Allogeneic Hematopoietic Cell Transplantation for Primary Refractory or Relapsed Hodgkin's and Non-Hodgkin's Lymphoma with B-cell or T-cell Origin

Title XVIII of the Social Security Act, §1862(a)(1)(A) allows coverage and payment for only those services that are considered to be reasonable and necessary for the diagnosis and treatment of illness or injury or to improve the functioning of a malformed body member.

CMS Internet-Only Manual, Pub. 100-03, Medicare National Coverage Determinations Manual, Chapter 1, Part 2, §110.23 Stem Cell Transplantation

CMS Internet-Only Manual, Pub. 100-03, Medicare National Coverage Determinations Manual, Chapter 1, Part 4, §310.1 Routine Costs in Clinical Trials

CMS Internet-Only Manual, Pub. 100-04, Medicare Claims Processing Manual, Chapter 3, §90.3 Stem Cell Transplantation

CMS Internet-Only Manual, Pub. 100-04, Medicare Claims Processing, Chapter 32, §90 Stem Cell Transplantation and §90.1 General

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. 

American Society of Hematology

American Society for Transplantation and Cellular Therapy

1. Shah NN, Ahn KW, Litovich C, et al. Outcomes for Medicare-age eligible NHL patients receiving RIC allogeneic transplantation: A CIBMTR analysis. Blood Advances. 2018;2(8):933-940.
2. Muffly L, Pasquini MC, Martens M, et al. Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States. Blood. 2017;130(9):1156-1164.
3. Majhail NS, Farnia SH, Carpenter PA, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: Guidelines from the American society for blood and marrow transplantation. Biol Blood Marrow Transplant. 2015:21(11):1863-1869.
4. Kharfan-Dabaja MA, Kumar A, Ayala E, et al. Clinical practice recommendations on indication and timing of hematopoietic cell transplantation in mature t cell and nk/t cell lymphomas: An international collaborative effort on behalf of the guidelines committee of the American society for blood and marrow transplantation. Biol Blood Marrow Transplant. 2017;23(11):1826-1838.
5. D’Souza A, Lee S, Zhu X, Pasquini M. Current use and trends in hematopoietic cell transplantation in the United States. Biol Blood Marrow Transplant. 2017;23(9):1417-1421.
6. Kanate AS, Majhail NS, Savani BN, et al. Indications for Hematopoietic cell transplantation and immune effector cell therapy: Guidelines from the American society for transplantation and cellular therapy. Biol Blood Marrow Transplant. 2020;26:1247-1256.
7. Deeg HJ, Sandmaier BM. Determining eligibility for allogeneic hematopoietic transplantation. In: Rosmarin AG, ed. UpToDate. 2022.
8. Khouri IF, Champlin RE. Nonmyeloablative allogeneic stem cell transplantation for non-hodgkin lymphoma. Cancer J. 2012;18(5):457-462.
9. Bellei M, Foss FM, Shustov AR, et al. The outcome of peripheral T-cell lymphoma patients failing first-line therapy: A report from the prospective, international t-Cell project. Haematologica. 2018;103(7):1191-1197.

• allogeneic
• stem cells
• Hodgkin's lymphoma
• non-Hodgkin's lymphoma
• hematopoietic cell transplantation