Per NCD 110.12 Stem cell transplantation is a process in which stem cells are
harvested from a patient's (autologous) or donor's (allogeneic) bone marrow or
peripheral blood for intravenous infusion to replace diseased and malignant
processes which have undergone therapeutic treatment and ablation. Autologous
Stem Cell Transplantation (AuSCT) is a technique for restoring stem cells
using the patient's own previously stored cells. Allogeneic hematopoietic stem
cell transplantation (Allo-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 to accomplish the hematopoietic restoration for those
individual unable to utilize their own cells. AuSCT must be used to affect
hematopoietic reconstitution following severely myelotoxic doses of
chemotherapy (HDCT) and/or radiotherapy used to treat various malignancies and
disease.

The Centers for Medicare & Medicaid Services (CMS) has clarified per NCD
110.23 "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 associated with 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 and reimbursement per Medicare allowed fee schedule.
When bone marrow or peripheral blood stem cell transplantation is non-covered,
none of the steps are covered."

NCD 110.23 Stem Cell Transplantation includes coverage for allogeneic
transplantation when meeting requirement criteria outlined within the Coverage
Determination. Please refer to NCD 110.23 for those provisions.

  * Leukemia, leukemia in remission
  * 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. For details pertaining to coverage criteria please refer to NCD
110.23.

  * Myelodysplastic Syndrome
  * Multiple myeloma limited to beneficiaries with Durie-Salmon Stage II or III multiple myeloma, or International Staging System (ISS) Stage II or Stage III multiple myeloma
  * Myelofibrosis (MF) limited to beneficiaries with Dynamic International Prognostic Scoring System (DIPSSplus) intermediate-2 or High primary or secondary MF; or
  * Sickle cell disease (SCD) limited to 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 Manual (NCD) _,_ 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 (MAC) discretion."

It is the intention of this Local Coverage Determination to formally notify
Medicare enrolled providers of Noridian Medicare's coverage and allowance for
reimbursement of services related to Allogeneic Stem Cell Transplantation in
compliance with NCD 110.23. Covered indications for allogeneic stem cell
transplant of hemopoietic cells extracted from healthy donor matched
peripheral blood and/or bone marrow for infusion as treatment of primary
refractory or relapsed Hodgkin's and non-Hodgkin's lymphoma, B-cell or T-cell
origin, is limited to Medicare beneficiaries for whom the primary disease is
refractory to standard-of-care treatment or for those whose disease has
relapsed and are without alternative potentially curative options.

Documentation to support medical necessity as well as the appropriateness of
the choice of therapy must be retained in the patient's chart and made
available to Medicare on request. It must include all elements mandated by NCD
110.23 for Stem Cell Transplantation as well as in-depth patient history and
physical exam, the nature and severity of the disease process, previous
therapeutic interventions, disease course and response to therapy, rationale
for choice of therapy, and evidence of patient (and family) education of risk
and benefit inherent to the intervention. Risk assessment as well as
documentation of concomitant disease and psychosocial factors affecting
outcome are suggested as components of the in-depth patient assessment.

Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT) has been
increasingly used for a variety of hematologic neoplasms and non-malignant
marrow disorders. Eligibility for Allo-HSCT varies among institutions and is
considered on a case-by-case basis, dependent upon a risk-benefit assessment,
and the needs of the patient.6

Historically Allogeneic-HSCT has been offered to patients having exhausted all
other treatment modalities. Current practice has shifted decision criteria to
an assessment of patient anticipated benefit relative to other treatment
options for refractory Hodgkins and non-Hodgkins lymphoma. For some lymphoma,
literature and data support an expected outcome superior to other treatment
options.6

The CMS National Coverage Determination (NCD 110.23) for Stem Cell
Transplantation describes nationally covered indications for stem cell
transplant without exclusion of the disease entities considered in this
Policy. Noridian considers Allogeneic Stem Cell Transplantation (Allo-HSCT)
combined with marrow ablative chemotherapy or radiation therapy, medically
reasonable and necessary 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. There are no age-related restrictions to coverage.

Multiple other disorders are under investigation as part of clinical trials
and remain unaffected by this determination. Refer to NCD NCD 310.1 Routine
Costs in Clinical Trials for coverage criteria. Those disorders specifically
excluded from coverage by NCD 110.23 remain noncovered.



**Analysis of Evidence**

Shah et al. analyzed outcomes for 1,629 non-Hodgkin lymphoma patients who had
undergone Allo-HCT. These patients were split into 2 cohorts. Four hundred
forty-six patients were 65 years and housed in 1 cohort (older cohort) while
the other 1,183 patients aged 55-64 comprised the younger cohort.1 In a
multivariant analysis, the older cohort did have increased non-relapse
mortality over the course of 4 years, but there was no difference over that
same 4-year period between the 2 cohorts in terms of relapse/progression,
progression-free survival or overall survival. The 4-year probabilities of
relapse/progression, progression-free survival, and overall survival were only
different in non-relapse mortality with an increased mortality in the older
group. The most common cause of death was disease progression in both cohorts.
There were no significant differences in the other measures, concluding "Age
alone should not determine Allo-HCT eligibility in NHL."

Muffly et al. reviewed the use of Allo-HSCT in patients 70 and over as
reported to a transplant registry. They found 1,106 patients 70 years
underwent Allo-HSCT across 103 transplant centers.2 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.

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. "Allo-HCT is not the only
therapeutic option available to older patients with relapsed/refractory or
highrisk NHL. The intent of 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
Transplantation3 asserting "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 "the number of both autologous and allogeneic transplants
for treatment of malignant diseases in older patients continues to increase."4
Illustrating this trend, between 1991 and 1997, 7% of allogeneic-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. reiterated "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 (NRM)[59-61].
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 pre-transplant comorbidity, geriatric assessments,
and biomarkers in older patients to predict post allograft NRM (NCT03992352).

This article includes a listing of the appropriate indications for allogeneic
stem cell transplants, including multiple forms of both B and T cell lymphoma.
Comments for that listing assert "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 requires normalization of [18F]2-fluoro-2-deoxy-D-
glucose positron emission tomography to be assessed as a first complete
remission [20]. 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".

Khouri et al.8 reviewed the status of non-myeloablative allogeneic
transplantation in the major lymphoma subgroups. As of 2012 when this article
was written, the widespread use of myeloablative allogeneic SCT in non-Hodgkin
lymphoma was demonstrating upfront mortality rates near 40% due to use in
patients with more advanced, chemo-refractory disease. It is also noted that
the way allogeneic SCT is done has changed due to less toxic non-myeloablative
or reduced-intensity conditioning regimens that help promote engraftment and
allow for graft-versus-lymphoma induction. As such, allogeneic SCT has only
become more feasible in an increased number of patients. It has become common
knowledge that benefits exist even for older patients and those with comorbid
conditions.

  
This group reported an 8-year experience with fludarabine, cyclophosphamide
and rituximab in 47 follicular lymphoma patients who underwent allogeneic
nonmyeloablative SCTs. The median patient age was 53 years with a range of
33-68 years and all the patients had chemo-sensitive disease. At the time of
SCT, 62% were in partial remission. After SCT, 100% had a complete response.
While 71% of these patients experienced chronic graft versus host disease, it
had no major negative impact on their survival. The 1-year transplant related
mortality was 13%. Only 6 of the 47 patients died of infections despite
receiving a chemo regimen that targeted both cellular and humoral immunity. At
a median of 60 months follow up, only 2 cases of disease progression had
occurred. The progression-free survival (PFS) and overall survival (OS) rates
were 83% and 85% respectively. With a median follow up of 107 months, the
11-year overall OS and PFS rates were 78% and 72%. These results suggested
that nonmyeloablative allogeneic SCT was curative for relapsed follicular
lymphoma.

These authors also spoke to their experience with mantle cell lymphoma. In a
pre-rituximab era, early autologous SCT extended median remission by 1-2
years, but then most patients relapsed. With rituximab and conditioning
regimens, the outcomes improved a bit. With relapsed or refractory disease,
the clinical results of autologous SCT were inadequate. And so, allogeneic SCT
began to be explored. This group studied 35 patients, median age 58 years who
had been treated with fludarabine, cyclophosphamide and high dose rituximab.
After SCT, the 6-year actuarial PFS rate was 46% and the 6-year actuarial OS
rate was 53%. Plateaus in the survival curves were observed for both PFS and
OS with no relapses or deaths in 9 patients followed up for 63-110 months.
These outcomes were reported as significantly superior to those of patients
who underwent autologous SCT for relapsed or refractory disease at this same
institution (MD Anderson) (P=0.01 for both PFS and OS).

Along these same lines, a study of 33 patients with relapsed or refractory
mantle cell lymphoma at Fred Hutchinson Cancer Center was done. These patients
underwent conditioning with fludarabine and 2 Gy total body irradiation
followed by allogenic SCT. The 2-year PFS was 60%. Both these small series
noted the number of prior therapies to be a major determinant of disease
control.

The authors noted that the results of these 2 reported series suggest that a
significant proportion of relapsed mantle cell lymphoma will be cured with
nonmyeloablative allogeneic SCT. And at that time, this treatment was the only
one that was associated with a long-term remission in relapsed mantle cell
lymphoma.

Lastly, this Khouri et al. group identified and reviewed several small studies
involving TCLs. Compared to B-cell lymphomas, TCLs are more resistant to
conventional chemotherapy and generally have poorer outcomes. Relapses are
more common. A small study of 17 relapsed chemo-sensitive peripheral T-cell
patients had a 3-year PFS rate of 80%.

Overall, it was noted that allogeneic SCT was fast becoming not a sole
procedure of stem cell infusion, but rather an integral part of comprehensive
treatment programs for refractory and relapsing lymphomas of T and B cell
origins.

A report from Bellei et al.9 regarding the prospective International T-cell
Project was published in 2018. This project represents the largest cohort of
prospective data on patients with aggressive TCLs. Data was analyzed from
1,020 patients with newly diagnosed disease enrolled between September 2006
and December 2015. Of 937 patients who got first-line treatment, 47% were
designated refractory and 21% designated as relapsed. The median time elapsed
since the end of their treatment had been 8 months. Seventy-five patients (8%)
had been consolidated with bone marrow transplant including 12 of the
refractory patients and 22 of the relapsed patients. After a median follow up
of 38 months, 440 patients overall had died. The median OS was 5.8 months. The
3-year OS rates were 21% and 28% for refractory and relapsed patients
respectively (p<0.001). Patients undergoing salvage bone marrow transplant had
a 3-year survival of 48% while those who did not get the transplant had an 18%
3-year survival rate (P<0.001). The authors noted this study accurately
reflected outcomes for patients treated according to standards of care
worldwide. The results also confirmed the tendency toward dismal outcomes for
relapsed peripheral TCL patients. The best chance of long-term remission and a
better outcome occurred in patients with relapses later than 12 months who
were then able to undergo high dose therapy followed by HCT with a median
survival after relapse of 48% at 3 years. There is much work to be done, but
bone marrow transplant can benefit patients with no other curative options.

**Rationale for Determination**

The overall review of the evidence was consistently supportive of potential
benefit for allogeneic HSCT in the treatment of various primary refractory or
relapsed B- or T-cell lymphomas. Patients who suffer from such diseases may
have no other available therapeutic options for curative intent. Effectiveness
of Allo-HSCT in such patients has been identified and accounts for its
inclusion in many national oncologic/hematologic clinical practice guidelines
that are evidence graded. The development of reduced intensity conditioning,
the adoption of maximum age increases for transplant program patients, and the
improved screening for and treatment of co-morbid conditions in an older
population, support the expanded therapeutic scope for Allo-HSCT. The
evidentiary analysis confirmed that age should not be a contraindication to
Allo-HSCT.

Allo-HSCT has become part of the standard of care for primary refractory or
relapsed B- and T-cell lymphomas and is neither addressed as covered no
explicitly non-covered in the current National Coverage Determination (NCD)
110.23. Subsequently Noridian is issuing this coverage determination addendum
to clarify and allay coverage and reimbursement concerns expressed by
providers, and to facilitate access for Medicare beneficiaries to the
therapeutic options outlined in this Local Coverage Determination.