Abstract
Abstract 1951
Both acute and chronic graft-versus-host disease (GVHD) are a major cause of morbidity and mortality in patients (pts) undergoing allogeniec hematopoietic stem cell transplantation (allo-HCT). Tacrolimus and mycophenolate mofetil (Tac-MMF) have shown encouraging results as GVHD prophylaxis in few prospective phase II trials with reduced intensity preparative regimens. Perkins et al. in a randomized phase II trial with myeloablative preparative regimen reported 11 and 26% incidence of grade III-IV aGVHD in related and unrelated donor transplants respectively.
We retrospectively evaluated clinical outcomes in a cohort of 414 consecutive pts who underwent related or unrelated allo-HCT with Tac-MMF for GVHD prophylaxis. Consecutive pts were transplanted with myeloablative or low intensity preparative regimens between January 2005 and June 2011 at Karmanos Cancer Center. Study end points were: Overall survival (OS), progression free survival (PFS) (Kaplan Meir), cumulative incidence (CI) of acute and chronic GVHD, relapse, CMV infection and non-relapse mortality (NRM).
Pt characteristics are summarized in Table 1. There were 211 pts who underwent allo-HCT from a related donor (RD) and 203 patients who had allo-HCT from an unrelated donor (UD). Sixty three pts (31%) of the UD were 7/8 HLA matched. Median follow up of all patients was 60 months with 95% confidence interval (95%CI) 54.4 – 64.7 months.
The CI of aGVHD for grades II-IV was 47.4% (95%CI 40.5–54.0), 55.2% (95%CI 48.0–61.7) in RD and UD groups respectively. The CI of aGVHD grades III-IV was 22.3% (95%CI 16.9–28.1), 36.5% (95%CI 29.9–43.1) in RD and UD groups respectively (Gray's test p-value 0.0007). The CI of cGVHD at 60 months was 56.2% (95%CI 48.7–63.1), 66.3% (95%CI 58.8–72.7) in RD and UD groups respectively (Gray's test p-value 0.015). The CI of severe cGVHD (NIH grade3) at 60 months was 28.1% (95%CI 22.2–34.3), 26.1% (95%CI 20.3–32.3) in RD and UD groups respectively. The CI of bronchiolitis obliterans at 60 months was 14.0% (95%CI 9.7 –19.1), 11.6% (95%CI 7.6–16.6) in RD and UD groups respectively (NS). The CI of CMV reactivation at 60 months was 27.2% (95%CI 21.3–33.4), 23.2% (95%CI 17.6–29.2) in RD and UD groups respectively (NS). NRM at 60 months was 32.5% (95%CI 25.9–39.2), 46.5% (95%CI 39.3–53.4) in RD and UD groups respectively (Gray's test p-value 0.001). The CI of relapse was 22.4% (95%CI 16.7–28.5) for UD and 28.8% (95%CI 22.6–35.2) for RD. One year survival was 61% (95%CI 55–68), 55% (95%CI 48–62) in RD and UD groups respectively. One year PFS was 55% (95%CI 48–62), 48% (95%CI 41–55) in RD and UD groups respectively. Five year OS was 43% (95%CI 35–51), 34% (95% CI 27–41) in RD and UD groups respectively. Causes of death for the RD group (n=115) were as follows: GVHD 49%, relapse 42%, sepsis 3%, multi-organ failure (MOF) 3%, Diffuse alveolar hemorrhage 2%, and secondary malignancy 3%. As for the UD group (n=133) causes of death were: GVHD 57%, relapse 29%, sepsis 7%, MOF 4%, graft failure 2%, and secondary malignancy 1%. Uni-variate and multi-variate analysis is being performed to evaluate disease risk, donor status, and regimen intensity as predictors of GVHD and survival.
The use of Tac-MMF for GVHD prophylaxis was associated with higher than previously reported incidence of severe aGVHD both in RD and UD allo-HCT. Furthermore, we observed a higher incidence of severe aGVHD, cGVHD and NRM in the UD group compared to RD. GVHD was the leading cause of mortality in both groups.
PATIENT CHARACTERISTICS
. | UNRELATED TRANSPLANTS N=203 . | MATCHED RELATED TRANSPLANTS N=211 . |
---|---|---|
PATIENT AGE | ||
RANGE(YRS)/MEDIAN | 18–69 (50) | 23–71 (52) |
DISEASE | ||
AML | 80 (39%) | 75 (36%) |
MDS | 21 (10%) | 26 (12%) |
CML | 15 (7%) | 11 (5%) |
ALL | 30 (15%) | 19 (9%) |
MPD | 6 (3%) | 6 (3%) |
MM | 3 (1%) | 5 (2%) |
NHL | 32 (16%) | 46 (22%) |
CLL/PLL | 11 (5%) | 16 (8%) |
HD | 5 (2%) | 7 (3%) |
CONDITIONING | ||
BU/FLU | 70 | 61 |
BU/FLU/TBI+(R) | 38+(2) | 43+(1) |
FLU/MEL/TBI+(R) | 11+(3) | 13+(5) |
VP16/TBI | 12 | 10 |
R+/− BEAM | 19 | 30 |
CY/TBI | 10 | 11 |
BAC | 28 | 32 |
CY/FLU/TBI | 1 | 1 |
CVB+(R) | 6 | 1+(1) |
BU/CY | 3 | 2 |
LOW INTENSITY PREP | 53 (26%) | 61 (28%) |
DONOR/RECEPIENT SEX | ||
F/F | 33 | 48 |
F/M | 35 | 55 |
M/F | 58 | 42 |
M/M | 77 | 66 |
DONOR/RECEPIENT CMV | ||
NEG/NEG | 62 | 69 |
NEG/POS | 65 | 48 |
POS/NEG | 22 | 28 |
POS/POS | 54 | 66 |
DONOR AGE | ||
RANGE (YRS)/MEDIAN | 18–60 (36.5) | 18–75 (46.5) |
CD 34+106ML/CUMM | ||
RANGE/MEDIAN | 1.49–19.12 (7.28) | 2.12–14.05 (5.78) |
HLA MATCH | ||
8/8 | 140 | 190 |
7/8 | 63 | 17 |
RELAPSE RISK | ||
0 | 75 | 88 |
1 | 128 | 123 |
STEM CELL SOURCE | ||
PBSC(BM) | 198 (5) | 208 (3) |
NUMBER OF PRIOR TRANSPLANTS | ||
0 | 193 | 190 |
1 | 9 | 21 |
2 | 1 | 0 |
. | UNRELATED TRANSPLANTS N=203 . | MATCHED RELATED TRANSPLANTS N=211 . |
---|---|---|
PATIENT AGE | ||
RANGE(YRS)/MEDIAN | 18–69 (50) | 23–71 (52) |
DISEASE | ||
AML | 80 (39%) | 75 (36%) |
MDS | 21 (10%) | 26 (12%) |
CML | 15 (7%) | 11 (5%) |
ALL | 30 (15%) | 19 (9%) |
MPD | 6 (3%) | 6 (3%) |
MM | 3 (1%) | 5 (2%) |
NHL | 32 (16%) | 46 (22%) |
CLL/PLL | 11 (5%) | 16 (8%) |
HD | 5 (2%) | 7 (3%) |
CONDITIONING | ||
BU/FLU | 70 | 61 |
BU/FLU/TBI+(R) | 38+(2) | 43+(1) |
FLU/MEL/TBI+(R) | 11+(3) | 13+(5) |
VP16/TBI | 12 | 10 |
R+/− BEAM | 19 | 30 |
CY/TBI | 10 | 11 |
BAC | 28 | 32 |
CY/FLU/TBI | 1 | 1 |
CVB+(R) | 6 | 1+(1) |
BU/CY | 3 | 2 |
LOW INTENSITY PREP | 53 (26%) | 61 (28%) |
DONOR/RECEPIENT SEX | ||
F/F | 33 | 48 |
F/M | 35 | 55 |
M/F | 58 | 42 |
M/M | 77 | 66 |
DONOR/RECEPIENT CMV | ||
NEG/NEG | 62 | 69 |
NEG/POS | 65 | 48 |
POS/NEG | 22 | 28 |
POS/POS | 54 | 66 |
DONOR AGE | ||
RANGE (YRS)/MEDIAN | 18–60 (36.5) | 18–75 (46.5) |
CD 34+106ML/CUMM | ||
RANGE/MEDIAN | 1.49–19.12 (7.28) | 2.12–14.05 (5.78) |
HLA MATCH | ||
8/8 | 140 | 190 |
7/8 | 63 | 17 |
RELAPSE RISK | ||
0 | 75 | 88 |
1 | 128 | 123 |
STEM CELL SOURCE | ||
PBSC(BM) | 198 (5) | 208 (3) |
NUMBER OF PRIOR TRANSPLANTS | ||
0 | 193 | 190 |
1 | 9 | 21 |
2 | 1 | 0 |
No relevant conflicts of interest to declare.
Author notes
Asterisk with author names denotes non-ASH members.