Paroxysmal Nocturnal Hemoglobinuria


Updates on Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria

conference reporter by Ronald S. Go, MD

Aplastic anemia and paroxysmal nocturnal hemoglobinuria (PNH) are closely related entities, but the understanding of each is incomplete. Researchers at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition presented new data as they explored some potentially relevant pathogenetic mechanisms.


Following these proceedings, featured expert Ronald S. Go, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Go’s clinical perspectives on these findings are presented here.

"To summarize the major developments in aplastic anemia and PNH in recent years, I would say that, in aplastic anemia, eltrombopag moving to the front line is one of them. . . . In PNH, I think that the major development is the availability of newer drugs.”
— Ronald S. Go, MD

We do not know everything about PNH or aplastic anemia, but we do know that they are closely related and that one can develop into the other. In bone marrow failure syndromes, especially the acquired ones, it is common to have a PNH clone. In the clinic, when somebody presents with pancytopenia or hypocellular bone marrow that is consistent with bone marrow failure syndromes, one of the tests that we perform is a PNH flow cytometry test. If you find a PNH clone, more than likely it is acquired as opposed to hereditary.


We do not know why people get PNH in the absence of overt bone marrow failure syndromes. However, there are some exciting hypotheses, including one that was touched on in an abstract presented at ASH 2023 (abstract 707). The group at Cleveland Clinic explored inborn errors of immunity and their potential relationship with immune cytopenias and bone marrow failure, hypothesizing that rare germline variants predisposing to such errors may contribute to the pathogenesis of aplastic anemia and its evolution to PNH. Some inborn errors of immunity are not detected by conventional testing, and patients with such mutations might not present with any symptoms that would make one suspicious of an immunodeficiency syndrome. So, these types of mutations, potentially along with other hits (eg, in a multi-hit model), are an interesting possible explanation.


Putting aside the relationship between PNH and immune-mediated bone marrow failure, I think that it is important to acknowledge the rarity of PNH. I was a community hematologist for 13 years after my training; during those 13 years as a pure hematologist, I diagnosed only 1 case of PNH. It is also important to note that a small PNH clone that is present in someone with aplastic anemia may not require treatment for PNH. Regarding when to initiate therapy for PNH, I believe that most experts would agree that treatment is indicated when someone presents with thrombosis and is diagnosed with PNH, if the 2 are linked. I also think that there is agreement on the treatment of patients with symptomatic cytopenia. Those with symptomatic anemia usually have hemoglobin levels that are less than 10 g/dL, as well as shortness of breath, chest pain, fatigue, muscular problems, and esophageal spasm.


I think that it is difficult to decide when to initiate therapy when PNH is found incidentally in asymptomatic patients or in those who have mild symptoms. For example, say someone has mild anemia and is found to have hemolysis, and then is subsequently diagnosed with PNH. Is having a PNH clone that is more than 50% or a lactate dehydrogenase burden that is twice above normal enough to treat this patient? That is the challenge, because there are no prospective studies looking at this. In fact, I think that experts probably vary as to their thresholds for treating asymptomatic patients, and the lack of consensus is due, in part, to the costs of these drugs.


To summarize the major developments in aplastic anemia and PNH in recent years, I would say that, in aplastic anemia, eltrombopag moving to the front line is one of them. This was based on the randomized trial comparing antithymocyte globulin (ATG) plus cyclosporine with or without eltrombopag. Using all 3 drugs was superior to using just ATG plus cyclosporine, and this was not unexpected. In PNH, I think that the major development is the availability of newer drugs.


Babushok DV. When does a PNH clone have clinical significance? Hematology Am Soc Hematol Educ Program. 2021;2021(1):143-152. doi:10.1182/hematology.2021000245


Bravo-Perez C, Gurnari C, Guarnera L, et al. Bone marrow failure and inborn errors of immunity: an immunogenomic crossroad [abstract 707]. Abstract presented at: 65th American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA.


Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood. 2021;137(10):1304-1309. doi:10.1182/blood.2019003812


Cançado RD, da Silva Araújo A, Sandes AF, et al. Consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria. Hematol Transfus Cell Ther. 2021;43(3):341-348. doi:10.1016/j.htct.2020.06.006


de Latour RP, Kulasekararaj A, Iacobelli S, et al; Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation. Eltrombopag added to immunosuppression in severe aplastic anemia. N Engl J Med. 2022;386(1):11-23. doi:10.1056/NEJMoa2109965


Oliver M, Patriquin CJ. Paroxysmal nocturnal hemoglobinuria: current management, unmet needs, and recommendations. J Blood Med. 2023;14:613-628. doi:10.2147/JBM.S431493


Prata PH, Galimard J-E, Sicre de Fontbrune F, et al. Rare germline complement factor H variants in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2023;141(15):1812-1816. doi:10.1182/blood.2022017019


Risitano AM, de Latour RP. How we(‘ll) treat paroxysmal nocturnal haemoglobinuria: diving into the future. Br J Haematol. 2022;196(2):288-303. doi:10.1111/bjh.17753



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Ronald S. Go, MD

Professor of Medicine
Chair, Classical Hematology Group
Division of Hematology, Department of Internal Medicine
Mayo Clinic
Rochester, MN