Real World Experience with Time Limited Venetoclax and Obinutuzumab (VO) for Frontline Treatment of CLL/SLL with MRD Determination By Clonoseq®
Authors: Winter Allison M. , Landever Olivia , Mendries Hiruni , Van Heeckeren Willem , Fu Chieh-Lin , Dean Robert M. , Brooks Taylor R. , Jagadeesh Deepa , Caimi Paolo F. , Hill Brian T. 
Published: December 2024

Introduction: Venetoclax with obinutuzumab (VO) has been approved for the frontline treatment of CLL/SLL since the publication of the CLL14 study in 2019 (Fischer, et al). Although VO was studied in patients with coexisting medical problems or impaired renal function, its use in the real world has expanded beyond these criteria given both its efficacy and the appeal of a time limited strategy. We captured the experience of patients (pts) treated with VO at an academic medical center and its regional community sites.
Methods: We conducted a retrospective review of CLL/SLL (pts) who received frontline VO at the Cleveland Clinic health care system. Pts were included if the intent to treat was with time-limited VO and received at least one dose of the regimen by 5/1/2023. We examined demographics, disease characteristics, completion of planned therapy, venetoclax (ven) dose reductions, tumor lysis syndrome (TLS) risk and incidence, debulking by obinutuzumab (obi) prior to ven, pt outcomes, and presence of minimal residual disease (MRD) by ClonoSeq®.
Results: Forty-eight pts met inclusion criteria. Twenty-five (52%) were treated in the regional setting which included 10 different facilities. Twenty-three (48%) initiated treatment at the main campus. The median age at diagnosis was 64 years (range 36-83) and the median age at the initiation of VO was 69 years (range 36-84). Thirty-five pts (73%) were male, 41 (85%) were white, 4 (8%) black, 2 (4%) Hispanic, and 1 (2%) multiracial. Six pts of the 45 with data available (13%) had a 17p deletion and 30 pts of the 38 with available data (79%) had unmutated IgVH.
Thirty-six (75%) pts completed all six cycles of obi. Reasons for reduced number of cycles included infections (25%), cytopenias (17%), patient choice/other (17%), back pain (8%), secondary cancer (8%), and elevated LFTs (8%). Thirty-eight (79%) completed a full year of ven therapy. Reasons for incomplete ven therapy included death prior to ven initiation (20%), death from lung cancer (10%), provider choice (10%), COVID infection (10%), and ongoing cytopenias (50%). Among pts who started ven (n = 46), 16 (33%) had a long term (&gt;7 day) dose reduction of ven not due to drug-drug interaction. The most common reason for dose reduction was cytopenia (n=11, 69%). The median WBC prior to obi was 53,000/mcl (range 4,000-395,500) and the median WBC prior to initiation of ven was 4,500/mcl (range 1,100-127,900). The risk of TLS prior to treatment initiation was low in 10 pts (21%), medium in 30 pts (62%), and high in 8 pts (17%). Two pts experienced laboratory TLS secondary to obi. Both cases developed after day 2 (900 mg dose) of obi, were Cairo-Bishop grade 1, and resolved with conservative management. Thirty three of 46 patients (72%) started ven in the outpatient setting and 13 (28%) in the inpatient setting and there were no cases of laboratory or clinical TLS.
Forty-six pts were response-evaluable because 2 pts died shortly after the first dose of obi (unrelated to CLL or obi treatment). All 46 pts responded to therapy; 43 (93%) achieved clinical CR/CRu and 3 (7%) achieved PR secondary to spleen &gt;13cm on imaging, plts remaining &lt;100K, or persistent lymph nodes &gt;1.5 cm on imaging.
After a median follow up of 28 months, no pts have experienced progressive disease or initiated subsequent CLL therapy. Seventeen cases were sent for MRD testing (13 ClonoSeq® and 4 by flow cytometry). Of the 13 cases of ClonoSeq®, 12 had undetectableMRD (uMRD) with a threshold of 10-6 and one pt was MRD detectable at a level of 10-4. Seven patients have died: two of the deaths occurred prior to the initiation of ven, one due to lung cancer while on ven, and the remaining 4 deaths occurred following completion of therapy (1 each from COVID, intraoperative cardiac arrest; 2 unknown). There were no CLL related deaths.
Conclusions: VO is highly effective and feasible in both academic and community settings. The ability of obi to debulk patients prior to ven initiation allowed most patients to receive ven initiation in the outpatient setting. TLS is rare and was only seen secondary to obi. Cytopenias were a common reason for dose reduction and early discontinuation. Deep uMRD was revealed by ClonoSeq® in 12 out of 13 (92%) of pts tested. These data support the use of VO as a time-limited treatment option in both academic and community settings for CLL pts initiating frontline therapy.