Intentional donor lymphocyte-induced limited acute graft-versus-host disease is essential for long-term survival of relapsed acute myeloid leukemia after allogeneic stem cell transplantation

Abstract

© F e r r a t a S t o r t i F o u n d a t i o nGvL response in relapsed AML, a rapid, large amplitude immune response is likely to be required, since the fast proliferation rate of an acute leukemia can lead to a high tumor burden, which will suppress the immune response. 19,20 A rapid and profound immune response is, however, likely to come at the cost of GvHD.To maximize the effect of combined cytoreductive treatment and DLI administration, we adopted a therapeutic strategy for post-allogeneic SCT relapsed AML based on disease control by salvage re-induction chemotherapy followed by DLI administration in the neutropenic phase. The pro-inflammatory milieu after chemotherapy might favor the induction of the immune response, whereas the expansion of infused donor cells is promoted by lymphopenia-induced homeostatic proliferation. 21,22 If no acute GvHD was observed within 3 weeks after DLI, the immune response was further stimulated by treatment with interferon-α. 23 We hypothesized that the combination of efficient cytoreduction by re-induction therapy for initial disease control, with DLI administered in rapid succession under circumstances favoring the development of an early and profound immune response may be essential to eradicate relapsed leukemia, but likely at the cost of GvHD. 24 Methods Data collectionBetween January 2000 and January 2010, 44 patients with relapsed AML after allogeneic SCT were treated. The patients were categorized according to their pre-transplant disease characteristics as having intermediate-risk, poor-risk, or very poor-risk AML (see Online Supplementary Methods). The study was approved by Leiden University Medical Center Research Ethics Committee. Informed consent was obtained from the patients prior to data collection. Data were analyzed as of November 2012. Transplantation protocolDetails about the transplantation protocols, T-cell depletion, donor matching, and diagnosis and treatment of GvHD are provided in the Online Supplementary Methods section. RelapseRelapse after allogeneic SCT was defined as an increase of morphologically determined blasts in the bone marrow to 5% or more, and/or by the presence of more than 1% blasts in peripheral blood, and/or by the reappearance of molecular and/or cytogenetic markers. Further details and definitions of smoldering relapse and high tumor burden relapse are provided in the Online Supplementary Methods section. Treatment strategies for relapsePatients with a poor performance status, defined as WHO performance status 3 or higher, and/or with severe GvHD requiring systemic immunosuppression at the time of relapse were unlikely to benefit from an intensive DLI-based strategy and received palliative treatment only.Patients with high tumor burden relapse received salvage reinduction therapy prior to infusion of donor lymphocytes. If a patient responded to re-induction therapy, with response being defined as absence of circulating leukemic blasts, unmanipulated donor lymphocytes collected from the original donor were administered 3 ...

Allo‐reactive T cells for the treatment of hematological malignancies

“…If initially profound T cell depletion is applied to prevent development of GVHD, the GVL reactivity must be reintroduced by postponed DLI. Balance between the beneficial GVL reactivity and GVHD is dependent on the dose of infused T cells and the time interval between transplantation and DLI and is obviously also dependent on the immunogenetic mismatch between donor and recipient (Barge et al., 2003; Eefting et al., 2014a, 2014b). At the time of stem cell transplantation early after conditioning of the patient inflammatory conditions, lymphopenia of the patient, and the high frequencies of patient derived activated APCs, will lead to profound immune responses which are likely to include clinical signs of GVHD.…”

Selective graft-versus-leukemia depends on magnitude and diversity of the alloreactive T cell response

“…T cell depletion of the graft can prevent GVHD but also impairs development of the associated GVL effect (5,6). Persistent or recurring malignant hematopoietic cells after allo-SCT will then require elimination by subsequent donor lymphocyte infusion (DLI) (7)(8)(9)(10)(11)(12). The observation that T cell depletion followed by postponed DLI reduces the development of GVHD after alloSCT can be explained by the timing of DLI, when prealloSCT chemotherapy-induced tissue damage and infections have largely been resolved, the "cytokine storm" has subsided, and patient-derived antigen-presenting cells (APC) that can induce an immune response are gradually being replaced by donor APCs (3,12,13).…”

Lymphodepleting chemotherapy with donor lymphocyte infusion post-allogeneic HCT for hematological malignancies is associated with severe, but therapy-responsive aGvHD

“…Some groups have administered interferon-alpha to promote GVHD in hopes of improving disease response. ( 16 , 17 ) DLI has been given along with chemotherapy and concurrent immunosuppression to reduce GVHD rates. Using this approach, Yan et al reported higher CR rates compared to chemotherapy alone, suggesting that despite the post-DLI immunosuppression, the GVL effect was still clinically evident.…”