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Diffuse alveolar hemorrhage after HCT
incidence curves for the endpoints of neutrophil engraftment, treatment-related mortality, DAH and infection.17 The Kaplan- Meier method was used to estimate the probabilities of disease- free survival and overall survival through 2 years after allogeneic HCT and the log-rank test was used for univariate comparisons.18 A Cox proportional hazard regression model was used to estimate differences between the adjusted survival curves,19 with DAH being treated as a time-dependent variable.
Factors that were considered in regression models included gen- der (male versus female), age at transplant (0-35 years versus ≥35 years), recipient’s cytomegalovirus serostatus (positive versus neg- ative), intensity of the transplant conditioning regimens (myeloab- lative versus reduced intensity), graft source (PB/BM versus UCB), TBI use (yes versus no), composite factor of TBI and conditioning intensity, diagnosis (malignant versus nonmalignant), neutrophil engraftment (treated as a time-dependent variable), platelet engraftment (treated as a time-dependent variable), disease risk (standard risk versus high risk) and greatest mismatch for HLA dis- parity considering the worst matched of the two UCB units (matched versus mismatched). Factors with a univariate P-value <0.15 or those with established potential clinical importance were included in the multivariate analysis. Prognostic factor models for all clinical outcomes were built using a backward selection method (P<0.05 was considered significant for remaining in the model). All statistical analyses were implemented using Statistical Analysis System statistical software version 9.3 (SAS Institute Inc., Cary, NC, USA). The cut-off significance level for all P values was 0.05.
Results
A total of 1228 patients undergoing allogenic HCT were included in the study: 658 received PB/BM grafts and 570 received UCB grafts. There were significant differences between PB/BM recipients and UCB graft recipients regarding patient- and disease-characteristics (Online Supplementary Table S1). The median total nucleated cell count was higher and the median time-to-engraftment was shorter in PB/BM graft recipients than in UCB graft recipients.
DAH was diagnosed in 59 patients (5%) (Table 1) at a median of 30 days (26 days for BM/PB and 33 days for UCB grafts) after HCT. The median time from HCT to neutrophil engraftment was 19 days (14 days for BM/PB and 22 days for UCB) while that for platelet engraftment was 63 days (20 days for BM/PB and 84 days for UCB grafts). Fifty-one percent of patients had DAH within the 2 weeks preceding or after neutrophil engraftment. Seventy-nine percent of patients with DAH had no platelet engraftment at the time of DAH.
The patients with DAH had a median age of 32 years, 66% were male, 85% had a malignant disease, 42% had a history of smoking, 5.1% had a history of pre-HCT lung disease, 54% were seropositive for cytomegalovirus, 59% received myeloablative conditioning, 86% received TBI, 64% were HLA-matched and 20% had a sibling donor. At the time of DAH, the median platelet count was 24x109/L (range, 1.0-114), 34% had renal dysfunction (creatinine >1.3 mg/dL), 34% had abnormal liver function (alanine transaminase >35 U/L), 8% had an elevated international normalized ratio >1.5, 25% had a prolonged partial thromboplastin time (≥37 s, although in most cases it was <40 s), and no tested patient (n=37) had a low fibrinogen level <180 mg/dL. Forty-six percent of patients had fever,
27% had a documented systemic infection, and in 19% of cases an infectious organism was isolated from the bron- choalveolar lavage fluid along with the findings of DAH. In patients with DAH, the incidence of grade II-IV acute graft-versus-host disease (GvHD) by day +100 was 36%, with most cases of grade II-IV GvHD (69.5%) occurring
Table 1. Patient and transplant characteristics.
NoDAHn(%) DAHn(%) Pvalue
Number
Sex
Age at HCT (years)
Malignant disease
Disease risk
Recipient CMV serology
Conditioning intensity
TBI
Conditioning intensity & TBI
Graft source
Graft source
Graft source &
conditioning intensity
Graft cell dose infused
TNC x108/kg, median (range)
CD34 dose, median (range)
HLA matching
Post-transplant events Neutrophil engraftment (n) Median days (range) Platelet engraftment (n) Median days (range) Engraftment day +1 Neutrophils, n (%)
Platelets, n (%)
Graft failure
Acute GvHD grade II-IV (n)
Median days (range)
<day 100 (n=360)
Male
1169 (95%)
708 (61)
461 (39)
591 (51) 578 (49)
830 (71)
339 (29)
800 (68) 369 (32)
651 (56)
506 (44)
534 (46) 635 (54)
865 (74)
304 (26)
339 (29) 195 (17) 635 (54) 639 (55) 530 (45)
342 (53) 297 (47)
261 (49)
273 (51)
59 (5%)
39 (66) 0.40
20 (34)
31 (52) 0.77 28 (47)
50 (85) 0.02 9 (15)
36 (61) 0.23 23 (39)
32 (55) 0.87
26 (45)
35 (59) 0.04 24 (41)
51 (86) 0.03 8 (14)
28 (47) 0.01 7 (12)
Female 0-35
≥35 Yes
No
Standard High
Positive
Negative
MAC RIC
Yes
No
MAC TBI MAC no TBI RIC
BM/PB UCB
PB BM
BM/PB-MAC
UCB-MAC
24 (40)
19 (32)
40 (68)
<0.01
BM/PB 5.22 (0.01-35.50)
UCB 0.46 (0.03-99.01) 2.67 (0.01-64.46)
10 (53) 0.97 9 (47)
10 (29) 0.02 25 (71)
3.10 (0.02-12.57) 0.01 0.39 (0.21-2.04) 0.01
M BM/PB MM BM/PB UCB
Yes No
Yes
No
Yes No
543 (46%) 96 (8%) 530 (45%)
1099 14 (0-42) 984
30 (0-175)
96 (8.2%) 1073 (91.8%)
18 (1.5%)
1151 (98.5%)
51 (4%) 1118 (96%)
383
35 (11-174)
360 (31)
0.95 (0.02-10.14)
13 (22%) 6 (10%) 40 (68%)
45
19 (0-41) 22
63 (0-168)
<0.01
<0.01
<0.01
<0.01 1 (1.6%) 0.04
58 (98.4%)
1 (1.6%) 0.61
58 (98.4%)
11 (19%) 48 (81%)
<0.01
23
34 (14-148) 0.40
21 (36) 0.13
BM: bone marrow; CMV: cytomegalovirus; DAH: diffuse alveolar hemorrhage; GvHD: graft-versus- host disease; HCT: hematopoietic stem cell transplantation; M: matched; MAC: myeloablative conditioning; MM: mismatched; TNC: total nucleated cell count; PB: peripheral blood; RIC: reduced-intensity conditioning; TBI: total body irradiation; TRM: treatment-related mortality; UCB: umbilical cord blood. Significant differences are shown in bold.
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