acalabrutinib (Calquence) is accepted for restricted use within NHSScotland....as monotherapy for the treatment of adult patients with previously untreated CLL who have a 17p deletion or TP53 mutation and in whom chemoimmunotherapy is unsuitable.

Acalabrutinib, taken as a twice daily tablet, is recommended as an option for adults with untreated chronic lymphocytic leukaemia (CLL)...NICE has recommended the use of acalabrutinib, as a monotherapy option for adults with...a 17p deletion...

Suggested treatment regimens...CLL/SLL with del(17p)/TP53 mutation…first line therapy…preferred regimen...Acalabrutinib ± obinutuzumab

Recommendations: TP53 mutation or del(17p): ibrutinib or acalabrutinib or venetoclax plus obinutuzumab or venetoclax alone or idelalisib plus rituximab [III, A].

In this randomized, multicenter, open-label, phase 3 study (NCT02970318), patients with R/R CLL were randomized 1:1 to receive acala 100 mg orally (PO) twice daily or investigator’s (INV) choice of IdR (Id: 150 mg PO twice daily; R: 375 x1 then 500 mg/m2 intravenously [IV] for 8 total infusions) or BR (B: 70 mg/m2 IV and R: 375 x1 then 500 mg/m2 IV for 6 total cycles)...in patients with the del(17p) mutation...36-month PFS rates were 66% and 5% for acala and IdR/BR, respectively. At 3 years of follow-up, the efficacy of acala monotherapy was maintained, showing a significant PFS benefit over standard-of-care regimens in patients with R/R CLL.

In patients with del(17p) and/or TP53, median PFS was NR (A+O and A) vs 17.5 months for O+Clb (P<0.0001).

533 pts (Aca, n = 268; Ib, n = 265) were randomized (median age 66 y; median 2 prior therapies; del(17p) 45.2%; del(11q) 64.2%). At median follow-up of 40.9 mo (range 0.0–59.1), Aca was noninferior to Ib with median PFS of 38.4 mo in both arms (HR 1.00; 95% CI 0.79–1.27).

CLL with high-risk features (presence of 17p deletion and/or 11q deletion)...Positive high-level results from the ELEVATE-RR Phase III trial showed AstraZeneca’s Calquence (acalabrutinib) met the primary endpoint demonstrating non-inferior progression-free survival (PFS) for adults with previously treated, high-risk chronic lymphocytic leukaemia (CLL) compared to ibrutinib.

Eligible patients, aged ≥ 18 years with R/R CLL, were randomly assigned 1:1 centrally and stratified by del(17p) status…a total of 398 patients were assessed for eligibility; 310 patients were randomly assigned to acalabrutinib monotherapy (n = 155) or investigator’s choice (n = 155; I-R, n = 119; B-R, n = 36). Patients had received a median of two prior therapies (range, 1-10). After a median follow-up of 16.1 months (range, 0.03-22.4 months), median PFS was significantly longer with acalabrutinib monotherapy (PFS not reached) compared with investigator’s choice (16.5 months [95% CI, 14.0 to 17.1 months]; hazard ratio, 0.31 [95% CI, 0.20 to 0.49]; P < .0001). Estimated 12-month PFS was 88% (95% CI, 81% to 92%) for acalabrutinib and 68% (95% CI, 59% to 75%) for investigator’s choice....Acalabrutinib significantly improved PFS compared with I-R or B-R and has an acceptable safety profile in patients with R/R CLL.

...Fluorescence in situ hybridization (FISH) for which the next-generation sequencing (NGS) method is preferred) within 60 days during screening up to before the first dose reflecting the presence or absence of del(17p), 13q del, 11q del, and trisomy of chromosome 12 along with the percentage of cells with the deletion, along with TP53 sequencing....

Data were pooled from CLL pts with higher-risk genomic features treated with A ± obinutuzumab (O) in 3 clinical studies...At 47.3 mo median follow-up (range 1.0–82.0), median PFS was not reached (NR) in TN pts with del(17p)/TP53m with A-based regimens; PFS rates at 48 mo suggest similar efficacy with A and A+O in TN pts with del(17p)/TP53m (76% and 77%, respectively) (Fig 1A)....In this pooled analysis of clinical trial data in 801 CLL pts with higher-risk genomic features, efficacy of A-based regimens led to high PFS and OS rates at a median follow-up of nearly 4 y.