ELEVATE-ing clinical trial reporting in CLL Free

In this issue of Blood, Sharman et al¹ report on the latest 6-year follow-up of the ELEVATE-TN trial, which previously reported the superiority of acalabrutinib with or without obinutuzumab vs chlorambucil plus obinutuzumab (ClbO) in the treatment of treatment-naive older or unfit patients with chronic lymphocytic leukemia (CLL).

Bruton tyrosine kinase inhibition (BTKi) therapy as an oral treatment taken continuously until disease progression or intolerance is 1 of the mainstays of modern CLL therapy. Starting with ibrutinib, the first-in-class agent, superiority over chemoimmunotherapeutic regimens with regard to progression-free survival (PFS) and then overall survival (OS) in the first-line and relapse settings was proven, leading to its approval in 2016.² 

As data on the specific side effect profile of ibrutinib, such as cardiotoxicity, bleeding complications, and significantly increased rates of hypertension emerged, second-generation BTKis such as zanubrutinib or acalabrutinib were already tested in clinical trials vs chemoimmunotherapy as frontline treatment and held the promise of reduced (cardio)toxicity through greater BTK specificity, later proven in head-to-head comparisons with ibrutinib in the relapse setting.^3,4 

Questions remained regarding the addition of a CD20 antibody for 6 months to deepen response and prolong PFS. This approach was used in the E1912 trial, which revealed a survival benefit of ibrutinib plus rituximab over fludarabine, cyclophosphamide, and rituximab, the former standard for young, fit patients.⁵ In contrast, the Alliance trial found no added benefit of rituximab when combined with ibrutinib, suggesting that type I CD20 antibodies, such as rituximab, offer limited value in this setting.⁶ Ibrutinib was also evaluated with obinutuzumab in the ILLUMINATE trial vs ClbO, but without an ibrutinib monotherapy arm; the benefit of adding a type II CD20 antibody remains unclear.

In the ELEVATE-TN trial, treatment-naive patients with CLL aged ≥65 years or 18 to 65 years with a higher comorbidity burden were randomized in a 1:1:1 fashion to 6 months of chlorambucil with the CD20 antibody obinutuzumab vs continuous acalabrutinib with/without 6 cycles of obinutuzumab. The primary end point of the trial was independent review committee–assessed PFS for acalabrutinib plus obinutuzumab (AO) vs ClbO. Previously reported were a PFS benefit for both acalabrutinib-based arms vs chemoimmunotherapy and a post hoc advantage in PFS for the AO vs monotherapy arm.

With >74 months of follow-up, updated efficacy and safety data for 535 randomized patients are provided, focusing on post hoc comparisons of the acalabrutinib-based arms. In line with previous findings on continuous BTKi, sustained disease control was observed, with 72-month PFS rates exceeding 60% in both acalabrutinib arms. In addition to this continued PFS benefit (hazard ratio [HR], 0.14 and 0.24 for AO and A, respectively), an OS benefit was reported for AO but not A vs ClbO. The addition of obinutuzumab resulted in higher response and undetectable measurable residual disease rates and ultimately a lower risk of progression or death compared with monotherapy (HR, 0.58; 95% confidence interval, 0.39-0.86). Among biologically high-risk subgroups, including TP53 alteration, unmutated immunoglobulin heavy chain variable region, and complex karyotype, no clear benefit from obinutuzumab was found, although analyses were limited by low numbers. Although approximately half of the patients in the continuous therapy arms had discontinued treatment at last follow-up, no new safety signals emerged, with stable rates of adverse events reported in >15% of patients.

The report provides reassuring data on the long-term tolerability of BTKi-based therapy and contributes to the ongoing discussion on BTKi combination strategies, particularly the short-term addition of a type II CD20 antibody. The observed PFS benefit, in the absence of increased late-onset toxicities, suggests that patients without a heightened infection risk at treatment initiation may be suitable candidates for this combination approach. Furthermore, a significant survival benefit of AO over ClbO was reported. However, the trial was not powered for this comparison or this end point, and no alpha was allocated to this analysis.

Several randomized trials in CLL, including SEQUOIA and CLL14,^7,8 have recently reported longer follow-up data. Thus, the continued observations in ELEVATE-TN are an important and commendable effort, given the substantial resources required to maintain extended trial follow-up. These long-term observations are essential to fully understand the implications of both continuous and time-limited treatment strategies, particularly with respect to long-term efficacy and toxicity. Certain outcomes, such as second primary malignancies, necessitate sufficiently long observation periods to yield clinically meaningful insights. For instance, in the ELEVATE-TN trial, >10% of patients treated with acalabrutinib developed second cancers, excluding nonmelanoma skin cancers, underscoring an ongoing challenge in the clinical management of CLL.

A caveat of ELEVATE-TN, and of many other trials comparing continuous- with fixed-duration therapies (eg, ClbO in this case), is the discrepancy in adverse event reporting timelines. In fixed-duration arms, adverse event documentation is typically limited to 30 days after the last dose, resulting in a substantial imbalance in the reporting period between treatment groups. Consequently, the true incidence of certain side effects may be either over- or underestimated.

Some treatment guidelines have moved away from the distinction between fit and unfit patients with CLL. However, although dedicated randomized studies on ibrutinib have been conducted in both fit and unfit populations, next-generation BTKis such as acalabrutinib and zanubrutinib have so far been evaluated only in select subgroups: acalabrutinib in unfit patients (ELEVATE-TN) and zanubrutinib in older, fit patients (SEQUOIA). As a result, direct comparisons of efficacy and safety across the available BTKis are limited by heterogeneity in patient populations across these trials.

Similar limitations are evident in the evaluation of fixed-duration BTKi regimens. For example, ibrutinib–venetoclax was studied in the GLOW trial in exclusively unfit patients,⁹ whereas acalabrutinib-venetoclax was investigated in the AMPLIFY trial in exclusively fit patients.¹⁰ These differences in study populations complicate the development of evidence-based guidelines for patient stratification and hinder the ability to identify the most appropriate treatment strategy for individual patients upfront.

Addressing these data gaps through randomized trials in all-comer populations, better reflecting the heterogeneity encountered in real-world clinical practice, remains an important task for the CLL research community.

Conflict-of-interest disclosure: F.S. reports receiving honoraria and institutional research support from AstraZeneca and travel support from Lilly. O.A.-S. reports receiving honoraria and personal fees from AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Eli Lilly, Genmab, Gilead, Janssen, and Roche. This study receives research funding from AbbVie, BeiGene, Janssen, and Roche.