lancet | new solution for the prevention of graft-九游会ag

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since the clinical application of allogeneic hematopoietic stem cell transplantation (allo-hsct) in the 1970s, it has become the main means to cure multiple blood diseases. the incidence and mortality of acute graft-versus-host disease (gvhd) were high after nonmyeloablative allogeneic hematopoietic stem cell transplantation. recently, lancet haematology published a study on prevention of gvhd, which evaluated the efficacy of sirolimus in combination with standard prevention regimens (cyclosporine and mycophenolate mofetil) in the prevention of acute gvhd. what is the research result? let’s look at it together.

research method

this multicenter, randomized, phase 3 trial was conducted at nine hsct centers in the united states, denmark, and germany. inclusion criteria: patients with advanced hematologic malignancies who were treated with allogeneic hsct, karnofsky score ≥ 60, age > 50 years, or age ≤ 50 years, considered high-risk patients with high-dose pre-treatment pre-treatment regimen-related toxicity. patients were randomized according to an adaptive randomization protocol stratified by the transplant center, receiving standard gvhd prophylaxis (cyclosporine and mycophenolate mofetil) or a combination of three drugs (cyclosporine, mycophenolate mofetil and sirolimus) )treatment.

all patients received fludarabine (30 mg/m2/day) on days 4, 3, and 2 before hsct, and received 2 or 3 gy whole body radiotherapy on the day of hsct (day 0). patients in both study groups received oral administration of 5 mg/kg cyclosporine twice daily for 3 days prior to hsct and (in the absence of gvhd) gradually decreased from day 96 to day 150. patients in the standard group received oral mycophenolate 15 mg 3 times a day from day 0 to day 30, then changed to 2 times daily until day 150, and (in the absence of gvhd) gradually decreased on day 180 the amount. patients in the triple drug group received the same dose of mycophenolate mofetil as the standard group, but discontinued on the 40th day; oral sirolimus 2 mg once daily for 3 days before hsct, and adjusted to maintain the trough concentration at 3- from 12 ng/ml to day 150, and (in the absence of gvhd) gradually reduced on day 180.

the primary endpoint was the cumulative incidence of grade 2-4 acute gvhd on day 100 post-transplantation. secondary endpoints were non-recurrent mortality, overall survival (os), progression-free survival (pfs), cumulative morbidity of grade 3-4 acute gvhd, and cumulative incidence of chronic gvhd. efficacy and safety analysis were performed on all patients who received treatment and were transplanted. toxicity was assessed according to the common terminology standard for adverse events (ctcae). based on the results of the pre-interim analysis, it was unhelpful and the study was terminated early on july 27, 2016, according to the recommendations of the data and safety monitoring committee (nct01231412).

research result

from november 1, 2010 to july 27, 2016, a total of 180 patients were enrolled in the study, 167 of whom underwent complete study intervention and were included in the safety and efficacy analysis: standard group 77 patients, triple drug group 90 a patient.

the median follow-up time was 48 months (iqr 31-60), and the cumulative incidence of grade 2-4 acute gvhd was lower in the triplet group on day 100 compared with the standard group (26% [95% ci 17-35]. ] vs 52% [95% ci 41-63]) (as shown below).

after 1 year and 4 years, the non-recurrence mortality rate of the triple drug group increased to 4% (95% ci 0-9) and 16% (95% ci 8-24), and the standard group increased to 16% (95% ci 8). -24) and 32% (95% ci 21-43) (figure a).
there was no difference in the cumulative rate of recurrence or progression between the two groups after hsct (19% in the triplet group [95% ci 11-27], 21% in the standard group [95% ci 12-30]); after hsct there was no difference in the cumulative rate of recurrence or progression between the two groups in 4 years (25% in the triple drug group [95% ci 16-34], 27% in the standard group [95% ci 17-37]) (figure b ).

the 1-year and 4-year pfs of the triple drug group were 77% (95% ci 68-85) and 59% (95% ci 49-70), respectively, and the standard group was 64% (95% ci 53-74) and 41%, respectively. (95% ci 30-53%) (figure c).
the 1- and 4-year os of the triple drug group were 86% (95% ci 78-93) and 64% (95% ci 54-75), respectively, and the standard group was 70% (95% ci 60-80) and 46%, respectively. (95% ci 34-57) (figure d).

there was no difference in the cumulative incidence of grade 3-4 acute gvhd between the two groups (2% in the triple drug group [95% ci 0-5], 8% in the standard group [95% ci 2-14]; hr = 0.55 [95%] ci 0.16-1.96]; p=0.36); there was no difference in the cumulative incidence of chronic gvhd (49% in the triplet group [95% ci 39-59], 50% in the standard group [95% ci 39-61]; hr = 0.94 [95% ci 0.62-1.40]; p = 0.74). in both groups, the most common grade 4 ctcae or stronger toxicity occurred in the lungs.

in conclusion
the addition of sirolimus to cyclosporine and mycophenolate mofetil significantly reduced the proportion of patients with acute gvhd compared with patients treated with cyclosporine and mycophenolate mofetil alone. based on these results, a combination of cyclosporine, mycophenolate mofetil and sirolimus has become the new standard gvhd prevention program for patients with unrelated non-myeloablative hsct treatment at the fred hutchinson cancer research center.

references: brenda m sandmaier, brian kornblit, et al. addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial. the lancet haematology, june 24, 2019. http://dx.doi.org/10.1016/s2352-3026(19)30088-2.