Regulatory Decisions and Research Boost Management Strategies for Hematologic Malignancies

Andrew Kuykendall, MD

Newly approved JAK inhibitors are paving the way for future developments in the treatment of patients with myelofibrosis, according to Andrew Kuykendall, MD, who added that methods such as combination therapies with ruxolitinib (Jakafi) may further broaden the armamentarium.

“The question is: How can we build upon the successes we’ve had and be able to get more meaningful responses for patients?” Kuykendall said in an interview with OncLive^® following a State of the Science Summit™ on leukemia and lymphoma, which he chaired.

In the interview, Kuykendall, an assistant member in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida, highlighted key points from the meeting, including the current role of JAK inhibitors such as momelotinib (Ojjaara) in myelofibrosis, the importance of chronic graft-vs-host disease (GVHD) awareness in patients with myeloid malignancies receiving transplant, and unmet needs for patients with chronic myelomonocytic leukemia (CMML) that may be addressed with further research.

OncLive: What cytoreductive treatment options exist for patients with polycythemia vera, and how do they compare with one another?

Kuykendall: For polycythemia vera [PV], frontline cytoreductive options include interferon [alpha] or hydroxyurea, largely. They’re different agents. One’s oral, one’s subcutaneous. One is short-acting, one’s long-acting. Both are relatively well tolerated, but their adverse effect profiles are quite different. We tend to use them in slightly different patient populations. We may favor using hydroxyurea in older patients and we may favor using interferon [alpha] in younger patients.

However, the rationale for using one over the other is often different, even though they’re both reasonable frontline options. Recently, there’s been a big push for using interferon [alpha] more frequently than we have in the past, and that comes from [the availability of] more tolerable formulations, as well as the potential for long-term disease modification with interferon [alpha] formulations. That is gaining more popularity and there’s a push to see whether we can do more than reduce thrombotic potential for patients.

How does momelotinib fit into the treatment sequence for patients with myelofibrosis?

For myelofibrosis, largely what we have are several different approved JAK inhibitors. JAK inhibitors have historically been good at improving spleen volume and disease-related symptoms. However, the initial JAK inhibitors that were approved, ruxolitinib and fedratinib [Inrebic], were able to accomplish that [but] tended to worsen anemia and thrombocytopenia, which can be a problem for a lot of patients with myelofibrosis.

Pacritinib [Vonjo] had gotten accelerated FDA approval in February 2022 for patients with severe, marked thrombocytopenia. That opened the door for some of the patients who wouldn’t have been appropriate for [previously approved] JAK inhibitors to at least receive and potentially get the benefit from JAK inhibition.

The addition of momelotinib into the treatment paradigm is more striking [and it was] approved with a broad indication for [patients with] myelofibrosis and anemia. Most patients are either anemic at [myelofibrosis] presentation or will become anemic soon after presentation. The potential to use momelotinib in this patient population will be interesting. [Many patients] are doing well on ruxolitinib, and ruxolitinib remains our mainstay treatment for [patients with] myelofibrosis. However, there may be an interest in using an agent like momelotinib that can help not just with splenomegaly disease-related symptoms, but can also potentially enhance or improve patients’ anemia.

What does the future look like for JAK inhibitors in myelofibrosis?

As we look forward for myelofibrosis, we need to move past this era of single-agent JAK inhibitors. We’ve done a good job of developing JAK inhibitors that help with disease-related symptoms and splenomegaly. Recently, we’ve done a better job of making sure most patients with myelofibrosis can receive the benefits of those agents by bringing [the agents] to the more thrombocytopenic and anemic patients. However, now we need to look further and think about how we get deeper and more durable responses for patients with myelofibrosis, and perhaps [this strategy] will include combination therapies or enhanced mutation-targeting approaches.

Regarding the presentation given by Gabriela S. Hobbs, MD, of Massachusetts General Hospital, how might the current treatment armamentarium for myelofibrosis with anemia evolve over time?

The focus of what we’ve been trying to accomplish lately is: How do we keep in mind that patients with myelofibrosis are inherently anemic? We still want to be able to treat them and get their disease under control. With the approvals of pacritinib and momelotinib, we’ve been able to open a lot of doors for that.

Momelotinib made its name based on its ability to improve transfusion requirements and anemia. Recently, we found that pacritinib may also have that potential with its ACVR1 inhibition. Going forward the question is: Can we build upon that? Can we bring deeper and more durable responses to patients with myelofibrosis while not sacrificing [higher levels of] anemia? Will that entail novel combinations with ruxolitinib that can mitigate that anemia? Or will it [entail] combining [ruxolitinib] with some of these more recently approved agents to never run into the problem of anemia in the first place?

What treatment options are available for patients with chronic GVHD, as discussed in the presentation by Aleksandr Lazaryan, MD, MPH, PhD, of Moffitt Cancer Center?

We often talk about the fact that we’re not sending enough patients to transplant. Transplant remains the only curative option for most patients who have myeloid malignancies, but when you’re counseling patients on transplant, you have to keep in mind that transplant is also not a perfect treatment.

Oftentimes, patients have to deal with the repercussions of transplant, first and foremost, chronic GVHD. In the past, that often seemed to include steroids, tapering, re-upping steroids, and being able to play around with some of these rejection medication regimens. However, now, a better understanding of the pathways involved in chronic GVHD has allowed for more biologically rational driven therapies to be brought to the table. It’s enlightening to read about those pathways and how they are transforming care for these patients to potentially allow patients to go into transplant with a better understanding that if they run into issues [such as GVHD], there are different options to get [those issues] under control.

Regarding the presentation by Rami Komrokji, MD, of Moffitt Cancer Center, on the management of low-risk myelodysplastic syndrome (MDS), what developments in this area have the potential to shift practice?

When we’re thinking about [treatment] developments in myeloid malignancies, we often talk about [those in] acute myeloid leukemia [AML] or high-risk MDS. [But], with some of the new regimens that are coming down the line, some of the greatest successes recently have been in low-risk MDS. For a long time, we were treating this patient population with active surveillance and perhaps erythropoiesis stimulating agents. However, with the approval and expanded indication of luspatercept-aamt [Reblozyl], as well as the positive phase 3 [IMerge study (NCT02598661) with imetelstat], it looks like we’re going to have multiple different options for patients with MDS to be able to restore effective hematopoiesis and [allow patients to] live better, longer lives that might be freer from interactions with the health care system.

David Sallman, MD, of Moffitt Cancer Center, presented on immunotherapy in myeloid neoplasms. What does the future look like for immunotherapy in this population?

[Immunotherapy] is a work in progress and we’ve all been excited about the integration of immunotherapy into oncology. It’s moving into the hematologic malignancy realm with CAR T-cell therapy and bispecific antibodies. Our partners [who treat] the lymphoid populations and the myeloma populations have [effective] agents.

In the myeloid population, it has been a lot more difficult to bring in immunotherapy options. We’ve had some exciting trials that have been ongoing. Unfortunately, none of those trials have succeeded across the finish line at this point. However, we’re getting a lot closer to figuring out how to rationally bring some of these immunotherapy options to patients [with myeloid malignancies].

What does the current and future management of CMML look like, as presented by Eric Padron, MD, of Moffitt Cancer Center?

[CMML] often gets lost in the shuffle. We often talk about MDS, AML, and myeloproliferative neoplasms [MPNs], and we forget that there’s an overlap between MDS and MPNs. The most common of those [overlap diseases] is CMML. In many ways, [CMML is] probably more apt for clinical investigation [than other diseases], given the fact that it has an exceedingly poor prognosis and no clear treatment options. It’s a huge unmet need, but also low-hanging fruit if we’re looking to investigate agents in a short period of time.

Dr Padron presented the [CMML] treatment landscape and the different thoughts we have going into [treating this disease]. The potential development of JAK inhibitors in this [population] could certainly transform care for a lot of proliferative patients. We’re also trying to understand the optimal treatment approach for patients who have more myelodysplastic forms of the disease. Dr Padron and his colleagues have done great work in the laboratory to bring new agents and novel pathways into our focus, and certainly we hope we can make some strides over the coming years.

What ongoing hematologic oncology research at Moffitt would you like to highlight?

We have a robust clinical trial portfolio at Moffitt. We’re investigating all the areas [we discussed]. We have specific expertise in MDS, CMML with Dr Padron’s lab, myelofibrosis, and MPNs. We have an ongoing phase 3 trial [NCT05210790] investigating rusfertide [PTG-300], which is a hepcidin mimetic that has shown a great ability in the phase 2 setting to eliminate the need for phlebotomies for patients with PV. [We are evaluating rusfertide in the] phase 3 setting understand how beneficial it can be for patients.

On the myelofibrosis side, we’re activating a couple studies here. [One phase 2 trial (NCT05467800) is investigating] an IL-1β inhibitor called canakinumab [Ilaris]. This research is part of the MPN Research Consortium study. IL-1βhas been shown to be important in the disease process pathogenesis and disease progression of myelofibrosis, so [canakinumab is an agent] we’re hoping we can bring to patients to potentially change the underlying biology [of their disease].

We also have a frontline study investigating the combination of a telomerase inhibitor, imetelstat, in combination with ruxolitinib [in patients with myelofibrosis]. We have to mix 2 different things: the impressive improvement in spleen and symptoms that we get with JAK inhibitors, and [imetelstat, an agent] that has more potential to modify the underlying disease. A lot of things are coming down the pipeline across myeloid malignancies, and [we are] always looking to have a trial for all patients who come in.

What is your main message for colleagues?

We have emerging therapies. We’ve been lucky enough to get several drugs approved, both in myelofibrosis as well as in MDS, over the past few years. However, these are baby steps. [These agents] are allowing more patients to achieve the benefits of JAK inhibitors [and] they are improving some anemia responses in patients with low-risk MDS, but we’ve yet to move the needle in terms of disease modification. That’s where we’re going to need to continue to think about clinical trials first and foremost. Even in the frontline setting, we need to think about what we can do to push [these agents forward] and get true histomorphologic remissions in patients. Unfortunately, we don’t see that with our current agents.