Sustained Eradication of Disease

The goal of HSCT for malignant disease or marrow disorders is sustained eradication of disease. This result can be obtained in certain circumstances with high-dose chemotherapy. However, it is clear from preclinical models and clinical studies that immune-mediated allogeneic effects, termed graft-versus-tumor (GVT) or graft-versus-leukemia (GVL) effects, are central to the therapeutic effect of allogeneic

TABLE 6.3. Pros and cons of T-cell depletion.



Decreased incidence of acute and chronic GVHD

Reduced or no requirement for posttransplant immunosuppression as GVHD prophylaxis Decreased organ toxicity Lower early transplant-related mortality

Higher incidence of graft failure

Loss of GVL activity (higher incidence of disease relapse, especially with CML)

Delayed immune reconstitution

Increased risk for posttransplant EBV-associated lymphoproliferative disorder

HSCT.182 Evidence to support the existence of GVL activity has come from several sources. First, a higher relapse rate has been noted in recipients of syngeneic transplants compared with allogeneic transplants from sibling donors, suggesting that the genetic/immunologic discrepancy between donor and host plays a role in disease control.140,183 Second, a reduced risk of relapse is observed in patients who develop GVHD after HSCT.184 Third, relapse rates are higher in recipients of T-cell-depleted grafts where alloreactive T cells are removed.167 Fourth, withdrawal of immunosuppression in some patients who have relapsed after transplant can induce a remission.185 All these lines of evidence still only provided indirect evidence of the existence of GVL activity. Direct evidence was finally obtained when donor lymphocyte infusions (DLI) were successfully used to treat patients with CML who had relapsed after BMT.

Many reports confirmed the efficacy of DLI in inducing remissions in patients who have relapsed after transplant, particularly in patients with CML.186-188 DLI induces complete cytogenetic remissions in more than 70% in patients with CML when treated in either cytogenetic or hematologic relapse. Responses are noted in other diseases, including multiple myeloma, MDS, CLL, and low-grade lymphoma. Acute leukemia and advanced CML may be less sensitive to DLI. DLI can cause GVHD. However, it is exciting to note that DLI can induce remissions in the absence of GVHD, demonstrating that GVL and GVHD can be separable.189 The dramatic activity of DLI is what has led to the exploration of nonmyeloablative conditioning regimens in clinical situations that rely predominantly on GVL activity for therapeutic benefit. It is hoped that current efforts to identify targets of DLI will lead to generation of vaccines that can be tested in clinical trials.190,191

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