Treatment of relapsed CLL “in the BAAG”?

In this issue of Blood, Fürstenau and colleagues report mature results of the phase 2 study of acalabrutinib, venetoclax and obinutuzumab after optional bendamustine debulking in relapsed/refractory chronic lymphocytic leukemia (CLL2-BAAG), another pioneering study from the German chronic lymphocytic leukemia (CLL) study group.¹ With a median follow-up of 36 months, undetectable minimal residual disease (uMRD) was achieved in the peripheral blood (PB) in 93% of patients including those with high-risk features such as TP53 aberrations and prior venetoclax/Bruton tyrosine kinase inhibitor (BTKi) exposure.

Although this is a small, single-arm study of 46 patients, it is important for several reasons including the use of a time-limited triple combination in patients with relapsed disease, inclusion of a substantial cohort previously exposed to novel agents, and the use of MRD monitoring to guide therapy duration.

uMRD in the PB was achieved early, with a median time of only 5.4 months. Furthermore, roughly 90% of patients destined to achieve uMRD had done so within 12 months from commencement. The optional debulking with bendamustine did not impact on the attainment of uMRD and, as the authors suggest, is unlikely to play a role in future clinical trials or practice.

In the CLL2-BAAG protocol, maintenance was continued until patients had achieved a complete response and uMRD in the PB on 2 consecutive measurements. As most had achieved uMRD after the second cycle of maintenance (roughly 14 months of treatment), a non-MRD-driven fixed duration treatment of approximately 14 to 17 months’ duration would achieve a similar outcome without the need for MRD monitoring.

For patients with CLL, one of the most important considerations is the duration of disease control. It stands to reason that for most, the presence of MRD in the absence of competing causes of morbidity or mortality will eventually herald clinical disease progression, with the timing dependent on both depth of response and CLL kinetics.

Not only the depth of MRD negativity attained, but the kinetics of CLL regrowth may vary according to the specific therapy delivered, and disease characteristics such as unmutated immunoglobulin heavy-chain variable region gene (IGHV), del(17p), or genomic complexity that have been associated with a shorter time to MRD conversion.² The kinetics of CLL progression following the attainment of MRD negativity in this study is not yet fully evaluable, given the paucity of MRD conversion events, though responses appear largely durable at 36 months.

The therapeutic landscape of CLL is rapidly changing with the widespread adoption of chemotherapy-free regimens administered either continuously until disease progression, for a fixed period, or a duration guided by response assessment.

Continuously administered therapy may have a lower side effect profile requiring less intense monitoring, which may be of benefit in elderly and comorbid patients and others whose access to monitoring facilities is more limited. However, continuously administered therapy may lead to the acquisition of resistance mutations and cumulative drug toxicity.

Limited-duration therapy involves the use of combinations with the aim of achieving deep remissions, enabling long treatment-free periods with possible benefits of immune restoration, low rates of resistance acquisition, and lower cost. However, combination therapy may increase side effects and require more complex monitoring.

Continuously administered and limited-duration therapy have both been extensively examined in patients with relapsed CLL. The optimal therapeutic strategy is still uncertain, but it is likely that individual disease characteristics and patient preference will be some of the important considerations.

In this study, the addition of circulating tumor DNA (ctDNA) analysis to conventional flow cytometry appeared to improve early detection of molecular relapse, particularly in patients with nodal progression with low peripheral lymphocytes. We look forward to the day when the ability to examine multiple compartments using ctDNA may eliminate the need for bone marrow examination and imaging.

The sensitivity of the ctDNA testing in this study was confined by the examination of only variable diversity-joining rearrangements (VDJ) plus a handful of CLL-related mutations. Newer techniques examining a broader range of recurrently mutated genes can achieve a higher level of sensitivity,³ but the clinical significance of very-low-level MRD positivity <10⁻⁶ remains to be determined with the benefit of increasing the remission depth beyond 10⁻⁴ balanced against the potential risks of combination therapy.

Many issues with ctDNA analysis are yet to be resolved, including standardization of testing, turnaround time, quality assurance, and cost. Until these issues are addressed, it is unlikely that ctDNA analysis will be widely adopted in routine practice. Flow cytometric MRD techniques are increasingly sensitive with detection down as low as 1 in 10⁵ achievable in routine practice.⁴ 

Although there is still uncertainty regarding the optimal number, combination, and duration of CLL-directed agents required, this study confirms the safety and efficacy of the obinutuzumab, acalabrutinib, and venetoclax triplet in patients with relapsed CLL. Studies in this group of patients are challenging due to age, comorbidity, adverse disease characteristics, and the changing initial treatment landscape.

In general, the treatment was well tolerated but it should be noted that all fatal adverse events in this study were due to severe acute respiratory syndrome coronavirus 2 infection, which not only reflects the time of study but highlights the need to ensure patients with CLL are immunized against vaccine-preventable diseases.

Conflict-of-interest disclosure: S.O. has received research funding from AbbVie, AstraZeneca, Beigene, Gilead, Janssen, Pharmacyclics, Roche, and Takeda (to the institution); and has acted in an advisory role and received honoraria from AbbVie, Antengene, AstraZeneca, Beigene, CSL Behring, Gilead, Janssen, Merck, Roche, and Takeda.