Paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia share common pathogenetic aspects that diverge, such that their clinical course may overlap or intersect. Analyses presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition touched on clonal trajectories and clonal evolution in patients with PNH.

Following these presentations, featured expert Jaroslaw P. Maciejewski, MD, PhD, FACP, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Maciejewski’s clinical perspectives are presented here.

Clonal trajectory typically refers to the dynamics of PNH progression, with manifestations ranging from tiny, asymptomatic clones to full-blown hemolytic clones in patients with PNH. The cutoff point that separates less significant, smaller clones from those that are associated with hemolytic PNH is a subject of debate, but the various definitions are usually dependent on the size of the clone and the value of lactate dehydrogenase. Thus, the term clonal trajectory implies that these presentations can be very different, ranging from a smoldering, small PNH clone persisting over years to a relentlessly evolving clone that quickly reaches the threshold of hemolytic PNH.

We also have patients who first present with a large PNH clone and hemolysis, which we call primary hemolytic PNH. In these cases, the history may be cryptic. A patient might have had a very steep trajectory, causing us to miss the initial starting point. Alternatively, the trajectory may have been very slow and asymptomatic, so that the diagnosis of PNH is established when a patient’s hemolysis is symptomatic and PNH clones are expanded.

While we refer to the often-variable clonal dynamics and clonal expansion in PNH as “clonal evolution,” it should be noted that, in patients with PNH and in those with aplastic anemia/PNH syndrome, there is a risk of clonal evolution, the acquisition of additional mutations, and progression to myelodysplastic syndrome (MDS). In patients with aplastic anemia, the risk of progression to MDS is higher, whereas progression to MDS in a patient with PNH is seemingly not as high; however, it is definitely many orders of magnitude higher than the risk in the general population.

We have found that there are very few predictive warning signs for clonal progression (ie, from a small, clinically insignificant PNH clone to a larger one that leads to the diagnosis of hemolytic PNH). In terms of monitoring clonal trajectory of PIGA-mutated disease, a change in the clinical picture warrants repeat testing. For the routine monitoring of PNH without a change in clinical features, once per year is probably sufficient, with the caveat that the PNH flow cytometry should be repeated if there is a change in clinical features.

There have been hypotheses that additional mutations might somehow contribute to the expansion of PIGA-mutated clones, as seen at the 65th ASH Annual Meeting and Exposition (abstract 2724). Essentially, however, factors that might be intuitively associated with progression, such as the coassociation of mutations with PIGA, have not been identified or widely accepted.

Regarding the clonal and molecular evolution that leads to secondary myeloid neoplasms, a modest association of predictive factors was seen in a more recent paper from our center by Gurnari et al. A multicenter, retrospective cohort of 1008 patients (median follow-up, 8.6 years) with aplastic anemia and PNH was studied to assess clinical and molecular determinants of clonal evolution. We reported that cross-sectional analysis of clonal dynamics from baseline to evolution showed that PIGA/human leukocyte antigen lesions decreased over time and were replaced by clones with myeloid hits. Additionally, PIGA and BCORL1 mutation carriers had a lower risk of secondary myeloid neoplasm progression, while those with myeloid driver lesions had a higher risk. Moreover, we have previously reported overrepresentation of HLA-DR15 antigen frequencies in MDS and aplastic anemia, with an association between HLA-DR15 positivity and coexistent PNH in patients with MDS.

Outcomes in patients with secondary MDS/acute myeloid leukemia following aplastic anemia/PNH continue to be an area of interest, including outcomes in patients who have received allogeneic hematopoietic stem cell transplantation. At ASH 2023, there was a retrospective study by Prata et al looking into overall survival among transplanted patients; however, as noted by the abstract’s authors, major limitations included nonadjusted analyses and missing data on complete cytogenetics, in addition to the retrospective design (abstract 704). I would want to see patients with aplastic anemia/PNH with and without monosomy seven, for instance. Progression is often associated with more aggressive disease, which, of course, could create the appearance of an underperformance of bone marrow transplantation as a treatment.