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Bortezomib-based RIC HSCT: Phase II RCT
Engraftment, chimerism, safety: the median time to neu- trophil (>500/μl) and platelet engraftment (>20,000/μl) among patients who experienced count nadir (i.e., neu- trophil count <500/vl and/or platelet count <20,000/μl) was 11 days (range: 2-45) and 19 days (range: 10-57), respectively, with no significant difference between treat- ment arms (P=0.9 and P=0.55 for neutrophils and platelets, respectively). For the entire cohort, 31% of patients did not experience count nadir (24% in arm A, 27% in arm B, 43% in arm C, P=0.11) and no subject failed neutrophil engraftment. Median total nucleated cell donor chimerism by day 30 was 96% (range: 42-100) and by day 100 was 97% (range: 0-100, with no significant dif- ference between treatment arms (P=0.84 and P=0.83, respectively). The bort-based regimens were well tolerat- ed. No bort doses were delayed or reduced due to toxicity. No serious adverse event (SAE) attributable to bort (e.g., neuropathy) was documented. Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 organ dys- function (hepatic, renal, pulmonary) did not differ signifi- cantly between treatment arms, including the incidence of acute kidney injury (AKI, 8.7% overall), thrombotic microangiopathy/hemolytic-uremic syndrome (TMA/HUS, 6.5% overall) or hepatic veno-occlusive dis- ease (VOD, 3.3% overall) (P=0.14, P=0.16 and P=0.41, respectively).
Acute GvHD: The primary endpoint of grade II-IV aGvHD incidence rate by day +180 did not differ signifi- cantly between treatment arms, at 32.6% (A) vs. 31.1% (B, one-sided P=0.53 for arm A vs. B) vs. 21% (C, one-sided P=0.16 for arm A vs. C) (Table 2). This result is consistent
with the cumulative incidence of aGvHD (P=0.36) (Table 3, Figure 2A). For seven patients, grade II-IV aGvHD occurred after hematologic malignancy relapse (six after early IS taper, and 1 after donor lymphocyte infusions [DLI]). Four of these (B, 1; C, 3) had aGvHD onset prior to day +180, and are included in the primary endpoint. This result was consistent with the result from multivariable analysis: subdistribution hazard ratio (sHR) was 0.87 (95% confidence interval [CI] 0.42-1.78, P=0.7) for arm B vs. arm A, and 0.68 (95% CI 0.33-1.4, P=0.29) for arm C vs. arm A. If patients with aGvHD onset after relapse are excluded from the analysis, the grade II-IV aGvHD inci- dence rate by day +180 was 32.6% (A) vs. 28.9% (B, one- sided P=0.44 for arm A vs. B) vs. 14.9% (C, one-sided P=0.04 for arm A vs. C) (Table 2). On multivariable analy- sis, sHR was 0.8 (95% CI 0.39-1.66, P=0.55) for arm B vs. A, and 0.53 (95% CI 0.23-1.18, P=0.12) for arm C vs. A. aGvHD incidence continued to rise after day +180 across arms, and the 1-year cumulative incidence of grade II-IV aGvHDwas40%inarmA,34%inarmB,and26%in arm C (P=0.71 for arm A vs. B, P=0.33 for arm A vs. C) (Figure 2A). For grade III-IV severe aGvHD, day +180 cumulative incidence was 2.2% (A) vs. 8.9% (B, P=0.64 for arm A vs. B) vs. 15% (C, P=0.07 for arm A vs. C) (Table 3, Figure 2B).
In an exploratory analysis in line with our protocol strat- ification, we repeated the analysis by HLA match status (Online Supplementary Table S1A). For the 8/8 HLA- matched recipients, when all grade II-IV aGvHD were counted, the six-month cumulative incidence was 33% (A) vs. 16% (B, P=0.1 for arm A vs. B) vs. 19% (C, P=0.21
A All chronic GvHD B
P=0.66
C
P=0.95
D GvHD-free, relapse-free survival
P=0.53 Figure 3. cGvHD: survival and GRFS outcomes. Cumulative incidence of (A) all cGvHD, and Kaplan-Meier survival plots of (B) progression-free survival (PFS), (C) overall survival (OS), and (D) grade III-IV aGvHD/cGvHD requiring sys- temic IS agents/relapse-free survival (GRFS) per treatment arm. Black indi- cates arm A (tac/mtx), red indicates arm B (bort/tac/mtx), and blue indi- cates arm C (bort/sir/tac). Tac: tacrolimus; Mtx: methotrexate; Bort: bortezomib; Sir: sirolimus; GvHD: graft-
P=0.98
versus-host disease.
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