Prophylactic donor lymphocyte infusions after moderately ablative chemotherapy and stem cell transplantation for hematological malignancies: high remission rate among poor prognosis patients at the expense of graft-versus-host disease

Abstract

Summary:We investigated the use of 'prophylactic' donor lymphocyte infusions (DLI) containing 1 ؋ 10 7 CD3 ؉ cells, given at 30, 60 and 90 days post-allogeneic blood and marrow transplantation (BMT), following conditioning with fludarabine 30 mg/m 2 /4 days and melphalan 70 mg/m 2 /2 days. GVHD prophylaxis consisted of cyclosporin A (CsA) 2 mg/kg daily with early tapering by day 60. Our goals were the rapid achievement of chimerism and disease control, providing an immunological platform for DLIs to treat refractory patients with hematological malignancies. Twelve heavily pre-treated patients with life expectancy less than 6 months were studied; none were in remission. Diagnoses were AML (n ‫؍‬ 4), MDS (n ‫؍‬ 1), ALL (n ‫؍‬ 3), CML (n ‫؍‬ 3) and multiple myeloma (n ‫؍‬ 1). Response rate was 75%. Three patients are alive at a median of 450 days (range, 450-540). Two patients are in remission of CML in blast crisis and AML for more than 14 months. Median survival is 116 days (range, 25-648). Six patients received 12 DLIs; three patients developed acute GVHD after the first infusion and were excluded from further DLIs, but no GVHD occurred among patients receiving subsequent DLIs. One patient with CML in blast crisis went into CR after the first DLI. The overall incidence of acute GVHD was 70%. Primary causes of death were infections (n ‫؍‬ 3), acute GVHD (n ‫؍‬ 3), chronic GVHD (n ‫؍‬ 1) and disease relapse (n ‫؍‬ 2). We observed high response and chimerism rates at the expense of an excessive incidence of GVHD. DLI given at day ؉30 post BMT caused GVHD in 50% of the patients, and its role in this setting remains unclear. The therapeutic benefit of allogeneic BMT is in part related to an immunological graft-versus-leukemia (GVL) effect that frequently evolves in the context of graft-versus-host disease (GVHD). The ability of donor lymphocytes to induce remission in patients relapsing after allogeneic transplantation illustrates the potency of this effect.1 Establishing donor-recipient tolerance with less toxic regimens may provide the basis for further immunological manipulations in order to maximize the GVL effect. However, rapidly evolving diseases may not be amenable to this strategy, considering that the immune-mediated elimination of malignant cells may take weeks or months to occur. This fact suggests the need for strategies to reinforce the immune-mediated phenomena in the post-transplant period.Groups in Jerusalem and Houston pioneered the use of sub-lethal doses of fludarabine-based conditioning regimens. These regimens have been shown to be less toxic and to provide enough immunosuppression to prevent graft rejection and establish stable mixed or complete chimerism.2,3 The combination of melphalan and fludarabine has enabled allogeneic stem cell engraftment in the majority of patients treated, at least in the setting of HLA-identical transplantation. Patients with refractory relapses of advanced leukemias appear to benefit the least.

Outcome of conditioning intensity in acute myeloid leukemia with monosomal karyotype in patients over 45 year‐old: A study from the acute leukemia working party (ALWP) of the European group of blood and marrow transplantation (EBMT)

“…In our cohort restricted to very bad-risk leukemia, we observed a reasonable long-term survival, with a relapse incidence of 50%. To improve outcomes, efforts have to be made to harness a graft-versus-leukemia effect after allogeneic SCT, by either early immunosuppression withdrawal, use of prophylactic donor leukocytes infusion [32], administration of some immunomodulatory drug such as azacytidine [33], or combination of those strategies.…”

Long-term results of adjuvant donor lymphocyte transfusion in AML after allogeneic stem cell transplantation

“…4 The interval of 4120 days after alloSCT seems to be suitable to reduce the incidence of severe GvHD, while preventing early relapses. The study of de Lima et al, 14 applying prophylactic DLTs at day +30, reported an incidence of GvHD of 50%, indicating that a short interval from transplantation to DLT may incorporate a high GvHD risk. Furthermore, the optimal interval between the courses of aDLTs remains to be established as this interval varies widely in published studies.…”

“…14,15 Our data represent, by far, the largest study on the use of aDLT in high-risk AML after RIC with long-term follow-up and incorporate a well-matched control group. Abbreviation: aDLT = adjuvant transfusion of donor lymphocyte.…”

“…Furthermore, the optimal interval between the courses of aDLTs remains to be established as this interval varies widely in published studies. 10,14,17,18 Alternatively, to the truly adjuvant application, DLT may also be administered in a preemptive setting guided by mixed chimerism or the detection of minimal residual disease. 10,15,19,20 In our study, five patients are included who have been treated with DLT in a preemptive setting.…”

Subclinical GvHD in non-irradiated F1 hybrids: severe lymphoid-tissue GvHD causing prolonged immune dysfunction

“…3 Indeed, abatement of conditioning-induced inflammation is thought to contribute to the observed reduced GvHD risk when DLI is delayed with several weeks or months after a transplant. [4][5][6][7][8][9] In contrast, the GvL response of DLI has been shown in mice to result from the interaction between donor T cells and recipient APC in the lymphohematopoietic tissues, resulting in a lymphohematopoietic GvH reaction (LHGvHR). 2 In mice, mixed chimerism and a LHGvHR with conversion of mixed to full donor chimerism have been shown essential for GvL responses after DLI.…”