Paroxysmal Nocturnal Hemoglobinuria (PNH)


Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disease that results in severe and even life-threatening clinical consequences.1 

The disease occurs due to a genetic mutation in the X-linked phosphatidylinositol glycan class A (PIGA) gene in hematopoietic stem cells. Mutations in this gene causes the formation of blood cells with reduced or missing glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs). These GPI-APs are responsible for the regulation of complement activity, particularly CD55 and CD59. The lack of these proteins on the surface of red blood cells produces a chronic state of complement-mediated hemolysis of PNH cells.2 

The mainstay of therapy for PNH involves drugs that block alternative complement pathways, such as Soliris® (eculizumab), Ultomiris® (ravulizumab), and Empaveli® (pegcetacoplan). Allogeneic hematopoietic stem cell transplantation (HSCT) can be used, but only after careful consideration. Supportive treatments in the form of blood transfusions and iron supplementation for repeated hemolysis and anemia are often required. Antithrombotic prophylaxis is needed to prevent thrombosis.2 The short-term use of corticosteroids helps to improve hemoglobin levels and decrease hemolysis.3 

Complement Inhibitors

The US Food and Drug Administration (FDA) has approved 3 monoclonal antibodies that act as complement inhibitors for the treatment of PNH: Soliris, Ultomiris, and Empaveli. Soliris was the first of these therapies to be approved (in 2007), changing the therapeutic landscape of PNH. Ultomiris was approved in 2018, with a similar mechanism of action to Soliris. The FDA then approved Empaveli in 2021.4,5 While Soliris and Ultomiris control intravascular hemolysis, Empaveli has the potential to control extravascular complement-mediated hemolysis as well due to its inhibition of C3, which is further upstream from C5 in the complement activation system.6

Soliris

Soliris is developed and manufactured by Alexion Pharmaceuticals, a subsidiary of AstraZeneca. It is administered as an intravenous infusion.7 

Soliris is a humanized monoclonal antibody that binds to the C5 complement component and prevents the formation of C5a and C5b, thus inhibiting the formation of proinflammatory cytokines (through C5a) and the membrane attack complex (MAC) (through C5b).8

It is a life-saving medication that is linked to a >50% decrease in the need for blood transfusions, a reduction of nearly 70% in the likelihood of thrombotic events, and a marked reduction in adverse vascular consequences.2

Patients who benefit the most from Soliris are those having a large clone (>50% PNH granulocytes and >10% PNH red blood cells) along with significantly raised lactate dehydrogenase levels and reticulocyte counts. Therefore, even in the absence of transfusion-dependent anemia, Soliris may be considered in patients with severe PNH symptoms.9

Read more about Soliris

Ultomiris

Ultomiris is also developed and manufactured by Alexion Pharmaceuticals, and it is indicated for the treatment of adult and pediatric patients over 1 month of age with PNH. It is given as an intravenous infusion.10 

Ultomiris is a long-acting C5 complement inhibitor that prevents complement system activation.11 Ultomiris has shown similar efficacy to Soliris across all endpoints in both C5 inhibitor-naive patients with PNH and those who had previously received Soliris. Ultomiris is also proving to be more cost effective than Soliris due to a lower incidence of breakthrough hemolysis. The lower dosing frequency also contributes to a high level of patient acceptability.5

Read more about Ultomiris

Empaveli

Empaveli is the first PNH drug that binds to complement protein C3. It is indicated for the treatment of adult patients with PNH.12 It is developed by Apellis Pharmaceuticals.13 

The drug is available as an injection for subcutaneous use. The active ingredient in Empaveli is pegcetacoplan, a pegylated peptide that is a complement inhibitor. It affects the complement cascade by binding to C3 and its activation fragment C3b. This binding controls extravascular hemolysis mediated by C3b and intravascular hemolysis mediated by the MAC.5,13 

Read more about Empaveli

Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation using allogeneic donors is the only curative treatment for PNH. HSCT is not considered as an initial treatment for the majority of patients with classic PNH, as there is a risk of transplant-related mortality, particularly with unrelated or mismatched donors. HSCT can also result in reduced quality of life and infertility. 

Indications for allogeneic HSCT include persistent hemolysis, persistent thrombosis, and associated marrow failure. HSCT remains the treatment of choice for PNH patients with refractory bone marrow failure (aplastic anemia [AA] or clonal evolution, such as myelodysplastic syndrome and acute myelogenous leukemia) and an unsatisfactory response to Soliris. Haploidentical donors are required for patients without a human leukocyte antigen-matched sibling or unrelated donor.5,9,14 

Read more about PNH guidelines

Steroids

No randomized studies have been conducted to validate the efficacy of steroid hormones in the treatment of PNH. However, short courses of prednisolone (1 mg/kg) given over 2 to 3 days can help reduce the severity and duration of hemolytic crises. Prolonged steroid therapy is not advised.8

Immunosuppressants 

Immunosuppressive therapies, such as antithymocyte globulin (ATG) and cyclosporine, are indicated for patients with PNH who also have AA. These therapies reduce the body’s immune response and thus prevent it from attacking the bone marrow.15 

Immunosuppressants are beneficial in older patients and those without a matched sibling donor. The presence of PNH clones also suggests a positive response to ATG or cyclosporine. However, HSCT is considered a curative treatment choice in patients aged ≤40 years with severe AA who have an matched sibling donor.14,15

Read more about PNH prognosis

Anticoagulant Therapy

When PNH clone size in granulocytes is ≥50% and there is an additional risk of thrombotic consequences, anticoagulant medication, such as warfarin or low-molecular-weight heparin (LMWH), may be necessary for primary thrombosis prevention. Long-term or lifelong anticoagulant therapy with warfarin or LMWH is advised after a thrombotic event.8 

Read more about PNH complications

References

  1. Sharma VR. Paroxysmal nocturnal hemoglobinuria: pathogenesis, testing, and diagnosis. Clin Adv Hematol Oncol. 2013;11(9):2-8.
  2. Shah N, Bhatt H. Paroxysmal nocturnal hemoglobinuria. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated August 1, 2022. Accessed November 22, 2022.
  3. Parker CJ. Update on the diagnosis and management of paroxysmal nocturnal hemoglobinuria. Hematology Am Soc Hematol Educ Program. 2016;2016(1):208-216. doi:10.1182/asheducation-2016.1.208 
  4. Kugler M. What is paroxysmal nocturnal hemoglobinuria? Verywell Health. Updated August 24, 2022. Accessed November 22, 2022.
  5. Besa EC. Paroxysmal nocturnal hemoglobinuria treatment & management. Medscape. Updated May 20, 2021. Accessed November 22, 2022.
  6. Wong RSM, Pullon HWH, Amine I, et al. Inhibition of C3 with pegcetacoplan results in normalization of hemolysis markers in paroxysmal nocturnal hemoglobinuria. Ann Hematol. 2022;101(9):1971-1986. doi:10.1007/s00277-022-04903-x
  7. Soliris for the treatment for PNH, aHUS, gMG and NMOSD. Clinical Trials Arena. September 15, 2021. Accessed November 22, 2022.
  8. Almomen AK, Al Bakistani AG, Alsaeed A, et al. Paroxysmal nocturnal hemoglobinuria: diagnosis and management protocol. Journal of Applied Hematology. 2014;5(2):37-44. doi:10.4103/1658-5127.137081
  9. Devos T, Meers S, Boeckx N, et al. Diagnosis and management of PNH: review and recommendations from a Belgian expert panel. Eur J Haematol. 2018;101(6):737-749. doi:10.1111/ejh.13166
  10. Ultomiris. Prescribing information. Alexion Pharmaceuticals, Inc; 2022. Accessed November 22, 2022.
  11. Ravulizumab-cwvz (Ultomiris®). The Aplastic Anemia and MDS International Foundation. Accessed November 22, 2022.
  12. Pegcetacoplan (Empaveli®). The Aplastic Anemia and MDS International Foundation. Accessed November 22, 2022.
  13. Empaveli (pegcetacoplan) for the treatment of paroxysmal nocturnal haemoglobinuria (PNH). Clinical Trials Arena. June 4, 2021. Accessed November 22, 2022.
  14. Du Y, Han B. Advances in hematopoietic stem cell transplantation for patients with paroxysmal nocturnal hemoglobinuria. Transplant Cell Ther. 2021;27(4):301-307. doi:10.1016/j.jtct.2020.11.004
  15. What are the treatments for PNH? The Aplastic Anemia and MDS International Foundation. Accessed November 22, 2022.

Reviewed by Hasan Avcu, MD, on 11/23/2022.

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