Naive T-Cell Depleted DLI Following Allo Stem Cell Transplant

Allogeneic stem cell transplantation (SCT) offers the hope of cure for a wide variety of
hematologic malignancies. Mature donor T-cells play a critical role in the success or failure
of this procedure. A subset of donor T-cells mediates graft-versus-host disease (GvHD). Other
subsets provide the foundation for immune recovery. Pan-depletion of mature donor T-cells is
an obligate step in haploidentical allogeneic stem cell transplantation. Without this step,
the recipient would succumb to lethal acute GVHD. We have had extensive experience with
in-vivo donor (and recipient) T-cell depletion using alemtuzumab as part of the bone marrow
conditioning regimen. We and others have also used anti-thymocyte globulin for the same
purpose. Pan-depletion of T-cells eliminates GvHD but significantly increases the risks of
tumor relapse and opportunistic infections. A delayed donor lymphocyte infusion augments
immune recovery and the graft versus tumor response, but it comes at the risk of inducing
lethal GvHD. This is particularly problematic when the donor and recipient are
HLA-discordant. Thus the major challenge in allogeneic stem cell transplantation is
determining how to maximally exploit the beneficial effects mediated by T-cells without
causing GvHD. This challenge could be overcome by selectively depleting the population of
donor T-cells responsible for eliciting the GvHD response. We have been interested in
selecting T-cells based on their naïve or memory phenotype to understand the contribution of
each of these cells to the pathogenesis of GvHD. Naïve T-cells (CD62L+ or CD45RA+) are
T-cells that have not encountered antigens specific for their T-cell receptor. Memory T-cells
(CD62L- or CD62L+ or CD45RA-) are T-cells that have previously been exposed to their
corresponding cognate antigens. If a donor has not encountered host alloantigens,
GvHD-inducing host-reactive T-cells should be contained in the naïve T-cell compartment. In
contrast, all the memory phenotype cells should not recognize host alloantigens. If this
hypothesis is correct as suggested by several published studies, CD62L- T-cells, which are
devoid of naïve T-cells and represent a subset of memory T-cells, should not be able to
induce GvHD. The study hypothesis is depletion of naïve T-cells from the donor lymphocyte
inoculum will abrogate GVHD while providing immunocompetent memory T-cells to affect an
anti-infection and a graft versus tumor response. In this study, we will determine the
maximum tolerated dose of a naïve T-cell depleted donor lymphocyte infusion given to patients
following HLA-matched allogeneic stem cell transplantation. We will assess the GVHD-inducing
potential of this donor lymphocyte infusion and further monitor the impact that this DLI will
have on post-transplant immune recovery.

Inclusion Criteria:

- Patients who have undergone an alemtuzumab or thymoglobulin-containing allogeneic
transplant procedure from an HLA-identical family donor, or an 8/8 HLA-matched
unrelated donor.

- At least 60 days from day of transplantation.

- Karnofsky performance status 50-100%.

- Donor myeloid engraftment (from peripheral blood or bone marrow) of at least 40%
documented ≤ 60 days from protocol therapy.

- No active acute GvHD ≥ grade II.

- Prednisone (or equivalent corticosteroid) dose ≤ 20mg, daily mycophenolate mofetil
dose ≤2000mg/d and cyclosporine/tacrolimus at ≤ therapeutic blood trough levels.

- No change in dosing of immunosuppressive agents 2 weeks before the naïve T-cell
depleted donor lymphocyte infusion.

- A commitment not to electively taper for a minimum of 60 days, the immunosuppressive
medications ongoing at time of naïve T-cell depleted donor lymphocyte infusion.

- No extensive chronic GvHD.

- Age ≥ 18 years of age.

Exclusion Criteria:

- Pregnant or lactating women.

- Patients with other major medical or psychiatric illnesses, which the treating
physician feels, could seriously compromise tolerance to this protocol.