A phase II study of sirolimus, tacrolimus and rabbit anti-thymocyte globulin as GVHD prophylaxis after unrelated-donor PBSC transplant

Abstract

We report on a prospective phase II trial of 32 patients who underwent unrelated donor hematopoietic cell transplantation, with a tacrolimus, sirolimus and rabbit anti-thymoctye globulin GVHD prophylactic regimen. The primary study endpoint was incidence of grades II-IV acute GVHD, with 80% power to detect a 30% decrease compared to institutional historical controls. Median age at transplant was 60 (19-71). Twenty-three patients (72%) received reduced-intensity conditioning, while the remainder received full-intensity regimens. Median follow up for surviving patients was 35 months (range: 21 - 49). The cumulative incidence of acute GVHD was 37.3% and the 2-year cumulative incidence of cGVHD was 63%. We observed TMA in seven patients (21.8%), one of whom also developed sinusoidal obstructive syndrome (SOS). Four patients of 32 (12.5%) failed to engraft, and three of these four died. As a result, enrollment to this trial was closed before the targeted accrual of 60 patients. Two-year overall survival was 65.5% and event-free survival was 61.3%. Two-year cumulative incidence of relapse was 12.5% and non-relapse mortality (NRM) was 15.6%. NRM and aGVHD rates were lower than historical rates; however, the unexpectedly high incidence of graft failure requires caution in the design of future studies with this regimen.

Risk factors for thrombotic microangiopathy in allogeneic hematopoietic stem cell recipients receiving GVHD prophylaxis with tacrolimus plus MTX or sirolimus

“…Unlike previously published evidence, 17,18,21,22 the combination of TAC and SIR did not appear to pose a higher risk of TA-TMA than with TAC/MTX±ATG. These results are in agreement with a retrospective study in which the incidence of TA-TMA in patients who were given TAC/SIR ± ATG was not significantly different from that in patients who received MTX with TAC or CYA (10.2% vs 4.3%), 23 or with those of a recently randomized phase II trial comparing TAC/SIR with TAC/MTX, 24 although the high incidence of TA-TMA reported in this latter trial (24.3% with TAC/SIR and 18.9% with TAC/MTX) should be noted.…”

“…1,3,5,8,[10][11][12][13][14] The use of TAC plus SIR as GVHD prophylaxis has been associated with an increased incidence of TA-TMA, which ranges from 10.8-55%, the latter in patients who received BU plus CY as part of their conditioning regimen. [17][18][19]21,22 In a recent phase II multicenter prospective trial conducted by our group, including some of the patients in this study, no differences were observed in the incidence of TA-TMA when TAC/SIR was compared with patients included in a prior prospective trial using CYA-mycophenolate (the overall incidences of TA-TMA were 10% and 6%, respectively). 25 In addition, very few studies 23,24 have evaluated the risk of TA-TMA among patients receiving the TAC/SIR combination in comparison with other TAC-based regimens.…”

“…16 The combination of TAC and SIR (TAC/SIR) in both solid organ transplantation and HSCT is associated with an increased risk of TA-TMA in some studies. [17][18][19][20][21][22] Moreover, few comparisons of TAC/ SIR with other TAC-based regimens have been reported. In fact, two recent studies suggest that TA-TMA incidence does not differ significantly between patients who received TAC/SIR and those who received TAC/MTX for GVHD prophylaxis.…”

The potential role of HLA-DRB1*11 in the development and outcome of haematopoietic stem cell transplantation-associated thrombotic microangiopathy

“…2-4 Several publications indicated that the risk of TA-TMA was substantially higher with the combination of TAC and sirolimus. [13][14][15] In our cohort, no higher risks with TAC and sirolimus combinations were observed compared with other TAC-containing regimens, in line with findings of Labrador et al 11 With regards to conditioning intensity, reports demonstrate controversial results. 2,5,[10][11][12] In this study, we detected an increased risk of TA-TMA, when MAC was applied.…”

“…1 Although the exact pathophysiology remains unclear, endothelial dysfunction with platelet activation and formation of platelet-rich thrombi in the microcirculation are regarded as key elements, leading to platelet consumption, mechanical damage to red blood cells and secondary organ damage. 2, 3 The role of predisposing risk factors has been addressed, 2,4-6 such as female gender, 7,8 older age, 9,10 lymphoid malignancy, 11 unrelated donor, 7,10 HLA mismatch, 9 conditioning and immunosuppressive regimens, 7,[10][11][12][13][14][15][16] infections, 3,9,11,17 acute GvHD (aGvHD) 7,[10][11][12]17,18 and ABO incompatibility. 19 Acquired idiopathic thrombotic thrombocytopenic purpura (TTP) also belongs to the family of thrombotic microangiopathies.…”