Journal of Hematology - Supplements - Haematologica

44
Discussion
Since the majority of children affected by PID
do not have a compatible donor (40% have a
matched unrelated donor 14 and only 10-15%
have a healthy matched sibling, haploidentical
BMT is the only curative treatment in this setting.
Nevertheless, only children affected by SCID
B + can be successfully treated (75% event-free
survival) (EFS) by haploidentical BMT. Results
of haploidentical BMT in other PID are still discouraging
with an EFS of about 35-50%, due to
failure to engraft or infectious complications
related to late immunologic reconstitution. 5,15
Graft failure in patients affected by PID, conventionally
conditioned with busulfan and
cyclophosphamide in haploidentical BMT, could
be related to insufficient myeloablation and
immunosuppression. 16,17 Jabado et al. 18 have
reported a new approach to enhance engraftment
based on the use of a combination of two
monoclonal antibodies: anti LFA-1 and anti-
CD2. The results of their study suggest an
increased rate of engraftment in non-SCID
patients. Nevertheless, long-term results of this
approach with regards to engraftment, infectious
complications and immunologic posttransplant
reconstitution remain to be evaluated.
Among the several mechanisms claimed to
explain the graft failure, insufficient conditioning
regimen seemed to be the most likely as it lead s
to insufficient inhibition of residual T-cell function.
19-21 An additional reason for failure of conventional
haploidentical transplant could be the
insufficient stem cell inoculum. In fact, it was
shown in animal models that resistance to
engraftment could be resolved if a large BM
inoculum was used. 8 The rationale of using a
conditioning regimen before BMT in PIDs is
based on the need for immunosuppression and
creation of “space" for the new hematopoesis. 22
However, these children receive a milder conditioning
regimen than patients affected by hematologic
malignancies. In patients affected by
hematologic diseases, who cannot receive TBI
and have diseases requiring an intensive conditioning
regimen (acute lymphoblastic leukemia,
myelodysplastic syndromes, thalassemia), the
addition of thiotepa, a potent myeloablative
drug, to the conventional busulfan-cyclophosphamide
protocol, has been suggested. 23 In our
group of patients, the conditioning regimen
intensified by addition of thiothepa achieved
good myeloablation. All patients tolerated the
conditioning regimen well, without major toxicities.
In haplodentical BMT profound T-cell
depletion is required in order to avoid GVHD.
However, an absence of T-lymphocytes in the
graft prolongs immunodeficiency after BMT and
may lead to an increased risk of opportunistic
infections. In fact, in sharp contrast to HLAmatched
BMT, a very delayed T-lymphocyte
reconstitution, together with B-lymphocyte deficiency,
has been observed in haploidentical
BMT. 24 Transplantation of autologous peripheral
blood stem cells is currently a well established
method to reconstitute hematopoiesis in
patients affected with lymphoma/leukemia or
solid tumors, receiving a myeloablative preparatory
regimen. Several reports showed how infusion
of PBSC shortens the post-BMT aplastic
phase with faster engraftment and allows
prompt immunologic reconstitution as confirmed
by conventional autologous BMT with
marrow stem cells alone. 25,26 Recent data,
regarding HLA-identical PBSC transplantation in
hematologic malignancies, showed successful
engraftment of all cell lineages without a significant
increase in GVHD. 27 Studies performed in
patients affected by leukemia show successful
engraftment of a T-cell depleted haploidentical
bone marrow by addition of recombinant
human granulocyte colony-stimulating factormobilized
peripheral blood progenitor cells to
marrow inoculum, with accelerated hematopoetic
recovery and without significant exacerbation
of GVHD. 7,28 Nevertheless the series of
patients treated in this report had advanced
hematologic diseases, so data on long-term
engraftment are not available. In PID, Friedrich
et al. 29 reported 10 consecutive patients with
SCID B + who received T-depleted haploidentical
PBSC transplants with encouraging results.
Again, longer follow-up of these patients is needed.
Mobilization of peripheral CD34 + cells by G-
CSF and their collection by leukapheresis gives
the possibility of obtaining at least 150-300×10 6
CD34 positive cells thus increasing the stem cell
inoculum. Although peripheral blood CD34 +
cells show different surface markers from bone
marrow cells, 30 studies in animals demonstrate
that they are capable of inducing prompter
immunologic reconstitution than bone marrow
cells. Also, data on survival in long-term cultures
of PBSC suggest their ability to repopulate bone
marrow. 31,32 A study by Dunbar et al. 33 demonstrated
long-term engraftment (18 months) in
an autologous setting of both BM and PB stem
cells using gene marking with two distinguishable
vectors. Nevertheless no conclusive data are
available to demonstrate that mobilized PBSC
alone can guarantee long-term engraftment. 34-36
We have therefore combined the infusion of haploidentical
T-cell-depleted bone marrow cells
with added peripheral CD34 + stem cells in order
to increase the stem cell load. The choice not to
positively select BM CD34 + cells came from the
consideration that, if the goal was to increase
the stem cell inoculum, the yield after the posi-
haematologica vol. 85(supplement to n. 11):November 2000