Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

302 15 Bone Marrow Transplantation for Immune Therapy
suppression triggers GvHD in some patients, with an associated decline in leukemic
cells. Abrupt discontinuation of cyclosporin may be indicated as a first step before
DLI in patients without severe GvHD. In many patients, the leukemia does not respond
immediately and leukocytosis may even increase before a response occurs.
The median time to cytogenetic negativity being observed was 4.5 months, with responses
as late as 12 months. The latency of the immunotherapeutic effect in a disease
with a so-marked susceptibility to GvL may justify the lower response rate of
DLI in diseases other than CML; in particular, acute leukemias, in which a rapid
growing tumor mass overcomes the alloreactivity of donor T cells (Tab. 15.5) [13, 15].
Furthermore, responses have not been as durable in patients with recurrent acute
leukemia, with overall actuarial survival not exceeding 10±15% at 3 years. Most patients
with acute leukemias and transformed-phase CML recurring after marrow
transplantation need cytotoxic chemotherapy to obtain a transient control of the disease,
before the infusion of donor lymphocytes; the use of chemotherapy in acute
lymphocytic leukemia (ALL) and acute myelocytic leukemia (AML) increases the rate
and durability of responses. Recently, the response of AML to donor lymphocytes
has been shown to be improved by the combination of donor lymphocytes with stem
cells and granulocyte macrophage colony stimulating factor (GM-CSF) [16]. Treatment
with stem cells and GM-CSF may improve antigen presentation, and favor
cross-priming of donor-derived dendritic cells with antigens of the host.
DLI has limited benefit in ALL. Approximately 75% of patients treated with DLI,
either alone or in the nadir after chemotherapy, did not achieve CR in registry studies,
showing a likelihood of survival of less than 15% at 3 years [15] and 0% at 4.5
years [17]. The reason for the low efficacy of DLI in ALL patients is uncertain: it is
likely that the leukemia burden is too high in patients with hematologic relapse ± patients
might die from rapid disease progression before GvT effects have a chance to
evolve. However, a large retrospective analysis has shown that the GvL effect in ALL
is particularly associated with GvHD [9]. Based on this observation in acute leukemias,
the response rate to DLI is not to be considered as an absolute predictor of
long-term disease eradication after allogeneic transplantation; in particular, a poor
response rate to DLI should not discourage candidate patients with advanced disease
from allogeneic transplantation as salvage treatment.
Tab. 15.5 GvLeffect of DLIs ± EBMT study
Diagnosis No. of patients studied Evaluable a
CRs (%)
CML
cytogenetic relapse 57 50 40 (80%)
hematological relapse 124 114 88 (77%)
transformed phase 42 36 13 (36%)
Polycythemia vera/myelodyslastic syndrome 2 1 1 (100%)
AML/myelodyslastic syndrome 97 59 15 (25%)
ALL 55 18 2 (11%)
Multiple myeloma 25 17 5 (29%)
a Patients surviving less than 30 days after DLIs were excluded from analysis.