Looking toward the future: an individualized approach to allogeneic transplantation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 494

specific to the underlying malignancy, the assay used, and other possible
factors such as the age of the patient. The optimal timing and frequency
of the analysis remain to be determined, in part because the efficacy and
toxicity of specific preemptive therapies is not yet clear. Further innovative
treatments, including novel immunotherapeutic agents and/or the infu-
sion of engineered lymphocyte populations (as listed below), are attractive
options for such high-risk patients.

Novel immunotherapeutics

The use of immunotherapeutic agents, including antibodies to cell surface
proteins, has become a standard component of the oncology armamen-
tarium. Inclusion of epratuzumab, a humanized anti-CD22 monoclonal
antibody, in a standard chemotherapy regimen reduced MRD in 7 of 12
evaluable children treated for B-cell ALL [58] . Blinatumomab, a bispecific
antibody recognizing both CD19 and CD3, activates CD3 + effector T cells
that in turn lyse CD19 + target cells held in close proximity by the antibody.
Clinically, blinatumomab is an effective reinduction agent for relapsed or
refractory B-cell ALL [59] , and there were no relapses observed in eight
patients who underwent subsequent allogeneic transplantation following
blinatumomab-based reinduction therapy. Agents such as blinatumomab
and epratuzumab are likely to play an integral role in the future of allo-
geneic transplant, as therapy for initial treatment, as reinduction chemo-
therapy prior to transplantation, or when included as maintenance therapy
post-transplant.

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Disease-specific conditioning regimens

Patients with active disease at the time of transplantation are at very high risk
for both relapse and transplant-related toxicity, making selection of a condi-
tioning regimen very difficult. Agents with anti-tumor efficacy that can also
ablate the recipient immune system are highly desirable in this situation.
Clofarabine may be one such agent. In 46 patients with active hematologic
relapse at the time of BMT, clofarabine conditioning combined with mye-
loablative doses of busulfan led to complete remission in 80% of patients by
day +30 (94% in 31 AML patients) [60] . All patients engrafted without addi-
tional immunosuppression and the 1-year cumulative incidence of relapse
was only 29% in AML patients. Gemtuzumab ozogamicin has been used in
a similar fashion for pediatric AML [61] , but its toxicity profile is significant,
especially with respect to veno-occlusive disease. Tyrosine kinase inhibitors
are also likely to be used more extensively, both in conditioning regimens
and as maintenance therapy, for Philadelphia chromosome-positive (Ph + )
disease (see below).

Cellular therapy for relapse: natural killer cells

NK cells are important effectors of host defense against infectious patho-
gens and malignancy. They express killer immunoglobulin-like receptors
(KIRs) to sense “self” major histocompatibility complex (MHC) class I mol-
ecules and will lyse cells lacking the proper MHC class I. NK cells can thus