Moving toward Individual Treatment Goals with Pegcetacoplan in Patients with PNH and Impaired Bone Marrow Function
<p>Mean haematological parameters over time for pegcetacoplan-treated PNH patients with and without impaired bone marrow function in the PEGASUS study. Patient numbers at week 16 and week 48 are as follows in the group of patients with impaired bone marrow function at baseline: haemoglobin, LDH and ARC, 3 patients each; platelets and neutrophils, 4 and 2 patients, respectively. Patient numbers at week 16 and week 48 are as follows in the group of patients without impaired bone marrow function at baseline: haemoglobin, 32 and 25 patients, respectively; LDH, 31 and 25 patients, respectively; ARC, 30 and 24 patients, respectively; platelets, 31 and 22 patients, respectively; neutrophils, 30 and 22 patients, respectively. ARC, absolute reticulocyte count; Hb, haemoglobin; LDH, lactate dehydrogenase; SE, standard error.</p> "> Figure 2
<p>Mean haematological parameters over time for pegcetacoplan-treated PNH patients with and without impaired bone marrow function in the PRINCE study. Patient numbers at week 26 are as follows in the group of patients with impaired bone marrow function at baseline: haemoglobin, LDH, ARC, platelets, neutrophils, 5 patients each. Patient numbers at week 26 are as follows in the group of patients without impaired bone marrow function at baseline: haemoglobin, 24 patients; LDH, 24 patients; ARC, 21 patients; platelets, 25 patients; neutrophils, 20 patients. ARC, absolute reticulocyte count; Hb, haemoglobin; LDH, lactate dehydrogenase; SE, standard error.</p> "> Figure 3
<p>Proportion of pegcetacoplan-treated PNH patients with and without impaired bone marrow function reaching clinically meaningful treatment outcomes vs. normalisation. CFB, change from baseline; FACIT, Functional Assessment of Chronic Illness Therapy; LDH, lactate dehydrogenase; LLN, lower limit of normal; ULN, upper limit of normal.</p> "> Figure 4
<p>(<b>A</b>) PEGASUS [<a href="#B14-ijms-25-08591" class="html-bibr">14</a>,<a href="#B15-ijms-25-08591" class="html-bibr">15</a>] and (<b>B</b>) PRINCE [<a href="#B11-ijms-25-08591" class="html-bibr">11</a>] study designs. * Pegcetacoplan run-in periods in PEGASUS: (1) before randomisation, for both treatment groups; and (2) at start of open-label period, for the patients randomised to the eculizumab monotherapy group during the randomised controlled period. <sup>†</sup> Haemoglobin levels: LLN males, <13.6 g/dL; LLN females, <12.0 g/dL; LDH, 1.5 × ULN ≥339 U/L. <sup>‡</sup> All patients screened in PRINCE had never received a complement inhibitor at any point. C5i, complement 5 inhibitor; LDH, lactate dehydrogenase; LLN, lower limit of normal; PNH, paroxysmal nocturnal haemoglobinuria; SC, subcutaneous; ULN, upper limit of normal.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Patient Baseline Characteristics
2.2. Normalisation of Haematological and Clinical Parameters
2.3. Assessment of Treatment Response Using Clinically Meaningful Changes as Target
3. Discussion
4. Materials and Methods
4.1. Study Design and Population
4.2. Outcome Measures
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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PEGASUS | PRINCE | |||||||
---|---|---|---|---|---|---|---|---|
PEG | ECU | PEG | Control | |||||
Baseline Characteristics | Impaired Bone Marrow Function (N = 5) | Non-Impaired Bone Marrow Function (N = 36) | Impaired Bone Marrow Function (N = 9) | Non-Impaired Bone Marrow Function (N = 30) | Impaired Bone Marrow Function (N = 7) | Non-Impaired Bone Marrow Function (N = 28) | Impaired Bone Marrow Function (N = 2) | Non-Impaired Bone Marrow Function (N = 5) |
Age, years (mean (range)) | 40.6 (19–81) | 51.6 (22–79) | 47.0 (30–71) | 47.4 (23–78) | 36.3 (29–45) | 43.7 (22–67) | 42.0 (28–56) | 47.6 (20–67) |
Female sex, n (%) | 4 (80) | 23 (63.9) | 6 (66.7) | 16 (53.3) | 2 (28.6) | 14 (50.0) | 0 (0) | 1 (20.0) |
Mean body-mass index, kg/m2 (SD) | 27.0 (7.50) | 26.7 (3.87) | 25.1 (5.25) | 26.1 (4.00) | 22.2 (5.42) | 24.4 (4.13) | 23.6 (0.53) | 22.7 (2.35) |
No transfusions within previous 12 months, n (%) | 1 (20.0) | 9 (25.0) | 0 (0) | 10 (33.3) | 1 (14.3) | 5 (17.9) | 1 (50.0) | 1 (20.0) |
Duration of prior treatment with eculizumab, years (mean (range)) | 1.9 (1–3) | 5.6 (0–17) | 4.3 (0–14) | 4.8 (0–14) | N/A | N/A | N/A | N/A |
Eculizumab dose at screening, n (%) | ||||||||
900 mg every 2 weeks | 4 (80.0) | 23 (63.9) | 7 (77.8) | 23 (76.7) | N/A | N/A | N/A | N/A |
1200 mg every 2 weeks | 0 (0) | 12 (33.3) | 2 (22.2) | 7 (23.3) | N/A | N/A | N/A | N/A |
1500 mg every 2 weeks | 1 (20.0) | 1 (2.8) | 0 (0) | 0 (0) | N/A | N/A | N/A | N/A |
History of thrombosis, n (%) | 3 (60.0) | 12 (33.3) | 4 (44.4) | 6 (20.0) | 2 (28.6) | (0) | 0 (0) | 0 (0) |
Mean haemoglobin, g/dL (SD) Normal reference range: males, 13.6–18; females, 12–16 | 7.9 (0.50) | 8.8 (1.09) | 8.5 (0.73) | 8.7 (0.93) | 9.0 (0.97) | 9.5 (1.49) | 9.2 (0.89) | 8.0 (0.83) |
Mean lactate dehydrogenase, U/L (SD) Normal reference range 113–226 | 263.8 (61.07) | 256.6 (102.30) | 211.4 (38.12) | 337.8 (319.53) | 2052.0 (961.79) | 2175.7 (912.54) | 805.8 (248.55) | 2183.7 (369.69) |
Mean absolute reticulocyte count, ×109/L (SD; median count) Normal reference range: males, 10–140; females, 10–120 | 173.3 (81.45; Median 155.0) | 223.7 (73.12; Median 197.5) | 184.6 (41.74; Median 193.3) | 225.6 (73.36; Median 220.0) | 200.5 (114.89; Median 190.0) | 237.6 (70.99; Median 257.5) | 90.0 (7.07; Median 90.0) | 189.0 (39.91; Median 185.0) |
Mean neutrophil count, ×109/L (SD) Normal reference range: 1–8 | 1.3 (0.09) | 3.3 (3.02) | 1.0 (0.33) | 2.8 (1.11) | 0.9 (0.44) | 3.4 (1.32) | 1.0 (0.03) | 2.5 (0.50) |
Mean platelet count, ×109/L (SD) Normal reference range: 140–400 | 121.6 (74.11) | 184.9 (85.23) | 116.3 (43.36) | 165.9 (81.31) | 153.0 (90.44) | 199.0 (125.05) | 76.0 (15.56) | 142.4 (23.18) |
Mean FACIT-Fatigue score (SD) Population norm 43.6 | 35.4 (12.32) | 31.7 (11.36) | 28.7 (10.26) | 32.4 (13.17) | 35.1 (11.14) | 36.6 (10.73) | 44.0 (4.24) | 37.0 (11.62) |
PNH red blood cells | ||||||||
Mean %CD59 dim Type II, % (SD) | 21.5 (26.29) | 20.0 (19.15) | 16.5 (11.33) | 24.5 (19.29) | 8.5 (13.75) | 13.9 (18.68) | 8.5 (6.66) | 23.2 (29.47) |
Mean %CD59 neg Type III, % (SD) | 34.1 (14.83) | 48.3 (21.98) | 49.5 (20.71) | 50.5 (22.10) | 26.9 (26.88) | 30.3 (16.39) | 16.2 (12.66) | 33.7 (14.85) |
Mean %CD59 (dim Type II and neg Type III), % (SD) | 55.6 (31.66) | 68.4 (25.88) | 65.9 (22.72) | 75.0 (26.61) | 35.3 (32.07) | 44.2 (21.67) | 24.7 (6.00) | 56.9 (20.10) |
PEGASUS Week 16 | PRINCE Week 26 | |||||||
---|---|---|---|---|---|---|---|---|
PEG | ECU | PEG | Control | |||||
Haematological and Clinical Response Parameters, n (%) | Impaired Bone Marrow Function (N = 5) | Non-Impaired Bone Marrow Function (N = 36) | Impaired Bone Marrow Function (N = 9) | Non-Impaired Bone Marrow Function (N = 30) | Impaired Bone Marrow Function (N = 7) | Non-Impaired Bone Marrow Function (N = 28) | Impaired Bone Marrow Function (N = 2) | Non-Impaired Bone Marrow Function (N = 5) |
Hb normalisation (≥gender-specific LLN: males, 13.6 g/dL; females, 12.0 g/dL) | 1 (20.0) | 13 (36.1) | 0 (0) | 0 (0) | 3 (42.9) | 13 (46.4) | 0 (0) | 0 (0) |
Hb ≥ 12 g/dL | 1 (20.0) | 15 (41.7) | 0 (0) | 0 (0) | 3 (42.9) | 14 (50.0) | 0 (0) | 0 (0) |
LDH normalisation (≤ULN [226 U/L]) | 3 (60.0) | 26 (72.2) | 6 (66.7) | 17 (56.7) | 4 (57.1) | 19 (67.9) | 0 (0) | 0 (0) |
ARC normalisation (<gender-specific ULN: males, 140 × 109 cells/L; females, 120 × 109 cells/L) | 3 (60.0) | 28 (77.8) | 3 (33.3) | 4 (13.3) | 4 (57.1) | 17 (60.7) | 1 (50.0) | 0 (0) |
Neutrophil normalisation (≥LLN [1 × 109 cells/L]) | 3 (60.0) | 30 (83.3) | 7 (77.8) | 29 (96.7) | 4 (57.1) | 18 (64.3) | 1 (50.0) | 3 (60.0) |
Platelet normalisation (≥LLN [140 × 109 cells/L]) | 2 (40.0) | 15 (41.7) | 1 (11.1) | 18 (60.0) | 2 (28.6) | 12 (42.9) | 0 (0) | 2 (40.0) |
Transfusion avoidance | 3 (60.0) | 31 (86.1) | 0 (0) | 6 (20.0) | 6 (85.7) | 26 (92.9) | 1 (50.0) | 0 (0) |
FACIT-Fatigue (≥population norm 43.6) | 2 (40.0) | 18 (50.0) | 0 (0) | 4 (13.3) | 2 (28.6) | 18 (64.3) | 1 (50.0) | 0 (0) |
PEGASUS Week 16 | PRINCE Week 26 | |||||||
---|---|---|---|---|---|---|---|---|
PEG | ECU | PEG | Control | |||||
Haematological and Clinical Response Parameters, n (%) | Impaired Bone Marrow Function (N = 5) | Non-Impaired Bone Marrow Function (N = 36) | Impaired Bone Marrow Function (N = 9) | Non-Impaired Bone Marrow Function (N = 30) | Impaired Bone Marrow Function (N = 7) | Non-Impaired Bone Marrow Function (N = 28) | Impaired Bone Marrow Function (N = 2) | Non-Impaired Bone Marrow Function (N = 5) |
Hb (CFB ≥ 2 g/dL) | 2 (40.0) | 23 (63.9) | 0 (0) | 0 (0) | 5 (71.4) | 18 (64.3) | 0 (0) | 0 (0) |
LDH (≤1.5 × ULN [339 U/L]) | 3 (60.0) | 30 (83.3) | 8 (88.9) | 23 (76.7) | 5 (71.4) | 23 (82.1) | 0 (0) | 0 (0) |
FACIT-Fatigue (CFB ≥ 5) | 3 (60.0) | 23 (63.9) | 2 (22.2) | 6 (20.0) | 3 (42.9) | 15 (53.6) | 1 (50.0) | 0 (0) |
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Szer, J.; Panse, J.; Kulasekararaj, A.; Oliver, M.; Fattizzo, B.; Nishimura, J.-i.; Horneff, R.; Szamosi, J.; Peffault de Latour, R. Moving toward Individual Treatment Goals with Pegcetacoplan in Patients with PNH and Impaired Bone Marrow Function. Int. J. Mol. Sci. 2024, 25, 8591. https://doi.org/10.3390/ijms25168591
Szer J, Panse J, Kulasekararaj A, Oliver M, Fattizzo B, Nishimura J-i, Horneff R, Szamosi J, Peffault de Latour R. Moving toward Individual Treatment Goals with Pegcetacoplan in Patients with PNH and Impaired Bone Marrow Function. International Journal of Molecular Sciences. 2024; 25(16):8591. https://doi.org/10.3390/ijms25168591
Chicago/Turabian StyleSzer, Jeff, Jens Panse, Austin Kulasekararaj, Monika Oliver, Bruno Fattizzo, Jun-ichi Nishimura, Regina Horneff, Johan Szamosi, and Régis Peffault de Latour. 2024. "Moving toward Individual Treatment Goals with Pegcetacoplan in Patients with PNH and Impaired Bone Marrow Function" International Journal of Molecular Sciences 25, no. 16: 8591. https://doi.org/10.3390/ijms25168591