The CLL2-BAAG trial provides further evidence supporting a minimal residual disease driven approach and triple therapy in relapsed chronic lymphocytic leukaemia

Introduction

The study explores three important aspects of chronic lymphocytic leukaemia (CLL) treatment, minimal residual disease (MRD) driven approach, triple therapy and circulating tumour DNA (ctDNA) based MRD assessment (1). The current standard of treatment in CLL is Bruton’s tyrosine kinase inhibitor (BTKi) or B-cell lymphoma 2 inhibitor (BCL2i) combined with either anti-CD20 antibody or a BTKi. Continuous treatment with BTKi has the benefit of less intense monitoring and equally effective in poor risk group including unmutated immunoglobulin heavy-chain variable region (IGHV) gene, TP53 aberration and complex cytogenetics especially if used in first line, but is associated with cumulative toxicity especially cardiac; even though it is better with newer generation of BTKi; and also associated with development of resistance to treatment with BTK and PLCG2 mutations. The challenges with current limited duration treatment are mainly intensity of initial monitoring and limitation of use in high-risk group especially patients with TP53 aberration, and possibly in unmutated IGHV and complex cytogenetics but has the advantage of long treatment free remission period where immune restoration is possible, low risk of acquiring resistance, low cost and possibly better quality of life. Triple therapy is not a standard option for treatment of CLL currently.

MRD status and survival outcome

Evidence indicates that achieving MRD negativity is associated with improved progression-free survival (PFS) and overall survival (OS), regardless of the treatment approach, in both chemoimmunotherapy and fixed-duration regimens. This principle was clearly demonstrated in the German CLL8 trial, where patients treated with fludarabine, cyclophosphamide, and rituximab (FCR) were more likely to achieve undetectable MRD (uMRD) compared to those receiving fludarabine and cyclophosphamide alone. However, among patients who attained uMRD in both treatment groups, the PFS and OS outcomes were comparable (2). BTKi monotherapy achieves uMRD in less than 10% of both treatment-naïve and relapsed/refractory patients, but effective control of the disease can be attained despite detectable MRD due to unique mechanism of the drugs which supresses clonal growth (3,4). In contrast to ibrutinib monotherapy, combining ibrutinib with obinutuzumab significantly increases the possibility of achieving uMRD. This was demonstrated in the iLLUMINATE trial, which reported uMRD rates of 33% in peripheral blood and 25% in bone marrow (BM) (sensitivity 0.01%). However, the PFS observed in the ibrutinib plus obinutuzumab group in iLLUMINATE was comparable to that of the ibrutinib monotherapy group in the RESONATE-2 trial (5,6).

In the context of BCL2i, a year of venetoclax monotherapy will give and uMRD rate of 26–36% in relapsed refractory setting (7). In the MURANO trial, combining venetoclax with rituximab achieved an uMRD rate of 62% in the relapsed/refractory setting, while in the CLL14 trial, venetoclax combined with obinutuzumab achieved a uMRD rate of 76% in the frontline setting (8,9). In both studies, patients who attained uMRD experienced the longest PFS. Survival outcome based on MRD status in the experimental arm of various phase 3 trials are summarised in Table 1.

CAPTIVATE trial reported high rates of end of treatment (EOT) uMRD4 (undetectable MRD to 1×10⁻⁴) in all sub-groups and continuing ibrutinib was not of much benefit in patients attaining uMRD after treatment with ibrutinib + venetoclax in treatment naïve patients (10). The 5-year PFS was significantly better for patients who attained uMRD at 3 months after the EOT compared to those with detectable MRD in peripheral blood or BM, with rates of 83% and 84% versus 48% and 50%, respectively (11). But in GLOW trial the concept of better PFS in all uMRD patients is somewhat disputed as ibrutinib + venetoclax combination gave higher uMRD (<10⁻⁵ rate in BM) in unmutated IGHV of 45.5%, compared to 29.6% in mutated IGHV patients. At 3 years post-treatment, PFS rates in the unmutated IGHV subgroup were 81% for those achieving uMRD at 3 months post-EOT and 56% for those with detectable MRD. In contrast, the mutated IGHV subgroup maintained high and comparable PFS rates exceeding 92%, regardless of MRD status at EOT +3. Additionally, 53% of responding patients sustained their uMRD status 38 months after completing treatment (12,13). MRD driven usage of ibrutinib + venetoclax in FLAIR trial has demonstrated that extending treatment from 2 to 6 years based on MRD assessment, improved the attainment of uMRD from 28.9% to 78.4%. Cumulative incidence of uMRD was significantly greater in the ibrutinib + venetoclax arm in comparison to the FCR arm with both PFS and OS superior in the ibrutinib + venetoclax arm (14).

Triple combinations

Triple therapy has been explored in various trials (Table 2). In a phase 2 study conducted by OHIO state university, triple combination with obinutuzumab, ibrutinib, and venetoclax, reported an uMRD in BM of 67% in treatment naïve and 50% in relapsed/refractory patients in blood and BM (15). The median PFS and OS were not yet reached after a median follow-up of 24.2 months in treatment-naïve patients and 21.5 months in relapsed/refractory patients, in phase 2 CLL2-GIVe trial treatment naïve patients with TP53 aberrations were treated with triple combination of ibrutinib, venetoclax and obinutuzumab for 6 cycles followed by consolidation with ibrutinib and venetoclax up to cycle 12. Ibrutinib was administered until cycle 15 or up to cycle 36 for patients who had not achieved a complete response and still had detectable MRD. Although 87.8% had uMRD at 12 cycles only 43.9% had uMRD at cycle 36 and others were either with detectable MRD or came out of protocol due to other reasons. After a median follow up of 38.4 months median PFS was not reached. The PFS and OS was 79.9% and 92.6% respectively at 36 months (16). CLL13 randomised patients into four groups-chemoimmunotherapy, venetoclax + rituximab, venetoclax + obinutuzumab and venetoclax + obinutuzumab + ibrutinib in treatment naïve patients. In ibrutinib containing arm ibrutinib could be extended to 36 months if remained MRD positive. At month 15, uMRD was greater in venetoclax + obinutuzumab (86.5%) and the venetoclax + obinutuzumab + ibrutinib group (92.2%) compared to the chemoimmunotherapy group (52.0%) and venetoclax + rituximab arm (57.0%) and the 3-year PFS was 87.7%, 90.5%, 75.5% and 80.8% respectively, but triple combination came with a toxicity profile of grade 3 and grade 4 infections of 21.2% which is higher than other venetoclax containing arms but comparable to chemoimmunotherapy arm (18.5%) (17). In Alliance A041702 trial, a randomised controlled trial comparing ibrutinib + obinutuzumab with or without venetoclax in treatment naïve older patients, ibrutinib was continued indefinitely in ibrutinib + obinutuzumab arm and continued only in venetoclax + obinutuzumab + ibrutinib arm if MRD positive at cycle 15. Early results demonstrated that PFS for venetoclax + obinutuzumab + ibrutinib is not superior to ibrutinib + obinutuzumab for this group of patients but leading cause of death was due to coronavirus disease 2019 (COVID-19) in both arms, more in venetoclax + obinutuzumab + ibrutinib arm (18). In frontline setting combining venetoclax, acalabrutinib and obinutuzumab showed high activity as demonstrated in a phase 2 trial by Davids et al. (19). Acalabrutinib and venetoclax treatment was stopped at cycle 15 or 25 for patients achieving a complete remission (CR) with uMRD in the BM. For others acalabrutinib and venetoclax was continued until unacceptable toxicity or disease progression. After a median follow-up of 35 months, uMRD4 rates were high with 86% in both peripheral blood and BM. The 3-year PFS and OS were 93% and 99%, respectively with no treatment discontinuation due to adverse events. In phase 2 BOVen trial zanubrutinib, obinutuzumab and venetoclax was given for 8 cycles and venetoclax was continues up to 24 cycles based on MRD. With a median of 10 cycles of treatment and after a median follow-up of 25.8 months, 89% had uMRD in both blood and BM (20).

The current trial explored the concept of triple therapy with venetoclax, acalabrutinib and obinutuzumab following an optional debulking with bendamustine in 45 patients with relapsed/refractory CLL in an MRD guided approach for deciding treatment duration. It is worth noting that even though the median exposure to previous treatment was 1 (range, 1–4), 40% had previously received a BTKi and/or venetoclax, 31.8% had TP53 aberrations, and 75.6% had unmutated IGHV, but excluded patients with BTK and PLCG2 mutations. Only 4.4% patients had to discontinue treatment due to cytopenia and 20.9% discontinued treatment earlier than foreseen due to various reasons. 75.6% attained uMRD at the end of induction which improved to 93.3% during maintenance phase. The study showed an excellent 3-year PFS of 85.0% with similar PFS in both patients with TP53 aberration and those exposed to previous BTKi and/or venetoclax. It also showed and excellent 3-year OS of 93.8% and all 3 deaths were related to COVID19 and were unrelated to study treatment. Both uMRD PFS and OS are comparable to those seen in treatment naïve patients in the acalabrutinib, venetoclax, and obinutuzumab trial. Debulking with bendamustine did not contribute to attainment of MRD and is unlikely to be used in future trials. Although most patients attained uMRD in induction phase substantial number attained it in the maintenance phase and there is a huge variability in the duration to attain uMRD suggesting diversity in the response in patients and a uniform approach in all patients may not be the right approach. On one aspect uniform approach adds toxicity due to unnecessarily prolonged exposure to the drug in early responders and on the other hand may not get adequate treatment who are slow responders.

In CLARITY trial doublet therapy with ibrutinib and venetoclax was given based on MRD assessment in relapsed refractory patients, but none of the patients received a BTKi or BCL2i prior to the therapy. Fifty-three percent in peripheral blood and 36% in BM attained MRD negativity at the end of 12 months of combined treatment and 44% attained uMRD by continuing treatment till month 26. In the current trial 75.6% attained uMRD after 6 months of triple therapy and 70% attained uMRD in the maintenance phase. This suggests that triple combination can attain earlier and higher rate of uMRD in relapsed refractory patient. Safety profile of the triple combination was not any worse than doublet combination, 3 deaths in the current study is possibly unrelated and due to COVID19.

ctDNA

The study analysed the concept of ctDNA for measuring MRD in addition to conventional flow cytometry based MRD assessment which showed 82.2% concordance rate. Some previous studies have indicated that plasma based MRD assessment using ctDNA may offer advantages over flow cytometry (FCM), particularly in patients with residual lymph nodes (21). Current study also suggests similar results even though with limited number of patients. This study has also shown that patients with earlier ctDNA detection had a higher proportion with high-risk genetic features, del(11q), and correlates with nodal CLL manifestation. Additionally, more of these patients had prior exposure to BTKi/venetoclax, and MRD recurrence occurred earlier (mean of 7.2 months after treatment completion) compared to those with earlier detection by FCM. These findings suggest that ctDNA-based analyses may be more effective in patients with more dynamic, high-risk disease. The study also discusses the limitation of ctDNA MRD analysis compared to cell based and more sensitive currently available PCR based assays. In future it is possible that, a combination of plasma based, and cellular based technique help us to analyse various compartments and may eliminate the need of frequent radiological remission assessment and more invasive investigations like bone marrow biopsies especially in trials. However further work is needed to standardise these assays before they can be routinely applied.

Conclusions

This study shows that an MRD-driven approach using the triple combination of acalabrutinib, venetoclax and obinutuzumab is a well-tolerated and highly effective treatment for relapsed/refractory CLL. Notably, all fatal events were related to COVID-19. Further investigation of this approach in larger trials is recommended. It is important to conduct the cost benefit analysis of MRD based treatment and triple therapy in future trials and it should be one of the important considerations in the long-term management of CLL patients particularly when addressing global accessibility for patients.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-199/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-199/coif). T.M. reports research support from Janssen and Abbvie; payments or honoraria from AstraZeneca, Abbvie, Janssen, Beigene, and Lilly; support for attending meetings and/or travel from Beigene, Janssen and Alexion; and has participated on the Data Safety Monitoring Boards or Advisory Boards of Abbvie, Janssen, AstraZeneca, Beigene, and Lilly. The other author has no conflicts of interest to declare.

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