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F. Keklik et al.
prior to DAH. Most patients (92%) received high-dose steroids for the treatment of DAH and seven patients (12%) additionally received an anti-tumor necrotizing fac- tor: etanercept in six cases and infliximab in one. In three patients, anti-tumor necrotizing factor was mainly used for the treatment of concurrent severe gut GvHD. Seventy-five percent of the patients required mechanical ventilator support.
Risk factors
DAH occurred more often in patients who received UCB grafts, TBI at a myeloablative dose, and HLA-mis- matched donor grafts: it was also more common among those who had a malignant disease (Table 1). The median time to platelet engraftment (63 days versus 30 days) and to neutrophil engraftment (19 days versus 14 days) was sig- nificantly delayed in the group with DAH compared with the group that did not develop DAH (P<0.01 for each). Primary graft failure was significantly more frequent in the DAH group (Table 1). Only 1.6% of patients who never experienced severe thrombocytopenia had DAH compared with 8.2% of patients with severe thrombocy- topenia (P=0.04). The median graft cell dose was signifi- cantly lower in the group that had DAH (3.1x108/kg) than in the group that did not develop DAH (5.22 x 108/kg) (P<0.01) among PB/BM HCT recipients, whereas among UCB HCT recipients it was lower in those with DAH than in those without (0.39x108/kg versus 0.46x108/kg, respec- tively; P<0.01) (Table 1). Sex, age, disease risk, recipient cytomegalovirus serology, and the incidence of acute GvHD were all similar between the groups with and without DAH.
DAH was observed in 7% (40/570) of the UCB graft recipients (Table 2). These UCB graft recipients received myeloablative TBI more often than UCB graft recipients without DAH did (90% versus 76%; P=0.05), more often had double UCB grafts (90% versus 62%; P<0.01) and received fewer cells/kg recipient weight [0.39x108/kg (range, 0.21-2.04x108/kg) versus 0.46x1088/kg (range, 0.03- 99.01x107/kg; P<0.01]. Neutrophil and platelet engraft- ment failure (by the time of death or DAH) was strongly associated with DAH (30% versus 9%, and 70% versus 21%, respectively, in the groups with and without DAH) (Table 2).
Multivariate analysis showed that UCB HCT recipients had a 2-fold higher incidence of DAH than PB/BM HCT recipients (HR: 2.08, 95% CI: 1.16-3.74; P=0.01). Delayed neutrophil engraftment or graft failure was a risk factor for DAH in PB/BM HCT recipients (HR: 5.51, 95% CI: 1.26- 24; P=0.02) whereas delayed platelet engraftment was associated with significantly increased DAH in UCB HCT recipients (HR: 6.96, 95% CI: 2.39-20.29; P<0.05) (Table 3A,B). Two different engraftment models were tested because neutrophil engraftment was strongly correlated with platelet engraftment. TBI at a myeloablative dose was also a risk factor for DAH (HR: 1.8, 95% CI: 1.03- 3.13; P=0.05), an effect that was more pronounced in UCB HCT recipients (HR: 1.87, 95% CI: 0.95-3.71; P=0.08) than in BM/PB HCT recipients (HR: 1.63, 95% CI: 0.62-4.31; P=0.60) (Table 3A,B).
Treatment-related mortality and survival
DAH was associated with higher treatment-related mortality at 6 months (HR: 6.09, 95% CI: 4.33-8.56; P<0.01) and a lower overall survival at 2 years (HR: 4.16,
95% CI: 3.06-5.64; P<0.01) following HCT with either graft source (PB/BM or UCB). UCB was also a risk factor for poorer treatment-related mortality at 6 months (HR: 1.43, 95% CI: 1.08-1.9; P=0.01) and overall survival (HR: 1.22, 95% CI: 1.02-1.48; P=0.03).
A total of 44 patients with DAH (74.5%) required intu- bation. Of the DAH patients requiring intubation, 54% and 66% died 30 and 60 days after intubation while only 13% and 26% of DAH patients not requiring intubation died by 30 and 60 days after the diagnosis of DAH (P=0.01). Among the intubated patients, UCB HCT recip- ients had a higher mortality at 6 months compared with the BM/PB graft recipients (84% versus 56%; P=0.05) (Online Supplementary Figure S1). Of seven patients who received an anti-tumor necrotizing factor drug, only one (14%) survived.
Table 2. Characteristics of patients receiving umbilical cord blood hematopoietic stem cell transplantation.
Number
Sex Male Female
Age at HCT (years) Median (range)
Malignant disease Yes
No
Disease risk Standard High
Conditioning intensity MAC
RIC
TBI Yes
No
Conditioning intensity & TBI MAC TBI
MAC no TBI
RIC
UCB units Single Double
TNC x 108/kg N
Median (Range)
TNC x 108/kg by unit number Single, median (range) Double, median (range)
ANC engraftment
Median days (range)
Platelet engraftment Median days (range)
Graft failure Yes
No
No DAH
N=530
317(60%)
213(40%)
28(0-73)
401(76%)
129(24%)
381(72%) 149(28%)
273(52%)
257(48%)
405(76%) 125(24%)
177 (33%) 86 (18%) 272 (48%)
199(38%) 331(62%)
530
DAH
N=40
25(63%)
15(38%)
32(2-72)
37(92%)
3(8%)
25(63%) 15(38%)
25(63%)
15(38%)
36(90%) 4(10%)
21 (53%) 4 (10%) 15 (37%)
4(10%) 36(90%)
40
P value 0.74
0.17
<0.01
0.21
0.18
0.05
0.04
<0.01
0.01
0.03
0.22
0.24
<0.01
<0.01
0.46 (0.03-99.01) 0.39 (0.21-2.04)
0.59 (0.03-14.28) 0.35 (0.21-0.37) 0.43 (0.19-99.01) 0.41 (0.23-2.04)
18 (0-42)
44 (0-175)
36 (7%)
494(93%)
22 (0-41)
84 (48-168)
9 (23%)
31(78%)
ANC: absolute neutrophil count; DAM: diffuse alveolar hemorrhage; HCT: hematopoi- etic stem cell transplant; MAC: myeloablative conditioning; RIC: reduced intensity conditioning; TBI: total body irradiation; TNC: total nucleated cell count; UCB: umbil- ical cord blood; Significant differences are shown in bold.
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haematologica | 2018; 103(12)