Matthew M. Hsieh,1Courtney D. Fitzhugh,1and John F. Tisdale1
1Molecular and Clinical Hematology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Heart, Lung, and Blood Institute,
National Institutes of Health, Bethesda, MD
Although sickle cell disease (SCD) has a
variable clinical course, many patients
associated with significant morbidity and
early mortality. Myeloablative allogeneic
historically performed only in children
younger than 16 years of age. Modest
modifications in the conditioning regi-
men and supportive care have improved
outcome such that the majority of chil-
dren with a suitable HLA-matched sibling
donor can expect a cure from this ap-
excluded from myeloablative allo-HSCT
because of anticipated excess toxicity
resulting from accumulated disease bur-
den. Efforts to use nonmyeloablative
transplantation strategies in adults logi-
cally followed but were initially met with
largely disappointing results. Recent re-
lative allo-HSCT in adult patients with
SCD allows for stable mixed hematopoi-
etic chimerism with associated full-donor
erythroid engraftment and normalization
of blood counts, and persistence in some
without continued immunosuppression
suggests immunologic tolerance. The at-
tainment of tolerance should allow exten-
sion of these potentially curative ap-
proaches to alternative donor sources.
Efforts to build on these experiences
should increase the use of allo-HSCT in
patients with SCD while minimizing mor-
bidity and mortality. (Blood. 2011;118(5):
Sickle cell disease (SCD) results from a single nucleotide mutation,
which changes the glutamate for valine in the 6th position of the
?-globin protein. This change results in a propensity for the
hemoglobin protein to polymerize when deoxygenated and causes
the characteristic sickle-shaped red cells. The disorder is character-
ized by anemia, ongoing hemolysis, along with acute and chronic
complications affecting multiple organs.Although transfusions can
prevent further neurologic events in patients at risk, iron overload
is common, resulting in significant end-organ toxicity. The imple-
evaluation and treatment for fever have improved the outlook for
children with SCD. Specific treatment has remained limited and
Hydroxyurea results in a significant reduction in the number of
painful crises per year and a decreased frequency of acute chest
syndrome1; it has become the treatment of choice for many patients
with SCD. Unfortunately, hydroxyurea is not curative and does not
appear to reverse established end-organ damage. The medical costs
of this disease are also enormous, with estimates of $40 000 per
patient per year (year 2000 figures) for chronic transfusion therapy
and chelation alone, but they do not include the impact on quality
of life of those with the disease.4It is astounding that a single
nucleotide substitution can lead to a multiorgan disease that
dramatically reduces the quality of life and shortens the lifespan of
those affected. Unfortunately, these existing treatments only ame-
liorate the manifestation of SCD, leaving an increasing number of
adults with accumulating end-organ damage. Although longstand-
ing efforts to deliver the correct ?-globin gene through gene
therapy approaches are progressing well, currently allo-HSCT
remains the only immediate cure. Because patients with SCD are
living longer and with chronic organ insufficiencies from sickle-
related organ damage or from transfusional iron overload, improv-
ing HSCT for children and adults with SCD has emerged as an area
of research interest with immediate potential clinical benefit.
Indications for HSCT
Although the curative potential of HSCT has been well established
in several nonmalignant disorders, there has always been difficulty
in determining which patients with SCD warrant the potential risks
of this technique. Early efforts to develop criteria to distinguish the
more severe patients proved difficult in a disorder with chronic, yet
mostly manageable complications, punctuated by rarer, more
severe, even life-threatening complications. There remains a temp-
tation to intervene early when patient status would improve the
tively, intervening later when chronic, irreversible disease compli-
cations clearly establish the severity of the patient’s phenotype
limits its application because the conditioning regimen is less likely
to be well tolerated. Transcranial Doppler (TCD) examination has
proven effective in predicting the risk of stroke and has been used
to predict the severity of disease. Although abnormal TCD
examinations predict subsequent development of stroke, and
prompt red cell transfusion therapy dramatically reduces that risk,5
data are beginning to show that TCDs can remain abnormal in a
small proportion of patients.6Furthermore, among children with a
first stroke on chronic transfusion therapy, a second event of overt
stroke, silent stroke, or CNS vasculopathy can occur.7These red
cell transfusions, even when extensively matched, can lead to red
Submitted January 25, 2011; accepted May 12, 2011. Prepublished online as
Blood First Edition paper, May 31, 2011: DOI 10.1182/blood-2011-01-332510.
1197 BLOOD, 4AUGUST 2011?VOLUME 118, NUMBER 5
cell8,9or HLA10allo-antibodies and iron overload in a significant
proportion of patients. Unfortunately, there are currently no reliable
predictors as to who will have persistently abnormal TCD or who
will develop a second stroke or red cell alloimmunization.
In the early 1990s, hydroxyurea was shown to decrease the
frequency and severity of vaso-occlusive crises and acute chest
syndromes. HSCT were thus performed in severely affected
pediatric patients who would not be expected to benefit from
hydroxyurea (stroke, red cell alloimmunizations, or avascular
necrosis affecting multiple joints) or in those who did not benefit
from hydroxyurea (recurrent vaso-occlusive crises or acute chest
syndrome on hydroxyurea).11,12The authors of recent studies have
regrettably shown that despite more widespread use of hy-
droxyurea, the average patient with SCD only lives ? 40 years.13,14
Unlike in pediatric patients, in whom the prediction of who will
have severe disease is not certain, the trajectory of adult patients
having a shortened lifespan and a large proportion of adult patients
developing irreversible organ damage are certain. This dramati-
cally reduced lifespan or irreversible end-organ damage (elevated
tricuspid regurgitant jet velocity,15renal insufficiency,16,17or hepa-
topathy,18,19all with associated increased mortality) should provide
physicians motivation to offer HSCT to those with matched
siblings at younger ages and to develop nonmyeloablative regi-
mens that are appropriate for adults with a high disease burden.The
responsibility is on the SCD transplant community to develop
HSCT regimens that are minimally toxic and that have a realistic
chance for success to extend their lives. Table 1 summarizes the
historical indications for HSCT, hydroxyurea, and the criteria that
we have developed, after incorporating recent clinical trials and
their impact on mortality.
HLA-matched sibling allo-HSCT
Allo-HSCT remains the only curative strategy for patients with
SCD. The first successful HSCT in a patient with SCD was
reported in 1984 in a pediatric patient with coexisting acute
myeloid leukemia.20Traditional myeloablative conditioning regi-
mens that use BM as the HSC source and myeloablative doses of
busulfan in combination with highly immunosuppressive doses of
cyclophosphamide were used with transplants first reported in
Europe,21,22and then in the United States.12Antithymocyte globu-
lin was later added more consistently to decrease the risk of graft
rejection in this population of patients who have been previously
transfused and are frequently alloimmunized.11In one early trial,
neurologic complications, including seizures and fatal intracranial
hemorrhage, occurred in 7 of 21 patients with SCD who underwent
myeloablative conditioning.23The incidence of neurologic compli-
cations subsequently decreased by maintaining a platelet threshold
of ? 50 000/?L and a hemoglobin level of 9-11 g/dL, adding
phenytoin prophylaxis, and preventing significant hypertension and
In one series, patients were divided into 2 groups by criteria
reflective of their access to care. The first group consisted of
patients who underwent transplantation according to traditional
severity criteria and were permanent residents of a European
country. The second group of patients underwent transplantation
because they would subsequently be returning to their country of
origin inAfrica, where access to chronic SCD care may be limited.
Although patients in the first group were older (median age 8.6 vs
2 years; P ? .0016), the first group had a greater rate of graft
rejection (25% vs 7%, P ? .001), and all of the patients who
developed severe GVHD were in group 1.21These data suggest that
transplantation for patients with SCD may be performed more
safely in pediatric patients who have not experienced end-organ
damage or other markers of disease severity.
The largest group to date was reported in 2007.11Overall
survival and event-free survival were 93% and 86%, respectively.
A major finding of this study was that after the addition of
antithymocyte globulin in 1992 to the conditioning regimen, the
rejection rate decreased from 22.6% to 3%, with an event-free
survival rate of 95% among patients who underwent transplanta-
tion after January 2000. These results establish that HLA-matched
transplants that use myeloablative conditioning should be the
standard of care for eligible pediatric patients with SCD. To date,
? 300-400 affected subjects mostly younger than the age of
16 years have undergone fully myeloablative allo-HSCT.11,12,24-27
The results of these studies are summarized in Table 2.
However, the number of patients who have undergone transplanta-
tion is small compared with the estimated 70 000 patients with
SCD in the United States alone, indicating that this curative therapy
is underused. Furthermore, a 15% to 20% GVHD rate with
tive setting has been reported, with some deaths directly attribut-
able to GVHD. What is remarkable is that despite myeloablative
dosing in the conditioning regimens, a mixture of both donor and
recipient hematopoietic cells, termed mixed donor chimerism, is
consistently observed in approximately 10% to 20% of these
children.25Interestingly, this mixed chimeric state is sufficient to
direct BM to produce donor-type hemoglobin and red cells, revert
the SCD phenotype, and minimize the risk of GVHD. This
Table 1. Indications for HSCT or hydroxyurea
Indications to start hydroxyurea
Historical indications for HSCT
(patients < 16 y)NIH indications for HSCT (patients > 16 y)
Three or more VOC requiring hospitalizations
Two or more acute chest syndromes
Two or more joints with osteonecrosis
Stroke or CNS event lasting longer than 24 hours
Abnormal brain MRI
ACS with recurrent hospitalizations
Irreversible end-organ damage
Stroke or clinically significant CNS event
Elevated TRV ? 2.6 m/s
Sickle-related renal insufficiency (Cr ? 1.5 times the upper limit
of normal or biopsy proven)
Sickle hepatopathy (including iron overload)Two or more VOC requiring hospitalizations for
Osteonecrosis of multiple joints
Red cell alloimmunization
Sickle cell lung disease
Reversible sickle complication not ameliorated by hydroxyurea
Two or more VOC requiring hospitalizations for several years
Any ACS while on hydroxyurea
ACS indicates acute chest syndrome; NIH, National Institutes of Health; MRI, magnetic resonance imaging; TCD, transcranial Doppler; TRV, tricuspid regurgitant velocity;
and VOC, vaso-occlusive crises.
1198HSIEH et alBLOOD, 4AUGUST 2011?VOLUME 118, NUMBER 5
cell disease and thalassemia after low-dose total
body irradiation, fludarabine, and rabbit anti-thy-
mocyte globulin. Bone Marrow Transplant. 2005;
46. Kottaridis PD, Milligan DW, Chopra R, et al. In
vivo CAMPATH-1H prevents graft-versus-host
disease following nonmyeloablative stem cell
transplantation. Blood. 2000;96(7):2419-2425.
47. Chakraverty R, Peggs K, Chopra R, et al. Limiting
transplantation-related mortality following unre-
lated donor stem cell transplantation by using a
nonmyeloablative conditioning regimen. Blood.
48. Hsieh MM, Kang EM, Fitzhugh CD, et al.Alloge-
neic hematopoietic stem-cell transplantation for
sickle cell disease. N Engl J Med. 2009;361(24):
49. Fitzhugh CD, Perl S, Hsieh MM. Late effects of
myeloablative bone marrow transplantation
(BMT) in sickle cell disease (SCD). Blood. 2008;
111(3):1742-1743; author reply 1744.
50. Krishnamurti L, Kharbanda S, Biernacki MA, et al.
Stable long-term donor engraftment following
reduced-intensity hematopoietic cell transplanta-
tion for sickle cell disease. Biol Blood Marrow
51. Horwitz ME, Spasojevic I, MorrisA, et al. Fludara-
bine-based nonmyeloablative stem cell transplan-
tation for sickle cell disease with and without renal
52. AiutiA, Cattaneo F, Galimberti S, et al. Gene
therapy for immunodeficiency due to adenosine
deaminase deficiency. N Engl J Med. 2009;
54. Stein S, Ott MG, Schultze-Strasser S, et al.
Genomic instability and myelodysplasia with
monosomy 7 consequent to EVI1 activation after
gene therapy for chronic granulomatous disease.
Nat Med. 2010;16(2):198-204.
55. Persons DA,Allay ER, Sabatino DE, Kelly P,
Bodine DM, NienhuisAW. Functional require-
ments for phenotypic correction of murine beta-
thalassemia: implications for human gene
therapy. Blood. 2001;97(10):3275-3282.
56. Andreani M, Testi M, Gaziev J, et al. Quantita-
tively different red cells/nucleated cell chimerism
in patients with long-term persistant hematopoi-
etic mixed chimerism after bone marrow trans-
plantation for thalassemia major or sickle cell dis-
ease. Haematologica. 2011;96(1):128-133.
57. Shenoy S, Grossman WJ, DiPersio J, et al.A
novel reduced-intensity stem cell transplant regi-
men for nonmalignant disorders. Bone Marrow
58. van Besien K, BartholomewA, Stock W, et al.
Fludarabine-based conditioning for allogeneic
transplantation in adults with sickle cell disease.
Bone Marrow Transplant. 2000;26(4):445-449.
59. Andreani M, Testi M, Battarra M, et al. Relation-
ship between mixed chimerism and rejection after
bone marrow transplantation in thalassaemia.
Blood Transfus. 2008;6(3):143-149.
60. Andreani M, Nesci S, Lucarelli G, et al. Long-term
survival of ex-thalassemic patients with persistent
mixed chimerism after bone marrow transplanta-
tion. Bone Marrow Transplant. 2000;25(4):401-
61. Nesci S, Manna M,Andreani M, Fattorini P,
Graziosi G, Lucarelli G. Mixed chimerism in
thalassemic patients after bone marrow trans-
plantation. Bone Marrow Transplant. 1992;10(2):
63. Walters MC, Patience M, Leisenring W, et al. Bar-
riers to bone marrow transplantation for sickle cell
anemia. Biol Blood Marrow Transplant. 1996;2(2):
64. Brichard B, Vermylen C, Ninane J, Cornu G. Per-
sistence of fetal hemoglobin production after suc-
cessful transplantation of cord blood stem cells in
a patient with sickle cell anemia [see comments].
J Pediatr. 1996;128(2):241-243.
65. Miniero R, Rocha V, Saracco P, et al. Cord blood
transplantation (CBT) in hemoglobinopathies.
Eurocord. Bone Marrow Transplant. 1998;
67. Locatelli F, Rocha V, Reed W, et al. Related um-
bilical cord blood transplantation in patients with
thalassemia and sickle cell disease. Blood. 2003;
68. Walters MC, Quirolo L, Trachtenberg ET, et al.
Sibling donor cord blood transplantation for thala-
ssemia major: Experience of the Sibling Donor
Cord Blood Program. Ann NYAcad Sci. 2005;
70. Mazur M, Kurtzberg J, Halperin E, Ciocci G,
Szabolcs P. Transplantation of a child with sickle
cell anemia with an unrelated cord blood unit after
reduced intensity conditioning. J Pediatr Hematol
71. Sauter C, RausenAR, Barker JN. Successful un-
related donor cord blood transplantation for adult
sickle cell disease and Hodgkin lymphoma. Bone
Marrow Transplant. 2010;45(7):1252.
72. Krishnamurti L,Abel S, Maiers M, Flesch S.Avail-
ability of unrelated donors for hematopoietic stem
cell transplantation for hemoglobinopathies. Bone
Marrow Transplant. 2003;31(7):547-550.
73. Adamkiewicz TV, Boyer MW, Bray R, HaightA,
YeagerAM. Identification of unrelated cord blood
units for hematopoietic stem cell transplantation
in children with sickle cell disease. J Pediatr He-
matol Oncol. 2006;28(1):29-32.
74. Hsieh M, Wilder J, Fitzhugh C, Link B, Tisdale JF.
Results of alternative donor search in adult pa-
tients with severe sickle cell disease (SCD) eli-
gible for hematopoietic stem cell transplantation
(HSCT). Paper presented atAnnual Meeting of
theAmerican Society of HematologyAnnual
MeetingmAtlanta, GA, December 2007.
75. DewA, Collins D,ArtzA, et al. Paucity of HLA-
identical unrelated donors forAfrican-Americans
with hematologic malignancies: the need for new
donor options. Biol Blood Marrow Transplant.
76. Kanda Y, Chiba S, Hirai H, et al.Allogeneic hema-
topoietic stem cell transplantation from family
members other than HLA-identical siblings over
the last decade (1991-2000). Blood. 2003;102(4):
77. Anasetti C,Amos D, Beatty PG, et al. Effect of
HLAcompatibility on engraftment of bone marrow
transplants in patients with leukemia or lym-
phoma. N Engl J Med. 1989;320(4):197-204.
78. Anasetti C, Beatty PG, Storb R, et al. Effect of
HLAincompatibility on graft-versus-host disease,
relapse, and survival after marrow transplantation
for patients with leukemia or lymphoma. Hum Im-
79. Wang HX, Yan HM, Duan LN, et al. Haploidenti-
cal hematopoietic stem cell transplantation in
child hematologic malignancies with G-CSF–mo-
bilized marrow grafts without T-cell depletion: a
single-center report of 45 cases. Pediatr Hematol
80. DoderoA, Carniti C, RaganatoA, et al. Hap-
loidentical stem cell transplantation after a re-
duced-intensity conditioning regimen for the treat-
ment of advanced hematologic malignancies:
posttransplantation CD8-depleted donor lympho-
cyte infusions contribute to improve T-cell recov-
ery. Blood. 2009;113(19):4771-4779.
81. Huang X, Liu D, Liu K, et al. Haploidentical hema-
topoietic stem cell transplantation without in vitro
T cell depletion for treatment of hematologic ma-
lignancies in children. Biol Blood Marrow Trans-
plant. 2009;15(1 suppl):91-94.
82. Huang XJ, Liu DH, Liu KY, et al. Haploidentical
hematopoietic stem cell transplantation without in
vitro T-cell depletion for the treatment of hemato-
logical malignancies. Bone Marrow Transplant.
83. Luznik L, O’Donnell PV, Symons HJ, et al. HLA-
haploidentical bone marrow transplantation for
hematologic malignancies using nonmyeloabla-
tive conditioning and high-dose, posttransplanta-
tion cyclophosphamide. Biol Blood Marrow Trans-
eases. Bone Marrow Transplant. 2008;42(8):523-527.
87. AiutiA, Vai S, MortellaroA, et al. Immune recon-
stitution inADA-SCID after PBL gene therapy and
discontinuation of enzyme replacement. Nat Med.
88. AiutiA, Slavin S,Aker M, et al. Correction ofADA-
SCID by stem cell gene therapy combined with
nonmyeloablative conditioning. Science. 2002;
89. Ott MG, Schmidt M, Schwarzwaelder K, et al.
Correction of X-linked chronic granulomatous dis-
ease by gene therapy, augmented by insertional
activation of MDS1-EVI1, PRDM16 or SETBP1.
Nat Med. 2006;12(4):401-409.
91. May C, Rivella S, Callegari J, et al. Therapeutic
haemoglobin synthesis in beta-thalassaemic
mice expressing lentivirus-encoded human beta-
globin. Nature. 2000;406(6791):82-86.
92. Persons DA,Allay ER, Sawai N, et al. Successful
93. Persons DA, Hargrove PW,Allay ER, Hanawa H,
NienhuisAW. The degree of phenotypic correc-
tion of murine beta -thalassemia intermedia fol-
lowing lentiviral-mediated transfer of a human
gamma-globin gene is influenced by chromo-
somal position effects and vector copy number.
94. Pawliuk R, Westerman KA, Fabry ME, et al. Cor-
rection of sickle cell disease in transgenic mouse
models by gene therapy. Science. 2001;
95. Imren S, Payen E, Westerman KA, et al. Perma-
nent and panerythroid correction of murine beta
thalassemia by multiple lentiviral integration in
hematopoietic stem cells. Proc Natl Acad Sci
U S A. 2002;99(22):14380-14385.
96. Ikeda K, Mason PJ, Bessler M. 3?UTR-truncated
Hmga2 cDNAcauses MPN-like hematopoiesis by
conferring a clonal growth advantage at the level
of HSC in mice. Blood. 2011;117(22):5860-5869.
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