**Background**

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 cells or bone marrow is obtained and
prepared for intravenous infusion.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a procedure in
which a portion of a healthy donor's stem cells or bone marrow is obtained and
prepared for intravenous infusion. Hematopoietic stem cells are multi-potent
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) has clarified 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.

NCD 110.23 Stem Cell Transplantation includes for allogenic transplantation:

  * Leukemia
  * Aplastic Anemia
  * Severe Combined Immunodeficiency disease (SCID)
  * Wiskott-Aldrich Syndrome

Allogeneic HSCT is covered only for Medicare beneficiaries with the following
indications when participating in an approved prospective clinical study
meeting specific criteria under the Coverage with Evidence Development (CED)
paradigm:

  * Myelodysplastic Syndrome
  * Multiple myeloma only for beneficiaries with Durie-Salmon Stage II or III multiple myeloma, or International Staging System (ISS) Stage II or Stage III multiple myeloma
  * Myelofibrosis (MF) only for beneficiaries with Dynamic International Prognostic Scoring System (DIPSSplus) intermediate-2 or High primary or secondary MF; or
  * Sickle cell disease (SCD) only for beneficiaries with severe, symptomatic SCD who participate in an approved prospective clinical study meeting specific criteria under the CED paradigm. (Please refer to CMS Publication 100-03, Medicare National Coverage Determinations (NCD) Manual _,_ Chapter 1, Part 2, 110.23)

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

Allogeneic hematopoietic cell transplantation, (HCT) has been increasingly
used for a variety of hematologic neoplasm and non-malignant marrow disorders.
Eligibility for Allogeneic HCT varies among institutions and is usually based
on a case-by-case basis dependent upon a risk-benefit assessment, and the
needs and wishes of the patient.1

Although historically allogeneic HCT was offered to patients who had exhausted
all other treatment modalities, currently the decision to perform a transplant
is dependent upon an assessment if the transplant will offer an outcome
superior to other treatment options.1

The CMS National Coverage Determination (NCD 110.23) for Stem Cell
Transplantation describes nationally covered indications for stem cell
transplant, the details of which will not be repeated within this policy. This
policy describes additional locally covered indications for Allogeneic stem
cell for primary refractory or relapsed Hodgkin's and non-Hodgkin's lymphoma
with B-cell or T-cell origin, for whom there are no other curative intent
options, and are medically necessary.

Multiple other disorders are under investigation as part of clinical trials
and are not covered unless the clinical trial meets the criteria of NCD 310.1
Routine Costs in Clinical Trials.

This policy describes additional locally covered indications for Allogeneic
stem cell for primary refractory or relapsed Hodgkin's and non-Hodgkin's
lymphoma with B-cell or T-cell origin, for whom there are no other curative
intent options, and are medically necessary.



**Coverage Indications, Limitations, and/or Medical Necessity**

****

Allogenic hematopoietic cell transplant is considered reasonable and necessary
when:

  1. Patient has primary refractory or relapse of Hodgkin's or non-Hodgkin's lymphoma with B-cell or T-cell origin
  2. Pre-transplantation assessment indicates good function status, low-comorbidities and patient is candidate for transplantation based on risk assessment
  3. There are no other treatment options available with curative intent

Shah et al. studied matched cohorts of patients 1 over 64 (N = 446) and the
other patients aged 55-64 (n-1183) who had non-Hodgkin's lymphoma.21 In a
multivariant analysis, the 4-year probabilities of relapse or progression,
progression free survival, and overall survival were only different in non-
relapse mortality with an increased mortality in the older group. There were
no significant differences in the other measures. Their conclusion was that
"Age alone should not determine allo-HCT eligibility in NHL."

Muffly et al. reviewed the use of allo-HCT in patients 70 and over as reported
to the transplant registry. They found that 1,106 patients 70 years underwent
HCT across 103 transplant centers.3 The number and proportion of allografts
performed in this population rose markedly over the past decade, accounting
for 0.1% of transplants in 2000 to 3.85% (N = 298) in 2013. Acute myeloid
leukemia and myelodysplastic syndromes represented the most common disease
indications. Two-year OS and PFS significantly improved over time (OS: 26%
[95% confidence interval (CI), 21% to 33%] in 2000-2007 to 39% [95% CI, 35% to
42%] in 2008-2013, _P_ < 0.001; PFS: 22% [16% to 28%] in 2000-2007 to 32% [95%
CI, 29% to 36%] in 2008-2013, _P_ = 0.003). Two-year TRM ranged from 33% to
35% and was unchanged over time ( _P_ = 0.54). Multivariable analysis of OS in
the modern era of 2008-2013 revealed higher comorbidity by HCT comorbidity
index 3 (hazard ratio [HR], 1.27; _P_ = 0.006), umbilical cord blood graft
(HR, 1.97; _P_ = 0.0002), and myeloablative conditioning (HR, 1.61; _P_ =
0.0002) as adverse factors.

They concluded that over the past decade, utilization and survival after
allogeneic transplant have increased in patients 70 years. Select adults 70
years with hematologic malignancies should be considered for transplant. They
also state that allo-HCT is not the only therapeutic option available to older
patients with relapsed/refractory or high-risk NHL. The intent of our analysis
is not to prove superiority of allo-HCT in older NHL patients relative to
other available tools (e.g., novel agents, autologous HCT, gene-modified
T-cell therapies). Rather, we aim to demonstrate that, in any given NHL
patient 2:65 years old, if after consideration of multiple variables, the
treating physician has decided that allo-HCT is the next best therapy, an
arbitrary age cutoff and lack of third-party (e.g., CMS) reimbursement should
not remain a barrier against transplantation. Our study utilizing a large
contemporary dataset suggests that survival outcomes of such Medicare-age
eligible patients are not dramatically inferior to a decade-younger patient
cohort undergoing similar allo-HCT procedures.

Majhail et al. published the guidelines for autologous and Allogeneic
hematopoietic cell transplant from the American Society for Blood and Marrow
Transplantation.4 The guidelines state that "age by itself should not be a
contraindication to transplantation in patients who may benefit from this
procedure. Selected older patients with

limited comorbidities and good functional status can safely receive HCT with a
relatively low and acceptable risk of non-relapse mortality. Instead of
chronological patient age, evaluations such as functional status, HCT
Comorbidity Index (HCT CI) score, EBMT risk score and Pre-transplantation
Assessment of Mortality (PAM) risk score can assist in determining risks of
non-relapse mortality and transplant candidacy for individual patients."
Included in this article is a table (table 3) listing the indicated diseases
for allogeneic transplant.

D'Souza et al. noted that "the number of both autologous and Allogeneic
transplants for treatment of malignant diseases in older patients continues to
increase."5 To illustrate this trend, between 1991 and 1997, 7% of ALLOGEN eic
HCTs were performed in patients age 50 years; between 2000 and 2015, this
percentage increased to 38%. In 2015, 25% of all Allogeneic HCT recipients
were age 60 years, up from 5% in 2000; 4.4% were age 70 years in 2015,
compared with 0.4% in 2000.

Kanate et al. stated in the section on patient selection and treatment: With
the addition of reduced

intensity/nonmyeloablative conditioning and improved supportive care, the use
of HCT to include older and more frail patients has indeed widened.
Chronologic age by itself should no longer be a contraindication to
transplantation in patients who may otherwise be eligible and benefit from
this procedure. Carefully selected older patients can safely receive HCT with
a relatively low and acceptable risk of non-relapse mortality. Instead of
patient age, evaluations such as functional status, patient frailty, HCT-
specific comorbidity index score, European Society for Blood and Marrow
Transplantation risk score, and pre-transplantation assessment of mortality
risk score can assist in determining risks of NRM and transplant candidacy for
individual patients. The ongoing Blood and Marrow Transplant Clinical Trials
Network 1704 CHARM (Composite Health Assessment Model) study is prospectively
evaluating pretransplant comorbidity, geriatric assessments, and biomarkers in
older patients to predict post allograft NRM (NCT03992352).6

This article includes a listing of the appropriate indications for Allogeneic
stem cell transplants, which includes multiple forms of both B and T cell
lymphoma. In the comments for that listing they state, "Lymphoma: For Hodgkin
lymphoma and high-grade B cell lymphoma, the subsection positron emission
tomography positive complete remission was removed because updated response
criteria for these lymphomas essentially require normalization of [
18F]2-fluoro-2-deoxy-D-glucose positron emission tomography to be assessed as
a first complete remission. An additional subsection was added to incorporate
double-/triple-hit, high-grade B cell lymphoma and primary central nervous
system lymphoma. The subsection of anaplastic T- cell lymphoma was removed to
be included with T cell lymphoma under pediatric indications. Follicular
lymphoma patients with early treatment failure defined as relapse or
progression of disease within 2 years of initial therapy undergoing autologous
HCT have a low NRM (5%) with good OS (70%) at 5- years compared with
historical control subjects (50%) [23,24]. Matched sibling donor HCT led to
lower relapse rates but higher NRM and, ultimately, similar OS (73%). These
data have been acknowledged under follicular lymphoma/first relapse,
sensitive".6



**Societal Guidance**

The American Society for Transplantation and Cellular Therapy (ASTCT)
Guidelines (2020) provides recommendations for the use of allo-HCT for
Hodgkin's and Non-Hodgkin's lymphomas which ranges from standard of care,
supported by evidence to not recommended. The guidance provides tables to
determine the clinical scenario and recommendation. Of significance to this
policy is that it is recommended as standard of care and supported by evidence
within the population addressed by this policy.6



Emerging evidence support the role of allogenic hematopoietic cell transplant
for primary or refractory Hodgkin's or non-Hodgkin's lymphoma when there are
no other treatment options with a curative intent, pre- transplant assessment
indicates a high probability of success with the transplantation. Multiple
tools to perform this assessment are available and include assessment of the
patient's functional status, co-morbidities, and other factors for candidacy
for transplantation. While age was considered a contraindication in the past
evidence supports removal of age restrictions as there have been improved
outcome in appropriately selected patients over age 70.