MRD-driven triple therapy
Roeker et al. conducted a phase II study with the aim of identifying a subset of patients responding to ibrutinib monotherapy who have persistent MRD and might benefit from a combined strategy . After ≥ 6 months of ibrutinib treatment in any line, the PI3Kδ inhibitor umbralisib and the anti-CD20 antibody ublituximab (U2) were added to ibrutinib in patients with detectable MRD. Treatment continued until they achieved uMRD in the peripheral blood on two sequential occasions. Overall, the triplet therapy was administered for a maximum of 24 cycles until the initiation of treatment-free observation regardless of MRD status. Durability of remission following treatment discontinuation was monitored using sequential MRD assessments. The study design permitted retreatment with ibrutinib and U2 upon clinical progression after ≥ 6 months of treatment-free observation. Twenty-eight and 27 patients were evaluable for safety and efficacy, respectively. Two thirds and one third had received ibrutinib in the first line and for relapsed/refractory disease, respectively. The uMRD rate was defined as the primary endpoint.
This was the first non–venetoclax-containing MRD-driven, time-limited approach utilizing the combination of BTK and PI3Kδ inhibitors with an anti-CD20 antibody. It gave rise to deep remissions, with a uMRD rate of 77 % and median time to first uMRD of 7.4 months. Only 4 % of patients completed 24 cycles of ibrutinib plus U2 without achieving MRD negativity, and 19 % remained on therapy with detectable MRD at the time of the analysis. PFS from study entry and from entering treatment-free observation was excellent, with only one progression event.
The AE profile of ibrutinib remained unchanged after the addition of U2. Most AEs observed in the study were rated as low-grade. Two patients discontinued all therapy due to AEs including rash and arthralgia; both had uMRD at that time and were able to enter treatment-free observation. Overall, this add-on approach for patients on continuous ibrutinib allowed for tailored, time-limited therapy and sustained treatment-free observation. The study continues to enroll, with other cohorts exploring the addition of U2 to acalabrutinib or venetoclax.
Three-year follow-up of ASCEND
Compared to ibrutinib, the next-generation BTK inhibitor acalabrutinib is more selective and has decreased alternative-target activity in vitro [3, 4]. According to the primary analysis of the phase III ASCEND trial after a median follow-up of 16.1 months, acalabrutinib monotherapy exhibited superior PFS and a favorable safety profile compared with physicians’ choice, i.e., idelalisib/rituximab (IdR) or bendamustine/rituximab (BR) in patients with relapsed/refractory CLL after ≥ 1 systemic therapy . Both the acalabrutinib arm and the IdR/BR arm contained 155 patients. As most of the doctors chose IdR (118 of 153 patients in the comparator arm), the study was in fact the first randomized comparison of BTK and PI3K inhibitors in relapsed/refractory CLL.
The updated results at 3 years of follow-up presented at ASH 2021 by Jurczak et al. showed maintained efficacy and safety of acalabrutinib that was favorable compared to the standard-of-care regimens . Median PFS for the experimental arm had not been reached yet, while this was 16.8 months in the control arm (HR, 0.29; p < 0.0001). At 36 months, the PFS rates amounted to 63 % vs. 21 %. Within the control population, patients treated with IdR fared better than those receiving BR; the 36-month PFS rates were 25 % vs. 9 % for IdR and BR, respectively. Acalabrutinib reduced the risk of progression or death by 69 % and 75 %, respectively (p < 0.0001 each). The advantage conferred by the novel BTK inhibitor held true irrespective of the presence of high-risk genetic features. In patients without and with del(17p), median PFS had not been reached on acalabrutinib treatment, while this was 20.3 and 13.8 months, respectively, in the control arm (Figure 2). A similar picture emerged with respect to IGHV mutation status. The PFS results favored acalabrutinib in all subgroups (e.g., number of prior therapies, presence of bulky disease, Rai stage at screening). Median OS had not been reached in either arm. At 36 months, 80 % vs. 73 % of patients were alive despite the crossover offered to 76 patients progressing in the control arm. Also, the overall response rates did not differ between acalabrutinib and IdR/BR (83 % vs. 85 %; p = 0.62).
The longer-term follow-up did not reveal any new safety findings in the experimental arm. Acalabrutinib maintained an acceptable tolerability profile, and fewer patients discontinued treatment due to AEs despite longer exposure. As the authors noted, these data support the use of acalabrutinib in patients with relapsed/refractory CLL including those with high-risk features.