A phase II pilot study of tacrolimus/sirolimus GVHD prophylaxis for sibling donor hematopoietic stem cell transplantation using 3 conditioning regimens

Abstract

Combination tacrolimus and sirolimus graft-versus-host disease (GVHD) prophylaxis for allogeneic transplant in patients conditioned with a fractionated total body irradiation-based regimen has shown encouraging results. We studied this prophylaxis combination in 85 patients receiving a matched-sibling transplant conditioned with 3 different regimens: fludarabine-melphalan (n ‫؍‬ 46); total body irradiation-etoposide (n ‫؍‬ 28), and busulfan-cyclophosphamide (n ‫؍‬ 11). The conditioning regimens were completed on day ؊4. Sirolimus and tacrolimus were started on day ؊3 to avoid overlap with conditioning therapy. All patients engrafted, with a median time to neutrophil engraftment of 15 days. The cumulative incidence of acute GVHD grades II to IV and III to IV was 43% and 19%, respectively, with no significant difference by conditioning regimen. The 2-year cumulative incidence of chronic GVHD was 46%. With a median follow-up of 26 months, disease-free survival was 58% and overall survival, 66%. The day-100 and 2-year nonrelapse mortality was 4.8% and 10.2%, respectively. The overall incidence of thrombotic microangiopathy was 19%, and it was significantly higher with busulfan/cyclophosphamide (55%, P ‫؍‬ .005). Tacrolimus plus sirolimus is an effective combination for acute GVHD prophylaxis and is associated with very low nonrelapse mortality. Thrombotic microangiopathy is a significant complication with this regimen, particularly in patients receiving busulfan/cyclophosphamide.

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.…”

“…17,20,34 Our results show that, although levels above the upper normal limit of TAC (410 ng/mL in the TAC/SIR group or 415 ng/mL in the TAC/MTX group) are not associated with TA-TMA, very high levels (425 ng/mL) are an independent risk factor for TA-TMA development. Accordingly, correct drug management is crucial to prevent this complication, 17,20,34,35 especially among patients who suffer from compromised organ function, either due to acute GVHD or from transplantation-related morbidity. This close monitoring is especially critical in the first 4 months after transplantation, as 75% of patients with TA-TMA were diagnosed before day þ 110 post HSCT, mainly when patients have developed severe grade III-IV acute GVHD.…”

“…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.…”

Aprepitant (Emend) significantly increases sirolimus levels in patients undergoing allogeneic hematopoietic SCT

“…Use of aprepitant in the context of SCT presents multiple opportunities for drug interactions. 3,4 Sirolimus and tacrolimus are immunosuppressive agents used for prevention of GVHD 5,6 that are also substrates for CYP3A4 isoenzyme and P-glycoprotein. 7,8 Drugs known to inhibit CYP3A4, such as aprepitant, have the potential to increase the bioavailability of these two agents, leading to overt toxicity.…”