Reinventing Bone Marrow Transplantation
Reinventing Bone Marrow Transplantation
Bone marrow transplantation (BMT) was initially
developed as a means to deliver supralethal doses of chemotherapy and
radiation for the treatment of malignancies.[1,2] Myelosuppression is
the dose-limiting toxicity for numerous chemotherapeutic drugs and
whole-body irradiation. Many malignancies exhibit a steep
dose-response relationship to chemotherapy or radiotherapy. Marrow
transplantation enables doses to be escalated beyond those that
produce severe bone marrow toxicity, allowing doses of many
chemotherapeutic agents, particularly alkylating agents, and
whole-body irradiation to be increased three- to fivefold above
conventional maximally tolerated levels.
Until recently, marrow transplantation was considered a
supportive-care modality for restoring hematopoiesis. It has become
clear, however, that high-dose therapy does not eradicate the
malignancy in many patients, and that the therapeutic benefit of
allogeneic marrow transplantation relates largely to an associated
immune-mediated graft-vs-malignancy effect.
Extensive clinical and experimental data support the presence of a
graft-vs-malignancy effect (Table 1).
Most of the data relates to the effects of allogeneic
transplantation in leukemia, or graft-vs-leukemia (GVL) effects.
These include a reduced risk of relapse in transplant recipients with
acute and chronic graft-vs-host disease (GVHD)[3-5] and a higher
relapse risk after syngeneic marrow transplantation.[6-8]
T-celldepleted allotransplants are also associated with an
increased risk of relapse, particularly in patients with chronic
myelogenous leukemia (CML). The most direct evidence of GVL is the
finding that, in many patients who relapse after allogeneic
transplantation, remission can be reinduced simply by infusing
additional donor lymphocytes.[9-11]
Malignancies differ with respect to their susceptibility to GVL
effects. In both acute myelogenous leukemia (AML) and CML, syngeneic
transplants are associated with an increased rate of relapse, as
compared with transplants from human lymphocyte antigen
(HLA)identical siblings; this indicates the involvement of
allogeneic minor histocompatibility target antigens. T-lymphocytes
are critical effector cells in CML, in which T-celldepleted
transplants are associated with a fivefold increase in the risk of relapse.
Minimal residual disease can be detected (using polymerase chain
reaction [PCR]based techniques for the bcr-abl rearrangement)
in most patients with CML following high-dose chemoradiation.[12,13]
The malignant cells are eliminated in most patients who receive an
unmodified marrow graft during the first 6 months posttransplant,
presumably due to the GVL effect. With syngeneic or T-cell-depleted
marrow transplantation, GVL does not occur, and if residual leukemia
cells are demonstrated, patients generally relapse.
Approximately 70% of CML patients who relapse following
transplantation achieve a complete remission after additional donor
lymphocyte infusions.[9,14,15] Similar results have been achieved
with donor lymphocyte infusions for HLA-identical sibling or matched
unrelated donors. The best results occur when relapses occur into
chronic phase and when infusions are administered early in the course
of relapse. Responding patients generally become negative for
minimal residual leukemia cells by PCR analysis, and these responses
are usually durable.
Acute myelogenous leukemia is also subject to graft-vs-malignancy
effects, but these are not as dramatic as those observed in CML. The
relapse rate for AML is increased threefold with syngeneic
transplantation but is only modestly affected by T-cell
depletion.[18,19] Approximately one-third of patients with AML or
myelodysplasia respond to donor lymphocyte infusions, but these
remissions are generally transient, and disease typically recurs
within the following year.
Among the leukemias, acute lymphocytic leukemia (ALL) is affected the
least by GVL, possibly due to the pace of the disease and the limited
capacity of the leukemic lymphoblasts to stimulate an effective
immune response.[20,21] Only rare patients with ALL have benefited
from donor lymphocyte infusions.
Relatively few patients have received allogeneic transplants for
indolent lymphoid malignancies, but available data indicate that
potent graft-vs-malignancy effects against these disorders do occur.
Allogeneic transplants are associated with a much lower relapse rate
than purged autologous transplants for low-grade lymphoma[22,23] and
CLL.[24,25] Selected patients who have CLL, lymphoma,[27,28] or
multiple myeloma[29-31] have also responded to donor lymphocyte
infusions or modification of immunosuppressive therapy.
The relationship between the graft-vs-malignancy effect and GVHD
suggests that the target antigens for graft-vs-malignancy may be
minor histocompatibility antigens shared by the malignant cells and
the tissues involved in GVHD (Table 2).
Following donor lymphocyte infusion, many patients achieve a GVL
response, ie, remission of their leukemia, without developing GVHD.
Although this finding is consistent with the premise that different
target antigens may be involved in each process, it could also result
from greater sensitivity of leukemic cells than visceral tissues to a
common immunologic mechanism.
Graft-vs-leukemia activity may also be due to reactivity against
polymorphic hematopoietic lineage-related antigens or
leukemia-specific targets. Minor histocompatibility antigens
restricted to hematopoietic tissues have been described.[32,33] There
is little evidence of a leukemia-specific response; donor-derived
T-cell clones from allogeneic chimeras typically react against both
host normal hematopoietic cells and leukemia cells.[34-36]
Overexpressed or abnormally expressed cellular constituents may also
serve as target antigens for GVL. Proteinase-3, a serine protease
present in myeloid primary granules, is overexpressed in CML and some
cases of AML; it may serve as a target for an antileukemic immune
response. Peptide antigens derived from proteinase-3 can stimulate
generation of autologous or allogeneic T-cell cytotoxicity against
A major question is whether graft-vs-tumor effects occur in
nonhematopoietic malignancies. Pilot studies in breast cancer have
reported antitumor responses in patients with GVHD, suggesting a
graft-vs-adenocarcinoma effect.[39,40] In order to justify the added
morbidity related to allogeneic transplantation, further studies are
required to determine whether immunodominant tissue-restricted minor
histocompatibility antigens are present in nonhematopoietic tumors
and whether a clinically meaningful graft-vs-tumor effect occurs.
The effector cells producing GVHD and GVL effects are incompletely
defined. Both CD4+ and CD8+ T-cells participate in the initiation of
GVHD. Natural killer (NK) cells and other populations are
subsequently recruited, and cytokines are involved as mediators of
In animals, both CD4+ and CD8+ effectors of GVL have been described.
In most models, CD8+ cells appear to the principal effectors of GVL effects.[34,45-48]
In human BMT recipients, both CD4+ and CD8+ cytotoxic antileukemic
T-cell lines or clones have been described. In patients with CML who
received transplants, several recent studies have identified CD4+
T-cell lines or clones that either inhibit the growth of leukemia
progenitors or are directly lytic.[36,46,49,50] Natural killer cells
have also been implicated as mediators of GVL effects.[48,51-54]
After infusion of donor lymphocytes, little change in peripheral
blood counts occurs initially. However, after a median of 4 months,
responding patients may suddenly become hypoplastic, followed by
recovery of blood counts from donor-derived hematopoietic cells and a
return to complete chimerism.[9,14,55] Antileukemic effectors
presumably proliferate in vivo following the infusion, and most
likely must reach a threshold level to eradicate the leukemia cells
and the normal, host-derived hematopoietic cells.
Marrow aplasia may occur unless sufficient donor-derived normal
progenitors are present to restore hematopoiesis. Consistent with
this premise, CML patients treated during advanced relapse, in which
the marrow is completely replaced with leukemic cells, develop marrow
aplasia more frequently than do patients treated during cytogenetic
or early hematologic relapse.
Most patients who become aplastic recover after a second infusion of
donor hematopoietic stem cells from either marrow or mobilized
peripheral blood. A critical factor following donor lymphocyte
infusion is the kinetics of leukemia growth. Rapid regrowth of
leukemic cells may outpace the development of an effective immune