Journal of Hematology - Supplements - Haematologica

13
ease. This observation is confirmed by a constant
post-transplant rate of relapse through the years.
Moreover it has became increasingly evident
that an important component of the curative
potential of allogeneic stem cell transplantation
may be achieved through the induction of a state
of host-versus-graft tolerance, giving donorderived
T-lymphocytes the opportunity to recognize
and eradicate tumor cells and host abnormal
as well as normal stem cells.
Data are accumulating showing that the therapeutic
benefit of allotransplants in preventing
relapse is largely explained by a donor T-lymphocyte
mediated immunologic effect (graft versus
leukemia = GVL) rather than by physical elimination
of tumor cells by high doses of cytoreductive
therapy. Eradication of the host
immuno-hematopoietic system by means of
adoptive allogeneic cell therapy was confirmed in
pre-clinical and clinical studies. This observation
is well-documented in patients with chronic
myeloid leukemia (CML) who gave relapsed after
transplant but who may achieve complete cytogenetic
and molecular remission following donor
lymphocyte infusion (DLI). Moreover acute
myeloid leukemia (AML), acute lymphoid
leukemia (ALL) and others malignancies such as
non-Hodgkin’s lymphoma (NHL), chronic lymphatic
leukemia (CLL), melanoma and some solid
tumors seem to be susceptible to a graft-versus-tumor
effect (GVT), although clinical data
are less impressive. Furthermore, the effectiveness
of DLI therapy sustains the hypothesis that
long-term disease control may be obtained without
myeloablative conditioning. 9,10,17,18
Despite progress in supportive therapy, myeloablative
regimen toxicity still leads to a high
incidence of acute side affects and contributes,
in combination with GVHD, to considerable
TRM. These complications occur more frequently
in adults or in the unrelated setting transplants,
especially from unrelated donors, are
therefore still performed mainly in young
patients with recurrence of leukemia, as the risk
of severe complications and mortality is too high
for routine application in non-malignant but
potentially curable diseases, such as hemoglobinopathies,
metabolic diseases, immunodeficiencies
or acquired aplastic anemia.
Clinical studies have recently shown that allogeneic
engraftment can be accomplished
through a different strategy without myeloablative
doses of chemotherapy. The possibility of
achieving stable engraftment without myeloablation
and of completely eradicating leukemia by
adoptive allogeneic cells suggested the working
hypothesis for developing a new approach for
allogeneic bone marrow transplantation. This
hypothesis is based on the possibility of using
donor T-cells to eradicate both host malignant
and non-malignant clones avoiding the need of
complete myeloablation. This strategy is primarily
designed to facilitate donor cell engraftment
(by achieving tolerance toward donor cells)
and less to eradicate the underlying disease by
means of conditioning. 9,10,19-36 The reduction of
acute and chronic complications related to
intensive therapy toxicity would improve the outcome
of the procedure, extending its feasibility to
patients otherwise deemed ineligible according
to standard criteria.
The development of less toxic and non-myeloablative
conditioning regimens was first investigated
at the Hadassah University in Jerusalem
and at the MD Anderson Institute in Houston
which have pioneered the new concept of nonmyeloablative
allograft (or miniallograft as
termed by some authors to highlight the lowintensity
of the protocol). Subsequently other
Institutions world-wide started pilot experiences
and an increased amount of data is now available.
9,10,19-42
The intensity of the proposed regimens may
differ in terms of the real capacity of hematopoietic
recovery without stem cell support. Indeed
most of the currently used protocols have never
been tested in clinical setting without stem cell
support; they are of lower in intensity than conventional
schedules but variable degrees of
hematopoietic recovery may result according to
the hematopoietic reserve of each patient. This
difference in intensity should be included in the
analysis of the results reported by different institutions
about the procedure toxicity.
If the underlying concept of this transplant is
that its curative activity is mediated by an immunologic
reaction rather than by chemical eradication
of the disease, the importance of tumor mass at
the time of transplant still remains a matter of
debate. Some authors suggest that even refractory
or progressive diseases may benefit from allogeneic
immunotherapy and emphasize that excessive
pre-transplant cytoreduction may lead to
normal host hematopoietic environment damage.
Others remark that allogeneic immunotherapy can
be promising only at the stage of minimal residual
disease. 10,11,17,20,25,27-29,32,40
Many non-ablative conditioning regimens have
been tested by various teams or by the same
team in different settings of patients. To date it
seems that fludarabine or low-doses of TBI play
a crucial role in these less intensive programs
providing enough immunosuppression to allow
allogeneic engraftment without severe myelotoxicity.
25,27,28
In most of these settings, allotransplant may
be considered the platform for subsequent adoptive
immunotherapy using donor lymphocytes. In
haematologica vol. 85(supplement to n. 11):November 2000