The addition of sirolimus to the graft‐versus‐host disease prophylaxis regimen in reduced intensity allogeneic stem cell transplantation for lymphoma: a multicentre randomized trial

Abstract

Inhibition of the mechanistic target of rapamycin (serine/threonine kinase) (mTOR) pathway has clinical activity in lymphoma. The mTOR inhibitor sirolimus has been used in the prevention and treatment of graft-versus-host disease (GVHD) after allogeneic haematopoietic stem cell transplantation (HSCT). A retrospective study suggested that patients with lymphoma undergoing reduced intensity conditioning (RIC) HSCT who received sirolimus as part of their GVHD prophylaxis regimen had a lower rate of relapse. We therefore performed a multicentre randomized trial comparing tacrolimus, sirolimus and methotrexate to standard regimens in adult patients undergoing RIC HSCT for lymphoma in order to assess the possible benefit of sirolimus on HSCT outcome. 139 patients were randomized. There was no difference overall in 2-year overall survival, progression-free survival, relapse, non-relapse mortality or chronic GVHD. However, the sirolimus-containing arm had a significantly lower incidence of grade II-i.v. acute GVHD (9% versus 25%, p=0.015), which was more marked for unrelated donor grafts. In conclusion, the addition of sirolimus for GVHD prophylaxis in RIC HSCT is associated with no increased overall toxicity and a lower risk of acute GVHD, although it does not improve survival; this regimen is an acceptable option for GVHD prevention in RIC HSCT. This trial is registered at clinicaltrials.gov (NCT00928018).

Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma

“…CIR at 1 year in this study compares favorably to that expected for this cohort based on the Disease Risk Index mix of patients (14% vs 26%). 26 Among the HL subgroup, the 1-year relapse rate appears lower than that observed in many historical series of HL patients undergoing RIC allogeneic transplant (16% vs 26% to 41%) 18,19,22,24,27 ; however, patients in most of these series likely had a higher disease burden at the time of HSCT compared with our cohort. Rates of relapse were similar to that seen in 1 small phase 2 trial of RIC for HL in which patients had a comparable rate of CR prior to transplant.…”

“…[22][23][24][25] Furthermore, HSCT after PD-1 blockade may be associated with lower than expected relapse rates. CIR at 1 year in this study compares favorably to that expected for this cohort based on the Disease Risk Index mix of patients (14% vs 26%).…”

Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT

“…The median time to neutrophil engraftment was 2 days shorter in the Tac/Sir arm compared with the Tac/Mtx arm (14 [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] vs 16 days, P , .001; Figure 2A), and the median time to platelet engraftment was 3 days shorter in the Tac/Sir arm (16 vs 19 days, P 5 .03; Figure 2B). Despite a more rapid time to engraftment, there was no significant difference in hospitalization time (20 vs 21 days, P 5 .37).…”

“…There was no difference in the incidence of malignant disease relapse in the 2 study arms (28% [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] (Figure 4A-B). In multivariable analysis, advanced disease status at transplantation predicted relapse (P 5 .026), disease-free survival (P 5 .017), and overall survival (P 5 .034).…”

“…10,11 In 2 recent randomized trials, the addition of sirolimus to Tac/Mtx in adults and children was associated with grades 2-4 acute GVHD risk reduction from 25% to 9% and 31% to 18%, respectively. 26,27 However, both of these trials included subjects with unrelated donors, and it is possible that the inclusion of these higher risk subjects is required to demonstrate a benefit. Although we were unable to demonstrate a reduction of the magnitude demonstrated in other randomized trials, we demonstrated a trend toward a reduction in the incidence of severe acute GVHD.…”