Consistent with section 1142 of the Act, the Agency for Healthcare Research and Quality (AHRQ)

supports clinical research studies that CMS determines meet the above-listed standards and address

the above-listed research questions.

II. Autologous Stem Cell Transplantation (AuSCT)

a) Effective for services performed on or after April 28, 1989, AuSCT is considered reasonable and

necessary under §l862(a)(1)(A) of the Act for the following conditions and is covered under

Medicare for patients with:

1. Acute leukemia in remission who have a high probability of relapse and who have no human

leucocyte antigens (HLA)-matched;

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

an initial response;

3. Recurrent or refractory neuroblastoma; or,

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

donor.

b) Effective October 1, 2000, single AuSCT is only covered for Durie-Salmon Stage II or III patients

that fit the following requirements:

• 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.)

110.24 Chimeric Antigen Receptor (CAR) T-cell therapy

(Rev. 10891, Issued: 07-20-21, Effective: 08-07-19, Implementation: 09-20-21)

A. General

Cancer is a collection of related diseases of dividing cells that can start almost anywhere in or on the body,

evade the immune system, and invade nearby tissues. Categories of cancer are typically organized by the

location in the body and specific type of cell. These categories may include carcinoma, sarcoma, leukemia,

lymphoma, multiple myeloma, melanoma, and brain and spinal cord tumors. There are also changes to these

cells that are not considered cancer. These changes include hyperplasia—when a cell divides faster than

normal—and dysplasia—a buildup of extra cells with abnormal shape and disorganization.

A person’s immune system contains cells to help fight substances that are foreign to the body, including

cancer. These cells are called white blood cells, most of which are lymphocytes. The two main types of

lymphocytes are B lymphocytes (B-cells) and T lymphocytes (T-cells). B-cells generate and release

antibodies to fight infection, especially bacterial infections, while T-cells employ a number of other

mechanisms to fight abnormal cells such as cancer. One type of therapy that leverages the immune

system—immunotherapy—is Chimeric Antigen Receptor (CAR) T-cell therapy.

CAR T-cells have been genetically altered in order to improve the ability of the T-cells to fight cancer. The

genetic modification creating a CAR can enhance the ability of the T-cell to recognize and attach to a

specific protein, called an antigen, on the surface of a cancer cell.

B. Nationally Covered Indications

A. Effective for services performed on or after August 7, 2019, the Centers for Medicare & Medicaid

Services (CMS) covers autologous treatment for cancer with T-cells expressing at least one chimeric antigen

receptor (CAR) when administered at healthcare facilities enrolled in the FDA risk evaluation and mitigation

strategies (REMS) and used for a medically accepted indication as defined at Social Security Act section

1861(t)(2) ‐i.e., is used for either an FDA-approved indication (according to the FDA-approved label for that

product), or for other uses when the product has been FDA-approved and the use is supported in one or more

CMS-approved compendia.

C. Nationally Non-Covered

Effective for services performed on or after August 7, 2019, the use of non-FDA-approved autologous T-cells expressing at least one CAR is non-covered. Autologous treatment for cancer with T-cells expressing at

least one CAR is non-covered when the requirements in Section A are not met.

D. Other

Effective for services performed on or after August 7, 2019, routine costs in clinical trials that use CAR T-cell therapy as an investigational agent that meet the requirements listed in NCD 310.1 will be covered.

(This NCD last reviewed August 2019.)