Favorable outcomes of tacrolimus compared with cyclosporine A for GVHD prophylaxis in HSCT for standard-risk hematological diseases

Abstract

Although calcineurin inhibitors (CNIs) with short-term methotrexate (stMTX) constitute standard prophylaxis for graft-versus-host diseases (GVHD) in hematopoietic stem cell transplantations (HSCT), comparative efficacy of cyclosporine A (CsA) and tacrolimus (Tac) still remains unclear. We have altered GVHD prophylaxis for standard-risk hematological malignancies from CsA (target trough level, 500 ng/mL) to Tac (15 ng/mL) both with stMTX in May 2008, enabling us to compare the efficacy of CNIs with little selection biases. The cumulative incidence of acute and chronic GVHD was comparable for CsA and Tac. Among the GVHD low-risk patients who received stem cells from matched sibling donors or cord blood, the Tac arm had a trend for favorable control of grade III-IV acute GVHD (6.7 vs. 30.0 %, p = 0.2), which may contribute to the significantly better overall survival (p = 0.048) and relapse-free survival (p = 0.043) in that group. Inadequate concentration of CNIs in early phase of HSCT affected the cumulative incidence of acute GVHD in the CsA but not in the Tac arm. There were no differences in the GVHD incidence and survival outcomes between CsA and Tac in the GVHD high-risk subgroup. This study underlies the significance of maintaining adequate CsA concentration in standard-risk HSCT.

Role of Toll‐like receptor 4 signaling in cutaneous chronic graft‐versus‐host disease

“…All of these manifestations were characterized by an exaggerated and immoderate inflammatory response . Although corticosteroid, a non‐specific anti‐inflammatory drug, alone or in combination with tacrolimus or cyclosporine , has been a common treatment for established cGVHD , its efficacy needs to be improved. Furthermore, the inevitably adverse effects promote the development of more specific anti‐inflammatory drug.…”

“…It is widely recognized that the activation and expansion of autoreactive CD4+ T cells is a pivotal process in cGVHD . Recent studies have reported that TLR stimulation on DCs or T cells is necessary for this induction of T‐cell expansion.…”

Time now toTORCtheTORC? New developments in mTORpathway inhibition in lymphoid malignancies

“…Rapamycin and its analogues (rapalogs) have traditionally been used as immunosuppression post‐solid organ transplant (SOT; Webster et al , ) and as graft‐versus‐host‐disease (GVHD) prophylaxis post‐haematopoietic stem cell transplantation (HSCT; Alyea et al , ; Nasu et al , ). First generation mammalian target of rapamycin (mTOR) inhibitors have had limited success in treating haematological cancer.…”

Roles of IL-2 in bridging adaptive and innate immunity, and as a tool for cellular immunotherapy

“…It was first shown that inhibition of the phosphatase activity of CN using the fungal isolate cyclosporine A (CsA) or the synthetic inhibitor FK506 resulted in impaired NFAT signaling, 8,16 leading to reduced expression of IL‐2, and an efficient immunosuppressive effect 16 . These immunosuppressive therapeutic approaches have since revolutionized the field of organ transplantation, reducing the rejection of solid grafts, 17 and limiting graft‐versus‐host disease (GVHD) in hematopoietic stem cell transplant recipients 18,19 . The success of CN inhibitors in the transplantation setting led to trials and eventual widespread use of CsA and FK506 in other pathologies, including psoriasis, eczema, rheumatoid arthritis, and Crohn's disease 20 .…”