Clinical characteristics of 512 eculizumab-naive paroxysmal nocturnal hemoglobinuria patients in China: a single-center observational study

Figures & data

Figure 1. Age distribution of all the patients and patients in different subtypes. A. Age distribution for the whole cohort. Patient number peaked at 21∼40 years (50.6%; N = 259), followed by 41∼60 years (25.4%; N = 130) and then ≤20 years and >60 years, which contributed 13.0% (N = 66) and 11.1% (N = 57) of patients, respectively. B. Age distribution for patients with different subtypes. No difference was found in age distribution for patients with classic PNH, BMF/PNH or subclinical PNH (P > 0.05).

Table 1. Baseline characteristics of the patients with different disease subtypes.

Parameter	BMF/PNH (264)			Classic PNH (240)	Sub-clinica (8)	Reference range	P** value	P*** value
	AA/PNH (233)	MDS/PNH (31)	P* value
Age at disease start (years), median (range)	32.5 (9, 80)	57 (11, 74)	0.001	32 (12, 75)	33.5 (12, 71)		0.001	0.09
Sex (F:M)	102/131	18/13	0.133	98/142	6/2		0.086	0.296
Disease duration (months)	64 (24,624)	94 (24,502)	0.507	96 (24,401)	102.5 (25,220)		0.002	<0.001
Symptoms % (No.)
Fatigue	209 (89.69)	31 (100.00)	0.089	224 (93.33)	8 (100)		0.125	0.315
Hemoglobinuria	184 (78.97)	12 (38.71)	<0.001	216 (90.00)	8 (100)		<0.001	<0.001
Shortness of breath, palpitation	121 (51.93)	6 (19.35)	0.001	144 (60.00)	8 (100)		<0.001	0.008
Headache	83 (35.62)	19 (61.29)	0.01	132 (55.00)	8 (100)		<0.001	<0.001
Abdominal pain	68 (29.18)	19 (61.29)	0.001	104 (43.33)	8 (100)		<0.001	0.017
Erectile dysfunction	53 (22.75)	0	0.001	68 (28.33)	0 (0)		0.002	0.03
Backache	44 (18.88)	6 (19.35)	>0.99	64 (26.67)	0 (0)		0.083	0.038
Dysphagia	29 (12.45)	12 (38.71)	0.001	28 (11.67)	4 (50.00)		<0.001	0.208
Easy abrasion of skin/mucous bleeding	39 (16.74)	6 (19.35)	0.799	24 (10.00)	0		0.079	0.022
PNH clone size
CD55/59- neutrophil (%)	55.45 ± 36.33	28.83 ± 31.8	0.001	77.15 ± 25.37	5.29 ± 6.4	≤5%	<0.001	<0.001
CD55/59- RBC (%)	31.36 ± 27.52	21.37 ± 27.01	0.06	49.54 ± 25.57	2 ± 2.77	≤5%	<0.001	<0.001
FLAER- neutrophil (%)	57.15 ± 36.82	30.39 ± 32.43	0.001	77.48 ± 25.98	5.57 ± 6.65	≤1%	<0.001	<0.001
Complete blood count
WBC (×10^9/L)	3.87 ± 2.21	3.44 ± 1.86	0.204	4.42 ± 2.12	5.65 ± 3.94	3.5∼9.5	<0.001	<0.001
NEUT# (×10^9/L)	2.04 ± 1.75	1.74 ± 1.5	0.275	2.82 ± 3.92	3.15 ± 2.89	2∼7.5	<0.001	<0.001
HGB (g/L)	79.88 ± 24.75	73.1 ± 22.99	0.307	82.7 ± 23.98	97.13 ± 21.12	110∼150	0.032	0.099
RBC (×10^12/L)	2.45 ± 0.80	2.32 ± 0.93	0.322	2.78 ± 0.82	3.01 ± 0.88	4∼5.5	<0.001	<0.001
RET# (×10^9/L)	4.59 ± 3.16	3.86 ± 3.69	0.101	6.27 ± 3.79	7.16 ± 6.46	0.8∼2	<0.001	<0.001
PLT (×109/L)	79.9 ± 72.55	136.63 ± 197.1	0.179	161.7 ± 90.54	162.75 ± 94.44	100∼350	<0.001	<0.001
Biochemistry
LDH (U/L)	1093.76 ± 882.56	788.79 ± 859.75	0.029	1555.45 ± 875.21	246.29 ± 94.1	0∼250	<0.001	<0.001
TBi l (mmol/L)	26.13 ± 19.13	20.1 ± 14.54	0.058	33.06 ± 20.4	31.56 ± 30.58	5.1∼22.2	<0.001	<0.001
DBil (mmol/L)	8.07 ± 7.40	6.37 ± 3.71	0.18	9.28 ± 8.85	7.5 ± 5.58	0∼6.8	0.002	<0.001
ALT (U/L)	30.3 ± 37.88	27.95 ± 28.63	0.595	25.69 ± 22.96	19.67 ± 5.65	7∼40	0.905	0.733
AST (U/L)	55.69 ± 42.82	48.85 ± 49.65	0.172	73.53 ± 49.87	22.67 ± 5.79	13∼35	<0.001	<0.001
Scr (μmol/L)	71.43 ± 42.96	73.17 ± 30.84	0.746	65.09 ± 25.57	56 ± 14.34	45∼84	0.11	0.02
Iron metabolism
Fer (ng/mL)	708.94 ± 1423.83	701.79 ± 758.65	0.149	148.54 ± 605.05	205.33 ± 130.02	1.4∼30.7	<0.001	<0.001
Thrombosis related
D-dimer (mg/L FEU)	1.64 ± 2.73	2.91 ± 5.03	0.488	0.79 ± 0.98	0.17	0∼0.55	0.006	<0.001
Urine test(%,(n/N))^&
Positive urine protein	25.3 (19/75)	0	0.112	31.9 (36/113)	0	Negative	0.072	0.127
Positive urine RBC	54.7 (41/75)	81.8 (9/11)	0.111	68.1 (77/113)	25.0 (1/4)	Negative	0.053	0.146

Note: ALT: alanine aminotransferase; AST: aspartate aminotransferase; DBil: direct bilirubin; Fer: ferritin; HGB: hemoglobin; LDH: lactate dehydrogenase; NEUT#: absolute value of neutrophils; NA: not available; No.: number; PLT: platelet count; RBC: red blood cell count; RET#: absolute value of reticulocytes; Scr: serum creatinine; SF: serum ferritin; TBil: total bilirubin; WBC: white blood cell count. * ‘easy to abrasion of skin/mucous bleeding’ was defined as patients with ecchymosis at more than 2 places or at least twice gum/nose bleeding. P*: comparison between AA/PNH and MDS/PNH. P**: comparison among BMF/PNH, classic PNH and sub-clinica PNH, P***: comparison between BMF/PNH and classic PNH. ^&‘%’ refers to the percent originated from number of positive urine protein (n) divided by the total number of urine tests (N).

Table 2. Complications, treatment and outcome for patients with BMF/PNH and classic PNH.

	Total** (N = 504)	BMF/PNH (N = 264)	Classic PNH (N = 240)	P value
Complications % (No.)
Thrombosis	18.3 (92)	15.5% (41)	21.3% (51)	0.66
Renal insufficiency	13.5% (68)	18.6% (49)	7.1% (17)	<0.0001
Hemorrhage	13.3% (67)	17.0% (45)	9.3% (22)	0.01
Glucocorticoid related side effects	3.9% (20)	4.5% (12)	3.3% (8)	0.24
Diabetes	2.4% (12)	2.7% (7)	2.1% (5)	0.56
Hypertension	1.0% (5)	1.5% (4)	0.4% (1)	0.19
Osteoporosis and necrosis of femoral head	0.6% (3)	0.4% (1)	0.8% (2)	1.00
Infections	3.2% (16)	3.8% (10)	4.2% (10)	0.82
Bacteria	1.4% (7)	1.9% (5)	2.9% (7)	0.78
Fungus	0.4% (2)	0.4% (1)	0.4% (1)	1.00
PCP	0.2% (1)	0.4% (1)	0	0.47
Tuberculosis	0.4% (2)	0	0.4% (1)	1.00
HBV/HCV	0.8% (4)	1.1% (3)	0.4% (1)	0.35
Tumor	1.8% (9)	0.4% (1)	2.9% (7)	0.07
Tumor kidney tumor	0.6% (3)	0	1.3% (3)	0.25
Thyroid cancer	0.2% (1)	0	0.4% (1)	1.00
Cranial tumor	0.2% (1)	0.4% (1)	0	0.47
Breast tumor	0.8% (4)	0	1.3% (3)	0.25
Lung cancer	0.2% (1)	0	0	1.00
Bile duct or urinary calculi stone	1.8% (9)	0.8% (2)	2.9% (7)	0.18
Immune diseases	1.2% (6)	1.1% (3)	0.8% (2)	0.67
Pulmonary hypertension	0.6% (3)	0.4% (1)	0.8% (2)	1.00
Treatment % (No.)
Androgen	33.7% (170)	35.2% (93)	15.2% (77)	0.01
Glucocorticoid	30.9% (156)	15.9% (42)	22.6% (114)	<0.001
CsA	29.9% (151)	46.9% (124)	11.25% (27)	<0.001
Iron supplement therapy	15.3% (77)	9.5% (25)	21.7% (52)	0.01
Stimulating factors	12.3% (62)	17.4% (46)	6.7% (16)	<0.001
Red blood cell transfusion	8.7% (44)	5.7% (15)	12.1% (29)	0.08
Anticoagulation therapy	7.5% (38)	5.7% (15)	9.6% (23)	0.40
Tacrolimus	6.2% (31)	9.8% (26)	2.1% (5)	<0.001
ATG/ALG	2.4% (12)	3.8% (10)	0.8% (2)	0.02
Allogeneic transplantation	1.6% (8)	1.0% (5)	1.3% (3)	0.48
Iron chelation therapy	1.2% (6)	1.0% (5)	0.4% (1)	0.10
Chemotherapy	0.4% (2)	0.7% (2)	0	0.22
Follow-up time (months)	71.5 (24,144)	66 (24,144)	76 (24,132)	0.46
Outcome % (No.)
Evolution to myeloid malignancies	1.0% (5)	1.9% (5)	0	0.02
Death	5.4% (27)	4.9% (13)	5.8% (14)	0.90
Cause of death % (No.)
Thrombosis	1.6% (8)	1.5% (4)	1.7% (4)	1.00
Hemorrhage	1.0% (5)	0.8% (2)	1.3% (3)	1.00
Infection	1.0% (5)	1.1% (3)	0.8% (2)	0.67
Anemia	0.8% (4)	0.8% (2)	0.8% (2)	1.00
Progression to MDS/AML	0.4% (2)	0.8% (2)	0	0.22
Lung cancer	0.2% (1)	0	0.4% (1)	1.00
NA	0.4% (2)	0.4% (1)	0.4% (1)	1.00

Note: ATG/ALG: anti-thymocyte globulin/antilymphocyte globulin; CsA: cyclosporine A; HBV/HCV: hepatitis B/C; MDS/AML: myelodysplastic syndrome/acute myeloid leukemia; PCP: pneumocystis carinii pneumonia; *Immune diseases including antiphospholipid antibody syndrome, Sjogren's syndrome, ankylosing spondylitis, autoimmune liver disease, systemic lupus erythematosus and wolf brain. **: not including sub-clinica PNH.

Figure 2. Change in PNH clone size in patients with different response to immunosuppressive therapy (IST). Neither those who responded (P = 0.829) nor those not responded (P = 0.133) to immunosuppressive therapy (IST) had change in their clone size during follow-up. However, those who relapsed to IST increased in PNH clone size during follow-up (P < 0.01). PNH clone size was calculated as FLAER negative neutrophils.

Figure 3. Kaplan-Meier curves for the whole cohort and patients in different subtypes. A. OS for the whole cohort. B. Patients with classic PNH had better OS than those with BMF/PNH (P = 0.013). C. Detail analysis showed that OS was similar between patients with classic PNH and AA/PNH (P = 0.147), whereas OS was lower in patients with MDS/PNH than classic PNH and AA/PNH patients (P < 0.001).