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Clinical

Andre H. Goy, MD; Sandra M. Swain, MD, FACP, FASCO Associate Dean for Research; Carolina Bernabe Ramirez, MD; Jonathan E. Rosenberg, MD; David H. Vesole, MD, PhD, FACP Director, Myeloma Program; Isabel Preeshagul, DO, MBS  
 

Community Practice Connections™: 5th Annual Precision Medicine Symposium – An Illustrated Tumor Board

Karen M. Winkfield, MD, PhD; Narjust Florez, MD, FASCO; Gilberto de Lima Lopes Junior, MD, MBA, FASCO; Coral Olazagasti, MD; Vonetta M. Williams, MD, PhD

 Fighting Disparities and Saving Lives: An Exploration of Challenges and Solutions in Cancer Care

The FDA has approved a re-engineered formulation of nilotinib with no mealtime restrictions for adult patients with newly diagnosed Ph-positive CP- and AP-CML, or for those resistant or intolerant to prior therapy, including imatinib.

FDA Approves Nilotinib With No Mealtime Restrictions in Ph-Positive CML

The SELECT-MDS-1 trial showed no significant complete response rate improvement with tamibarotene plus azacitidine for high-risk myelodysplastic syndrome, leading to the trial being discontinued.

SELECT-MDS-1 Trial of Tamibarotene Misses Primary End Point in MDS

In an interview with Targeted Oncology, Michael Mauro, MD, delved into the rapidly advancing field of chronic myeloid leukemia treatment. 

Balancing Clinical Data and Real-World Insights in CML Treatment 

The study is evaluating AJ1-11095, a novel agent for the treatment of myelofibrosis that did not respond to or relapsed following treatment with a type I JAK2 inhibitor.

Phase 1 Study of Type II JAK2 Inhibitor in Myelofibrosis Enrolls First Patient

A phase 1 study of tapotoclax in high-risk myelodysplastic syndromes demonstrated the agent was tolerable but showed limited efficacy.

Tapotoclax Shows Manageable Safety, Limited Efficacy in High-Risk MDS After HMA Therapy

Navigating Adverse Effects of JAK Inhibitors in Myeloproliferative Neoplasms

Prithviraj Bose, MD, professor in the Department of Leukemia at MD Anderson Cancer Center, discusses the most critical adverse effects (AEs) seen with each of the 4 approved JAK inhibitors for the treatment of myeloproliferative neoplasms.

He continues by explaining how the AEs observed typically are managed in these patients.

 The 4 approved drugs have different [adverse] effects. Ruxolitinib [Jakafi] is most known for the cytopenias that it causes, and same with fedratinib [Inrebic]. For both of them, anemia, thrombocytopenia, are big. Now we can dose-adjust, try and support the anemia with other agents like danazol, luspatercept [Reblozyl], erythropoiesis-stimulating agents, but then we have to think about some unique [adverse] effects for each drug which are not necessarily hematologic.

 With ruxolitinib, weight gain can be a problem in some patients. Shingles and basal and squamous cell skin cancer risk can be significant, especially in [patients] who have had these before. I give the shingles vaccine to every patient that gets ruxolitinib.

With fedratinib and pacritinib [Vonjo], [there are] a lot of [gastrointestinal adverse] effects like nausea, vomiting, and diarrhea. Diarrhea [and nausea are seen more] with pacritinib than fedratinib, but thankfully, mostly early on. We manage these with antiemetics and antidiarrheals, and one has to be proactive about that. I will be remiss not to mention that fedratinib has a black box warning about Wernicke encephalopathy, which is super rare, fortunately, but something that we want to prevent by giving thiamine supplementation and also by checking thiamine levels.

Finally, momelotinib [Ojjaara], again, the most recent, can cause thrombocytopenia. That is not trivial. It certainly occurs in about a quarter of the patients. Diarrhea, too, occurs in about a quarter of the patients. Then [there is] some rare stuff, like infections, peripheral neuropathy, but those are fortunately uncommon. There is one unique thing about momelotinib, which is that it can cause this first-dose hypotension. [Patients] are well advised to take it at bedtime, especially towards the beginning.

Videos

Prithviraj Bose, MD, discusses the most critical adverse effects seen with each of the 4 approved JAK inhibitors for the treatment of myeloproliferative neoplasms. 

News

Mechanism and Benefits of Rusfertide in Polycythemia Vera

Aniket Bankar, MD, Princess Margaret Cancer Center in Toronto, Canada, discusses why rusfertide is considered a promising therapeutic approach for patients with polycythemia vera.

In patients with polycythemia vera, research has shown that hepcidin levels are typically low. This deficiency leads to the continuous export of iron from the body’s iron stores, which in turn contributes to uncontrolled erythropoiesis. This excessive red blood cell production is primarily driven by the JAK2 V617F mutation. The dysregulation of iron homeostasis exacerbates the condition, making it essential to find effective treatments that address this underlying mechanism.

In response to this clinical challenge, a phase 2 randomized study known as REVIVE (NCT04057040) was conducted to evaluate the efficacy of rusfertide in patients with polycythemia vera who required frequent phlebotomies, either alone or with cytoreductive treatment. The results of this phase 2 study were promising, demonstrating that approximately 60% of patients treated with rusfertide became phlebotomy-independent, significantly reducing the need for this invasive procedure.

To further confirm these encouraging results, Bankar explains that a global 

phase 3, placebo-controlled, randomized trial

 is currently underway. This study aims to validate the findings from the phase 2 trial and solidify rusfertide's position as a novel therapeutic option for patients with polycythemia vera.

 Rusfertide is a hepcidin mimetic therapeutic peptide. The way it works is it blocks ferroportin, the channel that exports iron from its stores. A study had shown that in patients with PV, the hepcidin levels are low, leading to continuous export of iron from the iron stores to enable uncontrolled erythropoiesis, which is being driven primarily by the 

 Based on this preclinical data, the phase 2 randomized study was conducted in patients with PV who required phlebotomies with or without cytoreductive treatment. In that phase 2 study, the investigators saw that about 60% of patients became phlebotomy-independent. To confirm the results from the phase 2 study, we are now conducting a global, phase 3, placebo-controlled, randomized trial.

Aniket Bankar, MD, discusses why rusfertide is considered a promising therapeutic approach for patients with polycythemia vera.


Bose's Guide to Ruxolitinib, Fedratinib, Pacritinib, and Momelotinib

Prithviraj Bose, MD, professor in the Department of Leukemia at MD Anderson Cancer Center, provides an overview of the different JAK inhibitors currently available for patients with myeloproliferative neoplasms.

We have 4 JAK inhibitors approved for the treatment of myelofibrosis in the US. Important to note, pacritinib [Vonjo] is not approved outside the US. There is obviously a lot to say on this topic, especially, ruxolitinib [Jakafi] was approved in 2011, fedratinib [Inrebic] in 2019 and then pacritinib and momelotinib [Ojjaara], more recently, 2022 and 2023. But I think I will just hit some high points.

 So for ruxolitinib, the first thing I would say about that is that it is the JAK inhibitor with the most clearly demonstrated survival benefit in myelofibrosis. Now, is that an effect just of ruxolitinib and not of the others? We do not know that. It could be a class effect, but the data are the data and the data are that ruxolitinib is the one that has a clearly shown survival benefit. I think that needs to be considered as we use it, and it is usually the most frequently used frontline drug. Now, where you can get into trouble with ruxolitinib is with cytopenias, low blood counts, and this is a drug that you need to be able to dose well in order to get the benefit that you are seeking. The dose can get compromised by cytopenias.

 That is where I will tie that into the entry of pacritinib and momelotinib. These are easier to use in the setting of cytopenias. In fact, pacritinib has a label for platelets than 50, and momelotinib is for patients with anemia in myelofibrosis. So right there, you can see that they sort of have their place more in that cytopenic population, which could be frontline, or, more commonly, second-line, after ruxolitinib. I think those are great additions in the sense that you can give them at good doses despite low blood counts, which becomes difficult with ruxolitinib, like I just said. [They are] certainly very welcome additions to the arsenal.

 I will just say 1 last thing about fedratinib, which was the second one approved. This is a good drug, perhaps as good as ruxolitinib from an efficacy stand point, but really with no clear advantage over ruxolitinib. So, I do not use it in the frontline. I do use it, however, in post-ruxolitinib settings, where the blood counts are good. In those proliferative scenarios, as opposed to the cytopenic scenarios, in second-line and beyond, I do find fedratinib to be a useful drug. It has some toxicities that one has to pay attention to. All patients should get thiamine supplementation, stuff like that, but overall, I would say those are the kind of very high level points about the 4 drugs.

Prithviraj Bose, MD, provides an overview of the different JAK inhibitors currently available for patients with myeloproliferative neoplasms.

Evaluating Cytoreductive Approaches in MPNs

Douglas Tremblay, MD, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai, discusses the different 

cytoreduction approaches available to patients with myeloproliferative neoplasms

 (MPNs), specifically essential thrombocytopenia (ET) and polycythemia vera (PV), and the safety profiles of these agents.

The different set of cytoreductive approaches available for patients depends on which disease you have. If you have ET, the frontline therapies include hydroxyurea or pegylated interferon. If you have polycythemia vera, it is hydroxyurea, pegylated interferon, or ropeginterferon alfa-2b [Besremi] given at a once every 2-week dose. These options are available in the frontline.

 In second-line settings, there are additional options available such as the JAK 1/2 inhibitor ruxolitinib in polycythemia vera, as well as the selective platelet reducer anagrelide in patients with essential thrombocythemia.

In terms of safety profile, I'll focus first on hydroxyurea and interferon-based therapy. Hydroxyurea is an oral pill that is frequently taken once a day. [Adverse] effects of this include hematologic toxicity [in] other cell lines, including reducing white blood cell count, as well as reducing platelet count or hemoglobin, which is desirable in some patients, but also can introduce toxicities where you could try to control the blood count that is abnormally elevated in and PV or ET. [Adverse] effects of hydroxyurea outside of hematologic toxicities include some mouth ulcers, particularly in higher doses, or skin ulcers, particularly around the medial malleolus that can lead to discontinuation of the drug. There is also an increased risk of non-melanoma skin cancer that is induced with hydroxyurea.

 In terms of pegylated interferon, it is an injectable medication and a frequent [adverse] effect is a flu-like syndrome that happens after the first dose. It usually gets better over time. Concerning [adverse] effects that informed selection of this agent vs other agents include its neuropsychiatric [adverse] effects in patients who have severe depression or anxiety or psychiatric disorders. It is largely contraindicated in those diseases, as well as exacerbating autoimmune diseases. There is also hepatotoxicity and ocular toxicity which require monitoring as well. Importantly, in younger patients, particularly those who are trying to conceive or trying to get pregnant, pegylated interferon is safe in that setting and hydroxyurea cannot be used.

Douglas Tremblay, MD, discusses the different cytoreduction approaches available to patients with myeloproliferative neoplasms and their safety profiles.


Polycythemia Vera: Maintaining Hematocrit ≤ 45% for Better Outcomes

Aniket Bankar, MD, Princess Margaret Cancer Center in Toronto, Canada, discusses some of the current challenges that have been seen in managing patients with polycythemia vera (PV).

Managing hematocrit levels is critical for patients with conditions like PV that require phlebotomy or cytoreductive treatments, such as hydroxyurea or interferon. According to Bankar, hematocrit, the proportion of blood volume occupied by red blood cells, must be maintained at or below 45% to minimize risks. However, this control is particularly challenging for low-risk patients who rely on phlebotomies.

Regular monitoring is necessary, as suboptimal hematocrit management requires more frequent phlebotomies. Studies have indicated that higher hematocrit levels are linked with an increased risk of thrombosis and other symptoms, showing that maintaining appropriate hematocrit levels not only alleviates symptoms but also reduces the risk of potentially life-threatening events for these patients.

To optimize outcomes, healthcare providers must ensure vigilant monitoring and individualized treatment plans. This approach will help to maintain hematocrit within the desired range, minimize the need for frequent phlebotomies, and address iron deficiency promptly. Overall, this will enhance patients’ health and reduce the risk of severe complications.

Here, Bankar further discusses the importance of managing hematocrit in PV.

 The current challenges lie in making sure that their hematocrit is controlled [maintained ≤ 45%], irrespective of when they are visiting their phlebotomist, especially those low-risk patients who are managed with phlebotomies, or patients who are receiving cytoreductive treatment, including hydroxyurea and/or interferon.

 Many patients continue to need phlebotomies because of suboptimal hematocrit control. And when phlebotomies are frequently required, these patients lose iron and become iron-deficient, which can lead to worsening of symptoms. Some studies have also shown that when you have higher hematocrit levels, that can also increase the risk of developing symptoms and thrombosis.

Mascarenhas on the SENTRY Trial Design and Goals

John Mascarenhas, MD, professor, medicine, Icahn School of Medicine, Mount Sinai, director, Center of Excellence for Blood Cancers and Myeloid Disorders, member, The Tisch Cancer Institute, Mount Sinai, discusses the methods, design, and inclusion criteria of the phase 3 SENTRY trial (NCT04562389) for patients with JAK inhibitor treatment-naive myelofibrosis.

SENTRY is a global, multicenter, phase 1/3 study where investigators are assessing the efficacy and safety of selinexor (Xpovio) combined with ruxolitinib (Jakafi) in this patient population.

According to Mascarenhas, the primary end points of phase 3 of the trial include the proportion of patients with spleen volume reduction of greater than or equal to 35% at week 24 (SVR35), and the proportion of patients with a total symptom score reduction of greater than or equal to 50% at week 24 (TSS50), as measured by the myelofibrosis symptom assessment form V4.0.

 The study is a phase 3, randomized study that is going to include 306 patients who are JAK inhibitor-naive, and they will be randomized to 2:1 to ruxolitinib plus selinexor, the XPO1 inhibitor which is administered orally once a week at 60 mg weekly in a 28 day cycle vs placebo. And the coprimary end point of this global study is SVR35 at week 24 and TSS50 at week 24. A key secondary end point is an immune response at week 24.

The inclusion criteria are patients with a diagnosis of myelofibrosis, either primary or secondary myelofibrosis, and are JAK inhibitor-naive. They have to have a DIPSS score of intermediate 1 with symptoms or intermediate to or high-risk disease and a platelet count of at least 100,000 or greater. In theory, they should not be candidates for for immediate stem cell transplantation. Patients can eventually go to transplant, but if they are being considered for transplant immediately, this would not be an option for those patients.

 In terms of exclusion, we do exclude patients with blasts that are greater than 10% in the blood or the bone marrow, as these patients would likely benefit from other types of therapies, or previous JAK inhibitor therapy or previous XPO1 inhibitor therapy.

Transcription created with AI and edited for clarity.

John Mascarenhas, MD, discusses the methods, design, and inclusion criteria of the phase 3 SENTRY trial for patients with JAK inhibitor treatment-naive myelofibrosis.


Assessing Selinexor/Ruxolitinib in JAKi Treatment-Naive Myelofibrosis

John Mascarenhas, MD, professor, medicine, Icahn School of Medicine, Mount Sinai, director, Center of Excellence for Blood Cancers and Myeloid Disorders, member, The Tisch Cancer Institute, Mount Sinai, discusses phase 3 of the SENTRY (NCT04562389) trial, a global, multicenter, phase 1/3 study evaluating the efficacy and safety of selinexor (Xpovio) when given in combination with ruxolitinib (Jakafi) in patients with JAK inhibitor treatment-naive myelofibrosis.

The study is being conducted in 2 phases. In phase 1, the open-label portion of the study, enrollment has been completed and the safety and recommended dose of selinexor plus ruxolitinib was studied. Phase 1a utilized a standard 3+3 design, and phase 1b was the dose-expansion part. Phase 3 of the trial is enrolling patients with JAK inhibitor treatment-naive myelofibrosis and randomizing them 2:1 to receive the combination therapy of selinexor with ruxolitinib or placebo with ruxolitinib.

In phase 3, the primary end points are the proportion of patients with spleen volume reduction of greater than or equal to 35% at week 24, and the proportion of patients with a total symptom score reduction of greater than or equal to 50% at week 24, as measured by the myelofibrosis symptom assessment form V4.0.

 The study we are talking about is a global, phase 3 study. It is a randomized, double-blind study evaluating the safety and efficacy of selinexor, which is an XPL1 inhibitor, in combination with ruxolitinib in JAK inhibitor-naive patients with myelofibrosis. We call this the SENTRY study. So it is really capitalizing on data that has already been generated, both as a single-agent in the relapsed/refractory setting, but also in combination with ruxolitinib in phase 2, demonstrating synergy of the 2 agents in terms of spleen reduction, symptom improvement, bone marrow fibrosis reduction, and a safety profile that would suggest that durability of response can be maintained.

 So this is now the natural evolution of this agent in myelofibrosis in a phase 3 study in patients who are JAK inhibitor-naive, comparing ruxolitinib, which is the standard of care, plus selinexor, the XPL1 inhibitor, vs ruxolitinib plus placebo.

John Mascarenhas, MD, discusses phase 3 of the SENTRY study evaluating the efficacy and safety of selinexor plus ruxolitinib in patients with JAK inhibitor treatment-naive myelofibrosis. 


Individualized Approaches and Challenges in Myelofibrosis

Raajit K. Rampal, MD, PhD, hematologic oncologist at Memorial Sloan Kettering Cancer Center, discusses how the field of gene therapy and precision medicine is evolving in the context of myelofibrosis treatment. He also explains how treatment decisions are individualized for patients with myeloproliferative neoplasms, including myelofibrosis.


Rampal presented on this topic and more at the 

Fifth Annual Miami Cancer Institute Global Summit on Immunotherapies for Hematologic Malignancies

, hosted by Dr. Guenther Koehne and Miami Cancer Institute.

In addition, Rampal discusses some of the unmet needs that exist in this space, including the need for disease-modifying therapy in this interview with Targeted Oncology

 We are not really doing gene editing therapy. What we are doing is trying to target some of the other mutations. An example of this is patients who have a concurrent 

 mutation where there has now been data to combine a JAK inhibitor and IDH inhibitor in those types of patients.

That is something where we have to get a little better. There is a genetic part of it, where we need to kind of figure out if there is a way to leverage other mutations, like I just mentioned. That is 1 option. The other option is trying to understand, are there particular patient profiles that are going to be more responsive to certain therapies? We are not there yet. I do not think we know the answer to that, but I think that is where we need to go.

We need disease-modifying therapy. We need therapies that prevent people from progressing to bone marrow failure or to acute leukemia, and I do not think that we are there yet, or at least we need more data to substantiate whether that is going to happen. So more to come.

Raajit K. Rampal, MD, PhD, discusses how the field of gene therapy and precision medicine is evolving in the context of myelofibrosis treatment. 

MPNs

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