Acalabrutinib‐related second primary malignancies and nonmelanoma skin cancers in patients with chronic lymphocytic leukaemia (CLL): A systematic review and meta‐analysis of randomised controlled trials (RCTs)

Abstract Acalabrutinib is a second generation Bruton's tyrosine kinase inhibitor and was recently approved in the treatment of chronic lymphocytic leukaemia. We undertook a systematic review and meta‐analysis of randomised controlled trials to determine the risks of acalabrutinib‐related second primary malignancies (SPM) and nonmelanoma skin cancers (NMSC). The incidence of SPM was 4.7% higher in the acalabrutinib arm compared to control arm with risk ratio (RR) of 1.76 (5.32 vs 3.2 per 100 person‐years). Notably, NMSC was the most common SPM, and the incidence was 2.56 per 100 person‐years in the acalabrutinib group versus 1.12 per 100 person‐years in the control group (RR 2.43). Long‐term follow‐up and future studies are necessary to define the actual relationship and their risk factors.


INTRODUCTION
Acalabrutinib is a second generation and irreversible oral inhibitor of Bruton's tyrosine kinase (BTK) [3]. BTK is overly expressed on the surface of clonal B cells in chronic lymphocytic leukaemia (CLL) [12]. BTK inhibitors have revolutionized the treatment paradigm for patients with CLL over the recent years due to its survival benefits [2].
Acalabrutinib selectively inhibits BTK with significantly less off-target inhibition of other kinases including Tec protein tyrosine kinase (TEC), endothelial growth factor receptor, and interleukin-2-inducible T cell kinase (ITK) [3]. T lymphocytes and natural killer (NK) cells are the cornerstones of cancer surveillance due to their effect on early recognition and cytotoxic killing of cancerous cells. CLL is associated with T and NK cells dysfunction which ultimately lead to higher incidence of second primary malignancies (SPMs) and infections [4,8] BTK inhibitors have been studied in association with risk for secondary malignancies due to its potential interference on immune response [7].
We performed a meta-analysis of randomised controlled trials (RCTs) to determine the risk of SPMs and nonmelanoma skin cancers (NMSC) in patients with CLL treated with acalabrutinib.

METHODS
We conducted the systematic review as per the Cochrane Handbook for Systematic Reviews and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [9]. A comprehensive literature search was performed through MEDLINE, EMBASE databases and meeting abstracts up to 31st July 2020 using the keywords 'acalabrutinib OR ACP-196′ AND 'CLL' . We reviewed the references of all potential studies for any further relevant studies. We limited the search to 'humans' and 'RCTs' .
All studies written in English or non-English languages were retrieved.
The studies that were eligible to be included in the meta-analysis had to conform with the following characteristics: Phase III RCTs comparing acalabrutinib-based regimens and a control group in patients with CLL, and RCTs that mention SPM and NMSC as adverse effects. The endpoint of our meta-analysis was acalabrutinib-related SPM and NMSC including basal cell carcinoma, squamous cell carcinoma as adverse events.
We summarised the characteristic features of incorporated studies in was assessed with I 2 and Cochran's Q statistic [6]. A 'P value' of less than .05 was considered significant, and I 2 > 50% is considered substantially heterogeneous. A RR < 1.0 was in favour of acalabrutinib.
Risk of bias for each study was evaluated by Cochrane RevMan 5.3 software. Five main salient biases (selection bias, performance bias, detection bias, attrition bias, reporting bias and others) were categorised and were rated as low, high or unclear risk [6]. Publication bias was assessed by funnel plots.

RESULTS
The I 2 statistic for heterogeneity was low, suggesting homogeneity among RCT, and the fixed effects model was applied.  (Figures 1C and 1D). The pooled rate of NMSC in patients receiving acalabrutinib containing regimens was 2.56 per 100 person-years compared to 1.12 per 100 person-years in the control group. Detailed analysis on the subgroups of SPM excluding NMSC and the differences observed are depicted in Figure 1E-H.

CLL is the clonal expansion of B cells with the activation in B cell
receptor signalling [10]. Second malignancies are associated with worse prognosis in patients with CLL [7]. Acalabrutinib is an oral second generation, small-molecule irreversible BTK inhibitor, and the remarkable activity of acalabrutinib on progression free survival has been demonstrated in the recent phase III trials (ELEVATE-TN and ASCEND) [5,11]. Yet, the risks of acalabrutinib-related SPM and NMSC remain the areas of concerns.
Our meta-analysis showed that the incidence of SPM was 4.7 % higher in patients treated with acalabrutinib-based therapy than  It is also notable that median duration of treatment and follow-up were longer in acalabrutinib-based regimens than non-acalabrutinibbased regimens in both ELEVATE TN and ASCEND trial, which may potentially impact on emergence of treatment-related adverse events.
In ELEVATE TN trial, the median treatment duration was 27.7 months in the acalabrutinib containing regimens, and 5.6 months in the control group. Similarly, in the ASCEND trial, median duration of exposure was 15.7 months for acalabrutinib monotherapy, whereas 5.6-11.5 months in the control groups.
One of the limitations of our study is that only a limited number of

CONCLUSION
Our meta-analysis demonstrated that patients on acalabrutinib monotherapy or combination regimens experienced higher incidence of SPM and NMSC compared to non-acalabrutinib-based therapy.
Further prospective studies are necessary in the future to determine the actual relationship and the potential risk factors. Individual patient level pooled meta-analysis would provide further detailed and more accurate analyses. Early detection with prompt intervention is warranted.

CONFLICT OF INTEREST
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.