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Abstract
Presentation during EHA2022: Presentation during EHA2022: The Late-Breaking Oral Session will be held on Sunday, June 12, 2022 (09:45 - 11:15 CEST) and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: LB2369

Type: Late breaking oral

Session title: Late breaking abstract session

Background
Pathogenic variants in either the PIK3CD or PIK3R1 genes encoding PI3Kδ that cause kinase hyperactivity can result in a primary immunodeficiency called activated PI3Kδ syndrome (APDS) or PASLI. Patients with APDS have dysregulated B and T cells leading to lymphoproliferation, autoimmunity, immunodeficiency, and increased risk of lymphoma. Current treatments are mainly empirical.

Aims
We previously reported use of molecularly targeted inhibition of hyperactive PI3Kδ signaling with the investigational drug leniolisib (CDZ173) in 6 patients with APDS in a 12-week, open-label, within-subject dose-escalation Phase 2/3 clinical trial (Part 1 of NCT02435173; Rao VK, et al. Blood. 2017;130(21):2307-2316), as well as an interim analysis of the open-label extension study (Rao VK, et al. Blood. 2018;132(suppl1):3706). Here we report outcomes from a randomized 2:1, placebo-controlled, triple-blinded, fixed-dose study (Part 2 of NCT02435173).

Methods
Thirty-one patients aged ≥12 years were enrolled globally. Informed consent was obtained. Co-primary outcomes were change at 12 weeks from baseline in log10 transformed sum of product of diameters in index lymph nodes and change from baseline in percentage of naïve B cells out of total B cells. Additional observations included changes in size of non-index lymph nodes and spleen. Cytopenias were also evaluated.

Results
Lymph node and naïve B cell primary efficacy endpoints were met (p=0.0012 and p<0.0001, respectively). Leniolisib reduced the log10 transformed 3D volume in non-index lymph nodes from baseline to day 85 (D85; p=0.0011). Of note, several patient narratives revealed that the reduction in lymphoproliferation decreased neck soreness and difficulty swallowing. Analyses of the change from baseline at D85 in 3D volume and bi-dimensional size of the spleen demonstrated that leniolisib reduced spleen size (p=0.0009 and p=0.0079, respectively). Cytopenias varied and are described in Table 1. Eighty-two percent of cytopenias improved in patients receiving leniolisib, compared to 60% in patients receiving placebo.

Leniolisib was well tolerated; 23.8% of leniolisib and 30.0% of placebo adverse events (AEs) were reported as related to study treatment. No AEs led to discontinuation of study treatment. None of the serious AEs were suspected to be related to treatment. In the leniolisib arm, 4 of 21 patients (all of whom were <18 years of age) developed mild neutropenia by D85 which was not clinically meaningful. Neutrophil counts (x 109/L) for these patients at baseline, D15, D29, D57, and D85 are as follows:

  • Patient 8001002: 1.83, 1.06, 0.79, 1.97, 1.11
  • Patient 4001003: 2.90, 1.80, 2.60, 3.10, 0.90
  • Patient 5001002: 2.55, 1.20, 2.30, 1.70, 1.20
  • Patient 1001006: 2.35, 1.30, 2.80, 2.10, 1.30

Mean neutrophil level at D85 of all 21 patients receiving leniolisib was 2.94 x 109/L. Two patients developed lymphopenia by D85. In the placebo arm, 1 patient developed lymphopenia and 1 had mild neutropenia by D85 which was not clinically meaningful.

Conclusion
Leniolisib was well tolerated and met both primary efficacy endpoints in patients with APDS. Additional observations revealed changes to other key parameters.

Keyword(s): Immunodeficiency, Lymphoproliferative disorder, Anemia, Targeted therapy

Presentation during EHA2022: Presentation during EHA2022: The Late-Breaking Oral Session will be held on Sunday, June 12, 2022 (09:45 - 11:15 CEST) and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: LB2369

Type: Late breaking oral

Session title: Late breaking abstract session

Background
Pathogenic variants in either the PIK3CD or PIK3R1 genes encoding PI3Kδ that cause kinase hyperactivity can result in a primary immunodeficiency called activated PI3Kδ syndrome (APDS) or PASLI. Patients with APDS have dysregulated B and T cells leading to lymphoproliferation, autoimmunity, immunodeficiency, and increased risk of lymphoma. Current treatments are mainly empirical.

Aims
We previously reported use of molecularly targeted inhibition of hyperactive PI3Kδ signaling with the investigational drug leniolisib (CDZ173) in 6 patients with APDS in a 12-week, open-label, within-subject dose-escalation Phase 2/3 clinical trial (Part 1 of NCT02435173; Rao VK, et al. Blood. 2017;130(21):2307-2316), as well as an interim analysis of the open-label extension study (Rao VK, et al. Blood. 2018;132(suppl1):3706). Here we report outcomes from a randomized 2:1, placebo-controlled, triple-blinded, fixed-dose study (Part 2 of NCT02435173).

Methods
Thirty-one patients aged ≥12 years were enrolled globally. Informed consent was obtained. Co-primary outcomes were change at 12 weeks from baseline in log10 transformed sum of product of diameters in index lymph nodes and change from baseline in percentage of naïve B cells out of total B cells. Additional observations included changes in size of non-index lymph nodes and spleen. Cytopenias were also evaluated.

Results
Lymph node and naïve B cell primary efficacy endpoints were met (p=0.0012 and p<0.0001, respectively). Leniolisib reduced the log10 transformed 3D volume in non-index lymph nodes from baseline to day 85 (D85; p=0.0011). Of note, several patient narratives revealed that the reduction in lymphoproliferation decreased neck soreness and difficulty swallowing. Analyses of the change from baseline at D85 in 3D volume and bi-dimensional size of the spleen demonstrated that leniolisib reduced spleen size (p=0.0009 and p=0.0079, respectively). Cytopenias varied and are described in Table 1. Eighty-two percent of cytopenias improved in patients receiving leniolisib, compared to 60% in patients receiving placebo.

Leniolisib was well tolerated; 23.8% of leniolisib and 30.0% of placebo adverse events (AEs) were reported as related to study treatment. No AEs led to discontinuation of study treatment. None of the serious AEs were suspected to be related to treatment. In the leniolisib arm, 4 of 21 patients (all of whom were <18 years of age) developed mild neutropenia by D85 which was not clinically meaningful. Neutrophil counts (x 109/L) for these patients at baseline, D15, D29, D57, and D85 are as follows:

  • Patient 8001002: 1.83, 1.06, 0.79, 1.97, 1.11
  • Patient 4001003: 2.90, 1.80, 2.60, 3.10, 0.90
  • Patient 5001002: 2.55, 1.20, 2.30, 1.70, 1.20
  • Patient 1001006: 2.35, 1.30, 2.80, 2.10, 1.30

Mean neutrophil level at D85 of all 21 patients receiving leniolisib was 2.94 x 109/L. Two patients developed lymphopenia by D85. In the placebo arm, 1 patient developed lymphopenia and 1 had mild neutropenia by D85 which was not clinically meaningful.

Conclusion
Leniolisib was well tolerated and met both primary efficacy endpoints in patients with APDS. Additional observations revealed changes to other key parameters.

Keyword(s): Immunodeficiency, Lymphoproliferative disorder, Anemia, Targeted therapy

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