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Introduction
Bone marrow transplantation for nonmalignant hematological diseases
For more than 30 years, selected malignant and nonmalignant diseases have
been treated by hematopoietic cell transplantation (HCT) [1– 9]. The conven-
tional application of HCT for hematological disorders has relied on myeloablative
conditioning before human leukocyte antigen (HLA)-identical sibling bone
marrow transplantation to correct the underlying hematological defect. Employ-
ing this strategy, HCT successfully replaced defective erythrocytes among
patients with sickle cell anemia [7] and b-thalassemia [10] and restored normal
hematopoiesis in patients with severe aplastic anemia [11] and other bone marrow
failure disorders [12] (See box). Best results followed transplantation from HLA-
identical sibling donors. Survival among young patients with severe aplastic
anemia exceeded 90%[1] and event-free survival among children with sickle cell
anemia was approximately 85% after HCT (Fig. 1) [7,13]. Similar results for
b-thalassemia have been reported, although the probability of event-free survival
was affected by the degree of iron overload and liver dysfunction that existed
before transplantation (Fig. 2) [10,14]. Although applied less frequently for
Diamond-Blackfan anemia [15], dyskeratosis congenita [16,17], chronic gran-
ulomatous disease [18,19], amegakaryocytic thrombocytopenia [20,21], and
* Corresponding author:
E-mail address: paul.woodard@stjude.org (P. Woodard).
0031-3955/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved.
PII: S 0 0 3 1 - 3 9 5 5 ( 0 2 ) 0 0 0 2 6 - 3
990 P. Woodard et al / Pediatr Clin N Am 49 (2002) 989–1007
Kostmann’s disease [9], HCT also has curative potential for these disorders. HCT
effectively eliminates the hematological manifestations of Fanconi’s anemia
[4,22 – 24].
Fig. 1. Overall survival, event-free survival, and rejection rates after matched sibling donor HCT for
sickle cell disease. (From Walters MC, Storb R, Patience M, et al. Impact of bone marrow
transplantation for symptomatic sickle cell disease: an interim report. Blood 2000;95:1918 – 24.)
P. Woodard et al / Pediatr Clin N Am 49 (2002) 989–1007 991
Fig. 2. Overall survival, rejection-free survival, and rejection rates after matched sibling donor HCT
for beta thalassemia. (From Lucarelli G, Clift RA. Marrow transplantation in thalassemia. In: Thomas
ED, Blume KG, Forman SJ, eds. Hematopoietic Cell Transplantation, 2nd edition. Malden: Blackwell
Science; 1998, p. 1137 – 44; with permission.)
thalassemia [27,28]. Since 1997, the Pesaro team has augmented pre-transplant
immunosuppression with fludarabine, azathioprine and hydroxyurea followed
by conventional preparation with busulfan and cyclophosphamide (160 mg/kg)
for thalassemics with class III features who were less than 17 years of age. This
modification successfully improved disease-free survival to 96% [10]. These data
support the idea that reduced intensity conditioning before transplantation in
high-risk patients might not be required for engraftment of donor cells. In
addition, it is possible that a reduction in pre-transplant dose intensity will
translate into improved survival.
Fanconi anemia represents another clinical model where reducing pretrans-
plant dose intensity was translated into improved survival. This disorder presents
unique challenges for transplantation due in part to excessive sensitivity to
alkylating agents such as busulfan and cyclophosphamide that significantly
increases the morbidity of HCT. In general, pretransplant conditioning for
Fanconi anemia has included cyclophosphamide, anti-T cell antibodies with or
without reduced dose irradiation delivered to limited fields that include lymphoid
tissue [4,12,22]. Here too, the benefits of dose reduction have been observed in
several studies. De-escalation of dose intensity involving cyclophosphamide and
limited-field irradiation demonstrated survival rates that varied from 58% to 76%
with an incidence of graft rejection that was not significantly higher when
compared to more intensive transplant regimens. There was, however, a higher
rate of graft failure among older patients who had a lower pretransplant platelet
count. As in thalassemia, these data are consistent with the notion that selected
high-risk patients with hereditary hematological disorders might benefit from
reduced dose-intensity preparation for HCT.
Table 1
Donor source and GVHD
Grade II – IV Grade III – IV
Donor acute GVHD acute GVHD Chronic GVHD
HLA-ID sibling BM [85,86] 10 – 38% 3.4 – 15% 11 – 32%
recipient weight collected in 85% of the cases) have been collected and processed
by this program. These results demonstrate the value of a national cord blood
banking resource for families with children who might benefit from UCB
transplantation, which is being used to support prospective investigations of
UCB transplantation [66].
Fig. 3. Probability of disease-free survival after purified CD34+ HCT from HLA-mismatched parental
donors. (Adapted from Handgretinger R, Klingebiel T, Lang P, et al. Megadose transplantation of
purified peripheral blood CD34+ progenitor cells from HLA-mismatched parental donors in children.
Bone Marrow Transplant 2001;27:777 – 83; with permission.)
1002 P. Woodard et al / Pediatr Clin N Am 49 (2002) 989–1007
Natural killer cells (NK cells) recovered rapidly, while T- lymphocyte recovery of
> 0.1 109 CD3+ cell/l required a longer period of time (median, 72 days). This
approach will require vigilant monitoring for opportunistic infections from
pathogens such as cytomegalovirus (CMV) and adenovirus. This can be accom-
plished with highly sensitive techniques such as polymerase chain reaction (PCR)
to detect viral DNA. The successful and safe use of haploidentical donors utilizing
stem cell selection technology might expand the availability of transplantation to
most patients with nonmalignant diseases who might benefit from HCT.
Summary
Hematopoietic cell transplantation (HCT) has been used for more 30 years for
the treatment of selected malignant and nonmalignant diseases. Traditionally,
HCT for hematological disorders has relied on myeloablative conditioning before
HLA-identical sibling bone marrow transplantation to correct the underlying
hematological defect. Most children with hematological diseases who are referred
to HCT have features that portend significant morbidity and early mortality.
Among SAA patients who have HLA-identical sibling donors, younger patients
with profound pancytopenia might be considered early for HCT. For others who
lack sibling donors, patients who receive HCT from alternate sources have
generally failed one or more courses of intensive immunosuppressive therapy and
remain transfusion-dependent, some with hemosiderosis, red cell alloimmuniza-
tion, and platelet transfusion refractoriness [44,46,48]. Currently, HCT for SCD is
generally restricted to those who have experienced a significant sickle-related
complication such as stroke, recurrent acute chest syndrome, or recurrent painful
episodes [7,13]. In contrast, most reserve HCT in thalassemia for younger,
Lucarelli class I, good-risk patients who have HLA-identical sibling donors,
and veer away from older, high-risk thalassemics for whom transplantation is a
riskier clinical intervention.
For groups such as young adults with thalassemia major, HCT might become
more widely applicable if its toxicity was reduced. Several approaches under-
going development include reduced-intensity conditioning and attempts to
prevent GVHD. New methods to reduce the intensity and toxicity of conditioning
as well as to use highly purified stem cells with the reduction in graft versus host
disease may allow for the use of matched unrelated donors or haploidentical
donors. This would serve to provide potentially more children who could benefit
from stem cell transplantation with donors. These advances will hopefully lead to
benefits for the majority of children who lack HLA-identical donors.
Acknowledgments
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