Idelalisib (Zydelig®) Maintenance in B-Cell Non-Hodgkin's Lymphoma after High Dose Chemotherapy and Autologous Stem Cell Transplantation
Authors: Yared Jean A. , Singh Tanmay , Beitinjaneh Amer , Rapoport Aaron P. , Dahiya Saurabh , Atanackovic Djordje , Hardy Nancy M. , Kocoglu Mehmet H. , Toth Tara , Pineiro Deanna , Goloubeva Olga 
Published: December 2024

Background:
High dose chemotherapy and autologous stem cell transplantation (HDT/ACST) in patients (pts) with relapsed and/or refractory (r/r) indolent (i) or transformed indolent (ti) B-cell lymphoma (NHL) prolongs PFS. Unfortunately, the majority of pts will have relapsed NHL or die from NHL within 1-3 years (yrs) post ASCT.
Idelalisib (Zydelig®) was the 1st marketed PI3Kδ inhibitor (in 2014) that has been effective against iNHL (FL) with favorable activity in heavily treated pts, with an ORR of 54%, median PFS of 11 months (m), and a median DOR of 12.4 m. [DELTA trial (NCT1282424)]. Gilead Sciences, Inc, voluntarily withdrew Idelalisib (Id) in 2022 for poor enrollment in confirmatory studies.
In the post marketing period, we proposed to incorporate Id as a maintenance (Mx) treatment post ASCT for pts with iNHL and tiNHL. We aimed to investigate the safety and efficacy of Id Mx in pts with iNHL or tiNHL after ASCT. We hypothesize that Id Mx is well tolerated and could prolong the remission after ASCT.
Study Design:
This was a pilot, prospective, open-label, double-center (University of Maryland and University of Miami) study of Id Mx monotherapy in pts with iNHL or tiNHL after ASCT. Id was orally administered with the starting dose of 150 mg BID (or 100 mg BID for those who experience Gr 2 or 3 toxicity and recover to ≤ Gr 1) for continuous 28-day cycle for up to 1 year (yr) or 12 cycles after ASCT. Id was started in pts who were between 30 and 120 days after ASCT. Id was continued until progression, intolerance, or pt/physician discretion.
The primary objective was to determine the toxicity and safety of incorporating Id into the post ASCT Mx setting for iNHL and tiNHL. The secondary objective was to assess the efficacy of this strategy, looking at 1- and 2-yr PFS, and OS.
Results:
The accrual target was 31 pts. The study was closed to accrual prematurely in 2021 due to poor accrual. Causes of poor accrual were: SARS-CoV-2 pandemic and the decline in the number of ASCT for NHL due to the emergence of CD19 CAR-T therapy.
A total of 19 pts [median age 60 (range 44-72); 12 males and 5 females; 11 white non-Hispanic (NH), 2 black NH, 1 Asian NH, and 3 white Hispanic] with r/r iNHL or tiNHL (11 FL Gr 1,2,3a, 1 nodal MZL and 5 Gr3b/tFL) who received a median of 2 prior lines (range: 2-4) of treatment achieving PR or CR and underwent BEAM/ASCT were consented between Oct 2017 to Sep 2020. There were 2 screen failures, so a total of 17 pts was enrolled and started treatment. Dose de-escalation from 150 mg BID to 100 mg BID was required in 11 (65%) pts. 12 (71%) pts received a total of 12 cycles and 5 pts (29%) received 3 or less cycles. All pts who received &lt; 12 cycles stopped Id due to toxicity: elevated LFTs in 3 pts, rash in 1 pt, and weight loss and dysgeusia in 1 pt.
A total of 193 AEs was recorded: 29 probably related to Id, 98 possibly related, 40 unlikely related and 26 unrelated. 12 gr 3 and 1 gr 4 AEs were recorded and the rest were gr 1&2. The most common ones were: Transaminitis, leukopenia, rash, hyperglycemia, thrombocytopenia, infections, anemia, fatigue, diarrhea, cough, infections, dysgeusia and insomnia. Two SAEs were reported: One pt developed gr 3 diarrhea during Id necessitating treatment interruption and hospitalization for 3 days, treated successfully with budesonide and methylprednisolone; this SAE was deemed to be expected and probably related to Id. Another pt who finished 12 cycles of Id per protocol for over a yr before and was on f/up only, was admitted with severe SARS-CoV-2 pneumonia and died from respiratory failure; this SAE was deemed to be unrelated to Id. Pts were on herpes and PJP prophylaxis and were monitored for CMV viremia by blood CMV PCR. No clinically significant herpes, CMV infections or PJP pneumonia were noted.
At the time of ASCT, 11 pts were in complete remission (CR) and 6 pts were in partial remission (PR). All pts achieved CR after ASCT. The median follow-up was 4.83 yrs (95% CI:3.95-5.96). At 1-yr post ASCT, 1 pt had relapsed disease and at 2 yrs post ASCT, a total of 3 pts had relapsed disease. The median PFS and OS with the 95% CI have not been reached yet. PFS at 1 yr and 2 yrs were 94% and 82% respectively. OS at 1 yr and 2 yrs were 100%. At the date of last follow, 3 pts have died, 2 from relapsed NHL and 1 from SARS-CoV-2 pneumonia. The rest of the pts are alive and in remission.
Conclusion:
Post ASCT idelalisib Mx for r/r iNHL and tiNHL was relatively well tolerated, albeit at lower than conventional dose (100 mg BID instead of 150 mg BID) and yielded encouraging results.