Rapid Clearance of CMV-Antigenemia with Combination Treatment of Foscarnet and Leflunomide in a 2-Year Old Boy with Refractory CMV Disease after Allogeneic HSCT for JMML.

Introduction CMV disease post allogeneic hematopoietic stem cell transplantation is still associated with high mortality. Antiviral treatment is most commonly based on the use of ganciclovir, foscarnet and cidofovir, either alone or in combination. However, the toxicity profile of these drugs and the development of CMV-resistance to these agents are well-known problems in transplant recipients. Leflunomide is currently most often used in the therapy of patients with rheumatic diseases because of its antiproliferative capacity. The supposed mechanism of action with regard to its reported antiviral activity is the inhibition of the enzyme dihydro-orotate dehydrogenase and inhibition of phosphorylation of specific tyrosine kinases involved in B- and T-cell activity.

Case report A 1 1/2 year old male child was diagnosed with JMML in spring 2004 and underwent allogeneic HSCT from a MMUD (bone marrow) in July 2004. A first episode of CMV reactivation two months post-transplant could finally be controlled with the use of cidofovir. Prior to cidofovir, the patient had been treated with foscarnet and ganciclovir, which had not resulted in CMV clearance. Late graft rejection led to a second transplant with PBSC of the same donor in January 2005. Both recipient and donor were CMV positive. Since day +1 of his second transplant, the boy had been on prophylactic aciclovir. CMV-PCR became positive three weeks later. With regard to the graft rejection three months earlier, the early post-transplant period and the previously successful therapy with cidofovir we chose to switch him to cidofovir with a dose of 5mg/kg body weight once weekly. However, CMV-PCR and pp65-antigenemia were constantly rising in the following four weeks and finally reached a number of >100.000 copies/ml for the PCR and 490 pp65-positive cells/10E5 nucleated cells. By this time, the child had developed daily, high-spiking fevers, but otherwise did not reveal symptoms of CMV organ disease. Other causes of his febrile state could be ruled out. As ganciclovir is reported to yield in a higher rate of hematological toxicity than foscarnet or cidofovir, we proposed to the parents the use of leflunomide in combination with foscarnet (3x60mg/kg body weight daily) and CMV-immunoglobulins (1g/kg body weight every other day). After having obtained informed consent, the boy had a loading dose of leflunomide with 60mg/m² BSA on three consecutive days, followed by maintenance therapy with 10mg/m² BSA daily. Within two weeks the child’s CMV-load dropped to 1560 copies/ml for the PCR and negative results for pp65. The clinical response was excellent and enduring with complete resolution of the patient’s fever in the following four weeks. Leflunomide was tolerated well by the child; no hematological, hepatic or renal toxicity could be observed.

Conclusion Leflunomide is an immunosuppressive agent with anti-CMV-activity and might be of benefit in transplant recipients with CMV disease refractory to conventional therapy. In our patient, leflunomide led to a rapid clearance of CMV in the blood without the occurrence of adverse events.