New Approvals Heighten Expectations Throughout Hematologic Malignancies

Haris Ali, MD

The FDA approvals of pacritinib (Vonjo) in myelofibrosis, ruxolitinib (Jakafi) in chronic graft-vs-host-disease (GVHD), and ropeginterferon alfa-2b-njft (Besremi) in polycythemia vera provides a glimpse into the progress that is being made across hematologic malignancies, explained Haris Ali, MD, who added that ongoing research is continuing to evaluate areas of unmet need, including settings of treatment resistance, refractoriness, and intolerance.

“Going over these disease areas, including myelofibrosis, chronic lymphocytic leukemia [CLL], GVHD, and polycythemia vera, it’s clear that so much good work is being done looking at new exciting agents. Down the road, we will have some excellent treatment options for these patients that will prolong survival and improve quality of life,” Ali said in an interview with OncLive^® following an Institutional Perspectives in Cancer webinar that he chaired on hematologic malignancies.

In the interview, Ali, an associate professor in the Division of Leukemia and Department of Hematology and Hematopoietic Cell Transplantation at City of Hope, discussed updates in acute and chronic GVHD, current and emerging agents in myelofibrosis and polycythemia vera, and CLL management.

OncLive^®: In your presentation, which covered current and emerging agents in myelofibrosis, you highlighted the indications for JAK inhibitors. Could you elaborate on their current roles and what distinguishes them?

Ali: Three drugs are currently approved [in myelofibrosis]. The first one is ruxolitinib, which was approved more than 10 years ago for intermediate-2 and high-risk myelofibrosis, and it works by reducing spleen size and improving symptoms. Since then, 2 more drugs have been approved: fedratinib [Inrebic], which was approved in August 2019 for intermediate-2 and high-risk disease, both in patients who are JAK inhibitor naïve and patients who progressed on ruxolitinib [based on findings from the] JAKARTA [NCT01437787] and JAKARTA-2 [NCT01523171] trials. Most recently, pacritinib was approved for patients with low platelets. All the JAK inhibitors can cause thrombocytopenia, and pacritinib is unique in the sense that it does not cause worsening thrombocytopenia, so it’s especially useful in patients with low platelets, which is an area of unmet need.

Allogeneic transplant remains a curative treatment for these patients, especially patients with higher-risk disease, categorized as high risk, intermediate-2 risk, or very high risk according to the MIPSS70-plus criteria.

The rest of your presentation focused on clinical trials exploring other agents in this space. What was explored in the REFINE trial (NCT03222609) and what was notable about the findings?

Patients who are on ruxolitinib or any other JAK inhibitor may get an excellent response where they have excellent spleen volume reduction and improvement of symptoms. However, a significant number of patients may get only some benefit from the medication or may become unresponsive to the drug. These new trials are looking at this unmet need in patients who have not had a full response with a JAK inhibitor.

The REFINE trial is evaluating navitoclax, which is an oral inhibitor of BCL-xL and BCL-2, which are anti-apoptotic members of the BCL-2 family. These [proteins] are highly expressed in primary myelofibrosis and secondary myelofibrosis. They lead to prosurvival factors in these cells. The idea was to add navitoclax to treatment in patients who had a suboptimal response or progressive disease [on their current therapy] to improve responses.

The results showed that 27% of patients had spleen volume reduction at week 24 and about 30% of patients had improvement in symptoms, which was defined by a total symptom score reduction of more than 50%. The investigators also saw improvement in the fibrosis of the marrow, which was unique, and an improvement in transfusion [independence].

Moving to the ESSENTIAL study (NCT03627403), which evaluated selinexor (Xpovio), what was unique about the study?

This trial evaluated a slightly different approach. The study enrolled patients who were previously on JAK inhibitors; patients had to be refectory, resistant, or intolerant. In this study, patients received low-dose selinexor once a week at 60 mg to 80 mg until progression. This study was unique [because it took] patients who had progressed on JAK inhibitors. Another unique aspect of the study was that the medication was given once a week.

The results showed that selinexor causes spleen volume reduction, improvement in anemia, and improvement in symptoms. Patients were also able to continue treatment for up 2 years in some cases. These are the patients who otherwise have historically poor survival. The investigators also saw some indication of improvement in the marrow fibrosis, [indicating that the agent] is more disease modifying in this population.

Turning to the MANIFEST study (NCT02158858), what is this study evaluating? What has been seen with each study arm approach?

The MANIFEST study is a multi-arm study looking at several cohorts of patients, including patients who have untreated [disease] in which pelabresib was added to ruxolitinib. The end points are spleen volume reduction and improvement in symptoms. The investigators are also looking at the agent as an add on treatment in patients who are on ruxolitinib and getting benefit from it but maybe a suboptimal response. That’s where they add the medication to see whether they can improve the symptoms, [cause] spleen volume reduction, and decrease the transfusion requirement. In one of the arms in patients who are refractory, intolerant, or ineligible for JAK inhibitors, pelabresib is being used as a single agent, and the investigators are looking at the same end points.

The results showed that about 18% of patients in arm 1 had an improvement in spleen volume. About 31% of patients had about a 25% spleen volume reduction, and 28% of patients had more than a 50% improvement in symptoms. About 60% of patients who were transfusion dependent became transfusion independent and the median duration was about 41 weeks. Similarly, in patients who were transfusion dependent, there was an improvement in hemoglobin.

You also highlighted the PERSIST-2 study (NCT02055781), which evaluated pacritinib in patients with myelofibrosis and moderate to severe thrombocytopenia. What was the rationale of this study?

The rationale of the study was to use pacritinib in patients with low platelet counts. The original study looked at this agent in patients with a platelet count of less than 100,000/µL. The approved treatment at the time was ruxolitinib, which can cause thrombocytopenia. That’s a toxicity that limits the dose you can give to the patient. Patients who received pacritinib were able to tolerate the agent for longer and receive the [full] benefit of JAK inhibition in this study.

What important areas of research remain for patients with myelofibrosis?

Some of these trials are trying to address remaining unmet needs, including patients who become anemic and transfusion dependent, and eventually become thrombocytopenic and are not able to tolerate the common JAK inhibitor, although we have a new drug for that [with pacritinib].

Also, patients suffer disease progression. There are trials that are looking at ways of slowing the progression or looking at the effect of these new agents on progression-free survival. Some of the things that are being looked at are the changes in allogeneic stem cell transplant with new strategies to make stem cell transplant safer for patients, so it can be offered to more of the population, because that remains the only curative treatment.

How would you summarize the progress that has been made in myelofibrosis?

We’re in very exciting times. Just a few years ago, we only had 1 FDA-approved agent. Now we have 3 FDA-approved agents. We understand disease mechanisms and progression more now than before. We are in the process of targeting all these potential areas that lead to disease progression. We’re following the paradigm for CLL treatment, where there was very cytotoxic treatment and now there’s treatment without any cytotoxic agents and patients are living longer, with a much better quality of life, and improved survival rates. Down the road, we may have a couple of combination treatments, which could really make a dent on this disease.

Shifting to your colleague, Idoroenyi Amanam, MD, of City of Hope, who spoke about acute and chronic GVHD, how has the treatment landscape changed for patients with steroid-refractory disease?

It used to be that we didn’t have any good agents. Steroids were the mainstay of treatment along with some other agents, which were not really shown to be very efficacious in any of the phase 3 trials. In 2021, ruxolitinib was approved in chronic GVHD and a few years ago, it was approved in acute GVHD. For chronic GVHD, we have 3 approved drugs: ibrutinib [Imbruvica], ruxolitinib, and belumosudil [Rezurock]. These are good treatments that can help these patients. Some other treatments that are currently being looked at include anti-CSF3R antibodies, which look promising. Also, graph manipulation to prevent GVHD is under study. New treatments are also being looked at for prevention of GVHD. We’re hoping transplant can be safer without undue increased risk of acute and chronic GVHD.

Moving to the presentation, Salman Otoukesh, MD, of City of Hope, gave on polycythemia vera, what are the goals of treatment, and what are the preferred treatment options?

Current treatment options are meant to prevent thrombotic complications, so we use antiplatelet agent like aspirin and cytoreductive treatment like hydroxyurea. We also want to keep hematocrit under 45 for men and 42 for women to decrease some of the vascular complications and symptoms that may arise from their disease. We have been using pegylated interferon [alfa-2a (Pegasys)] for management of polycythemia vera, which has been beneficial. Ropeginterferon was also approved, which is even better in terms of adverse effect profile. That agent has been shown in some of the retrospective studies and the prospective study to control symptoms better [than other agents] and lead to improved survival.

Dr Otoukesh also spoke about some of the new agents that are under evaluation, including PTG-300, givinostat, and idasanutlin. How could those agents potentially affect the paradigm?

These agents are still early in development. We have to see down the road which patients will benefit more from these agents. Once we have more studies and results with these agents, we will be able to better define where exactly to use these agents.

Finally, Tanya Siddiqi, MD, of City of Hope, discussed the effect of BTK inhibitors in the management of CLL. How has this treatment class affected the paradigm?

[The approval of ibrutinib] was the big breakthrough point as far as the management of CLL is concerned. Prior to that, we were using cytotoxic agents and some immune therapies, like rituximab [Rituxan], which did improve survival, but they came with significant toxicity. Ibrutinib is an oral agent that showed that it really improves the survival of these patients, including high-risk patients with p53 mutations. This led to looking into other agents like venetoclax [Venclexta] and other forms of BTK inhibitors, such that we hardly use cytotoxic agents [anymore], and patients are living much longer.