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

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.

American Society of Hematology

American Society for Transplantation and Cellular Therapy

1. Deeg HJ, Sandmaier BM. Determining eligibility for Allogeneic hematopoietic transplantation. In: Rosmarin AG, ed. UpToDate; 2022.
2. Shah NN, Ahn KW, Litovich C, et al. Outcomes for Medicare-age eligible NHL patients receiving RIC ALLOGEN eic transplantation: A CIBMTR analysis. Blood Advances. 2018;2(8):933-940.
3. Mfflly 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.
4. 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.
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.

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