Renin Angiotensin Inhibitors Reduce Thrombotic Adverse Effects in Chronic Myeloproliferative Neoplasms

Kyle Doherty

Patients with essential thrombocythemia and polycythemia vera who also had arterial hypertension experienced a higher cumulative incidence of thrombotic adverse effects compared with those without hypertension and fewer thrombotic complications following treatment with renin angiotensin system inhibitors.

Patients with essential thrombocythemia and polycythemia vera (PV) who also had arterial hypertension experienced a higher cumulative incidence of thrombotic adverse effects (AEs) compared with those without hypertension and fewer thrombotic complications following treatment with renin‑angiotensin system (RAS) inhibitors, according to findings from a retrospective study published in Annals of Hematology.

In the overall cohort of patients with myeloproliferative neoplasms (MPNs; n = 404), treatment with RAS inhibitors conferred a protective effect from thrombotic AEs (HR, 0.46; 95% CI, 0.21-0.98; P = .04), including those with a thrombotic high-risk score (n = 272; HR, 0.49; 95% CI, 0.24-1.01; P = .04). Moreover, patients with essential thrombocythemia and a thrombotic high-risk score experienced an especially defined benefit following treatment with RAS inhibitors (HR, 0.27; 95% CI, 0.07-1.01; P = .03).

“The main goal of managing MPNs is to prevent thrombotic incidents,” study authors wrote. “The results indicated that patients [with MPNs] had a significantly higher risk [4.9-fold] of arterial thrombosis than the healthy controls. We found a protective association between the use of RAS inhibitors and the reduction in thrombotic AEs in our cohort of patients [with MPNs].”

To conduct their study, investigators collected data from patients diagnosed with PV or essential thrombocythemia by WHO 2016 classification who were treated at the Hematology Unit of the Businco Hospital in Cagliari, Italy, from November 2000 through August 2021. Patients with PV were stratified by low risk of developing thrombosis (age < 60 years and no history of thrombosis) and high risk of developing thrombosis (age ≥ 60 years or a history of thrombosis). Patients with essential thrombocythemia were stratified by International Prognostic Score for Essential Thrombocythemia score, cardiovascular risk factors, age over 60 years, thrombosis history, and the presence of a JAK2 V617F mutation. Study authors also collected clinical data at the time of diagnosis, including constitutional symptom, performance status, hemoglobin, white blood cell counts, and the presence of somatic driver gene mutations among other data.

Patients had PV (n = 133) or essential thrombocythemia (n = 271). The median age at diagnosis was 63 years (range, 17-98) and the median follow-up was 5.5 years (range, 0-24) in the overall population. Most patients had comorbidities at diagnosis (70%) and a high thrombotic risk score (67.3%). Cardiovascular AEs experienced before (66.3%) MPN diagnosis included ischemic heart disease (7.7%), peripheral arterial disease (3.5%), cerebrovascular event (6.9%), atrial fibrillation (6.2%), deep vein thrombosis (4.7%), and other (4.2%); after diagnosis, thrombotic AEs (15.0%) that occurred were ischemic heart disease (3.5%), peripheral arterial disease (2.9%), cerebrovascular event (3.7%), and deep vein thrombosis (4.4%).

Most patients also had a positive mutational status (89.3%), including mutations in JAK2 V617F (78.5%), calreticulin (8.9%), and MPL (1.5%); 48.2% of patients also had essential thrombocythemia JAK2 V617F positivity. The therapies received for MPNs were low-dose aspirin (72.3%), phlebotomy (30.0%), cytoreduction therapy (62.9%), and IFN-2a (0.2%).

Median values were 10.5 × 103 /μL (range, 1.0-96.1) for leukocytes, 15.0 g/dL (range, 7.0–15.0) for hemoglobin, and 696 × 103/μL (range, 87–2320) for platelets. Median hematocrit was 48% (range, 29.0%-77.0%).

Investigators noted that “there was a significant difference in the JAK2 V617F mutation status within the group of patients [with essential thrombocythemia] with hypertension (27% vs 21.2%, P = .01).”

Most patients in the study had hypertension (53.7%) and in this subgroup, patients had PV (n = 78/217) and essential thrombocythemia (n = 139/217). Those with positive mutational status (n = 197/217) had JAK2 V617F (n = 182/217), calreticulin (n = 12/217), MPL (n = 3/217), and essential thrombocythemia– positive JAK2 V617F (n = 109/217) mutations. Median values were 10.9 × 103/μL (range, 1.09-19.2) for leukocytes, 15.2 g/dL (range, 10.4-21.0) for hemoglobin, and 720 × 103/μL (139–1170) for platelets. Median hematocrit was 47.6% (range, 33.1%-69.0%).

The majority of patients with hypertension had cardiovascular AEs before being diagnosed with an MPN (n = 216/217) including ischemic heart disease (n = 20/217), peripheral arterial disease (n = 7/217), cerebrovascular event (n = 19/217), atrial fibrillation (n = 15/217), deep vein thrombosis (n = 11/217), and other (n = 9/217); after diagnosis, 39 patients experienced thrombotic AEs; these included ischemic heart disease (n = 10/217), peripheral arterial disease (n = 6/217), cerebrovascular event (n = 12/217), and deep vein thrombosis (n = 11/217).

Additionally, patients with hypertension underwent prior hypertension therapy with a RAS inhibitor (n = 147/217) including angiotensin receptors blockers (n = 87/217), angiotensin-converting enzyme inhibitors (n = 59/217), and inhibitors without association (n = 116/217). Calcium antagonists were given to 52 patients and other agents including thiazide diuretics, beta-blockers, and doxazosin were given to 101 patients. Patients with hypertension also received treatment with low-dose aspirin (148/217), phlebotomy (70/217), cytoreduction therapy (159/217) and IFN-2a (1/217) as therapy for their MPN.

Additional findings showed that the cumulative incidence of thrombotic AEs over 15 years was significantly higher among patients with hypertension (66.8% ± 10.3%) compared with those without (38.5% ± 8.4%; HR, 1.83; 95% CI, 1.08-3.1). Findings from a multivariate analysis also revealed that hypertension (HR, 1.8; 95% CI, 0.983-3.550; P = .05) and PV diagnosis (HR, 3.5; 95% CI, 1.928-6.451; P < .001) were both associated with an increased risk of developing thrombotic AEs. Considering only patients with MPNs and hypertension, diagnosis of PV displayed a predictive role in developing thrombotic AEs (HR, 4.4; 95% CI, 1.92-10.09; P < .01).

“In conclusion, to improve the treatment of patients with MPNs, it is crucial to pay close attention to their cardiovascular risk factors, as these factors play a significant role in the complications of the disease. A more targeted approach could provide more effective and personalized care for patients with MPNs. Although the study’s retrospective nature poses limitations, the robust connections between the RAS system and hematological disorders make it crucial to conduct a more comprehensive analysis of the effects of RAS inhibitors on MPNs,” investigators wrote in summary.

Reference

Mulas O, Mola B, Costa A, et al. Renin-angiotensin inhibitors reduce thrombotic complications in essential thrombocythemia and polycythemia vera patients with arterial hypertension. Ann Hematol. Published online August 21, 2023. doi:10.1007/s00277-023-05417-w

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Momelotinib Could Represent Pivotal New Treatment Option in Myelofibrosis

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/

Mind-Body Therapies for Anxiety, Depression a Critical Part of Comprehensive Cancer Care

August 30, 2023

The recent publication of a guideline recommending mindfulness-based interventions highlight how important it is as a tactic to address symptoms of anxiety and depression in patients with cancer.

Mind-body therapies have been shown — and are recommended in guidelines — to decrease symptoms of anxiety and depression in patients with cancer who may be at any part of the care continuum, an expert said.

With this whole-person system of care, patients can use techniques including mindfulness-based stress reduction, cognitive therapy, meditation and others to address depression and anxiety symptoms. Now that mindfulness-based interventions are now recommended in a guideline prepared by the Society for Integrative Oncology (SIO) and American Society of Clinical Oncology (ASCO) as a way to treat anxiety and depression during cancer treatment, this may allow more cancer centers to offer this as part of their multidisciplinary care.

CURE® spoke with Linda E. Carlson, Enbridge Research Chair in Psychosocial Oncology and professor in the department of oncology at Cumming School of Medicine at the University of Calgary in Canada, to learn more about the ASCO/SIO guideline that she and an expert committee prepared, why they are important for patients and how patients with cancer can advocate for themselves to obtain care related to integrative oncology.

CURE®: Why are these guidelines so important?

Carlson: We know that patients suffer high levels of anxiety and depression, quite commonly around the time of diagnosis, but also going forward through transitions in care, the end of care, trying to get back into regular life. And so anxiety and depression symptoms can haunt people for a very long time.

At the same time, there’s no really good pharmacological treatments, … and many people prefer to go non-pharmacological, more natural routes.

The integrative therapies, the mind-body therapies that are in this guideline are proven. You can see through the evidence they help decrease symptoms of anxiety and depression. And so they’re non-pharmacological alternatives for patients to help cope with these difficult symptoms.

What exactly is integrative oncology?

The definition of integrative oncology … is this idea that it’s incorporating a whole-person system of care that incorporates conventional treatments, as well as complementary therapies where appropriate to help manage symptoms throughout the continuum, from prevention through lifestyle interventions, things like exercise and nutrition, right through treatment with modalities like the mind-body therapies, natural health products, and into survivorship and even end of life.

The idea is that it’s consistent with the person’s beliefs and values. It takes these complementary therapies that have an evidence base to them, applies them throughout the whole cancer journey to improve treatment tolerance and symptom reduction.

Is integrative oncology meant for all patients regardless of disease, stage and other factors?

Absolutely. The evidence base is a bit lacking for some of the rarer forms of cancer. A lot of the research has been done on women with breast cancer. So there’s definitely some holes in the evidence that have limited the kinds of recommendations that could go into the guideline, because the guideline’s based on very strict criteria, randomized-controlled trials, etc. There have been many studies done with more diverse groups of patients, but not enough to get some of those things in the guideline.

Another side note is that just because a complementary therapy may not be included in the guideline, it doesn’t mean that it isn’t helpful or it doesn’t work. It just means there hasn’t been enough research to date. So for example, things like energy therapies or massage may still have potential, but just didn’t make it into the guideline because there hasn’t been the research done yet.

The strongest recommendation was given to mindfulness-based interventions like stress reduction, meditation and mindful movement. Can you go into more detail about what those are?

We use mindfulness-based interventions as an umbrella term to talk about, usually adaptations that stem from the mindfulness-based stress reduction program that was developed by Jon Kabat-Zinn back in the 1970s.

Mindfulness-based stress reduction has been around for about 40 years, but there’s many different takes on it, different adaptations. So there’s some that are specific for people with cancer, like mindfulness-based cancer recovery, or mindfulness-based stress reduction for breast cancer, there’s mindfulness-based cognitive therapy. But what these all have in common is they’re usually group programs, they usually meet once a week over a period of six to eight weeks.

And people are taught mindfulness meditation techniques. So usually, they practice at home for 20 minutes a day or so of meditation on the breath, on the body. And mindfulness is really this idea of bringing awareness into the present moment, non-judgmentally with kindness, self-compassion with openness. And so the meditation is training people on how to do that in a systematic way. Because often our minds are trained to be out of the present moment. We’re either reliving the past and saying, “Why me? If only this or that.” We have regrets, we get depressed or we’re worrying about the future. The mind’s going off to what if this? What if that? How am I going to cope, all the terrible things that could happen, the pressures. And so, we worry and get anxious.

Depression, regret, worry, anxiety, it’s all caused by the past and future focus. But mindfulness training is more about living in the moment. It’s easy to say, it’s a simple idea, but it’s not easy to do. So the mindfulness based intervention trains people in that capacity to be in the present moment, through sitting meditation, body scan, different kinds of awareness practices, everyday mindfulness.

Usually, they have the form of mindfulness meditation practice. And they also have mindful movement, or yoga, incorporated in them. And that is around bringing awareness into the body, learning to identify when there’s stress or tension, identifying our triggers of stress, we even get into the stories we tell ourselves and the interpretations we make and how that elevates stress. There are many components to a mindfulness-based intervention. But we do know that the studies, many of them have consistently shown that they really help people cope with anxiety and depression.

There has always been some thought that any form of mindfulness would be beneficial for patients with cancer. But why was it so important to put these into a formalized guideline?

The way the medical system works is that the guidelines drive treatment decisions, and they drive insurance reimbursement. So while many people have experienced these therapies and know they’re helpful, until we have it formalized with a recommendation from a trusted body like ASCO, like SIO, that’s the first step in really making it standard of care. In fact, it makes it almost compulsory that for cancer centers to be credited as comprehensive cancer centers, they need to include these types of therapies.

The recommendations around mindfulness-based interventions, the language is “should;” people with cancer should have access, not “may,” which is the less strong language. But they should be part of comprehensive cancer care because we know they’re helpful, and they’re less harmful than other pharmacological approaches and more useful, they’re more effective.

There’s no reason why we shouldn’t take advantage of these relatively low-cost interventions with very few side effects, little harm and make those available to everybody. Everybody who’s suffering from anxiety and depression can benefit. So this is a really important institutional step in moving more towards that idea of having them really part of standard of care.

If a patient thinks that this would be a good fit for their care, how should they bring it up to their cancer team?

I would advise patients to get a copy of those guidelines and put them on the desk the next time they go to see the oncologist and say, “How come we don’t have these programs at our cancer center? Why do I have to go to the community and seek this out and pay out of my pocket? Why isn’t this covered by my insurance?” I think we need the patients to stand up and advocate. And they can use (this guideline) as a tool, a very strong tool to help them do that.

This transcription has been edited for clarity and conciseness.

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Goals of Managing Cytopenic Myelofibrosis in Younger Patients

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

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

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

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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Patients with MPNs ‘Don’t Know What They Don’t Know’

Alex Biese

For patients with myeloproliferative neoplasms (MPNs) — blood cancers that cause the bone marrow to overproduce red or white blood cells or platelets — being able to engage in educated and productive conversations with their care team can be crucial.

“There are so many variables in cancer from not only the diagnoses, but ‘how do we treat it?’ to what the prognosis is, and that’s always evolving (so) that it’s hard for providers to keep up with that, let alone patients,” said Charina Toste, a nurse practitioner specializing in oncology and hematology at OptumCare Cancer Care and a professor at Chamberlain College of Nursing, both located in Las Vegas, Nevada.

When it comes to the vast category of MPNS (which includes a range of diseases such as myelofibrosis, essential thrombocythemia, and polycythemia vera) patients don’t know what they don’t know.

“(Patients) don’t always know, what is the treatment that’s out there? What are the clinical trials that are out there? Oh, and then let’s talk about symptom management, how is my life going to change? How is this going to affect me? How is this going to affect my family? These are questions patients don’t even know to ask. And they trust their health care provider to have the three or four hours it takes to educate them at an appointment that usually is only 15 to 30 minutes.”

Toste spoke with CUREⓇ about the importance of education for patients with MPNs in order to empower themselves to have informed conversations with their care team.

CUREⓇIn general, why is it so important for patients to educate themselves, and be prepared to have informed conversations with their care team as they’re going through their cancer journey?

pull quote: "I think it's important to at least have a solid basis of information about your disease, your cancer diagnosis, so you know what to ask."

Patients with myeloproliferative neoplams should learn about their disease to ensure that they know what questions to ask, a nurse practitioner said.

TosteI think because with any type of diagnosis, there’s kind of the shock factor. And once you get over the shock factor, it’s a different language that patients are learning, it’s a different lifestyle that they’re learning, they have to learn to adjust their entire life for it. And many patients don’t know what to ask because they don’t know what they don’t know.

So, I think it’s important to at least have a solid basis of information about your disease, your cancer diagnosis, so you know what to ask. There are so many variables in cancer, from not only the diagnoses, but how we treat it to what the prognosis is, and that’s always evolving (so) that it’s hard for providers to keep up with that, let alone patients.

What sorts of questions should patients be prioritizing, especially if they are early on in the experience?

‘What is their current diagnoses?’ specifically, so that they understand their diagnoses. Quite honestly, they hear the words and they don’t understand what those words mean; if they see myeloproliferative neoplasms, that’s all they might look up and not know their specific diagnoses (or) that there are different types underneath there.

As we well know, there are so many different hematological malignancies. And when you say the word leukemia, there are 200 different types of leukemia. So, you have to know exactly what you have. And what does that mean to you? What does that mean, as far as prognosis? What can I expect now? And what can I expect in the future? So they can adjust their life.

Because if anything, after a world pandemic has happened, we realize we can’t always predict the future and we have to enjoy what we have to the best (of our) abilities. So, does this mean I have to quit my job? Does this mean I need to adjust my family lifestyle? Should I move to where I have family and support? Will I be OK here on my own? I think those are the questions that they need to ask: how is it going to impact them personally now and in the future so they can prepare?

What are some specific challenges or roadblocks related to MPNs that make it a particularly disease type for patients to inform themselves on?

Not always but usually, most of these diagnoses are based in an elderly population. So, with the myelofibrosis and the polycythemia vera, you’re usually looking around the 60s or 70s age group. And for a lot of these patients, they don’t always have the best support, so they don’t always know how to go to Dr. Google and look everything up. They don’t always know what the latest clinical trials are, they don’t always know how to ask those questions. And they aren’t always surrounded by family members, their children are grown, they have their own lives. So, they don’t always have that support that others would have. Sometimes they’re on their own, and they don’t have transportation. They’re wondering about the basics: economics, transportation, those kinds of things. So that’s how it affects them. And those can be some of the obstacles going forward for these patients in obtaining information. And then (for) some of these patients, some are working, some aren’t some are active and family, some aren’t. Some are socially active.

And I also think in an elderly population, what are some of the symptoms, when you look at a patient and they go, ‘Well, yes, I’m tired. Yes, I have bone pain, but I’m 80. How do I know that this is disease related?’ So, I think those are also some of the obstacles. Whereas if you’re 20 or 30 years old, and you’re saying, ‘Wow, I have a lot of bone pain, I have a lot of fatigue, I have memory loss,’ that’s going to seem unusual at that age versus if you’re older, a lot of times you just take it as the age and the sands of time moving forward. First, is this actual disease might be progressing.

Say there is a patient who is kind of between doctor visits and is looking to inform themselves further, what are some resources that are out there for patients to turn to if they’ve got weeks or months to go before they see their provider for the next time?

Sometimes I always feel there’s not enough. I know there are associations that they can look up and reach out to. I know there are support groups, there are Facebook support group pages. Sometimes, though, you have to worry about the accuracy of information. I know there are pharmaceutical companies out there that also provide information about their medications, or sometimes just disease-related treatments and information. So, that’s out there.

But honestly, it’s (about) going to the journals of medicine or magazines or things like that to get more neutral, objective information, honestly, because you don’t know and I hear so many times as provider, ‘Well, I read this on the Internet,’ and I thought, ‘Oh, wow, that was a big waste of time.’ And it really skews what (information) they have. Or they get information from (people who) say, ‘Oh, well, in healthcare, I know this.’ Well, it’s not our healthcare system. They might have followed health care systems overseas. So different societies and different cultures have different decisions when it comes to treatment plans and pathways. So sometimes, I think it’s very challenging for them to find accurate information, even in today’s society.

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Hobbs Examines Frontline JAK Inhibition for Intermediate-Risk Myelofibrosis

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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Charina Toste Discusses the Educational Obstacles Patients With MPNs Face

Charina Toste, DNP, APRN-C, AOCNP, MSN, BSN, RN

As with any disease type, it is crucial that patients with myeloproliferative neoplasms (MPNs) are able to engage in educated and productive conversations with their care team. Yet, according to Charina Toste, DNP, APRN-C, AOCNP, MSN, BSN, RN, sometimes patients do not know where to begin or which questions they should ask.

“[Patients] don’t always know what treatments [are] out there. What are the clinical trials that are out there? [There’s also] symptom management [questions], how is [their] life going to change? How is this going to affect [them]? How is this going to affect [their] family?” said Toste, who is a nurse practitioner specializing in oncology and hematology at OptumCare Cancer Care and a professor at Chamberlain College of Nursing, both located in Las Vegas, Nevada.

“These are questions patients don’t even know to ask. And they trust their health care provider to have the 3 or 4 hours it takes to educate them at an appointment that usually is only 15 to 30 minutes.”

Further, when it comes to the vast category of MPNs—which includes a range of diseases including myelofibrosis, essential thrombocythemia, and polycythemia vera—patients oftentimes do not know what they do not know.

“There are so many variables in cancer from not only the diagnoses, but how do we treat it and what is the prognosis. That’s always evolving. It’s hard for providers to keep up with that, let alone patients,” she said.

In an interview with Oncology Nursing News, Toste addressed some of the hurdles patients may face when educating themselves about MPNs. She noted, for example, that many patients are in their 60s or 70s and do not always have the best support systems. Therefore, these patients do not always know how to use Google to conduct research. This makes it difficult for them to learn more about clinical trials and clinical trial availability.

Further, patients who lack social support sometimes struggle with simple aspects of treatment, including transportation to and from their appointment. According to Toste, this can all have a significant effect on the patient.

“Those can be obstacles going forward for these patients in obtaining information,” Toste said.

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