Category Archives: Myelofibrosis

Research Nurse Breaks Down Myelofibrosis-Related Anemia

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Brielle Benyon

Anemia is a common and potentially dangerous condition that can occur in patients with myelofibrosis, a type of myeloproliferative neoplasm. While anemia is a blanket term that describes low hemoglobin levels, myelofibrosis-related anemia behaves quite differently than anemia in patients with a blood cancer diagnosis, explained Sharon Bledsoe.

Bledsoe, a senior research nurse at The University of Texas MD Anderson Cancer Center in Houston, recently explained myelofibrosis-related anemia, including its cause and treatment.

CURE®: What causes anemia in patients with myelofibrosis?

Myelofibrosis is basically a disease in which the bone marrow gets replaced by connective tissue in a process called fibrosis. The bone marrow’s main objective is to produce blood cells, and in producing the blood cells — the red blood cells, the white blood cells and the platelets. When the fibrosis interferes with the production of the cells, scar tissue starts to form in the bone marrow, and the bone marrow is the soft spongy tissue in the center of the bones.

As the scar tissue starts to grow, the bone marrow loses its ability to make enough healthy blood cells. So, it produces too many abnormal blood cells. The lifespan of a true red blood cell or of a normal human red blood cell is 120 days, which is about roughly four months. When you have a patient dealing with myelofibrosis, with the scarring and all of that, they’re producing the red blood cells, but they’re not maturing; when they’re not mature, they die off faster. So, they’re producing a whole lot a whole lot, but they’re dying fast. Then you have the anemia that starts because they’re not living for enough time, so they’re not getting four months of life; within days, weeks, they’re dying off.

How is myelofibrosis-associated anemia treated?

When patients’ (hemoglobin levels) start to get low, we start to monitor their trends. We monitor their hemoglobin; we start to monitor in to see if they’re if they are going to need a transfusion. And if they need transfusions, how often are they needing the transfusions? So we’re going to monitor all of that, whether they need the transfusions and how often they need the transfusions.

That’s one way that it’s treated.

And then doctors may put them on drugs that will help the anemia, drugs like danazol and Jakafi (ruxolitinib). When those red blood cells are being produced so quickly, there’s not enough room within the bone marrow, so (they) go into the spleen, or into the liver, which is now causing them to have enlarged spleens and enlarged liver. And sometimes, because it can’t be treated, the spleen has to be removed.

(Jakafi) can take the spleen size down. However, with (Jakafi), you fall into the area where they can get skin cancers, secondary skin cancers, squamous cell carcinoma, basal cell carcinoma and things like that; you have to really, really watch for that. In treating the anemia, you have to watch for so many other things that may crop up.

What is the difference between myelofibrosis-related anemia and general anemia that is experienced in patients without an MPN?

There is a major difference, because anemia that a person would have that doesn’t have cancer presents differently than the anemia (related to MPNs). For a person who has a blood cancer, their anemia is going to come with other things (such as) possibly filling up faster (when eating), night sweats (and) extreme fatigue. And some of them have (feelings of) wanting to faint because the hemoglobin is so low.

In a person that has just routine anemia, they won’t have those types of symptoms, they’ll just probably feel a little tired or a little sluggish.

What advice do you have for patients with myelofibrosis who may be experiencing anemia?

We tell the patients to let us know if you have increased fatigue, let us know if any of your symptoms change, you have increased fatigue, you have increased night sweats, you start having fevers or things like that, let us know if any of those things are taking place. That way, I can give that information to the to the oncologist and then they know what to do for the patient.

Make sure that you are proactive as a patient, if there’s something that’s wrong, and you know that it hasn’t been an issue before, make sure that you follow up and follow through, don’t just accept (symptoms). If you have to go to 5 doctors, go to as many as it takes to get the diagnosis, because with time, time loss is not time that can be regained. So, you need to be proactive and monitor your care and know what your norms are and what’s not normal for you.

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Current Approaches to Diagnose and Treat Primary Myelofibrosis

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Targeted Oncology Staff

During a Targeted Oncology™ Case-Based Roundtable™ event, Rami Komrokji, MD, discussed elements to diagnosing myelofibrosis and how to approach risk stratification before treatment.

KOMROKJI: MF could be either primary de novo or coming from secondary from essential thrombocythemia [ET] or polycythemia vera [PT]. [Concerning] the major criteria listed [by the World Health Organization (WHO)], I always bring up the 2 points that not every fibrosis in the bone marrow is myelofibrosis.1 You can see it in lymphomas, hairy cell leukemia, connective tissue disease, etc, and you don’t need fibrosis in the early stages of myelofibrosis to make the diagnosis. The classical megakaryocytic atypia is enough and in the prefibrotic MF, that’s enough to diagnose the disease.

Prefibrotic MF is a relatively new entity that we talk about. Many patients in practice are labeled as ET, and sometimes it’s hard to tease those [differences] out. But those are the patients who we would think have ET, and in 3 to 4 years, they have overt MF. Usually, it will it take a decade to get there, but if a patient had ET and then in 3 or 4 years was in [overt] MF, those probably were patients with prefibrotic MF. There are few clues…most of the time, those patients will have high LDH [lactate dehydrogenase], on the bone marrow there will be more hypercellular granulocytic hyperplasia. There is more clustering of the megakaryocytes.

Currently, we manage them almost the same, but those are the patients who will transform earlier, at higher risk of leukemia. Maybe in the future, those are the patients we will target with some more interventions to try to prevent the overt MF.

The presence of a clonal marker excludes other diseases. [However], myelodysplastic syndrome [MDS] with fibrosis is sometimes hard to distinguish. Fibrosis can be seen in MDS; it’s typically associated with bad outcomes and the new WHO classification with the blast increase has MDS with fibrosis [as a] category on its own. In the clinical phenotype, they typically don’t have the hepatosplenomegaly as much as constitutional symptoms. They’re cytopenic, more like MDS. If a good pathologist sees myeloid or erythroid dysplasia, that will favor MDS with fibrosis. The megakaryocytes are tricky because you always see megakaryocytic atypia in MPNs [myeloproliferative neoplasms], and it depends on how experienced the hematopathologist is. If they are mistakenly calling them dysplasia, that could be deceiving. There are some minor criteria: the anemia, leukocytosis, splenomegaly, LDH, and leukoerythroblastosis.

What is the role of risk stratification when treating patients with MF?

Once we establish the diagnosis, we want to risk stratify the patients and there are many models in MF, 3 or 4 clinical and 2 molecular. I like the MIPSS70 [MIPSS70: Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients With Primary Myelofibrosis] most because it’s comprehensive and it was designed to look at the question of transplant or not in younger patients not counting the age as a factor.2 Anemia, transfusion dependency, thrombocytopenia, and leukocytosis… [lead to poor prognosis]. Circulating blasts, unfavorable karyotype, [etc], all of those are weighed in these models. Molecular models…account for bad mutations like ASXL1, SRFS2, or absence of calreticulin. But at the end, we are putting the patients into a spectrum of a low-risk disease, where the survival spans many years, to a high-risk disease where the survival is less than 2 years.

Why is it important to use prognostic models for MF?

The disease risk value in practice is deciding on transplant. If somebody is not eligible for stem cell transplant [SCT], you may argue that those models are not that important. Somebody who’s very low risk will rarely be symptomatic, because if they have any symptoms, they probably move up to intermediate-1 risk.

If somebody’s survival estimate is 2 to 3 years, or an intermediate-2 or higher risk by any of those models, we think of the SCT earlier on in the course of the disease [to consider if they are] eligible for transplant by functional status and comorbidities, not necessarily by age. The second thing is [having] enough disease risk to justify the SCT. In patients who have higher risk, the timing of the transplant is probably early on. In patients with lower risk, even if they are eligible for SCT, the optimal timing is probably to try to delay the SCT. It’s always a hard decision because you don’t want to go too early [because of] upfront transplant-related mortality. But you also never want to go into an MPN accelerated phase or acute myelocytic leukemia from MPN because those diseases have terrible outcomes.

What recommendations are there for treatment of higher-risk myelofibrosis?

Once we label the patients intermediate or higher risk, we are assessing the symptoms and deciding on treatment. We rarely see patients who just [have] transfusion-dependent anemia. Those patients are probably not the classical candidates for JAK2 inhibitors, at least the classical ruxolitinib [Jakafi] or fedratinib [Inrebic].

[For] most patients…you’re treating either constitutional symptoms or splenomegaly. For those patients, JAK2 inhibitors are reasonable. The National Comprehensive Cancer Network guidelines split that choice of JAK2 inhibitor based on the platelet count.3 If it’s below 50 × 109/L, pacritinib [Vonjo] is the choice; if it’s above 50 × 109/L, [the choice is] ruxolitinib or fedratinib. Most [physicians] are more used to ruxolitinib, [it has] more data…but fedratinib is a reasonable option as well. Sometimes I think even a platelet cutoff of 100 × 109/L would be reasonable to consider pacritinib; the platelet cutoff of 50 × 109/L was for the truly unmet need and accelerated approval of pacritinib.

If patients are candidates for SCT, many times we do start the JAK2 inhibitors before the SCT because the SCT will still take 3 to 4 months to happen. If patients have a big spleen [and] poor performance from the disease, shrinking the spleen and getting them ready for SCT is reasonable.

The 3 available JAK2 inhibitors, ruxolitnib, fedratinib, and pacritinib…have different targets. Ruxolitinib targets JAK1/JAK2, [and has] potent JAK1 [activity]. Pacritinib has different targets; it doesn’t have any JAK1 activity. It has some ACVR1 [activity] so some anemia response can be explained through that [and] other inflammatory pathways like IRAK1. Fedratinib also has some FLT3 activity and some JAK1 activity. Momelotinib has JAK1 and ACVR1 activity.

The choices are based on the cytopenia profile. Fedratinib most of the time is positioned as second line after ruxolitinib in patients that are still proliferative. Ruxolitinib is the first line in patients that are proliferative, not cytopenic. Pacritinib is for thrombocytopenia and when we have approval for momelotinib, hopefully that will be for the anemia phenotype.

References:

1. Barbui T, Thiele J, Gisslinger H, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018;8(2):15. doi:10.1038/s41408-018-0054-y

2. Guglielmelli P, Lasho TL, Rotunno G, et al. MIPSS70: Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients With Primary Myelofibrosis. J Clin Oncol. 2018;36(4):310-318. doi:10.1200/JCO.2017.76.4886

3. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 2.2023. Accessed September 7, 2023. https://tinyurl.com/yw9ka77m

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Prognostic Model Could Help Predict Survival Outcomes for Patients With Myelofibrosis Undergoing AlloHCT

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Megan Hollasch

A predictive system developed using data from United States and European stem cell transplant registries was prognostic of survival in patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation.

A predictive system developed using data from United States and European stem cell transplant registries was prognostic of survival in patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation (alloHCT), according to data from a retrospective study published in Blood Advances.

United States patients with myelofibrosis who underwent allogeneic hematopoietic cell transplantation from an HLA-matched related/unrelated donor or unrelated HLA-mismatched donor and had data available from the Center for International Blood and Marrow Transplant Research (CIBMTR) from 2000 to 2016 were included in the study (n = 623). Then, investigators assigned a weighted score using these factors to a cohort of patients who received a transplant in Europe (European Bone Marrow Transplant [EBMT] cohort; n = 623).

Study authors created the prognostic scoring system after a Cox multivariable model was used to identify factors prognostic of mortality. An age of more than 50 years (HR, 1.39; 95% CI, 0.98-1.96) and an HLA-matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with an increased risk of death and were each assigned 1 point. Hemoglobin levels less than 100 g/L at the time of transplantation (HR, 1.63; 95% CI, 1.2-2.19) and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25-2.52) were also found to be related to an increased risk of death, and these were each worth 2 points. Patients with 1 to 2 points were deemed to have a low score, 3 to 4 points was an intermediate score, and 5 points was a high score.

At 3 years, the overall survival (OS) rate for the CIBMTR cohort was 69% (95% CI, 61%-76%) for patients with a low score, 51% (95% CI, 46%-56.4%) for those with an intermediate score, and 34% (95% CI, 21%-49%) for those with a high score (P < .001). Using the low-risk group as reference, the intermediate-risk group had a HR of 1.64 (95% CI, 1.23-2.18), and the high-risk group had an HR of 2.65 (95% CI, 1.70-4.14; overall P = .0002).

“Increasing score was predictive of increased transplant-related mortality [TRM; P = .0017] but not of relapse [P = .12],” lead study author Roni Tamari, MD, and colleagues wrote. Tamari is an assistant attending physician and bone marrow transplant specialist at Memorial Sloan Kettering Cancer Center in New York, New York.

Additionally, the 3-category system was predictive for disease-free survival (DFS) in the intermediate-risk group (HR, 1.44; 95% CI, 1.14-1.81) and high-risk group (HR, 1.83; 95% CI, 1.24-2.71; overall P = .0015). It was also predictive for TRM in the intermediate-risk group (HR, 1.63; 95% CI, 1.10-2.44) and high-risk group (HR, 3.09 (95% CI, 1.75-5.48; overall P = .0017).

In the EBMT cohort, the 3-category system was prognostic of OS (P = .0011), DFS (P = .0007), and TRM (P = .0021), but it was not predictive of relapse (P = .1673).

The study included data from patients at least 40 years of age with myelofibrosis who underwent alloHCT. Patients were excluded if they underwent syngeneic umbilical cord blood or mismatched related-donor transplantation, had graft-versus-host disease (GVHD) prophylaxis by ex vivo T-cell depletion or CD34-positive selection procedure, or unknown GVHD prophylaxis. Additionally, those with donor data, diagnosis date, or complete 100-day follow-up data missing were excluded.

Patients in the CIBMTR and EBMT cohorts had a median age of 54 years (range, 40-75) and 52 years (range, 40-74) at diagnosis, respectively, and were mostly males (63% and 68%). Before alloHCT, Karnofsky performance status scores were between 90 and 100 in 60% and 50% of patients, respectively. At diagnosis, patients in the CIBMTR and EBMT cohorts had myelofibrosis (87% and 80%), polycythemia vera (5% and 8%), essential thrombocythemia (8% and 8%), and polycythemia vera/essential thrombocythemia (0% and 3%). Spleen status was normal (21% and 13%), splenomegaly (72% and 49%), or splenectomy (4% and 14%), and patients had received 0 (24% and 37%), 1 (41% and 20%), 2 (17% vand3%), or at least 3 (16% and 3%) prior lines of pretreatments. JAK2 mutations were present in 32% and 34% of patients, respectively, and the rates of patients who received ruxolitinib (Jakafi) were 28% and 14%, respectively.

Patients in the CIBMTR cohort had a Dynamic International Prognostic Scoring System score before alloHCT of low (12%), intermediate-1 (45%) intermediate-2 (38%), or high (2%). Cytogenetics were either normal (40%), other (18%), unfavorable (18%), or not tested (5%).

The median time from diagnosis was 18 months (range, 2-294) and 26 months (range, 2-268) in the CIBMTR and EBMT cohorts, respectively. Donors included an HLA-identical sibling (35% and 75%), well-matched unrelated donor (52% and 17%), and partially matched unrelated donor (13% and 8%). Sex matches of donor and recipient were male to male (41% and 41%), male to female (22% and 27%), female to male (22% and 17%), and female to female (15% and 15%), respectively. Additionally, patients received a graft from peripheral blood (89% and 90%), did not receive total body irradiation (84% and 85%), and received myeloablative (46% and 29%), reduced intensity (47% vs 71%), or nonmyeloablative (6% vs 0%) conditioning regimens.

At diagnosis, patients in the CIBMTR and EBMT cohorts had blast in peripheral blood of greater than 1% (14% and 17%), a hemoglobin level of greater than 100 g/L (35% and 34%), a white blood cell count greater than 25 × 109 /L (9% and 8%), a platelet count of 50 × 109 /L to 100 × 109 /L (13% and 14%), and constitutional symptoms (29% and 28%), respectively.

Before alloHCT, patients in the CIBMTR and EBMT cohorts had blast in peripheral blood of greater than 1% (30% and 32%), a hemoglobin level of greater than 100 g/L (71% and 66%), a white blood cell count greater than 25 × 109 /L (13% and 15%), a platelet count of 50 × 109 /L to 100 × 109 /L (21% and 17%), and constitutional symptoms (17% and 29%), respectively.

In the CIMBTR cohort, the 1-, 3-, and 5-year OS rates were 65.7% (95% CI, 61.9%-69.4%), 54.6% (95% CI, 50.4%-58.7%), and 49.9% (95% CI, 45.5%-54.3%), respectively. TRM rates at 1, 3, and 5 years were 20.6% (95% CI, 17.4%-23.9%), 24.7% (95% CI, 21.3%-28.3%), and 27.1% (95% CI, 23.5%-31.0%), respectively.

Additionally, the 1-, 3-, and 5-year DFS rates were 39.7% (95% CI, 35.7%-43.7%), 31.1% (95% CI, 27.3%-34.9%), and 26.5% (95% CI, 22.7%-30.5%), respectively. The relapse rates at 1, 3, and 5 years were 39.7% (95% CI, 35.8- 43.6), 44.2% (95% CI, 40.2-48.3), and 46.3% (95% CI, 42.2- 50.5), respectively.

In the EBMT cohort, the 1-, 3-, and 5-year OS rates were 68.6% (95% CI, 64.9%-72.2%), 55.0% (95% CI, 51.0%-58.9%), and 51.2% (95% CI, 47.1-55.2), respectively. The 3-year TRM rate was 27.9% (95% CI, 24.4%-31.6%), and the 3-year relapse rate was 24.3% (95% CI, 20.9%-27.8%).

Study authors noted that a limitation of the study was that it included patients treated over a long time period, and between 2000 to 2016, changes and advances were made in the field of stem cell transplantation.

“The proposed system was prognostic of survival in 2 large cohorts, CIBMTR and EBMT, and can easily be applied by clinicians consulting patients with myelofibrosis about the transplantation outcomes,” study authors concluded.

Reference

Tamari R, McLornan DP, Ahn KW, et al. A simple prognostic system in patients with myelofibrosis undergoing allogeneic stem cell transplantation: a CIBMTR/EBMT analysis. Blood Adv. 2023;7(15):3993-4002. doi:10.1182/bloodadvances.2023009886

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Momelotinib Could Represent Pivotal New Treatment Option in Myelofibrosis

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Ryan Scott
Aaron T. Gerds, MD, PhD, expands on the potential role of momelotinib in the treatment of patients with myelofibrosis who present with anemia, details the data from MOMENTUM, and explains what FDA approval of momelotinib could mean for the treatment of this patient population.

The benefits in symptom burden, spleen size, and transfusion dependence demonstrated by treatment momelotinib in patients with myelofibrosis represent a potential key advance for this treatment paradigm, according to Aaron T. Gerds, MD, PhD.

A new drug application (NDA) seeking the approval of momelotinib as a potential therapeutic option in patients with myelofibrosis is currently under review by the FDA, and the review period was extended to a target action date of September 16, 2023.1

The NDA is supported by data from the phase 3 MOMENTUM trial (NCT04173494), which evaluated the agent in patients with symptomatic and anemic myelofibrosis who received a prior JAK inhibitor. Data showed that 25% of patients treated with momelotinib (n = 130) experienced a reduction in tumor symptom score of at least 50% at week 24 compared with 9% of patients treated with danazol (n = 65; proportion difference, 16%; 95% CI, 6%-26%; P = .0095).2

Additionally, 39% of patients in the momelotinib arm achieved a spleen volume reduction of at least 25% from baseline to week 24 vs 6% in the danazol arm (P < .0001); moreover, 22% and 3% of patients, respectively, experienced a reduction of 35% or more (P = .0011). At week 24, the rates of transfusion independence were 30% (95% CI, 22%-39%) for momelotinib and 20% (95% CI, 11%-32%) for danazol (noninferiority difference, 14%; 95% CI, 2%-25%; 1-sided P = .0016).

“The potential approval of momelotinib is incredibly important for patients. Having additional agents to treat myelofibrosis would be welcomed. As little as a couple of years ago, we only had 1 approved therapy to treat myelofibrosis,” Gerds said in an interview with OncLive®. Gerds is an assistant professor in the Department of Medicine, a member of the Developmental Therapeutics Program, and medical director of the Case Comprehensive Cancer Center in Cleveland, Ohio.

In the interview, Gerds expanded on the potential role of momelotinib in the treatment of patients with myelofibrosis who present with anemia, detailed the data from MOMENTUM, and explained what FDA approval of momelotinib could mean for the treatment of this patient population. Gerds also serves as an associate professor of Medicine in the Department of Hematology and Medical Oncology at the Cleveland Clinic Taussig Cancer Institute.

OncLive: How could the potential approval of momelotinib affect current and future practice patterns for patients with myelofibrosis?

Gerds: The [potential] approval of momelotinib could be another pivotal moment in the care of patients with myelofibrosis. I would argue that the first pivotal moment was the discovery of recurrent JAK2 mutations, followed several years later by the approval of ruxolitinib [Jakafi], the first JAK inhibitor.

Momelotinib provides an extra opportunity for patients, specifically patients who have anemia along with enlarged spleens and significant symptom burden. This drug promises to try to hit all 3 of those key elements of care in patients with myelofibrosis with a single pill.

What unmet needs exist for patients with myelofibrosis and anemia?

Anemia itself in these patients is a key unmet need. Roughly 40% of patients will be anemic at the time of diagnosis. It is common diagnostic and prognostic criteria that is used to predict who may have aggressive disease. Anemia will also develop in patients within the first year after diagnosis, and at some point, every patient will develop anemia as the [bone] marrow begins to fail. Therefore, anemia is something that is incredibly common and difficult to treat.

We can give red blood cell transfusions to combat anemia, but that comes with adverse effects, such as iron overload, transfusion reactions, and the development of alloantibodies. Moreover, blood is a valuable and somewhat scarce resource. The Red Cross is constantly trying to get us to donate more blood because it is a scarce commodity, and it is also expensive to do red blood cell transfusions. In general, it’s one of the biggest costs in delivering health care for patients with hematologic malignancies. For all these reasons, treating anemia is incredibly important.

Treatments for anemia are somewhat limited. I mentioned transfusions already, and there are also erythropoiesis stimulating agents [ESAs] that can be given. Another drug, luspatercept-aamt [Reblozyl], is already approved to treat anemia in patients with myelodysplastic syndrome and beta thalassemia. It is used off-label to treat anemia in patients with myelofibrosis. danazol is also commonly used.

We already have these 3 agents; however, none of them are perfect or work 100% of the time, and there are still many patients who suffer from anemia who have [myelofibrosis]. Any new agent that is coming along that can potentially treat anemia in a different mechanism of action is always welcome.

What is the mechanism of action of momelotinib, and what prompted this agent’s examination in patients with myelofibrosis?

Momelotinib, in terms of treating anemia, works very differently than ESAs, luspatercept, and danazol. It works by inhibiting ACVR1, also known as ALK2, which is a regulator of hepcidin. Hepcidin is a key piece in what we think about in hematology in iron regulation and red blood cell production. It is a hot topic in myeloproliferative neoplasms right now, and it has been in the world of hematology for some time.

Hepcidin is a master iron regulator that helps regulate the shuttling of iron out of the iron stores, making it available for the body to use, for example, to make red blood cells. In patients with myelofibrosis, they have anemia or an inflammatory block, meaning that hepcidin levels are very high and can shut a lot of those iron stores. By lowering the levels of hepcidin by blocking ACVR1, we can restore effective erythropoiesis by dropping that anemia or inflammatory block. That component of a patient’s anemia can be reversed, potentially by this medication.

What were some of the key efficacy data from MOMENTUM?

The MOMENTUM study pitted momelotinib vs danazol, looking at a couple of key end points. The first was symptom burden reduction, and we also looked at spleen volume reduction—traditional end points for measuring response with JAK inhibitors in patients with myelofibrosis. Another key end point was transfusion independence, and that was the proportion of patients who were transfusion independent at weeks 24 and 48.

We saw that momelotinib outperformed danazol in terms of spleen volume reduction, as well as symptom burden reduction. Momelotinib was also statistically not inferior—this was a non-inferiority analysis—for transfusion independence at week 24 compared with danazol.

What does the safety profile look like for momelotinib in this population?

With respect to safety, one of the early concerns during the development of momelotinib was an increased risk of peripheral neuropathy. This was seen in some earlier studies. However, in subsequent investigations, such as the SIMPLIFY trials [NCT01969838; NCT02101268] and the MOMENTUM study, we did not see excess neuropathy in patients treated on momelotinib compared with best available therapy or danazol, respectively. The rates of peripheral neuropathy were similar in the 2 groups. That was a key take-home point in terms of safety data from the MOMENTUM study.

Certainly, some patients did develop cytopenias while on momelotinib, as well as danazol. There weren’t excess gastrointestinal toxicities, as we see with some of the other JAK inhibitors. There was no signal toward increased risk of non-melanoma skin cancers or bile reactivations. However, we certainly watch for those things whenever we’re treating a patient with a JAK inhibitor.

If it is approved, where do you see momelotinib fitting into the current treatment paradigm for this population?

With the potential approval of momelotinib, we will see what the uptake looks like in everyday practice. That will be a big part of what happens with this medication: how organically it is picked up by different oncologists and hematologists out there in the community. Clearly, it has efficacy in patients with anemia, so it would be right at home in the treatment of a patient who has myelofibrosis who needs spleen volume reduction and symptom control, and has anemia.

If we look closely at the MOMENTUM inclusion criteria, those patients did have prior exposure to a JAK inhibitor for at least one month, and they all had hemoglobin [levels] less than 10g/dL; that is where this drug tends to shine. However, the amount of JAK inhibition given to those patients prior to going on MOMENTUM was limited. We also do have up-front data in patients previously untreated [with a JAK inhibitor] from the SIMPLIFY trials. You could say that if a patient with myelofibrosis and is borderline anemic, they could also benefit from momelotinib, not just in the second line, but potentially in the frontline setting as well.

References

  1. Verstovsek S, Gerds AT, Vannuchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0
  2. GSK announces extension of FDA review period of momelotinib. News release. GlaxoSmithKline. June 16, 2023. Accessed August 31, 2023. https://www.gsk.com/en-gb/media/press-releases/gsk-announces-extension-of-fda-review-period-for-momelotinib/

Goals of Managing Cytopenic Myelofibrosis in Younger Patients

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Targeted Oncology Staff

During a Targeted Oncology™ Case-Based Roundtable™ event, Naveen Pemmaraju, MD, and participants discussed the role of JAK inhibitors in managing myelofibrosis particularly in younger patients who may receive allogeneic stem cell transplant. This is the first of 2 articles based on this event.

CASE SUMMARY

A 62-year-old man presented to his primary care physician (PCP) with symptoms of fatigue, night sweats, and increased bruising​. He had a history of type 2 diabetes, hypercholesteremia, and hypertension​. The PCP noticed lower hemoglobin concentration (11 to 9.5 g/dL) and platelet count (350 × 109/L to 195 × 109/L) from a previous annual physical examination. ​He was referred to a hematologist/oncologist for consultation and evaluation​. ​

Two months post-PCP visit, he went to a hematologic oncologist. Exam findings included a spleen 5 cm below left costal margin, fatigue and night sweats worsening​, bone pain​, hemoglobin of 8.7 g/dL, and platelet count of 135 × 109/L ​. He was diagnosed with primary myelofibrosis (MF); ​bone marrow fibrosis of grade 2, with 35% bone marrow blasts. He had a history of squamous cell carcinoma of the skin​.

Molecular analysis showed a JAK2 V617F mutation and normal cytogenetics​. Blood smear reveals leukoerythroblastosis: 1% blasts by manual count/flow cytometry​. His ECOG performance status (PS) was 2. ​

DISCUSSION QUESTIONS

  • In your practice:​
    • When do you initiate therapy for a patient with MF? ​
    • What is the importance of symptom control? ​
    • How important is it to initiate therapy early? ​
    • When do you start JAK inhibitor therapy?​
    • Do you choose your initial JAK inhibitor based on patient symptoms? ​

DAI CHU LUU, MD: My standpoint is that a 62-year-old is still young. I have transplant physician within 5 miles of my practice. I would definitely send to a transplant physician…see what they have to say, and then follow up on the recommendations. Usually they’ll give recommendations and then I’ll act on them. Whenever things get tough, I’ll send it to them to establish care.

NAVEEN PEMMARAJU, MD: That’s great. What do you think about JAK [Janus kinase] inhibitor therapy? [Would you use] monotherapy as standard of care up until the transplant?

LUU: Yes.

PEMMARAJU: If the platelets are below 50 × 109/L, what we’ve been doing [in the past] is either giving ruxolitinib [Jakafi] or low-dose ruxolitinib. Maybe you’re doing something different. Has anyone yet prescribed the new agent, pacritinib [Vonjo], which is approved in this lower than 50 × 109/L setting?

SRIKAR MALIREDDY, MD: I have prescribed pacritinib. I had a patient on ruxolitinib for the longest time and then eventually the disease progressed and I could not do any more administration of ruxolitinib. He’s been on [pacritinib] for at least 7 to 8 months.

PEMMARAJU: [Was there] any diarrhea or bleeding events? Or has it been well tolerated?

MALIREDDY: There were no [tolerability issues]. I was very careful with starting with a low dose, and then ramping up. We also watched the platelet counts, and so far…[he has] 30 × 109/L to 40 × 109/L platelets.

PEMMARAJU: What dose did you start? Did you start at 100 mg? Because the approved dose is 200 mg twice daily.1

MALIREDDY: Yes, I started at 100 mg. [Since] he was tolerating it, he is at the maximum dose right now. He’s at 200 mg.

PEMMARAJU: That’s a great story. Did you have any difficulty getting it through insurance or through your specialty pharmacy?

MALIREDDY: This was one of the patients…who initially got azacitidine [Onureg] in combination with ruxolitinib. He was on a clinical trial for that.

PEMMARAJU: For the ruxolitinib/azacitidine trial [NCT01787487]?

MALIREDDY: Yes, exactly. He had some severe cytopenias, myelosuppression, and all that [on the clinical trial]. Eventually, the cytopenias progressed, then [he started on pacritinib]. I didn’t have any issues with getting approval.

PEMMARAJU: That’s great. The combined answer from both of you is the cutting-edge state of the art, which is offering a JAK inhibitor [while] trying to get to [allogeneic stem cell] transplant. We all assume—and it ends up being correct a lot of the time in our patients with myeloproliferative neoplasms as opposed to leukemia or some of the other [disease] states— what happens is [patients have an] ECOG PS of 2 to 3, but they have PS of 0 to 1 after the initiation of JAK inhibitor. With ruxolitinib, it’s usually about 3 months that you see it. After 1 week to 1 month, you start feeling great; by month 2 and 3 is the plateau.

DISCUSSION QUESTIONS

  • What are the therapeutic goals of therapy for a patient with aggressive disease? ​
  • When do you consider clinical trial enrollment?

PEMMARAJU: All of us in the field are thinking about the significance of cytopenic MF. It helped lead to the drug approval for this JAK inhibitor [pacritinib], which is great because I have had several similar situations in prescribing it. It’s a very well tolerated drug. But…how frequent is this? Most people in our field think that the cytopenias are treatment related or they happened later on. That is common. But thrombocytopenia and anemia can occur in a quarter or more of our patients at baseline. Some of these patients present…with fairly advanced disease. How often do you encounter a baseline platelet count of less than 50 × 109/L at any point in the myelofibrosis trajectory? And before pacritinib…what were you giving these patients if you had to treat them?

JAGATHI CHALLAGALLA, MD: [I would give] low-dose ruxolitinib, or if they’re transfusion independent, just observation.

PEMMARAJU: Yes, exactly, [or] sometimes we would…give danazol or steroids. Now we know that delivering suboptimal doses is leading to suboptimal outcomes.2 If you’re not reducing the spleen, not improving the symptoms, patients won’t do as well. The benefit of pacritinib…is you can give the full dose of the drug. We heard 1 story of being very cautious, but you can prescribe it as the 200 mg dosing even in the thrombocytopenic setting.1 Just watch out for diarrhea, usually resolved in the first 4 to 6 weeks. It’s usually well managed, but you and the patient need to know about it. There was some concern about cardiac bleeding events…particularly for patients on anticoagulants, but it is a fairly well-tolerated drug.

Say the patient is 82 years old, and transplant is off the table. [For] low platelet count, you’re giving a low dose of ruxolitinib, [or] you’re giving pacritinib…or fedratinib [Inrebic]. What is the goal of therapy in a patient who’s a non-transplant candidate for whom you’re giving a JAK inhibitor?

ANANTH ARJUNAN, MD: For the patient, the symptom improvement is critical. Along with that getting the spleen [size] down is important, not just for survival benefit, but for the patient to feel better. In terms of discussing treatment options, we go through the different JAK inhibitors, typically based off comorbidities, and then their [blood cell] counts. I haven’t found a reason to use fedratinib. It’s usually a question of ruxolitinib or pacritinib. For clinical trial enrollment, any time is appropriate, although we might wait until they become JAK inhibitor resistant, although you have some options recently with momelotinib.

References:

1. Vonjo. Prescribing information. CTI BioPharma Corp; 2022. Accessed August 29, 2023. https://tinyurl.com/yxjnn7yu

2. Maffioli M, Mora B, Ball S, et al. A prognostic model to predict survival after 6 months of ruxolitinib in patients with myelofibrosis. Blood Adv. 2022;6(6):1855-1864. doi:10.1182/bloodadvances.2021006889

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CWP-291 by JW Pharmaceutical for Thrombocythemia Myelofibrosis: Likelihood of Approval

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August 30, 2023

CWP-291 is under clinical development by JW Pharmaceutical and currently in Phase I for Thrombocythemia Myelofibrosis. According to GlobalData, Phase I drugs for Thrombocythemia Myelofibrosis have a 90% phase transition success rate (PTSR) indication benchmark for progressing into Phase II. GlobalData’s report assesses how CWP-291’s drug-specific PTSR and Likelihood of Approval (LoA) scores compare to the indication benchmarks.

GlobalData tracks drug-specific phase transition and likelihood of approval scores, in addition to indication benchmarks based off 18 years of historical drug development data. Attributes of the drug, company and its clinical trials play a fundamental role in drug-specific PTSR and likelihood of approval.

CWP-291 overview

CWP-291 (CWP-232291) is under development for the treatment of hematological tumors including relapsed or refractory acute myeloid leukemia (AML), chronic myelomonocytic leukemia-2, relapsed and refractory multiple myeloma, gastric cancer, myelofibrosis (PMF), post-polycythemia vera (PPMF), castration-resistant prostate cancer (CRPC) and post-essential thrombocythemia (PTMF). The drug candidate is administered intravenously. It acts as Sam68 inhibitor. It was also under development for the treatment solid tumors such as breast cancer, liver, lung cancer and myelodysplastic syndrome.

JW Pharmaceutical overview

JW Pharmaceutical, a subsidiary of JW Holdings Corp, is a provider of generic drugs. The company develops and markets analgesics, antipyretics and cold remedies, antidote agents, antimicrobials, anticancer agents, and others. It offers multivitamins and antianemia agents, contact lens care and ophthalmic agents, antifungal agents, cardiovascular agents, and gastrointestinal agents. JW Pharmaceutical also offers topicals, amino acid solutions, flexible IV containers, IV solutions, respiratory agents, nephrology agents, CNS, urology agents and diabetic agents. The company offers products for cardiovascular, gastrointestinal, nephrology and antianemia, anticancer and neuropsychiatry. It operates through its production and manufacturing facilities in South Korea. JW Pharmaceutical is headquartered in Seoul, South Korea.

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Dr Halpern on the Investigation of Upfront Ruxolitinib and Navitoclax 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 investigational efforts being developed to expand on the use of ruxolitinib and navitoclax in earlier treatment lines for patients with myelofibrosis.

In cohort 3 of the phase 2 REFINE trial (NCT03222609), the combination of ruxolitinib and navitoclax was evaluated in the upfront setting for patients (n=32) who had not been previously exposed to a JAK inhibitor. The study’s primary end point was spleen volume reduction of 35% or greater from baseline at week 24.

An exploratory analysis of this cohort was presented at the 2022 ASH Annual Meeting and Exposition, Halpern begins. Findings showed that navitoclax plus ruxolitinib produced a spleen volume reduction of at least 35% at week 24 across specific patient subsets, she details. These subsets consisted of patients 75 years of age or older, those with a high Dynamic International Prognostic Scoring System score, and those with HMR mutations. The percentage of patients who experienced optimal spleen volume reduction in these subgroups are 50%, 33%, and 47%, respectively.

Notably, changes in bone marrow fibrosis and reductions in the variant allele frequency (VAF) of the driver gene mutation were seen with the combination regimen in many patients, Halpern continues. Half of patients achieved a greater than 20% reduction in VAF from baseline at week 12 or 24, while a greater than 50% VAF reduction from baseline occurred in 18% of patients. When comparing those with or without HMR mutations, no differences in greater than 20% VAF reduction from baseline to week 12 or 24 were observed between populations.

These results indicate the potential disease-modifying ability of ruxolitinib and navitoclax, suggesting that reductions in bone marrow fibrosis and VAF may serve as biomarkers for disease modification, Halpern states. Notably, long-term outcomes cannot be definitively assessed as correlates for leukemia, progression, and survival, she adds. The viability of these 2 biomarker candidates should be assessed more short term, and in larger study populations, Halpern concludes.

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Selinexor by Karyopharm Therapeutics for Chronic Idiopathic Myelofibrosis (Primary Myelofibrosis): Likelihood of Approval

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August 28, 2023

elinexor is under clinical development by Karyopharm Therapeutics and currently in Phase II for Chronic Idiopathic Myelofibrosis (Primary Myelofibrosis). According to GlobalData, Phase II drugs for Chronic Idiopathic Myelofibrosis (Primary Myelofibrosis) does not have sufficient historical data to build an indication benchmark PTSR for Phase II. GlobalData uses proprietary data and analytics to create drugs-specific PTSR and LoA in the Selinexor LoA Report. 

GlobalData tracks drug-specific phase transition and likelihood of approval scores, in addition to indication benchmarks based off 18 years of historical drug development data. Attributes of the drug, company and its clinical trials play a fundamental role in drug-specific PTSR and likelihood of approval.

Selinexor overview

Selinexor (Xpovio, Nexpovio) is an antineoplastic agent. It is formulated as film coated tablets for oral route of administration. Xpovio in combination with dexamethasone is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. Xpovio is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. Xpovio in combination with bortezomib and dexamethasone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. It is also under development for the treatment of soft tissue sarcoma, osteosarcoma, leiomyosarcoma, pleomorphic liposarcoma, synovial sarcoma, epithelial ovarian cancer.

Selinexor (KPT-330) is under development for the treatment of light chain amyloidosis, anaplastic astrocytoma, diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG), newly diagnosed advanced hepatocellular carcinoma, metastatic urothelial carcinoma, relapsed or refractory peripheral T cell lymphoma and natural killer T cell lymphomas,  relapsed/refractory indolent non-Hodgkin lymphoma (R/R iHNL), malignant peripheral nerve sheath tumor (MPNST), leiomyosarcoma, endometrial stromal sarcoma, ovarian carcinoma, endometrial carcinoma, fallopian tube cancer, metastatic triple negative breast cancer, thymoma, non-small cell lung cancer, cervical carcinoma, non-Hodgkin lymphoma, melanoma, colon cancer, gastroenteropancreatic tumors, prolymphocytic leukemia, small lymphocytic lymphoma, recurrent glioblastoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), relapsed/refractory multiple myeloma (MM), relapsed and refractory acute myelogenous leukemia (AML), diffuse large B-cell lymphoma, chondrosarcoma, synovial sarcoma, liposarcoma, leiomyosarcoma, blast-crisis chronic myelogenous leukemia (bc-CML), relapsed and refractory acute lymphoblastic leukemia, rectal cancer, lung cancer, gynecological cancer, Penta-refractory multiple myeloma, recurrent/refractory high-grade gliomas, myelofibrosis, primary myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF), Ewing sarcoma and myelodysplastic syndrome, gastrointestinal stromal tumor (GIST), non-small cell lung cancer and recurrent glioma. The drug candidate is administered orally as a tablet and topically as a gel. It is a SINE compound that acts by targeting CRM1 (chromosome region maintenance 1 protein, exportin 1 or XPO1). It is being developed based on Selective Inhibitor of Nuclear Export (SINE) compound technology.

It was also under development for the treatment of coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), refractory or relapsed Richter’s transformation, metastatic castrate-resistant prostate cancer, advanced squamous cell carcinoma of head and neck, lung cancer and esophageal cancer, relapsed/refractory cutaneous T cell lymphoma, relapsed small cell lung cancer, rectal adenocarcinoma, gastric cancer, metastatic colorectal cancer and diabetic foot ulcers.

It was also under development for the treatment of recurrent glioblastoma multiforme.

Karyopharm Therapeutics overview

Karyopharm Therapeutics (Karyopharm) discovers and develops novel drugs for the treatment of cancer and other diseases. The company’s core technology harnesses the inhibition of nuclear export as a mechanism to treat patients suffering from cancer. Karyopharm’s lead product, Xpovio, is being developed for the treatment of multiple myeloma, and relapsed or refractory diffuse large B-cell lymphoma. Its pipeline drug candidates include selinexor, eltanexor, verdinexor, and KPT-9274. Karyopharm’s drug candidates are indicated for the treatment of various hematological and solid tumor malignancies including multiple myeloma, diffuse large B-cell lymphoma, liposarcoma, glioblastoma and endometrial cancer. The company has operations in the US, Israel and Germany. Karyopharm is headquartered in Newton, Massachusetts, the US.

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Hobbs Examines Frontline JAK Inhibition for Intermediate-Risk Myelofibrosis

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Targeted Oncology Staff

CASE SUMMARY

  • A 68-year-old woman presented to her physician with symptoms of mild fatigue, moderate night sweats, and abdominal pain/fullness lasting 4 months; she also reported increased bruising and an unexplained 12-lb weight loss.
  • Her spleen was palpable 8 cm below the left costal margin.
  • Karyotype: 46XX
  • Bone marrow biopsy results: megakaryocyte proliferation and atypia with evidence of reticulin fibrosis
  • Genetic testing results: JAK2 V617F mutation; CALR negative
  • A blood smear revealed leukoerythroblastosis.
  • Laboratory values:
    • Red blood cell count: 3.40 × 1012/L
    • Hemoglobin level: 13.2 g/dL
    • Hematocrit: 36%
    • Mean corpuscular volume: 94 fL
    • White blood cell count: 23.0 × 109/L
    • Platelet count: 450 × 109/L
    • Peripheral blood blasts: 1%
  • Diagnosis: primary myelofibrosis
  • Risk:
    • International Prognostic Scoring System: intermediate-2
    • Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis in adults 70 and younger: intermediate

TARGETED ONCOLOGY: How do the 3 Janus kinase ( JAK) inhibitors that are approved in this setting compare with each other?

HOBBS: Ruxolitinib [Jakafi] was the first JAK inhibitor [to be approved].1 I think they got lucky that it got approved way before fedratinib [Inrebic]2 and pacritinib [Vonjo],3 even though I think it’s worth noting [that] fedratinib and pacritinib… started their process of clinical trials a long time ago. Unfortunately, they ended up getting held up during their trials.

The indications of these 3 drugs are fairly similar: intermediate- or high-risk myelofibrosis (for pacritinib, specifically for patients with platelet counts of less than 50 × 109/L).4-6 For ruxolitinib, the [starting dose] is based on platelet count, not on hemoglobin level.4

In practice, probably a lot of physicians don’t adhere strictly to the platelet criteria, and in a patient who is a little frail or cytopenic or who has anemia, you could maybe start at a lower dose and then escalate, depending on how they tolerate the treatment. Fedratinib is given as a [once-daily] dose of 400 mg, and it was studied in patients with a platelet count of at least 50 × 109/L.5 The dose of pacritinib is 200 mg twice daily.6 So ruxolitinib is the only one where you really [adjust] the dose a lot.

CASE UPDATE

The patient is not interested in transplant; a decision was made to initiate ruxolitinib.

What clinical trial data supported the use of ruxolitinib?

It’s amazing that these data are 11 years old. The studies were published in The New England Journal of Medicine. These data came from phase 3 randomized studies that compared ruxolitinib with placebo in COMFORT-I [NCT00952289] and ruxolitinib with best available therapy in COMFORT-II [NCT00934544].

The COMFORT-I and COMFORT-II studies demonstrated very similar things, [with ruxolitinib leading] to a significantly improved decrease in spleen volume [the percentage of patients with at least a 35% reduction; reductions of 41.9% and 28% were seen in the experimental arms of COMFORT-I and COMFORT-II, respectively]. Most patients on ruxolitinib had some improvement in splenomegaly, even if they didn’t meet the arbitrary 35% spleen volume reduction [cutoff].7,8

Similarly, patients on ruxolitinib compared with both placebo and best available therapy had a significant improvement in symptoms.7,8 In my experience, for patients who have lots of symptoms like itching and so on, there’s really nothing that can make those symptoms go away [as well as] the JAK inhibitors do.

The COMFORT studies used the Myeloproliferative Neoplasm Symptom Assessment Form plus other measures. These studies demonstrated that there was an improvement in symptoms like fatigue and appetite issues, and there was also overall improvement in global health status and functional status.7,8

The long-term data from the COMFORT studies have shown a survival benefit in the patients who were treated with ruxolitinib [median overall survival (pooled data from both studies), 5.3 years vs 3.8 years for the experimental and control arms, respectively].7,9

I think it’s interesting to think about why that was. Was it because of less transformation to leukemia, or was it because of an improved functional status and the ability to eat, drink, and be more functional and have a decreased inflammatory state? I think that is still unclear.

What was the relationship between spleen response and survival among patients treated with ruxolitinib?

Even though we don’t know the mechanism that’s driving the survival benefit, we do know that spleen response did correlate with outcomes [in a multicenter study of ruxolitinib]. Patients who had a spleen response seemed to do better than those who didn’t.10 And I think that’s intuitive. Patients who have more resistant disease obviously aren’t going to do as well.

What was the relationship between ruxolitinib dose and response (spleen volume or total symptom score) in the COMFORT-I trial?

An important point is that if you give a low dose of a JAK inhibitor, it’s not going to be that effective. That was definitely true for the spleen. Ruxolitinib was more effective at higher doses for spleen volume reduction. Interestingly, for symptom improvement, some patients had a good response with respect to some of their symptoms with a lower dose, but to get the maximal spleen response, you needed a higher dose. The responses didn’t always track exactly together.11

How was ruxolitinib tolerated in these studies?

It was, in general, well tolerated. But not surprisingly, ruxolitinib was associated with higher rates of anemia, thrombocytopenia, and neutropenia compared with placebo [and best available therapy].7,8

What data inform the use of ruxolitinib in patients with a platelet count in the range of 50 × 109/L to 100 × 109/L?

We know how to use ruxolitinib, [but] we use it on-label, [so when a patient’s platelet count is] below 100 × 109/L, we [don’t know] what to do. Do we give 5 mg? We know that a lower dose of ruxolitinib is not that effective. There was a study called EXPAND [NCT01317875], a phase 1b dose-finding study that evaluated different starting doses of ruxolitinib in patients with low platelet counts.

The patients were divided into a group of patients with platelet counts of 75 × 109/L to 99 × 109/L and another group of patients with platelet counts of 50 × 109/L to 74 × 109/L. They demonstrated that 10 mg twice daily was the maximal safe dose for both groups and showed that patients were able to stay on that dose.12,13

Similar to the COMFORT studies, the results of the EXPAND study showed that even if patients had low platelets, if they were treated with a slightly higher dose of ruxolitinib, they ended up having a pretty good response in terms of symptoms as well as in terms of spleen volume [Table].12,13 These data highlight that it’s probably safe to give ruxolitinib at lower platelet counts and also demonstrate that the higher dose, more than 5 mg, is associated with a greater improvement in spleen [volume reduction] in particular.

What data inform the use of ruxolitinib in patients with anemia of grade 3 or 4?

[Nearly half of the] patients on the COMFORT-I study had anemia at baseline.7,8 Importantly, efficacy was maintained despite anemia, and although some patients had to adjust their dose or receive a transfusion, [less than 1% of patients] had to discontinue ruxolitinib because of anemia.7 I would imagine that in the real world that would probably be different.

Some ruxolitinib studies have shown that if a patient develops anemia while on ruxolitinib, it’s not as bad as if they have anemia de novo, especially if that happens early in treatment.14 Of course, if a patient has been on ruxolitinib for a year or 2 and all of a sudden [develops] anemia, that’s different and probably related to disease progression.

It’s important to note that if you put a patient on ruxolitinib, they [can] become a little bit anemic. Some of them will [be anemic] the first month and then find their new baseline, which isn’t always exactly where they were before but is a little higher than the nadir. But that decrease at the beginning of treatment is not as concerning as that anemia that we see in patients who present up front with anemia.

How does a patient’s baseline hemoglobin level influence your decision of whether to give ruxolitinib?

I feel comfortable giving the drug. I would probably not give the on-label dose on the basis of their platelet count because especially those patients who are in the 7 [g/dL hemoglobin] range, I’m going to make them transfusion dependent.

But it’s something that warrants a conversation. It depends on how symptomatic that patient is. If a patient has horrible night sweats and is bothered by their spleen, they may not be as bothered by their anemia. But I do struggle with that, so if the patient is not that symptomatic, maybe I won’t push that JAK inhibitor as much or the dose as much.

It depends on the situation. Many times, I’ll do the JAK inhibitor alongside an erythropoiesis-stimulating agent [ESA] or something like that. I don’t love the recommendation to just give the [on-label] dose and give transfusions. I would prefer not to have to give transfusions.

Q:If the erythropoietin level is less than 500 mU/mL, do you give ruxolitinib? Do you add other agents?

I’ll try danazol or an ESA. Personally, I haven’t had that much success with ESAs in myelofibrosis. I’ve used luspatercept-aamt [Reblozyl] off-label, both with ruxolitinib and by itself, but…some of the insurances require that I try the ESA first.

Q:Would you consider using lenalidomide (Revlimid)?

I rarely end up using it. It is a little better tolerated than thalidomide [Thalomid]. It’s definitely an option, especially for those patients with thrombocytopenia [because] you don’t have much else to do. But I don’t find [these drugs] to be the most well tolerated. But that is definitely a recommendation. You can use [lenalidomide] to try to help with anemia.

REFERENCES

1. Deisseroth A, Kaminskas E, Grillo J, et al. U.S. Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis. Clin Cancer Res. 2012;18(12):3212-3217. doi:10.1158/1078-0432.CCR-12-0653

2. FDA approves fedratinib for myelofibrosis. FDA. Updated August 16, 2019. Accessed May 16, 2023. https://tinyurl.com/5ej7s4tx

3. FDA approves drug for adults with rare form of bone marrow disorder. News release. FDA. March 1, 2022. Accessed May 16, 2023. https://tinyurl.com/4jcus8km

4. Jakafi. Prescribing information. Incyte Corporation; 2023. Accessed May 16, 2023. https://tinyurl.com/ua3rzhwr

5. Inrebic. Prescribing information. Bristol Myers Squibb; 2023. Accessed May 16, 2023. https://tinyurl.com/ms6emc6k

6. Vonjo. Prescribing information. CTI BioPharma Corp; 2022. Accessed May 16, 2023. https://tinyurl.com/5bpdwhku

7. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. doi:10.1056/NEJMoa1110557

8. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798. doi:10.1056/NEJMoa1110556

9. Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017;10(1):156. doi:10.1186/s13045-017-0527-7

10. Palandri F, Palumbo GA, Bonifacio M, et al. Durability of spleen response affects the outcome of ruxolitinib-treated patients with myelofibrosis: results from a multicentre study on 284 patients. Leuk Res. 2018;74:86-88. doi:10.1016/j.leukres.2018.10.001

11. Verstovsek S, Gotlib J, Gupta V, et al. Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Onco Targets Ther. 2013;7:13-21. doi:10.2147/OTT.S53348

12. Vannucchi AM, Te Boekhorst PAW, Harrison CN, et al. EXPAND, a dose-finding study of ruxolitinib in patients with myelofibrosis and low platelet counts: 48-week follow-up analysis. Haematologica. 2019;104(5):947-954. doi:10.3324/haematol.2018.204602

13. Gugleilmelli P, Kiladijan JJ, Vannucchi A, et al. The final analysis of Expand: a phase 1b, open-label, dose-finding study of ruxolitinib (RUX) in patients (pts) with myelofibrosis (MF) and low platelet (PLT) count (50 × 109/L to < 100 × 109/L) at baseline. Poster presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Accessed May 16, 2023. https://tinyurl.com/bdzymsst

14. Gupta V, Harrison C, Hexner EO, et al. The impact of anemia on overall survival in patients with myelofibrosis treated with ruxolitinib in the COMFORT studies. Haematologica. 2016;101(12):e482-e484. doi:10.3324/haematol.2016.151449

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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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