Clinical Research Directory

Linperlisib in the Treatment of aPRCA

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.

MT2023-20: Hematopoietic Cell Transplant With Reduced Intensity Conditioning and Post-transplant Cyclophosphamide for Severe Aplastic Anemia and Other Forms of Acquired Bone Marrow Failure.

A phase II trial of a reduced intensity conditioned (RIC) allogeneic hematopoietic cell transplant (HCT) with post-transplant cyclophosphamide (PTCy) for idiopathic severe aplastic anemia (SAA), paroxysmal nocturnal hemoglobinuria (PNH), acquired pure red cell aplasia (aPRCA), or acquired amegakaryocytic thrombocytopenia (aAT) utilizing population pharmacokinetic (popPK)-guided individual dosing of pre-transplant conditioning and differential dosing of low dose total body irradiation based on age, presence of myelodysplasia and/or clonal hematopoiesis.