Outcomes of CLL Patients Exposed to Venetoclax+/-R after Ibrutinib in France: The Resist Retrospective Study from the Filo-CLL Group
Authors: Ysebaert Loic , Ferrant Emmanuelle , Dilhuydy Marie Sarah , Michallet Anne-Sophie , Inchiappa Luca , Guieze Romain , Tchernonog Emmanuelle , Cavillon Ana , Bene Marie Christine , Fornecker Luc-Matthieu 
Published: December 2023

Background: In chronic lymphocytic leukemia (CLL), despite the fact that Bruton tyrosine kinase inhibitors (BTKi) are increasingly used 1st or 2nd line therapy, and the Bcl-2 inhibitor (Bcl-2i) venetoclax +-rituximab (VEN-R) relapses, based on the good results of the MURANO trial (although it did not include BTKi-exposed patients [pts]), multicentric retrospective studies describing the real world outcomes of BTKi exposed pts under Bcl-2i treatment are still lacking. Most of the data published so far, extracted from USA databases, lack granularity to explain which clinical or biological factors define prognosis in the modern therapeutic era of CLL.
Here, results of the experience gathered by 10 FiLO-CLL-affiliated centers in France are presented, monitored by physicians in charge of the pts. The RESIST registry assembled outcomes from 150 pts, among whom 117 are presented here as a first efficacy analysis (the complete set of pts will be presented at the congress).
Results: Analysis of these 117 pts shows a predominance of men (68%) and a median age of 59 years (29-85). A median of two previous lines of treatment (range 1-5] was given before initiating VEN, with a majority of immunochemotherapy (FCR) in first line and progressive increase of ibrutinib use. As expected, the rate of complete response (CR) decreased over the lines, yet remained over 30%. Intolerance to ibrutinib was the main cause for discontinuation in 27.4%, and 66.7% were refractory or relapsed patients (45% presenting with BTK mutations before VEN, the other patients stopped due to other causes). At the time of VEN treatment (75% VEN-R), 35.3% of the pts had bulky disease, 63% elevated lactate dehydrogenase and 24.8% a bad performans status (3-4). High risk cytogenetic was found in nearly all patients: 63.8% del(17p) and/or TP53 mutation and 94% unmutated IGHV status. The sequence of VEN therapy was terminated as planned for 56.3% of the pts, while it was stopped for progression/relapse in 27.6% and for intolerance in 16.1%. The most common grade ≥ 3 adverse events observed with VEN, reported in 92 pts, were hematological (30.4%), gastro-intestinal (8.7%), infectious (3.3%) and cutaneous (4.4%). Tumor lysis syndrome during the ramp-up phase was infrequent (grade 1 = 8.4%, grade 2 = 1.9% and grade 3 = 0.9%).
At the time of analysis, the best response was CR for 69% of the pts (CR+Cri+PR: 95%). MRD assessment was done in 52 pts, 50% of which obtained MRD undetectable responses. With a median follow-up of 37.7 months (mo; 95% confidence interval [CI] 32.7-40.1), 27.6% of the pts had progressed. The mPFS is 35.9 mo (95%CI 29.8-53), mOS 59.4 mo (95%CI 44-Not Reached) and median time to next treatment (TNTT) 45.9 mo (95%CI 31.7-58.8), while in the 7-year update of the VenR arm of the MURANO trial the latter outcomes were much higher (54.7 mo, not reached, and 63 mo respectively).
On univariate and multivariate analyses, only TP53 mutations tended to be significantly associated with worse PFS (HR = 1.83 [0.99; 3.38], p=0.05) and OS (HR = 2.11 [0.91; 4.86], p=0.07).
A total of 44 patients relapsed after VEN, with a median time to next treatment-2 of 18.0 mo (95%CI 5.5-21.1). The updated results of this subset of patients will be presented at the congress.
Conclusion: Although slightly improved as compared to other real-life series in Italy or in the US, these data indicate that VEN or VEN+R after progression, relapse or intolerance to BTKi is moderately efficient with only about 35.9 months median PFS (in spite of undetectable MRD in 26/52 available patients). TP53 abnormalities were confirmed to be an important risk factor, yet not BTK mutations, or. This work is important to help designing clinical trials aiming at improving the outcomes with next generation BTKi/Bcl-2i, or even CAR-T cells.