Novel Targeted, Chemo-Free, and Cellular Therapies Are Poised to Transform Treatment Paradigms in B-Cell Malignancies

Alexey Danilov, MD, PhD

In an interview with OncLive®, Alexey Danilov, MD, PhD, shared insights and proceedings from the inaugural Bridging the Gaps in Leukemia, Lymphoma, and Multiple Myeloma Conference, which highlighted current challenges and ongoing innovations in the management of mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). This included recent advances and controversies in the treatment of select patients with hematologic malignancies, considerations for treatment selection in MCL and chronic lymphocytic leukemia (CLL), and how the introduction of chemotherapy-free regimens and chimeric antigen receptor (CAR) T-cell therapies have affected approaches to the management of these respective disease subtypes.

Following the meeting, Danilov and colleagues published a manuscript outlining key advances, unmet needs, and unresolved questions across the 3 disease types, with particular focus on treatment selection and sequencing strategies.

“[There are] guidelines published by different entities in all these respective fields, such as the National Comprehensive Cancer Network [NCCN] guidelines; however, these guidelines mostly focus on treatment approaches [dervied from] evidence that already exists, and [they] don't necessarily discuss controversies that physicians face on a daily basis in their clinical practice,” Danilov explained.

The authors noted that the meeting is expected to reconvene later in 2025 to further develop best practices and consensus recommendations for areas of ongoing debate.

Danilov is the Marianne and Gerhard Pinkus Professor of Early Clinical Therapeutics, medical director of the Early Phase Therapeutics Program for the Systems Clinical Trials Office, codirector of the Toni Stephenson Lymphoma Center, and a professor in the Division of Lymphoma in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope in Duarte, California.

OncLive: What is the importance of publishing this manuscript and providing additional perspective on challenges and treatment approaches in B-cell lymphoma?

Danilov: This manuscript summarizes the key findings of the meeting by experts in 3 respective fields: leukemia, lymphoma, and multiple myeloma. [These experts] discussed and highlighted some of the advances in these respective areas, as well as unmet needs and unanswered questions. In this meeting, we discussed some of these controversies, and we proposed solutions on how to approach the resolution of these controversies in the future.

How have chemotherapy-free regimens affected treatment for patients with MCL?

Chemotherapy-free regimens have begun to shift the treatment paradigm in patients with MCL. Chemoimmunotherapy has been a standard for a long time, and autologous stem cell transplant [ASCT] has also been used for a long time in patients with MCL. Building on recent advances such as the phase 3 TRIANGLE study [NCT02858258], cooperative group studies, as well as smaller studies—which demonstrate good efficacy of chemoimmunotherapy-free regimens and also question the role of ASCT—there has been a slow but steady shift in favor of these therapies.

So far, there is limited information in terms of how chemotherapy-free regimens perform in comparison with standard chemoimmunotherapy regimens. The phase 3 ENRICH trial [ISRCTN11038174], for example, did demonstrate that there may be some superiority of ibrutinib [Imbruvica]–based therapy over chemoimmunotherapy; however, that was mostly limited to R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone] in the control arm, which is not our standard in the treatment of frontline MCL. The difference [between an ibrutinib-based approach] vs bendamustine plus rituximab, which was also included in the control arm, was not so significant.

Many studies [of chemotherapy-free regimens] in patients with previously untreated MCL, [including] smaller phase 2 [trials] as well as randomized phase 3 studies, are either being planned or are currently enrolling. Although we see a lot of use of chemotherapy still in the community in MCL, there has been an increased use of BTK [Bruton tyrosine kinase] inhibitor–based regimens in frontline therapy, particularly in patients who have difficult-to-treat MCL, such as patients with TP53 mutations who do not respond well to chemotherapy.

Pirtobrutinib [Jaypirca] has been listed in NCCN guidelines for such patients now, and we do see increased use of this regimen. However, we also now know that BTK inhibitors are not a full answer for patients with high-risk MCL; therefore, new studies are needed that employ immunotherapy agents, such as bispecific antibodies, in frontline therapy for MCL to understand what is the best approach to treat these patients.

How do you approach the management of high-risk MCL in clinical practice?

I strongly believe that these patients should not receive chemoimmunotherapy, even though bendamustine plus rituximab still remains an option listed in NCCN guidelines, for example. I do believe that a clinical trial is the best option for those patients, and luckily, we do have access to such trials at our site. For example, we have a phase 1/2 trial [NCT03223610], which is evaluating the combination of ibrutinib, venetoclax [Venclexta], and lenalidomide [Revlimid], with obinutuzumab [Gazyva] pretreatment prior to ibrutinib. This trial is specifically designed for such patients, and it enrolled only patients with high-risk MCL, including patients with TP53 abnormalities.

In the absence of trials, I do believe that the BOVen regimen [of zanubrutinib (Brukinsa) plus venetoclax and obinutuzumab] is a good approach. It has demonstrated efficacy in these [high-risk] patients, although it is a smaller study, and it would be nice to have confirmation of these data in a larger patient population. Even using single-agent BTK inhibitors, potentially with the addition of venetoclax, is an approach that can be taken with or without rituximab. However, I do believe that we are potentially doing a disservice to these patients by using chemotherapy in the frontline setting, thereby promoting chromosomal instability that these patients already have and promoting the acquisition of new resistant mutations. [Additionally, it is clear that] ASCT does not play a role in this setting.

What are some key considerations for navigating BTK inhibitor selection in CLL?

In CLL, there have certainly been a lot of advances in the past 10 years. This is one field where chemoimmunotherapy has been essentially eliminated from the armamentarium, with very rare exceptions. I believe this is where MCL is heading as well, by the way.

In the frontline setting, we typically choose between time-limited regimens such as venetoclax and obinutuzumab, or single-agent BTK inhibitors. There are 3 BTK inhibitors currently approved: ibrutinib, acalabrutinib [Calquence], and zanubrutinib. [Based on] my practice and from talking to my colleagues who were at this meeting, ibrutinib is not being used as much anymore, given the randomized study data demonstrating better efficacy of zanubrutinib. Selective BTK inhibition with zanubrutinib or acalabrutinib is certainly the way to go, and there hasn’t necessarily been a consensus that one of those agents is better than the other.

There is now a third consideration, where we have seen exciting data from the [phase 3] AMPLIFY study [NCT03836261], which introduced the combination of acalabrutinib and venetoclax, and the triplet of acalabrutinib, venetoclax, and obinutuzumab in frontline therapy of CLL. Those regimens have not yet been approved; however, they are now being included in guidelines. I have successfully used those regimens in clinical trials, and I do believe that they will find common use in patients with CLL in frontline therapy.

Of course, acalabrutinib is part of that regimen, so we will see how that affects the use of other drugs. However, there are now emerging data with the combination of zanubrutinib and venetoclax, and zanubrutinib with sonrotoclax—an alternative BCL2 inhibitor. In the next few years, we will have an even more expanded armamentarium for the treatment of CLL.

How has the FDA approval of lisocabtagene maraleucel (liso-cel; Breyanzi) in CLL affected treatment selection for patients with double-refractory disease?

This is certainly a welcome development in the therapy of patients with double-refractory CLL, meaning patients who are refractory to BTK inhibitors and the BCL2 inhibitor venetoclax or alternative BCL2 inhibitors. This is an unmet medical need. This is a patient population where approvals so far are very limited, and information is still limited on how these patients do with new therapies.

We do currently have a noncovalent BTK inhibitor, pirtobrutinib, which is approved in that setting. We also have liso-cel. What transpired in that meeting is that pirtobrutinib is often an agent, in the absence of clinical trials, that physicians reach for when considering CAR T-cell therapy with liso-cel.

We do know that time to next therapy in patients with double-refractory disease on pirtobrutinib is typically less than 2 years. [This indicates that] we do have some time to achieve a response and manage the symptoms, but it is not a cure. [Therefore], considering liso-cel in that setting is something that my colleagues and I typically would do.

Of course, there are some problems with liso-cel: cytokine release syndrome [CRS], potential neurotoxicity, and risk of infections. However, I will also say that the [phase 1/2] TRANSCEND CLL 004 study [NCT03331198]​​, which led to liso-cel’s FDA approval, was conducted in a slightly different era; all the patients who were treated with that agent had previously received chemoimmunotherapy. Many patients had received up to a dozen therapies, so they entered the study with severe immune compromise, which may have negatively affected the efficacy of liso-cel and potentially increased the toxicities, including infectious complications.

In the future, we may see better durability and efficacy of liso-cel in patients who have not had multiple lines of chemotherapy in the past. We have also discussed what kinds of strategies might be employed to improve the efficacy and safety of liso-cel in patients with CLL. These could include some prophylactic measures for CRS. They could include combination studies with BTK inhibitors, where some early data are interesting—demonstrating increased efficacy as well as improved toxicity profiles. There are some additional strategies that we could deploy over the next few years to help improve outcomes in patients with CLL.

Reference

Danilov AV, Sauter C, Phillips T, et al. Perspectives on current challenges and emerging approaches for lymphoma management from the first Bridging the Gaps in Leukemia, Lymphoma, and Multiple Myeloma Conference. Clin Lymphoma Myeloma Leuk. 2025;25(6):e366-e373. doi:10.1016/j.clml.2025.01.005