1. Aetna considers donor lymphocyte infusion (DLI) medically necessary for persons who have a prior, medically necessary allogeneic bone marrow or peripheral stem cell transplantation.

2. Aetna considers the modification of donor lymphocytes (e.g., donor lymphocyte depletion, ex vivo expansion, expanding antigen-specific T-cell lines, T-cell depletion, genetic modification) experimental and investigational because the clinical value of these approaches in the treatment of malignancies has not been established.

See also CPB 641 - Adoptive Immunotherapy.

High dose chemotherapy (HDC) in combination with allogeneic bone marrow transplantation results in remission in significant numbers of patients with chronic myelogenous leukemia (CML), acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL).  However, disease relapse is a major cause of treatment failure, and salvage treatment options for these patients are limited.  Patients can either be treated with an additional course of conventional chemotherapy or a second round of HDC and repeat allogeneic transplantation.  Conventional chemotherapy is unlikely to result in a complete durable remission, and the morbidity and mortality of a second allogeneic transplant is unacceptably high.  Furthermore, patients with CML have been treated with interferon.  While this treatment can be associated with normalization of peripheral blood counts, interferon fails to eradicate the malignant clone of cells.

Donor lymphocyte infusion (DLI), also known as donor leukocyte or buffy coat infusion, has been used in an attempt to stimulate a donor versus leukemic reaction and thus eradicate the malignant clone of cells.  Donor lymphocyte infusion entails the collection (from the original donor) of peripheral lymphocytes during an apheresis procedure; donors generally undergo two to eight procedures.  The lymphocytes are then simply infused into the patient either immediately or after frozen storage.  Donor lymphocyte infusion differs from allogeneic bone marrow transplantation in that it is not preceded by chemotherapy and T cells are not depleted. Lymphocyte infusion with a defined T-cell dose can cause a profound graft-versus-leukemia (GVL) effect and is an effective form of salvage immunotherapy in allogeneic marrow transplanted recipients.  The advantage in using DLI versus second allogeneic transplantation is the lower treatment-related morbidity and mortality.

The GVL effect is a well-described phenomenon, which is associated with the presence of graft-versus-host disease (GVHD).  For example, the likelihood of relapse post-allogeneic transplantation is lower in those patients who experience either acute or chronic GVHD.  In addition, there is a higher rate of relapse in patients receiving a syngeneic (identical twin) transplant compared to allogeneic transplant.  However, the presence of GVL is not dependent on the presence of GVHD.  For example, the rate of leukemic relapse is higher in patients receiving T- cell depleted allogeneic marrow, even after controlling for the degree of GVHD.  This observation suggests that there may be a distinct subset of T cells responsible for GVL.  Donor lymphocyte infusion attempts to harness the anti-leukemic properties of donor T cells.

In a recent review on adoptive allogeneic cellular therapy, Peggs and Mackinnon (2001) stated that DLI is effective in generating anti-tumor responses, especially for relapsed chronic-phase CML.  Response rates and durability appear lower with myeloma, AML and myelodysplasia syndrome, and minimal with ALL.  There is relatively little data on indolent lymphoid malignancies. This is in agreement with the observation of Slavin and associates (2001) who reported that pre-clinical and clinical studies have indicated that much more effective eradication of the host immunohematopoietic system cells can be attained by adoptive allogeneic cellular therapy with DLI following bone marrow transplantation.  Thus, eradication of blood cancer cells, particularly in patients with CML and, less frequently, in patients with other hematological malignancies, can frequently be achieved despite the complete resistance of such tumor cells to maximally tolerated doses of chemo- and radio-therapy.

In a review on DLI for the treatment of hematologic malignancies in relapse following allogeneic blood or marrow transplantation, Luznik and Fuchs (2002) reported that DLI induces complete remissions in the majority of patients with CML in early-stage relapse and in less than 30% of patients with relapsed acute leukemia, myelodysplasia, and multiple myeloma. Remissions of chronic- phase CML induced by DLI are durable, but as many as half of patients with other diseases ultimately relapse.

Pre-planned donor lymphocyte infusion has also been used as part of transplant protocols in persons with hematologic malignant diseases who have not relapsed.  Donor lymphocyte infusion is intended to facilitate establishment of full donor chimerism (complete donor stem cell grafting in the recipient's bone marrow) and potentiation of antitumor effect (graft versus tumour reaction) (Cheong, et al., 2002).

There is also ongoing research on the genetic modification of donor lymphocytes.  Transplantation of suicide gene modified allogeneic T lymphocytes is an approach to prevent T-cell mediated GVHD while preserving the GVL effect of an allograft.  However, existing techniques allow insufficient transduction of T lymphocytes.  Further investigation is needed to develop more efficient gene transfer protocols and is possible value in the treatment of hematological malignancies.