Hematology

Paroxysmal Nocturnal Hemoglobinuria

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Complement Inhibitor Monitoring in Paroxysmal Nocturnal Hemoglobinuria: Tips and Tools for Clinicians and Researchers

conference reporter by Vahid Afshar-Kharghan, MD
Overview

Assays for monitoring complement inhibition in patients with paroxysmal nocturnal hemoglobinuria (PNH) are not universally available and do not assess alternative pathway inhibitors. Researchers at the recent 66th American Society of Hematology (ASH) Annual Meeting and Exposition presented emerging data from several studies assessing new complement assays and patient-monitoring applications.

 

 

 

Following these proceedings, featured expert Vahid Afshar-Kharghan, MD, was interviewed by Conference Reporter Medical Director Lauren Weinand, MD. Dr Afshar-Kharghan’s clinical perspectives on these findings are presented here.

“. . . any assay that is going to be useful in the clinic should be simple because many tissue- or cell-based assays are complicated, and only a few laboratories can perform them.”
— Vahid Afshar-Kharghan, MD

There are 2 key, intertwined concepts in complement inhibitor therapy. One is assays that can identify the involvement of the complement system in a particular disorder, which can then determine whether complement inhibitors are useful in treatment. The other concept is monitoring the effectiveness of treatment. These concepts go hand in hand; for example, if you have an assay that can show complement activity in a particular disorder, that same assay can also be used to monitor complement inhibitors.

 

However, the difficulty of identifying whether such an assay is useful in clinical practice lies in the fact that, in PNH and in many complement disorders, you need to monitor complement activity on the surface of tissue rather than in the plasma or serum because that is where injury occurs. In PNH, red blood cells are the major target, but that is not the only target because other organs are also involved. Thus, monitoring complement activity in the blood would not be sufficient. In addition, any assay that is going to be useful in the clinic should be simple because many tissue- or cell-based assays are complicated, and only a few laboratories can perform them. Thus, for future assays to become widely clinically applicable, they need to be not only sensitive and specific but also easy for laboratories to perform.

 

The total hemolytic complement (CH50) assay is currently used to monitor complement activity and to determine whether the complement inhibitor is doing its job. It is useful for monitoring patients who are receiving anti-C5 inhibitors such as eculizumab or ravulizumab. If a patient still has intravascular hemolysis despite being on therapy, I measure CH50 to determine whether there is adequate complement inhibition. If complement activity is less than 5% or 10%, this means that there is adequate inhibition, and I must look for other causes. However, CH50 is not as useful with alternative pathway inhibitors.

 

Two abstracts presented at ASH 2024 by Michael Cole, MD, DPhil, and colleagues examined new complement assays that the authors suggest may be useful for monitoring complement inhibition by alternative pathway inhibitors (abstracts 4071 and 1225). In particular, the bioluminescent modified Ham (bio mHam) test is a cell-based assay that can be adjusted to the reagent used, which can allow for the monitoring of different complement inhibitors. While this is an interesting assay for future consideration, many things need to be optimized before it can be incorporated into routine clinical practice. Like any new assay, bio mHam needs to be examined vigorously with a larger number of samples and in complement-independent pathological processes such as sepsis or hemolytic anemia to show that it is specific. It also needs to be proven in larger studies with positive and negative controls, and the threshold for complement inhibition must be established so that it can be used uniformly. It is also important to show whether the bio mHam assay is an improvement over the CH50 assay by being able to assess alternative pathway inhibition.

 

Another abstract presented at this year’s ASH meeting by David Dingli, MD, PhD, et al described the use of a web-based app that assesses patient-reported symptom burden and impacts on self- and home-reported outcomes (abstract 2327). Such an app is useful because it allows us to monitor how a patient feels with treatment. If somebody feels terrible but the drug levels are good, something else is wrong. The app would also be useful for complement disorders other than PNH, allowing you to monitor the patient after they have stopped treatment to ensure that they are not having symptoms that warrant medical attention for possible relapse.

References

Cole M, Ranjan N, Flores DG, et al. Optimizing complement inhibitor monitoring in PNH and beyond [abstract 4071] [session 508: Bone marrow failure: acquired: poster III]. Abstract presented at: 66th American Society of Hematology Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA.

 

Cole M, Ranjan N, Gerber GF, et al. Complement biosensors can be used to identify classical pathway and alternative pathway dysregulation in complement-mediated thrombotic microangiopathy [abstract 1225] [session 330: Vascular biology, thrombosis, and thrombotic microangiopathies: basic and translational: poster I]. Abstract presented at: 66th American Society of Hematology Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA.

 

Dingli D, Zhang C, McStocker S, et al. Baseline characteristics of individuals with paroxysmal nocturnal hemoglobinuria in an app-based home-reported outcomes study to evaluate disease burden [abstract 2327] [session 905: Outcomes research: non-malignant conditions excluding hemoglobinopathies: poster I]. Abstract presented at: 66th American Society of Hematology Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA.

 

 

 

This information is brought to you by Engage Health Media and is not sponsored, endorsed, or accredited by the American Society of Hematology.

Vahid Afshar-Kharghan, MD

    Professor
    Division of Internal Medicine
    Section of Benign Hematology
    The University of Texas MD Anderson Cancer Center
    Houston, TX
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