In adults, the routine use of haploidentical donors is limited by the delayed immune recovery and high transplant-related mortality (TRM). We conducted a phase I-II trial for pts with advanced hematological malignancies, employing a reduced intensity conditioning (RIC) regimen [thiotepa (10 mg/kg), fludarabine (120 mg/sqm), cyclophosphamide (60 mg/kg) and TBI (2 Gy)] with early add-backs of CD8-depleted donor lymphocyte infusions (DLIs) (from 1x10^4 up to 1x10^5 cells/kg starting at day +45 up to day +105 at monthly intervals) with the aim of improving immune reconstitution and thus reducing TRM. Ex.-vivo and in-vivo TCD were carried out by CD34+ cell selection using the CliniMACS device and alemtuzumab (15mg/m², day-2), respectively. Twenty patients were included [n= 11 NHL (n=5 CLL, n=6 high-grade NHL), n=6 HD, n=1 MM, n=1 ALL, n=1 AML], median age was 35 years (range, 15-65), 14 (70%) pts were chemorefractory and 6 (30%) were chemosensitive. Pts received a median of 10.4x10^6/Kg CD34+ and 1x10^4/kg CD3+ in the graft. All engrafted with full donor chimerism from day + 30. At a median follow-up of 9 months (5-34), 19 pts are evaluable: 14 pts are alive [5 CR (n=1 AML, n=3 CLL, n=1 NHL) and 5 PR] and 5 died (n=1 infection, n=4 disease). The estimated overall survival at 2 years was 62% (95%CI, 35%-89%). Of significance, the TRM at 1 year was 9%. For CD8 depletion of donor leukaphereses, a new depletion protocol using clinical grade CD8 microbeads (Miltenyi) was applied. This procedure is efficient to reduce the content of CD8 T cells by 3 logs while the median cell recovery of CD3+, CD4+, CD56+/CD3+, CD 20+ was 62%, 88%, 51%, 76%, respectively. Before DLIs, only 2 of 19 patients (11%) developed acute GVHD (grade II). A total of 28 CD8-depleted DLIs were administered to 14 pts without any acute toxicity. Following DLIs, 3 pts (21%) developed acute GVHD (grade II) and one patient limited cGVHD. Overall, the incidence of acute GVHD appeared higher (67% vs 0%, P<0.02) in pts receving larger numbers of donor cells (10-25x10^4/kg versus 3-6x10^4/kg CD8-depleted DLIs). The median values of CD4+/uL and CD8+/uL were 102 and 329 at 4 months; 242 and 300 at 5 months after allograft. NK/uL cells were 588 and 477 at 4 and 5 months, respectively. Our results suggest that: (1) haploidentical SCT with RIC regimen is feasible with a high rate of engraftment (2) CD8-depleted DLIs represents a safe and promising tool for improve the immune reconstitution.
|Titolo:||Pre-emptive CD8-depleted donor lymphocyte infusions to overcome long-lasting immune deficiency after haploidentical stem cell transplantation with a reduced-intensity conditioning regimen|
CORRADINI, PAOLO (Primo)
RAGANATO, ANNA (Secondo)
|Settore Scientifico Disciplinare:||Settore MED/15 - Malattie del Sangue|
|Data di pubblicazione:||20-mar-2006|
|Appare nelle tipologie:||01 - Articolo su periodico|