Allogenic Peripheral Blood Stem Cell Transplant Utilizing Rabbit Anti-Thymocyte Globulin as a Part of Non-Myeloablative Conditioning Therapy.

Background - Allogenic hematopoietic stem cell transplant results in significant transplant related morbidity and mortality, even with matched related donors. Transplant related mortality for matched related donor allogenic transplantation approaches 15–30% at one year, primarily resulting from the toxicities associated with the conditioning therapies, as well as from complications arising from acute graft versus host disease (GVHD.) Non-myeloablative conditioning therapy (NMACT) was developed to decrease morbidity and mortality associated with traditional conditioning regimen as also to help in establishment of a mixed lympho-hematopoietic chimera which could mediate a graft versus tumor effect that could be of therapeutic benefit.

Objective - We report our experience with Rabbit anti-thymocyte globulin (ATG) [Thymoglobulin/Sangstat] as part of the pre-transplant immunosuppressive regimen for allogenic peripheral blood stem cell transplantation.

Methods - 6 patients were enrolled between January 2001 and February 2003 in our study. NMACT used fludaribine, cyclophosphamide and rabbit ATG (Thymoglobulin/Sangstat.) Two dose levels of rabbit ATG were used:- 2.3 mg/kg and 1.5 mg/kg. Cyclosporine was also utilized as primary prophylaxis for GVHD prevention. Patients were assessed for clinical and cytogenetic remission at Day + 100 and at 1 year post-transplantation. Development of infectious complications as well as GVHD was measured.

Results - The mean age of patients was 56.67 years. There were 4 males and 2 females in the study group. Two patients carried the diagnosis of CLL and one each of CML, Myelfibrosis, Myelodysplasia and anaplastic lymphoma. Four out of six patients achieved complete remission at day + 100.Three patients were in continued remission at one year. Two patients had a partial response on day + 100. One patient developed progressive disease with Richter’s transformation of CLL and died of liver failure on day + 179. One out of six patients developed grade IV GVHD. He received steroids but went on to develop disseminated aspergillosis and expired on day + 216. The first two patients enrolled in the study received a higher dose of ATG i.e. 2.3 mg/kg and were noted to have a higher rate of infectious complications. One developed CMV pneumonia and retinitis as well as methicillin resistant staphylococcus aureus and herpes virus infection. She expired on day + 362. For subsequent enrollees the dose of ATG was decreased to 1.5 mg/kg. Of the three surviving patients one is 43 months post-transplant while the other two are 19 and 18 months post-transplant respectively. All six patients had achieved mixed chimerism on day + 100 (and also at 1 year in the three surviving patients.)

Conclusions - Rabbit ATG is well tolerated as part of NMACT for allogenic BMT. It leads to adequate immunosuppression with development of mixed chimera and subsequently full chimerism. Higher doses appear to be associated with increased morbidity, especially infectious complications. Lower doses appear to be as efficacious in achieving mixed chimera and appear to be well tolerated. These observations suggest that additional studies of larger cohorts of patients at alternative dose levels should be undertaken to determine the most appropriate dose of ATG.