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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1239-1246
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Nonmyeloablative stem cell transplantation for congenital
immunodeficiencies
Persis Amrolia,
Hubert B. Gaspar,
Amel Hassan,
David Webb,
Alison Jones,
Natalie Sturt,
Giorgina Mieli-Vergani,
Antonio Pagliuca,
Ghulam Mufti,
Nedim Hadzic,
Graham Davies, and
Paul Veys
From the Departments of Bone Marrow Transplantation and
Immunology, Great Ormond Street Hospital for Sick Children, and the
United Kingdom and Departments of Child Health and Haematological
Medicine, King's College Hospital, London, United Kingdom.
The optimal approach for stem cell transplantation in children with
immunodeficiency has yet to be determined. Conditioning therapy is
necessary for reliable engraftment and full immune reconstitution;
however, the beneficial effect of cytoreductive conditioning is
counterbalanced by increased short- and long-term treatment-related
toxicity. Whether bone marrow transplantation with a nonmyeloablative
preparative regimen was sufficient for the establishment of donor
immune reconstitution, with the resultant correction of disease
phenotype, was investigated. Eight patients with severe
immunodeficiency states underwent T-cell replete bone marrow
transplantation from a human leukocyte antigen-matched unrelated
(n = 6) or sibling (n = 2) donor with nonmyeloablative conditioning using a fludarabine-melphalan-anti-lymphocyte
globulin-based regimen. All patients had severe organ dysfunction that
precluded transplantation with conventional conditioning. All patients
were engrafted with predominantly donor hematopoiesis, and the
duration of neutropenia was brief. Significant acute graft-versus-host disease (GVHD) did not develop, but one patient had limited chronic GVHD. One patient died of disease recurrence, and 3 have stable, mixed
chimerism. At a median follow-up of 1 year, all patients have had good
recovery of CD3+ T-cell numbers, and 6 of 7 evaluable
patients have normal phytohemagglutinin stimulation indices. The rate
of immune reconstitution is comparable with that of historical controls
undergoing standard myeloablative protocols. Two patients with CD40
ligand deficiency now show significant expression, and a patient with
adenosine deaminase deficiency has improved deoxy adenosine
triphosphate metabolites. In summary, it has been demonstrated that
nonmyeloablative stem cell transplantation permits rapid engraftment
from both sibling and unrelated donors with minimal toxicity even in
the presence of severe organ dysfunction. If long-term immune
reconstitution of patients treated with this protocol is demonstrated,
it is believed this approach might offer significant advantages
compared with standard protocols by combining adequate immune
reconstitution with reduced short- and long-term toxicity.
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