Impact of Donor Age on Outcome after Allogeneic Hematopoietic Cell Transplantation

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Impact of Donor Age on Outcome after Allogeneic

Hematopoietic Cell Transplantation

Andrew R. Rezvani

1

, Barry E. Storer

2,3

, Katherine A. Guthrie

2

, H. Gary Schoch

2

,

David G. Maloney

2,4

, Brenda M. Sandmaier

2,4

, Rainer Storb

2,4,*

1Division of Blood & Marrow Transplantation, Stanford University Medical Center, Stanford, California 2Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington

3Deptartment of Biostatistics, University of Washington, School of Public Health and Community Medicine, Seattle, Washington 4Division of Oncology, University of Washington, School of Medicine, Seattle, Washington

Article history: Received 11 July 2014 Accepted 22 September 2014

Key Words:

Older allogeneic hematopoietic cell donor

Engraftment

Graft-versus-host disease Nonrelapse mortality

a b s t r a c t

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-versus-host disease (GVHD), and nonrelapse mortality (NRM) among 1174 consecutive patients undergoing myeloablative and 367 patients undergoing nonmyeloablative HCT from HLA-matched related or unrelated donors with granulocyte colonyestimulating factoremobilized peripheral blood mononuclear cell allografts. Sustained engraftment rates were 97% and 98% in patients undergoing myeloablative and nonmyeloablative conditioning, respectively, for grafts from donors< 60 years old (younger; n ¼ 1416) and 98% and 100%, respectively, for those from donors 60 years old (older; n¼ 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 pa-tients with older donors (P¼ .04). CD34þcell 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 nonmyeloablative recipients with older sibling donors had significantly less grade II to IV acute GVHD than recipients with grafts from younger unrelated donors. Rates of grade III and 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 with grafts from younger donors.

Ó 2015 American Society for Blood and Marrow Transplantation.

INTRODUCTION

With reductions in the intensity of conditioning regimens and improvements in supportive care, older patients have increasingly become eligible for allogeneic hematopoietic cell transplantation (HCT)[1,2]. As the age of allogeneic HCT re-cipients has increased, the age of sibling donors has increased, as well. The impact of patient age and medical comorbidities on transplantation outcome has been explored extensively

[3-6]. However, the impact of increasing donor age on the functionalfitness of hematopoietic cells has been controver-sial [7-16]. Most of the work on stem cell aging has been conducted in mice. As de Haan et al. 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 hematopoiet-ic cell frequency and function have been reported”[17]. Also, the longevity of 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 to 40 years old at the time of HCT) who had younger donors (4 to 50 years old) and were studied 20 to 30 years after trans-plantation[18,19]. Thefirst questions posed by the current

Financial disclosure: See Acknowledgments on page 111.

* Correspondence and reprint requests: Rainer Storb, MD, Fred Hutch-inson Cancer Research Center, 1100 Fairview Avenue N, D1-100, Seattle, WA 98109-1024.

E-mail address:rstorb@fhcrc.org(R. Storb).

http://dx.doi.org/10.1016/j.bbmt.2014.09.021

1083-8791/Ó 2015 American Society for Blood and Marrow Transplantation.

Biology of Blood and

Marrow Transplantation

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study were whether increasing age of donor hematopoietic cells impaired their ability to repopulate the recipient he-matopoietic niche, resulting in a delay of neutrophil and platelet recoveries, and whether aged stem cells increased the risk of post-transplantation clonal disorders. Another ques-tion 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, the devel-opment of clonal disorders and acute and chronic graft-versus-host disease (GVHD), and on the 5-year nonrelapse mortality (NRM) after allogeneic HCT among 1541 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 consider-ations: (1) the greater degree of marrow ablation with the former compared with the latter regimen imposes greater immediate replicative demands on the donor hematopoietic cells; (2) the incidence of acute GVHD at our center is historically higher among myeloablative compared with nonmyeloablative recipients[20]; and (3) as a rule, patients given nonmyeloablative conditioning at our center are either55 to 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 granulocyte colonyestimulating factoremobilized peripheral blood mononuclear cell (G-PBMC)ederived allografts from an HLA-matched related or unrelated donor for any diagnosis at Fred Hutchinson Cancer Research Center between January 1, 1999 and December 31, 2009 (n¼ 1174). Characteristics of patients undergoing myeloablative allogeneic HCT during the study period are given inTable 1. Patients had HLA-identical sibling donors (n¼ 604, 51%) or HLA-matched unrelated donors (n ¼ 570, 49%). Ninety-six percent of related older donors had 2 days of G-PBMC collections, where 4% had more than 2 collections. Forty-two percent of patients were conditioned with total body irradiation (TBI)ebased regimens, whereas the remaining 58% received chemotherapy-only conditioning. Most donors (95%) were younger than 60 years of age, whereas 60 (5%) of donors were 60 or older at the time of hematopoietic cell collection. The majority of re-cipients of grafts from older donors were 50 years or older, whereas most of the recipients of grafts from younger donors were less than 50 years old.

Nonmyeloablative conditioning

We also retrieved data on all patients receiving allogeneic HCT with a G-PBMCederived graft on prospective trials registered withClinicalTrials.gov for any diagnosis after nonmyeloablative conditioning, which we defined as 2 Gy TBI with or withoutfludarabine 90 mg/m2as reported previously

Table 1

Characteristics of Recipients of Allogeneic Hematopoietic Cell Transplantation after Myeloablative Conditioning

Characteristic Related Donor<60 yr (n ¼ 545) Unrelated Donor<60 yr (n ¼ 569) Donor60 yr (n ¼ 60) Patient age, yr <50 361 (66)* 355 (62)* 5 (8) 50 184 (34) 214 (38) 55 (92) Patient sex Female 235 (43) 258 (45) 21 (35) Male 310 (57) 311 (55) 39 (65)

Ideal body weight

Data available, n 488 515 55 Median (range), kg 66 (7-119) 66 (7-173) 68 (50-85) Donor Related 545 (100) 0 59 (98) Unrelated 0 569 (100) 1 (2) Recipient/donor CMV status e/e 179 (33) 194 (34) 20 (34) e/þ 75 (14) 57 (10) 6 (10) þ/e 105 (19) 199 (35) 14 (24) þ/þ 183 (34) 119 (21) 19 (32) Missing Received TBI No 324 (59)y 310 (54)y 44 (73) Yes 221 (41) 259 (46) 16 (27) CD34þcell dose/kg 106 Data available, n 512 513 55 Median (range) 7.5 (2.1-31.5)* 7.9 (.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) Transplantation yr 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 AML 210 (39) 242 (43) 24 (40) MDS 137 (25)y 166 (29)y 28 (47) CML 70 (13)y 38 (7) 4 (7) ALL 63 (12)y 93 (16)y 1 (2) CLL/HL/NHL 46 (8) 19 (3) 2 (3) Other 19 (3) 11 (2) 1 (2) Median follow-up, mo 50 49 43

CMV indicates cytomegalovirus; TNC, total nucleated cells; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; CML, chronic myeloid leukemia; ALL, acute lymphocytic leukemia; CLL, chronic lymphocytic leukemia; HL, Hodgkin lymphoma; NHL, non-Hodgkin lymphoma.

Data presented are n (%) unless otherwise indicated.

yP< .05 versus older donor group. *P< .001 versus older donor group.

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[21,22]during the same time period (n¼ 367). Donors were HLA matched, except that a single allele-level mismatch at an HLA-class I or class II locus was allowed.Table 2shows the characteristics of 367 patients receiving G-PBMC allografts after conditioning with 2 Gy TBI with or without fludar-abine 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, whereas 12% had a third day of collection.

Engraftment

Day of neutrophil engraftment was defined as the first day on which a patient reached an absolute neutrophil count 500 cells/mL for at least 3 consecutive days. Day of platelet engraftment was defined as the first day on which a patient reached a platelet count20,000 cells/mL for at least 7 consecutive days without transfusion support.

GVHD and NRM

For the GVHD and NRM analyses, patients were divided into 3 groups, those with HLA-matched related donors<60 years old, those with HLA-matched unrelated donors<60 years old, and those with HLA-matched related donors60 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 the chi-square 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), CD34þcell dose (continuous), and patient and donor cytomegalovirus serostatus. Compari-sons of patient characteristics were performed using the chi-square 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 within7-day windows (for example, data for“day þ28” was collected between day þ21 and day þ35).

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), CD34þcell dose (continuous), female donor to male recipient, and patient and donor cytomegalovirus serostatus. In assessment of NRM, only patients 50 years and older were included, because of the correlation of patient and donor age among related donors.

All reported P values are 2-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 inFigure 1. The percentages

Table 2

Characteristics of Recipients of Allogeneic Hematopoietic Cell Transplantation after Nonmyeloablative Conditioning

Related Donor<60 yr (n ¼ 104) Unrelated Donor<60 yr (n ¼ 198) Related Donor60 yr (n ¼ 65) Patient age, yr <50 33 (32%)* 36 (18%)y 4 (6%) 50 71 (68%) 162 (82%) 61 (94%) Patient sex Female 40 (38%) 69 (35%) 29 (45%) Male 64 (62%) 129 (65%) 36 (55%)

Ideal body weight

Data available, n 97 172 58 Median (range), kg 71 (46-86)y 66 (6-88) 65 (48-85) Donor Related 104 (100%) 0 65 (100%) Unrelated 0 198 (100%) 0 Recipient/donor CMV status e/e 33 (32%)* 63 (32%)* 7 (11%) e/þ 19 (18%) 15 (8%) 10 (16%) þ/e 26 (25%) 84 (42%)* 9 (14%) þ/þ 26 (25%)y 36 (18%)y 38 (59%) Missing 0 0 1 CD34þcell dose Data available, n 101 196 64

Median (range), cells/kg 106 10.1 (2.4-33.7)* 7.0 (1.2-37.2) 6.7 (1.7-17.8)

Transplantation year 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 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%)y 18 (9%) 1 (2%) Median follow-up, mo 49 35 45

HCT-CI scores (% of patients)

0 22 21

1-2 30 30

3þ 48 49

HCT-CI indicates hematopoietic cell transplantationespecific comorbidity index. Data presented are n (%) unless otherwise indicated.

The oldest donor was 83 years of age.

yP< .05 versus older donor group. *P< .001 versus older donor group.

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of patients achieving sustained neutrophil engraftment were 97% among those with younger donors and 98% among those with older donors (P ¼ .45). Among those engrafting, the estimated mean (SE) difference in time to engraftment among patients with older donors was þ1.7  .5 days (P¼ .001). In multivariate analysis (Table 3), the difference in time to engraftment associated with older donor age was attenuated toþ1.3  .6 days (P ¼ .04). This attenuation was likely due in part to adjustment for CD34þcell dose, which was decreased in older donors (median, 7.7 106cells/kg for younger donors versus 5.6 106 cells/kg for older donors, P < .0001). There were no other factors demonstrating a relationship with time to neutrophil engraftment.

The percentages of patients achieving sustained platelet engraftment were 88% among those with younger donors and 92% among those with older donors (P¼ .43). Among those engrafting, the estimated mean differences in time to platelet engraftment among patients with older donors were þ.2  1.3 days (P ¼ .86) in unadjusted analysis andþ.7  1.5 days (P ¼ .65) in multivariate analysis (Table 3). CD34þcell dose and donor relation were also related to time to platelet engraftment.

GVHD and NRM

Figure 2summarizes results for acute and chronic GVHD and NRM. The cumulative incidence of day 100 acute grade 2 to 4 GVHD was 61% for patients with HLA-matched related donors  60 years compared with 65% among related re-cipients with donors<60 years old (adjusted P ¼ .98) and 81% for recipients with unrelated donors <60 years old (adjusted P ¼ .008,Figure 2A). Grade 3 to 4 acute GVHD

incidences for the 3 groups of patients were 14%, 10%, and 20%, respectively (adjusted P¼ .60 and P ¼ .24, respectively). The cumulative 2-year incidences of chronic GVHD among the 3 groups of patients were 62%, 52%, and 53%, respectively (Figure 2B; adjusted P ¼ .89 and P ¼ .22, respectively). The cumulative 5-year rates of NRM for pa-tients aged 50 and older among the 3 groups were 30%, 31%, and 39%, respectively (Figure 2C; adjusted P¼ .99 and P ¼ .22, respectively).

Nonmyeloablative Conditioning Neutrophil and platelet engraftment

The trajectories of neutrophil and platelet engraftment according to donor age are shown inFigure 3. The percent-ages of patients achieving sustained neutrophil engraftment were 98% among those with younger donors and 100% among those with older donors (P ¼ .25). Among those engrafting, the estimated mean (SE) difference in time to neutrophil engraftment among patients with older donors wasþ.2  .7 days (P ¼ .81). In multivariate analysis (Table 3) the difference in time to engraftment associated with older donor age wasþ.6  .9 days (P ¼ .51). CD34þcell dose was the only factor significantly associated with neutrophil engraftment.

The percentages of patients achieving sustained platelet engraftment were 96% among those with younger donors and 95% among those with older donors (P¼ .43). Among those engrafting, the estimated mean differences in time to platelet engraftment among patients with older donors were þ.7  1.1 days (P ¼ .56) in unadjusted analysis and 2.3  1.5 days (P ¼ .14) in multivariate analysis (Table 3). In contrast to myeloablative patients, for patients with nonmyeloablative conditioning, grafts from unrelated donors were associated with earlier, rather than later, platelet engraftment. Because all older donors were related to the recipient, we separately analyzed the subgroup of transplant recipients with related donors, with similar re-sults (data not shown).

Table 3

Multivariate Regression Analysis of Patient and Transplantation Character-istics in Relation to Time to Engraftment*

Myeloablative Patients Neutrophils (n¼ 935)

Platelets (n¼ 860) Effect, d P Effect, d P Donor60 yr þ1.3 .04 þ.7 .65 CD34þcell dose, per log 2.8 <.0001 6.9 <.0001

TBI .2 .39 .7 .28

Unrelated donor .1 .79 þ1.9 .006

Male þ.2 .55 þ1.3 .11

Ideal body weight, per 10 kg þ.1 .66 .1 .65 Patient CMVþ þ.1 .72 þ.2 .75 Donor CMVþ þ.2 .48 þ.2 .72 Nonmyeloablative Patients Neutrophils

(n¼ 317)

Platelets (n¼ 310) Effect, d P Effect (days) P Donor60 yr þ.6 .51 2.3 .14 CD34þcell dose, per log 3.1 .01 4.0 .05 Unrelated donor þ.8 .30 3.9 .001

Male þ.4 .63 þ.8 .52

Ideal body weight, per 10 kg .2 .46 .3 .60 Patient CMVþ þ1.1 .08 þ1.1 .28 Donor CMVþ 1.1 .10 þ.5 .66

*Effect is the mean difference in time to engraftment associated with the listed variable.

Figure 1. Median neutrophil (A) and platelet (B) counts over time for mye-loablative patients, by donor age.

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T cell chimerism

Chimerism data were available at days þ28, þ56, andþ84 after HCT for 316, 223, and 239 patients, respec-tively. There were no significant differences in donor CD3þ chimerism between patients with donors ages 60 years compared with those with younger donors (P > .90 at all times) (Figure 4). Because 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 ac-cording to donor age.

Development of clonal malignant disorders in donor cells To date, no clonal malignant or nonmalignant disorders of hematopoiesis have been seen in any of the patients. GVHD and NRM

The cumulative incidence of day 100 grades II to IV acute GVHD was 47% for patients with HLA-matched related do-nors 60 years old, compared with 51% for those with related donors<60 years old (adjusted P ¼ .52) and 74% for those with unrelated donors <60 years old (Figure 5A, adjusted P¼ .01). The corresponding rates of grades 3 to 4 acute GVHD were 13%, 14%, and 16%, respectively (adjusted P¼ .94 and P ¼ .77, respectively).

The cumulative 2-year incidences of chronic GVHD for the 3 groups of patients were 40%, 53%, and 56%, respectively (Figure 5B, adjusted P¼ .83 and .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 ¼ .28 and P ¼ .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 colony-forming unit production and self-renewal compared with marrow from younger rats

[7]. However, the impact of aging on hematopoietic stem cell

Figure 2. Acute grades 2-4 GVHD (A), chronic GVHD (B), and NRM (C) out-comes among recipients given myeloablative conditioning. NRM outout-comes are shown among recipients aged 50 and older.

Figure 3. Median neutrophil (A) and platelet (B) counts over time for non-myeloablative recipients, by donor age.

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function in vivo remains a subject of some controversy. He-matopoietic 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 impli-cated 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 implica-tions are unclear for the transplantation 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 trans-planted 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 1 study has been reported in 2001 exploring the issue of replicative senescence in a large-animal model[13]. In this study, cohorts of 6 young (.5 years) and 6 old (8 years) canines were exposed to repeated nonlethal courses of 100 (50) cGy TBI to cause transient pancytopenia and to stress the hematopoietic system. There were no differences in the he-matopoietic recovery and marrow cellularity of older dogs compared with 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 1 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 2 aspects of allogeneic HCT as a function of donor age. Thefirst was the tempo of early

hematopoietic recovery and the second was long-term out-comes. As for thefirst 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 CD34þ cell doses

Figure 5. Acute grades 2-4 GVHD (A), chronic GVHD (B), and NRM (C) out-comes among recipients given nonmyeloablative conditioning. NRM outout-comes are shown among recipients aged 50 years and older.

Figure 4. T cell chimerism in nonmyeloablative recipients by donor age (black¼ younger [<60 years old], blue ¼ 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.

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obtained from older donors. Because virtually all older do-nors were siblings, we examined the possibility that donor type (HLA-identical sibling versus 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 ourfindings. Donor age did not affect platelet recovery.

In the setting of nonmyeloablative 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, CD34þ cell dose did influence the tempo of both neutrophil and platelet recoveries. Thus, whereas a standard plasmapheresis yielded, on average, less CD34þcells from an older donor, there appeared to be no clinically relevant effect of aging on the repopulating ability of donor cells after myeloablative and nonmyeloablative 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 ma-lignancies, 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 transplantations[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 comor-bidities 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 with recipients of HCT from related donors <60 years old. When compared with recipients of HCT from younger unrelated donors, re-cipients of grafts from older sibling donors showed signi fi-cantly less acute GVHD grades II to IV.

Among the nonmyeloablative group, recipients of HCT from sibling donors60 years of age showed no significant differences from their counterparts with younger donors, except for a reduction in acute GVHD grades II to IV compared with those with younger unrelated donors.

Published results on the subject vary. A 2001 National Marrow Donor Program study reported inferior overall survival in patients receiving allografts from donors >45 years old [27]. French investigators identified no sig-nificant impact of donor age among patients who under-went transplantation for acute myeloid leukemia and myelodysplasia[28,29]. In contrast, a later analysis by the same group found that donor age60 years had a significant negative impact on overall survival in patients receiving G-PBMC allografts for hematologic malignancies [30]. A more recent Center for International Blood and Marrow Transplant Research analysis published in 2013 found that outcomes were superior with HLA-identical sibling donors 50 years old compared with HLA-matched unrelated donors<50 years old[31]

Whereas uncertainties remain in the area of donor selec-tion, ourfindings provide additional guidance for the trans-plantation 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 to IV is significantly lower with older sibling donors compared with younger HLA-matched unrelated donors. Thesefindings 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 in-dividuals. Similarly, because this study confirms the impact of CD34þcell dose on engraftment, ourfindings might suggest investigating approaches aimed at optimally mobilizing stem cells for collection from older donors.

ACKNOWLEDGMENTS

Supported by grants CA76930, CA78902, CA15704, and CA18029 of the National Cancer Institute (National Institutes of Health), Bethesda, MD. A.R.R. received support from Gabrielle’s Angels Foundation and from Grant MRSG-12-162-01-LIB from the American Cancer Society.

Financial disclosure: The authors have no relevant finan-cial conflicts of interest to disclose.

Conflict of interest statement: There are no conflicts of in-terest to report.

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16. Flach J, Bakker ST, Mohrin M, et al. Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature. 2014; 512:198-202.

17. de Haan G, Nijhof W, Van Zant G. Mouse strain-dependent changes in frequency and proliferation of hematopoietic stem cells during aging: correlation between lifespan and cycling activity. Blood. 1997;89: 1543-1550.

18. Storek J, Joseph A, Espino G, et al. Immunity of patients surviving 20 to 30 years after allogeneic or syngeneic bone marrow transplantation (Plenary Paper). Blood. 2001;98:3505-3512.

19. Mathioudakis G, Storb R, McSweeney PA, et al. Polyclonal hematopoiesis with variable telomere shortening in human long-term allogeneic marrow graft recipients (Brief Report). Blood. 2000;96:3991-3994. 20. Mielcarek M, Martin PJ, Leisenring W, et al. Graft-versus-host disease

after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood. 2003;102:756-762.

21. McSweeney PA, Niederwieser D, Shizuru JA, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001;97:3390-3400.

22. Maris MB, Niederwieser D, Sandmaier BM, et al. HLA-matched unre-lated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood. 2003; 102:2021-2030.

23. Inamoto Y, Martin PJ, Storer BE, et al. Response endpoints and failure-free survival after initial treatment for acute graft-versus-host disease. Haematologica. 2014;99:385-391.

24. Flowers MED, Inamoto Y, Carpenter PA, et al. Comparative analysis of risk factors for acute versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood. 2011;117:3214-3219.

25. Storb R, Gyurkocza B, Storer BE, et al. Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell trans-plantation. J Clin Oncol. 2013;31:1530-1538.

26. Wiseman DH. Donor cell leukemia: a review. Biol Blood Marrow Transplant. 2011;17:771-789.

27. Kollman C, Howe CWS, Anasetti C, et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unre-lated donors: the effect of donor age. Blood. 2001;98:2043-2051. 28. Robin M, Porcher R, Ades L, et al. Matched unrelated or matched sibling

donors result in comparable outcomes after non-myeloablative HSCT in patients with AML or MDS. Bone Marrow Transplant. 2013;48: 1296-1301.

29. Peffault de Latour R, Brunstein CG, Porcher R, et al. Similar overall survival using sibling, unrelated donor, and cord blood grafts after reduced-intensity conditioning for older patients with acute myelog-enous leukemia. Biol Blood Marrow Transplant. 2013;19:1355-1360. 30. Servais S, Porcher R, Xhaard A, et al. Pre-transplant prognostic factors

of long-term survival after allogeneic peripheral blood stem cell transplantation with matched related/unrelated donors. Haematolog-ica. 2014;99:519-526.

31. Alousi AM, Le-Rademacher J, Saliba RM, et al. Who is the better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer? Blood. 2013;121:2567-2573.

Figure

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