Outcomes and risk factors of hemorrhagic cystitis in pediatric allogeneic hematopoietic stem cell transplantation recipients using different graft source and condition with severe aplastic anemia

Figures & data

Table 1. Patient characteristics.

Variable	No HC (n = 71)	HC (n = 26)	p Value
Recipient age in years, median (range)	7.75 (1.00–15.75)	5.71(2.42–11.33)	0.29
Disease course, months, median (range)	4.30 (1.00–114.40)	3.08 (0.73–76.97)	0.22
Sex
Male, n (%)	38 (54%)	14 (54%)	1.00
Female, n (%)	33 (46%)	12 (46%)
Disease
SAA, n (%)	47 (66%)	11 (42%)	0.04
VSAA, n (%)	24 (34%)	15 (58%)
Donor type			0.02
MRD, n (%)	19 (27%)	3 (12%)
HID, n (%)	40 (56%)	17 (65%)
UCB, n (%)	1 (1%)	4 (15%)
MUD, n (%)	11 (16%)	2 (8%)
HLA matching
10/10, n (%)	29 (41%)	6 (23%)	0.37
9/10, n (%)	1 (1%)	2 (8%)
8/10, n (%)	5 (7%)	3 (12%)
7/10, n (%)	11 (15%)	3 (12%)
6/10, n (%)	10 (14%)	5 (19%)
5/10, n (%)	15 (22%)	7 (26%)
ABO match			0.73
Matched, n (%)	38 (54%)	15 (57%)
Minor mismatched, n (%)	13 (18%)	3 (12%)
Major mismatched, n (%)	20 (28%)	8 (31%)
Conditioning intensity			0.02
RIC, n (%)	70 (99%)	22 (85%)
MAC, n (%)	1 (1%)	4 (15%)
CMV seropositive			0.35
Yes, n (%)	44 (62%)	13 (50%)
No, n (%)	27 (38%)	13 (50%)
EBV seropositive			0.16
Yes, n (%)	24 (34%)	13 (50%)
No, n (%)	47 (66%)	13 (50%)
Neutrophil engraftment time, median (range), Days	11 (8–22)	12 (10–21)	0.02
Platelet engraftment time, median (range), Days	15 (7–47)	18 (8–52)	0.006
Total infused cell count, median (range)
MNC, ×10^8/kg	6.04 (1.32–14.89)	8.71 (0.27–17.43)	0.026
CD34, ×10^6/kg	4.97 (0.16–12.50)	4.75 (0.06–10.42)	0.63
aGVHD
Occurrence time, days	16 (9–48)	20 (10–82)	0.271
Grade 0–1, n (%)	65 (91%)	16 (62%)	0.001
Grade 2–4, n (%)	6 (9%)	10 (38%)
aGVHD localization			0.004
Absent, n (%)	45 (63%)	9 (35%)
Skin, n (%)	20 (28%)	8 (31%)
Gut ± others, n (%)	6 (9%)	9 (34%)
cGVHD
Absent, n (%)	50 (70%)	18 (69%)	0.774
Mild, n (%)	10 (14%)	3 (12%)
Moderate, n (%)	4 (6%)	3 (12%)
Severe, n (%)	7 (10%)	2 (7%)
Engraftment syndrome
Occurrence time, days	10 (5–14)	8.5 (5–17)	0.48
Yes	33 (46%)	17 (65%)	0.11
No	38 (54%)	9 (35%)

Notes: Comparisons of patient ages and total infused cell count were analyzed using Mann–Whitney U test. Comparisons of patient characteristics (categorical variables) between HC groups were analyzed using chi-square test. HC, hemorrhagic cystitis; MRD, matched related donor; UCB, Umbilical cord blood; HID, A haplo-identical donor; MUD, matched unrelated donor; HLA, human leukocyte antigen; CMV, Cytomegalovirus; EBV, Epstein-Barr virus; aGVHD, acute graft versus host disease; cGVHD, chronic graft versus host disease; MNC, mononuclear cells; RIC, reduced-intensity conditioning; MAC, myeloablative conditioning; VSAA, very severe aplastic anemia; SAA, severe aplastic anemia.

Table 2. Characteristics of patients with HC.

Total number of HC patients	26
HC classification
Grade I, n (%)	5(19%)
Grade II, n (%)	15(58%)
Grade III, n (%)	6(23%)
Grade IV, n (%)	0(0%)
The time of HC onset, median (range), Days	21(1–95)
The time of HC duration, median (range), Days	14(3–95)

HC, hemorrhagic cystitis.

Figure 1. Neutrophil and platelet engraftment probability of AA patients after HSCT. Neutrophil and platelet engraftment were compared between HC group and no HC group.(A) Neutrophil engraftment probability of patients after HSCT.(p = 0.08) (B)Platelet engraftment probability of patients after HSCT. (p = 0.03).

Figure 2. Lymphocyte subsets were not associated with HC. The frequency and counts of CD3⁺T cells, CD4⁺T cells, CD8⁺T cells,CD19⁺B cells and CD16⁺CD56⁺NK cells were detected by flow cytometry at D30 after HSCT. Lymphocyte subsets were compared between HC group and no HC group.(A)The frequency of CD3⁺T.(B) The counts of CD3⁺T cells.(C)The frequency of CD4⁺T cells.(D) The counts of CD4⁺T cells. (E)The frequency of CD8⁺T cells.(F)The counts of CD8⁺T cells.(G)The frequency of CD19⁺B cells.(H)The counts of CD19⁺B cells. (I)The frequency of CD16⁺CD56⁺ NK cells.(J)The counts of CD16⁺CD56⁺ NK cells.(K) The counts of total lymphocyte.

Figure 3. Receiver operating characteristic (ROC) curve of MNC for patients with and without HC. The cut off was calculated by the largest Youden's index (74% sensitivity, 58% specificity). The threshold of the MNC level is at 8.53×10⁸/kg.

Figure 4. Cumulative incidence of engraftment syndrome in HC and no HC groups.

Figure 5. Cumulative incidence of aGVHD and cGVHD in HC and no HC groups. (A) Cumulative incidence of Grade I-IV aGVHD. (B) Cumulative incidence of Grade II-IV aGVHD. (C) Cumulative incidence of cGVHD. (D) Cumulative incidence of moderate and severe cGVHD.

Table 3. Univariate analysis of HC in children with AA receiving HSCT.

Variable	OR	95%CI	P value
Age	0.99	0.98–1.00	0.25
Sex female vs male	1.01	0.41–2.50	0.97
Disease course	0.99	0.97–1.02	0.79
Disease SAA vs VSAA	2.67	1.06–6.70	0.036*
Donor type
MRD	0.35	0.096–1.33	0.124
HID	0.42	0.58–3.72	0.42
UCB	12.7	1.35–119.92	0.026*
MUD	0.45	0.094–2.205	0.328
HLA matching
10/10	0.43	0.16–1.21	0.11
9/10	5.83	0.51–67.25	0.16
8/10	1.72	0.38–7.79	0.48
7/10	0.71	0.18–2.78	0.63
6/10	1.45	0.45–4.74	0.54
5/10	1.38	0.49–3.88	0.55
ABO match
Matched	1.18	0.48–2.93	0.72
Minor mismatched	0.58	0.15–2.23	0.43
Major mismatched	1.13	0.43–3.02	0.80
CMV seropositive	0.61	0.24–1.51	0.29
EBV seropositive	1.95	0.79–4.88	0.15
Neutrophil engraftment time	1.18	1.00–1.42	0.057*
Platelet engraftment time	1.06	1–1.12	0.056*
MNC	1.16	1.01–1.33	0.04*
CD34	0.94	0.80–1.12	0.52
Engraftment syndrome	2.17	0.86–5.53	0.10*
aGVHD 0-I vs II-IV	6.77	2.14–21.39	0.001*
aGVHD localization
Absent	0.31	0.12–0.78	0.014*
Skin	1.13	0.43–3.02	0.80
Gut ± others	5.74	1.79–18.35	0.003*

Notes: HC, hemorrhagic cystitis; MRD, matched related donor; UCB, Umbilical cord blood; HID, A haplo-identical donor; MUD, matched unrelated donor; HLA, human leukocyte antigen; CMV, Cytomegalovirus; EBV, Epstein-Barr virus; aGVHD, acute graft versus host disease; MNC, mononuclear cells; VSAA, very severe aplastic anemia; SAA, severe aplastic anemia.

* Significant at 0.1.

Table 4. Multivariate analysis of HC in children with AA receiving HSCT.

Variable	OR	95%CI	P value
Disease SAA vs VSAA	2.26	0.62–8.18	0.21
Donor type UCB vs others	0.99	0.99–1.00	0.99
Neutrophil engraftment time	1.37	0.99–1.89	0.06
Platelet engraftment time	1.02	0.98–1.12	0.60
MNC	1.43	1.14–1.78	0.002*
Engraftment syndrome	1.51	0.42–5.42	0.53
aGVHD 0-I vs II-IV	7.75	1.59–37.84	0.011*

Notes: HC, hemorrhagic cystitis; UCB, Umbilical cord blood; aGVHD, acute graft versus host disease; MNC, mononuclear cells; VSAA, very severe aplastic anemia; SAA, severe aplastic anemia.

* Significant at 0.05.

Table 5. Validation analysis of HC in children with AA receiving MRD, HID and MUD.

Donor type	Variable	OR	95%CI	P value
MRD (n = 22)	MNC	10.59	0.21–526.67	0.24
	aGVHD 0-I vs II-IV	9.00	0.39–206.53	0.17
HID (n = 57)	MNC	1.32	1.07–1.64	0.011*
	aGVHD 0-I vs II-IV	6.30	1.53–25.91	0.011*
MUD (n = 13)	MNC	1.35	0.81–2.25	0.25
	aGVHD 0-I vs II-IV	10.00	0.32–315.28	0.19

Notes: MRD, matched related donor; HID, Haplo-identical donor; MUD, matched unrelated donor; MNC, mononuclear cells; aGVHD, acute graft versus host disease.

*Significant at 0.05.

Figure 6. Overall survival of patients with and without hemorrhagic cystitis (HC).