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.