Increasing Treatment Pathways Pave the Way for Heartening Future Throughout Hematologic Malignancies

One theme throughout hematologic malignancies is the abundance of therapies available to patients, whether that’s JAK inhibitors in myelofibrosis, cellular therapies in diffuse large B-cell lymphoma (DLBCL), or targeted agents in chronic lymphocytic leukemia (CLL), explained Stephen Oh, MD, PhD, who added that the availability of these agents allows for increased personalization.

“We are going to see use of all these agents to some extent, and it’s going to be an evolving situation in terms of for whom these specific agents would be the best choice. Whether we’re talking about myelofibrosis, CLL, DLBCL, or GVHD [graft-vs-host-disease], all these fields are evolving rapidly. It’s important to keep up on latest developments because things are always changing,” Oh said in an interview with OncLive^® following an Institutional Perspectives in Cancer webinar on hematologic malignancies.

In the interview, Oh, associate professor, Department of Medicine, Division of Hematology, Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, hematologist, Siteman Cancer Center, discussed current and emerging agents in myelofibrosis, advances in the treatment of patients with relapsed/refractory DLBCL, updates in acute and chronic GVHD, and CLL management.

OncLive^®: In your presentation on myelofibrosis, you focused on some of the newer-generation JAK inhibitors. How do these agents distinguish themselves from ruxolitinib (Jakafi) and fedratinib (Inrebic)?

Oh: Currently, we have 2 FDA-approved oral therapies for myelofibrosis: the JAK inhibitors ruxolitinib and fedratinib.* Those drugs are commonly used for the treatment of patients with myelofibrosis, and the benefits of those drugs largely relate to improvement in symptoms, a reduction in symptomatic splenomegaly, and things like that. We are anticipating that 2 additional JAK inhibitors are going to be approved and become commercially available soon and those are pacritinib [Vonjo] and momelotinib, each of which have distinct properties in addition to providing similar aspects of spleen and symptom response as the other JAK inhibitors.

Pacritinib seems to cause little thrombocytopenia, so it may have a niche in those patients with myelofibrosis who have very low platelet counts. Momelotinib is unique in terms of ameliorating anemia, which is distinct compared with the other JAK inhibitors and likely relates, at least in part, to the drug targeting not just JAK1/2 but also ACVR1, which is involved in the production of hepcidin. With that mechanism, the drug does provide anemia benefits and, for that reason, could be a particularly useful option for patients with myelofibrosis who have severe anemia.

Where might these newer agents play a role in treatment among current staples like ruxolitinib?

Currently, ruxolitinib is the most widely used oral therapy for patients with myelofibrosis. As we go forward, it is going to continue to be frequently used, particularly as initial treatment for patients who have significant symptoms and large spleens and symptoms related to that, etc. Over time [we will see] subgroups of patients for whom choosing a different agent, either initially or as a second-line or beyond agent makes [more] sense [than ruxolitinib]. For patients whose primary problem is anemia, perhaps momelotinib would be a good choice. For those patients with severe thrombocytopenia, pacritinib would be a good choice.

In terms of development therapeutics, which agents are the most exciting to you?

It really is, overall, quite an exciting time in terms of developmental therapeutics for patients with myelofibrosis. There is approximately 9 ongoing phase 3 studies with novel agents for patients with myelofibrosis. We anticipate that at least some of those agents will be approved soon. Some of the specific agents that I would highlight include pelabresib, which is a BET inhibitor from Constellation.

That drug appears to provide some degree of symptom and spleen benefits, but also some degree of anemia benefits. This drug is being studied alone and in combination with ruxolitinib, and if it were to become commercially available, the one question would be: Can we pair it with a different JAK inhibitor besides ruxolitinib? There are so many different scenarios for which that drug could be used, but it’s looking very promising. We’ll see whether the ongoing phase 3 study leads to approval soon.

Other agents to be excited about include navitoclax, which is a BCL-XL/BCL-2 inhibitor, which is also currently in phase 3 studies. That agent also could potentially be paired with ruxolitinib or another JAK inhibitor or be used as monotherapy. There has been some hint from early data that it might, again, provide some degree of spleen and symptom benefit, but perhaps other measures of disease efficacy and perhaps some degree of molecular response. Those are things that we’ll be continuing to look out for.

We also have other agents such as parsaclisib, which is a PI3 kinase inhibitor and imetelstat, which is now in phase 3 testing. The list goes on and on, and beyond that, of course, there are agents in early-phase studies, which are looking intriguing.

Broadly speaking, as the field moves forward, and as we are seeing some promising developments with some of these novel agents, we’re looking at the fundamental question of whether we can or should focus on measures of efficacy that are beyond or distinct from symptom and spleen benefits. This is where this notion of what constitutes disease-modifying therapy has come into play and become the subject of vigorous debate in the field. By whatever definition one might use as far as disease-modifying therapy, [we then have to determine] which agents seem to have the capacity, potentially, to provide that. Historically, most of the studies have utilized spleen reduction or symptom benefit as the primary end points. Now we’re considering whether we can look at things like overall survival or other measures that might reflect disease-modifying activity as end points in these studies.

Turning to the presentation that Iskra Pusic, MD, of Siteman Cancer Center, gave on updates in acute and chronic GVHD, what stood out to you about the progress that has been in this setting?

It’s clear from Dr Pusic’s presentation, that there has been tremendous progress in the development of new agents to treat patients with acute and chronic GVHD, and that pertains to agents that are commercially available, as well as those that are currently under investigation, which is exciting. It has also become clear from some of the research that has been conducted at Washington University how that has evolved from bench to bedside in terms of, for instance, the application of JAK inhibitors in that setting. It has been an exciting development to see progress along those lines.

Moving on to the presentation Neha Mehta-Shah, MD, MSCI, of Siteman Cancer Center, gave on advances in the management of relapsed/refractory DLBCL, what has become clear about the treatment paradigm?

Relapsed/refractory DLBCL is a situation, again, where there has been tremendous progress over the past several years to the point that there’s a plethora of potential options or pathways to consider for patients in this category. Treating physicians have a bit of a conundrum as to whether to pursue cellular therapies or transplant or other novel agents and in what sequence makes sense for individual patients. It’s nothing but a good thing that now there are so many different types of options and specific therapies.

Brad S. Kahl, MD, of Siteman Cancer Center, closed out the night by speaking about CLL management. What distinguishes the treatment paradigm from that of other hematologic malignancies?

What I took from Dr Kahl’s presentation is that in the CLL field, once again, I’m very heartened to see that there has been quite a bit of progress in terms of new agents in this field. For some patients, it is a now a realistic option that traditional chemotherapy perhaps could be avoided in the appropriate setting. It’s also become quite clear that with more experience with the different targeted agents, now second-generation and even third-generation agents, which are coming to the forefront, in terms of efficacy and adverse effect profile, [physicians know] which agents might be preferentially used.

*Editor’s Note: This interview took place prior to the February 28, 2022, FDA approval of pacritinib for the treatment of adult patients with intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 10⁹/L.