Hematopoietic Stem Cell Transplantation in the Elderly
Hematopoietic Stem Cell Transplantation in the Elderly
The role of hematopoietic stem cell (HSC) transplantation has been under continuous expansion and revision in recent decades. Autologous HSC transplants rely primarily on the efficacy of a single (sometimes double) course of high-dose therapy (HDT) to eradicate the disease. The role of the autologous graft is simply limited to restoring hematopoiesis. Autologous HSC transplants can now be performed with transplant-related mortality rates generally well under 5%. Therefore, they have become more attractive to the previously excluded population of patients over age 65.
Standard myeloablative allogeneic HSC transplants add the potential benefit of a graft-vs-tumor effect to the antitumor activity of HDT. However, the high transplant-related mortality associated with this procedure has excluded patients over 55 years of age in most centers and from most clinical trials. In many clinical situations, recognition of the clinical benefits of a strong graft-vs-tumor effect has allowed for a reduction in the intensity of the conditioning regimen, in an attempt to decrease associated morbidity and mortality. The development of nonmyeloablative and reduced-intensity allogeneic HSC transplantation has made this approach feasible for the population of patients over 55 years old.
Critical questions relevant to the older patient are: (1) Can the older individual mobilize sufficient numbers of HSC to functionally restore stable and long-term hematopoiesis in the recipient? (2) Can the older patient tolerate HDT with reasonable safety? (3) Can the older patient expect clinical benefits similar to those demonstrated for young individuals? In this review, we will attempt to answer these questions based on the available data, consisting mainly of retrospective analysis of series with limited numbers of patients. While these studies establish feasibility and document positive outcomes in selected elderly patients, they cannot be used to formulate firm generalized recommendations. The lack of prospective randomized trials including older individuals remains the major impediment to clinical decision-making processes when evaluating elderly patients as candidates for HSC transplantation.
Stem Cell Reserve and Mobilization in the Elderly
A significant decline in hematopoietic reserve has been reported with aging in healthy individuals, raising serious concerns regarding their ability to become HSC donors. This applies to both the elderly patient as a candidate for autologous transplantation and the elderly donor in the allogeneic transplant setting. The issue is particularly valid for autologous transplants, since these patients would have been previously exposed (sometimes extensively) to chemotherapy and/or radiotherapy.
In a mouse model, granulocyte colony-stimulating factor (G-CSF, Neupogen) mobilized significantly larger numbers of HSC and progenitor cells (HPC) in aged mice compared to young animals.[2,3] This was observed despite the presence of mild anemia in the older mice. The higher numbers of HSC were functionally capable of restoring long-term hematopoiesis.
Competitive transplant experiments of mobilized peripheral blood stem cells from young and old mice revealed that 5 months after transplantation, HSC from aged mice contributed an average of 80% of peripheral blood cells (including myeloid cells, T and B lymphocytes) and > 75% of cells from other hematopoietic tissues (spleen, thymus, bone marrow). Enhanced mobilization appeared to be intrinsic to the aged HSC. In addition, adhesion of HSC to stromal cells was impaired in aged mice. This phenomenon was associated with increased levels of active Cdc42, a Rho GTPase involved in cell adhesion. Advanced donor or recipient age impaired homing of HPC to the bone marrow and spleen after transplantation. These experiments appear to document a role for changes with aging in the bone marrow microenvironment.
In healthy humans (aged 16–100 years), the basal numbers of CD34+ cells in peripheral blood decreased significantly as a function of age, particularly in individuals > 80 years old. The number of granulocyte-macrophage colony-forming units (CFU-GM)but not erythroid burst-forming units (BFU-E) or granulocyte/erythrocyte/monocyte/ megakaryocyte colony-forming units (CFU-GEMM)per 103 CD34+ cells plated, decreased significantly with age. In both animals and humans, investigators have described an intrinsic loss of T-cell generation capacity in old bone marrow CD34+ cells, with a preferential differentiation toward myeloid cells.
The response of HSC to hematopoietic growth factors may be different in older individuals. After 5 days of low-dose (30 μg) G-CSF administration, HPC measured by the CFU-GM assay increased threefold in young healthy individuals (mean age: 23 years), but this was associated with no significant increase from baseline in older subjects (mean age: 74 years). At standard dosages of G-CSF (300 μg), both young and old individuals experienced a significant increase in the number of CFU-GM in peripheral blood, but the increase was twofold higher in the young.
In spite of these findings, most elderly patients are able to collect adequate numbers of HSC for transplantation, even those who have been previously exposed to myelosuppressive treatments.
Higher numbers of transplanted CD34+ cells result in faster neutrophil and platelet recovery. But no significant impact on transplant-related mortality, response rates or survival has been demonstrated, as long as a minimum of 2 x 103 CD34+ cells per kg are infused.
Analysis of the database of 984 patients with multiple myeloma from the University of Arkansas, which included 106 patients over 70 years of age, revealed that age, more than 12 months of previous chemotherapy, and low platelet counts predicted for poor numbers of CD34+ cell collection. However, 85% of the older patients without the other two adverse factors were able to collect > 4 x 106/kg. There was no effect of age on kinetics of neutrophil engraftment, but platelet recovery was delayed in older patients receiving < 2 x 106 CD34+ cells per kg. This effect of platelet recovery was not observed in patients receiving > 4 x 106 CD34+ cells per kg.
These findings were confirmed by a study of 789 myeloma patients from the Spanish Myeloma Group (median age: 59 years, range: 20–72). After receiving four cycles of multiagent chemotherapy, including several alkylators (cyclophosphamide, melphalan [Alkeran], and carmustine [BCNU]), only 3% of cases could not proceed with transplantion due to a low CD34+ cell yield. On multivariate analysis, only age and time from diagnosis to mobilization were associated with lower numbers of HSC collected.
Similarly, in a study of patients with acute myelogenous leukemia (AML, N = 150) in first complete remission (CR), nearly identical successful rates of CD34+ cell mobilization (87% vs 80%) were observed in patients younger or older than 60.
Related allogeneic HSC donors are usually of similar age with the recipient. Therefore, any differences in engraftment patterns may not only reflect characteristics of the aged donated HSC but also those of the aged microenvironment of the recipient. In a study from the National Marrow Donor Program, matched unrelated grafts from donors aged > 45 years contained slightly lower nucleated cell numbers but resulted in no appreciable differences in engraftment (median age of the recipients was 35, not significantly different between groups). Transplants from older and young donors were associated with significant but small differences in transplant outcomes. Five-year disease-free (DFS) and overall survival (OS) for donors aged > 45 years were 21% and 25%, compared to 29% and 33% for donors aged < 30 years, and 26% and 29% for donors aged 31 to 45 years, respectively. Risk of relapse was not associated with donor age. Older age donor was associated with a higher risk for severe (grade III/ IV) acute and chronic graft-vs-host disease.