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.

Methods

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).

Results

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.

Conclusion:

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.

TABLE 1.

PATIENT CHARACTERISTICS

UNRELATED TRANSPLANTS
 N=203MATCHED 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 
    CVB+(R) 1+(1) 
    BU/CY 
    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 21 
    2 
UNRELATED TRANSPLANTS
 N=203MATCHED 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 
    CVB+(R) 1+(1) 
    BU/CY 
    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 21 
    2 
Disclosures:

No relevant conflicts of interest to declare.

Author notes

*

Asterisk with author names denotes non-ASH members.