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Bortezomib-based RIC HSCT: Phase II RCT
sion [DLI]), were counted in the estimation of cumulative inci- dence of GvHD in order to obtain comprehensive estimates, and both inclusive and exclusive estimates are presented for aGvHD endpoints. GRFS, PFS and OS were estimated using the Kaplan- Meier method. GRFS was defined as the time from stem cell infu- sion to incidence of grade III/IV aGvHD, cGvHD requiring sys- temic immunosuppression agents, relapse or death, whichever occured first. PFS and OS have been defined elsewhere. Cumulative incidences in the presence of competing events were compared using the Gray test, and Kaplan-Meier estimates were compared using the log-rank test.16 For time-to-event endpoints, P-values reflect comparing entire distributions along with point estimates for ease of presentation. For the primary endpoint, inci- dence rates of grade II-IV aGvHD by day +180 were compared at one-sided significance level of 0.05 using Fisher’s exact test; P-val- ues for secondary endpoints are two-sided at the significance level of 0.05, without adjusting for multiple comparisons. Multivariable analysis adjusting for variables, as listed in Table 1, were per- formed for OS and PFS using a Cox model, and a Fine and Gray model was used for grade II-IV aGvHD.17 Immunophenotype data
were compared using the Wilcoxon rank-sum test at each time point without adjusting for multiple comparisons. All statistical analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC, USA) and R version 3.1.3 (the CRAN project).
Results
Patient and transplant variables: one hundred and forty- two subjects enrolled and 138 randomized subjects were evaluable per the protocol-specified mITT criteria (four cancelled study participation before receiving transplanta- tion conditioning: two due to acute infection (one with subsequent disease relapse), one due to provider prefer- ence to continue protocol-excluded medications, and another due to disease relapse at transplantation admis- sion) (Figure 1). The treatment arms (A 46, B 45, C 47) were balanced for pre-transplant variables (Table 1), except lower cytomegalovirus (CMV) seropositivity in arm C (A, 78.3% vs. B, 77.8% vs. C, 53.2%, P=0.01).
Figure 1. CONSORT Diagram. *1 patient with relapse and infection. Tac: tacrolimus; Mtx: methotrexate; Bort: bortezomib; Sir: sirolimus.
Table 2. Summary of the primary endpoint (A) aGvHD after relapse with IS taper included
Arm
B (Bort/Tac/MTX)
31.1%(19.9, 44.3) 8.9% (3.1, 19.2)
28.9% (18, 42)
8.9% (3.1, 19.2)
P
Day 180 aGvHD rate*
grade II-IV (LL, UL) 32.6%(21.3, 45.7)
grade III-IV (LL, UL)
(B) aGvHD after relapse with IS taper excluded
Day 180 aGvHD rate*
2.2% (0.1, 9.9)
A (Tac/MTX)
C (Bort/Sir/Tac)
21% (12, 33.4) 14.9% (7.2, 26.2)
14.9% (7.2, 26.2) 10.6% (4.3, 21.1)
A vs. B 0.53 (1.0)
0.97 (0.2)
0.44 (0.82) 0.97 (0.2)
A vs. C 0.16 (0.25)
0.997 (0.06)
0.04 (0.054) 0.99 (0.2)
grade II-IV (LL, UL) 32.6%(21.3, 45.7)
grade III-IV (LL, UL) 2.2% (0.1, 9.9)
*proportion of aGvHD at Day +180. **P-values without parenthesis indicate one-sided testing of whether the aGvHD rate in arm B or C is lower than the aGvHD rate in arm A. P-values in parenthesis indicate two-sided testing. UL: upper one-sided confidence limit at 5% level; LL: lower one-sided confidence limit at 5% level; aGvHD: acute graft-versus- host disease; Tac: tacrolimus; Mtx: methotrexate; Bort: bortezomib; Sir: sirolimus.
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