Further Research Is Needed to Maximize Efficacy of Current Treatment Options in Hematologic Malignancies

Ricardo D. Parrondo, MD

Research is still needed to harness the efficacy of BTK inhibitors, CAR T-cell therapy, and bispecific antibodies in patients with hematologic malignancies while minimizing toxicities, identifying optimal sequencing strategies, and sorting through better options for patients post progression, according to Ricardo D. Parrondo, MD.

“We continue to get new treatments for all of these hematologic malignancies that are sure to improve prognosis for patients,” Parrondo said following an OncLive^® State of the Science Summit™ on hematologic malignancies, which he chaired. “...[However], a lot of questions remain regarding how we can sequence these agents.”

In an interview with OncLive, Parrondo highlighted the current use of covalent BTK inhibitors in chronic lymphocytic leukemia (CLL), potential roles for the non-covalent BTK inhibitor pirtobrutinib (Jaypirca), and the importance of future research on time-limited treatment options for patients with newly diagnosed CLL.

Parrondo, who is a hematologist/oncologist and assistant professor, also provided perspectives on key topics in lung cancer discussed by his colleagues from the Mayo Clinic in Rochester, Minnesota. This included the emerging role of momelotinib (Ojjaara) in myelofibrosis, key research in polycythemia vera, potential treatment strategies for patients who progressed on CAR T-cell therapy in diffuse large B-cell lymphoma (DLBCL), and the use of pirtobrutinib in mantle cell lymphoma (MCL).

OncLive: What current data help guide BTK inhibitor selection in CLL, particularly for patients who have pre-existing comorbidities?

Parrondo: The field is moving away from ibrutinib [Imbruvica] and most of us are using acalabrutinib [Calquence] and zanubrutinib [Brukinsa]. We have data, most of it from relapsed CLL, that zanubrutinib is superior to ibrutinib both in terms of efficacy and toxicity. In relapsed CLL, we have similar data. Acalabrutinib appears to be just as efficacious as ibrutinib, but the safety profile is much better. When you're going to use a covalent BTK inhibitor, acalabrutinib and zanubrutinib appear to be more efficacious and safer for patients [vs ibrutinib].

Hypertension appears to be the lowest with acalabrutinib, so for somebody with poorly controlled hypertension or hypertensive issues prior to starting [treatment], I would tend to use that agent. In terms of atrial fibrillation, both acalabrutinib and zanubrutinib appear to have lower rates of atrial fibrillation compared with ibrutinib. Either one of those [are viable options] for patients with pre-existing atrial fibrillation. You can [otherwise] tailor [the selection of these agents to individual circumstances]. For example, we know that acalabrutinib can cause headaches, so I would use zanubrutinib for people with headache disorders.

Following the approval for the non-covalent BTK inhibitor pirtobrutinib in MCL, how do you see this agent potentially fitting into the treatment landscape for CLL?

Even though [pirtobrutinib is] not approved yet in CLL, it is listed on the National Comprehensive Cancer Network guidelines, so myself and some of my colleagues have been able to get it for patients. It appears to be efficacious in patients who developed a C481S mutation after being treated with a covalent BTK inhibitor. It's another nice option to have for those patients. It [also] comes into play for patients with double-refractory CLL, or those who are refractory to a covalent BTK inhibitor and a BCL-2 inhibitor. It's nice to have pirtobrutinib in that setting because we know that it works well. The toxicity profile appears to be excellent, and it's very well tolerated and efficacious in that double-refractory CLL population.

What ongoing or planned areas of research in CLL are you most interested in?

The studies I'm most interested in are those with time-limited treatment. We know that all the covalent BTK inhibitors are given until disease progression, and you do get cumulative toxicities from them. This includes financial toxicity, as it can be very expensive for patients [to continue treatment indefinitely]. Time-limited options with a BTK inhibitor and a BCL-2 inhibitor are looking promising. We have data with ibrutinib plus venetoclax [Venclexta] from the phase 2 CAPTIVATE study [NCT02910583] and phase 3 GLOW study [NCT03462719], but I'm more excited about the next-generation covalent BTK inhibitors. [This includes acalabrutinib plus venetoclax in the phase 3 MAJIC study [NCT05057494] and zanubrutinib plus venetoclax in the phase 3 SEQUOIA trial [NCT03336333]. I'm looking forward to those combinations for patients with newly diagnosed CLL.

Regarding the presentation given by Candido E. Rivera, MD, how does the clinical benefit with momelotinib compare with other standard agents like ruxolitinib (Jakafi) in anemic myelofibrosis?

We know that ruxolitinib can cause cytopenias and may be difficult to tolerate in patients with thrombocytopenia or anemia. When [investigators] compared ruxolitinib with momelotinib, ruxolitinib appeared to be better at symptom control and shrinkage of the spleen. However, for patients with predominant anemia who are transfusion-dependent, momelotinib is ideal. Even though you don't get as much shrinkage of the spleen and symptom control [with momelotinib] as you do with ruxolitinib, you do get some and you also get improvement of anemia and transfusion dependence. So that's the ideal population to use it in.

Based on his second presentation, what key studies have had the most impact on the polycythemia vera treatment landscape?

The most impactful [study] was the [phase 1/2 PEGINVERA trial (NCT01193699)] of ropeginterferon alfa-2b [Besremi]. It is able to keep the hematocrit at goal more so than therapeutic phlebotomy is for these patients, and more patients achieve a complete hematologic response. It also does appear to be disease modifying. More data will be reported from the trial.

As per the presentation given by Muhamad Alhaj Moustafa, MD, MS, could you highlight the challenges associated with treating patients who relapse after CAR T-cell therapy? What could address this need for effective salvage therapy in the post–CAR T-cell setting?

Relapse after CAR T-cell therapy was a difficult spot to be in for these patients. Dr Moustafa did present interesting data on allogeneic transplant, which appears to be efficacious after CAR T-cell failure. However, transplant works better for patients who achieved complete remission. By the time you get to CAR T-cell therapy, patients are presumably chemotherapy-refractory and it is hard to achieve disease control. Bispecific antibodies [are] the next generation of treatment for [patients with] DLBCL, and they do show efficacy in patients who [progress on] CAR T-cell therapy. The most promising therapeutic strategy for patients with DLBCL who progress in the post–CAR T-cell setting is using these bispecific antibodies either until disease progression or complete remission. [In the latter scenario], if the patient is fit enough, you can take them to allogeneic transplant.

With the current success of BTK inhibitors in MCL, how is the field attempting to improve their use and explore novel roles for these agents?

We have approvals for acalabrutinib and zanubrutinib. The issue is that most patients progress after those therapies. Now we have the first FDA approval of pirtobrutinib in MCL. Pirtobrutinib is showing efficacy in patients who have progressed after a covalent BTK inhibitor, so it's good to have it in that space.

Could you briefly outline the current benefits and limitations associated with CAR T-cell therapy in patients with B-cell lymphoma outlined in the presentation by Hemant S. Murthy, MD. What did he suggest might be done to mitigate them?

CAR T-cell therapy is an efficacious therapy for [patients with] B-cell lymphomas. However, the time to manufacturing and cost of manufacturing continue to be issues. Patients can die waiting for manufacturing due to relapsed disease, and these drugs continue to be very expensive. If we can lower the cost of CAR T cells and manufacture them quicker that would make this therapy more available to more patients, and we'll be able to [administer] it sooner so patients don't die of relapsed or aggressive disease while waiting for [this therapy].

What main message would you like to convey to colleagues regarding this meeting?

[We have lots of exciting developments in] the field of small molecule inhibitors, next-generation BTK inhibitors, and immunotherapies. [We also need to continue efforts to] perfect CAR T-cell therapy and manufacture it faster, so that [the CAR T cells] persist for longer. Then [we also have] next-generation bispecific antibodies. [Overall], it is a very exciting time in hematologic malignancies.