2015 - VENETOCLAX RETREATMENT AFTER MRD-GUIDED VENETOCLAX +/- IBRUTINIB: THE IMPROVE STUDY COHORT

Background:
The efficacy and tolerability of venetoclax retreatment in patients with chronic lymphocytic leukemia (CLL) relapsing after venetoclax-based fixed-duration regimens is not yet fully elucidated. Data derived from small cohorts suggest that venetoclax retreatment can be effective and well tolerated, thus it is worth exploring in larger cohorts of well-characterized patients with CLL.

Aims:
We analyzed the efficacy and safety of venetoclax retreatment in patients with relapsed/refractory CLL enrolled in our clinical trial IMPROVE (NCT04754035).

Methods:
Patients enrolled into the study were treated with venetoclax single-agent for 12 months; those with undetectable measurable residual disease (uMRD) discontinued therapy while those with detectable MRD received the combination of ibrutinib and venetoclax until uMRD, toxicity or for up to 12 months. Patients with detectable MRD at the end the combination therapy stopped venetoclax and continued with ibrutinib only.
In patients experiencing relapse requiring treatment (PD), venetoclax 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 8-color flow cytometry panel validated by the ERIC (European Research Initiative on CLL) including CD45/CD5/CD19/CD20/CD43/CD79b/CD81/ROR1.

Results:
After a median follow-up of 54 months (5-62) from C1D1, 17/38 (44.5%) patients experienced PD requiring treatment after discontinuing therapy, including 16 after having reached confirmed uMRD (9 treated with venetoclax single-agent, 7 with the combination of venetoclax and ibrutinib), 1 who discontinued both venetoclax and ibrutinib 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 uMRD with venetoclax monotherapy, 6 uMRD with the combination of venetoclax and ibrutinib, 1 MRD+ on venetoclax + ibrutinib) received venetoclax retreatment at a median of 32 months (12-41) after the end of initial therapy (Table 1). Median progression-free survival (PFS) from the end of initial venetoclax +/- ibrutinib treatment was 23 months and the median PFS2 (from C1D1 of venetoclax +/- ibrutinib) 54 months (range 39-60). The 12 uMRD patients experienced MRD relapse at a median of 5 months (0-41) after stopping treatment, while the median time between MRD relapse and disease progression requiring treatment was 27 (0-37) months. The only patient who stopped treatment in PR with detectable MRD, due to an unrelated adverse event, restarted venetoclax after 13 months. At the time of venetoclax initiation tumor lysis syndrome (TLS) risk was high in 6, medium in 3, low in 4. Best overall response rate in 10 evaluable patients was partial response (8/10, 80%), and 2 stable disease. With a median time on treatment of 9.5 months, 2 patients achieved uMRD after 3 and 6 months, the second one maintained uMRD for 6 months and then became MRD positive again (Figure 1). Four out of 13 patients progressed after 7, 12 (n=2), and 14 months on venetoclax retreatment, 3/4 received next-line treatment with ibrutinib and achieved a partial response. At last follow-up 11/13 patients undergoing venetoclax retreatment were alive (1 death due to RT on ibrutinib, 1 due to CLL progression on non-covalent BTK inhibitor). Progression-free survival from venetoclax restart to PD on venetoclax retreatment, last follow-up or death was 14 months (0-23). Venetoclax retreatment was very well tolerated with no patients experiencing clinical or laboratory TLS, 5/13 having grade 3-4 neutropenia, 3/13 infections (2 grade 3, 1 grade 2). Only one patient discontinued venetoclax due to persistent grade 3-4 neutropenia.

Conclusion:
Venetoclax retreatment was effective and well-tolerated in a cohort of patients with relapsed/refractory CLL who have previously received MRD-guided treatment with venetoclax+/-ibrutinib. 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.