Patients with acquired pure red cell aplasia respond to <scp>PI3Kδ</scp> inhibitor rapidly
Authors: Zhenzhen Wang, Bo Jiang, Lin Song, Mingyuan Sun, Chunhong Li, Xiaoxia Li, Weiwei Zheng, Yuan Tao, Qi Sun, Junyuan Qi
Journal: American Journal of Hematology (2024)

Pure red cell aplasia (PRCA) is a rare disease for which large controlled trials are challenging and as such recommendations are mostly based on retrospective studies or case accumulations. Cyclosporine A (CsA) provides the most effective treatment for PRCA with an overall response rate of 65%–87%,1 leaving approximately one-third of patients in need of an alternative agent. Moreover, responders typically take 2–3 months to achieve transfusion-independence (TI) from the start of therapy.1 As a result, large proportions of PRCA patients require regular blood transfusions, leading to decreased quality-of-life and substantial healthcare utilization. Novel treatment strategies are required to improve this dismal situation. Linperlisib is a highly selective and potent PI3Kδ inhibitor that received orphan drug designations by the Food and Drug Administration for the treatment of follicular lymphoma, chronic lymphocytic leukemia, and T cell lymphoma. For the first time, we evaluated the effects of Linperlisib on patients with acquired PRCA, including one idiopathic case and three cases secondary to T cell large granular lymphocyte leukemia (T-LGLL), and observed surprisingly rapid responses and manageable safety. Hereby, we retrospectively reported our preliminary experience in the hope of providing novel therapy idea for this rare condition. This study was approved by our institutional review board and all patients signed informed consents. Clinical courses and patients' characteristics are shown in Figure 1 and Supplemental Materials, and elaborated upon below. Case 1: A 48-year-old female diagnosed with PRCA associated with T-LGLL and monoclonal gammopathy of undetermined significance (MGUS) started on Linperlisib 80 mg daily 12 months ago after failing to respond to CsA along with prednisone taper (Table S1). Subsequently, Hb increased from 7.6 to 10.4 g/dL by the 10th day, and then normalized by the 21st day without transfusion. Bone marrow (BM) examination post-Linperlisib confirmed remarkable improved erythropoiesis (Figure S1). Linperlisib treatment was interrupted after 119 days due to colitis and replaced with a 42-day third-line treatment of Stanozolol (2 mg three times a day). Nevertheless, hemoglobin level decreased, and the patient had to resume regular transfusions. In response, Linperlisib was restarted at 40 mg per day, resulting in a second complete remission (CR, Hb > 11.0 g/dL in female and >12.0 g/dL in male without transfusion) after 22 days without any adverse effects being recorded subsequently (Figure 1 and Table S1). Case 2: A 63-year-old female was diagnosed with T-LGLL associated PRCA 5 years ago. Her Hb maintained normal for 4 years with CsA and steroid taper. Linperlisib 80 mg per day was orally administered due to relapsed anemia and Hb level was elevated from 6.3 to 7.7 g/dL in 1 week. After 30 days, CR was reached and continued for 155 days (Figure 1 and Table S1) until Linperlisib was terminated due to maculopapular (depicted in Figure S2), which disappeared within 4 weeks after stopping the medication. Case 3: A 79-year-old man was confirmed to have T-LGLL associated PRCA 5 months ago. He was intolerant to first-line therapy composed of CsA and methylprednisolone due to severe transaminase elevation. The attempt of Linperlisib 80 mg daily resulted in a progressive and rapid rise of Hb level, peaking at 11.1 g/dL, effectively eliminating the requirement for transfusions. The reticulocyte counts also displayed a noteworthy upsurge from 5.7 to 130.8 × 109/L within 2 weeks. A temporary rise in transaminase levels was resolved after 1 week of supportive care. Pneumonia occurred concomitantly with severe neutropenia (minimum count 0.02 × 109/L), resulting in a 2-week interruption in treatment and a decrease of Hb level to 9.2 g/dL. After that, Linperlisib was reintroduced at a dosage of 40 mg per day and the complete blood count (CBC) on day 141 revealed a Hb value above 10.0 g/dL and a neutrophil count within the normal range (Figure 1 and Table S1). Case 4: A 54-year-old male with anemia was diagnosed with PRCA associated with MGUS 1 year ago. Initial therapy composed of stanozolol, followed by CsA and prednisone did not decrease transfusion requirements and led to the therapy of Linperlisib 80 mg daily. Hb value elevated from 5.7 to 7.0 g/dL in 5 days, with a remarkable rise in reticulocyte count from 5.9 to 44 × 109/L. He has been received Linperlisib for 12 weeks without any adverse reactions to date, and the latest CBC on the 87th day showed a normal Hb of 12.6 g/dL (Figure 1 and Table S1). Bone marrow re-examination on Day 59 revealed improved erythropoiesis and unexpectedly unchanged plasma cell clone (Figure S3). The etiological diagnosis was accordingly revised as idiopathic PRCA with a coincidental MGUS, which has been described previously.2 With current therapies, responders typically take months, more specifically, 29 ± 45 days for LGLL-associated PRCA and 82 ± 200 days for idiopathic PRCA according to PRCA Collaborative Study Group of Japan,3, 4 to achieve TI from the start of therapy. In this study, all patients were heavily dependent on blood transfusions before starting Linperlisib treatment, with a requirement of 2–6 units per month. The initiation of Linperlisib (80 mg daily) promptly improved Hb values and reticulocyte counts and virtually eliminated the need for blood transfusions from the start of the therapy, with the exception of patient 4 having a planned transfusion that was delayed until after receiving Linperlisib due to resource constraints (Figure 1). Time for best response (three CR and one near CR) ranged from 21 to 46 days. Three patients had to discontinue due to adverse events of ≥grade 3 (detailed in Table S1), resulting in declines in Hb levels. Nevertheless, two patients resumed at the lower dose of 40 mg per day which promptly elevated Hb levels with good tolerance. In conclusion, Linperlisib demonstrated rapid response and manageable tolerability in refractory or relapsed patients with T-LGLL associated as well as idiopathic PRCA, which is impressive especially considering the cost and medical burden associated with blood transfusions. The precise mechanisms responsible for the rapid effect of Linperlisib in PRCA of different etiologies have yet to be investigated. Nevertheless, existing knowledge on PRCA and PI3K can provide valuable clues and implications. The dominant expression of p110δ on immune cells5 and the pathogenic role of abnormal immunity in PRCA,1 hints the possibility that Linperlisib inhibits abnormal immune responses against erythroid precursors, which at least partially contributes to Hb improvement. Theoretically, PI3Kδ participates in multiple processes of different lymphocyte subsets and the overall effect of PI3Kδ inhibition in vivo is subject to the balance between opposing actions of these subsets.5 In the context of PRCA, we speculate that Linperlisib's effectiveness may be primarily due to its suppression of T cell immune responses, which have been identified as the common pathogenesis in both idiopathic and LGLL-associated PRCA.6 In addition, the lack of reduction in LGLs (Table S2) may be explained by the viewpoint that PI3K/Akt pathway is essential for effector function of T cells rather than their survival or proliferation.7 An additional plausible explanation for the rapid remission of anemia is that Linperlisib enhances erythropoiesis and accelerates the recovery of reticulocytes and Hb. This remains speculative but feasible, as PI3K inhibition can down-express c-myc8 and potentially inhibit mTOR, both of which are known to contribute to erythropoiesis by promoting enucleation and autophagy.9, 10 Detailed explorations are required to fully understand the mechanisms behind the efficacy and to identify potential responders with different etiologies. As is common knowledge, integration of cases and accumulation of experiences greatly contribute to advancements in treating rare diseases. Despite the small sample size, limited follow-up, and only two subtypes included, this case series provides the first evidence of clinical benefit and manageable tolerability of PI3Kδ inhibitor treatment for idiopathic and LGLL-associated PRCA. To expedite the improvement of the dismal situation of this rare condition, we expeditiously reported our preliminary experiences, thereby encouraging more studies to further confirm the long-term efficacy and safety of PI3Kδ inhibitor for PRCA with different etiologies. Zhenzhen Wang devised the manuscript, reviewed the data, wrote and edited the manuscript. Bo Jiang devised the manuscript, reviewed the data, reviewed and edited the manuscript. Lin Song, Mingyuan Sun, Chunhong Li, Xiaoxia Li and Weiwei Zheng treated the patients and reviewed the manuscript. Junyuan Qi conceived and designed the study and reviewed and edited the manuscript. Yuan Tao and Qi Sun performed the review of bone marrow biopsies. This study was supported by a grant (NCRC-1-020, to Bo Jiang) from National Clinical Research Center for Blood Disease of China; Chinese Society of Clinical Oncology, Beijing Xisike Clinical Oncology Research Foundation (Y-HR2022ZD-0774, to Junyuan Qi). The authors declare no competing financial interests. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.