<p>Allogeneic stem cell transplant (allo-SCT) is typically reserved for patients with paroxysmal nocturnal hemoglobinuria (PNH) who have severe disease or complications and are unresponsive to complement inhibition. With the advent of newer complement inhibitors, the need for transplant has decreased, but it remains a treatment option for those with refractory disease and severe bone marrow failure.</p>

In the United States and in Europe, patients with classical hemolytic PNH have access to complement inhibitor therapy and, if properly treated, would generally have an almost normal life expectancy compared with that of the general population. With the use of either proximal inhibitors or a combination of a proximal inhibitor and a C5 inhibitor, many patients will be able to achieve a substantial increase in hemoglobin—if not a normal hemoglobin—and transfusion requirements decrease dramatically in these individuals. Even though complement inhibitor therapy does not cure the disease, it can convert PNH into a chronic disease, where life expectancy is more or less normal, which is a major feat. So, the role of allo-SCT in this context would be very minimal because the risks from the transplant are quite high.

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Some patients with PNH may be compliant with complement inhibitor therapy and still not respond, although that is a rather rare population. For example, some patients have a peculiar C5 polymorphism that seems to be most common in people of Asian origins, making them more likely not to respond to eculizumab and ravulizumab. However, now we have alternatives, including proximal inhibitors and the C5 inhibitor crovalimab, which can work in the presence of that polymorphism.

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Once you have an allo-SCT, the potential long-term complications (eg, graft-versus-host disease, immunosuppression, and infection) never go away. It is easy to say, “The patient can be cured with this transplant,” but this does not consider the fact that the patient is still going to require a lot of follow-up care. In the short-term, I would say that the risk of death from allo-SCT is higher than that from being on a complement inhibitor. For patients who live in a country where complement inhibitor therapy is not available, allo-SCT can, in principle, be performed with a matched related donor, a matched unrelated donor, or a haploidentical donor and reduced-intensity conditioning to decrease the associated risks. However, here in the United States, I would be quite reluctant to perform a transplant in patients with classical hemolytic PNH.

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The patients with PNH who will need allo-SCT are more likely going to be the ones who have PNH in the context of a bone marrow failure syndrome (eg, patients with aplastic anemia who do not respond to immunosuppressive therapy, respond to immunosuppressive therapy but then relapse, or have a high risk of transformation to myelodysplastic syndromes [MDS] or acute myeloid leukemia). Also, patients with high-risk MDS who have a PNH clone will be considered for allo-SCT. Further, patients who have an evolving clone, meaning that they are likely to develop MDS, will also be considered for a transplant because of what is happening to their clone, which is potentially much more life-threatening than the actual presence of PNH, as PNH may be a small component of their disease.