The evidence base in support of fixed-duration, first-line approaches in medically fit patients with CLL is clearly strengthening, whether through combining targeted agents with immunochemotherapy or through chemotherapy-free combinations. The long-term PB MRD response rates with the investagators fixed-duration (15-month) immunochemotherapy approach remain the best to date, even compared to the new targeted agent combinations of ibrutinib-venetoclax or obinutuzumab-venetoclax.
The investigators' phase 2 ICLL07 trial in previously untreated fit CLL patients with a fixed-duration immunochemotherapy approach (with 4 cycles of FC-obinutuzumab and chemosparing strategy) carries a low risk for short and long term toxicities which still exist, including cardiac toxicities probably related to BTK inhibitors, moreover, two patients experienced treatment related myelodysplastic syndrome or acute myeloid leukemia beyond the end of treatment. Follow-up at 5,5 years from treatment start showed a persistent PB MRD benefit beyond end of treatment, high survival rates, and low long term toxicity with no difference in the durability of MRD response between the mutated and unmutated IGHV patients.
The investigators aim to explore the safety and efficacy of a fixed duration strategy combining a new BTK inhibitor with a favorable safety profile and a limited number of ICT courses.
The main goals and concerns are:
i) to ensure deep response and long lasting MRD ii) to reduce the duration of BTKi exposure and the risk of clonal evolution with the appearance of deleterious mutations iii) to limit the risk of hematopoietic secondary cancers (MDS/AML) by excluding patients in whom clonal hematopoiesis of undetermined potential (CHIP) is detected before inclusion and decreasing the number of courses of chemotherapy to 3 cycles. Moreover, patients with TP53 abnormalities will be excluded with a lower cut off (1% versus 10% in the previous studies) iv) to limit the risk of BTKi toxicity by using a non-covalent BTKi
Immunophenotypically confirmed CLL according to IWCLL 2018 guidelines
Binet stage C or Binet stage A and B with active disease could be considered for inclusion according to IWCLL 20108 for initiation of treatment.
Absence of Del(17p) and TP53 mutation in NGS (cut off 1%)
ECOG performance status 0-2
Presence of Clonal hematopoiesis of indetermined potential or CHIP (To define patients with CHIP: Presence of a myeloid mutation (whatever the mutation) with a VAF >2% in the granular fraction
Binet stage A without active disease according to IWCLL 20108 criteria
Life expectancy < 6 months
Current or past history or presence of clinically relevant disorder affecting the central nervous system (CNS)