Bone Marrow Transplantation (2006) 38, 95–100
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ORIGINAL ARTICLE
Does younger donor age affect the outcome of reduced-intensity allogeneic
hematopoietic stem cell transplantation for hematologic malignancies
beneficially?
J Mehta, LI Gordon, MS Tallman, JN Winter, AO Evens, O Frankfurt, SF Williams, D Grinblatt,
L Kaminer, R Meagher and S Singhal
The Feinberg School of Medicine, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
Sixty three patients aged 27–66 years (median 52) were
allografted from HLA-matched sibling (n ¼ 47), 10 of 10
allele-matched unrelated (n ¼ 19), or one-antigen/allelemismatched (n ¼ 7) donors aged 24–69 years (median 46)
after a conditioning regimen comprising 100 mg/m2
melphalan. Cyclophosphamide (50 mg/kg) was also
administered to patients who had not been autografted
previously. Cyclosporine or tacrolimus, and mycophenolate mofetil were administered to prevent graft-versus-host
disease (GVHD). The 2-year cumulative incidences of
relapse and TRM were 55 and 24% respectively, and
2-year probabilities of overall survival (OS) and diseasefree survival (DFS) were 36 and 21%, respectively.
Poor performance status, donor age 445 years and
elevated lactate dehydrogenase (LDH) increased the risk
of treatment-related mortality (TRM), refractory disease
and donor age 445 years increased the risk of relapse,
and OS and DFS were adversely influenced by refractory
disease, poor performance status, increased LDH, and
donor age 445 years. Our data suggest that younger
donor age is associated with better outcome after submyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic malignancies due to
lower TRM and relapse. This finding raises the question
of whether a young 10-allele-matched unrelated donor is
superior to an older matched sibling donor in patients
where the clinical situation permits a choice between such
donors.
Bone Marrow Transplantation (2006) 38, 95–100.
doi:10.1038/sj.bmt.1705388; published online 5 June 2006
Keywords: age; allograft; relapse
Correspondence: Dr J Mehta, 676 N Saint Clair Street, Suite 850,
Chicago, IL 60611, USA.
E-mail: [email protected]
Received 3 January 2006; revised 27 March 2006; accepted 28 March
2006; published online 5 June 2006
Introduction
In addition to its utility in patients considered unsuitable for
conventional-intensity (myeloablative) allogeneic hematopoietic stem cell transplantation (CI-HSCT), reducedintensity allogeneic HSCT (RI-HSCT) is increasingly being
used as an alternative in patients who could otherwise be
eligible for CI-HSCT and in a tandem autograft-allograft
setting.1–4 Older donor age has been shown to be associated
with poorer outcome of CI-HSCT through a combination
of higher treatment-related mortality (TRM) and relapse.5–8
However, it is not known if donor age affects the outcome
of RI-HSCT.
We studied the outcome of 63 adult patients undergoing
RI-HSCT from adult donors to study the effect of pretransplant patient-, donor- and disease-related variables
including donor age.
Patients and methods
Records of 63 consecutive patients undergoing RI-HSCT
using a uniform, melphalan-based conditioning regimen
were reviewed after approval from the institutional review
board. The treatment period comprised March 2001 to
May 2004.
All patients had hematologic malignancies requiring
allogeneic HSCT, and 58 were felt to be unsuitable for
CI-HSCT because of prior autograft, advanced age (X50
years), poor performance status (41), compromised organ
function, concomitant active medical conditions or a
combination of these features. There was no obvious
reason to choose RI-HSCT in five others than a feeling
that the underlying diseases were not aggressive enough
to require CI-HSCT. Of the 40 sibling donors, 37
were matched at six of six HLA antigens tested (A, B,
DR) using low-resolution DNA typing, and three were
mismatched at a single antigen. Of the 23 donors identified
through the National Marrow Donor Program, 19 were
matched at 10 of 10 alleles tested (A, B, C, DRB1 DQB1)
using high-resolution DNA typing, and four were mismatched at a single allele. Donors were aged 24–69 years
(median 46).
Donor age and outcome of allografts
J Mehta et al
96
Table 1
Patient characteristics
All patients
n
Patient age
Patient age X60 years
Male
Siblings
Unrelated
HLA-matched
HLA-mismatched
Acute leukemia
Lymphoma
Myeloma
Refractory disease
PS 0–1
PS 2–3
LDH
Elevated LDH
Prior autograft
CD3+ cell dose (108/kg)
CD34+ cell dose (106/kg)
52
11
38
40
23
56
7
19
29
15
38
47
16
182
28
21
3.0
5.0
Younger donors (p45 years)
63
(27–66)
(17%)
(60%)
(63%)
(37%)
(89%)
(11%)
(30%)
(46%)
(24%)
(60%)
(75%)
(25%)
(83–1919)
(44%)
(33%)
(0.9–14.9)
(1.4–11.8)
46
2
18
10
20
25
5
10
17
3
18
22
8
174
14
10
3.0
5.1
30
(27–62)
(7%)
(60%)
(33%)
(67%)
(83%)
(17%)
(33%)
(57%)
(10%)
(60%)
(73%)
(27%)
(105–1919)
(47%)
(33%)
(1.6–14.9)
(1.4–11.8)
Older donors (445 years)
54
9
20
30
3
31
2
9
12
12
20
25
8
182
14
11
3.1
5.0
33
(40–66)
(27%)
(61%)
(91%)
(9%)
(94%)
(6%)
(27%)
(36%)
(37%)
(61%)
(76%)
(24%)
(83–1298)
(42%)
(33%)
(0.9–8.6)
(2.6–8.9)
P-value
o0.0001
0.046
0.96
o0.0001
0.18
0.045
0.96
0.83
0.9
0.74
1
0.69
0.53
Abbreviations: LDH ¼ lactate dehydrogenase; PS ¼ performance status.
Table 1 shows patient characteristics for the entire group
of patients as well as a comparison between those with
younger donors (p45 years) and those with older donors
(445 years). Patients with older donors were significantly
older themselves, and tended to have myeloma more
frequently and lymphoma less frequently. Three of 23
unrelated donors were 445 years of age compared with 30
of 40 sibling donors (Po0.0001). Two patients with
relapsed disease were allografted without having received
salvage therapy and were considered non-refractory for the
purpose of analysis. All other patients had received primary
or salvage chemotherapy prior to HSCT, and could be
clearly classified as having refractory or sensitive (nonrefractory) disease based upon response (non-refractory)
or stability/progression (refractory).
Conditioning regimen
Patients who had relapsed after a previous autograft
received 100 mg/m2 melphalan followed 24 h later by donor
stem cell infusion. Those not autografted previously
received 50 mg/kg cyclophosphamide with mesna 24 h
before melphalan. The drugs were dosed based on the
actual body weight if it was less than the ideal weight, and
on adjusted body weight (ideal þ 25% of the difference
between actual and ideal) if the actual weight was greater
than the ideal.
Stem cell mobilization and graft characteristics
All donors underwent leukapheresis after stimulation with
granulocyte colony-stimulating factor (G-CSF), and bloodderived stem cells were used exclusively for transplantation.
The CD34 þ cell dose measurement was based upon
the patient’s ideal body weight.9,10 Based upon our previous
experience in myeloablative HSCT,11 3 106 CD34 þ cells/
kg was considered a minimum acceptable dose from sibling
donors. Siblings underwent leukapheresis on more than
one occasion if needed to meet the minimum cell dose
Bone Marrow Transplantation
requirement. While the same cell number was requested of
the unrelated donors, the final collection was determined by
the harvest center, and was below the minimum acceptable in four cases. All unrelated donor stem cells were
used fresh, and all sibling donor stem cells had been
collected and cryopreserved before starting the conditioning regimen.
Graft-versus-host disease prophylaxis
Patients allografted from HLA-identical sibling donors
received cyclosporine from day 1 at the dose of 3 mg/kg as
a continuous intravenous infusion. This was switched to
oral as soon as engraftment had occurred, and oral intake
was consistent and predictable. The target cyclosporine
levels (ng/ml) during the first 6–7 weeks and during periods
of significant graft-versus-host disease (GVHD) were 250–
350 (steady-state levels on intravenous therapy using highperformance liquid chromatography), 200–300 (trough
levels on oral therapy using high-performance liquid
chromatography), 475–675 (steady-state levels on intravenous therapy using TDX), or 375–575 (trough levels
on oral therapy using TDX). Patients allografted from
mismatched sibling donors or unrelated donors (irrespective of HLA match grade) received tacrolimus from day 1
at the dose of 0.05 mg/kg as a continuous intravenous
infusion. This was changed to oral as soon as engraftment
had occurred and oral intake was adequate. The target
tacrolimus level (ng/ml) was 10–15 (steady-state levels on
intravenous therapy using TDX) or 8–12 (trough levels on
oral therapy using TDX). The calcineurin inhibitor was
tapered from the seventh week post-transplant onwards
with a view to discontinuing it completely between 100
and 150 days post-transplant in the absence of clinically
significant GVHD requiring immunosuppressive therapy.
All patients also received mycophenolate mofetil 1000 mg
twice daily orally; from day 21 to 150 in recipients of
matched sibling cells and from day 1 to 150 in the others.
Donor age and outcome of allografts
J Mehta et al
97
GVHD was treated with corticosteroids in addition to
the prophylactic agents, and salvage agents were added as
needed, based upon response.
Supportive therapy
All patients received ciprofloxacin or levofloxacin from day
0 to day 60, valaciclovir 500 mg thrice daily from day 1 to
1 month beyond discontinuation of immunosuppression,
itraconazole liquid 200 mg twice daily from day 0 to
1 month beyond discontinuation of immunosuppression,
and monthly inhaled pentamidine or thrice-weekly trimethoprim-sulfamethoxazole from the time of engraftment
to 1 month beyond discontinuation of immunosuppression.
Itraconazole was switched to voriconazole if patients
received corticosteroids for the treatment of GVHD. Owing
to concerns about toxicity, no myeloid growth factors were
used routinely post-transplant but G-CSF 300–480 mg was
started daily if the total leukocyte count was p0.2 109/l
on day 14.12
Statistical analysis
Data were analyzed using SPSS for Windows (Release
10.0.5) as of 30 June 2005 (minimum follow-up of 41
year). The w2 test was used to compare categoric variables
and the Wilcoxon rank-sum test was used to compare
continuous variables. The probabilities of disease-free
survival (DFS) and overall survival (OS) were estimated
by the Kaplan–Meier method, and compared using the
log-rank test. Cumulative incidence of TRM and relapse
were estimated using each type of event as a competing
risk for the other. Cumulative incidence of acute and
chronic GVHD were estimated using TRM and relapse as
competing events.
Two patients dying in CR of causes clearly unrelated to
the transplant or the underlying disease (cardiac arrhythmia and exacerbation of pre-existing chronic obstructive
pulmonary disease at 15.4 and 26.8 months, respectively)
were censored at the time of death for computing OS and
DFS, and were considered to have experienced competing
events for calculating the cumulative incidence of TRM and
relapse.
A number of pre-transplant variables were analyzed
individually using the likelihood-ratio statistic of a proportional hazards regression model for their effect on OS. The
factors found to be statistically significant (Pp0.05) in
univariate fashion were entered into a step-wise Cox model
to determine their contribution to TRM, relapse, DFS,
and OS. These were patient age (o60 years vs X60 years),
performance status (0 vs 1 vs X2), chemosensitivity
(refractory vs non-refractory), donor (sibling vs unrelated),
HLA (match vs mismatch), donor age (p45 years vs 445
years), 108/kg CD3 þ cells infused (o3 vs X3), lactate
dehydrogenase (LDH) (normal vs increased), platelet
count (o100 vs X100 109/l), albumin (p3 vs 43 g/dl)
and hemoglobin (o9 vs X9 g/dl). The factors not found to
be significant in univariate analysis (and therefore not
entered into the Cox model) were diagnosis, patient sex,
race, donor sex, CD34 þ cell dose, prior autograft,
glomerular filtration rate, blood group and cytomegalovirus serostatus.
The patient and donor age cutoff values chosen were
based upon analyses of the effect of various cut-off values
on OS – and the values showing the most significant
disparity in outcome were chosen.
Results
Engraftment and GVHD
Prompt neutrophil recovery was seen in 62 patients; one
patient died of malignant hyperthermia and multi-organ
failure on day 12 before recovery of counts. The time to
neutrophil (median 14 days) and platelet (median 17 days)
recovery was comparable for patients with younger and
older donors. The cumulative incidence of any grade of
acute GVHD at 100 days was 57% (95% CI: 46–71%),
and that of grades III–IV acute GVHD was 34% (95% CI:
22–50%). The cumulative incidence of chronic GVHD at
1 and 2 years was 22% (95% CI: 14–35%) and 25% (95%
CI: 17–39%).
TRM, relapse and survival
Sixteen patients died of transplant-related causes at 0.4 to
30.9 months (median 3.7). The causes of death were multiorgan toxicity/failure (n ¼ 7), GVHD (n ¼ 6), renal failure
(n ¼ 1), aspiration pneumonia (n ¼ 1) and mucormycosis
(n ¼ 1). These were evenly distributed between patients with
younger and older donors. Three of the seven patients dying
from multi-organ failure had a PS of two or three, one had
significantly abnormal renal function, and one had neurological deficits related to whole-brain radiation. All four
patients receiving o3 106 CD34 þ cells/kg engrafted, but
eventually died of transplant-related causes (compared to 12
of 59 receiving an adequate CD34 þ cell dose; P ¼ 0.003).
Thirty-five patients were found to have recurrent or
persistent disease at 0.5 to 30.1 months (median 3.7).
Treatment for relapse was variable and comprised withdrawal of immunosuppression, donor cell infusions,
and salvage chemotherapy in varying combinations. Eight
relapsed patients were alive in CR 12.2 to 29.9 months after
relapse (median 24.6), whereas 27 died of relapsed disease
or consequences of subsequent therapy. Overall, 20 patients
were alive at 13–52 months (median 29).
The 2-year cumulative incidences of relapse and TRM
were 55% (95% CI: 44–69%) and 24% (95% CI: 15–37%)
respectively, and 2-year probabilities of OS and DFS were
36% (95% CI: 24–48%) and 21% (95% CI: 11–31%)
respectively.
Cox analysis
As shown in Table 2, relapse was higher with refractory
disease and donor age 445, TRM was higher with poorer
PS, donor age 445 and increased LDH, and OS and DFS
were lower with poorer PS, refractory disease, donor age
445, and increased LDH.
Figures 1 and 2 depict the impact of donor age on DFS
and OS in curves that have been adjusted for other
variables. The survival curves shown have been derived
from the final Cox model, and have been plotted at the
means of the other covariates. Similarly, Figure 3 depicts
Bone Marrow Transplantation
Donor age and outcome of allografts
J Mehta et al
98
Cox analysis of variables affecting outcome
Table 2
Variable
Adverse
P-value
Relative risk
95% CI
22.6
2.7
8.6
5.3
3.5–145.9
0.8–9.2
2.1–35.9
1.4–19.7
0.001
0.11
0.003
0.013
Favorable
Transplant-related mortality
Performance status 2–3
Performance status 0
Performance status 1
Normal LDH
Donor age p45
Increased LDH
Donor age 445
Relapse
Refractory disease
Donor age 445
Overall survival
Performance status 2–3
Increased LDH
Donor age 445
Refractory disease
Disease-free survival
Donor age 445
Performance status 2–3
Refractory disease
Increased LDH
Non-refractory disease
Donor age p45
3.2
2.7
1.5–6.7
1.3–5.7
0.003
0.007
Performance status 0
Performance status 1
Normal LDH
Donor age p45
Non-refractory disease
0.17
0.48
0.29
0.39
0.38
0.06–0.47
0.24–0.98
0.14–0.62
0.19–0.77
0.15–0.92
0.001
0.045
0.001
0.007
0.033
Donor age p45
Performance status 0
Performance status 1
Non-refractory disease
Normal LDH
0.27
0.28
0.5
0.36
0.43
0.14–0.53
0.11–0.78
0.24–1.03
0.17–0.77
0.22–0.83
o0.001
0.007
0.061
0.008
0.012
Abbreviations: LDH ¼ lactate dehydrogenase; PS ¼ performance status.
1.0
0.8
0.8
0.6
Overall survival
Disease-free survival
1.0
Donor age-45
0.4
0.2
0.0
Donor age >45
–0.2
0
6
12
18
Months
24
30
Donor-45, Patient< 60
0.6
0.4
Donor age>45,
Patient< 60
Donor-45,
Patient.60
0.2
Donor>45, Patient.60
Figure 1
The effect of donor age on disease-free survival; adjusted for all
other variables (plotted at the means of the other covariates using the Cox
model).
0.0
0
6
12
18
Months
24
30
Figure 3 The combined effect of donor and patient age on overall
survival; adjusted for all other variables (plotted at the means of the other
covariates using the Cox model).
Overall survival
1.0
0.8
0.6
Donor age-45
0.4
Donor age > 45
0.2
0.0
0
6
12
18
Months
24
30
Figure 2
The effect of donor age on overall survival; adjusted for all
other variables (plotted at the means of the other covariates using the Cox
model).
The 100-day cumulative incidence of acute GVHD with
younger donors was 60% compared to 55% with older
donors. The 2-year cumulative incidence of chronic GVHD
with younger donors was 37% compared to 15% with older
donors. This difference was not statistically significant (RR
1.6, 95% CI 0.5–4.6, P ¼ 0.39). The development of chronic
GVHD in patients alive at 100 days was associated with
significantly better survival. However, this effect was not
seen among those alive at 1 year, probably because of small
numbers.
Discussion
the combined effect of patient and donor age (donor and
patient age categories were combined into a single category
with four covariates) on OS in curves that have been
adjusted for other variables.
Bone Marrow Transplantation
Our data show that outcome of RI-HSCT is better in
patients with younger donors. Previous work has shown
superior outcome with younger donors in the setting of
Donor age and outcome of allografts
J Mehta et al
99
CI-HSCT from HLA-identical sibling donors,13 HLA-mismatched related donors8 and from unrelated donors.14,15
However, to the best of our knowledge, this has not been
shown with RI-HSCT previously.
The relevance of donor age may be greater with
RI-HSCT than with CI-HSCT because, as the patient
population treated is older than the CI-HSCT patient
population, the related donor pool is much older too.
In our group of patients, the related donors tended to
be significantly older than unrelated donors (Table 1). As
the donor type (unrelated vs sibling) did not affect outcome
in the Cox model in this study, the first question that
arises is whether the younger age of an unrelated donor
compensates for the possible adverse impact of inherently
higher immune incompatibility (which could increase graftversus-host reactivity and worsen outcome). The second,
more intriguing, question that arises is whether a younger
10 of 10 allele-matched unrelated donor is superior to an
older HLA-identical sibling donor.
The reasons for superior outcomes with younger donors
are unclear. Advanced donor age has been shown to result
in some loss of repopulating ability,16 impaired homing
ability,17 an overall loss of function,18 as well as accelerated
telomere shortening.19 Older T cells have also been shown
to possess diminished effector activity.20,21 These shortcomings of older donor cells could explain the finding of
better immune reconstitution among recipients of grafts
from younger donors22 and less donor-type chimerism in
recipients of HSCT from older donors.23 The functional
impairment of donor stem cells and T cells could explain
the increased TRM as well as the increased risk of relapse
seen in our study. A number of studies have suggested
a higher risk of GVHD with older donors.24–26 However,
in our study, donor age did not affect acute or chronic
GVHD significantly – which could simply be a shortcoming
of the small patient numbers.
The finding that neither older patient age nor limited
HLA-mismatch affected outcome, while encouraging,
should be interpreted with some caution because of the
relatively small number of old patients and HLAmismatched donors. Excluding the seven HLA-mismatched
transplants did not affect the analysis results (details not
shown). As patients with older sibling donors tended to be
older themselves, it is also possible that the superior
outcome after HSCT from younger donors reflects some
contribution of younger patient age too. As the underlying
diagnosis did not affect outcome, it is unlikely that the
higher prevalence of myeloma among patients with older
donors and of lymphoma among patients with younger
donors contributed to the differences in outcome. Finally,
since unrelated donor cells were always used fresh
and sibling cells were always cryopreserved, it is possible
that some of the outcome difference may be attributable
to this.
The limitations of this study are small patient numbers
and relatively short follow-up – and therefore this observation requires confirmation in larger groups of patients.
If it is confirmed, trying to identify a young unrelated
donor may be worthwhile for a patient who only has an old
sibling donor available – if the clinical situation permits the
additional time such an approach would entail.
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