Abstract

Introduction: Studies of children with paroxysmal nocturnal hemoglobinuria (PNH) are scarce and include a very limited number of patients. The objective of this analysis was to describe characteristics of PNH at enrollment for the largest available registry of pediatric patients, and to compare demographic and clinical characteristics with those of adult patients.

Methods: The International PNH Registry is a prospective, multi-center worldwide, observational study of patients with a PNH clone of 0.01-100%. Data are collected from patient medical records at the time of Registry enrollment and every six months thereafter. Adult patients were ³18 years of age at enrollment and disease start and pediatric patients were <18 years at enrollment. Demographics and clinical parameters in patients untreated with eculizumab at enrollment for the two age cohorts were compared using the Wilcoxon-Mann-Whitney test for medians and PearsonÕs chi-square for frequencies. The rate of thrombotic events (TE) between disease start (defined as the earliest reported PNH symptoms, granulocyte clone, or PNH diagnosis) and enrollment was calculated per 100 person-years.

Results: As of March 2, 2015, a total of 2,184 patients were eligible for analysis: 94 (4.3%) pediatric patients and 2,090 (95.7%) adult patients. Median age (range) at enrollment was 14.0 years (3-17) in pediatrics and 45.5 years (18-100) in adults; median disease duration was 0.7 years and 2.1 years, respectively (p<0.001). More pediatric than adult patients had a PNH clone of <10% and severe cytopenia (Table). Pediatric patients had lower percent of reticulocytes compared with adults (2.1% vs. 2.6%, respectively; p=0.015). History of aplastic or hypoplastic anemia was more frequent in pediatric than adult patients (76.5% vs 54.4%, respectively; p<0.001). History of TE and any major adverse vascular event was less frequent in pediatrics (2.1% vs 8.7%; p=0.025, and 4.3% vs. 14.4%; p=0.005). The rate of TE between disease start and enrollment was lower in pediatric patients, but not statistically significant: 1.4 per 100 person-years (95%CI 0.2-5.2) compared to adult patients (2.3 per 100 person-years (95%CI 2.0-2.6). More pediatric patients than adults had abdominal pain at enrollment.

Conclusions: The International PNH Registry provides the largest available pediatric cohort of patients with a PNH clone to characterize this understudied population and demonstrate an important disease burden. Pediatric patients were more likely to have smaller PNH clones and a higher component of aplastic/hypoplastic anemia. Pediatric patients had fewer vascular events. These findings may reflect the natural evolution of the disease and can be useful in the clinical management of PNH.

Table 1.

Clinical Characteristics at Enrollment of Pediatric and Adult Patients with PNH

 Pediatric
(n=94) 
Adult
(n=2,090) 
P-value 
Clone size (percent GPI-deficient granulocytes), n (%)
<10%
10 to < 50%
³50% 

47 (55.3)
16 (18.8)
22 (25.9) 

550 (38.3)
322 (22.4)
565 (39.3) 

0.006* 
Cytopenia status, n (%)
None (neutrophils ³ 1.5 x 109/L and platelets ³100 x 109/L)
Moderate (neutrophils <1.5 x 109/L or platelets <100 x 109/L)
Severe (neutrophils <0.5 x 109/L or platelets <20x109/L) 

22 (29.3)
28 (37.3)
25 (33.3) 

735 (42.2)
784 (45.1)
221 (12.7) 

<0.001* 
Percent reticulocytes
Median (Q1, Q3) 
2.1 (1.1, 3.5) 2.6 (1.6, 4.6) 0.015 
Hemolytic status, n (%)
Hemolytic (LDH ³1.5 x ULN and/or reticulocytes ³60 x 109/L)
Not hemolytic (LDH <1.5 x ULN and reticulocytes <60 x 109/L) 

33 (58.9)
23 (41.1) 

1,038 (65.3)
551 (34.7) 

NS 
LDH Ratio, n (%)
<1.5 x ULN
³1.5 x ULN 

30 (58.8)
21 (41.2) 

684 (47.0)
770 (53.0) 

NS  
History of TE, n (%)
Yes
No 

2 (2.1)
92 (97.9) 

181 (8.7)
1,902 (91.3) 

0.025 
Rate of TE
Number of TE, n
Person-years (disease start to enrollment)
Rate/100 person-years (95% CI) 

2
139.9
1.4 (0.2-5.2) 

255
11,119.8
2.3 (2.0-2.6) 

NS 
History of MAVE, n (%) 4 (4.3) 300 (14.4) 0.005 
 Pediatric
(n=94) 
Adult
(n=2,090) 
P-value 
Clone size (percent GPI-deficient granulocytes), n (%)
<10%
10 to < 50%
³50% 

47 (55.3)
16 (18.8)
22 (25.9) 

550 (38.3)
322 (22.4)
565 (39.3) 

0.006* 
Cytopenia status, n (%)
None (neutrophils ³ 1.5 x 109/L and platelets ³100 x 109/L)
Moderate (neutrophils <1.5 x 109/L or platelets <100 x 109/L)
Severe (neutrophils <0.5 x 109/L or platelets <20x109/L) 

22 (29.3)
28 (37.3)
25 (33.3) 

735 (42.2)
784 (45.1)
221 (12.7) 

<0.001* 
Percent reticulocytes
Median (Q1, Q3) 
2.1 (1.1, 3.5) 2.6 (1.6, 4.6) 0.015 
Hemolytic status, n (%)
Hemolytic (LDH ³1.5 x ULN and/or reticulocytes ³60 x 109/L)
Not hemolytic (LDH <1.5 x ULN and reticulocytes <60 x 109/L) 

33 (58.9)
23 (41.1) 

1,038 (65.3)
551 (34.7) 

NS 
LDH Ratio, n (%)
<1.5 x ULN
³1.5 x ULN 

30 (58.8)
21 (41.2) 

684 (47.0)
770 (53.0) 

NS  
History of TE, n (%)
Yes
No 

2 (2.1)
92 (97.9) 

181 (8.7)
1,902 (91.3) 

0.025 
Rate of TE
Number of TE, n
Person-years (disease start to enrollment)
Rate/100 person-years (95% CI) 

2
139.9
1.4 (0.2-5.2) 

255
11,119.8
2.3 (2.0-2.6) 

NS 
History of MAVE, n (%) 4 (4.3) 300 (14.4) 0.005 

GPI, glycosylphosphatidylinositol; LDH, lactate dehydrogenase; MAVE, major adverse vascular event; TE, thrombotic event; ULN, upper limit of normal

*P-values for clone size and cytopenia status represent overall comparison of categories.

Disclosures

Muus:Alexion Pharmaceuticals: Honoraria. Schrezenmeier:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Almeida:Celgene: Consultancy; Novartis: Consultancy; Bristol Meyer Squibb: Speakers Bureau; Shire: Speakers Bureau. Wilson:Alexion Pharmaceuticals: Employment. Ware:Bayer Pharmaceuticals: Consultancy; Biomedomics: Research Funding; Eli Lilly: Other: DSMB membership; Bristol Myers Squibb: Research Funding.

Author notes

*

Asterisk with author names denotes non-ASH members.