During the past decade a large body of experimental and clinical studies has focused on the hypothesis that nitric oxide (NO) depletion by plasma hemoglobin in the microcirculation plays a central ...role in the pathogenesis of many manifestations of sickle cell disease (SCD), particularly pulmonary hypertension. We have carefully examined those studies and believe that the conclusions drawn from them are not adequately supported by the data. We agree that NO depletion may well play a role in the pathophysiology of other hemolytic states such as paroxysmal nocturnal hemoglobinuria, in which plasma hemoglobin concentrations are often at least an order of magnitude greater than in SCD. Accordingly, we conclude that clinical trials in SCD designed to increase the bioavailability of NO or association studies in which SCD clinical manifestations are related to plasma hemoglobin via its surrogates should be viewed with caution.
Background
Eculizumab reduces intravascular haemolysis and improves disease symptoms in patients with paroxysmal nocturnal haemoglobinuria (PNH).
Aims
To characterise, in a real‐world setting, the ...effect of eculizumab in patients with haemolytic PNH (lactase dehydrogenase (LDH) ≥ 1.5 upper limit of normal) and no history of red blood cell transfusion, including those with high disease activity (HDA).
Methods
Three populations from the International PNH Registry were studied: (i) non‐transfused, untreated; (ii) non‐transfused, eculizumab‐treated and (iii) transfused, eculizumab‐treated (≥1 transfusions in 6 months prior to eculizumab initiation). Using multivariate linear regression, the primary outcome was mean absolute change from baseline to 6 months in LDH (U/L) in non‐transfused patients who were treated with eculizumab versus those who remained untreated. Secondary outcomes were mean changes in functional assessment of chronic illness therapy (FACIT)‐Fatigue and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC‐QLQ)‐C30 Fatigue scores from baseline to last available assessment.
Results
The study population included (i) 144 non‐transfused, untreated patients; (ii) 45 non‐transfused, eculizumab‐treated patients and (iii) 105 transfused, eculizumab‐treated patients. Of these, 136/144, 43/45 and 99/105 had HDA respectively. Compared with untreated patients, non‐transfused, treated patients had greater absolute reduction in LDH (−1318.8 vs −39.4; P < 0.001) and greater percentage reduction in LDH (−69.9 vs −1.6%; P < 0.001). Clinically meaningful improvements in FACIT‐Fatigue (73.7 vs 24.6%, respectively) and in EORTC‐QLQ‐C30 (84.2 vs 33.3%, respectively) were observed. Non‐transfused, treated patients with HDA had significantly reduced LDH levels (P < 0.001) and clinically meaningful improvements in FACIT‐Fatigue (P = 0.003) and EORTC‐QLQ‐C30 (P = 0.020) versus untreated patients.
Conclusion
Significant LDH reduction and clinically meaningful improvement in fatigue were observed in patients with PNH and HDA treated with eculizumab versus untreated patients, irrespective of transfusion history.
: To determine and directly compare the clinical course of white and Asian patients with paroxysmal nocturnal hemoglobinuria (PNH), data were collected for epidemiologic analysis on 176 patients from ...Duke University and 209 patients from Japan. White patients were younger with significantly more classical symptoms of PNH including thrombosis, hemoglobinuria, and infection, while Asian patients were older with more marrow aplasia. The mean fraction of CD59-negative polymorphonuclear cells (PMN) at initial analysis was higher among Duke patients than Japanese patients. In both cohorts, however, a larger PNH clone was associated with classical PNH symptoms, while a smaller PNH clone was associated with marrow aplasia. Thrombosis was significantly more prevalent in white patients than Asian patients, and was associated with a significantly higher proportion of CD59-negative PMN. For individual patients, CD59-negative populations varied considerably over time, but a decreasing PNH clone portended hematopoietic failure. Survival analysis revealed a similar death rate in each group, although causes of death were different and significantly more Duke patients died from thrombosis. Japanese patients had a longer mean survival time (32.1 yr vs. 19.4 yr), although Kaplan-Meier survival curves were not significantly different. Poor survival in both groups was associated with age over 50 years, severe leukopenia/neutropenia at diagnosis, and severe infection as a complication; additionally, thrombosis at diagnosis or follow-up for Duke patients and renal failure for Japanese patients were poor prognostic factors. These data identify important differences between white and Asian patients with PNH. Identification of prognostic factors will help the design of prospective clinical trials for PNH.
Information on life expectancy and risk factors for early death among patients with sickle cell disease (sickle cell anemia, sickle cell-hemoglobin C disease, and the sickle cell-beta-thalassemias) ...is needed to counsel patients, target therapy, and design clinical trials.
We followed 3764 patients who ranged from birth to 66 years of age at enrollment to determine the life expectancy and calculate the median age at death. In addition, we investigated the circumstances of death for all 209 adult patients who died during the study, and used proportional-hazards regression analysis to identify risk factors for early death among 964 adults with sickle cell anemia who were followed for at least two years.
Among children and adults with sickle cell anemia (homozygous for sickle hemoglobin), the median age at death was 42 years for males and 48 years for females. Among those with sickle cell-hemoglobin C disease, the median age at death was 60 years for males and 68 years for females. Among adults with sickle cell disease, 18 percent of the deaths occurred in patients with overt organ failure, predominantly renal. Thirty-three percent were clinically free of organ failure but died during an acute sickle crisis (78 percent had pain, the chest syndrome, or both; 22 percent had stroke). Modeling revealed that in patients with sickle cell anemia, the acute chest syndrome, renal failure, seizures, a base-line white-cell count above 15,000 cells per cubic millimeter, and a low level of fetal hemoglobin were associated with an increased risk of early death.
Fifty percent of patients with sickle cell anemia survived beyond the fifth decade. A large proportion of those who died had no overt chronic organ failure but died during an acute episode of pain, chest syndrome, or stroke. Early mortality was highest among patients whose disease was symptomatic. A high level of fetal hemoglobin predicted improved survival and is probably a reliable childhood forecaster of adult life expectancy.
The clinical pathology of paroxysmal nocturnal hemoglobinuria (PNH) involves 3 complications: hemolytic anemia, thrombosis, and hematopoietic deficiency. The first 2 are clearly the result of the ...cellular defect in PNH, the lack of proteins anchored to the membrane by the glycosylphosphatidylinositol anchor. The hemolytic anemia results in syndromes primarily related to the fact that the hemolysis is extracellular. Thrombosis is most significant in veins within the abdomen, although a number of other thrombotic syndromes have been described. The hematopoietic deficiency may be the same as that in aplastic anemia, a closely related disorder, and may not be due to the primary biochemical defect. The relationship to aplastic anemia suggests a nomenclature that emphasizes the predominant clinical manifestations in a patient. This relationship does not explain cases that appear to be related to myelodysplastic syndromes or the transition of some cases of PNH to leukemia. Treatment, except for bone marrow transplantation, remains noncurative and in need of improvement.
Hemolytic anemia due to immune function is one of the major causes of acquired hemolytic anemia. In recent years, as more is known about the immune system, these entities have become better ...understood and their treatment improved. In this section, we will discuss three areas in which this progress has been apparent. In Section I, Dr. Peter Hillmen outlines the recent findings in the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH), relating the biochemical defect (the lack of glycosylphosphatidylinositol GPI-linked proteins on the cell surface) to the clinical manifestations, particularly hemolysis (and its effects) and thrombosis. He discusses the pathogenesis of the disorder in the face of marrow dysfunction insofar as it is known. His major emphasis is on innovative therapies that are designed to decrease the effectiveness of complement activation, since the lack of cellular modulation of this system is the primary cause of the pathology of the disease. He recounts his considerable experience with a humanized monoclonal antibody against C5, which has a remarkable effect in controlling the manifestations of the disease. Other means of controlling the action of complement include replacing the missing modulatory proteins on the cell surface; these studies are not as developed as the former agent. In Section II, Dr. Alan Schreiber describes the biochemistry, genetics, and function of the Fc gamma receptors and their role in the pathobiology of autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura due to IgG antibodies. He outlines the complex varieties of these molecules, showing how they vary in genetic origin and in function. These variations can be related to three-dimensional topography, which is known in some detail. Liganding IgG results in the transduction of a signal through the tyrosine-based activation motif and Syk signaling. The role of these receptors in the pathogenesis of hematological diseases due to IgG antibodies is outlined and the potential of therapy of these diseases by regulation of these receptors is discussed. In Section III, Dr. Wendell Rosse discusses the forms of autoimmune hemolytic anemia characterized by antibodies that react preferentially in the cold-cold agglutinin disease and paroxysmal cold hemoglobinuria (PCH). The former is due to IgM antibodies with a common but particular structure that reacts primarily with carbohydrate or carbohydrate-containing antigens, an interaction that is diminished at body temperature. PCH is a less common but probably underdiagnosed illness due to an IgG antibody reacting with a carbohydrate antigen; improved techniques for the diagnosis of PCH are described. Therapy for the two disorders differs somewhat because of the differences in isotype of the antibody. Since the hemolysis in both is primarily due to complement activation, the potential role of its control, as by the monoclonal antibody described by Dr. Hillmen, is discussed.
Acute episodes of pain are the principal symptom of sickle cell disease, but little is known about the epidemiologic features of these episodes or risk factors for them, nor is it known whether ...patients with high rates of such episodes die prematurely. We prospectively studied the natural history of sickle cell disease in 3578 patients ranging from newborns to persons up to 66 years old who were followed at clinical centers across the United States.
There were 12,290 episodes of pain in 18,356 patient-years. The average rate was 0.8 episode per patient-year in sickle cell anemia, 1.0 episode per patient-year in sickle beta 0-thalassemia, and 0.4 episode per patient-year in hemoglobin SC disease and sickle beta(+)-thalassemia. The rate varied widely within each of these four groups--e.g., 39 percent of patients with sickle cell anemia had no episodes of pain, and 1 percent had more than six episodes per year. The 5.2 percent of patients with 3 to 10 episodes per year had 32.9 percent of all episodes. Among patients with sickle cell anemia who were more than 20 years old, those with high rates of pain episodes tended to die earlier than those with low rates. High rates were associated with a high hematocrit and low fetal hemoglobin levels. alpha-Thalassemia had no effect on pain apart from its association with an increased hematocrit.
The "pain rate" (episodes per year) is a measure of clinical severity and correlates with early death in patients with sickle cell anemia over the age of 20. Even when the fetal hemoglobin level is low, one can predict that small increments in the level may have an ameliorating effect on the pain rate and may ultimately improve survival. This outcome is particularly encouraging to investigators studying hydroxyurea and other treatments designed to increase the fetal hemoglobin level.
The characteristic, defining defect in paroxysmal nocturnal hemoglobinuria is the somatic mutation of the PIG-A gene (essential to the biosynthesis of the glycosylphosphatidylinositol moiety that ...affixes a number of proteins to the cellular surface) in hematopoietic cells. These cells thus lack the proteins usually held in place by this anchor. The absence of these proteins is the most reliable diagnostic criterion of the disease and is responsible for many of the clinical manifestations of PNH. The current hypothesis explaining the disorder suggests that there are two components: (1) hematopoietic stem cells with the characteristic defect are present in the marrow of many if not all normal individuals in very small numbers; (2) some aplastogenic influence suppresses the normal stem cells but does not suppress the defective stem cells, thus allowing the proportion of these cells to increase. Current research attempts to substantiate this hypothesis and design therapy consistent with the hypothesis. Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired stem cell disorder characterized by intravascular hemolysis, hypercoagulability, and relative bone marrow failure 1. It is characterized by a somatic mutation in the gene encoding the alpha1-6-N-acetylglucosaminyltransferase necessary for the formation of the glycosylphosphatidylinositol (GPI) anchor that binds certain proteins to the membrane surface (Fig. 1) 2,3*. Whereas many of the manifestations can be accounted for by the absence of these proteins on the cells of the hematopoietic system, it is not entirely clear whether this defect is sufficient to make the disease manifest. In this paper, the author reviews recent clinical observations and relates them to the underlying pathophysiology of the disease.
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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 1Baseline Patient Clinical CharacteristicsNon-transfusedTransfusedUntreated(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 granulocytesMean (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 2Change in LDH and FACIT-Fatigue and EORTC ScoresNon-transfusedTransfusedUntreated(N=144)Eculizumab Treated(N=45)Eculizumab Treated(N=105)LDH, U/LMean (SD) change from baseline to 6 months-39.4 (357.5)-1318.8 (1065.3)-1722.2 (1152.7)FACIT-FatigueAbsolute change nMean (SD) change from baseline to last available assessment69 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-FatigueAbsolute change n Mean (SD) change from baseline to last available assessment69 −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
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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.
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