Danilov on the Shifting Chronic Lymphocytic Leukemia Paradigm

Alexey Danilov, MD, PhD

The development of targeted therapies for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) has rapidly expanded the treatment landscape for this patient population.

Today, investigators have their choice of targeted agents, including Bruton tyrosine kinase (BTK) inhibitors, PI3K inhibitors, B-cell lymphoma 2 inhibitors, venetoclax (Venclexta), and more.

The 3 BTK inhibitors indicated for use in the relapsed/refractory CLL setting include ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa). Each of these agents have delivered improvements in quality of life, progression-free survival, and overall survival, for patients with CLL. Then, there are new and emerging treatment options currently in development, some of which include the noncovalent BTK inhibitors, vecabrutinib, AQQ-531, and LOXO305 (pirtobrutinib).

“Over the last few years, we have seen a major paradigm shift in therapies for chronic lymphocytic leukemia. Now, introductions of novel targeted therapies such as the BCL-2 inhibitor, venetoclax, as well as BTK inhibitors, including ibrutinib and acalabrutinib in the treatment of CLL, have resulted in a significant reduction of use of chemoimmunotherapy regimens,” stated Alexey Danilov, MD, PhD, in an interview with Targeted Oncology^TM.

In the interview, Danilov, associate director, Toni Stephenson Lymphoma Center, and professor, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, delved into the latest treatment strategies and approvals investigated for patients with CLL.

Targeted Oncology: Can you give an overview on the recent updates and research in the CLL space?

Danilov: There are some targeted therapies which are emerging, some interesting novel antibodies, we have several trials which are exploiting tafasitamab-cxix [Monjuvi], a CD19 targeting antibody in chronic lymphocytic leukemia, and there is also a novel class of agents called cyclin dependent kinase 9 inhibitors. There are several agents being explored there in CLL which targets an anti-apoptotic protein, MCL-1. There are also some immune therapies and cellular therapy approached in addition to CAR T cells. There are also CAR NK cells which have some very interesting data in CLL, but it is very early data.

What does the treatment landscape entail for CLL and how has it evolved?

Over the last few years, we have seen a major paradigm shift in therapies for chronic lymphocytic leukemia. Now, introductions of novel targeted therapies such as the BCL-2 inhibitor, venetoclax, as well as BTK inhibitors, including ibrutinib and acalabrutinib in the treatment of CLL, have resulted in a significant reduction of use of chemoimmunotherapy regimens. Fludarabine-based therapies are still occasionally used in younger patients with mutated IGHV status. However, given the significant survival advantage of novel therapies, the use of this regimen has declined by a lot. Novel regimens result in significantly better safety profile as well.

The most impactful approvals are the BTK inhibitors, ibrutinib and acalabrutinib. They are both approved in relapsed/refractory CLL and as frontline therapy of CLL. Venetoclax isapproved in combination with rituximab [Rituxan] in relapsed/refractory CLL and obinutuzumab [Gazyva] in the frontline setting.

What other mechanisms are currently being investigated?

There are many studies going on now, which use the combination therapy of both BTK inhibitors and BCL-2 inhibitors, such as acalabrutinib and venetoclax or ibrutinib and venetoclax. The data from the studies are already emerging, and the early data is very encouraging. Those are time limited therapies in CLL.

In addition, there are multiple other targeted agents being developed. For example, double refractory patients who have relapsed on both BTK inhibitors and the BCL-2 inhibitor venetoclax represent an unmet medical need now. Novel agents such as noncovalent BTK inhibitors like pirtobrutinib [L0X0-305] are being developed in that space. There are some novel BCL-2 inhibitors as well which are in clinical trials. BTK degraders, which have a slightly different mechanism where they don't just block the BTK, but lead to its degradation, are also In early phase clinical trials now with very limited data so far.

In terms of immune or cell therapy approaches, there are some exciting data emerging with the CAR T-cell therapies which show efficacy in double refractory CLL as well, and here are several trials with bispecific antibodies, such as mosunetuzumab [Lunsumio], which also show early promise.

Can you discuss the unmet needs in the CLL space?

The key unmet needs would include the double refractory patients, those who progressed on BTK, and BCL two inhibitors, as well as patients with high genetic risk disease. Just deletion17p or p53 mutation, those patients still have in furious progression free survival even on novel targeted agents. And if patients who are younger would still be candidate for allogeneic stem cell transplant, so we have to do better with that particular patient group. And there is, like I said, a lot of focus on time limited therapy, combination therapy with an effort to achieve deep responses in CLL and longer treatment free period.