March 2026 Research Update

This month adds to a clearer picture that some people with PNH can still have anemia or ongoing red blood cell breakdown even when a C5 blocker such as eculizumab or ravulizumab is controlling the usual hemolysis blood test (LDH). Across these studies, the newer "proximal" complement inhibitors (which block the complement system earlier) are mainly discussed as a way to address persistent anemia and transfusion needs that can remain under C5 inhibition. The evidence is a mix of exploratory comparisons, real-world observation, and single-patient experiences, so it helps explain possibilities rather than giving final answers. [1] [2] [3]

An indirect comparison using trial data from different studies reported larger hemoglobin increases and higher transfusion avoidance with iptacopan (a factor B inhibitor) than with pegcetacoplan (a C3 inhibitor) in people who still had anemia despite C5 inhibitors. In the same analysis, LDH and fatigue scores were reported as similar between the two options, and the authors emphasized that this kind of cross-trial comparison is exploratory. In plain terms, this suggests that different complement targets may not produce the same level of improvement in anemia, but the size of the difference is uncertain until more direct comparisons are available. [2]

A single-patient report described recurrent anemia and transfusion dependence after an initial response to eculizumab, even though LDH did not rise much, and other lab markers suggested ongoing intravascular hemolysis below the surface. After 6 weeks of iptacopan alone, hemolysis-related labs normalized and transfusions were no longer needed in that patient. This case highlights why some monitoring may look "okay" while symptoms persist, and why proximal inhibitors are being studied for people who remain anemic on C5 blockers. [3]

A Canadian consensus document focused on a practical way to think through suboptimal response on terminal complement inhibitors and discusses options such as switching to or adding a proximal inhibitor (including pegcetacoplan, iptacopan, or danicopan). It also points to specific lab checks used to separate different causes of anemia and ongoing hemolysis, such as looking for signs of C3-related red cell coating when C5 blockade is in place. For patients, this helps explain why care teams sometimes ask more targeted questions and repeat specific blood tests when symptoms do not match a single lab result like LDH. [1]

For patients and caregivers, these studies mainly add understanding of why anemia and transfusion needs can continue even when a C5 blocker has brought the usual hemolysis marker (LDH) down. The information may matter now for explaining conversations about "residual anemia" and why some people are evaluated for a switch to a different kind of complement blocker, but it does not settle which option is best for any one person. What remains uncertain is how well the indirect comparisons predict real-world outcomes and how consistently single-patient experiences will apply across the wider PNH community. [1] [2] [3]

This month, two large real-world datasets give a more complete view of ravulizumab (a long-acting C5 blocker): registry data support sustained control of hemolysis with a high proportion of people remaining transfusion-independent, while pharmacovigilance reports map out the kinds of side effects that are being reported after treatment starts. Put together, they reinforce that ravulizumab is generally used to keep hemolysis under control over months to years, while most reported side effects in spontaneous reports cluster early after starting treatment. These sources answer different questions, so they should be read as complementary rather than as a direct comparison. [4] [5]

In the International PNH Registry, adults treated with ravulizumab for at least 6 months had LDH ratios that stayed near normal in both those who previously used eculizumab and those who were new to C5 inhibitors. Transfusion independence was reported in both groups, and major adverse vascular events were reported rarely in the eculizumab-experienced group and not observed in the smaller C5 inhibitor-naive group. For patients, this supports the idea that in routine care ravulizumab can maintain biochemical control of hemolysis for many people. [4]

A pharmacovigilance analysis of FAERS reports described which adverse events were most frequently reported with ravulizumab and when they tended to occur. Many reports involved symptoms such as fatigue and headache, and the analysis also highlighted potential signals not listed on the label, while noting that voluntary reports cannot prove the drug caused the event. It also reported that most events occurred within 30 days of starting ravulizumab, and it counted reports of Neisseria meningitidis infection, which is a known concern with complement-blocking medicines. [5]

For patients, the registry findings may be most relevant now because they describe what has been observed in routine use: many people on ravulizumab had LDH kept near normal and did not need transfusions. The FAERS analysis is mainly an early-warning and pattern-finding tool, so it is more about what gets reported and when, rather than a clear estimate of true risk. What remains uncertain is how often the possible non-label signals occur in real life and how many reports reflect the medicine versus the underlying disease or other illnesses. [4] [5]

One study this month focused on allogeneic stem cell transplant in people with large PNH clones, looking at whether a particular immune-suppression approach after transplant might reduce graft-versus-host disease (GVHD). The reported outcomes were very good in this small group, with full donor engraftment and no transplant-related deaths. The main difference described was fewer GVHD problems in the post-transplant cyclophosphamide (PTCy) group compared with conventional GVHD prevention approaches. [6]

In this retrospective series of 19 transplanted patients, overall survival was reported as 100% with long follow-up, and event-free survival was also high. The subgroup that received PTCy-based GVHD prevention had no chronic GVHD and no grade II to IV acute GVHD, while GVHD was reported in the conventional-prophylaxis group. For patients, this suggests that if transplant is pursued, the details of the transplant platform may strongly affect the risk of GVHD, but these results come from a small non-randomized experience. [6]

For patients and caregivers, this study mainly adds to understanding of how transplant outcomes might be improved, especially around GVHD, in people with large PNH clones who undergo transplant. It may matter later as centers compare and refine transplant approaches, rather than changing expectations for most people living with PNH today. What remains uncertain is whether the same GVHD reductions would be seen in larger groups or in different transplant centers, since this was a small retrospective comparison. [6]

This month’s case reports highlight how varied PNH can look in real life, including infection-triggered complications, pregnancy, persistent anemia on treatment, and even largely silent disease found on testing. As a group, these reports underline that individual courses can be shaped by triggers such as viral infections or by co-existing bone marrow problems, and that responses to complement-blocking medicines can differ between people. Because each report describes a single person, these are best read as examples of what can happen rather than what usually happens. [7] [8] [9] [10] [3]

Several reports showed that viral infections can coincide with sudden worsening in PNH-related problems. One patient developed severe skin inflammation with clotting during parvovirus B19 infection and later had breakthrough hemolysis during varicella zoster infection, with rapid improvement after adding treatments including eculizumab and other supportive therapies. This helps explain why some people experience abrupt changes during infections, even if they are otherwise stable at baseline. [7]

Pregnancy was described in one report where eculizumab was used during a first pregnancy, and the woman had a vaginal delivery without PNH-related complications, with both mother and child well at 1 year. This adds one more real-world example that pregnancy with PNH can have a good outcome in some circumstances, while still not defining what will happen for others. [8]

Two reports focused on detection and monitoring rather than immediate symptoms. One man was diagnosed by flow cytometry despite being asymptomatic, even with a large PNH clone and lab signs of hemolysis, showing that symptoms and lab severity do not always match. Another case in severe aplastic anemia described expansion of PNH clones during long-term thrombopoietin receptor agonist therapy and a decrease in clone size after the drug was stopped, suggesting that clone size can shift over time in some marrow-failure settings. [9] [10]

For patients, these reports may matter now mainly as context: infections and other stressors can coincide with flare-ups, and PNH can sometimes be discovered or monitored through blood testing even when symptoms are mild. The pregnancy report provides reassurance that good outcomes are possible, but it is still a single experience and does not predict another person’s pregnancy course. What remains uncertain is how often these situations occur and which personal factors make them more likely, since case reports cannot measure typical risk. [7] [8] [9] [10]

One prospective study looked at "pigment nephropathy," a form of kidney injury that can follow heavy pigment release into the urine, including from hemolysis. Although many patients were very sick at presentation and most needed dialysis, kidney recovery at 1 year was reported as complete in those followed. For PNH readers, the main link is that hemolysis was one of the causes in this cohort, and PNH was listed as one underlying reason for hemolysis in some cases. [11]

In 20 patients with biopsy-proven pigment nephropathy, rhabdomyolysis was more common than hemolysis, and most patients required temporary dialysis. Among the 13 people who completed at least 1 year of follow-up, all had normal kidney function and none progressed to chronic kidney disease. This helps clarify that severe acute kidney injury from pigment-related causes can be reversible, but the study was small and not specific to PNH. [11]

For patients with PNH, this study is mainly background information rather than a direct study of PNH care. It may matter later by adding to understanding of kidney recovery after a severe pigment-related kidney injury that can sometimes involve hemolysis, including hemolysis from PNH. What remains uncertain for PNH specifically is how often PNH-related hemolysis leads to this biopsy-proven kidney pattern and whether outcomes are similar, since most participants had other causes like rhabdomyolysis. [11]