Biology Reference
In-Depth Information
to suppress GVHD while improving immune reconstitution. This approach
yields moderate rates of acute GVHD, but low rates of both chronic GVHD
and nonrelapse mortality (both 15% at 1 year) [47,48] . Furthermore, in 185
HLA-matched BMT patients, the use of post-transplant cyclophosphamide
as the sole prophylaxis led to an extremely low incidence of chronic GVHD
(9-11%). These patients also experienced prompt immune reconstitution,
without deaths from cytomegalovirus or invasive fungal infections, and
85% of surviving patients had discontinued all immunosuppressive therapy
1 year post-transplant [49] .
Prevention and treatment of relapse
As mentioned above, recurrent malignancy remains a major cause of mor-
tality after allogeneic transplantation and efforts to prevent it are often
counterpoised against efforts to reduce GVHD. Future approaches to mini-
mize the risk of relapse will consider factors specific to both the patient and
the underlying malignancy. Significant progress requires: [1] early identifi-
cation of very high risk patients, [2] transplantation prior to end organ dam-
age from malignancy or therapy, [3] maximal reduction of disease burden
before transplant conditioning, [4] improved disease-specific conditioning
regimens, [5] close monitoring for disease relapse, and [6] effective mainte-
nance therapy after BMT (modified from [50] ). In this section, we highlight
some novel strategies to prevent relapse while moderating GVHD, begin-
ning with measurement of minimal residual disease (MRD).
499
MRD analysis provides important prognostic information for a variety of
hematologic malignancies and influences the success of transplantation in
many ways [51,52] . First, MRD status can determine which patients might
benefit from BMT. As shown in a recent St. Jude acute myeloid leukemia
(AML) trial, persistent bone marrow MRD >0.1% made patients eligible for
HSCT regardless of the availability of an HLA-matched sibling donor [53] .
Second, pretransplant MRD analysis of disease burden predicts the risk of
eventual relapse [54] . One therapeutic response to this information is to
perform additional induction therapy prior to the transplant; indeed, dis-
ease burden was reduced in 71% of pediatric acute lymphoblastic leukemia
(ALL) patients receiving additional induction or intensification chemo-
therapy after a positive MRD result, which then correlated with improved
event-free survival at 12 months [55] . A second therapeutic response to
persistent MRD, when found post-transplant, is preemptive anti-tumor
therapy prior to frank relapse. One pediatric study tested preemptive immu-
notherapy for 31 patients, whose percentage of recipient cells continued
to rise after the discontinuation of immunosuppression [56] . In this case,
rising recipient cell numbers served as a surrogate marker for MRD. Pre-
emptive immunotherapy in 21 patients improved 3-year event-free survival
to 37% versus 0% in the 15 patients who did not receive additional ther-
apy. A similar approach (in 20 high-risk myelodysplastic syndrome (MDS)
patients) initiated azacitidine for donor chimerism <80%, which delayed or
prevented relapse in some patients (reviewed in [57] ).
Full implementation of preemptive therapy following MRD analysis requires
careful monitoring and clear threshold values. These thresholds should be
Search WWH ::




Custom Search