Leuprolide Acetate (GnRH Agonist) to Enhance Immune Function Post-Autologous Hematopoietic Stem Cell Transplantation (HSCT)

Adult patients receiving myeloablative autologous peripheral blood progenitor cell transplantation for lymphoma, Hodgkin's disease or multiple myeloma were eligible. Females and males, age 18–50 and 18–65 years, respectively, were included. Patients were required to be in remission or have chemosensitive relapse. Patients could not have received mediastinal radiation, or recent testosterone or estrogen treatment, or post transplant therapy that would affect immune function. Patients were randomized to receive 3 intramuscular injections of leuprolide acetate (Lupron 11.25 mg 3 Month Depot) or placebo approximately 3 months apart to cover the period from the date of transplantation to 8 months post HSCT. The primary endpoint was in vitro antibody and T cell response to vaccination with keyhole limpet haemocyanin (KLH) at 6 months post-HSCT. Immunoglobulins were measured by ELISA and interferon-gamma (IFNγ) by ELISpot.

25 subjects (19 males and 6 females) were enrolled into the study at 3 sites. 13 were randomized to placebo and 12 to leuprolide treatment. As expected, suppression of luteinizing hormone and total testosterone was observed in males in the leuprolide acetate group at all evaluation time points during treatment (P<0.1 vs. placebo). There was no significant difference in time to engraftment or in the adverse events and transplant related toxicities experienced by the leuprolide or the placebo group. One subject in the leuprolide acetate group died during the study due to pneumonia after hematopoietic recovery, which was not considered related to study drug. Early disease progression occurred in one patient in the leuprolide acetate and 3 in the placebo group. The study was closed due to slow patient accrual.

9 patients in each group completed 6 months on study. 8 patients in the leuprolide group and 5 in the placebo group received KLH vaccination and were evaluable for response one month later. There were significantly improved IgM and IgG1 responses in the leuprolide group; no significant difference was detected for IgG2, IgG3, IgG4 and IFNγ responses. The following table shows the difference in the assays performed prevaccination and 1 month post vaccination.

The output of naïve T-cell subsets and the production of TCR rearrangement excision circles (TRECs) were determined at screening, and post HSCT. There was an increase in naïve CD4+ TREC positive cells at the 6 month time point consistent with renewed thymus function.

Despite the limited number of patients, there was a trend to increased antibody responses to the de novo antigen KLH, which reached statistical significance for IgM and IgG1, reflecting increased primary and secondary immune responses. Another indicator of thymus function was the appearance of circulating naïve, TREC+ CD4+ cells at 6 months in the leuprolide acetate group. Further study of sex steroid inhibition is needed to fully establish the enhanced thymic function and immune reconstitution following HSCT.

Off Label Use: Leuprolide (Lupron) to enhance immune recovery after stem cell transplantation. Jiang:Abbott: Employment, Equity Ownership. Chwalisz:Abbott: Employment, Equity Ownership. Mattia-Goldberg:Abbott: Employment, Equity Ownership. Sajwani:Abbott: Employment, Equity Ownership. Boyd:Norwood Immunology: Employment.