Dear editor, Muenzer et al recently published an important and
comprehensive management and treatment guideline for MPS1 on behalf of a
consensus panel with the goal of providing standards for the care and
monitoring of these complex patients (Pediatrics 2009;123;19-29). We, as
an international blood and marrow transplantation group, including 4 major
hematopoietic stem cell transplant centers (Duke, Minnesota, Manchester
and Utrecht) providing care for these children are writing to delineate
our view of the benefits and risks of transplantation in MPS I.
Transplant outcomes in children with severe phenotype MPS I have
continuously improved over the almost 3 decades since transplantation
therapy was first used to treat children with this disease. Much of the
data referenced in regards to these outcomes, including the reports of
Boelens and Peters, describe data that were collected on patients
transplanted over a decade ago. The field of transplantation has evolved,
since that time, resulting in decreased risks of graft failure and graft-
versus-host disease, and decreasing or eliminating the use of radiation
therapy in the preparative regimen. These changes have lead to greatly
improved outcomes as evidenced by recent single and multicentre data
showing engrafted survival rates approximating 90%, as individuals are
identified early, and transplantation is expediently performed with grafts
including cord blood infusions (1-4). It is possible that outcomes may
further improve through the utilization of cord blood donor grafts and
development of new transplant preparative regimens and algorithms for
supportive care. The potential use of enzyme therapy prior to
transplantation, especially for older or more severely ill patients, may
also influence outcomes (5).
There are also data published that show the degree of substrate
reduction following SCT is much reduced compared with following ERT (4,
6). As disease severity appears associated with levels of substrate
accumulation, it seems reasonable to propose that those therapies that
achieve the best reduction in accumulated substrate will provide the best
clinical results. This may prove to be the case with transplantation. We
accept that further long-term studies of clinical outcome are necessary to
support these data on biochemical parameters and clinical outcome. These
have been currently initiated and ongoing in our transplant centres
including > 80% of the MPS1 patients transplanted over the last decades
(according to the EBMT and CIBMTR registries).
Finally, there is little information regarding the efficacy or safety
of intravenous ERT alone in preventing the long-term symptoms and signs of
MPSI. Data only exists in regards to short term surrogate markers of
disease, largely reflecting visceral enzyme delivery – e.g. liver size,
substrate reduction etc. Immunological hypersensitivity reactions, both
silent and clinically apparent, may occur after longer term exposure to
ERT neutralizing enzyme activity and decreasing efficacy of this therapy
after repeated doses of ERT. ERT is also offered at huge financial cost
which will preclude its use in some countries where SCT is offered.
We feel that the question of “best therapy” for children with MPS I
remains unanswered. As more information becomes available (e.g. the long
term follow up study mentioned above), it may become clear that SCT may
prove the treatment of choice in MPS I. We believe that trials extending
SCT therapy to patients with milder disease, perhaps comparing long term
outcomes of SCT with ERT, should be conducted. The transplant community
is committed to finding ways to increase the safety of SCT focusing on
reducing long-term toxicities, including infertility. In addition, earlier
diagnosis, by newborn screening may further improve the outcomes.
References:
1) Boelens JJ, Rocha V, Aldenhoven M, Wynn RF, O’Meara A, Michel G et
al, Risk Factor Analysis of Outcomes after Unrelated Cord Blood
Transplantation in Patients with Hurler Syndrome, BBMT 2009, in press
2) Staba SL, Escolar ML, Poe M, Kim Y, Martin PL, Szabolcs P, Allison
-Thacher J, Wood S, Wenger DA, Rubinstein P, Hopwood JJ, Krivit W,
Kurtzberg J et al. Cord-blood transplants from unrelated donors in
patients with Hurler's syndrome. N Engl J Med 2004; 350(19):1960-1969
3) Prasad VK, Mendizabal A, Parikh SH, Szabolcs P, Driscoll TA, Page
K, Lakshminarayanan S, Allison J, Wood S, Semmel D, Escolar ML, Martin PL,
Carter S, Kurtzberg J. Unrelated donor umbilical cord blood
transplantation for inherited metabolic disorders in 159 pediatric
patients from a single center: influence of cellular composition of the
graft on transplant outcomes. Blood. 2008; 112: 2979-89.
4) Wynn RF, Mercer J, Page J, Carr TF, Jones S, Wraith JE, Use of
enzyme replacement therapy (Laronidase) before Hemotopoietic stem cell
transplantation for Mucopolysaccaridosis I: experience in 18 patients, J
Pediatr. 2009;154:135-9
5) Tolar J, Grewal SS, Bjoraker KJ, Whitley CB, Shapiro EG, Charnas
L, Orchard PJ. Combination of enzyme replacement and hematopoietic stem
cell transplantation as therapy for hurler syndrome, Bone Marrow
Transplant. 2008 Mar;41(6):531-5.
6) Wynn R.F. Wraith E, Mercer J, O’Meara A, Tylee K, Thornley M,
Church HJ, Bigger BW, Improved metabolic correction in Lysosomal Storage
Disease treated with Hematopoietic Stem Cell Transplant compared with
Enzyme Replacement Therapy. J.Ped 2009, in press
Conflict of Interest:
None declared
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