Movement of Novel Agents Up Front Is Current Focus in Hematologic Cancers

Ann S. LaCasce, MD, MMSc

Advances in hematologic malignancies are largely owed to the use of genomic sequencing to identify targets, resulting in the development of cell signaling agents, immunotherapy, and CAR T-cell therapy, said Ann S. LaCasce, MD, MMSc, who added that the priority across the field now centers around combining novel agents, shifting treatments up front, and moving away from toxic chemotherapy options.

“We’re lucky in hematologic malignancies to really have seen dramatic improvements over [the past few years]. It’s been a long time coming, and it’s great to see so many trials that are yielding [positive] results,” LaCasce said in an interview with OncLive^® following an Institutional Perspectives in Cancer webinar on hematologic malignancies, which she chaired.

In the interview, LaCasce, director, Dana-Farber/Mass General Brigham Fellowship in Hematology/Oncology, chair, Fellowship Program in Hematology/Oncology, institute physician, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discussed the highlights from each presentation from the meeting, spanning lymphoma, myelofibrosis, and chronic lymphocytic leukemia (CLL).

OncLive^®: Jennifer Crombie, MD, of Dana-Farber Cancer Institute, gave a presentation on advances in diffuse large B-cell lymphoma (DLBCL). What are some agents that are defining the current treatment landscape?

LaCasce: We have a lot of new options in DLBCL, and those options may be changing soon if polatuzumab vedotin-piiq [Polivy] moves up front, but we have a number of great salvage therapies including CAR T-cell therapy, which currently is being used in the third-line setting but may be moving into the second-line setting for patients who are primary refractory or have early relapses.* There’s a lot of excitement about other agents, such as loncastuximab tesirine [Zynlonta], tafasitamab-cxix [Monjuvi] and lenalidomide [Revlimid], and polatuzumab vedotin plus bendamustine and rituximab [Rituxan]; all those agents have very good activity in a space where 7 or 8 years ago, we really had no good options. It’s really a very exciting time in DLBCL.

Jacqueline S. Garcia, MD, of Dana-Farber Cancer Institute, presented on new standards in myelofibrosis. What do recent advances signify about where the field is headed?

In the past, the only option that has been available was ruxolitinib [Jakafi] and for those who had failed ruxolitinib, [the outlook] did not look great. Regarding novel agents, pacritinib [Vonjo] has very encouraging data [in this setting] and will certainly help patients, and then there are several other drugs in clinical trials, including navitoclax that look extremely promising. Myelofibrosis is sort of becoming the CLL of the myeloid diseases and [we hope to] turn it into a chronic disease where patients are treated with oral agents for long periods.

Inhye Ahn, MD, of Dana-Farber Cancer Institute, presented on CLL management. What is the current utility of fixed-duration and continuous therapy in this space?

This is another area where we have seen unprecedented expansion of therapeutic options. Up front, we have the option of using venetoclax [Venclexta] plus obinutuzumab [Gazyva] for time-limited therapy, probably for all patients except maybe those who have 17p deletion. There’s some controversy for younger patients who have mutated immunoglobulin heavy chain genes; that small proportion of patients may benefit from chemoimmunotherapy, but everybody else gets novel agents.

The BTK inhibitors, first with ibrutinib [Imbruvica], which is an extremely active drug, and now with acalabrutinib [Calquence] and zanubrutinib [Brukinsa], which has not yet been approved in this space, [have shown tremendous impact]. We hope [acalabrutinib] will be approved soon because both [acalabrutinib and zanubrutinib] offer significant improvements in tolerability beyond ibrutinib and are incredibly efficacious. It’s exciting to live in this new era of therapies for CLL where patients tolerate treatment and can continue their lives.

Caron A. Jacobson, MD, MMSc, of Dana-Farber Cancer Institute, presented on CAR T-cell therapy across lymphoma. In which settings could CAR T-cell therapy have the greatest impact?

We’re really looking for [axi-cel] to be approved because we all know in our hearts that when you treat someone who is primary refractory, you lose time by giving them additional chemotherapy, and those patients inevitably [develop progressive disease] and then you’re scrambling to try to get CAR T-cell therapy in the third-line setting. To have [CAR T-cell therapy] available in the second-line setting, both axi-cel and lisocabtagene maraleucel [liso-cel; Breyanzi], [the latter] from the TRANSFORM study [NCT03575351], would be incredible. We hope those products get approved soon because we have patients who really need these approaches.

In mantle cell lymphoma, CAR T-cell therapy has been a welcome addition to our therapies for patients who either were not candidates for autologous transplant or have relapsed or are TP53 mutated and have very aggressive disease. For these patients, CAR T-cell therapy is a great option.

In follicular lymphoma, for patients who progress early, everything else we really do, aside from transplantation, doesn’t have the ability to potentially keep patients in long-term remission, although we need longer follow-up on the [ZUMA-5 trial (NCT03105336)] because the plateau on those curves looks very promising.

How have management strategies for adverse effects evolved with the use of CAR T-cell therapy?

We have learned a lot since when we were first using these agents and patients were getting very sick. With the algorithms that are so tightly described, we now know exactly what to do. Using tocilizumab [Actemra] early for cytokine release syndrome with steroids if [the toxicity is] high grade and the early use of dexamethasone for patients with neurotoxicity has changed how we manage these patients. We’re much more comfortable taking even older patients through CAR T-cell therapy [because of that].

Liso-cel [has a] 4-1BB [costimulatory domain], so the cells don’t expand as quickly. It really is a feasible option in our elderly patients for whom we’ve had limited options in the past. It’s been very gratifying to get comfortable managing these therapies, and there are even newer mitigation strategies such as anakinra [Kineret] and other things being studied, which may make [CAR T-cell therapy] even more manageable for older patients.

Reid W. Merryman, MD, of Dana-Farber Cancer Institute, spoke on follicular lymphoma and the use of novel agents. How do these agents distinguish themselves?

We have tazemetostat [Tazverik], the EZH2 inhibitor, which has a higher response rate in patients who are mutated, but it also works in patients who are wild type. The progression-free survival [PFS] is similar [between those 2 populations]. It’s also a very well-tolerated drug.

We also have 2 PI3K inhibitors currently available: copanlisib [Aliqopa], which, although it’s intravenous and can cause hypertension and diabetes, is a good option and is active in patients with relapsed/refractory disease. Umbralisib is more of a standard oral drug.

The bispecifics are in clinical trials right now but look very promising. In terms of the current landscape, the combination of lenalidomide and rituximab is a very good option in the second-line setting. We’re moving away from chemotherapy drugs like bendamustine, which is very effective, but for older patients can have significant toxicity—particularly with regard to infections.

You mentioned how there’s activity with tazemetostat in patients who are EZH2 wild type. Would you use that agent in this population?

Yes. For an older patient who has comorbidities, the PFS was nearly identical. Someone who can live with stable disease for a period, that’s an attractive option. For people who have bulky disease or are symptomatic and are wild type, it’s probably not the best choice, but for other patients who are slowly progressing, it may offer some good time before doing something more aggressive.

Is there any ongoing or planned research at Dana-Farber Cancer Institute that you would like to highlight?

We have a lot of trials in CLL that are ongoing, and we will have an up-front trial comparing venetoclax-based therapy with BTK-based therapy in the MAJIC study [NCT05057494]. We’re looking forward to having that study open to figure out which is the better option up front. We are participating in several Hodgkin lymphoma studies looking at adding novel agents up front in early disease through a City of Hope multicenter study and through a US cooperative group study, which will randomize patients to brentuximab vedotin [Adcetris] plus AVD [doxorubicin, vinblastine, and dacarbazine] vs nivolumab [Opdivo] plus AVD. That’s a very important study that is enrolling ahead of schedule, which is almost unheard of for a cooperative group study.

We have several CAR T-cell studies ongoing looking at some of these novel CD19- and CD20-directed or allogeneic CAR T cells, and we hope those are going to be good, tolerable options for patients. We have some investigator-initiated studies incorporating bispecifics up front coming down the line in large cell lymphoma and in follicular lymphoma, which is going to be a very important space. There’s a lot going on in lymphoma. It really is such a gratifying disease to treat because we have good standard options and being able to incorporate these novel agents that have favorable toxicity and benefit patients is remarkable.

Do these advances with targeted therapies extend to other hematologic malignancies, such as acute leukemia and multiple myeloma?

Although I don’t treat acute leukemia, it’s been really gratifying to see some novel agents coming into that space [such as] the FLT3 inhibitors and venetoclax and seeing that patients aren’t just getting 7 + 3 standard chemotherapy.

Myeloma is like lymphoma; they have an explosion of new drugs. When I was a fellow, everyone shied away from myeloma because it was a difficult disease to treat, and the patients really seemed to suffer. Now, it’s a completely different field. It’s quite remarkable.

*Editor’s Note: This interview took place prior to the April 1, 2022, FDA approval of axi-cel for second-line relapsed/refractory large B-cell lymphoma.