Background: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare clonal disorder of hematopoietic stem cells causing complement-mediated intravascular haemolysis, bone marrow aplasia and thromboembolic events. Allogeneic stem cell transplantation (SCT) has the potential to cure the disease but it is burdened by transplant-related mortality (TRM), which is lower in younger patients and with reduced-intensity conditioning regimens. Eculizumab is a monoclonal antibody suited to stop the abnormal complement cascade and capable of reducing thromboembolic events and related fatalities. Which of the two therapeutic options achieves the best health-care benefit to patients is uncertain as well as the economic burden of the two options onto health-care budget.

Methods: We built a decision tree comparing upfront allogeneic SCT with lifelong eculizumab. Only patients with no prior thrombosis were analysed. A Markov model tracked PNH patients lifelong and accounted for persisting health-care modifications (states, such as transfusion-dependence, long-term disability related to severe thromboembolic events or GVHD, as well as for transitory modifications (events), such as acute phase of thromboembolic events and the first 3 months after SCT. TRM for sibling and unrelated fully matched donors was considered to be 15%, as reported by EBMT for patients transplanted for aplastic anemia after the year 2002 and by other institutions after reduced-intensity conditioning (de Latour 2012; Pantin 2014). However, patients 30-40 years of age were assigned a TRM of 20% and those older than 40 a TRM of 30%. The probability of thrombotic events was estimated based onthe reported cumulative rate of 40% in 15 years (de Latour 2008), but the risk was 4 times as higher for recurrent events. The fatality rate of thrombotic events was assumed to be 10%. The probability of death not related to thrombotic events was calculated based on the rate (8% in 10 years) reported by the French retrospective study (de Latour 2008) for individuals diagnosed after 1996. Patients being treated with eculizumab, however, were assigned thrice as higher the mortality probability of age-matched general population according to the 2008 Italian life tables (Hillmen 2011). Quality of life for PNH patients was calculated from EORTC scores reported by the International PNH Registry (conversion algorithm reported by Kontodimopoulos 2009): it was 0.81 in non-transfused patients, but decreased to 0.71 after thrombotic events, and to 0.51 in transfusion-dependent patients and in those with severe GVHD. Allogeneic SCT was assigned a cost of €80,000 upfront and €100 per month subsequently. Eculizumab was assigned a monthly cost of €20,000 assuming standard scheduling (600 mg weekly for 4 weeks followed by 900 mg biweekly). Future life years and costs were discounted by 3.5% per year, according to international guidelines. The model was built and analyzed with TreeAgePro2014.

Results: At baseline analysis, patients aged 35 years would expect 41.32 life years after allogeneic SCT versus 35.0 on lifelong eculizumab. At two-way sensitivity analysis, we analyzed the role of TRM and relative survival of patients treated with eculizumab, as compared with healthy individuals. Allogeneic SCT is expected to provide better life expectancy so far as mortality in patients treated with eculizumab is >38% higher than general population. At TRM rates of 30%, allogeneic SCT keeps more effective than eculizumab only provided that PNH-related mortality is > 100% higher than general population. Similar results were obtained for discounted quality-adjusted life expectancy, which was 37.1 QALYs after allogeneic SCT versus 26.8 QALYs with lifelong eculizumab. In patients aged more than 52 years, eculizumab provided a better life expectancy than SCT. Lifelong discounted costs were estimated to be €113,341 after allogeneic SCT versus €8,362,079 with eculizumab.

Conclusions: In an era of improved transplant yield and of budget constraints, allogeneic SCT should still be considered a therapeutic option for younger PNH patients with an aplastic phenotype.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.

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