What is the graft-versus-leukemia effect after bone marrow transplantation?

Updated: Mar 20, 2018
  • Author: Crystal L Mackall, MD; Chief Editor: Jennifer Reikes Willert, MD  more...
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Answer

Development of bone marrow transplantation as a clinical approach to malignancy initially rested on the assumption that high doses of chemotherapy were necessary to eradicate relatively chemoresistant leukemia. In this paradigm, the marrow graft served only to rescue marrow function that was irreversibly ablated by high-dose therapy or irradiation.

However, clinical evidence accumulated over the past 25 years has shown that an important component of the graft-versus-leukemia effect in bone marrow transplantation is related to an immunologic reaction that occurs between donor T cells contained in the marrow graft and residual tumor cells that remain after high-dose chemotherapy. [41, 42, 43, 44, 45, 46]

  • Patients who develop some evidence of graft versus host disease (GVHD) experience a lower incidence of leukemic relapse. [47]

  • Increased intensity of immunosuppression used to prevent GVHD is also associated with increased leukemic relapses after bone marrow transplantation. [43, 46]

  • T-cell depletion of the marrow graft increases the rate of leukemic recurrence especially in chronic myelogenous leukemia (CML) and myelodysplasia/acute myeloid leukemia (AML). [48, 49, 50]

  • Leukemic relapse can sometimes be successfully treated by the infusion of donor lymphocyte infusions (DLIs) composed of peripheral blood T cells that can reinduce remission. [51, 52, 53, 54]

Perhaps the most important principle gleaned from the clinical experience is the potency with which T cells can permanently eradicate aggressive, recurrent, and chemoresistant leukemic cells.

Several other lessons are also pertinent. Immune responses can sometimes occur at a relatively slower tempo than that observed with cytotoxic therapies. For example, in CML, detection of molecular evidence of leukemia for at least 6-9 months after bone marrow transplantation is not uncommon, with gradual resolution of molecular evidence of residual leukemia occurring over 1-2 years. [55]

A second important principle is that not all leukemias are equally susceptible to the graft-versus-leukemia effect. For instance, DLIs induce complete responses in 60-80% of patients with stable chronic-phase CML; the response rate is approximately 30% in accelerated-phase CML, and less than 20% of patients in CML blast crisis respond. [53] However, DLIs have had less promising results in other leukemias, including 15-29% response rates in AML and less than 15% in acute lymphoblastic leukemia (ALL). [56]

Thus, polyclonal T cells mediate antitumor responses with a wide range of efficacy, even within a given tumor. The reasons for the differences in susceptibility are not well understood but no doubt hold important clues to the understanding of immune-based mechanisms of antitumor activity.

A growing body of literature suggests that T cells can also exert antitumor effects in some solid tumors, including a 25% response rate in renal cell carcinoma. [57, 58, 59] Whether similar activity is observed against pediatric solid tumors is unknown, but a few institutions have begun trials, ranging from adoptive immunotherapy of vaccine-primed T cells after chemotherapy to allogeneic stem cell transplants for pediatric patients with solid tumors. [60, 61, 62, 63, 64]

New approaches in bone marrow transplantation are also focusing on ways to diminish the toxicity of bone marrow transplantation by reducing the myelosuppression of the preparative regimen while preserving the antileukemic effect that is mediated by T cells contained within the graft. [65] Thus, bone marrow transplantation appears to be evolving away from high-dose myelosuppression and toward adoptive immunotherapy, thereby creating an environment that can enhance the immune-mediated effects.


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