Low-Dose Total Marrow Lymphoid Irradiation (Tmli) For Donor Chimerism Before T-Replete Haploidentical Transplantation

Nonmyeloablative (NMA) T replete haploidentical transplantation (TR-H) has been increasingly applied in high-risk hematologic patients when a HLA-matched donor was absent. Some data suggested that the outcome was similar to those obtained with matched related bone marrow transplantation, mainly in lymphoproliferative diseases. Recently, the Baltimore group reported a low dose TBI-based NMA regimen followed by T cell replete bone marrow, with post-infusion cyclophosphamide (Cy) to control graft versus host disease (GVHD) and graft rejection. The aims of the study were to evaluate the engraftment and chimerism of a NMA regimen containing low dose TMLI instead of TBI, in patients with advanced disease and bone marrow involvement. Since January 2009, patients received a TR-H at our institution. NMA or reduced intensity conditioning (RIC) regimen was used in 66 patients. For 12 patients (18%), TMLI (2 Gy) was used instead of TBI with advanced malignancies. The median age was 41 years (range 22-68). NMA consisted of fludarabine (30 mg/m2/day) on day -6 to -2, Cy (14.5 mg/kg/day) on days -6 and -5, total marrow and lymphoid irradiation (200 cGy in a single fraction) on day -1, followed by bone marrow or peripheral blood stem cell graft in all patients. Post engraftment immunosuppression consisted of Cy (50 mg/kg/day) on days +3 and +4, mycophenolate mofetil for 30 days, and tacrolimus or cyclosporine A. Median age was 41y (22-68y). 50% had Hodgkin’s lymphoma. Immediate tolerance was good and no patients developed nausea or vomiting or parotid hyperplasia. No patients had oral mucositis. The median time to ANC >500/μL, and platelet recovery >20,000/μL was 22 and 30 days, respectively, and this was not different from data obtained with conventional low grade TBI (data not shown). Full donor chimerism was evident at day 30 in all evaluable patients (11/12). Two (17%) patients developed acute GVHD ≥2 and four (33%) patients developed limited chronic GVHD. Four of 12 (33%) died because of: PML, invasive lung aspergillosis, liver failure and pneumonia. Two (17%) patients died due to disease progression and 6 patients are alive in complete remission after a median follow-up time of 15 (2-25) months. This analysis suggests that TMLI could substitute conventional low dose TBI, with recipient immunosuppression, allowing engraftment and full donor chimerism. The mortality due to toxicity was felt to be due to poor patients’ characteristics.