Of the 102 patients evaluable for GVHD, nineteen patients had no a-GVHD (Overall a-GVHD Score of 0). One patient had lower GI tract biopsy-proven GVHD without any skin rash. The remaining eighty-two patients (80,3%) presented a skin rash as the first sign of acute GVHD. During the first week after the skin rash appeared, thirty-one patients (37.8%) progressed to stage 2; in 18/31 patients the progression was registered within 48 hours (Group 1) while in 13/31 from day 3 to day 7 (Group 2).
The remaining fraction of patients, 51/82 (62%), presented skin-only acute GVHD which did not progress to Grade 2 for at least one week (Group 3). These patients left untreated during the first week, were then daily re-evaluated and treated only if they progressed to Grade 2. However, the dynamic of skin involvement was heterogenic and in some patients, on day 8 skin rash had regression compared to the involvement which had existed on the day the rash appeared. Some others on day 8 showed a progression (Fig. 1). Thus, Group 3 patients were divided into two subgroups, 3A and 3B; Group 3A -patients were those who at 1 week still had Overall GVHD Grade 1 but showed skin improvement compared to the day of rash appearance (n 31); Group 3B were those who at 1 week still had Overall Grade 1 but showed worsening of skin rash (n 20). The schema of patients who presented a skin rash and their numeric distribution in groups 1, 2, 3A and 3B are reported in a flow chart (Fig. 2). Of the 51 patients of groups 3A and 3B, 19/51 showed spontaneous regression of skin rash and were spared the start of CS therapy
Table 2 reports the results of the whole patient set, the GVHD evaluable set and the previously defined sub-groups in terms of OS, TRM and the need for primary and secondary lines of anti-GVHD treatment. Subgroup 3B had a higher rate of TRM and inferior survival (Fig. 3). Poor OS in patients belonging to the 3B Group was also confirmed by multivariable analysis (Table 3).
Table 2
Clinical Results in patients groups Based on skin rash dynamic
|
OS
At 2 years
(95% CL)
|
Cum Inc TRM
At 2 years
(95% CL)
|
Cum Inc
RR
At 2 years
(95% CL)
|
a-GVHD treatment
|
Second line
a-GVHD
treatment
|
Whole cases set (n 108)
|
54.9
(41–62)
|
28.0
(19–39)
|
20.5
(12–30)
|
---
|
----
|
a-GVHD evaluable set
(n 102)
|
59.6
(47.9–69.6)
|
22.8
(14.3–32.5)
|
19.3
(11.5–28.6)
|
62.8%
(64/102)
|
53.1%
(34/64)
|
Group Grade 0 GVHD (n 19)
|
66.4
(35.7–85.0)
|
5.6
(0.3–23.1)
|
35.0
(10.8–61.0)
|
---
|
---
|
Group 1 (n 18)
(progressing to Grade 2 within 2 days)
|
50.1
(21.9–73)
|
41.6
(15.0-66.7)
|
6.4
(10.4–26.0)
|
100%
(18/18)
|
50%
(9/18)
|
Group 2 (n 13)
(progressing to Grade 2 after
2–7 days)
|
64.8
(31.5–85.2)
|
16.8
(2.3–42.8)
|
17.1
(2.3–44.0)
|
100%
(13/13)
|
30.7%
(4/13)
|
Group 3a (n 31)
(untreated skin only GVHD at day 8 but improving)
|
75.1
(54.6–87.4)
|
10.4
(2.5–24.9)
|
18.2
(6.4–34.9)
|
48.4%
(15/31)
|
46.6%
(7/15)
|
Group 3b (n 20)
(untreated skin only GVHD at day 8 but worsening)
|
39.8
(15.8–63.0)
|
39.2
(15.0–63.0)
|
19.9
(4.4–43.1)
|
85%
(17/20)
|
76.4%
(13/17)
|
|
Group 3 A
versus 3 B
Log-rank
P = 0.03
|
Group 3 A
versus 3 B
Gray test
P = 0.05
|
Group 3 A
versus 3 B
Gray test
NS
|
Group 3 A
versus 3 B
Chi-square
P = 0.006
|
Group 3 A
versus 3 B
Chi-square
P = 0.002
|
Footnote: NS = not significant |
Table 3
Multivariate analysis of factors important for Overall Survival.
|
Univariate Cox proportional hazard
for OS
|
Multivariate Cox proportional hazard
for OS
|
|
HR
|
95% CI
|
p
|
HR
|
95% CI
|
p
|
Age*
|
1.037
|
1.005–1.070
|
0.02
|
1.102
|
1.027–1.182
|
0.007
|
Group 3B
versus 3A*
|
2.755
|
1.054–7.205
|
0.03
|
3.160
|
1.039–9.612
|
0.042
|
Phase of disease* (active versus 1–2 RC)
|
2.632
|
1.252–5.535
|
0.01
|
---
|
---
|
---
|
Donor *
(other than HLA-ID sibling versus HLA-ID sibling)
|
1.387
|
0.668–2.903
|
0.38
|
---
|
---
|
---
|
RIC *
versus MAC
|
2.608
|
1.327–5.124
|
0.005
|
---
|
---
|
---
|
Footnote: * = factors entered the multivariate analysis |
Group 3A patients had also a higher need for primary CS treatment. In fact, primary GVHD treatment was started on 15/31 patients, at a median of 38 days from transplant in group A, while in group 3B CS was started on 17/20 patients at a median of 27 days from the transplant (chi-test: p 0.006).
Secondary treatment was administered in 33 in our GVHD evaluable patients set. The second line was: -anti-JAK-2: 17 cases, -anti-TNF: 6 cases, -Extracorporeal photopheresis (ECP): 9 cases. More than 50% of all patients needing a second line of therapy were found in cases belonging to group 3A or 3B (20/33). Second-line treatments were more frequent in Group 3B compared to Group 3 a − 76.4% versus 46.6% (Chi-test: p 0.002).