Obinutuzumab, acalabrutinib, and venetoclax, after an optional debulking with bendamustine in relapsed or refractory chronic lymphocytic leukaemia (CLL2-BAAG): a multicentre, open-label, phase 2 trial
Mené sur 45 patients atteints d'une leucémie lymphoïde chronique réfractaire ou récidivante, cet essai de phase II évalue l'efficacité, du point de vue de la maladie résiduelle mesurée dans le sang périphérique (seuil inférieur à 10 puissance 4 à la fin de la phase d'induction) d'un traitement combinant obinutuzumab, acalabrutinib et vénétoclax, après une administration optionnelle de bendamustine
Background :Although BTK inhibitors provide long-term disease-control in patients with chroniclymphocytic leukaemia, they need to be combined with BCL2 inhibitors or antibodiesto achieve deep responses with undetectable minimal residual disease (uMRD), which allows for time-limited treatment. This trial aims to evaluate the triple combination of obinutuzumab, acalabrutinib, and venetoclax after an optional debulking with bendamustine. Methods : This multicentre, open-label, investigator-initiated, phase 2 study evaluates a sequential treatment consisting of a debulking with two cycles of bendamustine for patients with a higher tumour load (70 mg/m2 intravenously on days 1 and 2, repeated after 28 days), followed by an inductionand a maintenance with obinutuzumab (1000 mg intravenously on days 1–2, 8, and 15of the first induction cycle, every 4 weeks in induction cycles 2–6 and every 12 weeksin the maintenance phase), acalabrutinib (100 mg orally twice daily continuously frominduction cycle 2 day 1 onwards) and venetoclax (starting in induction cycle 3 with20 mg per day with a weekly dose ramp-up over 5 weeks to the target dose of 400 mgper day). Eligible patients were aged 18 years or older with an ECOG performance score0–2 and had relapsed or refractory chronic lymphocytic leukaemia requiring treatment according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria.The primary endpoint was uMRD (<10−4) in peripheral blood at the end of induction treatment assessed centrally at thefinal restaging, 12 weeks after the start of the last induction cycle. As per protocol,all patients with more than two induction cycles were included in the analyses. Thisstudy is registered with ClinicalTrials.gov, number NCT03787264, and is ongoing. Findings : Between Jan 14, 2019, and June 25, 2020, 45 evaluable patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled; 13 (29%) were female, 32 (71%) were male,21 (47%) had already received a targeted agent, and 14 (32%) had del(17)(p13.1) or TP53 mutation. Ethnicity–race data was not collected. At data cutoff (Feb 25, 2021), allpatients had completed the induction treatment. 34 patients (76%; 95% CI 61–87, p=0·26)had uMRD in peripheral blood after 6 months of triple therapy. Until data cutoff,32 (71%) patients started maintenance and nine (28%) were able to stop with uMRD.After a median observation time of 13·8 months (IQR 10·4–18·4), there were two (4%)Richter transformations, but no progressions and no deaths observed. The most commonadverse events of grade 3 and 4 during the entire treatment were thrombocytopeniaand neutropenia (12 [27%] of 45 patients each), tumour lysis syndrome and infections(five [11%] of 45 patients each, grade 3 adverse events only), infusion-associatedreactions (four [9%] of 45 patients) and anaemia (four [9%] of 45 patients). Interpretation : With 76% of patients achieving uMRD in peripheral blood, this trial did not reacht he prespecified activity threshold. Triple therapy with obinutuzumab, acalabrutinib,and venetoclax after an optional debulking with bendamustine regimen requires furtherevaluation in larger trials to define its value compared with double treatment witha BTK or BCL2 inhibitor combined with obinutuzumab or a combination of the two oraltargeted drugs. Until these trials show a clear benefit, the use of the triple combinationin routine practice cannot be recommended.