Venetoclax: Shaking CLL Off the Tree

Sometimes, you can still be important, even if you come second. True, the first B cell lymphoma gene (bcl-1, now termed CCND1) encodes cyclin D1 and was found to play a critical role in many cancers, including mantle cell lymphoma. However, its younger brother bcl-2 retained its original name, became identified as the gatekeeper of apoptosis, and has now become a target for one of the most impressive new drugs within hemato-oncology. How did this happen?

This critical regulator of apoptosis, bcl-2 was originally cloned by Dr. Stanley Korsmeyer following its identification as a partner of the t(14;18) translocation in follicular lymphoma (FL). Early mechanistic research was followed by the surprising discovery of its localization on the outer membrane of the mitochondrion. It later transpired that this reflected a role in regulation of voltage‐dependent anion channels. It is this role that has been tied to prevention of cytochrome c release into the cytosol as a trigger for apoptosis.

The critical importance of apoptosis-resistance in the development of malignant cells led inevitably to a screen for drugs that could block this phenotype. bcl-2 has several natural inhibitors including a family called the BH3-only proteins. Venetoclax (ABT-199) was developed as a BH-3 mimetic drug, and the aim was to inhibit bcl-2 and promote apoptosis. The next step was to assess its effect in lymphoid tumors. Although FL might seem to be the obvious target, it is often overlooked that bcl-2 levels are also markedly increased in chronic lymphocytic leukemia (CLL). The mechanisms that underlie this increase in expression are not entirely clear but may include promoter hypomethylation or alterations in transcriptional regulation secondary to loss of miRNA-15a and miRNA-16-1 within the minimal 13q deletion. As such, CLL represents an excellent opportunity for clinical assessment of this BH3 mimetic.

Like all new agents, venetoclax had to start at the back of the queue when introduced for the treatment of CLL, and the early trials were in relapsed or refractory disease. One of its trump cards is that it can kill malignant cells independently of whether they carry a functional p53 protein and it is therefore not surprising that venetoclax is highly effective in CLL tumors that carry mutations in the TP53 gene or harbor a 17p deletion. Indeed, the M13-982 TRIAL was designed to administer oral venetoclax monotherapy to patients with relapsed/refractory and 17p-deleted CLL and proved to be pivotal in gaining the drug license. Patients in this study were heavily pre-treated, with a median of two prior therapies. An additional key point is that 11 percent of patients had previously received a B-cell receptor signaling inhibitor (BCRi) such as ibrutinib and/or idelalisib. This setting of BCRi-failure has previously represented an area of great unmet need.

The results were encouraging. Within the first 158 patients the investigator-assessed overall response rate was 77 percent with a complete response rate of 18 percent. The 24-month estimates for progression-free survival (PFS) and overall survival (OS) were also very high at 52 percent and 72 percent, respectively. However, perhaps the most striking feature of venetoclax is the depth of response that is achieved in a proportion of patients. Forty-two (27%) of the 158 patients achieved a state of negative minimal residual disease (MRD) in blood samples, as defined by flow cytometry to a sensitivity of one in 10,000 cells. Nineteen of this group were also in complete remission (CR) and not one of these patients showed progression after two years of treatment. The PFS in those with partial remission (usually nodal masses) and MRD-negative status was also excellent at 78.5 percent after two years. Importantly, recent updates show that for the subgroup of patients with BCRi therapy-failure the response rate was still 61 percent, and 11 percent achieve CR. The 12-month PFS was 50 percent and OS 54 percent.

The U.S. license is for treatment of CLL patients with 17p deletion who have received at least one prior therapy. Elsewhere it has achieved approval for all BCRi failures or for first line use in patients with 17p deletion. However, although monotherapy is achieving impressive responses, a range of experimental combination treatments are now becoming available. Dr. Peter Hillmen reported on the Clarity TAP trial which comprises eight weeks of ibrutinib before the introduction of venetoclax as combined dual therapy. The aim is to achieve MRD negativity and then test if this is maintained after the drugs are stopped. After eight weeks of combined therapy, 42 percent of patients have already shown a three-log reduction in circulating CLL count. The M13-365 study is combining venetoclax with rituximab and 59 percent of patients have achieved MRD-negative bone marrow status. An exciting innovation in this study is that patients who achieve MRD can stop therapy and long-term disease-free remissions have been observed in most cases.

The German CLL14 study looks at an older patient group with co-morbidities and combines venetoclax with obinutuzumab. Again, the combination was tolerated reasonably well and very early results suggest very promising results. The overall response rate in 13 patients who completed therapy was 100 percent, and 92 percent of these achieved MRD negativity in the blood within three months of completion of the 12-month therapy. The delivery of venetoclax is not without its challenges; the most significant being the risk of tumour lysis syndrome, ironically a dramatic example of its therapeutic power. In this regard, the introduction of a gradual “ramp up” of the oral dosage has markedly reduced the frequency and severity of this complication although rigorous compliance with protocol is still required. Cytopenias are also significant with grade 3 to 4 neutropenia (39% in the M13-982 TRIAL), thrombocytopenia (15%), and anemia (14%) proving common, and requiring dose adjustment or symptomatic support.

These results pave the way towards the use of venetoclax as a new backbone within a range of combination therapies that should be able to achieve extremely “deep” therapeutic responses in CLL and with the reasonable hope that cessation of treatment may lead to sustained long-term remission. Dare we even say cure? When Dr. John Kerr and colleagues reported on the phenomenon of programmed cell death in 1972 they had the challenge of finding a name for this new phenomenon. Apoptosis (apo-ptosis) was chosen to describe the “dropping off” or “falling off” of petals from flowers or leaves from trees. (We recognize the clinical sign of a “falling eyelid” as ptosis). The spectacular early observations on the use of venetoclax appear destined to ensure that CLL will itself now inevitably fall from the tangled branches of burdensome lymphoproliferative diseases.