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Allogeneic hematopoietic stem cell transplantation for hematological malignancies from mismatched 9/10 HLA unrelated donors: Comparison with transplantations from 10/10 unrelated donors and HLA identical siblingsMauricette Michallet, Mohamad Sobh, Caroline Serrier, Stéphane Morisset, Hélène Labussière, Sophie Ducastelle, Fiorenza Barraco, Lila Gilis, Xavier Thomas, Franck E Nicolini

Doi: 10.3109/10428194.2014.944518

ABSTRACT

We retrospectively studied the outcome of 213 consecutive patients who received allo-HSCT for hematological malignancies, 121 (57%) from HLA identical siblings, 63 (29%) from 10/10 HLA identical unrelated donors and 29 (14%) from 9/10 HLA mismatched unrelated donors between 2006 and 2011 in our institution. Engraftment was significantly lower in the 9/10 HLA group (90%) than in the 10/10 HLA group (95%) than in the siblings group (99%), (p=0.03). The median OS was 10 months (5-21), 18 months (11-NR) and 60 months (31-NR) respectively with a 2-years probability of 19% (8-44), 43% (31-59) and 63% (54-74) respectively. TRM was significantly higher in the 9/10 HLA group with 1 year cumulative incidence of 45% (35-55), compared to 33% (27-39) in the unrelated 10/10 HLA group and 12% (9-15) in the siblings group (p<0.001). Disease status at transplantation less than first CR/chronic phase was associated with worse OS [HR=3 (1.4-6), p=0.003].

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Allogeneic hematopoietic stem cell transplantation for

hematological malignancies from mismatched 9/10 HLA

unrelated donors: Comparison with transplantations from 10/10

unrelated donors and HLA identical siblings

Mauricette Michallet, Mohamad Sobh, Caroline Serrier, Stéphane Morisset, Hélène

Labussière, Sophie Ducastelle, Fiorenza Barraco, Lila Gilis, Xavier Thomas, Franck E

Nicolini

Blood and Marrow Transplant Unit, Department of Hematology, Centre Hospitalier Lyon

Sud, Pierre Benite, France.

Correspondence: Mauricette Michallet, MD, PhD, Blood and Marrow Transplant Unit, Department of Hematology, Centre Hospitalier Lyon Sud, University of Lyon, Lyon, France, Pavillon Marcel Berard bâtiment 1G, 165 Chemin du Grand Revoyet, 69495 Pierre Bénite CEDEX France. Tel: +33 4 78 86 22 33. Fax: +33 4 72 66 64 40. E-mail: mauricette.michallet@chu-lyon.fr

Short title: Allo-HSCT from 9/10 HLA unrelated donors

ABSTRACT

We retrospectively studied the outcome of 213 consecutive patients who received allo-HSCT for hematological malignancies, 121 (57%) from HLA identical siblings, 63 (29%) from 10/10 HLA identical unrelated donors and 29 (14%) from 9/10 HLA mismatched unrelated donors between 2006 and 2011 in our institution. Engraftment was significantly lower in the 9/10 HLA group (90%) than in the 10/10 HLA group (95%) than in the siblings group (99%), (p=0.03). The median OS was 10 months (5-21), 18 months (11-NR) and 60 months (31-NR) respectively with a 2-years probability of 19% (8-44), 43% (31-59) and 63% (54-74) respectively. TRM was significantly higher in the 9/10 HLA group with 1 year cumulative incidence of 45% (35-55), compared to 33% (27-39) in the unrelated 10/10 HLA group and 12% (9-15) in the siblings group (p<0.001). Disease status at transplantation less than first CR/chronic phase was associated with worse OS [HR=3 (1.4-6), p=0.003].

Key words: unrelated donors, 9/10 HLA, 10/10 HLA, identical siblings

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INTRODUCTION

Allogeneic hematopoietic stem cell transplantation (allo-HSCT)

represents the only potential treatment strategy to cure wide types of

hematological malignancies aiming to eradicate the malignant clone

using the immunological conflict inherent to donor hematopoietic stem

cells installation in the recipient. The potential benefits of allogeneic

hematopoietic cell transplantation accrue from the ability to use

myeloablative chemoradiotherapy and the immune-mediated reaction

of donor lymphocytes directly against residual disease cells in the

recipient (i.e. the graft versus leukemia reaction). Myeloablative

conditioning regimens are limited to younger patients and to those in

good medical condition [1]. Reduced intensity conditioning (RIC)

regimens were developed with the aim to decrease transplantation-

related-mortality (TRM) in elderly patients, in heavily pretreated

patients or in those with medical comorbidities precluding the use of

standard conditioning regimens [2-4]. However, one risk of RIC

regimens is graft failure because of the low intensity of the

conditioning and the higher risk of disease relapse. The different

possible cell sources, either bone marrow, peripheral blood or cord

blood and the better knowledge of HLA typing has led to the

development of new transplantation techniques and modalities which

have improved patient survival and transplantation outcomes. Best

outcomes were obtained when the donor was an HLA-identical sibling

[5-7]. A patient has 30% of chance to find a HLA-identical sibling

donor while the rest of patients should find an alternative unrelated

donor through the Bone Marrow Donor Worldwide (BMDW registry)

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[8]. The use of 10/10 HLA matched unrelated transplants has been

used as a main alternative and with its unavailability, when available,

a 9/10 HLA mismatched unrelated transplant has been used. The

outcome of this last mismatched transplant is not very clear and its

use according to patient and disease conditions has not been well

defined yet. Previous studies have shown that matching for all alleles

of the HLA-A, -B, -C, and -DRB1 loci was associated with the highest

survival rates in transplantation with unrelated donors (URD) [9-12].

Recently, the National Marrow Donor Program (NMDP) and the

Center for International Blood and Marrow Transplant Research

(CIBMTR) published guidelines defining the minimal requirements for

appropriate HLA typing resolution and matching criteria for URD, they

recommended whenever possible, donors who are high-resolution

matched at HLA-A, -B, -C, and -DRB1, and when such a donor is not

available, a single-locus mismatched donor (HLA-A, -B, -C, or -DRB1)

can be used with acceptable risks of transplant related mortality

(TRM) [13,14]. We aimed in this study to evaluate the outcome of allo-

HSCT in patients with hematological malignancies with either 9/10

HLA mismatched unrelated donors, 10/10 HLA identical unrelated

donors or HLA identical siblings; and to define which category of

patients can benefit the most of each strategy.

MATERIAL AND METHODS

We have retrospectively studied the outcome of 213 consecutive

patients who received allo-HSCT for different hematological

malignancies, 121 (57%) from HLA identical siblings, 63 (29%) from

10/10 HLA identical unrelated donors and 29 (14%) from 9/10 HLA

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mismatched unrelated donors between 2006 and 2011 at our bone

marrow transplantation center. There were 124 (58%) males and 89

(42%) females with a median age of 44 years (range: 18-66), 52%

had myeloid malignancy, and 48% had lymphoid malignancy. At time

of transplantation, 34% of patients were in first complete remission

(CR1) or first chronic phase (CP1), 19% were in CR2 or CP2 and 47%

were in less than CR. The median time between diagnosis and allo-

HSCT was 13.5 months (range: 2-219). As conditioning regimen, 53%

received a myelo-ablative conditioning and 47% a reduced intensity

one, while the HSC source was bone marrow in 55% of cases and

peripheral blood stem cells in 45% of cases. For sex-matching, in

22% of patients, it was a female donor to a male recipient and in 23%

of patients it was a male donor to a female recipient. Major ABO

incompatibility was present in 23% of cases and minor incompatibility

in 16%. All HLA typings were performed at high resolution levels,

thus, in the 9/10 HLA mismatched group, 12 of 29 patients (41, 4%)

had the mismatch at HLA-A locus, 7 patients (24,1%) at the HLA-B, 7

(24,1%) at the HLA-C and 3 (10,4%) at the HLA-DQ. The different

characteristics according to the 3 HLA groups are detailed in Table 1.

ENDPOINTS

Neutrophil recovery was defined by an absolute neutrophil count of at

least 500 cells/mm3 for three consecutive days. GVHD was reported

and graded according to published criteria [15]. Chronic GVHD was

diagnosed according to standard criteria on patients who survived at

least 90 days after transplantation [16]. Transplantation-related

mortality (TRM) was defined as death from any cause other than

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relapse occurring after transplantation. Relapse was defined on basis

of morphologic evidence of hematopoietic disease in bone marrow or

other sites. Overall survival (OS) was defined as the time from

transplantation to any cause of death and progression-free survival

(PFS) was defined as survival from transplantation to disease

progression or death.

STATISTICAL ANALYSIS

Categorical variables related to patients, disease and transplantation

procedure were analyzed using chi-square statistic and continuous

variables with Mann-Whitney test. Cumulative incidence curves in

competing-risks settings were used to estimate incidence over time for

neutrophil recovery, acute and chronic GVHD, TRM and relapse. Fine

and Gray models [17] were used to estimate pre-transplant variables

and the competing risks regression for the multivariate analysis. OS

and PFS were estimated by the Kaplan-Meier method with log-rank

test for univariate analysis [18]. Cox proportional-hazards regression

models were used to assess the influence of pre-transplant variables

on OS and PFS [19]. The multivariate analysis on OS, PFS and TRM

was made after stratification on diagnosis studying the following

variables: pre-transplant disease status, age of the recipient, sex

matching, HLA group, ABO matching, CMV matching, HSC source

(bone marrow or peripheral blood) and conditioning regimen.

Statistical analysis was performed with R statistical software (version

2.9.2).

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RESULTS Engraftment and chimerism results

After HSCT, the cumulative incidence of engraftment was significantly

lower in the 9/10 HLA group (90%) than in the 10/10 HLA group (95%)

than in the sibling group (99%), (p=0.03). The cumulative incidence of

complete donor chimerism among evaluable patients, defined as

having at least 95% of donor cells, was at 3 months after allo-HSCT,

90% in the 9/10 HLA group, 91% in the 10/10 HLA group and 93% in

the siblings group.

Graft versus host disease

The cumulative incidence of acute GVHD≥2 at 3 months was 32%

(23-41), 20% (15-26) and 27% (23-32) for HLA 9/10 group, unrelated

HLA 10/10 and siblings groups respectively [(p=not significant (NS)]

(Figure 1). The cumulative incidence of limited GVHD at one year was

14% (11-18), 11% (7-15) and 4% (0-8), and for the extensive GVHD,

it was 21% (13-30), 9% (5-13) and 17% (14-21) for the 3 groups

respectively (global, p= NS).

Overall survival, relapse incidence and transplant related

mortality

After a median follow-up of 8 months (0-54) in the 9/10 HLA group, 10

months (0-60) in the 10/10 HLA group and 18 months in the siblings

group, the median overall survival (OS) was 10 months (5-21), 18

months (11-NR) and 60 months (31-NR) respectively with a 2-years

probability of 19% (8-44), 43% (31-59) and 63% (54-74) respectively

(Figure 2). Interestingly, when we stratified the patients on disease

status pre-transplantation, all patients from unrelated groups

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(matched or mismatched) in CR1/CP1 showed similar results to HLA

identical siblings group in terms of OS (Figure 3A, B). There was a

higher but not significant relapse incidence at one year in the 9/10

HLA group (26%, 95% CI: 17-35) compared to the unrelated 10/10

HLA group (15%, 95% CI: 9-20) and identical siblings group (17%,

95%CI: 14-20) (Figure 4). The transplant related mortality (TRM) was

significantly higher in the 9/10 HLA group with a cumulative incidence

at 1 year of 45% (35-55), compared to 33% (27-39) in the unrelated

10/10 HLA group and 12% (9-15) in the identical siblings group

(p<0.001) (Figure 5). No statistical difference was observed according

to infection related death between the different groups.

Multivariate analysis

In multivariate analysis, OS was negatively affected by unrelated

donors [9/10 HLA mismatched unrelated group: HR=5 (95% CI: 2.7-

10), p=0.0001; 10/10 HLA matched unrelated group: HR=2 (95% CI:

1.2-4), p=0.01], female donors to male patients [HR=2 (95% CI: 1.4-

4), p=0.03] and disease status <CR1 or <chronic phase (CP)1 [HR=3

(95% CI: 1.4-6), p=0.003]; while the TRM was negatively affected by

unrelated donors [9/10 HLA mismatched unrelated group: HR=9 (95%

CI: 4-20), p<0.001; 10/10 HLA matched unrelated group: HR=4 (95%

CI: 1.2-10), p=0.03], female donors to male patients [HR=3 (95% CI:

1.2-7), p=0.01] and ABO minor incompatibility [HR=2.5 (95% CI: 1.2-

5), p=0.01]. The funnel plot showing the adjusted TRM according to all

covariates and comparing to the global population death rate, shows

that the 9/10 HLA group has the worse TRM independently of any

other factor.

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DISCUSSION

We showed that allo-HSCT from 9/10 HLA mismatched unrelated

donors have a significantly worse OS than those from 10/10 HLA

matched unrelated donors and from HLA identical siblings, this was

mainly due to an increased TRM. Patients in this group also showed a

significantly lower engraftment rate compared to other groups while

acute and chronic GVHD incidences were not statistically different.

Kröger et al. showed similar results in terms of GVHD incidence, OS,

TRM, and relapse between patients receiving allo-HSCT from fully

matched unrelated donors, having one mismatch (9/10) or more (6-

8/10). This study showed the interest of pre-transplant anti-

thymoglobulin use in the HSCT settings [20], where only unrelated

10/10 and 9/10 have received ATG during the conditioning regimen.

Recently, Saber et al. found that 8/8 matched HSCT recipients had a

similar survival rate compared with HLA identical siblings recipients

while 7/8 matched HSCT recipients had higher early mortality than

matched siblings HCT; this study included only patients with acute

myeloid leukemia [21]. With the emergence of cord blood use as HSC

source, recent studies have compared their outcomes to outcomes

from HLA mismatched donors with the unavailability of matched

related or unrelated donors; results seem similar but still uncertainties

about the type of mismatched locus, the retrospective nature of these

studies and the heterogeneous patients and the different HSCT

settings limits their validation [22,23]. When stratified on disease

status pre-transplantation, patients in our study in first CR or CP and

receiving transplants from 9/10 HLA mismatched donors showed

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comparable outcomes to other groups suggesting the more weight the

disease status has, when compared to HLA matching. It is important

to note that the effect of a single-allele mismatch may vary with the

underlying diagnosis. In a study on 948 donor-recipient pairs at the

Fred Hutchinson Cancer Research Center, it was found that a single-

allele mismatch conferred a higher risk of death, but only for low risk

patients, defined as those with chronic myeloid leukemia (CML) within

2 years of diagnosis [24]. In contrast, a single allele mismatch had no

effect on survival among higher risk patients, such as those with more

advanced CML, acute leukemia, or myelodysplastic syndromes.

Similar outcomes are reported in a recent report from an Italian group

[25]. When only a single HLA mismatch was present, the mortality risk

was higher than among 10/10 matched unrelated pairs in patients

transplanted with acute leukemia in the first CR, but not in patients

with advanced diseases. These results suggest that the potential

benefit of HLA matching was offset by the negative impact of

advanced disease. Concerning the type of mismatch, the results from

different studies are very discordant; ones confirmed that mismatches

at HLA-B or -C level were better tolerated than those at HLA-A or -

DRB1 level, whereas others suggested worse survival for HLA-C but

not HLA-A mismatches [11,26]. On the other hand, the effect of

isolated mismatches in the low expression loci HLA-DRB3, -DRB4, -

DRB5, -DQ, and -DP in transplant outcome has been difficult to prove

and their effect may be demonstrable only in combination with

mismatches in other loci [9,10]. Although, in our study, the

mismatched group contained only 29 patients distributed among the

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different loci which makes difficult to do a sub-analysis and does not

allow us to draw any conclusions on this point.

Finally, the debate on the donor choice with the absence of HLA

matched donor is still ongoing. We showed that patients with 9/10

HLA matched donors experience higher TRM rates, not for CR

patients. Results from other studies show controversial results

concerning the involvement of the type of HLA locus and especially

with heterogeneous patients, disease and transplantation

characteristics. Cord blood source has been used in this settings with

satisfying outcomes, we stress out the need of prospective

randomized studies evaluating the different unrelated sources with

more homogeneous populations and transplantation settings.

Potential conflict of interest: None

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Figures Legends:

Figure 1. Cumulative incidence of acute GVHD grade ≥ II according to different HLA groups.

Figure 2. Overall survival according to different HLA groups.

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Figure 3. (A) Overall survival for patients in first complete response or chronic phase. (B) Overall survival for patients in less than first complete response or chronic phase.

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Figure 4. Cumulative incidence of relapse according to different HLA groups.

Figure 5. Cumulative incidence of transplant related mortality according to different HLA groups.

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Table 1. patients characteristics

HLA identical siblings group

N=121 10/10 HLA unrelated

group N=63 9/10 HLA unrelated

group N=29 p-valuePATIENTS DESCRIPTION

Gender Male 69 (62%) 37 (59%) 18 (62%) NS Female 52 (38%) 26 (41%) 11 (38% NS Age Median, years 45 (18-66) 44 (20-64) 38 (19-61) NS Disease Myeloid leukemia 71 (59%) 23 (37%) 16 (55%) NS

AML / MDS 54 / 7 15 / 0 13 / 2 CML / MPS 3 / 7 2 / 6 1 / 0

Lymphoid leukemia 50 (41%) 40 (63%) 13 (45%) NS ALL / MM 18 / 13 20 / 15 7 / 2

Lymphoma / CLL 14 / 5 5 / 0 4 / 0 Disease status NS

CR1/CP1 40 (33%) 23 (37%) 9 (31%) CR2/CP2 26 (21%) 7 (11%) 7 (24%)

<CR2/CP2 55 (45%) 33 (52%) 13 (45%) Conditioning NS

Full-intensity 64 (53%) 32 (51%) 16 (55%) Reduced-intensity 57 (47%) 31 (49%) 13 (45%)

Cell source PBSC 55 (45%) 28 (44%) 13 (45%)

BM 66 (55%) 35 (56%) 16 (55%) Sex-mismatching 0,03

Fd-Mr 30 (25%) 9 (14%) 8 (28%) Md-Fr 22 (18%) 19 (30%) 9 (31%)

CMV-mismatching 0,07D- R+ 25 (21%) 13 (21%) 8 (28%) D+ R- 16 (13%) 14 (22%) 6 (21%)

ABO-mactching major 22 (18%) 21 (33%) 6 (21%) <0,0001minor 7 (9%) 20 (32%) 8 (28%)

Interval diag-HSCT 16 months (2-219) 14 months (4-136) 9 months (4-87) NS Median FU 18 months (0-60) 10 months (0-48) 8 months (0-54)

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