Linperlisib in the Treatment of aPRCA

Chinese Academy of Medical Sciences & Peking Union Medical College

Status and phase: Not yet enrolling; Phase 2

Conditions: Acquired Pure Red Cell Aplasia

Treatments: Drug: Linperlisib

Study type: Interventional

Funder types: Other

Identifiers

NCT07031115

Linperlisib-PRCA

Details and patient eligibility

About

Pure red cell aplasia (PRCA) is a syndrome characterized by normocytic normochromic anemia, reticulocytopenia, and reduced erythroid precursors in an otherwise normocellular bone marrow. It primarily affects erythropoiesis, while granulocytic and megakaryocytic lineages typically remain unaffected. First-line therapies for PRCA include corticosteroids (CS) and cyclosporine A（CsA). Although CS demonstrates high response rates, relapse frequently occurs upon dose reduction or discontinuation. CsA achieves response rates of 65%-87%, yet exhibits a delayed onset of action, often requiring 2-3 months to achieve transfusion independence. Sirolimus constitutes a second-line option, with additional therapeutic agents including methotrexate and cyclophosphamide.

Phosphatidylinositol 3-kinases (PI3Ks) represent a family of lipid kinases. The δ and γ isoforms are predominantly expressed in leukocytes and are frequently activated in various B-cell lymphomas, serving as the primary therapeutic targets for currently approved PI3K inhibitors in hematological malignancies. PI3K also plays a critical role in modulating cells of both the adaptive and innate immune systems. Studies indicate that engagement of multiple immune receptors on leukocytes triggers PI3K activation. Consequently, isoform-selective (δ or γ) or dual δ/γ inhibitors are being investigated for autoimmune conditions such as COPD, asthma, allergies, and Sjögren's syndrome. Leniolisib, the first oral PI3Kδ inhibitor approved by the FDA for immunodeficiency, exemplifies this therapeutic strategy. Several other PI3K-targeting agents are under clinical evaluation, including Parsaclisib (Phase II trial in relapsed/refractory autoimmune hemolytic anemia) and Linperlisib (Phase I trial in relapsed/refractory AIHA).

T-lymphocyte dysfunction is a pivotal factor in PRCA pathogenesis. RNA sequencing analyses have revealed significant upregulation of genes associated with the PI3K/AKT/mTOR pathway in bone marrow CD8+ T lymphocytes of patients with acquired PRCA, suggesting that targeting this pathway may represent a novel therapeutic strategy. Linperlisib, a highly selective PI3Kδ inhibitor approved for relapsed/refractory follicular lymphoma, suppresses PI3Kδ protein expression and reduces AKT phosphorylation, thereby inducing apoptosis and inhibiting lymphocyte proliferation. In 2024, a seminal report documented rapid responses and manageable tolerability with Linperlisib in four patients with acquired PRCA.

Currently, no cohort studies have been conducted on Linperlisib for PRCA treatment. This study seeks to characterize the dosing regimen, efficacy, and safety profile of Linperlisib in relapsed/refractory pure red cell aplasia.

Enrollment: 15 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Age ≥ 18 years;
• Patients meeting the diagnostic criteria for acquired PRCA;
• Patients who are relapsed or refractory after at least two lines of prior therapy. Refractory is defined as failure to achieve partial remission after 3 months of treatment at a stable dose of immunosuppressive agents.
• Hb ≤ 100 g/L;
• Patients with complete clinical data, demonstrated good treatment compliance, and who have signed the informed consent form;
• If taking glucocorticoids, must have discontinued them or been on a stable low maintenance dose (prednisone ≤ 15 mg/day) for at least 2 weeks prior to enrollment, and continue this dose;
• If taking immunosuppressive agents such as cyclosporine or sirolimus, must have been on a stable dose for at least 3 months, and discontinue them upon enrollment.

Exclusion criteria

• Patients with organ dysfunction (e.g., heart, liver, or lung) or acute renal insufficiency;
• Patients who have used PI3Kδ inhibitors within the past 6 months;
• Patients with severe infectious diseases;
• Patients with malignant tumors;
• Patients with psychiatric disorders or cognitive impairment;
• Pregnant or lactating women;
• Patients who have participated in other clinical trials within the past 3 months.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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15 participants in 1 patient group

Linperlisib in the Treatment of aPRCA

Experimental group

Description:

Linperlisib 40 mg, orally, once daily. Following 2 weeks of treatment, efficacy was assessed. If the reticulocyte count remained \<20×10⁹/L, the dose was escalated to 60 mg, once daily. After an additional 2 weeks of therapy, a second efficacy assessment was performed. Patients failing to achieve partial response (PR) underwent further dose escalation to 80 mg, once daily. Treatment was discontinued if PR was not attained after 8 weeks at the maximum dose. Responding patients maintained therapy at their effective dose level. The core study period comprised 12 weeks, with responders continuing treatment at the investigator's discretion.

Treatment:

Drug: Linperlisib