Background

Welcome to Part 2 of the 2022 Forum on Complement Case Discussion Series.

PNH is an ultra-rare, and under-recognized complement-mediated disease. Despite its rarity this disease warrants our attention because without adequate management, mortality from PNH is significant (35% at 5 years). In December 2021- January 2022, insights on current perceptions and practice patterns were collected from hematology specialists across Canada via a needs assessment questionnaire.

Key learning from the assessment:

  • There remains a lack of confidence with PNH treatment and uncertainty around satisfaction with current therapies, differences between complement inhibitors (approved and novel), and how novel approaches should be integrated in practice with current standards. (Data below)

To what extent do you agree with the following:
[1 being strongly disagree, 3 being neutral and 5 being strongly agree]

See the Appendix for more data gathered from the assessment on testing and diagnosis!

(Click on Image to Enlarge)

The intent of this 2-part series is to shed light on the education gaps identified through the assessment, and the challenges many PNH patients encounter during their (often-convoluted) patient journey.

Part 1 explored the importance of timely diagnosis and treatment and can be accessed here: https://careeducation.ca/pnh-part1/

This issue, Part 2, focuses on current approaches to management and treatment following a confirmed PNH Diagnosis.

We are pleased to have Dr. Christopher Patriquin (University Health Network, Toronto) provide the content contained in this issue.

Introduction

After a PNH diagnosis is confirmed, the patient should be referred for treatment promptly.

The role of the complement system in PNH

Complement-mediated intravascular hemolysis is the defining feature of classical PNH, and is a significant driver of disease. However, it must be remembered that PNH phenotype platelets and leukocytes also contribute, particularly to the elevated thrombotic risk.

PNH results from a somatic mutation in PIGA, an X-linked gene whose product is required for the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. This results in the absence of complement regulatory proteins CD55 and CD59 being expressed on the membrane, leading to reduced or absent protection from complement activation and damage (e.g., intravascular hemolysis of the PNH erythrocytes). The events which trigger expansion of the PNH clone in some and not in others remains unclear.

Figure. (across) Action of complement in healthy subjects (A) and PNH patients (B). Due to the presence of membrane proteins, DAF (CD55) and MIRL (CD59), a normal RBC is protected from complement activation. (B) DAF (CD55) and MIRL (CD59) deficiency makes the RBC sensitive to complement attack, resulting in hemolysis. DAF = decay accelerating factor, MAC=membrane attack complex, MIRL = membrane inhibitor of reactive lysis, RBC = red blood cells.

Figure Reference. Devalet, Bérangère & Mullier, François & Chatelain, Bernard & dogné, jean-michel & Chatelain, Christian. (2014). The central role of extracellular vesicles in the mechanisms of thrombosis in paroxysmal nocturnal haemoglobinuria: A review. Journal of extracellular vesicles. 3. 10.3402/jev.v3.23304.

“After a PNH diagnosis is confirmed, the patient should be referred for treatment promptly.”

Currently Available Options

Complement Inhibition with eculizumab (Soliris) is the current standard-of-care treatment for PNH in Canada. It is a monoclonal antibody that inhibits C5 in the terminal complement cascade, thereby blocking membrane attack complex formation, and has revolutionized treatment for PNH. It effectively inhibits intravascular hemolysis, reduces transfusion dependence, alleviates symptoms, and protects against thrombosis. Patients on eculizumab have been shown to experience a near normal life expectancy and improved quality of life (see clinical trial references below).

Key clinical data demonstrating safety and efficacy:

  • Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006;355:1233-1243.
  • Brodsky RA, Young, NS, Antonioli E., et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008;111:1840-1847.
  • Hillmen P, Muus P, Dührsen U, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 2007; 110 (12): 4123–4128. doi: https://doi.org/10.1182/blood-2007-06-095646
  • Socié G, Caby-Tosi MP, Marantz JL, et al. Eculizumab in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome: 10-year pharmacovigilance analysis. Br J Haematol. 2019 Apr;185(2):297-310. doi: 10.1111/bjh.15790. Epub 2019 Feb 15. PMID: 30768680; PMCID: PMC6594003.

Additional supportive/symptomatic treatment varies depending on the patient’s age, general health, presence of associated disorders, severity of PNH, and degree of underlying bone marrow failure (BMF). Options include:

  • Bone marrow transplant and/or immunosuppression (e.g. ATG, cyclosporine) for patients with severe aplastic anemia. Immunosuppression can be used concurrently with complement inhibition in patients with both processes active simultaneously.
  • Transfusions may be necessary for patients with ongoing intravascular hemolysis (uncommon), associated BMF, bleeding, or other causes of anemia. Of note, patients may develop extravascular hemolysis following introduction of C5 inhibition. Novel therapies are being assessed in clinical trials to try and address this iatrogenic outcome. Of note, corticosteroids are not typically effective in this situation and are associated with unacceptable side effect profile in relation to the minimal benefit.
  • Anticoagulants reduce the risk of thrombosis, particularly if a patient has already had a thrombotic event, or as primary thromboprophylaxis in patients who do not yet qualify for Ministry of Health approval criteria yet are at risk for thrombosis.
  • Folic acid and iron supplements assist the production of blood cells to counteract the increased turnover related to hemolysis. Of note, heavily transfused patients may alternatively require iron chelation.

The following case study explores best practices with currently available options.

Case Study

A 32-year-old female with PNH not on complement inhibition presents with acute kidney failure.

PNH History: This young patient was diagnosed PNH during a work-up for DAT-negative hemolysis. Her initial flow cytometry showed a GPI-negative granulocyte population of 95.4%, monocytes 93.9%, type-III RBC 29.52%, and type-II RBC 23.99%. Her LDH was approximately 900-1000 u/L (NR 125-220), with reticulocytes 240 x 109/L and undetectable haptoglobin. Despite ongoing intravascular hemolysis, her hemoglobin ranged from 105-115 g/L. Given the current approval criteria for eculizumab, she did not qualify for treatment despite her evidence of intravascular hemolysis. Though anemic, her hemoglobin was consistently above 100 g/L, and approval requires <100 g/L with symptoms or <70 g/L. Though there was a history of abdominal pain, this had not required hospital admission or opioid analgesia. To protect her from development of PNH-related thrombosis, she was started on prophylaxis with rivaroxaban 15 mg and monitored closely.

Comorbidities: irritable bowel syndrome, iron deficiency anemia.

Medications: folic acid 5mg, ferrous fumarate 300 mg daily, rivaroxaban 15 mg daily.

Allergies: NDKA.

History of Presenting Illness: In the winter of 2021, she developed an acute hemolytic crisis triggered by COVID-19 infection. Alongside mild respiratory symptoms, she had worsening abdominal pain, nausea, and on presentation to her local ER had a hemoglobin of 54 g/L, LDH of 2150 u/L, and oliguric acute kidney injury (creatinine 1300 µmol/L and hyperkalemia). She was started on hemodialysis, transfused 2 units of red cells, and eculizumab was arranged to start the next day. Meningococcal vaccinations (ACWY + B) were given and penicillin prophylaxis was started for additional antimicrobial protection.

Investigations did not find a thrombotic explanation for the renal failure. As such, prophylactic anticoagulation – which was changed to tinzaparin in the context of her AKI – was stopped once her LDH normalized. After three weeks, she was able to be weaned off dialysis and had complete renal recovery. At last follow-up, her LDH is in the normal range and she is transfusion-independent with hemoglobin range of 90-100 g/L. Other than headaches associated with the first few eculizumab infusions, she has tolerated treatment well. Once available, she will likely be transitioned to ravulizumab (given q-8-weeks) from eculizumab (given q-2-weeks) to reduce treatment burden.

Discussion

What was the strategy used for the patient in the case (and why)?
The treatment strategy in this case was initially limited to supportive and preventive care. Exceptional access criteria remain quite limiting, with the patient being denied eculizumab at the time of her initial diagnosis. Folate and iron supplementation were started, as was rivaroxaban for thromboprophylaxis. There is increased incidence of thrombosis in PNH patients with LDH values over 1.5x the upper limit of normal, and it remains the most common cause of death in untreated PNH.

The acute hemolytic episode triggered by COVID-19 infection led to profound anemia and oliguric acute kidney failure. Eculizumab was urgently initiated to control complement-mediated intravascular hemolysis and prevent further end-organ damage.

What other factors should be considered when providing therapy?
Outside of clinical trials, complement inhibitor therapy for PNH is restricted by approval criteria essentially unchanged since eculizumab’s approval. Symptomatic anemia is the most common criterion leading to approval; however, there are patients with intravascular hemolysis but without sufficient anemia given robust marrow response. In these patients, prophylactic anticoagulation should be considered to protect patients from thrombotic events. Regular clinical and laboratory monitoring is essential to identify if and when these patients may qualify for targeted therapy and discontinuation of thromboprophylaxis. If, however, a PNH patient experiences a thromboembolic event, anticoagulation would typically be continued assuming no complications or contraindications (e.g. thrombocytopenia).

Terminal complement inhibition is typically well-tolerated. The most common side effect is post-infusion headaches, most likely due to the rapid return of circulating nitric oxide and associated vasodilation. These headaches typically respond to acetaminophen and/or ibuprofen, and become less common and less severe over time. Some patients benefit from pre-infusion acetaminophen which can prevent the onset of headaches entirely.

The adverse event that is most concerning is N. meningitidis infection, including both sepsis (more common) and meningitis. To reduce this risk, patients must be vaccinated and, if complement inhibition is started before 14 days post-vaccination, anti-meningococcal antibiotics should also be prescribed (typically penicillin or azithromycin). Longer-term antibiotics should also be discussed with patients, to protect against the possibility of meningococcal infection from serotypes not covered by current vaccines (i.e. ACWY + B). Patients must be counselled to present to their closest ER should they ever develop symptoms of meningismus or otherwise unexplained fever.

What does the future of PNH treatment look like in Canada
Therapy for PNH is evolving rapidly, spurred by the availability of therapies that target the underlying complement-mediated hemolysis. New research has focused on different methods of drug delivery (i.e., subcutaneous injections, oral treatments), extending time between doses, inhibition of novel targets and combination therapies for patients not optimally controlled on eculizumab.

Novel Agents that are expected to enter the Canadian Market in the near future include:

  • Ravulizumab: a longer acting intravenous C5 inhibitor now licensed by the FDA and EMA. It is delivered every 8 weeks, and clinical trial evidence showed that it is at least as clinically effective as eculizumab.
  • Pegcetacoplan: a pegylated compstatin analogue which binds to C3. This agent showed significant increases in hemoglobin in the PEGASUS Trial in patients with persistent anemia despite eculizumab.

Other agents which are currently in clinical trial include:

  • Anti-factor B: iptacopan
  • Anti-factor D: danicopan (in combination with C5 inhibition), BCX9930, vemircopan
  • Anti-C5: crovalimab, pozelimab + cemdisiran

Additional Resources:
Previous issues of Forum on Complement (2017) can be accessed at the following link: https://careeducation.ca/reports/forum-on-complement-case-series/?_sf_s=PNH

Concluding Remarks

We now have two decades of experience with eculizumab in the treatment of PNH. This has demonstrated that terminal complement inhibition can reduce hemolysis and associated complications, improve quality of life, and even extend survival in our patients. Mature safety and pharmacovigilance data are also available for eculizumab in PNH and other complement-mediated disorders.

A minority of patients (~10-20%) on standard-dose eculizumab may have incomplete terminal complement inhibition. Response can be improved in some cases by increasing the infused dose and/or frequency; however, other issues such as extravascular hemolysis and associated anemia cannot be corrected. Proximal complement inhibition can address this by reducing the C3 loading and phagocytosis of GPI-negative RBCs. Several novel proximal inhibitors are currently in clinical trial, with a similar focus on improving anemia. Any drug, regardless of its target, will also need to ensure terminal complement-mediated intravascular hemolysis is controlled. We are relatively early on in our understanding of the efficacy and safety of targeting alternative complement proteins, though data thus far are encouraging.

Access to eculizumab for PNH patients is currently limited to those who meet the restricted criteria as set out by provincial exceptional access programs. Patients with active disease but not meeting criteria should be monitored closely and started on therapy as soon as they are eligible. It remains to be seen if updated and more inclusive reimbursement criteria will be approved in the future, particularly as new therapies become available. Canadian participation in PNH research will hopefully increase the likelihood of providing additional or alternative therapies for our patients. How we manage PNH 5-10 years from now will likely be quite different, with more options for our patients that continue to control the disease while also improving quality of life and reducing treatment burden.

“Patients with active disease but not meeting criteria should be monitored closely and started on therapy as soon as they are eligible.”
Appendix: Relevant Data from Needs Assessment – Treatment

Other than anemia, what presenting feature(s) have led to the diagnosis of PNH in your patients?
[Responders selected all that apply]

What is your current standard treatment for PNH? Response included*:
[*The list below is a consolidation of all responses given]

  • Eculizumab (93%)
  • Ultomiris/ second-gen complement inhibitors (7%)
  • Referral to PNH provider (10%)
  • Varies according to patient and symptoms.
  • Observation
  • Vaccines
  • Folic acid

For PNH patients on anticoagulation, do you ever discontinue the anticoagulation?

To what extent do you agree with the following:
[1 being strongly disagree, 3 being neutral and 5 being strongly agre]

(Click on Images to Enlarge)