Is venetoclax a new wonder drug in CLL?

The fate of a differentiated cell, once it is unable to perform its prescribed function, is senescence or cell death. This latter process was originally described by Kerr et al (1972) who observed cell membrane blebbing, cytoplasmic shrinkage, chromatin condensation and later DNA fragmentation or “laddering” implying a controlled, active, cell death; a process they termed “apoptosis” or programmed cell death (Kerr et al, 1972; Wyllie et al, 1980). This led to the identification of the apoptosis regulating BCL2 family of proteins and the recognition of a new class of oncogenes – inhibitors of cell death (Korsmeyer, 1992; Yu & Zhang, 2003) (Fig 1). There is ubiquitous over expression of the antiapoptotic protein BCL2 in chronic lymphocytic leukaemia (CLL), which was originally attributed to hypomethylation of the promoter region of the BCL2 gene (Hanada et al, 1993). However, the discovery of small non-coding micro RNAs (miRs) that interact with RNA transcripts to induce silencing complexes raises the possibility that BCL2 expression is regulated by multiple mechanisms (Huntzinger & Izaurralde, 2001). It has been shown that miR-15 and miR-16, located on chromosome 13q14, are deleted or down-regulated in the majority of CLL cells, especially those with the commonest genetic abnormality in CLL: deletion of 13q (Calin et al, 2002; Cimmino et al, 2005). Subsequent studies showed that high BCL2 expression by CLL cells was associated with high CD38 expression, advanced clinical stage, in vitro and in vivo fludarabine resistance, reduced time to first treatment and reduced overall survival (OS) (Schena et al, 1993; McConkey et al, 1996; Pepper et al, 1996, 1997, 1998, 1999a, 2007, 2008; Robertson et al, 1996; Thomas et al, 1996; Osorio et al, 1997; Kitada et al, 1998; Molica et al, 1998). A longitudinal analysis showed an upward trend in BCL2 expression that was particularly marked in patients who received chemotherapy (Pepper et al, 2008). Given their role in the aetiology, progression, and survival in CLL patients and the observations that standard chemotherapy acts, at least in part, via manipulation of the BCL2 apoptotic family, more targeted approaches to the BCL2 family-dependent therapeutics have been developed. The first agent used clinically was a BCL2 antisense oligonucleotide, which in pre-clinical studies was shown to downregulate BCL2 mRNA and BCL2 protein expression but the first phase I/II studies in relapsed and refractory CLL showed disappointing results (Pepper et al, 1999b, 2001; O’Brien et al, 2005, 2007). The development of pro-apoptotic drugs has largely revolved around identifying drugs that imitate the action of BH3-only proteins, the so-called BH3 mimetics. ABT-737 and its oral equivalent, ABT-263, bind strongly to BCL2 and BCL-XL (also termed BCL2L1) in primary CLL cells (Del Gaizo Moore et al, 2007). ABT-737 was shown to displace BIM (BCL2L11) from the BCL2 BH3 binding pocket and induce apoptosis. In a phase I dose escalation study in patients with advanced relapsed and refractory CLL, 19/21 patients had a >50% reduction in lymphocytosis (Roberts et al, 2012), with responses in all prognostic groups, including patients with fludarabine refractoriness, bulky disease and 17p deletions and a median progression-free survival (PFS) of 25 months. The major dose-limiting toxicity was thrombocytopenia, which was perhaps not surprising as platelets express high levels of BCL-XL. The first clinical experience of a new BH3 mimetic ABT199 (Venetoclax) with BCL-XL-sparing characteristics (500fold more selective for BCL2), showed dose-limiting tumour lysis syndrome (TLS) (Leverson et al, 2015). Larger studies followed which confirmed the early promise of venetoclax. The most important adverse event remained TLS as a consequence of its remarkable apoptotic potency. In the phase I dose-escalation study and subsequent expansion cohort, clinical TLS was observed after a primary single dose of 100 mg or 200 mg venetoclax (Roberts et al, 2016). The overall response rate (ORR) was 79% in all patients (77% in doseescalation cohort, 82% in expansion cohort) and did not vary markedly among differing prognostic subgroups, with a complete response (CR) rate of 20% in all patients (CR rate 30% in the dose-escalation cohort, 10% in the subsequent expansion cohort). Median duration of PFS of 25 months was shown in the dose-escalation cohort (Roberts et al, 2016). In patients with fludarabine resistance, an ORR of 79% was achieved, with a CR rate of 16%. Patients with del Correspondence: Chris Fegan, Department of Haematology, University Hospital of Wales, Health Park, Cardiff CF14 4XW, UK. E-mail: christopher.fegan@wales.nhs. uk editorial comment