Acute graft-versus-host disease ( GVHD ) remains a barrier to more widespread application of allogeneic haemopoietic stem-cell transplantation.
Vorinostat ( Zolinza ) is an inhibitor of histone deacetylases and was shown to attenuate GVHD in preclinical models.
The aim of the study was assessed the safety and activity of Vorinostat, in combination with standard immunoprophylaxis, for prevention of GVHD in patients undergoing related-donor reduced-intensity conditioning haemopoietic stem-cell transplantation.
During the period 2009-2013, researchers did a prospective, single-arm, phase 1/2 study at two centres in the USA. Adults ( aged 18 years or more ) with high-risk haematological malignant diseases who were candidates for reduced-intensity conditioning haemopoietic stem-cell transplantation and had an available 8/8 or 7/8 HLA-matched related donor, were recruited.
All patients received a conditioning regimen of Fludarabine ( Fludara ) ( 40 mg/m2 daily for 4 days ) and Busulfan ( Busilvex ) ( 3.2 mg/kg daily for 2 days ) and GVHD immunoprophylaxis of Mycophenolate mofetil ( CellCept ) ( 1 g three times a day, days 0-28 ) and Tacrolimus ( Prograf ) ( 0.03 mg/kg a day, titrated to a goal level of 8-12 ng/mL, starting day -3 until day 180 ).
Vorinostat ( either 100 mg or 200 mg, twice a day ) was initiated 10 days before haemopoietic stem-cell transplantation until day 100.
The primary endpoint was the cumulative incidence of grade 2-4 acute GVHD by day 100.
50 patients were assessable for both toxic effects and response; eight additional patients were included in the analysis of toxic effects.
All patients engrafted neutrophils and platelets at expected times after haemopoietic stem-cell transplantation.
The cumulative incidence of grade 2-4 acute GVHD by day 100 was 22%.
The most common non-haematological adverse events included electrolyte disturbances ( n=15 ), hyperglycaemia ( n=11 ), infections ( n=6 ), mucositis ( n=4 ), and increased activity of liver enzymes ( n=3 ).
Non-symptomatic thrombocytopenia after engraftment was the most common haematological grade 3-4 adverse event ( n=9 ) but was transient and all cases resolved swiftly.
The administration of Vorinostat in combination with standard GVHD prophylaxis after related-donor reduced-intensity conditioning haemopoietic stem-cell transplantation is safe and is associated with a lower than expected incidence of severe acute GVHD.
Future studies are needed to assess the effect of Vorinostat for prevention of GVHD in broader settings of haemopoietic stem-cell transplantation. ( Xagena )
Choi SW et al, The Lancet Oncology 2014; 15: 87-95