Symptom Assessments, Guidelines Inform Nurses Whether They Are ‘Moving in the Right Direction’ in MPN Treatment

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Darlene Dobkowski, MA

Although patients with myeloproliferative neoplasms (MPN) often experience many symptoms either related to the disease or from treatment itself, nurses can help patients navigate symptom management and help seek relief, one expert said.

Oncology Nursing News® spoke with Tetyana Furmanets, CRNP, MSN, an oncology nurse practitioner at Penn Medicine Abramson Cancer Center in Philadelphia, to learn more about how nurses can advise patients with MPN on symptom relief and tools available for nurses to gauge treatment responses.

Oncology Nursing News: What are some of the symptoms associated with MPN and what are some ways nurses can help patients manage them?

Furmanets: MPN comes with a lot of symptoms, the most prominent one being probably fatigue. A lot of patients report debilitating, generalized fatigue. That is probably one of the hardest ones to manage as well because there’s no specific targeted agent for that. I recommend [that] our patients continue to exercise as much as possible while listening to their body, going on daily walks while taking time to rest at home. Certain medications that patients are taking for MPN might help with the symptoms of fatigue.

Some of the other symptoms that we see with myeloproliferative neoplasms are itching. That’s one of the big ones. Specifically, patients report severe itching after they take a shower. Our recommendation is either lowering the temperature of the water before taking a shower or using topicals. There is one lotion—which is over the counter—that we use a lot, Sarna cream, which is very helpful for our patients. We recommend applying that after taking a shower while their skin is still wet.

There are some side effects of the myeloproliferative neoplasms that are very tricky to deal with. Some of them may be fevers, which you can take Tylenol, but there comes a point of the disease process where Tylenol is just not helping with it. So promote fluids, hydration. Sometimes that can be very helpful with symptoms of fevers as well as bone pain, which we see a lot with this patient population as well.

Some of the more vague symptoms that we see is difficulty with concentration, which is a little hard to get out of the patients to talk more about, but when you ask them about it, they’re like, ‘I definitely started noticing I’m having more issues with that.’ This one is a little harder to treat. But I feel like going for those walks and trying to like breaks, take rest and listen to your body and don’t push it too hard, have been definitely helpful.

The other big one we see with myeloproliferative neoplasms is getting full after a few bites of food. A lot of patients are not able to finish full meals because of their spleen size. They have some discomfort associated with their spleen. That comes hand in hand along with fatigue and is probably one of the biggest symptoms we see in this patient population. Again, some of the treatments help with reducing the spleen size. When patients do experience that, they’re so grateful and they feel amazing. They’re like, ‘I could finally finish a full plate and I’m able to sleep on that side.’ So that’s very encouraging.

Unfortunately, sometimes patients don’t respond that well to treatment, so they’ll experience some of that left-sided abdominal pain. We work with nutritionists a lot for those patients; we encourage them to [try] some small, frequent meals that are high-protein, high-calorie content, so that even though they’re not getting a lot of food in at one time, they are still getting their adequate nutrition and their caloric amount during the day.

We work a lot with our palliative care team to help with the pain management aspects when we get to severe cases of myelofibrosis. Pain medication might help with that, as well [as] avoiding sleeping on that side, avoiding certain types of activity or exercise to avoid more trauma to the spleen.

Are there tools that nurses can use to educate their patients about the side effects?

I utilize NCCN guidelines a lot during the treatment phase. We use an MPN treatment symptom assessment during our visits. It’s a questionnaire; patients score [their symptoms] on a scale from zero to 10, zero being no symptoms at all and 10 being the worst imaginable. It lists all of the most common symptoms, fatigue, pain, itching, abdominal pain. It is very helpful as far as determining where the patients are on the scale of the severity.

It might be beneficial if the nurses utilize it and give it to the provider, something to compare it to because a lot of times when you ask the patients, how are you feeling and they’re telling you they feel fine. And when you give them the questionnaire it’s like everything’s like nine or 10 out of 10, so you have to dig a little deeper with those questions.

It is a very tricky disease to manage because everybody’s so different as far as that goes. But we have been utilizing that symptom assessment form a lot and have been helpful to determine if we’re moving in the right direction or making any progress, if we are addressing those symptoms at all.

What’s the most important thing for nurses to keep in mind when caring for patients with MPN who are experiencing symptoms?

Unfortunately, a lot of treatments don’t work overnight. It takes weeks to a month to fully kick in. It can be very frustrating for our patients. We have a lot of patients who are coming in and reporting that they just started this medication, they’re still not feeling too great, and they get a little discouraged. Reinforce that it might take some time for the medication to kick in.

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Research Reveals Potential Achille’s Heel in Treatment-Resistant MPN

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Research By: Mohammad Azam, PhD

Post Date: August 21, 2023

Cincinnati Children’s experts show, in mice, that targeting DUSP1 eradicates JAK2 mutated MPN

Myeloproliferative neoplasms (MPNs) are malignant bone marrow diseases that cause dangerous overproduction of red blood cells, white blood cells, and/or platelets. These conditions mostly strike adults around age 60 but can occur at any age. Some of these patients ultimately develop acute myeloid leukemia (AML).

Based on successes achieved in treating chronic myeloid leukemia (CML) with a class of drugs called ABL tyrosine kinase inhibitors (TKI), cancer researchers had high hopes that a similar class of drugs called JAK2 inhibitors would be a breakthrough for treating MPNs. However, clinical studies have found that JAK2 inhibitors are ineffective.

Now, a study recently published in the journal Leukemia reports achieving curative response in mice when they selectively knock-out a negative regulator of MAPK signaling: DUSP1. This highly complex study took a team of scientists at three institutions seven years to complete. The work was led by senior author Mohammad Azam, PhD, Divisions of Cancer Pathology and Experimental Hematology and Cancer Biology.

“This study, for the first time, provides mechanistic understanding why JAK2 inhibitors are ineffective in vivo and how JAK2V617F signaling suppresses P53 function required for MPN transformation and progression,” Azam says. “Selective targeting of DUSP1 opens up a completely novel therapeutic approach and a potentially curative treatment outcome in MPNs.”

OVERCOMING DEAD ENDS

Inspired by the clinical efficacy of TKI therapy for treating CML, a race began to identify similar molecular drivers in MPN that could be targeted for intervention.

Scientists initially found mutations of interest within three genes JAK2, MPL, and CALR. Further study of mouse genetic models revealed that all the mutations produced a common outcome: elevated and persistent JAK-STAT and MAPK signaling. This provided a strong rationale for developing small molecule inhibitors to target JAK2 kinase activity.

Numerous JAK inhibitors have been assessed in MPN and myelofibrosis (MF), another rare, chronic blood cancer. So far, three JAK2 inhibitors are approved by the FDA to treat MPN and MF while almost a dozen JAK inhibitors are currently undergoing pre-clinical and clinical assessment for potentially treating conditions such as arthritis, psoriasis, inflammation, graft-versus-host disease (GVHD), and autoimmune disorders.

However–unlike the success of TKI therapy in CML–JAK2 inhibitors do not induce remission. Instead, they simply slow cell division. Similarly, inhibitors targeting the MAPK pathway by blocking MEK1/2 or ERK1/2 either alone or in combination with JAK2 inhibitors failed to induce remission.

“Even the most potent kinase inhibitors failed to kill MPN cells in vivo,” Azam says.

It became clear that other mechanisms must be involved in preventing the effectiveness of JAK2 inhibitors. In prior studies, Azam’s lab had explored another mouse model of MPN that involved a different cancer cell growth factor called BCR-ABL kinase. That work revealed that growth-factor signaling in the context of oncogenic signaling induces the expression of c-FOS and DUSP1 that causes resistance to TKI treatment.

Inflammatory cytokine signaling is one of the cardinal features of MPN, with about 60 different cytokines induced in the context of these conditions. Azam reasoned that inflammatory cytokine signaling drives TKI persistence in JAK2 targeted MPNs.

ZEROING IN ON DUSP1

 In addition to Azam, the research team on this project included first author Meenu Kesarwani, PhD, Division of Pathology; H. Leighton Grimes, PhD, director of the Cancer Pathology Program; and six other members of the pathology division at Cincinnati Children’s. Experts from the Medical College of Wisconsin and the Memorial Sloan-Kettering Cancer Center also contributed.

The team worked for seven years to conduct numerous experiments to tease apart the reasons for the persistent cellular resistance to JAK2 inhibitors in MPN. The co-authors conducted an extensive set of genetic analyses that revealed deregulation of 19 genes in TKI resistant cells. Ultimately, the team focused on DUSP1 because this gene appears to dampen the MAPK signaling that suppresses the P53 apoptotic pathway.

NOVEL APPROACH FOR MPN THERAPY

Importantly, their work revealed that mice lacking DUSP1 exhibit normal growth and reproduction, thus supporting the notion that a treatment targeting this gene’s function would have minimal side effects.  When mice without the DUSP1 gene were further tested, the team gained crucial insight into the cell signaling mechanisms that help MPNs resist JAK2 inhibitors.

“In essence, inflammatory cytokine and JAK2V617F signaling converge to induce the expression of DUSP1, which prevents the function of P53.” (See figure)

P53 is often referred to as the “guardian of the genome” due to its role in regulating diverse external or internal stresses, such as DNA damage, activation of oncogenes, nutrient deprivation, and hypoxia. Importantly, it plays a critical role in deciding the cell fate, cell death or division arrest for DNA repair. Consequently, it plays a significant role in treatment outcomes to chemotherapy as most resistant patients harbor P53 inactivating mutations.

NEXT STEPS

While the genes and signaling pathways involved in the mouse research also appear to exist in humans, much more research is needed to determine whether a selective eradication of DUSP1 can be achieved to cure JAK2-induced MPN, Azam says.

Meanwhile, co-authors say the new discoveries about how to control growth factor signaling in MPN cells may also lead to improved treatments for other forms of cancer.

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Double funding success to improve detection and risk classification of myeloproliferative neoplasms (MPNs)

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August 21, 2023

Blood Cancer UK and Cancer Research UK recognise the need and impact of artificial intelligence approaches developed by Professor Daniel Royston and Professor Jens Rittscher for early detection and assessment of these blood cancers.

Cancer Research UK and Blood Cancer UK have awarded funding to a multidisciplinary team from the University of Oxford. These awards will help to advance the AI-based methods and predict the progression of myeloproliferative neoplasms (MPNs) more accurately.

MPNs are a group of closely related disorders of the bone marrow affecting around 5000 people every year in the UK. Patients with MPNs are at higher risk of developing leukaemia, especially those with a subtype called myelofibrosis (the most severe) where this develops in >10% of patients.

Because the treatment strategy varies depending on the MPN subtype, accurate assessment of MPN type at diagnosis is crucial for optimal treatment selection. In addition to mutational and blood count analysis, morphological analysis of a bone marrow biopsy is a key component for classification. Unfortunately, this is highly subjective, reliant on qualitative observations and there is great variability even when it is done by expert haematopathologists.

There is unmet clinical need for a more accurate method for diagnosing MPN from a bone marrow biopsy. The team, led by Professor Daniel Royston (Radcliffe Department of Medicine and Oxford University Hospitals NHS Foundation Trust) and Professor Jens Rittscher (Institute of Biomedical Engineering and Big Data Institute), have already developed artificial intelligence approaches to help pathologists extract quantitative data from scanned images of bone marrow biopsies. These algorithms will enable more accurate and reliable classification of MPN type.

With the new funding, the team now wish to refine and validate these methods with the aim of integrating them into existing NHS pathology workflows to bring about earlier diagnosis of MPNs in the clinic. Importantly, this work will include input from patient representatives from the Oxford Blood Group. They will give feedback on the visualisation tools designed to help patients better understand what’s happening in their bone marrow and the progress of their disease.

Better diagnostics and management of MPN disease are key priorities for our patients. Receiving this funding from Cancer Research UK and Blood Cancer UK will allow us to make significant progress towards our aim of applying our AI-based tool for more accurately diagnosing MPN type in the clinic so that patients can benefit. – Professor Daniel Royston (Radcliffe Department of Medicine and Oxford University Hospitals NHS Foundation Trust), research lead.

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Evolving Drug Classes Expand Treatment Options Across Hematologic Malignancies

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August 18, 2023

Ashling Wahner

Individualized myelofibrosis treatment begins with correctly identifying a patient’s disease subtype and considering their symptoms, from which accurate decisions regarding the use of JAK inhibitors vs radiation vs hypomethylating agents (HMAs) can lead to spleen and symptom burden reductions, according to Raajit K. Rampal, MD, PhD.

During an OncLive® State of the Science Summit™ on hematologic malignancies, Rampal and colleagues highlighted the role of JAK inhibitors in myelofibrosis; considerations for CAR T-cell therapy in follicular lymphoma (FL); efficacy and safety findings with asciminib (Scemblix) in chronic myeloid leukemia (CML); the future of BTK inhibitors in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL); unmet needs in diffuse large B-cell lymphoma (DLBCL); and research on the horizon in lower-risk myelodysplastic syndrome (MDS).

Rampal, who chaired the event, is the director of the Myeloproliferative Neoplasms Program and an associate attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.

Rampal was joined by his colleagues:

  • Alexander P. Boardman, MD, assistant attending physician, Memorial Sloan Kettering Cancer Center
  • Michael J. Mauro, MD, leader, Myeloproliferative Neoplasm Program, Leukemia Service, Memorial Sloan Kettering Cancer Center
  • Prioty Islam, MD, MSc, assistant attending physician, Memorial Sloan Kettering Cancer Center
  • Jennifer K. Lue, MD, clinical director, Lymphoma Service, Memorial Sloan Kettering Cancer Center
  • Jan Philipp Bewersdorf, MD, hematology/oncology fellow, Memorial Sloan Kettering Cancer Center

Below, Rampal, Boardman, Mauro, Islam, Lue, and Bewersdorf summarize the main messages from their presentations.

Current and Emerging Treatments in Myelofibrosis

Rampal: [Myelofibrosis] treatment depends on the issue. This is 1 of the major principles in treating [patients with] myelofibrosis. It’s not a monolithic entity. This disease has different manifestations, and we need to treat the manifestation that is causing the patient the major issue. [When] some patients [present with myelofibrosis], anemia is the major [symptom] they’re [experiencing], not spleen [issues]––nothing else, just anemia. For those patients, a JAK inhibitor may not necessarily be the right choice, but [treatments such as] erythropoiesis-stimulating agents [ESAs], danazol, corticosteroids, or even immunomodulatory agents may be an appropriate first-line choice.

However, for patients with symptomatic splenomegaly or constitutional symptoms, JAK inhibitors have made their mark. Compared with [treatments such as] hydroxyurea, JAK inhibitors have superior efficacy, reducing both spleen size and symptom burden. We have 3 FDA-approved [JAK inhibitors] currently.

For other manifestations of this disease, there are other [treatments] we can use. For patients with extramedullary hematopoiesis in the lungs or bones, radiation is appropriate. For patients who are early in their disease, sometimes pegylated interferon can be useful; some data support that. When patients progress to accelerated or blast-phase disease, HMAs are the backbone of therapy, usually in combination with other agents.

CAR T-Cell Therapy in FL

Boardman: CAR T-cell therapy is clearly active in relapsed/refractory FL, with high response rates, and is effective in patients with high-risk disease. Current data suggest that these remissions are durable but given [that FL is] an indolent lymphoma, we need more time to [confirm these data]. Adverse effects [AEs] [including] cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome are common and must be considered when weighing treatment options for patients, especially those who may be frailer. Lastly, the optimal timing of CAR T-cell therapy vs bispecific antibodies and other targeted agents will require further study.

Current and Novel TKIs in CML

Mauro: We might think of ponatinib [Iclusig] being favored [over asciminib] in patients with primary resistance [and] high transcript levels. For patients with compound mutations and pan cytopenias, neither drug may be successful. These can be challenges. Patients with a mixture of intolerance and resistance who have perhaps more preserved response or at least more residual response from prior therapy exposure may have a better AE experience and better long-term outcomes with asciminib, at least speculatively.

The T315I [mutation] is up for grabs. [Either ponatinib or asciminib may effectively target this mutation] because [both drugs seem to have activity there], and we don’t have concerns about the differences in dosing [between] asciminib [and ponatinib].

Looking into the future, other drugs are under further study. Olverembatinib, which is approved In China, is the drug that is closest to ponatinib and is in trials in the United States [US] now. [Regarding] other agents, we have some trials at Memorial Sloan Kettering Cancer Center. The [phase 1] ELVN-001 trial [NCT05304377] is open, [investigating an] ATP-competitive inhibitor that’s probably [similar to] ponatinib in its activity but may be much safer. Some other second-line allosteric inhibitors, such as TERN-701, [will also be investigated in clinical trials].

[The evolution of TKIs in CML is] a good story. A growing number of patients with CML are surviving CML, so survivorship is another effort and project at Memorial Sloan Kettering Cancer Center. The number of patients living with CML in the US will probably be 10 times what it used to be by the middle of the century. Asciminib will be a big help, [because] it offers better safety [than other TKIs]. We’ll see how other trials look.

BTK Inhibitors in CLL and MCL

Islam: BTK inhibition with small-molecule–targeted drugs has transformed the way we treat [patients with] B-cell malignancies over the past decade, ever since the advent of ibrutinib [Imbruvica] in the early 2010s. Newer-generation BTK inhibitors continue to improve safety and efficacy and are now even trying to overcome the resistance mechanisms we’ve seen with covalent BTK inhibitors. These drugs are being studied as monotherapies and have promising efficacy as single agents. [They] are also being combined with already-approved and emerging therapies. This has been a paradigm shift in both CLL and MCL, away from combination chemoimmunotherapy and more intensive therapies like autologous stem cell transplantation, potentially. There’s much to come, and many exciting data will be published in the next couple of years.

Updates in DLBCL Management

Lue: POLA-R-CHP [rituximab (Rituxan), cyclophosphamide, doxorubicin, polatuzumab vedotin-piiq (Polivy), and prednisone], has become the standard of care [(SOC) for patients with DLBCL with an] International Prognostic Index [score of] 2 and activated B-cell biology. We still believe dose-adjusted R-EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab] or more intensive therapies for high-grade B-cell lymphoma or double-hit or triple-hit lymphoma should be the SOC. The role of central nervous system prophylaxis in DLBCL is controversial. [We may] need to develop ways to identify truly high-risk patients, [such as through] novel assays like cell-free DNA to find subclone populations. Long-term follow-up for CD19-targeting CAR T-cell therapies [demonstrated] an overall survival benefit in refractory patients, and bispecific antibodies are having significant efficacy in the relapsed/refractory setting, although patients who relapse after bispecific antibodies and CD19-targeting agents [have] an unmet need.

Updates in Lower-Risk MDS Management

Bewersdorf: The treatment landscape for anemia in lower-risk MDS is finally moving. The [phase 3] COMMANDS trial [NCT03682536] showed luspatercept-aamt [Reblozyl] to be superior to ESA in patients with lower-risk MDS. In the second-line setting, imetelstat seems to be an effective option in ESA-refractory patients, independent of their [disease’s] molecular subtype.

At this point, [the role of] roxadustat is unclear. We’ll see what the final presentation of the [phase 3] MATTERHORN trial [NCT03263091] yields. There are still many open questions in the field. How do we sequence luspatercept and imetelstat? What do intriguing data [regarding] allele fraction reduction [show about roxadustat] as a disease-modifying effect? There’s more work to be done, but finally [we’re seeing] some progress.

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Dr Halpern on the MANIFEST Trial of Pelabresib and Ruxolitinib in Myelofibrosis

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Anna B. Halpern, MD

Anna B. Halpern, MD, physician, assistant professor, Clinical Research Division, Fred Hutch, assistant professor, hematology, University of Washington School of Medicine, discusses key efficacy data from the phase 1/2 MANIFEST trial (NCT02158858) investigating the BET inhibitor pelabresib (CPI-0610) plus ruxolitinib (Jakafi), and highlights the agents clinical significance in patients with myelofibrosis.

The global, open-label, nonrandomized, multicohort study evaluated the efficacy of the JAK inhibitor combination therapy vs pelabresib alone for treatment-naive or pretreated patient populations, Halpern begins. The trial involved 4 separate cohorts. These cohorts included the use of pelabresib in patients with JAK inhibitorpretreated myelofibrosis, pelabresib plus ruxolitinib in patients with ruxolitinib-pretreated myelofibrosis, pelabresib plus ruxolitinib in patients with JAK inhibitor–naïve myelofibrosis, and pelabresib alone in patients with essential thrombocythemia.

Halpern reports that results from the JAK inhibitor–naïve cohort showed that pelebresib plus ruxolitinib reduced spleen volume by at least 35% in 68% of patients, emphasizeing that total symptom score decreased by at least 50% in 56% of patients at 24 weeks. The data cutoff date for these findings was July 29, 2022.

Moreover, exploratory analysis revealed that 28% of patients had a grade 1 or greater improvement in fibrosis, while 29.5% experienced a greater than 25% reduction in JAK2 V617F VAF by week 24, Halpern details. These outcomes are of particular interest because they may indicate the disease-modifying ability of this combination, Halpern explains.

Based on these findings, the ongoing randomized, double-blind, phase 3 MANIFEST-2 trial (NCT04603495) is evaluating upfront pelabresib plus ruxolitinib vs ruxolitinib alone in a larger cohort of patients with JAK inhibitor–naïve myelofibrosis, Halpern concludes. Enrollment to this study was completed in May 2023, and topline findings are anticipated to report out in late 2023.

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Optimizing Hydroxyurea Management Among Patients With Polycythemia Vera

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August 8, 2023

Amber Denham

Results of a retrospective, real-world analysis determined that many patients with chronic myeloproliferative neoplasm (MPN) polycythemia vera (PV) received underdosed hydroxyurea, which led to lower complete response and toxicity rates, as well as proceeded with hydroxyurea regardless of poor clinical or hematological responses. These results highlight the need for more optimized [hydroxyurea] management and intervention in less-than-optimal responders.

“Hydroxyurea is currently the most used cytoreductive therapy for PV patients at high risk of thrombosis, with most patients achieving adequate control of the disease with acceptable tolerance,” Francesca Palandri, MD, Universitaria di Bologna, Bologna, Italy, and coauthors explained. “However, many patients may only obtain a poor response to [hydroxyurea] or develop drug-related toxicities during therapy.”

This study sought to define clinical characteristics associated with the achievement of complete response (CR) to hydroxyurea, investigate whether the type of suboptimal response may influence a decision to switch to ruxolitinib, and assess if a patient achieving CR to hydroxyurea would improve outcome parameters. The analysis included 563 patients with polycythemia vera treated with hydroxyurea for ≥12 months during an observational “PV-NET” Italian study. Among this patient population, 166 patients achieved complete response (CR), 264 achieved partial response (PR), and 133 achieved no response (NR).

In a multivariate analysis, the absence of splenomegaly (P = 0.03), pruritus (P = 0.002), and a median hydroxyurea dose of ≥1 g/day (P < 0.001) remained associated with CR. Overall, 283 patients who received either CR or PR continued hydroxyurea, and 114 patients switched to ruxolitinib. It was noted that many patients continued hydroxyurea despite a PR/NR and that splenomegaly and other symptoms were the main drivers of an early switch.

A median hydroxyurea dose of ≥1 g/day was correlated with more frequent adverse events. In the 449 patients who were receiving only hydroxyurea, rates of thrombosis, hemorrhages, progression, and overall survival (OS) were comparable among the CR, PR, and NR groups.

Palandri et al concluded, “Better [hydroxyurea] management, standardization of the criteria for and timing of responses to [hydroxyurea], and adequate intervention in poor responders should be advised.”

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Advocacy, Education of Individuals With Myeloproliferative Neoplasms Are Important to Support Patient Outcomes

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Erin Hunter, Assistant Editor

Patients with hematologic myeloproliferative neoplasms (MPNs)—a group of rare blood diseases that include primary myelofibrosis, essential thrombocythemia (ET), and polycythemia vera (PV)—should be more active in their treatment plan, according to experts in oncology pharmacy who participated in a Pharmacy Times clinical forum in Chicago, Illinois, in June 2023. “Our role as pharmacists is to give [patients] as much information as we possibly can, then encourage them to move forward with advocating for themselves,” said Krystal Preston, PharmD, BCPS, a senior clinical oncology pharmacist at CVS Health and a clinical pharmacist at the University of Chicago Medicine.

Patients who are serious about taking an active role in their treatment could inspire health care providers to collaborate more, both with them and with other members of the care team, according to discussion leader Zahra Mahmoudjafari, PharmD, MBA, BCOP, FHOPA, clinical pharmacy manager of hematology, blood and marrow transplant, and cellular therapy at the University of Kansas Health System in Mission.

Subtypes of MPNs, ET, and PV typically transform into myelofibrosis, which can subsequently turn into acute myelocytic leukemia (AML). At least 20% of MPNs may transform into AML; therefore, the goal for treatment is to prevent this from occurring, Mahmoudjafari explained.

With more than 90% of patients with PV having a JAK2 mutation, “it is probably, by far, the mutation that we have the most actionable ability to do something about,” Mahmoudjafari said. She noted that there are 3 FDA-approved Janus kinase (JAK) inhibitors for MPN—ruxolitinib (Opzelura; Incyte), fedratinib (Inrebic; Bristol Myers Squibb), and pacritinib (Vonjo; CTI BioPharma Corp)—which were approved based on results from the COMFORT-I (NCT00952289), JAKARTA (NCT01437787), and PERSIST-2 (NCT02055781) pivotal trials, respectively.

Ruxolitinib and fedratinib are primarily for patients with intermediate- or high-risk myelofibrosis, including intermediate-2 risk and primary and post-PV/ET myelofibrosis, Mahmoudjafari explained. Pacritinib is indicated for patients with a platelet count below 50,000; all 3 JAK inhibitors have expected adverse event (AE) profiles, which include thrombocytopenia, anemia, bruising, dizziness, headache, and diarrhea.

Although the only true potentially curative treatment for myelofibrosis is transplant, there is a 30% mortality risk associated with it, Mahmoudjafari said. Further, patient adherence remains a predominant issue in patient care, according to Connor Roth, PharmD, BCOP, hematology/oncology pharmacy specialist with Franciscan Alliance, Inc in Chicago, Illinois. Whether due to dosing schedule, toxicities, cost, or all these reasons, people remain forgetful, Roth said. It is much harder to contact patients with a reminder via phone call because “nobody picks up [a call from] a phone number they don’t know,” Roth added.

Tammy McClellan, PharmD, a clinical oncology pharmacist at Riverside Healthcare in Kankakee, Illinois, said one of the greatest unmet needs she is seeing is timely access to medications. The faster a patient can get on a proper treatment regimen, the better they can prevent a blood-clotting event.

Insurance is another barrier to access; however, pharmacists understand how to work within the system and are best positioned to advocate for patients, according to Roth. Location is equally important for access to medications because patients living close to a city can access treatment centers and pharmacies more easily than those in a rural setting. Patients in cities also have better access to clinical trials, Preston said.

McClellan noted that an unmet patient need is effective communication with care providers. She said patients frequently mention that their provider does not listen to their input often enough.

McClellan said a solution may be individualized patient care. Further, Latha Radhakrishnan, PharmD, BCOP, BCPS, a clinical oncology pharmacist and an assistant professor in the College of Pharmacy at the University of Illinois at Chicago, noted that pharmacists and providers can foster improved individualized care through better organized collaboration with the patient and care team. This can make it easier to manage AEs and drug-drug interactions because treatment can be exceedingly difficult, according to Mahmoudjafari. Therefore, improving AE management can improve patient quality of life. “[Symptoms can be] enough to drive these patients absolutely insane,” McClellan added.

Additionally, financial burden is a significant issue for many patients. For this reason, some clinics have financial navigators who work with pharmacists and patients to coordinate benefits, co-pays, and prior authorization. Other institutions may assign these tasks to specialty pharmacists, who typically have experience with patient assistance programs that help older adults or individuals with limited resources to access affordable medications via grants, foundational support, or other means. Ideally, insurance or patient assistance would be connected to the patient’s electronic medical record, according to Roth. The panelists also emphasized patient education. “I really try to explain to [patients], in layman’s terms, what’s going on and just listen to what their issues are,” Preston said.

The panelists said that a best practice is to provide as much information about the disease state and treatment as possible. Because many patients do not understand their disease state, improving their understanding can provide the patient with more control, which can lead them to feeling better able to express concerns and be their own advocate.

“You can’t make the assumption that the patient already knows [everything],” Mahmoudjafari said. This is especially important because oncologists or other providers may be struggling to keep up with a complicated, changing treatment and guidelines landscape.

“Guidelines are dividing, and there’s so many things to know [about the drugs],” Roth said. “Pharmacists can be the ones to extend the hands of the physicians and be a patient advocate when [the patient] doesn’t always have one.”

Reference

American Society for Clinical Oncology. Pharmacy Times Clinical forum. 2023 American Society of Clinical Oncology Annual Meeting; June 2-6, 2023; Chicago, IL. Accessed July 13, 2023. https://conferences.asco.org/am/attend

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FDA Grants Fast Track Designation to Myelofibrosis, Nasopharyngeal Cancer Therapies

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July 21, 2023

By Matthew Shinkle

The FDA granted fast track designation to two oncology therapies.

Selinexor (Karyopharm Therapeutics) — a selective inhibitor of nuclear export — received the designation for treatment of myelofibrosis, including primary myelofibrosis, post-essential thrombocythemia myelofibrosis and post-polycythemia vera myelofibrosis.

“Selinexor’s unique mechanism of action, XPO1 inhibition, is a novel and potentially fundamental mechanism in myelofibrosis,” Reshma Rangwala, MD, PhD, chief medical officer of Karyopharm, said in a company-issued press release.

The company initiated a pivotal phase 3 trial to assess the efficacy and safety of once-weekly selinexor in combination with ruxolitinib (Jakafi, Incyte) for JAK-naive patients with myelofibrosis. Initial data are expected in 2025.

BRG01 (Biosyngen) — an adoptive immune cell therapy — received the designation for treatment of certain patients with relapsed or metastatic nasopharyngeal carcinoma. The designation applies to use of the agent by patients with Epstein-Barr virus-positive disease.

FDA granted orphan drug designation to BRG01 earlier this year.

  • Karyopharm receives FDA fast track designation for selinexor for the treatment of myelofibrosis (press release). Available at: https://investors.karyopharm.com/2023-07-17-Karyopharm-Receives-FDA-Fast-Track-Designation-for-Selinexor-for-the-Treatment-of-Myelofibrosis. Published July 17, 2023. Accessed July 19, 2023.
  • Biosyngen’s first-in-class cell therapy BRG01 receives FDA fast track designation (press release). Available at: https://www.biosyngen.com/index.php?m=home&c=View&a=index&aid=107. Published July 10, 2023. Accessed July 19, 2023.

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BMS-986158–Based Combos May Provide Another Viable Treatment Approach in Myelofibrosis

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August 4, 2023

Courtney Flaherty

Haifa Kathrin Al-Ali, MD, provides background on the phase 1/2 study of BMS-986158, presents initial efficacy and safety data from the study, and discusses her hope that novel combination regimens like these could achieve the challenging goal of disease modification in myelofibrosis in the future.

The investigational, oral BET inhibitor BMS-986158 administered with either first-line ruxolitinib (Rituxan) or second-line fedratinib (Inrebic) showcased early efficacy and tolerability in patients with intermediate- or high-risk myelofibrosis. These data suggest that strategies combining BET and JAK inhibition can not only address myelofibrosis-related symptoms but may show potential for disease modification, according to Haifa Kathrin Al-Ali, MD.

Findings from the dose-escalation portion of the phase 1/2 CA011-023 trial (NCT04817007) were reported at the 2023 EHA Congress, and showed that both regimens had manageable toxicity profiles. In part 1A of the study, 82% of patients given BMS-986158 plus ruxolitinib experienced an any-grade treatment-related adverse effect (TRAE); this percentage was 75% in part 1B, which evaluated BMS-986158 plus fedratinib. Dose-limiting toxicities (DLTs) occurred in 2 patients in part 1A and 3 patients in part 1B.

Early efficacy data demonstrated that first-line BMS-986158 plus ruxolitinib led to spleen volume reduction (SVR) that became particularly robust by week 24. By week 48, 80% of patients (95% CI, 28%-100%) given the first-line ruxolitinib combination (n = 5) and 50% of those given the second-line fedratinib regimen experienced an SVR of at least 35%. In the ruxolitinib arm, the mean spleen volume change was –46.7% at week 12, –59.9% at week 24, and –56.3% at week 48; in the fedratinib arm, these percentages were –29.1%, -30.8%, and -33.0%, respectively.

“There is still a way to go, but these preliminary data are quite encouraging,” said Al-Ali, a professor of Translational Oncology and head of the Krukenberg Cancer Center at the University Hospital of Halle (Saale) in Germany.

In an interview with OncLive®, Al-Ali provided background on the phase 1/2 study of BMS-986158, presented initial efficacy and safety data from the study, and discussed her hope that novel combination regimens like these could achieve the challenging goal of disease modification in myelofibrosis in the future.

OncLive: What was the rationale for investigating the use of BET inhibitors as monotherapy or in combination with JAK inhibitors in myelofibrosis?

Al-Ali: We know that in patients [with myelofibrosis] there is a NF-κB–mediated pro-inflammatory cytokine profile. [This] leads to a dysregulated bone marrow microenvironment and osteoblastic differentiation, which contributes to the bone marrow fibrosis. It’s rational to use BET inhibitors because they have been shown to reduce or inhibit the expression of BET-targeted oncogenes like c-MYC and MYC.

Please describe the design of this study. Which patients were included this analysis, and what were the key objectives of the research?

This is an open-label, phase 1b/2 study. It mainly included patients with myelofibrosis who had splenomegaly and [had] either intermediate-1 [disease] plus symptoms, intermediate-2 [disease], or high-risk [disease, according to the Dynamic International Prognostic Scoring System]. The trial consisted of a dose-escalation phase followed by a dose-expansion phase. In the dose-escalation phase, there were also 2 parts. Part 1A [involved] first-line treatment with the BET inhibitor plus ruxolitinib in patients who had no previous exposure to ruxolitinib. [Part 1B consisted of] the second-line combination, [where] the BET inhibitor was combined with 400 mg of fedratinib and [was administered] once daily [to] patients with either intolerance or resistance to ruxolitinib.

This was a phase 1 study. [At the 2023 EHA Congress,] we presented the data from the dose-escalation phase, so the primary objective is always safety. The secondary objective was efficacy in terms of SVR. There were some exploratory analyses on JAK2 allele burden as well as bone marrow fibrosis.

According to data presented at the congress, what should be known about the safety of BMS-986158?

Regarding safety, [we] found that both the first-line combination with ruxolitinib or the second-line combination with fedratinib were feasible, tolerable, and the safety profiles were manageable. The main AE was thrombocytopenia, which is a class effect; it’s manageable and transient with dose modification or dose holding. The second major AEs were gastrointestinal [toxicities, including] diarrhea and nausea. Generally, these [effects] were mild, never led to the discontinuation of patients from the trial and were quite manageable.

What were the efficacy findings reported with these combinations?

Regarding efficacy, there are very promising results [showing] SVR of at least 35% from baseline by MRI. In the first-line cohort, there was a rapid and relevant reduction from baseline spleen volume [of at least 35%] in [73%] of patients [at week 12]. This seemed to be sustainable. Looking at SVR at week 24, 100% of patients [experienced] SVR. This is a phase 1 [study], and we should be careful, but these are encouraging results.

[Similar results were seen] with the second-line treatment, although the [duration of] follow-up was shorter. At week 12, at least [38%] of the patients [experienced] more than a 35% reduction in spleen volume. These are also encouraging results.

Finally, evidence for disease modification might be seen regarding JAK2 allele burden reduction. [This was] seen quite early, starting by cycle 6 in all the patients [with] JAK2-mutated [disease]. Additionally, in patients with follow-up bone marrow biopsies that could be evaluated, there seems to be a significant reduction in at least 1 grade of fibrosis by week 12 or week 24. [The study includes a] small number of patients, and these are preliminary, encouraging data. This bone marrow fibrosis regression seems to be associated with a hematological, [specifically] anemic, response.

You mentioned that potential evidence for disease modification may have been observed with this in the form of JAK2 allele burden reduction. In myelofibrosis, what efforts are currently underway to develop disease-modifying therapies that go beyond standard approaches focused on symptom management?

One of the major challenges [in myelofibrosis] is to see [clear evidence of successful] disease modification. All the biomarkers you can measure, like bone marrow fibrosis or a reduction in allele mutational burden, should have a clinical outcome correlation. This is a big challenge.

In the future, it is crucial to move away from only SVR and symptom improvement. We have great drugs that could do that. We have to wait for data from phase 3 randomized trials, and we need time to learn and [understand] the benefit of these combination treatments. My wish is to [achieve] sustainable, durable, clinical responses for patients with these combinations, but this is still an area with a lot of unanswered questions.

Are any next steps planned for the investigation of BMS-986158 in this disease?

The next step [for this research] is going further with the trial. The expansion phase has started for the first-line combination treatment in patients who are ruxolitinib naïve. The same will hopefully be happening for the second-line treatment. If these all [show] positive signals, we will move to a phase 3 clinical trial.

What is your main takeaway message for colleagues regarding this presentation?

The takeaway message is that it is feasible to have these combinations. We have learned how to dose [them] and how to manage AEs, which is the first step [for] every treatment. We have [also] shown encouraging preliminary clinical data regarding SVR, [as well as] some encouraging translational aspects like reduction in JAK allele burden or improvement in bone marrow fibrosis.

Overall, what was most exciting about this year’s EHA Congress?

[This year’s EHA Congress has] been particularly exciting. It is almost [solely] a myeloproliferative neoplasm congress because [there are] so many new, exciting datasets [being presented]—not only for a myelofibrosis, but also for polycythemia vera and essential thrombocythemia. At the end of the day, the most important winners will be the patients.

Reference

Ayala R, Lopez N, Abulafia AS, et al. BMS-986158, a potent BET inhibitor, as monotherapy and in combination with ruxolitinib or fedratinib in intermediate- or high-risk myelofibrosis (MF): results from a phase 1/2 study. Presented at the 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S213.

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New Study Demonstrates Ropeginterferon Alfa-2b-njft Is a Cost-Effective Treatment Option for a Broad Range of Patients with Polycythemia Vera

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Published August 4, 2023

Analysis published in the Journal of Comparative Effectiveness Research shows ropeginterferon alfa-2b-njft provided a cost-effective benefit in quality-adjusted life years compared to a commonly used treatment pathway

BURLINGTON, Mass.–(BUSINESS WIRE)– PharmaEssentia USA Corporation, a subsidiary of PharmaEssentia Corporation (TPEx:6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology and oncology, today announced the publication of a cost-effectiveness analysis of ropeginterferon alfa-2b-njft (marketed as BESREMi®) in the Journal of Comparative Effectiveness Research. The analysis, titled “Cost-Effectiveness of Ropeginterferon Alfa-2b-njft for the Treatment of Polycythemia Vera,” showed that ropeginterferon alfa-2b-njft provided a cost-effective benefit for a broad range of patients with polycythemia vera (PV) versus first-line hydroxyurea followed by ruxolitinib. Cost effectiveness was demonstrated in a modeled population including both low- and high-risk patients receiving first- or second-line treatment with ropeginterferon alfa-2b-njft.

“PV is a chronic blood cancer that requires lifelong therapy, which can prevent or delay negative clinical outcomes, but is also associated with additional costs to patients and payers. These new data demonstrate ropeginterferon alfa-2b-njft’s value not only to people living with PV, but also to the healthcare system at large,” said Dr. Aaron Gerds, MD, MS, Medical Director at Case Comprehensive Cancer Center and lead study author. “This study shows ropeginterferon alfa-2b-njft is a cost-effective treatment option over the modeled lifetime and that earlier initiation of treatment of PV with effective therapy can translate to more favorable cost to benefit ratios.”

PV is the most common myeloproliferative neoplasm (MPN) and a long-term, potentially life-threatening disease with limited approved treatment options. Patients with PV are at risk for disease progression to myelofibrosis (post-PV MF) or transformation to blast phase (MPN-BP) which is akin to acute myeloid leukemia1-3. Patients are also at an increased risk for arterial and venous thromboembolic events (TEs) which are associated with higher mortality, lower quality of life, and higher healthcare costs4-7.

This new study used an economic model developed from the United States healthcare system perspective. Inputs were informed by the data from randomized clinical trials, including the PROUD-PV and CONTINUATION-PV studies, and from real-world sources. The model compared ropeginterferon alfa-2b-njft used either as first- or second-line therapy versus an alternative treatment pathway of first-line hydroxyurea followed by ruxolitinib. To reflect the long-term consequences of treating PV, results were presented over a lifetime horizon.

Findings from the study conclude ropeginterferon alfa-2b-njft is a cost-effective treatment option for a broad range of patients with PV, including both low- and high-risk patients and patients with and without prior cytoreductive treatment with hydroxyurea. Of note:

  • These data show that over the modeled lifetime, patients who receive ropeginterferon alfa-2b-njft have more years alive (0.4), higher quality-adjusted life years (QALYs) (0.4), and higher cost ($60,175) as compared to the alternative treatment pathway. Weighing the additional costs versus the additional QALY gains results in a cost per QALY of $141,783.
  • This cost per QALY is less than a standard willingness to pay threshold of $150,000 per QALY8.
  • In this study, treating patients at a younger age or those with low-risk disease led to more cost-effective results, suggesting that earlier initiation of treatment of PV with effective therapy can translate to more favorable cost to benefit ratios.
  • The model was sensitive to treatment costs, the percentage of patients who discontinue hydroxyurea, the percentage of ropeginterferon alfa-2b-njft users who switch to monthly dosing, the percentage of ropeginterferon alfa-2b-njft users as 2nd line treatment, and the treatment response rates.

“Ropeginterferon alfa-2b-njft has demonstrated safety and efficacy in studies including both low- and high-risk patients and patients with and without prior cytoreductive treatment with HU. Recently, the National Comprehensive Cancer Network (NCCN) updated their treatment guidelines to include ropeginterferon as a preferred treatment regimen for both low- and high-risk PV patients9. As ropeginterferon continues to be more widely used in clinical practice, this study was imperative to demonstrate the cost-effectiveness of ropeginterferon alfa-2b-njft for a broad range of patients with PV,” said Raymond Urbanski, M.D., Ph.D., Senior Vice President and U.S. Head of Clinical Development and Medical Affairs at PharmaEssentia. “This analysis also underscores the importance of treating low-risk patients and patients early in their disease journey to help minimize more severe events and their corresponding costs to the healthcare system.”

The full benefits of ropeginterferon alfa-2b-njft may not be fully captured in the model, and in particular, data on disutility of phlebotomy are lacking. Although some patients may tolerate regular phlebotomies, others can experience iron deficiency which can negatively impact quality of life. While the results from a scenario analysis incorporating a small decrement in utility had minimal impact on the cost-effectiveness results, due to the lack of data in this area, this estimate remains conservative. This study took a U.S. healthcare perspective, and the results may not generalize to other countries given the differences in healthcare resource use, costs and cost-effectiveness thresholds.

About Polycythemia Vera (PV)

Polycythemia vera (PV) is a cancer originating from a disease-initiating stem cell in the bone marrow resulting in a chronic increase of red blood cells, white blood cells, and platelets. PV may result in cardiovascular complications such as thrombosis and embolism, and often transforms to secondary myelofibrosis or leukemia. While the molecular mechanism underlying PV is still subject of intense research, current results point to a set of acquired mutations, the most important being a mutant form of JAK2.10

About BESREMi® (ropeginterferon alfa-2b-njft)

BESREMi is an innovative monopegylated, long-acting interferon. With its unique pegylation technology, BESREMi has a long duration of activity in the body and is aimed to be administered once every two weeks (or every four weeks with hematological stability for at least one year), allowing flexible dosing that helps meet the individual needs of patients.

BESREMi has orphan drug designation for the treatment of polycythemia vera (PV) in adults in the United States. The product was approved by the European Medicines Agency (EMA) in 2019, in the United States in 2021, and has recently received approval in Taiwan and South Korea. The drug candidate was invented by PharmaEssentia and is manufactured in the company’s Taichung plant, which was cGMP certified by TFDA in 2017 and by EMA in January 2018. PharmaEssentia retains full global intellectual property rights for the product in all indications.

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