Hematopoietic Stem Cell Transplantation in the Elderly

November 15, 2007

Hematopoietic stem cell (HSC) transplantation may improve outcomes of patients with hematologic malignancies not curable with conventional therapies. In some clinical settings, transplantation represents the only curative option. The feasibility and efficacy of this approach in older patients are undefined, since this population has been excluded from nearly all clinical trials. Advances in supportive care, HSC harvesting, and safer conditioning regimens have made this therapy available to patients well into their 6th and 7th decades of life. Recent evidence suggests that elderly patients with good performance status and no comorbidities could, in fact, not only survive the transplant with reasonable risk, but also benefit in the same measure as younger patients.

Hematopoietic stem cell (HSC) transplantation may improve outcomes of patients with hematologic malignancies not curable with conventional therapies. In some clinical settings, transplantation represents the only curative option. The feasibility and efficacy of this approach in older patients are undefined, since this population has been excluded from nearly all clinical trials. Advances in supportive care, HSC harvesting, and safer conditioning regimens have made this therapy available to patients well into their 6th and 7th decades of life. Recent evidence suggests that elderly patients with good performance status and no comorbidities could, in fact, not only survive the transplant with reasonable risk, but also benefit in the same measure as younger patients.

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.[1] 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.

Animal Studies

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.

Human Studies

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.[4] 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.[5] 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.[6]

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.[7] 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).[8] 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.[9]

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).[10] 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.

Over the past decade, numerous reports have documented that the elderly can tolerate standard HDT regimens, with a mild but manageable increased incidence of toxicity. Transplant-related morbidity and mortality are primarily determined by host-related factors, with disease related factors generally playing no significant role.

Autologous HSC Transplants

In a series of 500 consecutive autologous HSC transplants from 1988 to 1995 for various hematologic malignancies at Stanford University, the median age was 40 years (range: 1–65).[11] Transplant-related mortality (nonrelapse deaths in the first 100 days posttransplant) was 7.4% for patients < 50 and 12.7% for those > 50 (P = .07). Over the 7 years of the study, transplant-related mortality significantly decreased over time. For the later cohort treated from 1992 to 1995, transplant-related mortality was 5.8% for patients < 50 and 9.4% for patients > 50.

A review of more recent series of patients over age 60 who received autologous HSC transplants for various hematologic malignancies demonstrates transplant-related mortality rates ranging from 0% to 8%. These patients received established HDT regimens such as BEAM (BCNU, etoposide, cytarabine [Ara-C], melphalan), BUCY (busulfan [Myleran, Busulfex], cyclophosphamide) and others including total-body irradiation (TBI). One study reported a high incidence of grade III cardiac toxicity, in particular atrial fibrillation in elderly patients,[12] but a study that evaluated left-ventricular ejection fraction pre- and posttransplant showed no significant decrease in cardiac function.[13] In a study of non-Hodgkin's lymphoma (NHL) patients undergoing autologous HSC transplants, a trend toward a higher incidence of oral mucositis was found in patients aged > 60 years compared with younger patients. No differences were found in transplant-related mortality or other organ toxicities.[14]

High-dose melphalan at 200 mg/m2 with autologous HSC transplantation was well tolerated in 22 myeloma patients aged > 65 years. While the occurrence of mucositis was increased compared to patients under 65, no transplant-related mortality was reported in the older patients.[15] In the University of Arkansas experience, melphalan at 200 mg/m2 resulted in a transplant-related mortality rate of 16% in multiple myeloma patients older than 70 years. With a reduction of the dosage to 140 mg/m2, transplant-related mortality decreased to 2%. Approximately 44% of patients were able to complete two (tandem) transplants.[16]

TBI was poorly tolerated by elderly patients and significantly increased transplant-related mortality in some but not all studies. In a study reported from Seattle, including 53 NHL patients receiving autologous HSC transplants from 1979 to 1999, transplant-related mortality was 9.4%. Prior mediastinal irradiation was found to significantly increase mortality. In this study, no deaths were reported among 16 patients conditioned with cyclophosphamide/etoposide and TBI, whereas a 29% transplant-related mortality was observed among 24 patients treated with busulfan/melphalan/thiotepa.[17]

At 3 months posttransplant, quality-of-life measures showed good functional and social scores in elderly patients who have received autologous HSC transplants.[18] Fatigue and nausea were the most common symptoms, but these occurred at an acceptable level.

Allogeneic HSC Transplants

In addition to the toxicity of HDT regimens, allogeneic HSC transplantation is associated with toxicities related to prolonged use of immunosuppressive drugs, graft-vs-host disease, and a high incidence of infections. Age over 50 is an independent predictor for high transplant-related mortality and poor OS in this setting, but not for relapse risk or progression-free survival (PFS).[19] Nonmyeloablative/reduced-intensity conditioning (RIC) transplants were designed to reduce mortality related to high-dose therapy conditioning regimens while preserving the clinical benefits of a graft-vs-tumor effect. This approach is particularly suitable for the elderly individual.

Table 1 summarizes several nonrandomized studies comparing nonmyeloablative/RIC transplants with myeloablative allogeneic HSC transplants in older patients.[20-23] In general, they demonstrate a significantly reduced transplant-related mortality without significant differences in outcomes (PFS and OS), despite the fact that nonmyeloablative patients were more frequently older and had high-risk disease.

In the larger of these reports, issued by the European Bone Marrow Transplant Registry, 722 AML patients > 50 years of age received allogeneic HSC transplants.[22] A nonmyeloablative/RIC approach was used in 315, who were compared with 407 patients receiving myeloablative transplants. Transplant-related mortality at 2 years was reduced from 32% with myeloablative transplants to 18% with nonmyeloablative procedures. While nonmyeloablative patients had a higher relapse rate (41% vs 24%), the incidence of severe acute graft-vs-host disease (grade 3/4), leukemia-free survival, and OS were not different between the groups.

In a study of 60 patients over age 55 with advanced hematologic malignancies who received nonmyeloablative/RIC allogeneic HSC transplants, nonrelapse mortality at 5 years was 19%, which was not statistically different from that of 90 patients under 55 (13%). Similarly, OS was not different (61% vs 66%, respectively).[24]

Among 145 patients over 60 years old who were ineligible for myeloablative transplants and received RIC allogeneic HSC transplants, a previous autologous transplant and an Eastern Cooperative Oncology Group (ECOG) performance status > 1 were associated with high risk for transplant-related mortality.[25] However, elderly patients without the other adverse factors had an acceptable transplant-related mortality rate of 17%.

Comorbidities

Comorbidities and performance status are pretransplant variables that adversely affect transplant-related mortality and OS and therefore, can be used as predictors to select low and high risk patients.

Comorbidities are common in older cancer patients. Several studies have documented their significant impact on treatment outcomes. A hematopoietic cell transplant comorbidity index (HCT-CI) has been developed based on the analysis of 1,055 patients (median age: 44.8 years; range: 0.8–72.7) receiving allogeneic transplants (see Table 2). For patients with low risk (score 0), the nonrelapse mortality at 2 years was 14% and the OS was 71%, compared to 21% and 60% in patients with intermediate risk (scores 1–2) and 41% and 34% in patients with high risk (score 3), respectively.[26]

This HCT-CI was recently used in a series of 177 patients over the age of 60 receiving standard intensive induction therapy for acute myelogenous leukemia[27] and in a group of 80 patients (median age: 56 years, range: 42–76) with Hodgkin's and non-Hodgkin's lymphomas receiving HDT with autologous HSC transplants.[28] In both studies, the HCT-CI was predictive of early death and OS.

Outcomes of Transplants for Specific Disorders

When assessing outcomes of HSC transplantation in the elderly, one needs to bear in mind that in many clinical settings there are significant differences in the intrinsic biologic characteristics of the disease in older patients compared with the younger population. These differences may profoundly affect outcomes to standard therapy and transplantation alike, to a larger measure than factors related to the host's age. For instance, the prognosis of AML with standard chemotherapy in patients over 60 is abysmal, whereas a long-term DFS of 30% or higher can be achieved in younger patients. In the Stanford University study previously mentioned,[11] patients > 50 years of age had a higher relapse rate (62% vs 44%) and lower event-free survival (34% vs 46%) than younger patients after autologous HSC transplantation. This difference was primarily related to a larger number of AML cases in the older age group.

One of the problems with HSC transplantation in elderly patients is that only a small proportion of potential candidates are eventually transplanted. This point is illustrated with the study of a series of AML patients over age 60 (median: 72 years, range: 61–94). Out of the 155 consecutive patients, 90 were considered candidates for aggressive induction chemotherapy; 45 (50%) achieved a CR and were considered eligible for intensive consolidation with autologous HSC transplantation. A successful HSC collection was obtained in 25 of the 32 in whom the procedure was attempted, and only 20 eventually received autografts.[29] Similarly, in a cohort of patients aged > 60 with AML in first CR, only 27% of potential candidates underwent autologous HSC transplantation. This group's 2-year PFS was 39%, compared to 22% for candidates who did not receive transplants.[30]

Acute Myelogenous Leukemia/Myelodysplastic Syndromes

The primary role of autologous HSC transplantation in AML is for patients in first CR. The European Organisation for Research and Treatment of Cancer (EORTC)–Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA) AML-13 trial included 61 patients aged 61 to 70 with good performance status (World Health Organization [WHO] 0–1) who were mobilized with G-CSF. Adequate HSC numbers were achieved in 38 of 52 patients in whom harvesting was attempted; 35 were actually transplanted. DFS and OS at 3 years were 28 and 39%, and eight patients remain in continuous CR.[31]

In a series of 193 patients with AML aged 60 to 75 who received autografts in first CR (n = 147) or second CR (n = 46) from 1984 to 1998, PFS was 36% and OS was 47% at 3 years. Outcomes improved for those patients transplanted after 1996, with a PFS of 53% and OS of 72%.[32]

Standard myeloablative allogeneic HSC transplants can potentially cure high-risk AML, although the experience is limited in patients > 55 years of age. In a report on 50 patients with AML or myelodysplastic syndromes (MDS) aged 55 to 66, the 3-year DFS correlated with disease risk group: 59% for patients with refractory anemia, 46% for refractory anemia with excess of blasts, and 33% for those with disease in transformation, AML, or chronic myelomonocytic leukemia.[33]

Preliminary reports appear to indicate that in the older population, a nonmyeloablative/RIC transplant may result in similar outcomes to those reported with myeloablative transplants. Among 24 high-risk MDS or AML patients aged >60 years (median: 64 years, range: 60–71), a nonmyeloablative/RIC-related allogeneic HSC transplant resulted in a 2 year PFS of 45% and an OS of 52%. Transplant-related mortality was 8% at 100 days and 25% at 2 years.[34]

In a series of 105 patients with AML and high-risk cytogenetics, 53 achieved CR after induction chemotherapy and 42 of them proceeded with a first course of consolidation. Based on donor availability, 23 received a second course of consolidation while 12 got an allogeneic transplant with a nonmyeloablative regimen. At 4 years, PFS was 42% after transplant and 15% after chemotherapy.[35]

Acute Lymphoblastic Leukemia

The role of autologous HSC transplants remains undefined in acute lymphoblastic leukemia (ALL), although some studies have suggested a potential benefit for younger patients in first CR. Clinical trials have demonstrated a benefit for adult ALL patients receiving allogeneic HSC transplants. In adults under 50 years of age, standard myeloablative allogeneic HSC transplantation in first CR resulted in improved long-term PFS and OS. A correlation between the development of graft-vs-host disease and a decreased relapse risk has been reported, suggesting that establishing chimerism with a nonmyeloablative/RIC approach could be of potential benefit.

In a retrospective analysis of 33 adults with high-risk ALL (20 beyond first remission), including 17 older than 55 receiving nonmyeloablative/RIC allogeneic transplants from related and unrelated donors, nonrelapse mortality was 30%. At 1 year, DFS was 29% and OS was 30%. Of the 17 older patients, 6 were reported alive and in CR.[36]

Multiple Myeloma

The largest database of autologous transplants in elderly individuals comes from patients with multiple myeloma. This is primarily because high-dose melphalan is very well tolerated, and also because of its clear clinical benefits demonstrated in prospective randomized clinical trials.

In the first reported series, 49 patients aged > 65 were compared to a cohort of younger patients matched for recognized risk factors. While the CR rate was lower in elderly patients, on multivariate analysis age was not recognized as an adverse prognostic factor in terms of DFS and OS.[37] From 1994 to 1998, 119 patients over age 60 (median: 63 years, range: 60–73) were reported to the Autologous Bone Marrow Transplant Registry.[38] Their outcomes were compared to those of 382 younger patients (median age: 52 years, range: 30–59). The groups were otherwise comparable, except for higher beta2-microglobulin serum levels in the older patients. Transplant-related mortality was 4% in younger patients and 3% in those over 60. CR rates (34% vs 33%), PFS at 3 years (44% vs 35%), and median OS (39 vs 39 months) were not statistically different in younger and older patients.

A population-based study by the Nordic Myeloma Study Group included 452 patients under 65 eligible to receive intensive therapy. An improved OS was observed in transplanted patients compared to a matched control group who received standard therapy. The improved OS was seen in patients under 60 as well as in those aged 60 to 64 years.[39]

The largest series reported to date included 137 patients over 65 from the Mayo Clinic. Investigators reported no impact of age on any measure of outcome when these patients were compared to a cohort of 541 younger patients.[40]

A report from the University of Arkansas included 70 patients older than 70, (median: 72 years, range: 70–82).[41] Of these patients, 34 were newly diagnosed and 36 had relapsed or refractory disease. More than 12 months of prior therapy adversely affected PFS and OS. PFS was improved for the 31 patients receiving a second transplant.

Standard myeloablative allogeneic HSC transplants for myeloma have been associated with a high transplant-related mortality, even in younger patients. However, long-term follow-up suggests that a significant proportion of these patients can potentially be cured.[42] Nonmyeloablative/RIC transplants result in a lower transplant-related mortality but higher relapse rates.[43] A new approach includes an initial autologous HSC transplant for tumor debulking, followed by a nonmyeloablative allogeneic transplant to eliminate residual disease via a graft-vs-tumor effect. When compared to a tandem autologous HSC transplant, patients treated with a nonmyeloablative allogeneic transplant had significantly improved outcomes.[44] This approach has not been tested in elderly patients.

Non-Hodgkin's Lymphomas

Outcomes after autologous HSC transplantation for NHL are dependent on the histologic subtype and the state of responsiveness of the disease to chemotherapy.

A report from Finland documents the long-term outcomes of 88 patients aged > 60 (median: 63 years, range: 60–70) with various NHL subtypes transplanted from 1994 to 2004.[45] Patients were conditioned with BEAM or cyclophosphamide/TBI. Transplant-related mortality was 11%. The 5-year OS was 44% for the entire group; 50% for patients with mantle cell lymphoma; 38% for those with diffuse large B-cell lymphoma (DLBCL); 28% for follicular cell lymphoma; and 20% for peripheral T-cell lymphomas.

Similar results were reported for a group of 11 patients aged > 65 with DLBCL in chemosensitive relapse.[46] The HDT regimen used was TBI/etoposide or BEAM. The investigators noted one transplant related death (9%). Nine patients achieved a CR; DFS and OS rates at 4 years were both 44%.

In a Seattle series of 53 patients aged > 60 receiving autologous HSC transplants during the 1980s and 1990s, 83% had an aggressive histology.[17] OS at 4 years was significantly better for patients transplanted with chemosensitive disease (39%) than for those transplanted with resistant disease (15%). Exposure to three or fewer lines of prior therapy was also associated with better survival.

High-dose anti-CD20 radioimmunotherapy with autologous transplantation appears particularly suitable for the elderly patient.[47] In a report of 24 patients over 60 (range: 60–76) with advanced and refractory NHL, high-dose tositumomab/I-131 tositumomab (Bexxar) followed by autologous HSC transplantation resulted in a 3-year DFS and OS of 51% and 59%, respectively, with no transplant-related mortality.

Other Disorders

HDT and autologous HSC transplantation can improve outcomes of patients with primary (AL) amyloidosis. In a study of 65 patients aged 65 years or older, toxicity, response rates, and survival after HDT and autologous HSC transplantation were not significantly different than those of 280 younger patients.[48]

Allogeneic HSC transplantation can be a curative option for patients with other hematologic malignancies. These include chronic lymphocytic leukemia,[49] chronic myelogenous leukemia, idiopathic myelofibrosis, polycythemia vera, and essential thrombocythemia. However, available data are even more limited for these disorders.[50]

Conclusions and Summary

Age alone should not be a criterion for exclusion of patients from HSC transplantation, when this procedure could result in significant clinical benefit. Instead, the patient's individualized risk profile for transplant-related mortality should first be assessed. This is best done by evaluating performance status measures and comorbidity indexes. If the risk is acceptable, age does not predict for a poorer outcome. The risk of relapse is primarily dependent on intrinsic disease characteristics, not on the patient's age.

As shown from the data reviewed here, it is apparent that older patients with multiple myeloma and chemosensitive DLBCL derive benefits from autologous HSC transplants similar to those seen in younger patients. Patients with high-risk MDS, AML, and possibly ALL could be expected to benefit from nonmyeloablative/RIC allogeneic HSC transplantation. The option of an HSC transplant should be considered early in the course of the disease. Avoidance of extensive exposure to chemotherapy and/or radiation therapy should reduce the chances of an insufficient HSC collection, decrease the risk of transplant-related mortality, and prevent the development of chemoresistance-all factors that could affect the ultimate outcome.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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