Gerds Takes a Closer Look at Treatment Sequencing in Hematologic Malignancies

Disease risk, disease burden, and duration of treatment, as well as the reason for progression and generation of the drug are being used to tailor treatment sequencing strategies in hematologic malignancies where treatments are abundant, explained Aaron T. Gerds, MD, MS.

He who added that even the field of myelofibrosis, which currently has only 2 approved agents available for use, may experience an influx of options in the next few years as drugs like pacritinib, momelotinib, pelabresib, and navitoclax move through development.

“The meeting covered a broad area of diseases, ranging from CML [chronic myeloid leukemia] to the lymphoid disorders like CLL [chronic lymphocytic leukemia], and we were able to cover a lot of different topics,” Gerds, an assistant professor in medicine (hematology and medical oncology), and physician in the Department of Hematology and Medical Oncology at Taussig Cancer Institute, Cleveland Clinic, said in an interview with OncLive^® following an Institutional Perspectives in Cancer webinar on hematologic malignancies. “One of the major themes was: How do we sequence all these new treatments that we have or are about to have in the clinic?”

In the interview, Gerds, who is also assistant professor in the Department of Medicine, School of Medicine, member, Developmental Therapeutics Program, Case Comprehensive Cancer Center, Case Western Reserve University, discussed key discussion topics from the meeting, spanning the use of TKIs, targeted agents, JAK inhibitors, and cellular therapy.

OncLive^®: What are some of the key themes that came out of the meeting?

Gerds: One of the key themes that emerged throughout the discussion was that there are a lot of new treatments coming down the pipeline and those that are already in the clinic for these diseases. It’s not so much an embarrassment of riches. Really, the question is: How do we best sequence these therapies for all these disorders?

For CML, there is a new TKI that’s approved in addition to all the other TKIs that are out there. We have come a long way from just imatinib [Gleevec], but: How do we best sequence these agents? In particular, Dr Suite pulled out how we can sequence first-, second-, and third-generation TKIs and how they may overlap in functionality and when you may want to consider moving on from dasatinib [Sprycel] to asciminib [Scemblix] or some of these newer drugs that are coming along.

For lymphoid malignancies, we have CAR T cells. CAR T cells are such a departure from a lot of the other inhibitors that we have and traditional chemotherapies for the lymphoid diseases. [We discussed] how we are going to weave CAR T cells into the treatment of patients with lymphomas, CLL, and ALL [acute lymphoblastic leukemia]. Dr RyanCassaday brought up a couple of points in ALL on how to sequence inotuzumab ozogamicin [Besponsa] and blinatumomab [Blincyto], two treatments that are now used readily for relapsed or refractory ALL.

Starting with the presentation Kendra Sweet, MD, of Moffitt Cancer Center, gave on CML, how should practitioners be navigating among available TKIs? Is there any rationale for choosing one vs the other in terms of treatment sequencing?

During the discussion section, I asked Dr Suite how she thinks about sequencing the TKIs in CML and she brought up that for higher-risk disease, we certainly want to think about starting at least with second-generation TKIs. In lower-risk disease, there’s a debate whether imatinib versus a second-generation TKI is the right thing to do. In the face of persistent or recurrent disease: How do we switch agents? She also brought up that if [the patient is dealing with] intolerance, certainly staying within the class makes sense.

If the patient has intolerance on a second-generation TKI, it makes sense to go with a different second-generation TKI instead of moving to more advanced treatments for CML. Treatment selection is often based on the adverse effect [AE] profile. For someone who has a significant cardiac history, you may want to avoid nilotinib [Tasigna], and for someone who has a pulmonary history, you may want to avoid dasatinib, so you don’t incur compounding AEs.

Shifting to the presentation Brian Hill, MD, PhD, of Cleveland Clinic, gave on CLL, as more time-limited treatments are approved, what research directions will be important to pursue?

The exciting thing about CLL is over the course of my not-so-long career, we’ve moved from chemotherapy being the cornerstone of CLL treatment to these non–chemotherapy targeted agents as really being the place we start and finish with treatment, which is both amazing and exciting. One of the things that is interesting about CLL treatment with these targeted agents is the indefinite nature of some of them. In the earlier studies you would go on whatever BTK inhibitor, and you would be on it forever and there would be no place to stop it or interrupt it.

Thinking about a discrete course of chemotherapy, and the value there, [there may be more] benefit and the cost of doing that therapy may be more valuable than some of these oral agents that you go on and are on for years and years and years, because they are expensive. The [oral agents] lead to remissions, but they’re more expensive [than chemotherapy]. [Cost] does change the balance of the value equation. Introducing the idea of limited time for treatment on some of these things, or if you start on 2 agents and maybe drop off one of them over time and stay on one for maintenance is an important concept that’s been developed in CLL. That way we can increase the value of these new treatments.

Moving to the presentation Gabriela Hobbs, MD, of Massachusetts General Hospital, gave on current standards and new therapy options in myelofibrosis, what agents are we seeing move into the paradigm?

Dr Hobbs did a great job presenting the current standards as well as things that are on the horizon for myelofibrosis. Unlike CML, CLL, and ALL, myelofibrosis doesn’t have a lot of approved agents at the go right now. In fact, we have 2: ruxolitinib [Jakafi] and fedratinib [Inrebic]. These next couple of years for myelofibrosis are going to be incredibly exciting. We have 2 JAK inhibitors that could potentially be approved within the next year: pacritinib and momelotinib. There was a recent press release for momelotinib showing that it did reach its primary end point in the MOMENTUM study [NCT04173494], so it’s exciting times for myelofibrosis.

There are several other agents that are moving along quickly. One of the drugs that we know is coming along quickly is pelabresib, which is a BET inhibitor being used in the frontline setting in combination with ruxolitinib and other drugs like navitoclax that are targeting pathways that are independent of JAK-STAT, which is a new and exciting way outside the traditional place we go after to augment responses and attack this disease. Given the number of big, randomized phase 3 trials going on today, certainly at hematologic congresses in the next year or two, it’s going to get exciting when these studies read out and we can get into the weeds of all these new treatments and then hopefully, someday, have the problem that CML and CLL has with all their drugs and how to sequence them.

Do you foresee some of these current standards retaining a role if some of these newer agents also demonstrate utility?

We have seen ruxolitinib maintain a very important role in the treatment of myelofibrosis. We have a wealth of experience, and it performs well day to day. There are certainly some areas where momelotinib and ruxolitinib perform equally well, in which case it would probably be more valuable to use ruxolitinib over momelotinib. An abstract presented at the 2021 ASH Annual Meeting and Exposition looked at biomarkers or predictors of anemia responses in patients treated with momelotinib versus ruxolitinib from the SIMPLIFY-1 [NCT01969838] and SIMPLIFY-2 [NCT02101268] trials. It seemed like patients who had relatively preserved hemoglobin and lower ferritin did just as well on ruxolitinib as they did on momelotinib. Hopefully we’ll develop biomarkers soon that we can use in the clinic to identify which JAK inhibitor a patient might be best suited for from this multitude of options we will hopefully have soon.

In the presentation Ryan Cassaday, MD, of the University of Washington, gave on ALL, he spotlighted the use of blinatumomab and inotuzumab ozogamicin. In which clinical scenarios are these agents best used? 

Dr Cassady got [audience members] up to speed with what the standard treatments and approaches are for up-front and relapsed/refractory AML. Really there are 2 major players in the relapsed/refractory area in addition to the traditional chemotherapies that are available, and that’s blinatumomab and inotuzumab ozogamicin, which are 2 very different drugs. Blinatumomab basically reinvigorates the immune system to kill the ALL cells being a bispecific antibody, where inotuzumab ozogamicin is like a smart bomb. It’s got a targeting half, which targets the ALL cells, and the other half of the drug is a toxin that has taken inside the ALL cell to kill it.

It makes sense that these drugs perform well in different settings. Dr Cassady made the point that blinatumomab has really got a home for patients who have very low levels of disease. Minimal residual disease is such that when we look on our microscope, we don’t see any overt disease, but when we use advanced techniques like flow cytometry or molecular studies, we can still detect the disease that’s present in the patient. That’s really where blinatumomab seems to shine. It certainly can work when there’s bulkier disease, or even more detectable or overt disease, but it seems to do well when there’s smaller amounts disease. There also seems to be a better AE profile, as well as very good efficacy [with blinatumomab]. It can convert a lot of these patients who do have detectable disease at a very low level into having undetectable disease, which is a much better place to be.

Inotuzumab ozogamicin seems to be better when there is overt disease. If your patient has relapsed, and they have a significant amount of ALL detectable in their bloodstream, or in their bone marrow, inotuzumab ozogamicin seems to be a better fit there and can quickly cytoreduce a patient. The idea that with any of these agents, that once patients do relapse, we can then take them to allogeneic transplant to, hopefully, cure the disease for good.