UT Health San Antonio MD Anderson Cancer Center

Ruben Mesa, MD, the director of the Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, discusses the use of ruxolitinib (Jakafi) versus fedratinib (Inrebic) in patients with myelofibrosis and baseline thrombocytopenia.

Individuals with baseline thrombocytopenia are traditionally given ruxolitinib at a reduced dose based on the degree of thrombocytopenia, says Mesa. Although there are also some concerns regarding safety or a suboptimal benefit due to patients receiving a reduced dose. A full dose of fedratinib in that group of patients suggests that it is an option to consider for the second-line setting. However, based on recent data, it would also be a reasonable option for the frontline setting as well, in a patient with baseline thrombocytopenia in the 50,000 to 100,000 platelet range, concludes Mesa.

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Ruben Mesa, MD, discusses the use of ruxolitinib versus fedratinib in patients with myelofibrosis and baseline thrombocytopenia.

Dr. Mesa on the Utility of Ruxolitinib Versus Fedratinib in Myelofibrosis

Ruben A. Mesa, MD, director, UT Health San Antonio MD Anderson Cancer Center, discusses advancements made in the treatment of patients with myeloproliferative neoplasms (MPNs).

It is an exciting time in terms of therapeutic progress made in MPNs, says Mesa. First, there have been further updates on the important role of long-acting interferons in the treatment of patients with essential thrombocythemia or polycythemia vera. Long-acting interferons are having an impact on outcomes and are possibly superior to the use of hydroxyurea, in both the first- and second-line settings. Data presented at the 2019 ASH Annual Meeting with long-acting interferons showed both thrombosis-free survival as well as a potential molecular impact in this space, says Mesa.

In myelofibrosis, a very robust set of therapies are being developed, adds Mesa. For example, investigators are examining a group of JAK inhibitors that are expected to complement each other in terms of their activity. Additionally, novel combinations comprised of drugs with different mechanisms of action, such as BET, TGF-β, and LSD1 inhibition, are also under exploration. New drugs are also in development for use as single agents, says Mesa.

We’re seeing parallel advances in the treatment of patients with myelodysplastic syndromes with oral hypomethylating agents; these agents will certainly have a benefit for patients with advanced MPNs, as well, concludes Mesa.

Ruben A. Mesa, MD, discusses advancements made in the treatment of patients with myeloproliferative neoplasms.

Dr. Mesa on Treatment Advancements Made in MPNs

The diagnosis and treatment of patients with essential thrombocythemia (ET) can be complex and should include thoughtful discussions with patients, explained Ruben A. Mesa, MD, who added that ongoing research will help augment the advances that have been made to date.

"The science is evolving to allow us to try to understand and predict which patients are likely to progress," said Mesa. "Are there any markers of progression early on? Then, does that give us any insight as to which therapies we should be using or developing to try to prevent progression in the majority of patients with ET?"

Importantly, patients who achieve stable disease are unlikely to develop complications from ET, unless they progress, explained Mesa.

"If we keep patients from progressing, they will live out their normal lifespan," Mesa said. "The avoidance of progression is a key goal because we still have a scientific gap in terms of having enough information to develop rationally designed drugs to block disease progression. However, I think the future is indeed bright."

, Mesa, director of the Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, discussed the current state of ET treatment, the challenges of diagnosing the disease, and available educational resources for healthcare providers and patients.

: Patients with ET have a disease that, in the short-term, can lead to elevated blood counts, a risk of blood clots or bleeding, and, more rarely, enlargement of the spleen. How ET affects an individual can be very different from how it affects another on the basis of whether there is a significant risk of blood clots or bleeding, whether that’s how we found the disease to begin with, and what the individual's risk is in the future.

Second, there is a risk of the disease progressing to an advanced phase, which we call myelofibrosis, or rarely, to acute leukemia. Fortunately, the majority of patients with ET will live out their normal lifespan. The minority of individuals have progressive disease. However, even in those patients who do live a normal lifespan, we need to be mindful of controlling their disease to help minimize the symptom burden and decrease the risk of blood clots or bleeding.

How do you approach the conversation on diagnosis with your patients?

The discussion we have around ET is a complex one because ET is technically a cancer; it is technically a leukemia. It is a clonal neoplasm, but its behavior is quite different than what people associate with [a cancer diagnosis].

First, I try to frame [ET] as a chronic disease. There are many other chronic diseases that patients are more familiar with such as diabetes, rheumatoid arthritis, lupus, and high blood pressure. These are different diseases, but they are chronic conditions that we don't typically have a cure for. While there is a subset of patients who pass away from complications from those diseases, the majority of patients will live out their normal lifespan. [Those chronic diseases are] a fairly good analogy for ET.

A lot of education needs to occur [when a patient is diagnosed with ET]. Perhaps it can all be done within the first visit, but the patient might be overwhelmed, or lack sufficient insight into the disease that to be able to cover all the points in the first visit. It is important to be mindful of what we know and what we do not know.

[Historically], patients with ET may have been told that their life expectancy was 15 years. While that is probably true, it is a little misleading because the average age at which we diagnose ET is in the mid-60s. That average life expectancy of 15 years is the average life expectancy in the United States. Therefore, while the number is true, that doesn't mean that patients are passing away from ET.

It is important to realize that when you are visiting with a patient, this is likely the first time they have heard anything about a disease like this. They don't have a frame of reference, so you need to be cautious and clear in terms of trying to explain it in a way the patient is likely to understand.

Then, I revisit the key parts of that discussion every time I visit with my patients because sometimes it takes a few visits for them to become familiar with the disease, and to frame some of the online reading that they may be doing in parallel with our discussions.

What are some of the challenges of diagnosing myeloproliferative neoplasms (MPNs) and, specifically, ET?

The diagnosis of an MPN begins with a suspicion that is based sometimes on a blood clot that occurred in an unexpected location. We know that [patients who have] blood clots in the portal venous system [or] various unexplained thrombotic events have a much higher rate of having an MPN.

Most commonly, [our suspicion is based on] a finding in the peripheral blood, [such as] clear erythrocytosis, elevated red blood cell count, unexplained elevated platelet count, or more rarely, an unexplained elevated white blood cell count, or splenomegaly.

Over time, we have had a greater level of diagnostic certainly with the discovery of the 

 V617F mutation that can now be easily tested for by peripheral blood, as well as the less common but important calreticulin or 

One of the challenges that remains in 2020 is that there is still reluctance to obtain a bone marrow biopsy from individuals who have been found to have an increased blood count and a 

In particular, this relates to ET because the majority of individuals who have a 

 mutation and thrombocytosis will have ET, but not everyone. These individuals might have associated MPN or myelodysplastic/myeloproliferative overlap syndromes, such as refractory anemia with ring sideroblasts or chronic myelomonocytic leukemia (CML), or they may have early myelofibrosis.

Even more rarely, there have been individuals who have CML and have a small incidental 

 mutation that was present as well. I do find the diagnostic work-up for ET is sometimes incomplete. There may be individuals who we assume have ET who really have a [related] disorder, which may have important implications in terms of choice of therapy and/or prognosis.

What is the standard course of treatment for patients with ET?

In ET, the key treatment goals are to try to control the patient's symptoms, get their platelet count below 400,000, decrease the risk of blood clots and bleeding, and have the therapy be well-tolerated. We also want to avoid disease progression, but that can be difficult to quantify.

Typically, the first therapy for patients begins with a baby aspirin; almost everyone receives it. After, our current National Comprehensive Cancer Network guidelines list hydroxyurea, interferon alfa-2b, or pegylated interferon, as available options for the frontline treatment of patients with ET. These treatments are not technically approved by the FDA, but they are available and efficacious. They have not been compared head-to-head in randomized clinical trials.

In ET, they appear to be relatively equivalent with some differences in toxicity. There may be a slight advantage with interferon in terms of avoiding disease progression.

In polycythemia vera, where there have been further randomized studies, it is probably clearer that interferon is slightly better than hydroxyurea, but I wouldn't say it is dramatically better.

In some cases, [the amount of these] medications [that is needed] to fully control the counts can lead to unacceptable adverse events. There are individuals who will feel better with a little bit of 2 agents as opposed to a lot of 1 agent. All of these agents have a dose-associated toxicity profile. Sometimes a lower dose is better tolerated.

It is all part of trying to personalize therapy to an individual to decrease their symptoms, control their blood counts, and manage the toxicity.

What resources are available to physicians and patients to gain more knowledge of MPNs?

There is good educational information out there online and at in-person events such as national meetings.

Online, there is great content from Patient Power, 

, Physician's Education Resource, and TotalCME. There are many robust platforms. [We should be discussing] updates [with our patients], [as well as having] case-based discussions regarding new options, how they are applied, and how to balance challenging situations [with them].

Medicine is art and science—–that has been well-recognized. The science is knowing what the options are. We know for ET that includes hydroxyurea, pegylated interferon, perhaps a JAK inhibitor like ruxolitinib (Jakafi), or even other chemotherapeutic drugs. We know drugs like trastuzumab (Herceptin) or pembrolizumab (Keytruda) [are not part of] our arsenal.

The art of medicine is knowing what [therapy] to use in which patient, adjusting it in the appropriate way, knowing how long it takes to see a response, and asking the right questions of the patient to understand whether they are tolerating the therapy.

In a disease like ET, [we should] strive to get to a plateau where the patient feels reasonably well. Then you watch them and adjust therapy if needed. Once an individual reaches that plateau, they may remain in it for many years. [That’s important because we know] achieving stable disease state is important in a disease like ET.

Where should ongoing research efforts be focused in the space?

Without question, we know there are clear unmet needs in ET. There are still patients who progress or those on our available therapies who have unacceptable toxicities or little response.

There are several therapies in development. Ruxolitinib has been in phase III trials for patients with refractory ET in an attempt to define the role of ruxolitinib in patients who have more difficult symptoms like splenomegaly and who have progressed on hydroxyurea. Second, pegylated interferon alfa-2a, which is commonly used in the United States, is not FDA approved. I’m co-leading an international phase III trial with a new interferon—ropeginterferon alfa-2b&mdash;which is evaluating the benefit of that agent as second-line therapy compared with anagrelide (Agrylin) in high-risk patients who progressed on hydroxyurea.

Third, there may be benefit from LSD1 inhibition. There is a clinical trial that will be tested at [UT Health San Antonio MD Anderson Cancer Center], as well as another company-sponsored study for patients who have refractory ET.

Articles

Ruben A. Mesa, MD, discusses the current state of ET treatment, the challenges of diagnosing the disease, and available educational resources for healthcare providers and patients.

Mesa Provides Perspective on Diagnosis and Treatment in Essential Thrombocythemia

Ruben Mesa, MD, the director of the Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, discusses remaining challenges in treating myelofibrosis.

Many challenges remain in treating patients with myelofibrosis because although many therapies are active, they are not curative, explains Mesa. Further research needs to focus on determining how to deepen and lengthen responses to treatment, says Mesa.

To date, research has largely focused on single-agent therapy, adds Mesa. The next steps may be to investigate what combinations will make an incremental benefit, according to Mesa. The reasons why patients progress on treatment are still not fully understood, but once more information is obtained, investigators will be in a better position to monitor any surrogate end points and target progression-free survival, concludes Mesa.

Ruben Mesa, MD, discusses remaining challenges in treating myelofibrosis.

Dr. Mesa on Challenges in Myelofibrosis Treatment

Ruben Mesa, MD, the director of the Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, discusses therapies under investigation in myelofibrosis.

Several therapies are currently under investigation in the second-line setting to be used alone or in combination, says Mesa. There is some interest in examining the use of a BET inhibitor to treat patients with myelofibrosis, which is working on the pathways at a variety of different levels and is particularly helpful for patients with the 

 mutation. Some data from the phase II MANIFEST study demonstrated that BET inhibitors, when used alone or in combination, could have positive effects in patients with myelofibrosis, says Mesa. Some research is even examining the use of these agents in combination with JAK inhibition in the frontline setting.

Additionally, there are data looking at the addition of venetoclax (Venclexta) to ruxolitinib (Jakafi) in patients who are experiencing suboptimal response. Promising data from a phase II study showed that a LSD1 inhibitor had a benefit in the second-line setting. Furthermore, data showed a benefit with luspatercept in improving anemia in these patients, according to Mesa.

In collaboration with the National Cancer Institute—funded MPN Research Consortium, Mesa participates in a variety of studies being conducted in the myelofibrosis setting. For example, a phase I study is being done on AVID200 looking at TGF-ß and there is hope that it will be active, Mesa concludes.

Ruben Mesa, MD, discusses therapiesunder investigation in myelofibrosis.

Dr. Mesa on Investigative Therapies in Myelofibrosis

The August 2019 FDA approval of fedratinib (Inrebic) for adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis was a solid advance for the field, said Ruben Mesa, MD.

“The key takeaway is now we have fedratinib approved as second-line therapy and in the frontline setting. That is an incremental increase now that we have a second drug available. There are probably patients on ruxolitinib who are having suboptimal responses, so considering them for second-line therapy is important,” said Mesa.

Fedratinib was explored in patients with myelofibrosis previously treated with ruxolitinib in the multicenter, single-arm phase II JAKARTA-2 trial. In the ITT population (n=97), the proportion of patients who exhibited a 35% or greater reduction in spleen volume at the end of cycle 6 was 31% (95% CI, 22-41). In addition, the proportion of patients who exhibited a 50% or greater symptom response rate was 27% (95% CI, 18-37) in the ITT population.

, Mesa, director of the Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, discussed the latest advancements in the treatment paradigm for patients with myelofibrosis.

: What are the current upfront options for myelofibrosis?

: The current upfront options for myelofibrosis include ruxolitinib, which has been approved for several years as a JAK 1/2 inhibitor, and fedratinib, which is also approved in frontline therapy for its ability to improve splenomegaly and burden symptoms in patients with intermediate- to high-risk myelofibrosis.

What are the data we see with first-generation JAK inhibitors?

These agents in the frontline setting have shown the ability to improve splenomegaly and burden symptoms in patients with both intermediate- and advanced-risk diseases. Additionally, there is a benefit that we believe will likely extend to improvements in survival with less debilitation and long-term patients having an impact. Some of these benefits are also in terms of bone marrow histologic features of the disease and other subtle evidence of disease modification.

What are the treatment options after these JAK inhibitors?

After patients have failed a frontline JAK inhibitor, fedratinib is an option in the second-line setting. My colleagues and I have previously conducted a second-line trial of fedratinib for patients who have failed ruxolitinib called the JAKARTA-2 study. In this study, we observed that patients who failed ruxolitinib would have a significant benefit in splenomegaly and burden symptoms.

Recently, we did an updated analysis looking at a stringent criterion for defining what constitutes ruxolitinib failure and found that there is about one-third of patients who have a clear response in terms of splenomegaly and burden symptoms with fedratinib if they failed ruxolitinib.

What are the challenges of using these agents?

The challenge with JAK inhibitors is that they can lead to the development of cytopenias. We need to manage that with dosage and, sometimes, in terms of patients as they become used to the agents. Additionally, with fedratinib, we need to be mindful of monitoring for thiamine levels and thiamine replacement. This is not a barrier in terms of use but something we need to be mindful of based on a very rare likelihood of Wernicke's that has developed in the past in a small percentage of patients. It is also managing around some gastrointestinal (GI) adverse events, but they are usually well managed, and some patients do not have it at all.

Are there other therapies under investigation in this space?

There are multiple therapies under investigation as second-line therapies either to be used alone or in combination. Some of interest include a BET inhibitor, which is working on the pathways at a variety of different levels and is particularly helpful for patients with the ASXL1 mutation. There were some favorable data from the MANIFEST study showing that BET inhibitors alone or in combination could be helpful. There is even some data looking at using it in combination with JAK inhibition in the frontline setting.

Additionally, there is data of adding navitoclax along with ruxolitinib in patients having a suboptimal response. There were some favorable data from a phase II study [showing that a] LSD1 inhibitor had a benefit in the second-line setting. In addition, there are data with luspatercept trying to improve anemia which we also saw a benefit.

There are other agents in the pipeline. I myself participated with the National Cancer Institute—funded MPN Research Consortium where we have a variety of studies in this setting. There is one on AVID200 looking at TGF-ß. That is a phase I study so we are hopeful that it will be active.

What are the remaining challenges in treating myelofibrosis?

Many challenges remain. We have therapies that are active, but they are not curative. We looked to see how we can better deepen and lengthen the responses. We have largely been looking at single agents so what combinations will make an incremental benefit and how we measure those. We still do not fully understand why patients progress, but once we do understand that, we will be in a better situation to monitor any surrogate endpoints.

What combinations look the most promising?

The current time both the BET inhibitors and navitoclax combinations with ruxolitinib are very interesting. Certainly, the data we have shown a strong path moving forward, as well as the combination of luspatercept with ruxolitinib. In addition, there is a benefit in patients with more advanced disease moving toward acute leukemia that has been shown with ruxolitinib and hypomethylating therapy, such as decitabine or azacitidine, that both can be given together and are safely tolerated and have activity.

How do fedratinib and ruxolitinib compare with regard to toxicities?

Their toxicities are slightly different, with ruxolitinib we know that there is an increased risk with secondary skin cancers. There can be some degree of immunosuppression and rare immunocompromised infections, as well. For fedratinib, GI toxicities are probably more prevalent than they are with ruxolitinib and there is the issue of thymine.

What is the key takeaway from your presentation?

There are clinical trials available, but these drugs are more accessible for patients to be able to have second-line therapy now. There is also a tremendous amount of investigation and focus for these patients in terms of new therapies being developed and more therapies coming in the future.

I would also say that there are 2 other JAK inhibitors that are completing their rounds of testing that may become available in the future. Momelotinib, which may have differentiation around cytopenias and anemia, and pacritinib, which may be safe in patients with macrothrombocytopenia. I would love to see a situation where we have multiple agents available and tailor our therapies more appropriately in the frontline and second-line settings as it relates to JAK inhibition.

Harrison CN, Schaap N, Vannucchi AM, et al. Fedratinib (FEDR) in myelofibrosis (MF) patients previously treated with ruxolitinib (RUX): A reanalysis of the JAKARTA-2 study. 

 37, 2019 (suppl; abstr 7057). doi: 10.1200/JCO.2019.37.15_suppl.7057

Ruben Mesa, MD, discusses the latest advancements in the treatment paradigm for patients with myelofibrosis.

Mesa Discusses Next Steps in Myelofibrosis

Ruben Mesa, MD, the director of the Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, discusses the challenges with using JAK inhibitors in myelofibrosis.

The use of JAK inhibitors can lead to the development of cytopenias in patients with myelofibrosis, but that can be managed by adjusting the dosage of these agents. With fedratinib (Inrebic), patients need to have their thiamine levels monitored and possibly receive thiamine replacement. Low thiamine levels are not a barrier in terms of using these agents, but thiamine levels must be monitored due to a small percentage of patients in the past developing Wernicke encephalopathy.

Furthermore, JAK inhibitors can cause some gastrointestinal adverse events (AEs). However, prophylaxis can be used for diarrhea and nausea, and those AEs are usually well managed. In fact, some patients do not experience any AEs associated with these agents, but one should be mindful of these toxicities, concludes Mesa.

Ruben Mesa, MD, discusses the challenges with using JAK inhibitors in myelofibrosis.

Dr. Mesa on Challenges With JAK Inhibitors in Myelofibrosis

Ruben Mesa, MD, the director of the Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, discusses the adverse events associated with ruxolitinib (Jakafi) and fedratinib (Inrebic) in myelofibrosis.

It is known that both ruxolitinib and fedratinib can cause anemia and thrombocytopenia in these patients, but additional differences in adverse events may be discovered over time, explains Mesa. The duration of treatment can also have an effect on safety. For example, a longer duration of treatment with ruxolitinib can cause increased rates of non-melanoma skin cancers and certain infections, such as herpes zoster infection, says Mesa.

The safety profile of fedratinib in relation to its duration of use is not fully understood yet, but research will continue to follow the agent over time, says Mesa. Fedratinib is associated with additional toxicities compared with ruxolitinib that need to be monitored. For example, some gastrointestinal disturbances have been observed with the agent. However, in studies examining the agent, investigators showed that pretreating patients with antinausea and antidiarrheal medications aggregated those symptoms to a significant degree and did not cause major issues, concludes Mesa.

Ruben Mesa, MD, discusses the adverse events of ruxolitinib and fedratinib in myelofibrosis.

Dr. Mesa on the Safety Profiles of JAK Inhibitors in Myelofibrosis

Ruben A. Mesa, MD, director, The Mays Cancer Center, the newly named center of UT Health San Antonio MD Anderson Cancer Center, discusses the approval of fedratinib (Inrebic) in myelofibrosis and other JAK inhibitors in the treatment pipeline.

 for use in adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, is available in the frontline and second-line setting, explains Mesa. Whether fedratinib or ruxolitinib (Jakafi) will be used will depend on the comfort level of patients and physicians for each drug, according to Mesa.

Other JAK inhibitors in the pipeline include 2 mature drugs that are close to FDA approval: momelotinib and pacritinib, says Mesa. The phase III MOMENTUM trial is evaluating the efficacy of momelotinib, a JAK1, JAK2, and ACVR1 inhibitor, versus active comparator danazol (Danocrine) in patients with symptomatic and anemic myelofibrosis who previously received a JAK inhibitor. Momelotinib can improve spleen symptoms and anemia, says Mesa. If the trial turns out to be successful, the aggregated data observed with the agent might result in regulatory approval, Mesa postulates.

The JAK2 and FLT3 inhibitor pacritinib has also had successful phase III trials, such as the PERSIST-1 trial, says Mesa. The recently launched phase III PACIFICA trial is examining the agent versus physician’s choice in patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocytopenia myelofibrosis with severe thrombocytopenia. Pacritinib is the only JAK inhibitor that has been used in patients with a platelet count <50,000, concludes Mesa.

Ruben A. Mesa, MD, discusses the approval of fedratinib in myelofibrosis and other JAK inhibitors in the treatment pipeline.

Dr. Mesa on JAK Inhibitors in the Pipeline for Myelofibrosis

Ruben A. Mesa, MD, director, The Mays Cancer Center, the newly named center of UT Health San Antonio MD Anderson Cancer Center, discusses the efficacy of fedratinib (Inrebic) in patients with myelofibrosis who have low platelet counts.

Fedratinib is a JAK2 and FLT3 inhibitor that was approved in August 2019 for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. Efficacy data from the phase III JAKARTA trial and safety data from the phase II JAKARTA-2 trial served as the basis for the agent’s approval.

Prior to the approval of fedratinib, ruxolitinib (Jakafi) was approved for use at a reduced dose in patients with a platelet count between 50,000 and 100,000. At the 2019 ASH Annual Meeting, investigators looked at the outcomes of patients with a platelet count between 50,000 and 100,000 who received 400 mg of fedratinib.

Results from the pooled analysis of the JAKARTA trials demonstrated that patients with a platelet count between 50,000 and 100,000 and ≥100,000 had a similar symptom resolution rate and spleen response rate, says Mesa. Moreover, 400 mg of daily fedratinib was found to be safe in patients with a platelet count between 50,000 and 100,000. However, several patients developed grade 3/4 thrombocytopenia and required dose modifications, concludes Mesa.