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Defining Disease Burden and Treatment Efficacy in Paroxysmal Nocturnal Hemoglobinuria

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 52nd Annual Meeting and Exposition of the American Society of Hematology

Orlando, Florida / December 4-7, 2010

According to Dr. Richard J. Kelly, St. James University Hospital, Leeds, UK, the complement inhibitor eculizumab has demonstrated multiple beneficial effects in paroxysmal nocturnal hemoglobinuria (PNH), including prevention of intravascular hemolysis, reduced need for transfusion, improved quality of life and protection against pulmonary hypertension, chronic renal impairment and thromboses. However, in most clinical trials to date, follow-up was short-term, leaving unanswered the question of the agent’s effect on survival.

To examine the long-term effects of eculizumab, Dr. Kelly and colleagues retrospectively reviewed medical records of 79 treated patients with PNH from May 2002 through July 2010. Criteria for eculizumab treatment included hemolytic disease necessitating at least 4 transfusions within the previous 12 months, a confirmed thrombotic event and other significant PNH-related complications (such as moderate or severe renal dysfunction). The analysis focused on mortality and a comparison of symptoms and complications before and after initiation of treatment.

At the onset of therapy, patient median age was 46 years; median levels of lactate dehydrogenase (LDH) were 2872 U/L, neutrophil count 2.2 x 109/L, platelet count 149 x 109/L, reticulocyte count 171 x 109/L, PNH granulocyte clone 96.4%, type II erythrocyte clone 3.8% and type III erythrocyte clone 25.0%. Concurrent therapies at the start of eculizumab included anticoagulation in 46 patients, cyclosporine in 14 and androgens in 2.

In the 12 months prior to starting the complement inhibitor, 21 patients had 34 thrombotic events, half of which occurred while patients were on anticoagulation. In the most recent 12 months, only 2 thrombotic events occurred. The thrombotic event rate decreased from 5.60/100 patient-years before the start of eculizumab to 0.8/100 patient-years in the past year (P=0.001). “Importantly, 21 patients have stopped prophylactic warfarin, which they had required for as long as 14 years,” Dr. Kelly told delegates. “None of the 21 patients has had a thrombotic episode since discontinuing anticoagulation.”

Transfusion requirements declined significantly after initiation of eculizumab. Only 21 of the 79 patients still need transfusions, noted Dr. Kelly. Among the 21, the mean transfusion requirement decreased from 24.6 units to 14.6 units (P=0.03).

Two patients (ages 71 and 75) had transformation to myelodysplastic syndrome and 1 patient had transformation to acute myeloid leukemia 27 years after diagnosis of PNH. All 3 patients remained on eculizumab during the study period.

A review of medical records for 80 PNH patients treated before the complement inhibitor became available showed a consistently and dramatically higher mortality rate compared with an age-matched control population. Dr. Kelly said that only 30% of patients remained alive 25 years after diagnosis, compared with about 80% survival in the general population.

Mortality Normalized

In contrast, the 79 patients treated since 2002 had a survival indistinguishable from that of an age-matched population of individuals without PNH (Figure 1). Three patients died during the study period. One patient died of pre-existing cecal cancer; a 76-year-old woman with a history of recurrent bronchopneumonia died of pneumonia; and a 79-year-old man with a history of ischemic heart disease died of congestive heart failure. Dr. Kelly stated, “Treatment results in a survival that appears similar to the normal age- and sex-matched population. Thrombosis rates declined by more than 80%. Among patients treated with eculizumab for at least 12 months, 74% have had a reduction in the amount of transfusions required and 66% are transfusion-independent.”

In another study, an analysis of almost 200 patients who received treatment with this agent in clinical trials showed that its safety and efficacy are maintained during long-term therapy. Patients had a median treatment duration of 29 months.

Figure 1.


At baseline, patients’ median LDH was 2133 U/L, which declined to 310 U/L after 1 month of therapy and remained at 272 U/L at last follow-up (P<0.0001), reported Dr. Robert Brodsky, Johns Hopkins University, Baltimore, Maryland. Thrombotic events declined by 81% (P<0.0005) from 52 at baseline to 10 during the clinical trials, including 7 patients who had events while on treatment. Five of the 7 patients had a history of thrombotic episodes and the other 2 were treated concomitantly with anticoagulants.

Overall, the complement inhibitor was well tolerated, according to Dr. Brodsky. Most adverse events were mild or moderate in severity and >90% of the events were deemed unrelated to study drug. Adverse events included nasopharyngitis (40%), headache (37%) and upper respiratory tract infections (31%).

Disease Burden

An investigation of PNH disease burden included one of the largest patient populations assimilated into a single data repository. The study involved 657 patients from 117 clinical sites in 16 countries.

“Few reports have addressed the disease burden of PNH from the patient’s perspective,” observed Dr. Petra Muus, Radboud University Medical Center, Nijmegen, The Netherlands. “Our objective was to describe patient-reported qualify of life, hospitalization and missed work and evaluate the relationship of these patient-reported outcomes with demographics, patient-reported symptoms and clinical characteristics.”

Of the 657 patients enrolled in the registry, 377 completed a baseline questionnaire which formed the basis for the study of patient-reported outcomes. Study participants had a mean age of 45.8 years and women accounted for a majority of the respondents (54%).

Patients had a median PNH clone size of 75% and two-thirds of respondents had a clone size =50%. Almost half (45%) of patients had a bone marrow disorder (primarily aplastic anemia) and 12% had a history of a thrombotic event.

Symptoms reported within the past 6 months included abdominal pain in 45% of patients, chest pain in 28% and hemoglobinuria in 64%. EORTC quality-of-life scores averaged about 10% less (ranging to 16% less) as compared with the general population, including global health, physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning.

Men had better physical, emotional and social functioning scores and less fatigue compared to women (P<0.05). Patients with a prior thrombotic episode had worse global health, worse physical, role and cognitive functioning and more fatigue compared with patients who had no prior thrombotic episodes (P<0.05). Abdominal pain, chest pain and hemoglobinuria all were significantly associated with worse quality-of-life and fatigue scores (P<0.05).

Dr. Muus reported that 26% of patients had been hospitalized within the previous 6 months. Factors significantly associated with hospitalization included abdominal pain, chest pain, hemoglobinuria and thrombotic episodes (P<0.05).

Among employed patients, 30% had missed work because of PNH within the previous 6 months. Patients were more likely to miss work if they had abdominal pain (47% vs. 19%, P<0.01) or hemoglobinuria (42% vs. 7%, P<0.01). This global PNH registry remains open to patient accrual and should help redefine prospectively the long-term natural history of PNH, its treatments and the outcomes of treatment, including outcomes measured from the patient’s perspective.

A final investigation examined the burden of PNH from the perspective of transfusion requirements. The study involved 740 patients enrolled in an international registry. In the 12 months prior to enrolment, 56% of the patients required at least 1 transfusion, regardless of whether or not they had a history of aplastic anemia, reported Prof. Hubert Schrezenmeier, German Red Cross Blood Transfusion Service, Ulm. ?

Summary

When overt PNH develops, the mortality risk is high with more than a third of patients dying within 5 years. The monoclonal antibody eculizumab binds to the C5 complement protein to inhibit the complement activation that causes PNH, bringing about a significant reduction in the rate of thrombosis. This was shown to normalize mortality risk to that of matched controls, in addition to reducing the anticoagulation and transfusions and improving quality of life.

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