LCD L39434: Allogeneic Hematopoietic Cell Transplantation for Primary Refractory or Relapsed Hodgkin's and Non-Hodgkin's Lymphoma with B-cell or T-cell Origin

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:

• Patient has primary refractory or relapse of Hodgkin's or non-Hodgkin's lymphoma with B-cell or T-cell origin

• Pre-transplantation assessment indicates good function status, low-comorbidities and patient is candidate for transplantation based on risk assessment

• 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 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