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Clinical

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 investigational immunotherapy bexmarilimab has been granted orphan drug designation from the FDA for patients with myelodysplastic syndromes.

FDA Grants Bexmarilimab Orphan Drug Designation for MDS 

Rusfertide outperformed placebo in polycythemia vera, meeting all primary and secondary end points in the phase 3 VERIFY study.

Rusfertide Shows Superior Efficacy in Phase 3 Polycythemia Vera Trial

The first patient with myelodysplastic syndrome has received iadademstat plus azacitidine in a phase 1 trial at the Medical College of Wisconsin.

First Patient Dosed in Study of Iadademstat Combo in MDS 

Hany Elmariah, MD, discussed the safety profile of fedratinib and its evolving role in the post-transplant setting for patients with myeloproliferative neoplasms.

Fedratinib Shows Safety, Potential as Post-Transplant Therapy in MPNs 

During a Case-Based Roundtable® event, Jay Yang, MD, discussed the trial comparing luspatercept with ESA in myelodysplastic syndrome. 

Yang Highlights Positive COMMANDS Trial Data for Luspatercept in MDS

How AI is Revolutionizing MDS Diagnosis

Palak Dave, postdoctoral fellow at Moffitt Cancer Center and Research Institute, discusses the potential role of artificial intelligence (AI) in improving the accuracy of myelodysplastic syndromes (MDS) diagnosis.

Dave addressed the challenges of distinguishing MDS from pre-MDS conditions like idiopathic cytopenia of undetermined significance (ICUS) and clonal cytopenia of undetermined significance (CCUS) in a presentation of an innovative study at the 

2024 American Society of Hematology (ASH) Annual Meeting and Exposition

. The study explored how AI can help standardize and accelerate MDS diagnosis.

This approach consisted of using a deep learning model that analyzes bone marrow aspirate smear images, and early findings showed that the AI achieved about 70% accuracy in internal validation.

In addition, Dave discusses how this AI pipeline standardized bone marrow smear analysis.

I would say the focus is not just on accuracy but also on standardization and speed. Experienced hematopathologists can achieve high diagnostic accuracy, but the process can be time-consuming. Additionally, there is inherent subjectivity among experts, which can lead to variability in diagnoses. By standardizing these processes, we can make them faster and more consistent, ultimately benefiting patients.

So I can go into a little more depth when I say there exists subjectivity. Why does that exist? Basically, in these kinds of diseases, the hematopathologist looks at individual cells in the bone marrow aspirate smear and makes a decision about what category the cell belongs to, out of many categories and possible abnormalities. So in this visual review, there can be subjectivity. I may think it is Category A, and another person may think it is Category B, because the differences are very minute. So when a machine does it, it is kind of standardized.

Transcription was edited for clarity with AI.

Dave P, Rai J, Zhang L, et al. A deep-learning pipeline for diagnosis of myelodysplastic syndromes/neoplasms using bone marrow smears. Presented at the 2024 American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10; San Diego, CA; abstract 4991.

Videos

Palak Dave discusses the potential role of artificial intelligence in improving the accuracy of myelodysplastic syndromes diagnosis.


News

Exploring Fedratinib in Rare Myeloid Neoplasms

Andrew Kuykendall, MD, an assistant member at the H. Lee Moffitt Cancer Center of University of South Florida in Tampa, FL, discusses the background, methods, and design of a phase 2, multi-institutional, investigator-initiated study (NCT05177211) which evaluated fedratinib (Inrebic) for the treatment of patients with atypical chronic myeloid leukemia (CML), chronic neutrophilic leukemia, myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN)-unclassifiable, and MDS/MPN-ring sideroblasts and thrombocytosis.

 When we designed the study, we wanted to serve an underserved population of patients that often get excluded from clinical trials, and so we were in a bit of a unique situation as a standalone cancer center where we see a lot of these rare diseases more frequently than they are seen out in the community. We feel like we can offer something to these patients that often get excluded and not enrolled in trials because people think it would be hard to accrue.

 We designed this study specifically for patients with MDS/MPN overlap syndromes and chronic neutrophilic leukemia. We excluded patients with chronic myelomonocytic leukemia, as those are more common, and individual trials can often be conducted for that specific diagnosis. This trial included patients with MDS/MPN-unclassifiable, atypical CML, MDS/MPN with ring sideroblasts and thrombocytosis, and chronic neutrophilic leukemia. These diseases fall under the category of MDS/MPN overlap syndromes.

 Prior studies have suggested that these are not as distinct as we would like them to be; instead, they should be viewed more as a spectrum of diseases. This perspective was the rationale for including them together in this study. [For this] phase 2 trial, we enrolled patients with these diagnoses based on specific criteria. Patients needed to have either disease-related symptoms or an enlarged spleen, as we believe this is where JAK inhibitors could offer a benefit. We used a Simon two-stage design for this study. Our goal was to enroll around 25 patients, but after the first 9, we conducted an interim analysis to ensure the treatment showed some benefit. If we observed benefit in the initial group, we would proceed with enrolling the remaining patients.

Andrew Kuykendall, MD, discusses the background, methods, and design of a phase 2 study which evaluated fedratinib.

Evaluating Fedratinib in Rare Myeloproliferative Diseases

Andrew Kuykendall, MD, an assistant member at the H. Lee Moffitt Cancer Center of University of South Florida in Tampa, FL, discusses the rationale behind choosing to evaluate fedratinib (Inrebic) in a phase 2, multi-institutional, investigator-initiated study (NCT05177211) for patients with atypical chronic myeloid leukemia, chronic neutrophilic leukemia, myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN)-unclassifiable, and MDS/MPN-ring sideroblasts and thrombocytosis.

He then discusses how fedratinib’s broader kinase inhibition profile differs from ruxolitinib (Jakafi) in this space.

Overall, the rationale is kind of multipronged. Initially, as someone who focuses a lot on myelofibrosis, fedratinib as an agent is a JAK2 inhibitor that is quite potent, and probably the most potent of the JAK inhibitors that we have in terms of achieving spleen volume reduction and symptom improvement. Unfortunately, it really does not have a clear space in myelofibrosis, given the fact that it is competing with agents that were approved nearly a decade before it. It still has some of the anemia and thrombocytopenia adverse events that may make it not as attractive as an option for some of our patients with more profound cytopenias, where we have other JAK inhibitors.

But fedratinib is kind of this potent agent. We wanted to see if maybe there was a place for it in more aggressive diseases that have overlapped phenotypically with myelofibrosis. That was the initial kind of thought process. Maybe this is just a natural fit. But when you look at fedratinib, it also has kind of a distinct kinase inhibition profile, where, in addition to JAK2, it is a weaker JAK1 inhibitor, so may avoid some of the [adverse events] that come from that.

 Also, it inhibits BRD4, which is part of this BET protein complex. That is something that we have been evaluating in myeloproliferative neoplasms and may play a role in NF-κB inflammatory signaling. It also hits FLT3, which has unclear benefits, but maybe something that is helpful and then also potently down regulates MYC, which we often think about in lymphomas.

 Recently, work from some physician-scientists in our group has suggested that MYC can be a potent proliferative driver, particularly overrepresented in triple-negative myelofibrosis or possibly in MDS/MPN overlap syndromes that harbor mutations activating MYC pathways. The rationale for this approach is multi-pronged. First, MYC represents a potent target, potentially better suited for more aggressive diseases. Additionally, the kinase inhibition profile of the agent may uniquely position it for use in these MDS/MPN overlap syndromes.

Andrew Kuykendall, MD, discusses the rationale behind choosing to evaluate fedratinib in a phase 2 study for patients with atypical chronic myeloid leukemia, chronic neutrophilic leukemia, MDS/MPN-unclassifiable, and MDS/MPN-ring sideroblasts and thrombocytosis.


Impact of Non-ABL1 Mutations on Outcomes in Chronic Myeloid Leukemia

Akriti Jain, MD, Department of Hematology and Medical Oncology, Cleveland Clinic, discusses her presentation from the 2024 American Society of Hematology Meeting and Exposition, where she presented findings on how non-

 mutations influence outcomes for patients with chronic myeloid leukemia (CML).

With advancements enabling near-normal life expectancy for patients with CML, understanding factors impacting progression and treatment response remains vital. Retrospective data has revealed that mutations like 

 may affect progression rates to advanced disease stages, major molecular remission, and success in treatment-free remission.

Using next-generation sequencing, Jain highlights how the team analyzed patients in the chronic phase of CML to explore how such mutations impacted overall survival, event-free survival, and failure-free survival. These insights could guide personalized treatment strategies and improve long-term outcomes.

 We [were] presenting an abstract on impact of non-

 mutations on outcomes in patients with chronic myeloid leukemia. As we know these days, patients with chronic myeloid leukemia have a life expectancy of normal individuals or people without cancer, so we are always trying to see what we can do to continue to improve these outcomes that we have for our patients [with CML]. And we have seen in small retrospective studies that non-

 can have an impact on rates of progression to blast phase or accelerated phase from chronic phase of CML. It can impact rates of major molecular response or major molecular remission, as well as the success of treatment-free remission.

So, we wanted to see in our center, which is Cleveland Clinic, where we treat a lot of [patients with] CML in chronic phase, and we do have access to next generation sequencing through our in house laboratory, retrospectively, we wanted to look at patients that have had next generation sequencing or mutation testing done in chronic phase CML, if they had mutations, what impact that had on overall survival, event-free survival, and failure free survival.

Akriti Jain, MD, discusses her presentation from the 2024 American Society of Hematology Meeting and Exposition.


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.

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

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.

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


MPNs

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