Targeted Therapies Are Finding Their Footing in Hematologic Malignancies

The potential utility of CAR T-cell therapy for relapsed or refractory lymphomas, such as diffuse large B-cell lymphoma (DLBCL), is ushering in a new era of treatment for patients with hematologic malignancies, according to Eduardo M. Sotomayor, MD; however, sequencing considerations between CAR T-cell therapy and bispecific antibody treatment options remain to be addressed in this space.

Furthermore, updates and advancements in the management of myelofibrosis as well as myelodysplastic syndromes (MDS), and the evolving treatment landscape of BTK inhibitors in chronic lymphocytic leukemia (CLL), underscore the continued impact of targeted therapies in these cancers.

“[Although] there is still debate on when to use and how to sequence CAR T-cell therapy and bispecific antibodies, it is great that we have this problem because 10 years ago we didn’t have either CAR T-cell therapy or bispecific antibodies for patients who would [otherwise have] progressed after transplant because of their disease. Overall, it’s a good problem to have,” Sotomayor reported in an interview with OncLive® following an OncLive State of the Science Summit™.

In an interview with OncLive, Sotomayor expanded on the current treatment paradigm for hematologic malignancies such as myelofibrosis and MDS, highlighted the growing landscape of treatment with CAR T-cell therapy, and highlighted key takeaways from the SOSS event, which he chaired. Sotomayor is the president and executive director of the Tampa General Hospital Cancer Institute, the Cancer Center of South Florida.

OncLive: What are the advantages and limitations of CAR T-cell therapy vs bispecific antibodies for the treatment of B-cell lymphomas?

Sotomayor: [For] my patients with aggressive lymphomas, if they relapse quickly after first treatment with chemoimmunotherapy, my recommendation will be CAR T-cell therapy. This is because studies have shown that we can cure approximately 40% of patients with relapsed/refractory [disease]. However, if the patient cannot take CAR T-cell therapy because of comorbidities, insurance, or the adverse effects [AEs], then it’s a different story, but I would always recommend CAR T-cell therapy as a curative treatment for relapsed or refractory lymphoma.

If a patient with aggressive lymphoma refuses [treatment with CAR T-cell therapy], they still have options such as bispecific antibodies. However, in other lymphomas—low-grade, follicular, or mantle cell lymphoma—the data is not there yet that CAR T-cell therapy is curing patients. Therefore, I am more flexible in that situation.

I favor using bispecific antibodies first in low-grade lymphomas because of the easy-to-manage AEs. If the patient then does not respond to a bispecific antibody, then I will start thinking about CAR T-cell therapy. I want to emphasize that this is a good problem to have and different physicians are going to have different experiences and preferences. However, for DLBCL and aggressive lymphoma, CAR T-cell therapy—given the long-term data and the ability to cure patients—is what I pursue as a second- or third-line of treatment.

How are you hoping to see questions that remain regarding sequencing addressed in future trials or research?

With bispecific antibodies in aggressive lymphomas, the data is quite interesting—we are seeing some patients achieve a complete response and the complete response is sustained. If those patients remain in remission longer than 2 or 3 years, there is a possibility that we might also be able to cure aggressive lymphomas with bispecific antibodies, but the data is not there yet. We are waiting for mature data with bispecific antibodies in aggressive lymphomas to determine whether the efficacy is similar or not to CAR T-cell therapies in that patient population.

Can you use a bispecific antibody after CAR T-cell therapy? The answer [to that] is yes; there are plenty of data. All the clinical trials with bispecific antibodies include patients who have progressed following CAR T-cell therapy or after transplant, so the answer is yes. The big question is if you can use bispecific antibodies before CAR T-cell therapy in low-grade lymphomas I will say, yes; however, in aggressive lymphomas, [the answer is] no unless the patient is not a candidate for CAR T-cell therapy or because insurance cannot receive CAR T-cell therapy. There are emerging data that you can use bispecific antibodies first without affecting the efficacy of CAR T-cell therapy down the road.

Anthony Hunter, MD, of Emory University, discussed the management of myelofibrosis. What were they key takeaways from this presentation?

I liked his presentation because he provided an update on the increasing knowledge about the different subtypes [of this disease], as well as the possibility to start using better targeted therapy for myelofibrosis. Although this is not my area of expertise, as we advance with fundamental knowledge—[and answer] what pathways are affected in myelofibrosis—we are going to be able to develop better therapies.

For many years, this was an orphan disease as there were no significant advances in the understanding of the disease. Overall, I am very happy to hear that things are changing. We are making significant strides in understanding the biology of myelofibrosis.

David Swoboda, MD, of the Tampa General Hospital Cancer Institute, discussed MDS. What did you feel were the most important updates according to this presentation?

For the audience and myself, the ability of Dr Swoboda to make this complicated topic into a very easy [one] to understand [was vital]. I don’t treat MDS anymore though I follow the literature, and he was able to refresh my memory and give me an update on the advances in the classification of MDS as well as provide novel insights into the biology of the disease and the new therapies that are available.

Javier Pinilla, MD, of Moffitt Cancer Center, provided a presentation on the treatment sequencing of BTK inhibitors in chronic lymphocytic leukemia (CLL). With new data forthcoming on noncovalent BTK inhibitors in this space, how may these products be sequenced?

Dr Pinilla is an expert in CLL and it’s good to have this problem—we have several types of BTK inhibitors including the third and second-generation BTK inhibitors. We have options [and who] do you want to limit the therapy [for], so you can use venetoclax [Venclexta] with obinutuzumab [Gazyva]? You then treat your patient frontline for 12 months, and then after follow-up, you make your opinion based on MRD results.

In terms of BTK inhibitors, the efficacy seems to be similar, but there are differences in AEs. Every physician is going to be used to a BTK inhibitor that they feel more comfortable with and have more experience with. These agents have transformed the way that we treat CLL.

Fifteen years ago, we used chemotherapy or bendamustine [Bendeka] and rituximab [Rituxan], but now we have targeted therapies. They are not chemotherapies, and therefore they have their own set of AEs, but we are very comfortable dealing with these AEs. In patients who progress after first-line BTK inhibitors, there is another option: pirtobrutinib [Jaypirca], the second-generation BTK inhibitor. There are also combinations, doublets, and triplets, but the field of CLL is moving toward limited therapy. Now because we have MRD we can stop or continue treatment based on MRD status in patients.