Key outcomes in treatment of activated phosphoinositide 3-kinase delta syndrome: An e-Delphi panel study and responder threshold application

Abstract

Background: Activated phosphoinositide 3-kinase delta syndrome (APDS) is an ultra-rare, underrecognized inborn error of immunity. This study aimed to identify outcomes important in evaluating APDS treatment effectiveness and percent change in specific outcomes indicating a clinically meaningful benefit.

Methods: In this e-Delphi panel study, 28 globally based APDS experts used a 5-point Likert scale (Strongly Disagree to Strongly Agree) to indicate level of agreement that an outcome was an important measure of APDS treatment effectiveness in adult and pediatric patients at 3 and 6 months after treatment initiation. A threshold of ≥75% responding with "Agree" or "Strongly Agree" was considered consensus. Percent meaningful improvement in 6 outcomes was assessed and applied to APDS trial data (NCT02435173).

Results: Twenty-four panelists participated; e-Delphi rounds 1-5 were completed by 23, 21, 18, 17, and 16 panelists, respectively. Outcomes with the highest degree of consensus included lymph node size/volume, clinician overall impression of disease activity, antibiotic use, patient/caregiver-reported social outcomes and patient quality of life, hospitalizations, thrombocytopenia, spleen volume, lymphopenia, and anemia. Panelists indicated within-patient clinically meaningful improvements in adult patients ranged from median values of 20%-25% in lymph nodes, naïve B-cell to total B-cell ratio, spleen volume, hemoglobin, platelets, and lymphocytes at 3 months, and 25%-30% at 6 months. Panelists indicated within-patient clinically meaningful improvements in pediatric patients ranged from median values of 20%-27.5% at 3 months and 22.5%-45% at 6 months in the same 6 outcomes. In an application of responder thresholds, treatment with leniolisib resulted in significant and meaningful improvements in disease hallmarks, including lymph node size, spleen volume, and naïve B-cell ratio.

Conclusion: This study provides expert consensus on outcomes important in assessing APDS treatment effectiveness and improvement thresholds in 6 treatment outcomes indicative of a clinically meaningful benefit. These outcomes may help optimize APDS treatment in the clinic.

Fig 1. Treatment Outcome Frequencies ≥2 From Clinician Interviews.

This figure includes the total number of times that an outcome was mentioned overall. A single outcome may have been mentioned more than once in the interview. Each clinician could provide more than one response; therefore, the sum of the counts in the figure does not equal 9. Outcomes receiving 1 comment included pulmonary function, patient experience, metabolic activity, malignancy, lymphoma risk (with associated comment that a surrogate would be needed to measure), joint pain, inflammation/autoimmune, vaccination response, IgG treatment, hospital visits, fever, exercise intolerance, energy level, EBV, EBV load, easy bleeding and bruising, side effects, coughing, clinical outcomes–general organ involvement, chest therapy/inhaler, bruising, school attendance, autoimmunity symptoms, autoimmune disease, appetite, rash, adenopathy/organomegaly, able to sleep, viral loads, serum immunoglobulins, PD-1⁺CD4⁺ and PD-1⁺CD8⁺, naïve T cells, naïve B cells, memory B cells, CD4/CD8 T-cell ratio, B cells, B-cell function, and all B- and T-cell panel information. Additional single-mention comments included patient heterogeneity, CVID, and unavailability of some outcomes in the clinic. CD, cluster of differentiation; CVID, common variable immunodeficiency; EBV, Epstein-Barr virus; GI, gastrointestinal; Ig, immunoglobulin; PD-1, programmed cell death protein 1; QOL, quality of life.

Fig 2. Overview of the E-Delphi Panel Study Process.

^aSelect outcomes from Round 1 were expanded or consolidated to optimize panelist review in Round 2. Outcomes identified as less relevant in adult patients (e.g., growth, height, weight) were removed from consideration but were retained for pediatric patients. ^bOriginal outcomes from Round 2 were evaluated for a second time in Round 3; modified items were listed as new and evaluated for the first time.

Fig 3. Percent Agreement (Agree or Strongly Agree) for Treatment Outcomes in Adult Patients at 3 Months and 6 Months After Starting Treatment (Round 3).

Outcomes not meeting the ≥ 75% threshold for consensus, represented by the vertical blue line, are indicated with pattern fill. Outcomes meeting the ≥ 75% threshold for consensus were considered to be finalized. Ig, immunoglobulin; IRT, immunoglobulin replacement therapy; QOL, quality of life; TNF-α, tumor necrosis factor α.

Fig 4. Percent Agreement (Agree or Strongly Agree) for Treatment Outcomes in Pediatric Patients at 3 Months and 6 Months After Starting Treatment (Round 3).

Outcomes not meeting the ≥ 75% threshold for consensus, as represented by the vertical blue line, are indicated with pattern fill. Ig, immunoglobulin; IRT, immunoglobulin replacement therapy; QOL, quality of life; TNF-α, tumor necrosis factor α.

Fig 5. Percent Agreement (Agree or Strongly Agree) for Revised Treatment Outcomes in Adult Patients at 3 Months and 6 Months After Starting Treatment (Round 4).

Outcomes not meeting the ≥ 75% threshold for consensus, as represented by the vertical blue line, are indicated with pattern fill. CD, cluster of differentiation; CMV, cytomegalovirus; EBV, Epstein-Barr virus; GFR, glomerular filtration rate; GI, gastrointestinal; Ig, immunoglobulin; MELD, Model for End-Stage Liver Disease; pAKT, phosphorylated protein kinase B; pS6, phospho-S6 ribosomal protein.

Fig 6. Percent Agreement (Agree or Strongly Agree) for Revised Treatment Outcomes in Pediatric Patients at 3 Months and 6 Months After Starting Treatment (Round 4).

Outcomes not meeting the ≥ 75% threshold for consensus, represented by the vertical blue line, are indicated with pattern fill. CD, cluster of differentiation; CMV, cytomegalovirus; EBV, Epstein-Barr virus; GFR, glomerular filtration rate; GI, gastrointestinal; Ig, immunoglobulin; MELD, Model for End-Stage Liver Disease; pAKT, phosphorylated protein kinase B; pS6, phospho-S6 ribosomal protein.

Fig 7. Meeting Responder Thresholds at 3 Months in 6 Outcomes Using Data From a Randomized Phase 3 Study [20].

^aA statistical comparison between the proportion of responders in the leniolisib and placebo treatment arms was not conducted for lymphocytes, as there were no patients in the placebo arm with an abnormal lymphocyte count at baseline. ^bResponder threshold definitions were selected through an e-Delphi panel of APDS clinicians. APDS, activated phosphoinositide 3-kinase delta syndrome; NC, not calculable; NS, not significant.