Blood, 1 December 2000, Vol. 96, No. 12, pp. 3997-3999
BRIEF REPORT
Successful stem cell transplantation following orthotopic liver
transplantation from the same haploidentical family donor in a girl
with hemophagocytic lymphohistiocytosis
Susanne Matthes-Martin,
Christina Peters,
Alfred Königsrainer,
Gerhard Fritsch,
Thomas Lion,
Andreas Heitger,
Klaus Kapelari,
Martina Kronberger,
Felix Offner,
Fritz Wrba,
Raimund Margreiter, and
Helmut Gadner
From St Anna Children's Hospital, the
Children's Cancer Research Institute, and the
Institute for Clinical Pathology, Vienna, Austria, and the
Department of Transplant Surgery, University Hospital
Innsbruck, the University Children's Hospital, and the
Institute for Pathology, Innsbruck, Austria.
 |
Abstract |
The case of a 4-month-old girl with familial
hemophagocytic lymphohistiocytosis is described. The patient underwent
stem cell transplantation from her haploidentical mother 2 months after receiving a living-related liver transplant from the same donor for
acute hepatic failure. Conditioning regimen consisted of 16 mg/kg
busulfan, 200 mg/kg cyclophosphamide, 10 mg/kg thiothepa, and
antithymocyte globulin. Myeloid engraftment occurred on day +10, but CD3+ cells of recipient origin remained.
To convert the T-cell chimerism, the patient received donor lymphocyte
infusion on day +43, and subsequently the allelic pattern changed to
complete donor genotype on day +57. Four months after stem cell
transplantation the patient is disease free, with complete donor
chimerism in bone marrow and stable hepatic graft function without any
immunosuppressive therapy.
(Blood. 2000;96:3997-3999)
© 2000 by The American Society of Hematology.
| |
Introduction |
Familial hemophagocytic lymphohistiocytosis
(FHL) is a rare fatal genetic disorder in early infancy that is
characterized by hypercytokinemia; activation of T cells and
macrophages; and the presence of hemophagocytosis predominantly in bone
marrow, liver, and spleen.1 Central nervous system (CNS)
involvement can be observed in more than 70% of
patients.2 Hepatic dysfunction is commonly observed, and
fulminant hepatorenal failure may be a fatal complication of
FHL.3 Diagnosis is mostly established late, often only at
autopsy. Chemotherapy, including corticosteroids or cyclosporine A and
etoposide, may lead to stabilization, but the overall 5-year survival
is poor (10%). The only curative approach is allogeneic stem cell
transplantation (SCT), in which there is an overall survival of
66%.1,4-6,7 Living-related liver transplantation has
become a therapeutic option for young children with acute hepatic
failure.8,9 Successful orthotopic cadaveric or
living-related liver transplantation for veno-occlusive disease occurring as a complication of bone marrow transplantation has been
reported during the last years.10,11 SCT following
unrelated orthotopic liver transplantation has been reported in 3 cases. There has been one reported case of human leukocyte antigen
(HLA)-identical sibling SCT unrelated cadaveric liver transplantation,
and one case of matched unrelated bone marrow transplantation was
performed shortly after cadaveric liver transplantation in a patient
with hyperimmunoglobulin M (hyper-IgM) syndrome and hepatic
failure.12,13 Recently Ringden et al14
reported a combined transplantation of bone marrow and liver from a
cadaveric donor.
| |
Study design |
A 4-month-old girl with the diagnosis of FHL who had received a
living-related liver transplantation from her mother as an emergency
procedure for acute hepatic failure at the University Hospital of
Innsbruck, Innsbruck, Austria, was transferred to our center for SCT.
The diagnosis of FHL had been made from the histology of the
explanted liver and from bone marrow biopsies. Following the
liver transplantation (LTX), immunosuppression comprised tacrolimus and methylprednisolone, and the patient received
conventional treatment for FHL according to the HLH-94 protocol. On
admission the girl presented with a markedly poor general condition
with reduced muscular tone, no spontaneous motor activity, poor head control, and weak crying. Reactivation of the underlying
disease was confirmed by hypertriglyceridemia of 411 mg/dL, serum
ferritin level of 2226 µg/L, and active bone marrow disease with 13%
histiomonocytic cells and phagocytosis. Before SCT, microchimerism
analysis by allele-specific polymerase chain reaction (PCR)
amplification of a donor-derived HLA-allele (DRB*107) revealed
the presence of maternal cells in the peripheral blood.
Chemotherapy (150 mg/m2 etoposide once weekly and 0.6 mg/kg per day dexamethasone) for the underlying disease was continued until day 
10 before SCT. The conditioning regimen consisted of 12 mg/kg busulfan, 10 mg/kg thiothepa, 200 mg/kg cyclophosphamide, and 30 mg/kg/d antithymocyte globulin (ATG) (rabbit). Immunosuppression with
tacrolimus was continued, and an additional 30 mg/kg mycophenolate mofetil was administered starting from day 1. Except for mucositis and WHO grade 2I skin toxicity, the conditioning regimen was well tolerated, and liver function tests remained within the pretransplant range.
The patient's mother, who had an HLA-mismatch of 3 of 6 antigens, was stimulated with 10 µg/kg/d granulocyte
colony-stimulating factor (G-CSF) subcutaneously for 4 days and
underwent stem cell apheresis on day zero. CD34+ cells were
prepared by CD34+ CD4/CD8/CD19
selection on
an Isolex 300i (Nexell Therapeutics Inc, Irvine, CA) with a
purity of 98.6%.15 On day +70 after LTX, the patient received 2.5 × 104 T cells and 25.6 × 106
CD34+ cells per kg body weight.
During aplasia, the girl experienced one septic episode, which was
readily controlled by adequate antibiotic treatment. Engraftment was
monitored by fluorescence-activated cell sorter (FACS) analysis and by
short tandem repeats (STR)-PCR analysis for donor-recipient chimerism
from FACS-sorted cell populations as described
elsewhere.16 The patient showed prompt engraftment with a
leukocyte count of 1.7 × 109/L on day +10.
Engraftment data are shown in Figure 1,
and chimerism kinetics are shown in Figure
2. Natural killer (NK) cells, monocytes, and granulocytes were of pure donor origin, but
CD3+/CD4+ and CD3+/CD8+
cells in peripheral blood, detectable on day +29, were of recipient origin. To convert the T-cell chimerism, the patient received donor
lymphocyte infusion (DLI) with 1 × 104 CD3+
cells per kg on day +43. By day +52 the allelic pattern had changed to
mixed chimerism, and subsequently the pattern changed to complete donor
genotype on day +57.
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| Figure 1.
Time course of the reconstitution of the leukocyte
subsets monitored by flow cytometric phenotype analysis.
DLI was given on day +43. Chimerism data are shown in Figure
2.
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| Figure 2.
T-cell chimerism following haploidentical STC and DLI on
day +43 monitored by STR-PCR analysis of FACS-sorted cell populations.
Neutrophils and NK cells were of pure donor genotype. After DLI, the
allelic pattern of CD3+ cells changed to mixed chimerism
and subsequently to complete donor genotype. R indicates recipient; D,
donor.
|
|
Immunosuppression with tacrolimus and mycophenolate mofetil was
maintained until stable, complete donor-recipient chimerism was
documented. Three weeks after DLI, the girl developed grade I
graft-versus-host disease (GVHD) of the skin, which resolved completely
after 4 days of prednisolone treatment. Steroid therapy was
discontinued 2 weeks later.
A liver biopsy was performed on day +44 after SCT (day +114 after LTX),
and bone marrow biopsies were performed on days +28 and +100; both
revealed no signs of FHL. During the first 2 months after SCT, the girl
showed a surprisingly good improvement in her neuropsychological
performance, with normalization of spontaneous motor activity and
social development. She was discharged on day +100 in excellent
clinical condition.
| |
Results and discussion |
Living-related liver transplantation has been established as a
life-saving therapy, particularly for children younger than 1 year of
age. However, Epstein-Barr virus (EBV)-associated lymphoproliferative disorders due to prolonged immunosuppression are a major
posttransplantation complication, occurring in 19% of the
patients.17,18 There is some evidence that organ
transplantation with simultaneous infusion of donor bone marrow might
be able to induce tolerance and thus reduce the incidence of
rejection.14,19
In the case reported, diagnosis of FHL was established only after
living-related liver transplantation, which had been performed for the
treatment of acute liver failure. Haploidentical SCT has turned out to
be a feasible alternative for children with FHL lacking an
HLA-identical donor.5,6,20 In this particular patient, an
unrelated donor search was not initiated, and haploidentical SCT from
the organ donor was considered the first choice for 2 reasons: (1)
Microchimerism after liver transplantation might facilitate donor stem
cell engraftment. (2) Complete bone marrow donor chimerism in the organ
recipient might not only cure the underlying disease, but the chimerism
might also prevent organ rejection without the necessity of prolonged
immunosuppression, thus reducing the risk of EBV-associated
lymphoproliferative disease. In the case of persistent mixed chimerism
after allogeneic SCT, DLI is able to displace residual host
cells.14,21,22 Because the circulating CD8+
and CD4+ T cells were of recipient origin on day +29, a DLI
was given to promote donor T-cell engraftment. We have shown that SCT
after living-related liver transplantation from the same haploidentical donor is feasible, and LTX might provide an attractive option for young
children with acute or chronic liver failure due to diseases that can
be cured by allogeneic SCT such as FHL, hyper-IgM syndrome, or
generalized Langerhans cell histiocytosis.
| |
Footnotes |
Submitted June 16, 2000; accepted August 15, 2000.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Helmut Gadner, St Anna Kinderspital,
Kinderspitalgasse 6, A-1090 Vienna, Austria; e-mail:
gadner{at}ccri.univie.ac.at.
| |
References |
1.
Arico M, Janka G, Fischer A, et al.
Hemophagocytic lymphohistiocytosis: report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society.
Leukemia.
1996;10:197-203[Medline]
[Order article via Infotrieve].
2.
Haddad E, Sulis ML, Jabado N, Blanche S, Fischer A, Tardieu M.
Frequency and severity of central nervous system lesions in hemophagocytic lymphohistiocytosis.
Blood.
1997;89:794-800[Abstract/Free Full Text].
3.
Alarabi AA, Danielson BG, Wikstrom B, Kreuger A, Tufvenson G.
Artificial renal and liver support in a severe hepatorenal syndrome of childhood.
Acta Pediatr.
1991;81:75-78.
4.
Baker KS, DeLaat CA, Steinbuch M, et al.
Successful correction of hemophagocytic lymphohistiocytosis with related or unrelated bone marrow transplantation.
Blood.
1997;89:3857-3863[Abstract/Free Full Text].
5.
Collins P, Watts M, Brocklesby M, Gerritsen B, Veys P.
Successful engraftment of haploidentical stem cell transplant for familial haemophagocytic lymphohistiocytosis using both bone marrow and peripheral blood stem cells.
Br J Haematol.
1997;96:644-646[Medline]
[Order article via Infotrieve].
6.
Jabado N, de-Graeff ME, Cavazzana CM, et al.
Treatment of familial hemophagocytic lymphohistiocytosis with bone marrow transplantation from HLA genetically nonidentical donors.
Blood.
1997;90:4743-4748[Abstract/Free Full Text].
7.
Durken M, Horstmann M, Bieling P, et al.
Improved outcome in haemophagocytic lymphohistiocytosis after bone marrow transplantation from related and unrelated donors: a single-centre experience of 12 patients.
Br J Haematol.
1999;106:1052-1058[Medline]
[Order article via Infotrieve].
8.
Emre S, Schwartz ME, Shneider B, et al.
Living related liver transplantation for acute liver failure in children.
Liver Transpl Surg.
1999;5:161-165[Medline]
[Order article via Infotrieve].
9.
Reding R, deGoyet J, Delbeke I, et al.
Paediatric liver transplantation with cadaveric or living related donors: comparative results in 90 elective recipients of primary grafts.
J Pediatr.
1999;134:280-286[Medline]
[Order article via Infotrieve].
10.
Bunin N, Leahey A, Dunn S.
Related donor liver transplant for veno-occlusive disease following T-depleted unrelated donor bone marrow transplantation.
Transplantation.
1996;61:664-666[Medline]
[Order article via Infotrieve].
11.
Rosen HR, Martin P, Schiller GJ, et al.
Orthotopic liver transplantation for bone-marrow transplant-associated veno-occlusive disease and graft-versus-host disease of the liver.
Liver Transpl Surg.
1996;2:225-232[Medline]
[Order article via Infotrieve].
12.
Hadzic N, Pagliuca A, Rela M, et al.
Brief report: correction of the hyper-IgM syndrome after liver and bone marrow transplantation.
N Engl J Med.
2000;342:320-324[Free Full Text].
13.
Kawahara K, Storb R, Sanders J, Petersen FB.
Successful allogeneic bone marrow transplantation in a 6.5-year-old male for severe aplastic anemia complicating orthotopic liver transplantation for fulminant non-A-non-B hepatitis.
Blood.
1991;78:1140-1143[Abstract/Free Full Text].
14.
Ringden O, Soderdahl G, Mattson J, et al.
Transplantation of autologous and allogeneic bone marrow with liver from a cadaveric donor for primary liver cancer.
Transplantation.
2000;27:2043-2048.
15. Fritsch G, Scharner D, Fröschl G, et al. Selection of CD34
positive blood cells for allogeneic transplantation: approaches to
optimise CD34 cell recovery, purity, viability and T cell depletion.
Onkologie. In press.
16.
Dubovsky J, Daxberger H, Fritsch G, et al.
Kinetics of chimerism during the early posttransplant period in pediatric patients with malignant hematologic disorders: implications for timely detection of engraftment, graft failure and rejection.
Leukemia.
1999;13:2060-2069.
17.
Cox KL, Lawrence-Miyasaki LS, Garcia-Kennedy R, et al.
An increased incidence of Epstein-Barr virus infection and lymphoproliferative disorder in young children on FK506 after liver transplantation.
Transplantation.
1995;59:524-529[Medline]
[Order article via Infotrieve].
18.
Newell KA, Alonso E, Kelly SM, Rubin CM, Thistlethwaite JR, Whitington PF.
Association between liver transplantation for Langerhans cell histiocytosis, rejection, and development of posttransplant lymphoproliferative disease in children.
J Pediatr.
1997;131:98-104[Medline]
[Order article via Infotrieve].
19.
Rao AS, Fontes P, Dodson F, et al.
Augmentation of natural chimerism with donor bone marrow in orthotopic liver recipients.
Transplant Proc.
1996;28:2959-2965[Medline]
[Order article via Infotrieve].
20.
Peters C, Matthes-Martin S, Fritsch G, et al.
Transplantation of highly purified peripheral blood CD34+ cells from HLA-mismatched parental donors in 14 children: evaluation of early monitoring of engraftment.
Leukemia.
1999;13:2070-2078[Medline]
[Order article via Infotrieve].
21.
Aker M, Kapelushnik J, Pugatsch T, et al.
Donor lymphocyte infusions to displace residual host hematopoietic cells after allogeneic bone marrow transplantation for beta-thalassemia major.
J Pediatr Hematol Oncol.
1998;20:145-148[Medline]
[Order article via Infotrieve].
22.
Nagler A, Ackerstein A, Kapelushnik J, Or R, Naparstek E, Slavin S.
Donor lymphocyte infusion post-non-myeloablative allogeneic peripheral blood stem cell transplantation for chronic granulomatous disease.
Bone Marrow Transplant.
1999;24:339-342[Medline]
[Order article via Infotrieve].
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Abstract
Introduction