New and Anticipated Advances Across Hematologic Malignancies Necessitate Improved Navigation of Current Options

John M. Burke, MD

Recent approvals of BTK inhibitors, antibody-drug conjugates, and other targeted therapies for B-cell malignancies have rapidly expanded the treatment armamentarium and improved the standard of care. With several more potentially paradigm-shifting approvals on the horizon, a nuanced understanding of current decision-making in the absence of optimal sequencing, as well as a renewed focus on incorporating these agents into clinical practice, is still required to improve patient outcomes in this space, according to John M. Burke, MD.

“A lot of promising drugs are in development or have been approved in B-cell malignancies, myelofibrosis, and polycythemia vera,” Burke said following an OncLive^® State of the Science Summit^™ on leukemia and lymphoma, which he chaired. “Treating physicians, oncologists, and hematologists should be aware of these new developments and [use this knowledge to] help their patients make informed decisions about what’s best for them in a particular situation.”

Burke expanded on key topics discussed by himself and his colleagues at the meeting in an interview with OncLive, including the use of novel BTK inhibitor regimens in mantle cell lymphoma (MCL), treatment sequencing challenges and other unmet needs indiffuse-large B-cell lymphoma (DLBCL), the evolution of management strategies for myeloproliferative neoplasms, and the potential influence of new and emerging therapeutics in chronic lymphocytic leukemia (CLL).

Burke is the associate chair of the Hematology Research Program for US Oncology, and a medical oncologist and hematologist at Rocky Mountain Cancer Centers in Aurora, Colorado.

OncLive: What BTK inhibitor studies have had the most influence on the treatment landscape in treatment-naïve and relapsed/refractory MCL?

Burke: In the treatment-naive space, the two recent trials that made a splash were [the phase 3] SHINE [NCT01776840] and TRIANGLE [NCT02858258] studies. Both [SHINE and TRIANGLE] showed that adding the BTK inhibitor ibrutinib [Imbruvica] to conventional therapy for transplant-eligible and -ineligible patients improved progression-free survival [PFS] and failure-free survival [in each respective trial]. Adding the BTK inhibitor to initial therapy [kept] patients in remission for a longer period. Those are important findings, and experts [in the] community are debating exactly how to incorporate them into practice. [This is] made more complex by the recent withdrawal of ibrutinib from the market for MCL. That’s added a little bit of complexity to decision-making when we treat these patients.

As for combination studies [in the] relapsed/refractory [setting], there’s studies of BTK inhibitors with venetoclax [Venclexta], [as well as] some with CD20[-directed] antibodies. There’s a lot of novel combinations being looked at in the relapsed space. None of them have recently led to new approvals, but we’re seeing exciting, chemotherapy-free regimens being used. There’s quite a lot of exciting [things] going on in MCL.

Could you highlight some of the factors that influence the selection of current BTK inhibitor regimens in MCL?

It depends on where the patient is in their disease course. For those who are treatment-naive, [you’d ask]: Is this someone where the potential benefits of adding a drug into the treatment program may outweigh any added risks? [Are they] transplant-eligible? What chemotherapy and immunotherapy partner [would] you administer along with the BTK inhibitor? In the patients [who are] relapsed/refractory, you’re thinking about what treatment they received before, and weighing the pros and cons. What are the benefits? What are the risks? Is this the best treatment for the patient at that time? What are their comorbidities? Those are all factors that [contribute to] the decision when you’re picking a regimen for a patient with relapsed MCL.

What ongoing or upcoming trials in MCL are you interested to see conducted?

One of the trials I’m excited about looks at the recently approved pirtobrutinib [Jayprica] and compares that with conventional BTK inhibitors in MCL. That’s the ongoing [phase 3 BRUIN-MCL-321] trial [(NCT04662255) assessing] how the new non-covalent BTK inhibitor pirtobrutinib compares [with] covalent BTK inhibitors.

At the 2022 ASH Annual Meeting, we saw a presentation [of findings from a single-arm, phase 2 study (NCT03863184)] on acalabrutinib [Calquence] in combination with lenalidomide [Revlimid] and rituximab [Rituxan] as an exciting, novel chemotherapy-free regimen. We’re [also] seeing trials of venetoclax in combination with BTK inhibitors with or without CD20 antibodies that look promising.

One wonders whether, and how much, chemotherapy is going to be used in the future with these promising novel agents emerging. Right now, chemotherapy is part of standard practice, but we’ll see how the field moves. It is moving towards an increasing use of novel targeted therapies.

Regarding your second presentation, what major changes have occurred for the management of relapsed/refractory DLBCL?

One huge paradigm shift that occurred about a year ago was the demonstration that [some] CAR T-cell products are superior to conventional salvage chemotherapy and stem-cell transplant in patients whose DLBCL relapsed within a year of initial therapy. The other thing we’re seeing is an increasing utilization of novel targeted agents in the relapsed setting. Examples of that are polatuzumab vedotin-piiq [Polivy] along with chemotherapy, tafasitamab-cxix [Monjuvi] along with lenalidomide, and loncastuximab tesirine-lpyl [Zylonta].

[Overall], a number of novel therapies have demonstrated benefit [in this space]. Recently [we had] the approval of the bispecific antibody epcoritamab-bysp (Epkinly) for patients with relapsed DLBCL. [This approval signals the start of] a new era where we’re hopefully going to see a few [more] bispecific antibodies being approved for relapsed DLBCL. Moving forward [we’ll also see attempts to] incorporate those effective agents into earlier lines of therapy to hopefully cure more people with DLBCL.

The other huge paradigm shift in DLBCL in the frontline [setting] is a demonstration of benefit [with] polatuzumab vedotin in combination with [rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP)]. [This was] compared with [cyclophosphamide, doxorubicin, prednisone, rituximab, and vincristine (R-CHOP), which] has been the standard therapy for several decades. The paradigm shifts in DLBCL [occurred in the] frontline, early relapse, and salvage [settings], with novel agents becoming available and taking the place of chemoimmunotherapy in relatively heavily pretreated patients.

Despite these advances, what unanswered questions remain in DLBCL?

[One] unanswered question will be: how do we sequence all these novel agents? That’s what everyone has been asking recently. In the past couple of years since we’ve seen approvals of [tafasitamab plus lenalidomide], [polatuzumab vedotin, bendamustine and rituximab (Pola-BR)], loncastuximab, selinexor [Xpovio], and now bispecific antibodies, [but we still don’t know if] there is a best sequence [of treatment options].

Another [unanswered question] is how can we utilize these [approved agents] more effectively? There are very few patients with relapsed DLBCL who benefit from all these drugs, because they don’t live long enough to receive all of them if they relapse. We need to do a better job of getting patients [earlier] exposure to these drugs to cure more people earlier.

How can these agents be incorporated [into clinical practice]? Ongoing studies have been [attempting to answer] that question for a couple of years and will continue to do so. For example, there’s been [the phase 3 frontMIND] trial [NCT04824092] of R-CHOP with or without tafasitamab and lenalidomide as a frontline therapy for DLBCL. [This study asks whether] we can and should incorporate that novel combination into the frontline setting to try to cure more people. [There is also] the use of pola-R-CHP in the frontline [setting], [which] bested R-CHOP in terms of PFS and changed the paradigm for frontline therapy in DLBCL. [Other unanswered] questions [include whether] we can incorporate bispecific [antibodies] into earlier lines, [whether] CAR T-cell therapy should be utilized earlier for patients with high-risk DLBCL or those who [don’t respond] well to initial R-CHOP, and [if] we can use novel therapies for elderly patients who can’t tolerate conventional R-CHOP chemotherapy. [There are] ongoing studies of loncastuximab and other [agents] in that space [to address this question.]

The key question here is: can we use some of these agents earlier in the treatment algorithm? Can we move these [approved agents] earlier [in the treatment course] and expose more patients to them to [help them] derive [more] benefit and hopefully [lead to more] cures.

Shifting to the presentation given by Christopher Benton, of Rocky Mountain Cancer Centers, how has the management of myelofibrosis changed in recent years?

Myelofibrosis is an interesting and changing disease. The JAK-2 inhibitor ruxolitinib [Jakafi] is the key drug approved for that disease, but there are a lot of promising new agents emerging. Examples include pacritinib (Vonjo) for those with low platelet counts, and we hope to see an approval soon for momelotinib, which might help patients with anemia. We saw a number of agents demonstrating benefit for patients with myelofibrosis in clinical trials, including improvement in anemia. One was called pelabresib [CPI-0610], and selinexor [also] looks promising.

[Overall, there are] a lot of promising agents that could help practitioners and patients overcome some of the problems that we [have in myelofibrosis]. Right now, we don’t have a great drug to treat anemia in patients with myelofibrosis and it’s a common [toxicity]. In fact, ruxolitinib can make anemia worse in patients with myelofibrosis. It would be great to have options [that] add to the benefit of ruxolitinib [but also] help people with anemia. Dr Benton reviewed several [agents] on the horizon [that] may be able to help folks with myelofibrosis.

How does the approval of zanubrutinib in CLL illustrate the importance of next-generation BTK inhibitors in that setting per the presentation given by Luke Mountjoy, of Colorado Blood Cancer Institute?

Zanubrutinib [Brukinsa] demonstrated benefit compared with chemoimmunotherapy, specifically BR, in treatment-naive CLL. [It also] led to improvements in PFS, [higher] response rates, and a more favorable toxicity profile compared with ibrutinib in the [phase 3] ALPINE study [NCT03734016] in patients with relapsed CLL. The next-generation BTK inhibitors including acalabrutinib [Calquence] and zanubrutinib have demonstrated enough favorable comparative results compared with ibrutinib, and most of us have transitioned from recommending ibrutinib to new patients to using one of the newer second-generation BTK inhibitors in that space.

As to whether patients who are on ibrutinib and doing fine should switch, [that] is a tougher question. My practice is not to do that, and most doctors I know are doing the same. But clearly the new, second-generation BTKs are here to stay and have some real advantages over ibrutinib for patients. They are probably the preferred BTK inhibitors for most people with CLL.

Dr Mountjoy also briefly touched on the phase 3 TRANSFORM study (NCT0357535) of lisocabtagene maraleucel (liso-cel; Breyanzi) in B-cell lymphoma. What data have been seen with the use of liso-cel so far, and what unmet needs could be addressed by the continued investigation of liso-cel in this space?

It’s an interesting backstory. Some of the first patients treated with CAR T-cell therapy had CLL and case reports [from a pilot, phase 1 study (NCT01029366) that] were published in the New England Journal of Medicine more than a decade ago. Ten-year follow up [data for] those patients were published about a year ago and showed that 2 individuals have no evidence of CLL in their bodies 10 years later, with evidence of CAR T cells still circulating. The presumption is that those patients are cured. With these initial extremely promising results, there was a hope and expectation that [CAR T-cell therapy was] going to be a homerun, and [that we’d] get the trials done and get it approved [quickly]. More than a decade later, the trials are still rolling along and nothing’s approved. [CAR T-cell therapy] is not available commercially for use for CLL.

In the session Q&A, we talked informally about why that is and [discussed] some of the challenges faced when treating [patients with] CLL and delivering these therapies in CAR T-cell trials. Liso-cel is demonstrating great promise and good results in CLL. [There are] still relatively small numbers of patients [being] reported in the trials, but [it is] showing good enough results where there’s still optimism and hope that CAR T-cell therapy will become available and utilized in CLL.* Perhaps [it will not be used] for most patients but certainly [could be an option] for those whose disease is very aggressive, continues to relapse, and is threatening their lives. CAR T-cell therapies, like liso-cel, offer promise for these patients.

Would you like to highlight any trials in the field of hematologic malignancies that are being conducted at your institution?

It’s a complex field, and it’s tough to stay up on everything, but [these advances are] exciting.

One trial I would choose to highlight would be the pirtobrutinib vs other BTK inhibitor trial in MCL that I mentioned earlier. It’s not the most common disease or situation, but if I had relapsed MCL [that study] is one that I would choose to go on.

I also [want to] highlight some ongoing trials in other lymphomas. We have [the phase 2 LOTIS-9 trial (NCT05144009)] in DLBCL with loncastuximab plus rituximab [in] elderly [patients]. I find that one to be particularly exciting because elderly patients with DLBCL are not well served by current standards of care, if there is such a thing. We need better treatments for [this population].

Everyone is excited about bispecific antibodies, and we have some very exciting bispecific antibody trials of both mosunetuzumab [Lunsumio] and epcoritamab in various lymphomas in various stages. Some [involve] treatment-naive patients, and some [are enrolling those with] relapsed/refractory disease. [Ultimately, there are] a lot of fun [trials] going on.

*Editor’s Note: This interview took place prior to the read out of the phase 1/2 TRANSCEND CLL 004 trial at the 2023 ASCO Annual Meeting.