Venetoclax (Venclyxto®) is accepted for restricted use within NHSScotland....In combination with obinutuzumab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL)....for use in (1) patients without del (17p)/TP53 mutation who are not fit to receive FCR (fludarabine, cyclophosphamide and rituximab) chemo-immunotherapy and (2) patients with del (17p)/TP53 mutation.

NICE has...recommended a new chemotherapy-free treatment option for people with untreated chronic lymphocytic leukemia (CLL)...Venetoclax plus obinutuzumab will be offered as a first-line treatment to people with CLL, with certain genetic abnormalities (such as a 17p deletion or TP53 mutation).

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

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

CONTRADICTED EVIDENCE:...OS was shorter with del(17p) and TP53 mutation in both treatment arms (GClb: HR 5.7 and HR 3.1, VenG: HR 3.5 and HR 3.0, all p < 0.01) and with mutated SF3B1 (HR 2.0, p = 0.05)…

CONTRADICTED EVIDENCE:...gene mutations in the CLL14 trial comparing obinutuzumab+chlorambucil (GClb) vs. obinutuzumab+venetoclax (VenG) in 432 patients...Overall survival (OS) was shorter with del(17p) and TP53 mutation in both treatment arms (GClb: HR 5.7 and HR 3.1, VenG: HR 3.5 and HR 3.0, all p<0.01)...

...- TP53 mutation status (if completed) must be obtained within 12 months prior to registration...

PFS remained superior for Ven-Obi compared to Clb-Obi (median 76.2 vs. 36.4 months; hazard ratio [HR] 0.40 [95% CI 0.31–0.52], p<0.0001)…Multivariate analysis identified TP53 deletion/mutation, unmutated IGHV and lymph node size ≥5cm as independent negative prognostic factors for PFS in patients treated with Ven-Obi...These long-term data confirm a continued PFS benefit of fixed-duration Ven-Obi treatment compared to Clb-Obi, including patients with high-risk CLL.

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.

Pts with previously untreated CLL and coexisting conditions were randomized 1:1 to receive 12 cycles of Ven with 6 cycles of Obi or 12 cycles of Clb with 6 cycles of Obi....At 4 years after randomization, the estimated PFS rate was 74.0% in the Ven-Obi arm and 35.4% in the Clb-Obi arm. This improvement was observed across all clinical and biological risk groups, including pts with TP53 mutation/deletion (4-year PFS 53.0% vs 20.8%)...

...At 3 years, the estimated progression-free survival rate was 81.9% in the VenG arm and 49.5% in the ClbG arm. This benefit was consistently observed across all clinical and biological risk groups, including patients with TP53 mutation/deletion and unmutated IGHV status....The results suggest that the superior efficacy and deep remissions after fixed-duration VenG are maintained during extended follow-up, and show the long-term benefits of 12 cycles of VenG across all known risk categories.