Rationale for Novel Combinations in CLL

Javier Pinilla-Ibarz, MD, PhD: Combination therapies for the treatment of chronic lymphocytic leukemia are currently under development, and there are many trials that are really trying to address this problem. There is a recent report, although it is not really fully done. This is not published in an abstract form; it is in a press release. The combination of ibrutinib with a monoclonal antibody, obinutuzumab, can produce significant progression-free survival in comparison with obinutuzumab/chlorambucil alone, something that is pretty much similar to what we have shown in other trials. In this case, it is important to consider that ibrutinib is given for a long period of time until disease progression or unacceptable toxicity, and those patients have a very low rate of progression. So, with this combination, it is still unclear how they’re going to pan out in the introduction of the change of paradigm in the treatment of CLL.

However, there are other combinations with ibrutinib and a BCL-2 inhibitor, venetoclax, that are really showing very remarkable responses in terms of complete responses and, even more, absence of minimal residual disease by flow cytometry in the bone marrow. MRD negativity in the bone marrow is becoming, with the introduction of venetoclax, a goal to be achieved in patients with chronic lymphocytic leukemia. However, MRD negativity, although it is very well established for the past years after chemoimmunotherapy, is not incorporated into any guidelines—no iwCLL or NCCN guidelines. But in the future, it may be a goal to achieve in patients treated with these more complex combinations, such as ibrutinib and venetoclax…to have duration times of therapy and to be able to stop therapy and wait until patients progress or, in this case, to really have long period of time without any treatment.

There are, today, several combinations that are being studied for the treatment of frontline or even relapsed/refractory CLL. Most of these combinations really entail the use of a BCR inhibitor in the form of BTK inhibitors, such as ibrutinib, or even other drugs such as acalabrutinib or other second-generation BTK inhibitors. Otherwise, the use of PI3K delta or gamma/delta inhibitors is another area of investigation, alone or in combination with monoclonal antibodies. Once again, these strategies really continue to deliver the oral drug until disease progression or unacceptable toxicity.

However, a second strategy and a second combination is the introduction of venetoclax, a BCL-2 inhibitor, with a BCR inhibitor—in general, any of the BCR inhibitors available, BTK or PI3K. And even more recently, we have seen the combination with a triple monoclonal antibody: anti-CD20, BCR inhibitor, mostly in the form of BTK inhibitors such as ibrutinib, and a BCL-2 inhibitor such as venetoclax.

Lastly, the German group is now working on several trials trying to stratify and sequence several therapies, such as induction with a very short chemotherapy with bendamustine, followed by all the combinations I just discussed briefly a second ago, such as a monoclonal antibody with a PI3K and a monoclonal antibody with a BTK inhibitor, as well the use of different monoclonal antibodies, anti-CD20.