Evolving Treatments Seek to Address Unanswered Questions in Hematologic Malignancies

Gary J. Schiller, MD

Novel agents such as momelotinib and pacritinib (Vonjo) are expanding the myelofibrosis treatment landscape, and additional research will further define the options available for patients with this disease, as well as those with other leukemias and lymphomas, according to Gary J. Schiller, MD.

"A number of drugs have activity in myelofibrosis. There is still an unmet medical need. Patients are better served on clinical trials instead of with standard practice, for the most part," Schiller said. He spoke with OncLive^® after serving as chair for an Institutional Perspectives in Cancer webinar on leukemia and lymphoma.

In the interview, Schiller highlighted key insights from the meeting, such as novel myelofibrosis agents under investigation, the benefits of CAR T-cell therapy in diffuse large B-cell lymphoma (DLBCL), and the remaining unmet needs that future clinical trials should focus on. Schiller is a professor-in-residence of medicine at the David Geffen School of Medicine at University of California, Los Angeles (UCLA).

OncLive^®: Could you provide an overview of your presentation on updates in the treatment of myelofibrosis?

Schiller: I talked a bit about the diagnosis of myelofibrosis and current concepts about pathophysiology, the mechanisms of disease. I discussed staging and categorizing disease on the basis of both clinical and biologic factors. I also talked about current FDA-approved therapies, as well as some potential investigational avenues that are being studied right now in disease management.

Additionally, I discussed a bit about overlap disorders, which have characteristics of myelofibrosis but are also characterized by prominent dysplasia, and the absence of trials that address this emerging population. I discussed many myeloproliferative diseases, [including] the backgrounds of chronic myelomonocytic leukemia [CML] and mastocytosis.

What novel myelofibrosis therapies are on the horizon?

In distinction from therapy for chronic myeloid leukemia, the challenge in myelofibrosis is that many of the drugs are directed against the JAK-STAT pathway. Although the JAK mutation is common in myelofibrosis, it by no means constitutes all cases of myelofibrosis. We’re not even sure if the mutation is etiologic in the advantage that the clone has, which becomes dominant in hematopoiesis.

Several other mutations are commonly identified [in myelofibrosis], and these may or may not have an effect on that pathway. However, most of the drugs have been developed directly against that pathway, and most have some effect on JAK1 signaling as well.

JAK1 signaling is associated with inflammation and red blood cell [RBC] production. There may be some therapeutic benefits to addressing JAK1 as well as the mutated JAK2, but [targeting those can also] contribute significantly to the adverse effect [AE] profile. Many newer drugs still target the [JAK-STAT] pathway, such as momelotinib and pacritinib, so it’s not surprising that ruxolitinib [Jakafi], which is the parent drug; fedratinib [Inrebic], and maybe others as well, are all characterized by some anemia, thrombocytopenia, or neutropenia.

There are potential other mechanisms and other treatments. For example, imetelstat, which targets telomerase, already has a long history as an investigational agent in this setting. Parsaclisib is a PI3K inhibitor that has activity and is being studied alone and with ruxolitinib [Opzelura] in myelofibrosis management. Idasanutlin [RG-7388], which is directed against MDM2, is under study. Navitoclax [ABT-263], which acts on BCL2, is under study.

We also have a clinical trial with the lysine-specific histone deacetylase, bomedemstat [IMG-7289]. Additionally, pelabresib [CPI-0610] is a BET inhibitor that has had quite a bit of exposure to the scientific community with early clinical trials demonstrating efficacy. It’s been studied alone and in combination with ruxolitinib.

Finally, there’s allogeneic transplant. [Although not new or investigational, we’re] trying to define its role as definitive management continues.

How might remaining unmet needs in myelofibrosis be addressed?

There’s quite a bit of unmet need. Although we have therapies that can ameliorate some of the [AEs such as] inflammatory symptoms and fatigue that are associated with myelofibrosis and other myeloproliferative diseases, the approved therapies come at the cost of marrow toxicity and suppression of RBC and platelet production.

We need better drugs that are operative on the clonal disturbance without having a cost on normal hematopoiesis. We also need to define the role of allogeneic transplant or try to decrease treatment-related mortality, which has made allogeneic transplant so difficult to operationalize in myelofibrosis. [Additionally, we have a] big area of unmet need in patients who have overlapping myeloproliferative and myelodysplastic [diseases].

What main message from your presentation would you like to impart to colleagues?

We need to develop a better understanding [of this disease] and not view myelofibrosis as a stepchild of CML.

What important distinctions between BTK inhibitors did your colleague, Herbert A. Eradat, MD, of UCLA, discuss in his presentation on the evolving landscape of chronic lymphocytic leukemia?

Dr Eradat presented the different toxicity profiles of existing BTK inhibitors, and gave some insight into some potential mechanisms by which different drugs will have different off-target effects, or maybe on-target, off-disease effects. He also talked about alternative agents that are not involved in the BTK pathway.

What key therapies did John M. Timmerman, MD, also of UCLA, discuss in his presentation on BTK inhibitors in mantle cell lymphoma (MCL)?

Dr Timmerman discussed the evolving role of single agents and combination therapies involving BTK inhibitors in MCL, mostly in the relapsed setting, but with some suggestions of potential activity in upfront management as well.

Regarding the presentation Sven de Vos, MD, PhD, another UCLA colleague, gave on recent updates in the treatment of DLBCL, what role does CAR T-cell therapy play in this disease?

A key takeaway [from this presentation] was the role of engineered T-cell therapy in the management of early relapsed DLBCL. We know about the studies that were last presented at the [2021 ASH Annual Meeting and Exposition], and the subsequent FDA approval of cellular therapy for managing these patients at high risk of disease progression and death from lymphoma. [These patients are] grouped as individuals with early relapsed or refractory disease. Clearly, engineered T-cell therapy has supplanted the role of high-dose chemotherapy and autologous transplant in the management of DLBCL with early relapse.

What ongoing or upcoming research at UCLA are you excited about?

We have about 40 clinical trials in the hematologic malignancy area and many more in non-Hodgkin lymphoma. The trials that are being conducted to address the problem of relapsed and refractory acute leukemia, particularly acute myeloid leukemia, are important. The evolving role of immunotherapy in the management of hematologic malignancies is also a crucial area of research. Addressing some of the disease-related AEs in myeloproliferative diseases is also important.