Analysis of Evidence
Shah et al. analyzed outcomes for 1,629 non-Hodgkin lymphoma patients who had undergone Allo-HSCT. 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 cohort1. 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 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.
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 pretransplant 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 . 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 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.
Rationale for Determination
The overall review of the evidence was consistently supportive of potential benefit for allogeneic HSCTs 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.