Chemotherapy-Free Approaches Are at the Forefront in MCL

Alexey Danilov, MD, PhD

There has been a significant shift towards investigating non-chemotherapy treatment options in mantle cell lymphoma (MCL), particularly for patients with TP53 mutations who do not benefit from traditional chemotherapy, according to Alexey Danilov, MD, PhD. He added that this necessitates pre-treatment genetic screening and participation in clinical trials to determine alternative therapies.

In an interview with OncLive^®, Danilov also highlighted the utility of recently approved agents for patients with myelodysplastic syndromes (MDS), reported on the implementation of JAK inhibitors in myelofibrosis, and expanded on ongoing and planned research to take place in MCL at City of Hope in Duarte, California. Danilov is a hematologist-oncologist, professor in the Division of Leukemia, and associate director of the Toni Stephenson Lymphoma Center at City of Hope.

Danilov also shared key perspectives on the treatment of MCL, chronic lymphocytic leukemia (CLL), and other hematologic malignancy updates, in another interview with OncLive.

OncLive: How have treatments shifted in MCL with non-chemotherapy regimens?

Danilov: In MCL, there have been a lot of changes [as] we investigate non-chemotherapy options for this disease, even in the frontline setting. Patients with TP53 mutations are a group who we know do not benefit from chemotherapy and transplant, which has been our standard approach for decades in patients with previously untreated MCL.

That tells us that we need to screen patients prior to starting therapy using either Sanger sequencing or next-generation sequencing methods to identify patients with TP53 aberrations. Those patients should go on [to receive therapy in] a clinical trial, so at the very least they can be treated with non-chemotherapy options and not be subjected to transplant. Even [for] patients who do not have a TP53 mutation, the field is changing. There are many ongoing trials which use chemotherapy-free regimens.

Findings from the phase 3 TRIANGLE trial [NCT02858258] have put autologous stem cell transplant [ASCT] into question by introducing ibrutinib [Imbruvica] in the frontline setting in combination with chemotherapy. However, we didn’t quite yet answer the question of whether transplant is completely unnecessary, and if so, is it unnecessary in all patients or a subset of patients? I still believe that ASCT remains part of standard therapeutic approaches. However, with so many trials ongoing, the field is shifting to frontline BTK inhibitor-based combinations or lenalidomide [Revlimid]-based combinations. We will need longer follow-up data with these studies and some randomized studies to determine whether patients do better with chemotherapy-free options.

What research at City of Hope is ongoing in MCL and CLL with chemotherapy-free approaches?

At City of Hope, we certainly have a lot of trials in lymphoma; we are very active in many areas. In regard to MCL, I would like to highlight a couple of chemotherapy-free approaches which my colleague, Dr Tycel Phillips, MD, is pioneering. There is a phase 1/2 study [NCT05861050] evaluating the combination of glofitamab-gxbm [Columvi], venetoclax [Venclexta], lenalidomide, and obinutuzumab [Gazyva] for patients with high-risk MCL who have TP53 mutations, complex karyotypes, or other high-risk features. We also have a study of venetoclax, lenalidomide, and rituximab [Rituxan], which is a frontline treatment approach for patients with standard-risk MCL.

For all patients with MCL, we are initiating a trial of nemtabrutinib in combination with rituximab. This is going to open in 3 or 4 months and I serve as the primary investigator on that study. We have multiple studies for patients with relapsed MCL using CAR T-cell therapies and bispecific antibodies as well.

We also have exciting studies in CLL [with] chemotherapy-free [approaches with] frontline time-limited therapy studies of different doublets. In the relapsed setting, we have trials with BTK degraders [and] bispecific antibodies in both patients with CLL and Richter [transformation].

[Overall], we certainly would encourage patients to inquire about trial eligibility and obtain second opinions when treatment is needed.

In myelofibrosis, how has the implementation of JAK inhibitors impacted treatment?

Several JAK inhibitors have been used in the treatment of patients with myelofibrosis in the past few years, and they all have specific features. There are certain symptoms which are managed better with one JAK inhibitor vs the other. However, often improvement with JAK inhibitors is temporary and ASCT does remain a key modality in the treatment of patients with myelofibrosis who are eligible for this type of therapy.

There needs to be more development [of agents resulting in] more treatment options for patients with myelofibrosis. It’s a bit difficult because it’s a rare disease and is associated with cytopenias which can progress fairly rapidly, making it difficult for patients to participate in clinical trials. This is also a disease of older age, so comorbidities often become a problem, but there has been some progress with JAK inhibitors and more progress is needed.

How has the treatment of patients with MDS recently evolved?

Prognostic models, as well as novel agents, have recently been introduced for the treatment of patients with MDS. [In] patients with del(5q) MDS, lenalidomide is used in therapy on a consistent basis. For patients with MDS with ring sideroblasts, luspatercept-aamt [Reblozyl] has been recently introduced based on phase 3 trial results. There has been quite a lot of development in MDS and imetelstat [Rytelo] is another drug which has been introduced for the treatment of patients who have anemia. All of these have been very recent developments in the past 2 years, so there has been a lot of progress in the space.