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 (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. 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 covers allo-HSCT for the following
conditions, when reasonable and necessary:

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

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

  * Myelodysplastic Syndromes
  * Multiple myeloma with Durie-Salmon Stage II or III disease, or International Staging System (ISS) Stage II or Stage III disease 
  * Myelofibrosis (MF) with Dynamic International Prognostic Scoring System (DIPSSplus) intermediate-2 or High primary or secondary disease; or
  * Sickle cell disease (SCD) that is severe and symptomatic

(Please refer to CMS Internet-Only Manual, Pub. 100-03, Medicare National
Coverage Determinations Manual _,_ Chapter 1, Part 2, 110.23 Stem Cell
Transplantation)

Per the NCD, all other indications for stem cell transplantation not otherwise
noted as covered or non-covered remain at local Medicare Administrative
Contractor (MAC) discretion.

This policy describes additional locally covered indications for allo-HSCT for
primary refractory or relapsed Hodgkin's and non-Hodgkin's lymphomas with
B-cell or T-cell origin that are medically necessary in patients for whom
there are no other curative intent options.

Documentation to support the reasonable and necessary nature of allo-HSCTs
must speak to the serious illness of the patient, the reasons why the patient
is considered to have relapsed or refractory disease, relevant clinical
contextual information such as age, frailty, performance status,
cardiopulmonary function, any associated organ dysfunction that could impact
complications or recovery, screening for infectious diseases that could impact
transplant care, nutritional status and patient specific psychosocial and
financial support structures. Risk assessment scoring, such as the European
Society for Blood and Bone Marrow Transplantation (EBMT) or the HCT
Comorbidity Index (HCT-CI), should be strongly considered and in the case of
any nationally covered indications per NCD 110.23 would of course be required.

Allogeneic hematopoietic cell transplantation (allo-HCT has been increasingly
used for a variety of hematologic neoplasms and non-malignant bone marrow
disorders. Eligibility for allo-HCT varies amongst 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.7

Although historically allo-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.7

The CMS National Coverage Determination (NCD 110.23) for Stem Cell
Transplantation describes nationally covered indications for SCT, the details
of which will not be fully 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 lymphomas 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.

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 nonrelapse
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 most common cause of death
was disease relapse in both cohorts. The 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 a transplant registry.2 One thousand, one hundred six patients 70 years
who underwent allo-HCT across 103 transplant centers from 2000 to 2013 were
reviewed. The number and proportion of allografts performed in this population
rose markedly over that 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 overall survival
(OS) and progression-free survival (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 transplant-
related mortality (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 increased in patients 70 years and that select adults
70 years with hematologic malignancies should be considered for transplant.
Patient selection is acknowledged to be critical insofar as decreasing
toxicity and morbidity in older adults. Interior survival was associated with
high comorbidity, but only modestly (HR, 1.27; 95% CI, 1.07-1.51). Patients 75
or older did not do worse than those aged 70-74. Thus, the study authors
concluded that age alone or moderate degrees of comorbidity are insufficient
to determine transplant eligibility. Patient selection for allo-HCT may be
enhanced by geriatric assessment pre-procedure. Geriatric assessments
themselves warrant additional research.

Majhail et al. published the 2015 guidelines for autologous and allogeneic
hematopoietic cell transplant from the American Society for Blood and Marrow
Transplantation.3  This Task Force emphasizes that these guidelines should not
be used for decision making regarding an individual patient. The decision to
treat an individual patient is a clinical decision between the patient and the
provider after careful consideration of alternatives, risks and benefits--all
of which should be individualized. 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-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 is a tabular list
which notes standard of care or standard of care with evidence designations
for allo-HCT in all acute myeloid leukemia and promyelocyte leukemia except
CR1, low risk type, all acute lymphoblastic leukemia, all chronic leukemia,
all myelodysplastic syndromes, all therapy related acute myeloid leukemia or
myelodysplastic syndrome, all MF and myeloproliferative diseases (except
refractory hypereosinophilic syndromes, most multiple myeloma with some
ongoing study, plasma cell leukemia, refractory or relapsed Hodgkin's
lymphoma, refractory or relapsed diffuse large B-cell lymphomas, refractory or
relapsed or high grade transforming follicular lymphomas, mantle cell
lymphomas, T-cell lymphomas (TCL), Burkitt's lymphoma, cutaneous TCL, high-
risk chronic lymphocytic leukemia (CLL) or CLL transforming to high grade
lymphoma (but not T- or B-cell prolymphocytic leukemias), and aplastic anemia.

The 2017 Clinical Practice Recommendations on Indication and Timing of
Hematopoietic Cell Transplantation in Mature T-Cell and NK/T-Cell Lymphomas on
behalf of the American Society for Blood and Marrow Transplantation4 speaks to
allo-HCT in front-line consolidation therapy for acute and lymphoma types of
adult TCL/leukemia (HTLV-1 associated) and its recommended role for relapsed-
sensitive disease adult TCL/leukemia that is acute, lymphoma type or
smoldering/chronic.

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 allo-HCTs
were performed in patients age 50 years; between 2000 and 2015, this
percentage increased to 38%. In 2015, 25% of all allo-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. on behalf of the American Society for Transplantation and
Cellular Therapy provided an update on indications for autologous and
allogeneic hematopoietic cell transplantation.6 This was needed due to the
improvements over just 5 years in transplantation technology which had
expanded the therapeutic reach of allo-HCT amongst many other therapies. No
new indications for allo-HCT were identified as compared to the 2015
guidelines noted above. However, these current 2020 guidelines state, "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 nonrelapse
mortality." They additionally state, "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 nonrelapse mortality and transplant candidacy for individual
patients." The ongoing Blood and Marrow Transplant Clinical Trials Network
1704 CHARM (Composite Health Assessment Model) study may be illuminating as it
is currently prospectively evaluating pretransplant comorbidity, geriatric
assessments, and biomarkers in older patients to predict post allograft
nonrelapse mortality.

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, chemorefractory 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 chemosensitive 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 chemosensitive 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.

The overall review of the evidence was consistently supportive of potential
benefit for allogeneic SCTs 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-HCT in such patients has been identified and accounts for its
inclusion in many national oncologic/hematologic clinical practice guidelines
that are evidence graded. Much has changed over recent years and allo-HCT has
its niche within the standard of care for these difficult oncologic issues.
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 all support the
expanded therapeutic scope for allo-HCT. The evidentiary analysis confirmed
that age should not be a contraindication to allo-HCT in and of itself.
Therefore, this policy most definitely is applicable and potentially
beneficial to many Medicare beneficiaries.

Allo-HCT is part of the standard of care for primary refractory or relapsed B-
and T-cell lymphomas, but is not addressed in the current national coverage
determination. This MAC has engaged its discretionary abilities to implement
this local coverage determination in order to allow access for Medicare
beneficiaries to potentially curative therapy.