Abstract

Introduction: Studies in patients with paroxysmal nocturnal hemoglobinuria (PNH) have shown that eculizumab reduces intravascular hemolysis, improves disease symptoms, and increases life expectancy. The objective of this analysis was to characterize, in a real-world setting, the benefit of eculizumab therapy in patients with PNH with no history of red blood cell (RBC) transfusion, with a special focus on high disease activity (HDA).

Methods: The International PNH Registry is a prospective, observational study of patients with a PNH clone of 0.01-100%. Three patient populations were studied: 1) non-transfused untreated patients, 2) non-transfused eculizumab-treated patients, 3) eculizumab-treated patients who received ≥1 RBC transfusions in the 6 months prior to initiation of eculizumab. Transfused treated patients served as an additional comparison group. The primary outcome, assessed using multivariate linear regression, was mean absolute change from baseline to 6 months in LDH (U/L) in non-transfused treated and non-transfused untreated patients. Secondary outcomes were mean changes in patient-reported FACIT-Fatigue and EORTC-QLQ-C30 Fatigue scores from baseline to last available assessment.

Results: A total of 1,547 patients were enrolled on or before April 30, 2012. The total study population (N=294) consisted of 1) 144 non-transfused untreated patients, 2) 45 non-transfused eculizumab-treated patients, and 3) 105 transfused eculizumab-treated patients. Of these, 136/144, 43/45, and 99/105 had HDA, respectively (Figure). At baseline, non-transfused untreated patients had the highest mean hemoglobin and lowest clone size (Table 1). Mean absolute reticulocytes were highest in the transfused treated group. Non-transfused untreated patients had the least mean absolute change in LDH from baseline to 6 months (-39.4 U/L) compared to non-transfused treated patients (-1318.8 U/L) and transfused treated patients (-1722.2 U/L) (Table 2). Non-transfused treated patients had a clinically meaningful mean percentage change in LDH compared with untreated patients (-69.9% versus -1.6%; p<0.001 in multivariate linear regression model evaluating absolute change). Statistically significant and clinically meaningful improvements in FACIT-Fatigue scores (increase by ≥4 points) were seen in 73.7% of non-transfused treated patients vs. 24.6% of untreated patients; for EORTC-Fatigue (decrease ≥10 points) in 84.2% vs. 33.3%, respectively. Similarly, non-transfused treated patients with HDA (n=43) had significantly reduced LDH levels (p<0.001) and clinically meaningful improvements in FACIT-Fatigue (p=0.004) and EORTC (p=0.02) compared with untreated patients (n=136).

Conclusions: Data from the International PNH Registry demonstrate that patients with PNH carry a heavy disease burden. Findings show statistically significant and clinically meaningful differences in LDH reduction and improvement in fatigue in patients treated with eculizumab, irrespective of transfusion history, and in patients with HDA.

Table 1.

Baseline Patient Clinical Characteristics

 Non-transfused Transfused  
 Untreated
(N=144) 
Eculizumab
Treated
(N=45) 
Eculizumab
Treated
(N=105) 
Hemoglobin (g/L)
Mean (SD) 
114.1 (24.0) 103.3 (20.6) 101.3 (88.2) 
Absolute reticulocytes (x109 /L)
Mean (SD) 
128.7 (95.02) 124.4 (68.9) 157.4 (79.0) 
%GPI-deficient granulocytes
Mean (SD) 
61.7 (28.0) 68.0 (24.2) 82.1 (18.4) 
History of TE, n (%) 16 (11.1) 13 (28.9) 23 (21.9) 
 Non-transfused Transfused  
 Untreated
(N=144) 
Eculizumab
Treated
(N=45) 
Eculizumab
Treated
(N=105) 
Hemoglobin (g/L)
Mean (SD) 
114.1 (24.0) 103.3 (20.6) 101.3 (88.2) 
Absolute reticulocytes (x109 /L)
Mean (SD) 
128.7 (95.02) 124.4 (68.9) 157.4 (79.0) 
%GPI-deficient granulocytes
Mean (SD) 
61.7 (28.0) 68.0 (24.2) 82.1 (18.4) 
History of TE, n (%) 16 (11.1) 13 (28.9) 23 (21.9) 

GPI, glycosylphosphatidylinositol; RBC, red blood cell; SD, standard deviation; TE, thrombotic event

Table 2.

Change in LDH and FACIT-Fatigue and EORTC Scores

 Non-transfused Transfused 
 Untreated
(N=144) 
Eculizumab Treated
(N=45) 
Eculizumab Treated
(N=105) 
LDH, U/L
Mean (SD) change from baseline to 6 months 
-39.4 (357.5) 
-1318.8 (1065.3) 

-1722.2 (1152.7) 

FACIT-Fatigue 
Absolute change
n
Mean (SD) change from baseline to last available assessment 

69
0.1 (9.6) 

19
10.5 (11.6)* 

29
5.5 (12.3) 
Clinically meaningful
improvement, % (n) 
24.6 (17) 73.7 (14) 55.2 (16) 

EORTC-Fatigue 
Absolute change
n
Mean (SD) change from baseline to last available assessment 
69
−1.5 (26.9) 
19
−22.8 (22.1) 
30
-11.9 (29.3) 
Clinically meaningful
improvement, % (n) 
33.3 (23) 84.2 (16) 46.7 (14) 
 Non-transfused Transfused 
 Untreated
(N=144) 
Eculizumab Treated
(N=45) 
Eculizumab Treated
(N=105) 
LDH, U/L
Mean (SD) change from baseline to 6 months 
-39.4 (357.5) 
-1318.8 (1065.3) 

-1722.2 (1152.7) 

FACIT-Fatigue 
Absolute change
n
Mean (SD) change from baseline to last available assessment 

69
0.1 (9.6) 

19
10.5 (11.6)* 

29
5.5 (12.3) 
Clinically meaningful
improvement, % (n) 
24.6 (17) 73.7 (14) 55.2 (16) 

EORTC-Fatigue 
Absolute change
n
Mean (SD) change from baseline to last available assessment 
69
−1.5 (26.9) 
19
−22.8 (22.1) 
30
-11.9 (29.3) 
Clinically meaningful
improvement, % (n) 
33.3 (23) 84.2 (16) 46.7 (14) 

LDH, lactate dehydrogenase; SD, standard deviation

*p<0.01 vs. untreated group and p<0.05 vs. untreated group in multivariable models

Disclosures

Almeida:Celgene: Consultancy; Novartis: Consultancy; Bristol Meyer Squibb: Speakers Bureau; Shire: Speakers Bureau. Bedrosian:Alexion Pharmaceutials: Employment, Equity Ownership, Patents & Royalties. Cole:Alexion Pharmaceuticals: Employment, Equity Ownership. Muus:Alexion Pharmaceuticals: Honoraria. Schrezenmeier:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Szer:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire Australia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer Australia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals Australasia Pty Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rosse:Alexion Pharmaceuticals: Consultancy.

Author notes

*

Asterisk with author names denotes non-ASH members.

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