Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation

Abstract

A sequential regimen of chemotherapy, reduced-intensity conditioning (RIC) for allogeneic stem cell transplantation (SCT), and prophylactic donor lymphocyte transfusion (pDLT) was studied in 103 patients with refractory acute myeloid leukemia (AML). According to published criteria, refractoriness was defined by primary induction failure (PIF; n ‫؍‬ 37), early (n ‫؍‬ 53), refractory (n ‫؍‬ 8), or second (n ‫؍‬ 5) relapse. Chemotherapy consisted of fludarabine (4 ؋ 30 mg/m 2 ), cytarabine (4 ؋ 2 g/m 2 ), and amsacrine (4 ؋ 100 mg/ m 2 ), followed 4 days later by RIC, comprising 4 Gy total body irradiation (TBI), cyclophosphamide, and antithymocyte globulin. Patients without graft-versus-host disease (GvHD) at day ؉120 received pDLT in escalating doses. Patients' median age was 51.8 years. Before conditioning, 99 patients had active disease, 3 were aplastic, 1 was in second complete remission (CR2). Forty-one patients had family donors, 62 had unrelated donors. With a 25-month median follow-up, overall survival (OS) at 1, 2, and 4 years was 54%, 40%, and 32%; the respective leukemiafree survival (LFS) was 47%, 37%, and 30%. Patients with PIF showed a 2-year OS of 62.5%. OS was 87% in 17 patients receiving pDLT. One-year cumulative incidence of leukemic death and non-relapsemortality was 28.7% and 17.2%. In a multivariate analysis, more than 2 courses of prior chemotherapy were the strongest predictor for poor outcome (P ‫؍‬ .007; HR ‫؍‬ 3.01 [OS]; P ‫؍‬ .002; HR ‫؍‬ 3.25 [LFS]). These results indicate a high activity of the regimen in refractory AML.

Calcineurin inhibitor-free GVHD prophylaxis with sirolimus, mycophenolate mofetil and ATG in Allo-SCT for leukemia patients with high relapse risk: an observational cohort study

“…However, time to neutrophil engraftment was 6 days longer, as it has been reported with the same regimen and a CYA-based GVHD prophylaxis. 1,2 No significant contributing factor could be identified by Fisher's exact test, but it should be stressed that no granulopoiesisstimulating agents were used. By contrast, no prolonged period of thrombocytopenia was observed.…”

“…It was also lower than in the earlier reported FLAMSA studies utilizing CYA, MMF and ATG as GVHD prophylaxis, and the reported incidence of grades II-IV acute GVHD was 49 and 28% without correction for the competing risk factor death. 1,2 Possibly by enhancing the numbers and function of CD4 þ CD25 þ regulatory T cells, 5 the combination of sirolimus and MMF seems to be a very efficient strategy for prophylaxis of acute GVHD and is at least as effective as CNI-based protocols. The 30% incidence of chronic GVHD is comparable with what we have seen in earlier studies 1,2 utilizing the FLAMSA preparative regimen (32-45%), but is much lower than in those studies (59-90%) that combined CNI and sirolimus.…”

“…1 Also this protocol seems to be rather effective even in refractory leukemia, 2 early relapses remain a serious challenge in very high-risk leukemia. Besides the biological nature of these very high-risk leukemias, immunosuppression after allografting with calcineurin inhibitors (CNIs) might contribute to an increased risk of relapse by interfering with a possible GVL effect.…”

Cytokine Release Patterns in Mixed Lymphocyte Culture (MLC) of T-Cells with Dendritic Cells (DC) Generated from AML Blasts Contribute to Predict anti-Leukaemic T-Cell Reactions and Patients’ Response to Immunotherapy

“…However, graft-versus-host reactions (GVH) of donor T-cells directed against host tissue (e.g. HLA-) antigens can jeopardize the efficiency of SCT or relapse therapy (Kolb et al 1995;Schmid et al 2006;Ferrara et al 2009;Schmid et al 2011;Schmetzer & Schmid 2012). Since cytokines, interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor-necrosis-factor-a (TNF-a) and interferon-c (IFN-c) in particular, are a main part of the pathophysiology of GVHD, they can be monitored and/or used to develop therapeutic strategies (Ferrara et al 2009).…”

“…After reduced intensity SCT in AML in CR, relapse rates between 20% and 55% have been reported, being significantly higher than those observed after myeloablative conditioning . Therapeutic donor lymphocyte infusions (DLI) applied in relapsed patients (pts) after SCT demonstrate the pivotal role of donor T-cells in anti-leukaemic reactions (Kolb et al 1995;Schmid et al 2006;Schmid et al 2011;Schmetzer & Schmid 2012). However, graft-versus-host reactions (GVH) of donor T-cells directed against host tissue (e.g.…”