Page 51 - Haematologica May 2022

Improved survival after acute GvHD
Outcomes after aGvHD grades II-IV
Survival at 36 months after aGvHD grades II-IV increased significantly (P<0.001) from 38% (36-41%) to 40% (38-42%), 43% (42-45%), 44% (43-45%), and 45% (44-46%), respectively, for the times periods studied (Figure 3A). Causes of death are shown in Online Supplementary Table 2: though GvHD- and infection-asso- ciated deaths decreased over time, mortality due to relapse/progression of underlying malignant disease increased.
Results of multivariate analysis are shown in Table 3. In multivariate analysis, URD (HR 1.14; 1.09-1.2; P<0.001), not in CR at HSCT (HR 1.47; 1.4-1.55; P<0.001), PBSC as stem cell source (HR 1.09 (1.03-1.15); P=0.004), a female donor for a male recipient (HR 1.11; 1.05-1.18; P<0.001), and use of ATG/alemtuzumab (HR 1.27 (1.18-1.36); P<0.001) were all associated with increased mortality after aGvHD grades II-IV whereas RIC (HR 0.92; 0.87-0.97; P=0.004) was associated with lower mortality, respective- ly. Patients transplanted more recently and given BM had improved outcomes after experiencing aGvHD: in earlier HSCT periods, BM as stem cell source had no significant impact on mortality (HR 0.95 (0.89-1.02); P=0.2) per decade but, in later periods, BM was associated with sig- nificantly reduced mortality after aGvHD (HR 0.89 (0.82- 0.96); P=0.003). Of note is mortality increasing with increasing patient age (HR 1.15 per decade; 1.13-1.18; P<0.001) e.g., three-year OS was 60% (57-63%) in patients aged 20 years and 40% (37-44%) in patients aged 70 years, respectively. Mortality decreased in the more recent transplant years (HR 0.73; 0.7-0.78; P<0.001).
Three-year NRM after experiencing aGvHD grades II-IV significantly (P<0.001) decreased from 47% (45-50%), to 42% (40-44%), 35% (34-37%), 37% (36-38%), and 36% (35-37%) for the periods 1990-1995, 1996-2000, 2001-
2005, 2006-2010, and 2011-2015, respectively (Figure 4). In multivariate analysis (Table 3), age (HR 1.22 (1.18- 1.25); P<0.001), URD (HR 1.23 (1.15-1.31); P<0.001), not in CR at HSCT (HR 1.21 (1.13-1.29); P<0.001), and female donor for a male recipient (HR 1.22; 1.14-1.31; P<0.001) were associated with increased NRM whereas more recent HSCT year (HR 0.72 (0.67-0.77); p<0.001) and RIC (HR 0.89 (0.83-0.95); P<0.001) were associated with
decreased NRM.
Three-year DFS after aGvHD grades II-IV significantly
(P<0.001) increased from 34% (32-37%), to 35% (33- 36%), 38% (36-39%), 39% (38-40%), and 40% (38-41%), respectively.
In multivariate analysis, use of RIC (HR 0.95 (0.9-1); P=0.04) was associated with improved DFS after experi- encing aGvHD grades II-IV whereas URD (HR 1.09 (1.04- 1.14); P<0.001) and not in CR at HSCT (HR 1.48 (1.42- 1.56); P<0.001) had reduced DFS, respectively. Of note is that DFS reduced with increasing patient age (HR 1.12; 1.09-1.14; P<0.001), but improved in more recent trans- plants in patients not treated with ATG/alemtuzumab (HR 0.8 (0.76-0.84); P<0.001) and in patients treated with ATG/alemtuzumab (HR 0.79 (0.74-0.85); P<0.001).
Three-year relapse incidence after aGvHD grades II-IV significantly (P<0.001) increased from 19% (17-21%), to 23% (22-24%), 27% (26-28%), 25% (24-26%), and 25% (24-26%), respectively (Figure 5).
In multivariate analysis, use of URD (HR 0.9; 0.84-0.98; P=0.01) and female donor for a male recipient (HR 0.83 (0.76-0.9); P<0.001) and use of BM as stem cell source (HR 0.87 (0.8-0.95); P=0.002) were associated with reduced relapse incidence whereas not being in CR at HSCT (HR 2.02 (1.87-2.18); P<0.001), and use of PBSC as stem cell source (HR 1.15; 1.05-1.25; P=0.002) were associated with increased relapse risk. Although conditioning intensity
Table 3. Multivariable Cox regression analysis regarding outcome after aGvHD grades II-IV.
OS DFS Relapse NRM HR(95%CI) P HR(95%CI) P HR(95%CI) P HR(95%CI) P
Age at HSCT (dec) Conditioning intensity
Donor/recipient relationship
standard reduced related unrelated
1.16 (1.13-1.18) 0.92 (0.87-0.97) 1.14 (1.09-1.2)
<0.001 0.004 <0.001 <0.001
0.4 0.004
<0.001 0.2 0.08
<0.001 <0.001 <0.001
1.12 (1.09-1.14)
0.95 (0.9-1)
1.09 (1.04-1.14)
1.48 (1.42-1.56) 1.04 (0.93-1.16)
0.92 (0.87-0.97)
1.05 (1-1.11) 0.96 (0.91-1.01) 0.94 (0.89-1)
1.34 (1.25-1.43) 0.8 (0.76-0.84) 0.79 (0.74-0.85)
<0.001 0.041 <0.001 <0.001
0.5
0.002
0.07 0.14 0.047
<0.001 <0.001 <0.001
0.99 (0.96-1.02) 0.7 1.03 (0.95-1.13) 0.4
0.9(0.84-0.98) 0.011
2.02 (1.87-2.18)<0.001 0.94 (0.77-1.15) 0.5
0.87(0.8-0.95) 0.002
0.83 (0.76-0.9) <0.001 0.92 (0.84-1) 0.05 0.93 (0.85-1.02) 0.11
1.3 (1.16-1.45) <0.001 0.93 (0.86-1) 0.06 0.88 (0.78-0.99) 0.03
1.22 (1.18-1.25)
0.89 (0.83-0.95)
1.23 (1.15-1.31)
1.21 (1.13-1.29) 1.07 (0.94-1.22)
0.94 (0.88-1.01)
1.22 (1.14-1.31) 0.99 (0.92-1.07) 0.95 (0.88-1.03)
1.34 (1.23-1.45) 0.72 (0.67-0.77) 0.75 (0.69-0.82)
<0.001 <0.001 <0.001 <0.001
0.3 0.12
<0.001 0.8 0.2
<0.001 <0.001 <0.001
Disease status at HSCT CR
noCR 1.47 (1.4-1.55)
untreated Stem cell source PB
1.05 (0.94-1.17)
BM 0.92 (0.87-0.97) Recipient/donor sex match MM
MF 1.11 (1.05-1.18) FM 0.96 (0.91-1.02) FF 0.95 (0.89-1.01)
ATG/Alemtuzumab no
yes 1.27 (1.18-1.36)
HSCT year (dec)
ATG/Alemtuzumab x HSCT year (dec)
0.76 (0.72-0.8) 0.81 (0.75-0.87)
OS: overall survival; DFS: disease-free survival; NRM: non-relapse mortality; CR: complete remission; BM: bone marrow; PBSC: peripheral blood stem cells; ATG: antithymocyte globulin; HSCT: hematopoietic stem cell transplantation.
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