Superior Graft-versus-Leukemia Effect Associated
with Transplantation of Haploidentical Compared with
HLA-Identical Sibling Donor Grafts for High-Risk Acute
Leukemia: An Historic Comparison
Yu Wang, Dai-Hong Liu, Lan-Ping Xu, Kai-Yan Liu, Huan Chen, Yu-Hong Chen, Wei Han,
Hong-Xia Shi, Xiao-Jun Huang
The outcomes of an historic comparison of 117 consecutive, high-risk, acute leukemia patients undergoing he-
matopoietic stem cell transplantation (HSCT) from HLA-mismatched/haploidentical donors (HID, n 5 81) or
of January 2005 and April 2009 were compared. Full engraftment was achieved in 98% of patients in the HID
group and 97% in the ISD group. The cumulative incidences of grades II–IV acute graft-versus-host disease
(aGVHD) in the HID and ISD cohorts were 49% and 24%, respectively (P 5.014) with a relative risk (RR) of
2.99 (1.25-7.21) (P 5.014). The incidence of chronic GVHD (cGVHD) did not differ significantly between the
2 cohorts. The 2-yearcumulative incidence of relapsewas significantly lower in HID (26%) than in ISD patients
of HID (34%) andISD grafts (38%) (P 5.85). The 3-yearprobabilityof overall survival (OS) was higher in HID
patients (42%) than in ISD (20%) (P 5.048) patients. Our comparisons suggest that HID transplants can
achieve a stronger graft-versus-leukemia (GVL) effect than ISD for high-risk acute leukemia patients.
Biol Blood Marrow Transplant 17: 821-830 (2011) ? 2011 American Society for Blood and Marrow Transplantation
KEY WORDS: Hematopoietic stem cell transplantation, HLA, Mismatched
Hematopoietic stem cell transplantation (HSCT)
is 1 of the best, and sometimes the only, option for
the treatment of leukemia, particularly for patients
with high-risk leukemia. It is widely known that the
relapse rate of allogeneic HSCT (allo-HSCT) is lower
than that of auto- or syngeneic HSCT. Immune cells
derived from the donor contribute to the eradication
of leukemia after allo-HSCT, whereas auto- or synge-
neic HSCT have no graft-versus-leukemia (GVL)
effect. The GVL effect is usually identified in retro-
spective analyses of relapse rates following HSCT
donors for leukemia  and has subsequently been
extensively confirmed in other transplant settings.
Kanda et al.  reported that the incidence of relapse
was dramatically decreased with 1-locus–mismatched
family member HSCT compared to matched HSCT
for high-risk diseases (19% versus 47%; P 5 .004).
Reports from IBMTR also showed that in acute
leukemia, relapse risk was lower after alternative-
donor compared with HLA-identical sibling trans-
plants. This difference was statistically significant
(P \ .05) for 2-HLA-antigen–mismatched related
and HLA-antigen–mismatched unrelated donors .
Great progress has been made in haploidentical
donor (HID) HSCT over the past 20 years, and it
has become a feasible option for leukemia patients
especially with high-risk features without a HLA-
identical sibling donor (ISD). It has been speculated
that HID HSCT may potentially exert a strong GVL
effect. However, comparative clinical studies to con-
firm the potential beneficial GVL effects are lacking.
One possible reason for the lack of such studies is
that most HID HSCT is performed with an in vitro
T cell depletion (TCD) modality [4-13]. The lack of
a rapid donor T cell recovery secondary to profound
graft TCD limits the overall antileukemia potential
of the TCD modality compared with alternative
T cell–replete options.
ogy, Beijing, People’s Republic of China.
Financial disclosure: See Acknowledgments on page 829.
University People’s Hospital, Institute of Hematology, Beijing
100044, P.R. China (e-mail: email@example.com).
Received April 15, 2010; accepted August 31, 2010
? 2011 American Society for Blood and Marrow Transplantation
Recently, we developed a new method for HLA-
mismatched/haploidentical transplantation without in
vitro TCD. The strategy comprises sequential, in
vivo modulation of the recipient and donor T cell
functions and the determination of the dose of donor
hematopoietic stem cells using the GIAC protocol
(G, donor treatment with recombinant granulocyte
colony-stimulating factor [rhG-CSF]; I, intensified
immunological suppression; A, antihuman thymocyte
graft-versus-host disease [GVHD]; C, combination of
peripheral blood stem cell transplantation [PBSCT],
and bone marrow transplantation [BMT]) . Using
this protocol, promising results for HID HSCT
without in vitro TCD have been achieved at our insti-
effect is under consideration under our new transplant
protocol. The purpose of this nonrandomized, single-
center, retrospective study was to comparatively ana-
lyze transplantation outcomes in a consecutive series
of high-risk acute leukemia patients who underwent
HSCT from either HID or ISD without in vitro
TCD at our institute.
for theprevention of
MATERIALS AND METHODS
Consecutive patients with high-risk acute leuke-
mia (n 5 117) receiving HSCT from either ISD (n 5
36) or HID (n 5 81) between January 2005 and April
2009 were enrolled. Patients receiving HSCT as a sec-
ond transplant following relapse after a first auto- or
allogeneic transplantation were excluded. Thirty of
the 81 high-risk acute leukemia patients from the
HID cohort were previously reported in 2009 ,
and 19 of those 30 patients were previously reported
in another report in 2009 as well ; additionally, 1
of those 19 patients was previously reported in 2006
. All these patients reported before were enrolled
and further followed in this study. The protocols
were approved by the institutional review board of
the Peking University Institute of Hematology, and
all patients and their donors signed consent forms. Pa-
in CR2 were classified as intermediate risk in most
studies), nonremission, or CR1 with poor-risk cytoge-
netic abnormalities were classified as high risk. For
patients with acute myelogenous leukemia (AML),
poor-risk cytogenetic abnormalities included t(9;22)
1 other, –5 or del(5) 1 other, –7 or del(7) only, –7
or del(7) 1 other, del(11) only, del(11) 1 other .
For patients with acute lymphoblastic leukemia
(ALL), poor-risk cytogenetic abnormalities included
t(4;11), t(9;22), or t(8;14). A small proportion of
patients were evaluated for the Flt3 internal tandem
duplication (patients undergoing HSCT after year
2008), so this part of the information was not provided
inthis study.Characteristicsof thepatients anddonors
are summarized in Table 1.
A human leukocyte antigen (HLA)-matched
sibling donor was the first choice for allo-HSCT. If
amatched siblingdonorwasunavailable asafirst treat-
ment option, patients without a suitable closely HLA-
matched unrelated donor, that is, with more than 8 of
10 matching HLA-A, B, C, DR, and DQ loci and at
disease status left insufficient time for an unrelated
donor search, were eligible for HID HSCT. To
determine HLA-A and HLA-B status, low-resolution
DNA techniques were used. High-resolution tech-
niques were used for HLA-DRB1 typing. All donor-
recipient pairs were typed at the HLA-A, B, and DR
loci at our institute. Patients who had undergone an
unrelated donor search were typed at the HLA-A, B,
C, DR, and DQ loci in China at an unrelated marrow
bank. Thirty-six sibling donor-recipient pairs were
fully HLA matched at the HLA-A, B, and DR loci.
For the other 81 donor-recipient pairs, each patient
received stem cells from a family member who shared
able degree for the HLA-A, B, and D antigens of
the haplotype not shared. Apart from each donor-
recipient pair, HLA typing was done for parents and
offspring to be strictly analyzed to guarantee true
haploid genetic background. The HLA disparities in
the mismatched cohort are shown in Table 1.
The conditioning therapy for the HID group
was modified BUCY2 plus ATG (thymoglobulin)
consisting of cytarabine (4 g/m2/day) intravenously
on days –10 to –9; busulfan (4 mg/kg/day) orally on
days –8 to –6 before January 2008, and busulfan (3.2
mg/kg/day) intravenously on days –8 to –6 after Janu-
ary 2008; cyclophosphamide (1.8 g/m2/day) intrave-
nously on days –5 to –4; Me-CCNU (250 mg/m2)
orally once on day –3; and ATG (thymoglobulin, 2.5
mg/kg/day; Sang Stat, Lyon, France) intravenously
on days –5 to –2. Patients in the ISD group received
hydroxycarbamide (80 mg/kg) orally on day –10 and
a lower dose of cytarabine (2 g/m2/day) on day –9,
but otherwise, an identical regimen to the HLA-
mismatched patients without ATG.
All patients received cyclosporine A (CSA), myco-
phenolate mofetil (MMF), and short-term methotrex-
ate (MTX) for GVHD prophylaxis . On day 11,
MTX (15 mg/m2) was administered intravenously fol-
lowed by administration at 10 mg/m2on days 13 and
Biol Blood Marrow Transplant 17:821-830, 2011 Y. Wang et al.
7. Reisner Y, Kapoor N, Kirkpatrick D, et al. Transplantation for
severe combined immunodeficiency with HLA-A, B, D, DR in-
compatible parental marrow cells fractioned by soybean aggluti-
nin and sheep red blood cells. Blood. 1983;61:341-348.
8. Aversa F, Tabilio A, Terenzi A, et al. Successful engraftment of
T cell-depleted haploidentical ‘‘3-loci’’ incompatibal transplants
in leukemia patients by addition of recombinant human granulo-
cyte colony-stimulating factor-mobilized peripheral blood pro-
9. Aversa F, Tabilio A, Velardi A, et al. Treatment high-risk acute
leukemia with T-cell-depleted stem cells from related donors
with on fully mismatched HLA haplotype. N Engl J Med.
10. Aversa F, Terenzi A, Tabilio A, et al. Full haplotype-
mismatched hematopoietic stem-cell transplantation: a phase
II study in patients with acute leukemia at high risk of relapse.
J Clin Oncol. 2005;23:3447-3454.
11. Liu D, Tammik C, Zou JZ, et al. Effect of combined T- and
B-cell depletion of allogeniec HLA-mismatched bone marrow
graft on the magnitude and kinetics of Epstein-Barr virus load
in the peripheral blood of bone marrow transplant recipients.
Clin Transplant. 2004;18:518-524.
12. Aversa F, Reisner Y, Martelli MF. The haploidentical option for
13. Ciceri F, Labopin M, Aversa F, et al. A survey of fully haploi-
dentical hematopoietic stem cell transplantation in adults with
high-risk acute leukemia: a risk factor analysis of outcomes for
patients in remission at transplantation. Blood. 2008;112:
14. Huang XJ, Liu DH, Liu KY, et al. Haplo-identical hematopoi-
etic stem cell transplantation without in vitro T cell depletion
for the treatment of hematological malignancies. Bone Marrow
with unmanipulated HLA-mismatched/haploidentical blood
and bone marrow transplantation. Biol Bone Marrow Transplant.
transplantation can achieve outcomes comparable to unrelated
donor transplantation for patients with hematologic malignan-
cies. Clin Cancer Res. 2009;15:4777-4783.
17. Gale RP, Horowitz MM, Weiner RS, et al. Impact of cytoge-
netic abnormalities on outcome of bone marrow transplants in
acute myelogenous leukemia in first remission. Bone Marrow
18. Huang XJ, Liu DH, Liu KY, et al. Modified donor lymphocyte
infusion after HLA-mismatched/haplo-identical T-cell-replete
hematopoietic stem cell transplantation for prophylaxis of
relapse of leukemia in patients with advanced leukemia. J Clin
19. Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W. Donor
lymphocyte infusion for the treatment of leukemia relapse after
HLA-mismatched/haplo-identical T-cell-replete hematopoi-
etic stem cell transplantation. Haematologica. 2007;92:414-417.
20. Huang XJ, Guo NL, Ren HY, et al. An improved anti-leukemic
effect achieved with donor progenitor cell infusion for relapse
patients after allogeneic bone marrow transplantation. Chin
Med J. 2003;116:736-741.
21. Thomas ED, Storb R, Clift RA, et al. Bone marrow transplanta-
tion. N Engl J Med. 1975;292:895-902.
22. Shulman HM, Sullivan KM, Weiden PL, et al. Chronic graft-
versus-host syndrome in man: a long-term clinicopathologic
study of 20 Seattle patients. Am J Med. 1980;69:204-217.
23. Scrucca L, Santucci A, Aversa F. Regression modeling of com-
Transplant. 2010. E-pub ahead of print 11 January 2010;
from unrelated donors for treatment of hematologic malignan-
cies: effect of mismatching for 1 HLA locus. Blood. 1993;81:
25. Ringde ´n O, Pavletic SZ, Anasetti C, et al. The graft-versus-
leukemia effect using matched unrelated donors is not superior
to HLA-identical siblingsforhematopoieticstemcelltransplan-
tation. Blood. 2009;113:3110-3118.
26. Drobyski WR, Klein J, Flomenberg N, et al. Superior survival
associated with transplantation of matched unrelated versus
1-antigen-mismatched unrelated or highly human leukocyte
antigen-disparate haploidentical family donor marrow grafts
for the treatment of hematologic malignancies: establishing
a treatment algorithm for recipients of alternative donor grafts.
27. Carpenter PA, Snyder DS, Flowers ME, et al. Prophylactic
administration of imatinib after hematopoietic cell transplanta-
tion for high-risk Philadelphia chromosome-positive leukemia.
28. Burke MJ, Trotz B, Luo X, et al. Allo-hematopoietic cell trans-
on relapse and survival. Bone Marrow Transplant. 2009;43:
29. Duggan P, Booth K, Chaudhry A, et al. Unrelated donor BMT
recipients given pretransplant low-dose antithymocyte globulin
have outcomes equivalent to matched sibling BMT: a matched
pair analysis. Bone Marrow Transplant. 2002;30:681-686.
30. Basara N, Baurmann H, Kolbe K, et al. Antithymocyte globulin
for the prevention of graft-versus-host disease after unrelated
mia: results from the multicenter German cooperative study
group. Bone Marrow Transplant. 2005;35:1011-1018.
31. RembergerM, StorerB, Ringden O, Anasetti C. Associationbe-
tween pretransplant thymoglobulin and reduced non-relapse
mortality rate after marrow transplantation from unrelated
donors. Bone Marrow Transplant. 2002;29:391-397.
32. Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leuke-
33. Lu DP, Dong L, Wu T, et al. Conditioning including
antithymocyte globulin followed by unmanipulated HLA-
mismatched/haplo-identical blood and marrow transplantation
can achieve comparable outcomes with HLA-identical sibling
transplantation. Blood. 2006;107:3065-3073.
acute GVHD treatment trials. Blood. 2010;115:5412-5417.
35. Anasetti C, Beatty PG, Storb R, et al. Effect of HLA incompati-
bility on graft-versus-host disease, relapse, and survival after
Hum Immunol. 1990;29:79-91.
Biol Blood Marrow Transplant 17:821-830, 2011Y. Wang et al.