Abstract
As older patients are eligible for allogeneic hematopoietic cell transplantation (HCT), older siblings are increasingly proposed as donors. We studied the impact of donor age on the tempo of hematopoietic engraftment and donor chimerism, acute and chronic graft-vs.-host disease (GVHD), and non-relapse mortality (NRM) among 1,174 consecutive patients undergoing myeloablative and 367 patients undergoing non-myeloablative HCT from HLA-matched related or unrelated donors with G-CSF-mobilized peripheral blood mononuclear cell (G-PBMC) allografts. Sustained engraftment rates were 97% and 98% in patients undergoing myeloablative and non-myeloablative conditioning, respectively, for grafts from donors <60 years old (younger; n=1,416) and 98% and 100%, respectively, for those from donors ≥60 years old (older; n=125). No significant differences were seen in the tempo of neutrophil and platelet recoveries and donor chimerism except for an average 1.3-day delay in neutrophil recovery among myeloablative patients with older donors (P = 0.04). CD34+ cell dose had an independent effect on the tempo of engraftment. Aged stem cells did not convey an increased risk of donor-derived clonal disorders after HCT. Myeloablative and non-myeloablative recipients with older sibling donors had significantly less grade II–IV acute GVHD than recipients with grafts from younger unrelated donors. Rates of grade III–IV acute GVHD, chronic GVHD, and NRM for recipients with older donors were not significantly different from recipients with younger donors. In conclusion, grafts from donors ≥60 years old do not adversely affect outcomes of allogeneic HCT compared to grafts from younger donors.
Keywords: Older allogeneic hematopoietic cell donor, Engraftment, GVHD, Non-relapse mortality
INTRODUCTION
With reductions in the intensity of conditioning regimens and improved supportive care, older patients have increasingly become eligible for allogeneic hematopoietic cell transplantation (HCT) [1,2]. As the age of allogeneic HCT recipients has increased, the age of sibling donors has increased as well. The impact of patient age and medical comorbidities on transplant outcome has been explored extensively [3–6]. However, the impact of increasing donor age on the functional fitness of hematopoietic cells has been controversial [7–16] Most of the work on stem cell aging has been conducted in mice. As de Haan and colleagues observed, “the discrepant conclusions of these studies, however, could be partly caused by differences in mouse strains used, because strain-dependent increases or decreases in primitive hematopoietic cell frequency and function have been reported” [17]. Also, the longevity hematopoietic stem cells makes them ideal targets for mutagenic changes, which raises the theoretical concern that recipients of aged stem cells are at an increased risk of developing malignant clonal disorders [15]. The uncertainties raised both by these theoretical considerations and the preclinical work prompted the current clinical report. In allogeneic HCT for treatment of human blood disorders, a relatively small inoculum of donor hematopoietic cells is called upon to recapitulate a diverse and fully functional hematopoietic system in the recipient. In earlier reports, we described polyclonal normal hematopoiesis and normal or near-normal immune function in younger patients (3–40 years old at the time of HCT) who had younger donors (4–50 years old) and were studied 20–30 years after transplantation [18,19]. The first questions posed by the current study were whether increasing age of donor hematopoietic cells impaired their ability to repopulate the recipient hematopoietic niche, resulting in a delay of neutrophil and platelet recoveries, and whether aged stem cells increased the risk of post-transplant clonal disorders. A second question was whether grafts from older donors adversely affected long-term transplantation-related outcomes apart from relapse of the underlying disease. To obtain the answers, we used data from a single center and studied the impact of donor age on the tempo of hematopoietic engraftment, development of clonal disorders, acute and chronic graft-vs.-host disease (GVHD), and 5-year non-relapse mortality (NRM) after allogeneic HCT among 1,541 patients, the majority of whom had hematologic malignancies.
PATIENTS AND METHODS
The decision to analyze patients given myeloablative conditioning and nonmyeloablative conditioning separately was based on several considerations:
The greater degree of marrow ablation with the former compared to the latter regimen imposes greater immediate replicative demands on the donor hematopoietic cells.
The incidence of acute GVHD at our Center is historically higher among myeloablative compared to non-myeloablative recipients [20].
As a rule, patients given non-myeloablative conditioning at our Center are either ≥ 55–65 years old or, if younger, have medical comorbidities that preclude myeloablative conditioning.
Patients
Myeloablative Conditioning
We retrieved data for all patients receiving myeloablative conditioning and G-CSF-mobilized peripheral blood mononuclear cell (G-PBMC) derived allografts from an HLA-matched related or unrelated donor for any diagnosis at Fred Hutchinson Cancer Research Center (FHCRC) between 1 January 1999 and 31 December 2009 (n=1,174). Characteristics of patients undergoing myeloablative allogeneic HCT during the study period are given in Table 1. Patients had HLA-identical sibling donors (n=604, 51%) or HLA-matched unrelated donors (n=570, 49%). Ninety-six percent of related older donors had 2 days of G-PBMC collections while 4% had more than two collections. Forty-two percent of patients were conditioned with TBI-based regimens, while the remaining 58% received chemotherapy-only conditioning. Most donors (95%) were younger than 60 years of age, while 60 (5%) of donors were 60 or older at the time of hematopoietic cell collection. The majority of recipients of grafts from older donors were 50 years or older, while most of the recipients of grafts from younger donors were less than 50 years old.
Table 1.
Characteristics of 1,174 recipients of allogeneic hematopoietic cell transplantation after myeloablative conditioning.
| Related Donor <60 years (n=545) | Unrelated Donor <60 years (n=569) | Donor ≥60 years (n=60) | |
|---|---|---|---|
|
| |||
| Patient age, years: n (%) | |||
| <50 | 361 (66)† | 355 (62)† | 5 (8) |
| ≥50 | 184 (34) | 214 (38) | 55 (92) |
|
| |||
| Patient sex: n (%) | |||
| Female | 235 (43) | 258 (45) | 21 (35) |
| Male | 310 (57) | 311 (55) | 39 (65) |
|
| |||
| Ideal body weight | |||
| Data available (n) | 488 | 515 | 55 |
| Median, kg (range) | 66 (7–119) | 66 (7–173) | 68 (50–85) |
|
| |||
| Donor: n (%) | |||
| Related | 545 (100) | 0 | 59 (98) |
| Unrelated | 0 | 569 (100) | 1 (2) |
|
| |||
| Recipient/donor CMV status: n (%) | |||
|
| |||
| −/− | 179 (33) | 194 (34) | 20 (34) |
|
| |||
| −/+ | 75 (14) | 57 (10) | 6 (10) |
|
| |||
| +/− | 105 (19) | 199 (35) | 14 (24) |
|
| |||
| +/+ | 183 (34) | 119 (21) | 19 (32) |
|
| |||
| Missing | |||
|
| |||
| Received TBI: n (%) | |||
| No | 324 (59)* | 310 (54)* | 44 (73) |
| Yes | 221 (41) | 259 (46) | 16 (27) |
|
| |||
| CD34+ cell dose/kg × 106 | |||
| Data available (n) | 512 | 513 | 55 |
| Median (range) | 7.5 (2.1–31.5)† | 7.9 (0.7–57.9)† | 5.7 (2.1–17.4) |
|
| |||
| TNC cell dose/kg × 108 | |||
|
| |||
| Data available (n) | 512 | 513 | 55 |
|
| |||
| Median (range) | 11.6 (3.4–43.0)† | 10.5 (2.0–46.7)† | 14.7 (5.9–45.0) |
|
| |||
| Transplant year: n (%) | |||
| 1999–2000 | 105 (19) | 34 (6) | 7 (12) |
| 2001–2002 | 114 (21) | 132 (23) | 9 (15) |
| 2003–2005 | 188 (35) | 235 (41) | 22 (37) |
| 2006–2009 | 138 (25) | 168 (30) | 22 (37) |
| Diagnosis: n (%) | |||
| AML | 210 (39) | 242 (43) | 24 (40) |
| MDS | 137 (25)* | 166 (29)* | 28 (47) |
| CML | 70 (13)* | 38 (7) | 4 (7) |
| ALL | 63 (12)* | 93 (16)* | 1 (2) |
| CLL/HL/NHL | 46 (8) | 19 (3) | 2 (3) |
| Other | 19 (3) | 11 (2) | 1 (2) |
|
| |||
| Median follow-up (months) | 50 | 49 | 43 |
Abbreviations: CMV=cytomegalovirus; AML=acute myeloid leukemia; ALL=acute lymphocytic leukemia; MDS= myelodysplastic syndrome; CML= chronic myeloid leukemia; CLL= chronic lymphocytic leukemia; HL= Hodgkin lymphoma; NHL=non-Hodgkin lymphoma.
p<0.05 vs. older-donor group
p<0.001 vs. older-donor group
Non-myeloablative Conditioning
We also retrieved data on all patients receiving allogeneic HCT with a G-PBMC derived graft on prospective trials registered with ClinicalTrials.gov for any diagnosis after non-myeloablative conditioning, which we defined as 2 Gy total body irradiation (TBI) with or without fludarabine 90 mg/m2 as reported previously [21,22] during the same time period (n=367). Donors were HLA-matched, except that a single allele-level mismatch at an HLA-class I or class II locus was allowed. Table 2 shows the characteristics of 367 patients receiving G-PBMC allografts following conditioning with 2 Gy TBI with or without fludarabine 90 mg/m2. Sixty-five patients (18%) had donors aged ≥60 years, all of whom were siblings. The oldest donor was 83 years of age. Among patients with donors younger than 60 years, the majority (198, 66%) had unrelated donors. Eighty-eight percent of older donors had a standard 2-day G-PBMC collection, while 12% had a third day of collection.
Table 2.
Characteristics of 367 recipients of allogeneic hematopoietic cell transplantation after non-myeloablative conditioning.
| Related Donor <60 years (n=104) | Unrelated Donor <60 years (n=198) | Related Donor ≥60 years (n=65) | |
|---|---|---|---|
|
| |||
| Patient age, years: n (%) | |||
| <50 | 33 (32%)† | 36 (18%)* | 4 (6%) |
| ≥50 | 71 (68%) | 162 (82%) | 61 (94%) |
|
| |||
| Patient sex: n (%) | |||
| Female | 40 (38%) | 69 (35%) | 29 (45%) |
| Male | 64 (62%) | 129 (65%) | 36 (55%) |
|
| |||
| Ideal body weight | |||
| Data available (n) | 97 | 172 | 58 |
| Median, kg (range) | 71 (46–86)* | 66 (6–88) | 65 (48–85) |
|
| |||
| Donor: n (%) | |||
| Related | 104 (100%) | 0 | 65 (100%) |
| Unrelated | 0 | 198 (100%) | 0 |
|
| |||
| Recipient/donor CMV status: n (%) | |||
| −/− | 33 (32%)† | 63 (32%)† | 7 (11%) |
| −/+ | 19 (18%) | 15 (8%) | 10 (16%) |
| +/− | 26 (25%) | 84 (42%)† | 9 (14%) |
| +/+ | 26 (25%)† | 36 (18%)† | 38 (59%) |
| Missing | 0 | 0 | 1 |
|
| |||
| CD34+ cell dose | |||
| Data available (n) | 101 | 196 | 64 |
| Median, cells/kg × 106 (range) | 10.1 (2.4–33.7)† | 7.0 (1.2–37.2) | 6.7 (1.7–17.8) |
|
| |||
| Transplant year: n (%) | |||
| 1999–2000 | 32 (31%) | 15 (8%) | 12 (18%) |
| 2001–2002 | 20 (19%) | 42 (21%) | 14 (22%) |
| 2003–2005 | 24 (23%) | 60 (30%) | 14 (22%) |
| 2006–2009 | 28 (27%) | 81 (41%) | 25 (38%) |
| Diagnosis: n (%) | |||
| AML | 26 (25%)† | 83 (42%) | 25 (38%) |
| MDS | 8 (8%)† | 25 (13%) | 14 (22%) |
| CML | 5 (5%) | 10 (5%) | 2 (3%) |
| ALL | 2 (2%) | 19 (10%) | 4 (6%) |
| CLL/HL/NHL | 39 (38%) | 43 (22%) | 19 (29%) |
| Other | 24 (23%)† | 18 (9%) | 1 (2%) |
|
| |||
| Median follow-up (months) | 49 | 35 | 45 |
|
| |||
| HCT-CI scores (% of patients) |
|
||
| 0 | 22 | 21 | |
| 1–2 | 30 | 30 | |
| 3+ | 48 | 49 | |
Abbreviations: CMV=cytomegalovirus; AML=acute myeloid leukemia; ALL=acute lymphocytic leukemia; MDS= myelodysplastic syndrome; CML= chronic myeloid leukemia; CLL= chronic lymphocytic leukemia; HL= Hodgkin lymphoma; NHL=non-Hodgkin lymphoma. The oldest donor was 83 years of age.
p<0.05 vs. older-donor group
p<0.001 vs. older-donor group
Engraftment
Day of neutrophil engraftment was defined as the first day on which a patient reached an absolute neutrophil count (ANC) ≥500 cells/μL for at least 3 consecutive days. Day of platelet engraftment was defined as the first day on which a patient reached a platelet count ≥20,000 cells/μL for at least 7 consecutive days without transfusion support.
GVHD and NRM
For the GVHD and NRM analyses, patients were divided into three groups, those with HLA-matched related donors <60 years old, HLA-matched unrelated donors <60 years old, and HLA-matched related donors ≥60 years old.
Acute and chronic GVHD were graded as described [23–25]. NRM included all deaths without relapse or progression of the underlying malignancies.
Statistical analysis
The proportion of patients engrafting was analyzed by chi-squared test. Among engrafted patients, time to engraftment was analyzed using linear regression. Factors considered as potential confounders of the relationship between donor age and engraftment included donor type, patient sex, ideal body weight (continuous), TBI (in myeloablative patients), CD34+ cell dose (continuous), and patient and donor CMV serostatus. Comparisons of patient characteristics were performed using the chi-squared test for categorical variables and Wilcoxon rank-sum test for continuous variables.
Donor chimerism data were summarized by choosing, for each patient, the value closest to the day of interest within ±7 day windows (for example, data for “day +28” was collected between day +21 and day +35).
Cumulative incidences of acute and chronic GVHD and NRM were estimated by standard methods. Death was a competing risk for GVHD, and relapse or progression was a competing risk for NRM. Differences according to donor age were assessed using Cox regression. Models were adjusted for donor relation, patient age (continuous), TBI (in myeloablative patients), CD34+ cell dose (continuous), female donor to male recipient, and patient and donor CMV serostatus. In assessment of NRM, only patients aged 50 years and older were included, due to the correlation of patient and donor age among related donors.
All reported p-values are two-sided, and no adjustments were made for multiple comparisons. Statistical analyses were performed using SAS (SAS Institute Inc., Cary, NC).
RESULTS
Myeloablative conditioning
Neutrophil and platelet engraftment
The trajectories of neutrophil and platelet engraftment according to donor age are shown in Figure 1. The percentages of patients achieving sustained neutrophil engraftment were 97% among those with younger donors and 98% among those with older donors (P = 0.45). Among those engrafting, the estimated mean (± SE) difference in time to engraftment among patients with older donors was +1.7 ± 0.5 days (P = 0.001). In multivariate analysis (Table 3) the difference in time to engraftment associated with older donor age was attenuated to +1.3 ± 0.6 days (P = 0.04). This attenuation was likely due in part to adjustment for CD34+ cell dose, which was decreased in older donors (median 7.7 × 106 cells/kg for younger donors vs. 5.6 × 106 cells/kg for older donors, P < 0.0001). There were no other factors demonstrating a relationship with time to neutrophil engraftment.
Figure 1.
Median neutrophil and platelet counts over time for myeloablative patients, by donor age.
Table 3.
Multivariate regression analysis of patient and transplant characteristics in relation to time to engraftment.*
| Myeloablative patients | ||||
|---|---|---|---|---|
| Neutrophils (n=935) | Platelets (n=860) | |||
| Effect (days) | P | Effect (days) | P | |
| Donor ≥60 years | +1.3 | 0.04 | +0.7 | 0.65 |
| CD34+ cell dose (per log) | −2.8 | <0.0001 | −6.9 | <0.0001 |
| TBI | −0.2 | 0.39 | −0.7 | 0.28 |
| Unrelated donor | −0.1 | 0.79 | +1.9 | 0.006 |
| Male | +0.2 | 0.55 | +1.3 | 0.11 |
| Ideal body wgt (per 10 kg) | +0.1 | 0.66 | −0.1 | 0.65 |
| Patient CMV + | +0.1 | 0.72 | +0.2 | 0.75 |
| Donor CMV + | +0.2 | 0.48 | +0.2 | 0.72 |
| Non-myeloablative patients | ||||
|---|---|---|---|---|
| Neutrophils (n=317) | Platelets (n=310) | |||
| Effect (days) | P | Effect (days) | P | |
| Donor ≥60 years | +0.6 | 0.51 | −2.3 | 0.14 |
| CD34+ cell dose (per log) | −3.1 | 0.01 | −4.0 | 0.05 |
| Unrelated donor | +0.8 | 0.30 | −3.9 | 0.001 |
| Male | +0.4 | 0.63 | +0.8 | 0.52 |
| Ideal body wgt (per 10 kg) | −0.2 | 0.46 | −0.3 | 0.60 |
| Patient CMV + | +1.1 | 0.08 | +1.1 | 0.28 |
| Donor CMV + | −1.1 | 0.10 | +0.5 | 0.66 |
Abbreviations: TBI=total body irradiation.
Effect is the mean difference in time to engraftment associated with the listed variable.
The percentages of patients achieving sustained platelet engraftment were 88% among those with younger donors and 92% among those with older donors (P = 0.43). Among those engrafting, the estimated mean differences in time to platelet engraftment among patients with older donors were +0.2 ± 1.3 days (P = 0.86) in unadjusted analysis, and +0.7 ± 1.5 days (P = 0.65) in multivariate analysis (Table 3). CD34+ cell dose and donor relation were also related to time to platelet engraftment.
GVHD and NRM
Figure 2 summarizes results for acute and chronic GVHD and NRM. The cumulative incidence of day 100 acute grade 2–4 GVHD was 61% for patients with HLA-matched related donors ≥60 years compared to 65% among related recipients with donors <60 years old (adjusted P = 0.98) and 81% for recipients with unrelated donors <60 years old (adjusted P = 0.008, Figure 2A). Grade 3–4 acute GVHD incidences for the three groups of patients were 14%, 10%, and 20%, respectively (adjusted P = 0.60 and P = 0.24, respectively).
Figure 2.
GVHD and NRM outcomes among recipients given myeloablative conditioning. NRM outcomes are shown among recipients aged 50 and older.
The cumulative 2-year incidences of chronic GVHD among the three groups of patients were 62%, 52%, and 53%, respectively (Figure 2B; adjusted P = 0.89 and P = 0.22, respectively). The cumulative 5-year rates of NRM for patients aged 50 and older among the three groups were 30%, 31%, and 39%, respectively (Figure 2C; adjusted P = 0.99 and P = 0.22, respectively).
Non-myeloablative conditioning
Neutrophil and platelet engraftment
The trajectories of neutrophil and platelet engraftment according to donor age are shown in Figure 3. The percentages of patients achieving sustained neutrophil engraftment were 98% among those with younger donors and 100% among those with older donors (P = 0.25). Among those engrafting, the estimated mean (± SE) difference in time to neutrophil engraftment among patients with older donors was +0.2 ± 0.7 days (P = 0.81). In multivariate analysis (Table 3) the difference in time to engraftment associated with older donor age was +0.6 ± 0.9 days (P = 0.51). CD34+ cell dose was the only factor significantly associated with neutrophil engraftment.
Figure 3.
Median neutrophil and platelet counts over time for non-myeloablative recipients, by donor age.
The percentages of patients achieving sustained platelet engraftment were 96% among those with younger donors and 95% among those with older donors (P = 0.43). Among those engrafting, the estimated mean differences in time to platelet engraftment among patients with older donors were +0.7 ± 1.1 days (P = 0.56) in unadjusted analysis, and -2.3 ± 1.5 days (P = 0.14) in multivariate analysis (Table 3). In contrast to the myeloablative patients, grafts from unrelated donors were associated with earlier, rather than later, platelet engraftment. Since all older donors were related to the recipient, we separately analyzed the subgroup of transplant recipients with related donors, with similar results (data not shown).
T-cell chimerism
Chimerism data were available at days +28, +56, and +84 after HCT for 316, 223, and 239 patients, respectively. There were no significant differences in donor CD3+ chimerism between patients with donors aged ≥60 years compared to those with younger donors (P > 0.90 at all times) (Figure 4). Since all older donors were related to their recipients, we separately analyzed the subgroup of transplant recipients with related donors, and again found no significant differences in chimerism at any time according to donor age.
Figure 4.
T-cell chimerism in non-myeloablative recipients by donor age (black=younger [<60 years old], blue=older [≥60 years old]). Median donor T-cell chimerism is the center bar in each box; the bottom and top edges of the boxes represent 25th and 75th percentiles; and whiskers represent the 10th and 90th percentiles.
Development of clonal malignant disorders in donor cells
As of to-date no clonal malignant or non-malignant disorders of hematopoiesis have been seen in any of the patients.
GVHD and NRM
The cumulative incidence of day 100 grade II–IV acute GVHD was 47% for patients with HLA-matched related donors ≥60 years old compared to 51% for those with related donors <60 years old (adjusted P = 0.52) and 74% for those with unrelated donors <60 years old (Figure 5A, adjusted P = 0.01). The corresponding rates of grade 3–4 acute GVHD were 13%, 14%, and 16%, respectively (adjusted P = 0.94 and P = 0.77, respectively).
Figure 5.
GVHD and NRM outcomes among recipients given non-myeloablative conditioning. NRM outcomes are shown among recipients aged 50 years and older.
The cumulative 2-year incidences of chronic GVHD for the three groups of patients were 40%, 53%, and 56%, respectively (Figure 5B, adjusted P = 0.83 and 0.53, respectively).
The corresponding 5-year cumulative incidences of NRM among patients aged 50 and older were 24%, 21%, and 26%, respectively (Figure 5C; adjusted P = 0.28 and P = 0.89, respectively).
DISCUSSION
Hematopoietic cells, like all cells, are subject to aging mechanisms such as telomere shortening, accumulated DNA damage, and epigenetic modification. In 1982, Mauch et al. showed that bone marrow from older rats, grown in culture, had a reduced capacity for CFU production and self-renewal as compared to marrow from younger rats [7]. However, the impact of aging on hematopoietic stem cell function in vivo remains a subject of some controversy. Hematopoietic stem cell aging is thought to be a complex, heterogeneous, and incompletely understood process on the basis of existing animal (mostly murine) models [8–17]. Both cell-intrinsic and epigenetic mechanisms have been implicated in stem cell aging [14]. Very recent work identified “replication stress as a potent driver of functional decline in aging hematopoietic (murine) stem cells” [16]. The implications are unclear for the transplant clinician faced with an elderly potential hematopoietic cell donor, especially given the often discrepant results of murine studies [17].
The high turnover of the hematopoietic system places a substantial burden on a relatively small population of stem cells, but hematopoietic reserve is typically not exhausted during the normal lifespan of an organism. Efforts to quantify the excess hematopoietic reserve have relied upon stressors such as ionizing radiation or serial transplantation to further increase the demand on hematopoietic cells [11]. Using competitive repopulation assays, Harrison and Astle showed in 1982 that a single HCT placed the equivalent of 3 to 7 lifetimes of stress on the transplanted hematopoietic system in mice. They found that hematopoietic cells could be serially transplanted at least 5 times before losing their ability to restore marrow function in lethally irradiated hosts, suggesting by extrapolation that the hematopoietic system has sufficient reserve for approximately 15 to 50 lifetimes in their model [12].
Only one study has been reported in 2001 exploring the issue of replicative senescence in a large-animal model [13]. In this study, cohorts of six young (0.5 years) and six old (8 years) canines were exposed to repeated non-lethal courses of 100 (50) cGy TBI in order to cause transient pancytopenia and to stress the hematopoietic system. There were no differences in the hematopoietic recovery and marrow cellularity of older dogs as compared to younger dogs after 7 courses of TBI over a period of 1 year, and the degree of telomere shortening was likewise equivalent. The respective telomere shortening experienced by both cohorts of dogs after one year of repeated TBI corresponded roughly to that seen in untreated dogs over an 8-year lifespan. These results suggested that the aging hematopoietic system retained adequate reserve to respond to supranormal stresses and demands.
The current study compared two aspects of allogeneic HCT as a function of donor age. The first was the tempo of early hematopoietic recovery, and the second was long-term outcomes. As for the first aspect, we were swayed by the canine data [13] and some of the murine studies [12,17] and postulated that hematopoietic cells from older donors would respond equally well as those of younger donors when challenged to restore host hematopoiesis. This question has substantial clinical relevance, as the extension of allogeneic HCT to older patients has been accompanied by an increasing number of older (sibling) donors.
We found that advanced donor age was associated with a minimal delay in neutrophil engraftment that was seen only after myeloablative allogeneic HCT. However, this association appeared to be driven by the lower CD34+ cell doses obtained from older donors. Since virtually all older donors were siblings, we examined the possibility that donor type (HLA-identical sibling vs. HLA-matched unrelated) might confound our analysis. The results held constant when the analysis of neutrophil change was restricted to patients with HLA-identical sibling donors, suggesting that the higher proportion of HLA-identical siblings among older donors did not compromise the validity of our findings. Donor age did not affect platelet recovery.
In the setting of non-myeloablative HCT, we examined both donor T-cell chimerism and recoveries in neutrophil and platelet counts over time as clinically relevant markers of engraftment. We found no significant effect of donor age on these markers. However, as with myeloablative allogeneic HCT, CD34+ cell dose did influence the tempo of both neutrophil and platelet recoveries. Thus, while a standard plasmapheresis yielded on average less CD34+ cells from an older donor, there appeared to be no clinically relevant effect of aging on the repopulating ability of donor cells after myeloablative and non-myeloablative allogeneic HCT.
Long-lived hematopoietic stem cells are targets for the accumulation of mutagenic changes and are at risk of losing the capacity to adequately maintain tissue homeostasis after stress [15]. As these authors say, an extreme example of disrupted homeostasis is the development of myeloid malignancies, which have an increased incidence in the elderly. These considerations raised the concern that recipients of aged stem cells would be at higher risk of developing clonal malignant disorders, especially given the enormous stress placed on donor cells by rebuilding hematopoiesis in the recipient. We have found no evidence so far to support this theoretical concern. The risk of donor-derived leukemias among younger patients with younger donors has been estimated to be 124 in 100,000 transplants [26].
The second aspect of the study was to examine the impact of donor age on overall outcomes, which is more complex and difficult to answer as recipient age-associated comorbidities may affect prognosis.
In the myeloablative group, recipients of HCT from donors ≥60 years old had similar rates of acute and chronic GVHD and similar 5-year NRM when compared to recipients of HCT from related donors <60 years old. When compared to recipients of HCT from younger unrelated donors, recipients of grafts from older sibling donors showed significantly less acute GVHD grades II–IV.
Among the non-myeloablative group, recipients of HCT from sibling donors ≥60 years of age showed no significant differences from their counterparts with younger donors except for a reduction in acute GVHD grades II–IV compared to those with younger unrelated donors.
Published results on the subject vary. A 2001 NMDP study reported inferior overall survival in patients receiving allografts from donors >45 years old [27]. French investigators identified no significant impact of donor age among patients transplanted for acute myeloid leukemia and myelodysplasia [28,29]. In contrast, a later analysis by the same group found that donor age ≥60 years had a significant negative impact on overall survival in patients receiving G-PBMC allografts for hematologic malignancies [30]. A more recent CIBMTR analysis published in 2013 found that outcomes were superior with HLA-identical sibling donors ≥ 50 years old as compared to HLA-matched unrelated donors < 50 years old [31]
While uncertainties remain in the area of donor selection, our findings provide additional guidance for the transplant clinician who considers an older hematopoietic cell donor. Advanced donor age does not appear to place the recipient at increased risk of delayed engraftment, prolonged neutropenia, prolonged thrombocytopenia, graft rejection, or the development of malignant clonal disorders arising from donor cells. Moreover, no major long-term adverse effects on GVHD and 5-year NRM were seen with grafts from older donors. Importantly, the risk of acute GVHD grades II–IV is significantly lower with older sibling donors compared to younger HLA-matched unrelated donors. These findings may help guide the complex task of assessing potential donors for allogeneic HCT. Given the increasing age of both recipients and sibling donors, additional research should explore the safety implications of the donation process for older individuals. Similarly, since this study confirms the impact of CD34+ cell dose on engraftment, our findings might suggest investigating approaches aimed at optimally mobilizing stem cells for collection from older donors.
Highlights.
Donor age and functional fitness of hematopoietic cells
Donor age and risk of malignant clonal disorders after transplantation
Donor age and non-relapse mortality
Acknowledgments
Supported by grants CA76930, CA78902, CA15704, and CA18029, National Cancer Institute, National Institutes of Health, Bethesda, MD. A.R.R. has received support from Gabrielle’s Angels Foundation and from a Mentored Research Scholar Grant from the American Cancer Society.
Footnotes
Financial disclosure statement: The authors have no relevant financial conflicts of interest to disclose.
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References
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