Effect of KGF (Palifermin) On Immune Reconstitution After Autologous Transplantation for Multiple Myeloma.

Human-keratinocyte growth factor 1(KGF) is currently being evaluated in clinical trials for its safety and efficacy in preventing mucosal damage from irradiation and after bone marrow transplantation (BMT). It has been suggested that, besides having preventive effects on oral mucositis, it may also have immunomodulating effects by uniquely protecting thymic epithelial cells. A potential clinical application of KGF is the amelioration of prolonged post BMT-immune deficiency in BMT recipients. In animal models of autologous and allogeneic BMT, KGF administration during BMT resulted in enhanced thymopoiesis and increased peripheral T-cell numbers. Therefore, a potential clinical application of KGF is the improvement of prolonged post BMT-immune deficiency in BMT recipients. Thymopoiesis can be assessed by analysis of T-cell receptor excision circles (TREC). This marker for recent thymic emigrants might be a novel prognostic factor for outcome after transplantation in multiple myeloma patients. We investigated the potential influence of KGF on immune reconstitution after autologous transplantation for myeloma using this marker.

Twenty-four myeloma patients from a single institution were treated homogeneously with the induction combination bortezomib (Velcade®) plus dexamethasone (DXM), followed by high dose melphalan (140-200 mg/m²) and an autologous transplantation with peripheral blood stem cells. Patients were randomized for KGF treatment in 2 groups, 11 having received three doses of palifermin (Kepivance®) (60 μg/kg once daily i.v.) pre- and post-conditioning regimen (total six doses). Blood samples were drawn at diagnosis, before BMT, and at 1, 3, 6, 9, 12 and 18 months post BMT. We analysed signal joint (sj) TREC in peripheral blood lymphocytes using quantitative RT-PCR. The percentage and absolute numbers of lymphocyte populations were monitored by flow cytometry. Values were expressed as means ± SEM. Patient groups were compared by the Mann-Whitney test.

Both CD4+ and CD8+ naïve T cells (CD45RA+ CCR7+) were strongly decreased by pretransplantation bortezomib plus DXM treatment. SjTREC decreased sharply after transplantation and returned to baseline after 1 year without differences between the two groups of patients. Natural regulatory T lymphocytes (phenotypically assessed as CD4+ CD25 ^high, CD127 ^low) were not modified by KGF treatment either. Notably, the CD3+ cell population was significantly higher during the first 3 months post BMT in KGF treated patients (1518 ± 380 vs 821 ± 105 CD3+/blood mL, p = 0.032 at 1 month post BMT). This was related to a higher CD8+ cell counts, specifically in the CD8 effector memory cells (assessed as CD45 RA- CCR7-) (790 ± 320 vs 292 ± 55, p< 0.05 at 1 month post BMT). No correlation was found with documented infectious complications, relapse or survival.

These data suggest that, unexpectedly, the main effect of KGF on immunity in that autologous BMT setting, is not to be accounted by changes in thymic function but rather by the peripheral expansion of CD8+ effector memory cells which could be favoured by the treatment prior BMT and/or by the post-BMT lymphopenia.

No relevant conflicts of interest to declare.