Table 2.
Treatment options for patients with HES and EGPA
| Treatment | Disease and approval status | Indications | Considerations | |
|---|---|---|---|---|
| Steroids | OCS 6, 38, 40, 68 | HES, EGPA | Appropriate first-line therapy for many patients with HES or EGPA, with exception of patients with suspected or confirmed eosinophil clonality such as FIP1L1::PDGFRA fusion. Typically leads to rapid reductions in eosinophil counts. Patients with EGPA should initially be treated with systemic CS with the aim of achieving remission; severe manifestations warrant early initiation of an immunosuppressant. | Long-term use is associated with substantial toxicity. Initiate empirical/preventive anti-parasite treatment in patients with a travel history suggesting possible strongyloides exposure to avoid hyperinfestation syndrome. |
| Kinase inhibitors | Imatinib mesylate (tyrosine kinase inhibitor) 6, 13, 26, 27, 40, 41, 43–45, 64 | M-HES (Approved) | First-line therapy for patients with M-HES associated with rearrangements involving PDGFRA/PDGFRB. Initial recommended dose is 100–400 mg daily for patients with M-HES depending on the cytogenetic rearrangements, followed by lowering for maintenance. May also be considered for patients with myeloid features in the absence of a detectable mutation, with initial recommended dose of 400–800 mg daily. | The low-dose maintenance regimen required for FIP1L1::PDGFRA fusion kinase-positive HES (ie, 100 mg/day) is well tolerated. Molecular remission is the goal of treatment and is achieved rapidly in most cases. Several studies indicate a potential for a cure in patients with FIP1L1::PDGFRA fusion kinase-positive HES if treatment is maintained for several years. Higher doses may cause side effects. Should be used in combination with OCS for a brief period at treatment initiation to prevent potential cardiac toxicity, likely related to eosinophil destruction. |
| Ruxolitinib (JAK1/2 kinase inhibitor) 4, 47, 86 | M-HES (In development) | Phase II trials are ongoing for patients with M-HES associated with rearrangements involving JAK2 (PCM1-JAK2, ETV6-JAK2, BCR-JAK2); two trials are currently recruiting patients (NCT03801434 and NCT00044304). | Further studies are needed to confirm efficacy and safety. Allogeneic HSCT may be suitable for some patients depending on co-morbidities and risk/benefit considerations. | |
| Tofacitinib (JAK1/3 kinase inhibitor) 46, 47 | L-HES and I-HES (In development) | A small case study showed gain of function mutations in STAT3 in 1 patient with L-HES and over-expression of STAT-3 dependent genes in a further 2 patients which suggested disruption of the JAK/STAT pathway could be effective in treating patients with HES. A follow-up small therapeutic trial of tofacitinib or ruxolitinib in 2 patients with L-HES and 3 patients with I-HES, all with cutaneous involvement, showed efficacy in reducing blood eosinophil counts and OCS-sparing capability. | Further studies are required to confirm efficacy and safety. | |
| Cytotoxic/immunomodulatory agents | Interferon-α (IFN-α) 6, 13, 40, 48 | HES | Second-line option for patients with HES, with case reports and case series showing efficacy in I-HES, M-HES, and L-HES. Pegylated form seems equally effective and is both more convenient (weekly dosing) and better tolerated. Response rates vary. Preferred second-line option when available for L-HES. |
Frequent requirement for incremental increase in dosing for improved tolerance. May be associated with poor tolerance (flu-like symptoms) and/or significant toxicity. Often discontinued. Secondary resistance has been reported. |
| Hydroxyurea (HU) 6, 13, 40, 49 | HES | For patients with I-HES, combination of low-dose OCS and HU following induction of remission has shown success in stabilizing disease. | Often discontinued due to lack of efficacy or hematologic/gastrointestinal side effects. | |
| Cyclophosphamide 38, 50, 68 | EGPA | Used at treatment initiation in combination with OCS to induce remission for patients with severe organ-or life-threatening manifestations of EGPA. Can be used in either continuous oral or pulsed intravenous dosing regimens. Treatment typically has a duration of 3–6 months. | Associated with significant treatment-related urinary tract toxicity and decreased fertility. May require fertility preservation considerations. | |
| Rituximab 50–54, 68 | EGPA | Demonstrated efficacy as maintenance therapy in observational studies of patients with EGPA. | Possible infusion reactions (can be avoided with systematic preventive measures). Associated with immunosuppression and reduced responses to vaccination. | |
| Methotrexate 38, 50, 68 | EGPA | Used in combination with OCS as maintenance therapy | To be used after the successful induction of remission. Case reports and small series in HES did not show efficacy. |
|
| Azathioprine 38, 50, 68 | EGPA | Used in combination with OCS as maintenance therapy | To be used after the successful induction of remission. Not typically used for treatment of HES, with the exception of rare cases with liver involvement. |
|
| Novel eosinophil-targeting therapies | Mepolizumab (Anti–IL-5) 6, 55–60 | HES, EGPA (Approved for use in patients with EGPA or HES in multiple regions worldwide) | HES: Reduced eosinophil count and clinical benefit (reduced flares and reduction in maintenance OCS therapy) shown in Phase III trials. An expanded access program ongoing since 2005 has treated and shown efficacy in hundreds of patients with HES (mepolizumab exposure >1500 patient years). EGPA: In a Phase III trial in EGPA, treatment increased the proportion of patients in remission and reduced the relapse rate. Although remission and relapse definitions included a vasculitis component, efficacy on vasculitis in EGPA remains to be determined. |
Approved dose for HES and EGPA is 300 mg given as subcutaneous injections every 4 weeks. |
| Reslizumab (Anti–IL-5) 61–63 | HES, EGPA (Studied) | Reduced eosinophil counts and clinical benefit (reduced OCS dose and/or symptoms) shown in patients with EGPA and HES in small open-label studies. | Given intravenously with dosing according to weight, in contrast to mepolizumab and benralizumab. May be interesting to determine efficacy in patients with high BMI who fail to respond to other IL-5(R)–targeted therapies. | |
| Benralizumab (Anti–IL-5R) 64, 65 | HES, EGPA (In development) | Reduced blood eosinophil counts and tissue eosinophilia with clinical improvement shown in patients with PDGFRA-negative HES and reduced OCS use and exacerbation rates shown in patients with EGPA in Phase II trials. | Yet to be confirmed whether beneficial in HES/EGPA in the setting of Phase III studies (ongoing: NCT04191304 and NCT04157348). | |
| Dexpramipexole (small molecule) 66 | HES (In development) | OCS-sparing capability in a subset of patients with HES shown in proof-of-principle investigator-initiated Phase II study. | N/A | |
| Lirentelimab (Anti–Siglec-8) 67 | HES (In development) | Not yet explored for use in HES or EGPA but shown to deplete eosinophils in Phase II trial in patients with peripheral blood eosinophilia and eosinophilic gastritis and/or eosinophilic duodenitis. | N/A |
ALS, amyotrophic lateral sclerosis; BCR, Bruton’s tyrosine; BMI, body mass index; CS, corticosteroids; EGPA, eosinophilic granulomatosis with polyangiitis; ETV6, ETS-variant6; FIP1L1, factor interacting with PAPOLA And CPSF1; HES, hypereosinophilic syndrome; HU, hydroxyurea; HSCT, hematopoietic stem cell transplant; IFN-α, interferon-alpha; IL, interleukin; JAK, Janus activated kinase; M-HES, myeloid hypereosinophilic syndrome; OCS, oral corticosteroids; PCM1, pericentriolar material gene 1; PDGFRA, platelet-derived growth factor receptor alpha; Siglec-8, sialic acid-binding immunoglobulin-like lectin 8; STAT, signal transducer and activation of transcription.