Chronic lymphocytic leukaemia (CLL) is the most common adult-onset haematologic malignancy that typically affects people over the age of 60 years. While currently incurable, CLL usually progresses slowly, and some patients may remain asymptomatic for many years.¹ As such, treatment for CLL is not usually initiated until patients become symptomatic or reach advanced disease stages.^2,3 In recent years, the advent of highly effective targeted therapies has dramatically shifted the landscape of CLL treatment, increasing options for frontline chemotherapy-free regimens for treatment-naïve (TN) patients. In particular, the Bruton tyrosine kinase (BTK) inhibitors are now considered standard of care for TN CLL.^1,4 Acalabrutinib is a second-generation, highly selective BTK inhibitor that was approved for TN CLL based on positive efficacy and safety outcomes from the pivotal ELEVATE-TN clinical trial.⁵ The updated 4-year data from the ELEVATE-TN study, first presented at the ASCO 2021 virtual meeting, was presented at the recent European Hematology Association (EHA) Virtual Meeting held in June 2021.⁶ In this article, we review this new data and its implications for frontline treatment for CLL in Australia, with key insights from haematologist Professor John Seymour, Director of Haematology at the Peter MacCallum Cancer Centre & Royal Melbourne Hospital in Victoria.

Current treatment landscape for TN CLL

Until recently, the standard of care for TN CLL was fludarabine, cyclophosphamide and rituximab (FCR) or bendamustine with rituximab.¹ For the elderly, standard of care also includes chlorambucil plus obinutuzumab.¹ With the development of BTK and B-cell lymphoma-2 (BCL-2) inhibitors that target intracellular signalling pathways to block the proliferation and survival of malignant B cells, avenues for chemotherapy-free frontline treatment emerged.^1,4 The addition of these agents to the treatment landscape for TN CLL offer broader options for high-risk patients with disease that harbours mutations affecting the TP53 gene (deletions or mutations). Chemotherapy-free treatment also provides management options for elderly or unfit patients with comorbidities who may gain less benefit from – or have lower tolerance for – chemoimmunotherapy regimens.¹

“We had an expectation, given what we had seen in terms of performance of BTK inhibitors and anti-CD20 monoclonal antibodies is that the result of different inhibitors would be very similar,” explained Prof Seymour. “What we didn’t expect to find in ELEVATE-TN was some possible differences” he said.

ELEVATE-TN: Pivotal trial for acalabrutinib in TN CLL

Acalabrutinib is a second-generation, highly selective, irreversible covalent BTK inhibitor. With greater kinase selectivity and less off-target activity than ibrutinib, acalabrutinib is likely to be associated with fewer treatment-related cardiovascular toxicities and side effects – improving tolerability and reducing discontinuations.^4,7

Acalabrutinib was approved for treating TN CLL based on results from the ELEVATE-TN global, multicentre, phase 3, randomised controlled trial. In this study, 535 adult patients with previously untreated CLL aged either ≥65 years of age or <65 years of age with significant comorbidities were randomised to one of three treatment arms: combination therapy with acalabrutinib plus the anti-CD20 antibody obinutuzumab, acalabrutinib monotherapy, or chemoimmunotherapy with obinutuzumab plus chlorambucil.⁵

The interim analysis from ELEVATE-TN was performed after a median follow-up of 28.3 months and demonstrated longer median progression-free survival (PFS) with acalabrutinib with or without obinutuzumab (not reached in either group) than with obinutuzumab plus chlorambucil (22.6 months; p<0.0001 for both comparisons).⁵

Prof Seymour pointed out that the improved efficacy of acalabrutinib plus obinutuzumab in the ELEVATE-TN trial cannot be translated to other BTK inhibitors in the absence of comparative clinical trial data with the other agents. “One has to be cautious in interpreting how acalabrutinib might stack up to other BTK inhibitors,” he said.

The study also demonstrated an acceptable side-effect profile with both acalabrutinib arms that was consistent with the known safety signals for these agents, although Prof Seymour noted the higher grade 3+ infection risk in the acalabrutinib plus obinutuzumab group (21% versus 14% in patients given acalabrutinib monotherapy and 8% given obinutuzumab plus chlorambucil).

Overall, this study supports acalabrutinib with or without obinutuzumab as an effective and well-tolerated, chemotherapy-free treatment for patients with TN CLL.⁵

Acalabrutinib maintains efficacy and safety at 4 years

The data presented at EHA in June updates the efficacy and safety data from the ELEVATE-TN study after a median follow-up duration of 46.9 months and demonstrates that acalabrutinib maintains its safety at 4 years.⁶ Importantly, the analysis at 4 years’ follow-up showed that efficacy was maintained since the interim analysis (which was published in 2020⁵), with an increase in CR with acalabrutinib plus obinutuzumab (from 21% to 27%) and with acalabrutinib monotherapy (from 7% to 11%)⁶ and low rates of discontinuation.

“What the 4-year data shows is that the earlier separation of the PFS curves appears to continue over time, which gives us some increased confidence of what we’re seeing in this trial,” noted Prof Seymour.

When looking at efficacy outcomes, median PFS was significantly longer in patients treated with acalabrutinib with or without obinutuzumab than with obinutuzumab plus chlorambucil, with estimated PFS at 48 months over three times longer in the two acalabrutinib arms than in the chemoimmunotherapy arm (Table 1).⁶ Median overall survival was not reached in any treatment group, with a nonsignificant difference favouring acalabrutinib plus obinutuzumab over obinutuzumab plus chlorambucil (Table 1).⁶ The overall response rate was significantly higher with acalabrutinib with or without obinutuzumab than with obinutuzumab plus chlorambucil (Table 1).⁶ The complete response rate and the complete response with incomplete haematologic recovery rate were higher with acalabrutinib with obinutuzumab than with obinutuzumab plus chlorambucil or acalabrutinib monotherapy (Table 1).⁶

TABLE 1: Progression-free survival, overall survival, and response rates⁶

*p<0.0001 vs O+Clb; †p<0.005 vs O+Clb; ‡p=0.064 vs O+Clb; ^§p=0.035 vs O+Clb

Abbreviations: Clb, chlorambucil; CR, complete response; CRi, complete response with incomplete haematologic recovery; PFS, progression-free survival; O, obinutuzumab; ORR, overall response rate; OS, overall survival.

Moving to the safety data, the most common adverse events (AEs) of any grade occurring in ≥30% of patients in any treatment arm included diarrhoea, headache, and nausea (Table 2). The most common serious AE (grade 3 or higher) in all arms was neutropenia, but its occurrence was lowest with acalabrutinib monotherapy (Table 2).⁶ Bleeding, hypertension, and atrial fibrillation were evaluated as AEs of clinical interest for acalabrutinib, as these cardiovascular toxicities are associated with use of the first-generation BTK inhibitor ibrutinib;⁷ however, the rates of grade 3 or higher bleeding, hypertension, and atrial fibrillation were low (<4%) in patients treated with acalabrutinib with or without obinutuzumab (Table 2).⁶ Despite the difference in treatment duration between the acalabrutinib groups (continuous treatment until progression or unacceptable toxicity) and the chemoimmunotherapy group (fixed-duration treatment of 6 months), the rate of discontinuation from AEs was similar across all treatment arms (Table 2).^5,6

TABLE 2: Adverse events and treatment discontinuations⁶

Where does acalabrutinib fit into treatment sequencing for TN CLL?

“The latest results of ELEVATE-TN establish the efficacy and demonstrate continued tolerability of acalabrutinib therapy. Once reimbursed, this data would support its use as suggested in recent guidelines,” noted Prof Seymour.

The most recent international guidelines for frontline treatment of symptomatic CLL recommend continuous treatment with a BTK inhibitor (ibrutinib or acalabrutinib) or fixed-duration therapy with venetoclax plus obinutuzumab – irrespective of age, comorbidities, and mutation status.^2,8 These recommendations are based on superior efficacy of these targeted agents in comparison with various chemoimmunotherapy regimens. However, in the absence of direct head-to-head studies to the compare effectiveness of the targeted agents in TN CLL, the safety and tolerability profiles often come into play when considering frontline treatment for CLL.

For this reason, selection of therapy for patients with TN CLL should always include evaluation of mutation status, as well as patient-driven factors such as comorbidities and medications, personal preferences for duration of treatment and route of administration that can influence treatment adherence, and in some cases, drug availability and affordability.^2,3 For example, the BTK inhibitors offer the convenience of oral administration but require good adherence to a continuous once or twice daily medication, while the BCL-2 inhibitor plus anti-CD20 antibody combination offers a time-limited treatment option including both oral administration (for the BCL-2 inhibitor) but also intravenous infusions for the anti-CD20 component).³

In terms of side effect profiles, venetoclax may be preferable to ibrutinib for patients with cardiovascular comorbidities or a high risk for bleeding, while ibrutinib or acalabrutinib may be preferable to venetoclax in patients with a high tumour burden or high risk of developing tumour lysis syndrome.³ The addition of anti-CD20 antibodies also incurs risks that require careful consideration of individual patient circumstances, such as the higher levels of neutropenia and infusion-related reactions observed in patients treated with acalabrutinib plus obinutuzumab in the ELEVATE-TN study.^5,6

Touching on availability and affordability, it’s important to note that while acalabrutinib, either as monotherapy or in combination with obinutuzumab, is approved for use in both frontline and relapsed/refractory CLL in Australia, it is only PBS-listed in the relapsed/refractory setting.^9,10 The release of the positive 4-year outcomes for acalabrutinib with or without obinutuzumab provides further evidence of its benefits in the untreated patient population.

This article was commissioned by Astra Zeneca. The content is independent and based on studies and the author’s opinion. The views expressed do not necessarily reflect the views of Astra Zeneca. Before prescribing, please review the Calquence^® (acalabrutinib) full product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.

References:

1. Pérez-Carretero C, et al. The evolving landscape of chronic lymphocytic leukemia on diagnosis, prognosis and treatment.Diagnostics (Basel). 2021;11(5):853.
2. Eichhorst B, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2021;32(1):23-33.
3. Bewarder M, et al. Current Treatment Options in CLL.Cancers (Basel). 2021;13(10):2468.
4. Patel K, Pagel JM. Current and future treatment strategies in chronic lymphocytic leukemia.J Hematol Oncol. 2021;14(1):69.
5. Sharman JP, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291.
6. Sharman J, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: ELEVATE-TN 4-year follow-up. EHA Library. 06/09/2021;324556;S148.
7. Abbas HA, Wierda WG. Acalabrutinib: A selective bruton tyrosine kinase inhibitor for the treatment of B-cell malignancies.Front Oncol. 2021;11:668162.
8. Wierda WG, et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma, Version 4.2020, NCCN Clinical Practice Guidelines in Oncology.J Natl Compr Canc Netw. 2020;18(2):185-217.
9. Calquence (acalabrutinib) Approved Product Information. 22 November 2019.
10. Pharmaceutical Benefits Scheme General Schedule. Acalabrutinib. Available: https://www.pbs.gov.au (accessed June 2021).