Page 168 - Haematologica3

J. Koreth et al.
for arm A vs. C) (Online Supplementary Figure S1). When arms B and C were combined, the six-month cumulative incidence was 17% (P=0.08 for arm A vs. arm B or C). When we repeated the analysis after excluding aGvHD that occurred after relapse and IS taper, the six-month cumulative incidence was 33% (A) vs. 13% (B, P=0.046 for arm A vs. B) vs. 16% (C, P=0.13 for arm A vs. C). When arms B and C were combined, the cumulative incidence was 15% (P=0.03 for arm A vs. arm B or C). However, for 7/8 MMD recipients such a benefit was not appreciable (albeit with limited sample size) (Online Supplementary Table S1A, Online Supplementary Figure S1).
NRM, relapse, chronic GvHD, and survival: NRM did not differ significantly between treatment arms (Table 3), with a 2-year cumulative incidence of 14% (A, 95% CI, 5-26) vs. 16% (B, 95% CI, 7-29) vs. 6.4% (C, 95% CI, 1.6-16; P=0.62) (Figure 2C). Relapse did not differ significantly between treatment arms, with a 2-year cumulative inci- dence of 32% (A, 95% CI, 18-46) vs. 32% (B, 95% CI, 19- 47) vs. 38% (C, 95% CI, 24-52; P=0.74) (Figure 2D). The 2- year cumulative incidence of cGvHD did not differ signif-
Figure 4. Immune reconstitution outcomes. Reconstitution of (A) median of absolute CD3+ T-cell count/μL, and (B) median values of CD4+ Treg:Tcon cell ratio per treatment arm. Blue indicates arm A (tac/mtx), red indicates arm B (bort/tac/mtx), and green indicates arm C (bort/sir/tac). Treg: regulatory T cells; Tcon: conventional T cells; Tac: tacrolimus; Mtx: methotrexate; Bort: bortezomib; Sir: sirolimus; W1: week 1; W2: week 2; M: month.
icantly between treatment arms, at 59% (A) vs. 60% (B) vs. 55% (C; P=0.66) (Figure 3A). For five patients, cGvHD occurred after documented hematologic malignancy relapse (A, 1; B, 2; C, 2) and these were included in the estimation of cumulative incidence of cGvHD. Two had early IS taper, none received DLI. The 2-year PFS did not differ significantly between treatment arms, at 54% (A) vs. 52% (B) vs. 55% (C; P=0.95) (Figure 3B). The 2-year OS did not differ significantly between treatment arms, at 61% (A) vs. 62% (B) vs. 62% (C; P=0.98) (Figure 3C). The composite 2-year GRFS endpoint did not differ significant- ly between treatment arms, at 11% (A) vs. 12% (B) vs. 8% (C; P=0.53) (Figure 3D).
Immune reconstitution: The median total CD3+ T-cell count/μl at one month after transplantation was 401 in arm A (Q1-Q3, 248-681) vs. 414 in arm B (Q1-Q3, 195- 898) vs. 190 in arm C (Q1-Q3, 137-340; P<0.0001), and remained lower in arm C through months two and three (A, 602 and 728 vs. B, 639 and 571 vs. C, 221 and 269, respectively; P<0.0001). At six months after transplanta- tion, CD3+ T-cell counts were similar in all three arms at 763 (A, Q1-Q3, 463-1120) vs. 535 (B, Q1-Q3, 333-907) vs. 508 (C, Q1-Q3, 322-728; P=0.10) (Figure 4A). This reflect- ed both a lower median CD8+ and CD4+ T-cell count/μl at one to three months after transplantation in arm C (P<0.0001, data not shown). Similarly, the median CD19+ B- cell and the median CD56+CD3– NK cell count/μl was lower for arm C during the one to three months following transplantation (P<0.05, data not shown).
A Absolute CD3+ T-cell count per μL
B
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While the total CD4+ Tcon cell count/μl at one, two, and three months after transplantation was lower for arm C (P=0.005, P=0.0006, P=0.024 at one, two and three months after transplantation, respectively), the total CD4+ Treg cell count/μl was unimpaired in arm C at those time points, resulting in an improved ratio of Treg:Tcon recon- stitution at one and three months after transplantation (A: 0.049 and 0.05 vs. B: 0.051 and 0.032 vs. C: 0.088 and 0.067; P=0.006 and P=0.012, respectively) (Figure 4B).
Discussion
Most adult hematologic malignancy patients who may benefit from allogeneic HSCT lack an available sibling donor and are considered for a MUD or 1-locus MMD, with umbilical cord blood (UCB) and haploidentical (haplo) donors being additional alternative options. Regarding 8/8 MUD, as a result of improvements in DNA- based typing and supportive care, survival outcomes are considered similar to those of MRD HSCT,18,19 although studies indicate that MUD HSCT is associated with increased grade II-IV aGvHD (52% vs. 34%), grade III-IV aGvHD (21% vs.16%), and NRM (RR 2.76; P<0.01).20 The use of 1-locus MMD adds risk. A large registry analysis of 2,588 patients with acute leukemias, MDS or chronic myeloid leukemia (CML) undergoing RIC HSCT com- pared 7/8 with 8/8 HLA-matched donors, and document- ed higher rates of grade II-IV aGvHD and NRM, and lower 3-year OS (30% vs. 38%, respectively; P=0.01) with a mis- matched graft.2 Novel regimens to improve GvHD out- comes for patients lacking a preferred sibling donor would represent a major advance, and is the focus of our efforts.
Proteasome inhibition with bort has immunomodulato- ry properties relevant to allogeneic HSCT, as previously highlighted. Based on encouraging phase I/II results in
haematologica | 2018; 103(3)
Treg: Tcon Ratio