Mismatched Donor Lymphocyte Infusions for Relapsed Disease Following Allogeneic Stem Cell Transplantation
Patients receiving allogeneic stem cell transplantation for hematological malignancies who
suffer a relapse of their disease post-transplant have limited treatment options and a poor
prognosis. With the exception of patients with chronic leukemias who may achieve prolonged
remissions after donor lymphocyte infusions (DLIs), treatments using either chemotherapy or
a DLI achieve less than a 10% median survival beyond 6 months. Most of these patients die of
progressive leukemia, underlying the need for new therapeutic approaches.
HLA-mismatched DLIs appear to possess a more potent graft-versus-leukemia (GvL) effect.
However, when given after an HLA-mismatched transplant DLIs have a high risk of causing
graft-versus-host disease (GvHD), which can be severe. To reduce the risk of GvHD, infusions
of mismatched lymphocytes from an alternative donor may be used to avoid permanent
engraftment and associated risk of GvHD.
In this study, we propose to use a novel strategy to treat leukemias relapsing after HLA
matched allogeneic stem cell transplantation by using haplo-identical DLIs to promote the
associated antileukemic effect while minimizing the possibility of permanent engraftment and
associated GvHD. To achieve only temporary engraftment and to promote disease control we
will give fludarabine immunosuppression prior to the DLI. We anticipate the infusion of
HLA-mismatched donor lymphocytes in this setting will produce no detectible engraftment or
only temporary engraftment, but may result in a strong GvL effect regardless of engraftment
outcome. We will select patients for this protocol who fall into the worst category for
post-transplant relapse. Specifically, we will enroll patients with acute leukemia or MDS
relapsing within 6 months of transplant, of which less than 5% survive beyond a year from
The primary objective of this phase II clinical trial will be to evaluate the safety and
efficacy of using a non-engraftment model and a lymphocytes infusion from a haplo-identical
donor to treat relapsed disease following matched sibling stem cell transplantation in
subjects who are not candidates for alternative treatment options.
We therefore propose this is a phase II clinical trial is to evaluate the safety and
efficacy of an infusion of unmanipulated lymphocytes from a haplo-identical donor in
subjects with relapsed disease following matched sibling stem cell transplantation who are
not candidates for alternative treatment options.
The primary endpoint of this phase 2 study is survival at 6 month post-relapse of disease.
Successful outcome of the study will be a survival of 100% greater than the NHLBI historical
25% at 6-months.
Secondary endpoints will include: incidence and severity of induced GvHD, proportion of DLI
engraftment, peak chimerism, leukemia response at 21 days post DLI, residual leukemia
measured by patient chimerism, leukemia free survival from date relapse, and safety of the
mismatched DLI procedure.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment
Overall survival at 6-month post-relapse time point.
Minocher M Battiwalla, M.D.
National Heart, Lung, and Blood Institute (NHLBI)
United States: Federal Government
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