Pomalidomide successfully treated transfusion-dependent epistaxis in hereditary hemorrhagic telangiectasia: a case report

Technical Summary: Pomalidomide for Transfusion-Dependent Epistaxis in Hereditary Hemorrhagic Telangiectasia

Problem Statement
Hereditary Hemorrhagic Telangiectasia (HHT), or Osler disease, is an autosomal dominant vascular disorder characterized by fragile telangiectatic vessels that lead to recurrent bleeding. Epistaxis is the most prevalent manifestation, affecting over 90% of patients and frequently resulting in chronic iron deficiency anemia and transfusion dependence. While management strategies include local procedures, antifibrinolytics, and anti-angiogenic therapies, many patients remain refractory. Immunomodulatory drugs (IMiDs), specifically thalidomide, have shown efficacy by promoting vascular maturation; however, their long-term utility is often constrained by significant toxicity, including peripheral neuropathy and thromboembolic events. Furthermore, reports of successful withdrawal from chronic transfusion support in severe cases remain scarce.

Methodology and Case Design
This report details the clinical course of a 75-year-old male patient with a confirmed molecular diagnosis of HHT (heterozygous germline ACVRL1 p.Arg374Trp variant) and concomitant smoldering multiple myeloma (IgG-κ monoclonal protein). The patient presented with chronic, transfusion-dependent epistaxis.

The study followed a sequential treatment and observation protocol:

1. Thalidomide Trial: The patient was initially treated with thalidomide (100 mg/day) for his hematological condition. Despite this, his epistaxis severity score (ESS) remained high (8.08), and he required weekly red blood cell transfusions.
2. Pomalidomide Initiation: Due to the lack of efficacy of thalidomide for his epistaxis, therapy was switched to pomalidomide (2 mg/day).
3. Dechallenge: Pomalidomide was temporarily discontinued after three weeks due to worsening pleural effusion, which was subsequently attributed to congestive heart failure secondary to severe iron deficiency anemia rather than the drug itself.
4. Rechallenge: Approximately nine weeks after discontinuation, the patient's epistaxis recurred, and transfusion dependence returned. Pomalidomide was reintroduced at the same dosage (2 mg/day).
5. Observation: The patient was monitored for clinical response, transfusion requirements, and adverse events, including the recurrence of pleural effusion.

Key Results

• Initial Response: Within three weeks of initiating pomalidomide, the patient experienced a marked decrease in epistaxis. Hemoglobin levels improved, and he achieved complete independence from red blood cell transfusions.
• Dechallenge Effect: Upon discontinuation of the drug, epistaxis progressively worsened over nine weeks, leading to a return of transfusion dependence.
• Rechallenge Confirmation: Following the reintroduction of pomalidomide, epistaxis improved rapidly again (ESS reduced to 3.44 within four weeks). The patient maintained sustained transfusion independence.
• Safety Profile: Crucially, the pleural effusion that initially prompted drug cessation did not recur during the second course of treatment, supporting the hypothesis that the effusion was secondary to heart failure rather than a direct adverse effect of pomalidomide.

Significance and Claims
The authors posit that this case provides compelling real-world evidence for the therapeutic efficacy of pomalidomide in severe, transfusion-dependent HHT-associated epistaxis. The primary significance of the report lies in the documented dechallenge–rechallenge response, which establishes a strong causal link between pomalidomide administration and the resolution of bleeding.

Key claims include:

• Superiority in Specific Contexts: While the PATH-HHT trial and other literature suggest pomalidomide is effective, this case highlights its utility in a patient who failed thalidomide therapy, suggesting that pomalidomide's higher affinity for cereblon and more potent immunomodulatory activity may offer benefits where thalidomide fails.
• Genotype Considerations: Although exploratory analyses in the PATH-HHT trial suggested patients with ACVRL1 variants might derive less benefit than those with ENG variants, this patient (who harbors an ACVRL1 variant) achieved complete transfusion independence. The authors claim this indicates that ACVRL1 genotype alone should not preclude the use of pomalidomide.
• Clinical Utility: Pomalidomide is presented as a promising oral therapeutic option for patients with severe HHT who are refractory to conventional treatments, particularly those requiring chronic transfusion support.

The authors conclude that while these findings are encouraging, further prospective studies are necessary to define optimal dosing, treatment duration, long-term safety, and the drug's precise position within current therapeutic algorithms.