P646: venetoclax retreatment after mrd-guided venetoclax +/- ibrutinib: the improve study cohort

Background: The efficacy and tolerability of venetoclax (VEN) retreatment in patients (pts) with chronic lymphocytic leukemia (CLL) relapsing after VEN-based fixed-duration regimens still remains to be clarified. Data collected in small cohorts suggest that VEN retreatment can be effective and well tolerated, thus it is worth exploiting in larger cohorts of well-characterized pts with CLL. Aims: We analyzed the efficacy and safety of VEN retreatment in pts with relapsed/refractory CLL enrolled in our clinical trial IMPROVE (NCT04754035). Methods: Pts enrolled into the study were treated with VEN single-agent for 12 months; those with undetectable measurable residual disease (uMRD) discontinued therapy while those with detectable MRD received the combination of ibrutinib (IBR) and VEN until uMRD, toxicity or for up to 12 months. Those with detectable MRD at the end the combination therapy stopped VEN and continued with IBR only. In pts who relapsed due to confirmed progression (PD), VEN was restarted according to the standard schedule with an initial 5-week dose escalation ramp-up and continued until PD or unacceptable toxicity. MRD was tested every 3 months in peripheral blood using the 6-color flow cytometry panel validated by the ERIC (European Research Initiative on CLL). Results: After a median follow-up of 54 months (5-62) from C1D1, 17/38 (44.5%) pts experienced PD requiring treatment after discontinuing therapy, including 16 upon reaching confirmed uMRD (9 treated with VEN single-agent, 8 with the combination of VEN+IBR), 1 who discontinued both VEN and IBR in response with detectable MRD due to an unrelated adverse event. Two out of 17 had Richter transformation (RT), 2 developed autoimmune hemolytic anemia, and all 4 went off study. The remaining 13 pts (6 who previously achieved uMRD with VEN monotherapy, 7 who were treated with the combination of VEN+IBR) received VEN retreatment at a median of 32 months (12-41) after the end of initial therapy (Table 1). All 13 subjects experienced MRD relapse at a median of 5 months (0-41) after stopping treatment, 27 (0-37) months before disease progression requiring therapy; the only pt who stopped treatment in PR with detectable MRD, due to an unrelated adverse event, restarted VEN after 13 months. At the time of VEN initiation tumor lysis syndrome (TLS) risk was high in 6, medium in 3, low in 4. Among those evaluable for response (n=10), best overall response was partial response n=8 (80%), and 2 stable disease. With a median time on treatment of 9.5 months, 2 pts achieved uMRD after 3 and 6 months, the second one maintaining uMRD for 6 months and then becoming MRD positive again. Four out of 13 pts progressed after 7, 12 (n=2), and 14 months on VEN retreatment, 3/4 received next-line treatment with IBR and achieved a partial response. At last follow-up 11/13 patients undergoing VEN retreatment were alive (1 death due to RT on IBR, 1 due to CLL progression on non-covalent BTK inhibitor). Progression-free survival from VEN restart to PD on VEN retreatment, last follow-up or death was 14 months (0-23). VEN retreatment was very well tolerated with no patients experiencing TLS, 5/13 having grade 3-4 neutropenia (in 1 case leading to treatment discontinuation), 3/13 infections (2 grade 3, 1 grade 2). Summary/Conclusion: VEN retreatment was effective and well-tolerated in a cohort of pts with relapsed/refractory CLL who have previously received MRD-guided treatment with VEN+/-IBR. MRD relapse occurred at a median of about 2 years before clinical progression requiring treatment. Updated results with longer follow-up will be presented at the meeting.Keywords: ibrutinib, MRD, B-CLL, Venetoclax