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Clinical

During a Targeted Oncology™ Case-Based Roundtable™ event, Naveen Pemmaraju, MD, discussed the development of Janus kinase inhibitors and how newer therapies meet needs of patients with cytopenic myelofibrosis. 

Evolving Roles of JAK Inhibitors in Cytopenic Myelofibrosis

The FDA has granted fast track designation to MWTX-003 for the treatment of patients with polycythemia vera.

FDA Fast Tracks MWTX-003 for Polycythemia Vera Treatment

In an interview with Targeted Oncology, Aaron T. Gerds, MD, MS, delves further into the background of momelotinib, how to manage toxicities with the agent, and its role in clinical practice moving forward.

Behind the FDA Approval: Momelotinib for Myelofibrosis and Anemia

Momelotinib has emerged as a new FDA-approved treatment option for patients with myelofibrosis and anemia.

FDA Approves Momelotinib for the Treatment of Myelofibrosis and Anemia

According to Ruben A. Mesa, MD, FACP, confirming the benefit of long-acting interferon for essential thrombocytopenia is key.

Ropeginterferon Alfa-2b-Njft Challenges Standard Chemotherapy in Patients With ET

Aaron T. Gerds, MD, MS, assistant professor in medicine (Hematology and Medical Oncology) at the Cleveland Clinic, provides advice to community oncologists on how to utilize momelotinib (Ojjaara) for patients with myelofibrosis.

 for the treatment of adult patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia. The approval was supported by results of the international, randomized, double-blind, active-controlled, phase 3 MOMENTUM trial (NCT04173494), in which all of the primary and secondary end points of the study were met. Data from a subpopulation of adult patients with anemia who were assessed in the double-blind, active-controlled, phase 3 SIMPLIFY-1 trial (NCT01969838) further support the approval.

With this approval, momelotinib provides potential to establish a new standard-of-care for patients with myelofibrosis who have anemia. Still, Gerds encourages community oncologists to partner with specialists to provide the best outcomes when managing patients with myelofibrosis with momelotinib.

 In the MOMENTUM study, as well as in the SIMPLIFY studies, momelotinib is a highly effective and highly active agent in treating spleen volumes and symptom burdens, as well as a potential anemia benefit. Certainly, this drug is very valuable in the space and toxicities were not excessive and were on par with what we expect normally with the JAK inhibitor. I would have little reservation using it in everyday practice, but of course, myelofibrosis is a very uncommon disease. I would encourage any practicing hematologist or oncologist to [partner with a] specialist in order to help manage their patients.

 Again, I can’t imagine anyone keeping up on everything all the time, and it is just so hard. There’s a lot of nuance in the care of patients with myelofibrosis and for myeloproliferative neoplasms, and certainly partnering with someone who spends a vast majority of their time dealing with these things could be a benefit.

Videos

Aaron T. Gerds, MD, MS, provides advice to community oncologists on how to utilize momelotinib for patients with myelofibrosis.


News

Gerds Provides Advice on Newly-Approved Momelotinib for Myelofibrosis 

Raajit K. Rampal, MD, PhD, hematologic oncologist at Memorial Sloan Kettering Cancer Center, discusses the evolution of the treatment landscape for patients with myelofibrosis, and notes what he is excited to see more of in the future.

According to Rampal, some of the most practice changing data in the myeloproliferative neoplasm space has led to the FDA approvals of JAK inhibitors. In addition to the JAK inhibitor ruxolitinib (Jakafi), the FDA also has approved fedratinib (Inrebic), and most recently pacritinib (Vonjo), for the treatment of patients with myelofibrosis and severe thrombocytopenia.

In addition to these approvals, a number of trials are ongoing and working to develop new agents that have the potential to completely change the way patients with myelofibrosis are treated. Rampal expects these data to be read out within the next few years.

 It has changed remarkably, and is changing more now, in the last couple of years, than it has in the last 10 years. In the span of the last few years, we've had fedratinib approved, and pacritinib approved, so that has been a dramatic change.

 Right now, there are a number of agents that are in phase 3 trials, which you know, all earlier phases of study have looked really good. Those agents, if they are successful in their phase 3 trials, are going to completely change the landscape of how we treat this disease. I think that change will come within the next 2 to 3 years.

 The number of new drugs that are entering trials and new ideas that are entering into trials is amazing. This is just an exciting time in this field. We've got to see what the data shows us and if any of these things do pan out, but I think that in the next 2-3 years we could see a completely different paradigm and how we choose to treat these patients.

Raajit K. Rampal, MD, PhD, discusses the evolution of treatments for patients with myelofibrosis, and notes what he is excited to see more of in the future.


Rampal on Developments Shaping the Myelofibrosis Treatment Landscape 

Lucia Masarova, MD, PhD, assistant professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses some of the therapeutic options available for patients with polycythemia vera (PV) who are refractory to hydroxyurea.


Masarova first highlights the phase 3 RESPONSE (NCT01243944) and phase 3b RESPONSE-2 (NCT02038036) trials which each evaluated ruxolitinib (Jakafi) in this patient population. In these studies, ruxolitinib demonstrated superiority vs best available therapy (BAT). In the RESPONSE-2 trial, this was in terms of hematocrit control, normalizing blood cell counts, and improving PV symptoms at week 28. Findings from both the RESPONSE and RESPONSE-2 trials provide long-term, clinical trial data supporting the use of ruxolitinib in patients with PV.


Then, she discusses results from the MAJIC-PV (ISRCTN61925716) study which compared ruxolitinib to BAT among patients with PV. In this trial, patients with PV who are intolerant or resistant to hydroxycarbamide chemotherapy had 

superior responses when treated with ruxolitinib

 For patients with PV refractory to [hydroxyurea], we have approved ruxolitinib, which is the JAK inhibitor that has solid data in the field after [being refractory to] hydroxyurea, based on results from the RESPONSE and RESPONSE-2 trials. It will be 10 years since we had refractory patients treated with ruxolitinib. It is an excellent drug for controlling the symptoms and spleen count.

Last year, we had a very exciting study called MAGIC-PV, which was reported by our European colleagues that showed the advantage of ruxolitinib for decreasing the rate of thrombosis hemorrhage. It also improved event-free survival, death, and adverse events in terms of progression to myelofibrosis. So, it was exciting. If we consider disease modification as what is going to prevent the disease from going into myelofibrosis, I think that it will be exciting to see how far we can get in that field.

Lucia Masarova, MD, PhD, discusses therapeutic options for patients with polycythemia vera who are refractory to hydroxyurea.


Masarova Discusses Ruxolitinib for Polycythemia Vera After Hydroxyurea

Joseph M. Scandura, MD, PhD, Weill Cornell Medicine, discusses next steps for research of pelabresib (CPI-0610) for use in patients with myeloproliferative neoplasms.

Pelabresib is an oral, small molecule inhibitor of BET, which has the potential to downregulate the expression of genes that reside within the pathogenic pathways that underlie MPN progression.

One study evaluating pelabresib is the phase 3 MANIFEST-2 trial (NCT04603495). In this multicenter, double-blind, placebo-controlled trial, investigators are examining the safety and efficacy of pelabresib plus ruxolitinib (Jakafi) vs ruxolitinib alone in patients with JAK inhibitor-naïve myelofibrosis.

Patients aged 18 years and older with primary, post-polycythemia vera, or post-essential thrombocytopenia myelofibrosis, who had advanced disease requiring therapy, splenomegaly by computed tomography or magnetic resonance imaging, and were symptomatic were eligible for enrollment. Patients must also have had a prognostic risk-factor score of intermediate-1 or higher per the Dynamic International Prognostic Scoring System.

In the study, patients were randomly assigned in a 1:1 ratio to receive ruxolitinib in addition to oral pelabresib or matched placebo daily for 14 days, which was followed by 7 days off treatment. The starting dose of pelabresib was 125 mg daily. Then, ruxolitinib was given to patients twice a day in doses of 10 mg or 15 mg. Dose increases for both were allowed per protocol criteria.

The first one is that we need to wait for the data to mature. My personal bias is, all of these biomarkers are invaluable until we know outcomes such as survival or time to treatment failure or event-free survival. Until we know that, we are just kind of stuck in this circular loop of what should be, what we hope will be, what our intuitive beliefs are, but we do not really know what any of these things mean until we have those outcomes. That just takes time.

The nice thing is there are a number of phase 3 studies, randomized trials, collaborative studies. MANIFEST-2 is a randomized phase 3 study, and that will allow us to address and follow up on some of these findings, and hopefully get to those answers about whether or not these changes that we're observing in the short-term are predicting these long-term beneficial outcomes. It just takes time for that data to mature

Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2) (MANIFEST-2). ClinicalTrials.gov. Updated April 6, 2023. Accessed July 6, 2023. 

https://clinicaltrials.gov/ct2/show/NCT04603495

Joseph M. Scandura, MD, PhD, discusses research regarding pelabresib for patients with myeloproliferative neoplasms. 


Examining Pelabresib for Patients With Myelofibrosis

Lucia Masarova, MD, an assistant professor in the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discusses available treatment options for patients with essential thrombocythemia (ET).

Here, Masarova highlights interferons for patients with myeloproliferative neoplasms, such as ET or polycythemia vera (PV), as well as previous and ongoing research regarding peginterferon alfa-2a (Pegasys) and ropeginterferon alfa-2b (Besremi) in this space.

ET is considered a benign disease, so people live with it for a very long time. The current treatment is for only those [with] high-risk disease, so patients that had thrombosis in the past, and then patients that are over the age of 60 years and have a 

 mutation. That is according to the revised IPSET score. Those patients are treated to decrease the risk of thrombosis, not to do anything else or disease modify, just to simply disease the thrombosis risk. So that's hydroxyurea. It's a standard frontline agent, which is an easy to take oral drug. However, it could lead to some resistance in about 30% of patients.

 Because ET also affects younger people, plenty of younger females, they don't want to take chemotherapy forever, which I don't blame him for. They are interested in taking something else. So then interferon, the standard interferon recombinant or the pegylated form, which is called [peginterferon alfa-2a]. We recently used [peginterferon alfa-2a] for a couple of years, and it has been around the MPNs, particularly in ET and PV, I will say for about 40 years almost. So a lot of data, a lot of implications about how this may be a disease modifying agent, which is an agent that actually could decrease the allele burden, could eradicate the malignant clone, and ultimately change the disease behavior.

 We were really excited that we had a novel interferon called ropeginterferon interferon approved in patients with PV back in 2021. That has been preceded by approval in the European Union before, in 2019. That's an excellent option in terms of interferon, subcutaneous items. Patients will have to inject themselves and the pegylated is once a week. The standard recombinant is more than weekly, so the novel alternative way, the ropeginterferon which is the novel monoregulated form, is kind of more convenient because it's used every other week. Once we reach complete hematologic control, it's used once a month. So that's a significant improvement in convenience for patients and tolerability, as well as compliance issues. We were excited to get it in PV. We have it in some studies in PV to expand the access and maybe try some different schedules, and will also move it to patients [with ET]. That's something that we're going to be looking at

Lucia Masarova, MD, discusses available treatment options for patients with essential thrombocythemia.


Management and Treatment of Essential Thrombocythemia

Aaron T. Gerds, MD, MS, assistant professor in Medicine (Hematology and Medical Oncology) at the Cleveland Clinic, discusses the 48-week results of the MOMENTUM trial (NCT04173494) of momelotinib, a JAK1/JAK2 inhibitor that is being investigated specifically for the treatment of anemic patients with myelofibrosis.

The phase 3 trial randomly assigned patients with myelofibrosis who had received a prior JAK inhibitor and were anemic to receive momelotinib or danazol. Momelotinib is a JAK inhibitor that also inhibits ACVR1, potentially improving anemia, according to Gerds. The primary end points were outcomes at 24 weeks, at which point momelotinib was previously shown to improve anemia in addition to reducing spleen size and symptoms.

Gerds says that after 24 weeks was an open-label period where patients could cross over to receive momelotinib. In the momelotinib arm, 93 out of 130 patients continued in the open-label period, and 41 out of 65 who initially received danazol crossed over. Investigators saw no new safety signals in this period, which is important according to Gerds since patients will likely be on momelotinib for a longer period of time if this agent is used commercially. Additionally, the longer follow-up showed the response to momelotinib to be durable; only a small number of patients in the momelotinib arm lost symptom response or transfusion independence, and none had an increase in spleen size from baseline.

 MOMENTUM is a phase 3 randomized trial pitting momelotinib versus danazol in patients with myelofibrosis. This study selected patients who had previous JAK inhibitor exposure, were anemic and also significantly symptomatic, and had enlarged spleens. It was looking to see if momelotinib was a better option for these patients. Danazol was chosen as a comparator because it is an active agent in remedying anemia in these folks. Momelotinib is a special JAK inhibitor that not only can shrink spleens and improve symptom burden, but it can also have a potential effect on anemia through inhibition of ACVR1. The week 24 primary end points were already reported at a prior Congress, and this was the updated results for week 48. At week 24, patients were allowed to cross over to open-label momelotinib, even if they were on the momelotinib arm or the danazol arm. So [it was] basically an open-label extension at this point, but we get to continue data.

I think the first key take home point from the data we presented was that there were no new toxicity or safety signal seen. The data was very consistent with what we saw in the original 24-week analyses. This is of course incredibly important when you think about the fact that these folks might be on this medication for a long time. Moreover, the responses were quite durable; patients who responded at week 24 continue to respond through week 48, whether we're talking about transfusion independence, spleen volume response or symptom burden and improvement.

Aaron T. Gerds, MD, MS, discusses the 48-week results of the MOMENTUM trial of momelotinib, a JAK1/JAK2 inhibitor that is being investigated specifically for the treatment of anemic patients with myelofibrosis.

Momelotinib Shows Durability and Safety in Myelofibrosis at 48 Weeks

Andrew Kuykendall, MD, an assistant member at the H. Lee Moffitt Cancer Center of University of South Florida in Tampa, FL, discusses some of the most recent approvals seen in the myeloproliferative neoplasm (MPN) space.

Ruxolitinib (Jakafi) was the first JAK1/2 inhibitor to receive FDA approval for the treatment of MPNs. Others, including fedratinib (Inrebic) and pacritinib (Vonjo), have since gained FDA approval, and are showing benefit for this patient population.

With ropeginterferon, for a long time, we've been using interferon formulations within polycythemia vera and essential thrombocythemia, maybe to a lesser extent within myelofibrosis. This is going back to the 90s. We know that it's effective, it can help control counts, and we have seen in small numbers of patients that it may be able to decrease the JAK2 allele burden and potentially could correlate with delayed disease progression and potential disease modification. That's something that has been exciting to patients.

Historically, interferon has been challenged by toxicity, especially the short acting forms. As we got pegylated interferon, we had longer acting, better tolerated, and lower doses, and patients stayed on for a longer period of time, did better, could appreciate some of those durable responses that you get when you're on long term therapy. With ropeginterferon, we've now got an approved agent as opposed to using something off-label. It's given less frequently, so every 2 weeks, and we have seen good long-term data with more robust datasets that have shown the ability to decrease allele fractions and 

 mutations. What that's brought to the table is something not completely new, because we've been using interferons, but something that has stronger data to support it. It's something that we can use as an approved on-label medication for many patients. I think it's gotten patients very excited about potentially having something that can alter the natural history of disease.

Pacritinib on the other hand is something that was approved for an unmet need. It's an accelerated approval for patients with thrombocytopenia with less than 50,000 platelets, and for those patients, we don't have many great options. We have ruxolitinib and fedratinib that are approved, but typically, they've been given in patients with over 50,000 platelets. We have struggled to treat these patients with lower platelet counts. Pacritinib has great data in the PERSIST-1 trial and PERSIST-2 trials [NCT01773187; NCT02055781], and in the ongoing PACIFICA study [NCT03165734]. It shows that it can be safely leveraged in these patients with lower platelet counts. We were happy to get the accelerated approval because now, we have an option for those patients, and we're not having to do things off-label or give modified doses. Now, we have something we can fully dose and bring an effective treatment for these patients that have an unmet need.

Andrew Kuykendall, MD, discusses recent approvals seen for patients with myeloproliferative neoplasms.


Discussing the Ever-Changing MPN Treatment Landscape 

Andrew Kuykendall, MD, an assistant member at the H. Lee Moffitt Cancer Center of University of South Florida in Tampa, FL, discusses some of the recent changes there have been for patients with myeloproliferative neoplasms (MPNs).

 over the past few years with a number of clinical developments. Some of these novel treatments include ruxolitinib (Jakafi), fedratinib (Inrebic), and pacritinib (Vonjo).

In August 2019, the FDA approved fedratinib for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis, including post-polycythemia vera or post-essential thrombocythemia myelofibrosis based on data from multiple studies.

Then in February 2022, pacritinib, an oral macrocyclic member of the JAK family, was granted an accelerated approval by the FDA for the treatment of myelofibrosis for patients with severe thrombocytopenia. The basis of pacritinib’s approval comes from results of the phase 3 PERSIST-1 (NCT01773187), the phase 3 PERSIST-2 (NCT02055781), and phase 2 dose-finding PAC203 trial.

Currently, investigators are evaluating treatment with momelotinib, which has previously shown clinically significant improvements vs danazol for patients with anemia and intermediate-risk or high-risk myelofibrosis in the phase 3 MOMENTUM (NCT04173494) study.

Things with MPNs are changing relatively fast. Going back to November of [2021], we had the approval of ropeginterferon alfa-2b-nj for polycythemia vera, which was kind of the second approval we've had of a polycythemia vera medication, and certainly has transformed how we think about treating that disease with an idea of potential for disease modification. In February [2022], we had the accelerated approval of pacritinib for the treatment of myelofibrosis for patients that have severe thrombocytopenia. It was very exciting to get 2 drugs approved within the context of a year. Then, we have the continued enrollment of many phase 3 clinical trials that are potentially practice changing and may bring new therapeutic options to the table.

Andrew Kuykendall, MD, discusses some of the recent changes there have been for patients with myeloproliferative neoplasms.

Discussing Currently Available Therapies for Patients With MPNs

Srdan Verstovsek, MD, PhD, professor of medicine and hematologic oncologist at the University of Texas MD Anderson Cancer Center, discusses the key outcome of the MOMENTUM trial (NCT04173494) for managing anemia and symptoms for patients with intermediate-risk or high-risk myelofibrosis.

The international, double-blind, randomized, controlled, phase 3 study recently showed that 25% of patients on momelotinib (n = 130) had a 50%, or more, 

 vs 9% with of patients treated in the danazol arm (n = 65). The difference of proportion between both arms was 16%, which researchers deemed statistically significant (95% CI, 6–26; 

Srdan Verstovsek, MD, PhD, discusses the importance of the findings of the MOMENTUM trial, which assessed the use of momelotinib in managing anemia for patients with myelofibrosis.  

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