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

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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.

Toste: I 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

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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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Charina Toste Discusses the Educational Obstacles Patients With MPNs Face

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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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Scientists create a tool to identify individuals at risk of developing different myeloid leukemias

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August 24, 2023

by Wellcome-MRC Cambridge Stem Cell Institute

Scientists have created a new test for identifying people at risk of developing acute myeloid leukemia and related cancers, years before they do. The new platform, “MN-predict,” will allow doctors and scientists to identify those at risk and to design new treatments to prevent them from developing these potentially lethal cancers.

Researchers at the Wellcome-MRC Cambridge Stem Cell Institute (CSCI), the University of Cambridge’s Department of Haematology, and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA) analyzed data from more than 400,000 individuals participating in the United Kingdom Biobank.

Using this data, the scientists have created “MN-predict,” a platform for predicting the risk of developing blood cancers such as acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms over a 10–15-year period.

This test, now available in NHS clinics, requires patients to provide a blood sample from which DNA is extracted for limited sequencing, alongside basic blood cell counts. With this information, MN-predict identifies those at high risk of any of these cancers and can be used in specialist clinics for leukemia prevention.

Professor George Vassiliou, senior author of the study said, “We all know that prevention is better than cure, but it is not easy to prevent diseases like leukemia without knowing who is at risk. MN-predict makes it possible to identify at-risk individuals, and we hope it can become an essential part of future leukemia prevention programs.”

The myeloid neoplasms are a group of related cancers encompassing acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms. Treatments for these cancers have improved in the last few years, but most cases remain incurable.

In the last few years, scientists discovered that these cancers develop over decades through the accumulation of DNA mutations in blood stem cells, the cells responsible for normal blood formation. These mutations encourage these stem cells to grow faster than normal and, as more mutations accumulate, they can progress towards leukemia.

Thankfully, while mutations that promote cell growth are common, leukemia develops only in a small minority of cases. Identifying these cases early on helps efforts to prevent the cancers from developing.

Dr. Muxin Gu, first author of the paper, said, “We hope that MN-predict will help clinicians to identify people at risk of myeloid cancers and use novel treatment to prevent the cancers from developing.”

Dr. Pedro M. Quiros, joint senior author of the study, said, “Despite some recent advances in their treatment, these cancers remain lethal to many sufferers. We hope that our efforts will help advance prevention in favor of treating the full-blown disease.”

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Patients With Polycythemia Vera Seek Guidance on Exercise

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August 23, 2023

Andrea S. Blevins Primeau, PhD, MBA

In a multicenter survey, patients with polycythemia vera (PV) shared their preferences and needs regarding physical activity (PA), including the frequency of PA per week and the type and location of activity. Notably, lower educational level was associated with higher levels of inactivity.

The study, which was published in the journal Cancer Medicine, surveyed 182 adult patients with PV about their disease burden and PA preferences and needs. The mean age of the cohort was 61 and 68% of patients were female. There were 57% of patients with more than 10 years of education and 48% were currently working. The mean time since diagnosis was 8 years.

Moderate-to-severe symptoms were present among 60% of patients, which most commonly included fatigue, concentration problems, and bone/muscle pain. Skin reactions, splenomegaly, tendency to bleed, and weight gain were also commonly reported symptoms.

There were 67% of patients who reported that they would like more information about PA. Patients with a lower educational level were significantly less likely to be engaged in PA at 50% compared with 69% of patients with a higher education level (P =.021).

Patients who were currently inactive preferred PA sessions 1 to 2 times per week for a duration of 15 to 45 minutes. Patients who already exercised, preferred PA 3 to 4 times per week for a duration of 30 to 60 minutes.

The majority of patients preferred individual training at 79%, whereas 40% preferred group training. The most common location that was preferred for PA was outdoors at 79% followed by at home at 56%. There was no significant difference in training setting or location among patients who were currently active or inactive.

The authors provided recommendations for the frequency, intensity, duration, and type of exercise for patient, as well as special recommendations depending on the symptom or side effect that an individual is experiencing. For example, yoga or tai-chi was recommended for patients with fatigue or concentration problems, whereas endurance training or yoga was recommended for patients with anxiety or depression.

Reference
Felser S, Rogahn J, Hollenbach L, et al. Physical exercise recommendations for patients with polycythemia vera based on preferences identified in a large international patient survey study of the East German Study Group for Hematology and Oncology (OSHO #97). Cancer Med. Published online August 9, 2023. doi: 10.1002/cam4.6413

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Ajax Therapeutics Appoints Dr. David Steensma as Chief Medical Officer

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– A leading expert in hematologic malignancies with more than 25 years of oncology clinical and research experience, Dr. Steensma joins Ajax as its lead JAK2 inhibitor advances to the clinic –

NEW YORK–(BUSINESS WIRE)–Ajax Therapeutics, Inc., a biopharmaceutical company applying computational chemistry and structure-based technologies to develop next generation JAK inhibitors for patients with myeloproliferative neoplasms (MPNs), today announced the appointment of David P. Steensma, MD, FACP, as Chief Medical Officer. A renowned expert in hematologic malignancies, Dr. Steensma was formerly the Global Head of Hematology at Novartis Institutes for Biomedical Research, where he led early clinical development in malignant and non-malignant hematology conditions.

“His deep knowledge of hematologic malignancies and extensive experience leading clinical studies will be invaluable as we prepare to enter our first in human studies in myelofibrosis in 1H 2024.”

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“We are very fortunate to have such a veteran hematology drug developer as David join the Ajax team as we near the clinic with our next generation Type II JAK2 inhibitor program for MPNs,” said Martin Vogelbaum, CEO of Ajax Therapeutics. “His deep knowledge of hematologic malignancies and extensive experience leading clinical studies will be invaluable as we prepare to enter our first in human studies in myelofibrosis in 1H 2024.”

“I have collaborated with David for many years and consider him one of the top thought leaders in hematology oncology,” said Dr. Ross Levine, Chair of Ajax’s SAB and Deputy Physician-in-Chief, Translational Research, Laurence Joseph Dineen Chair in Leukemia Research and Member of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center. “We are very pleased to have David on board as his unique combination of translational and clinical skills will help us effectively design and execute clinical studies to demonstrate the unique and differentiating clinical properties of our lead Type II JAK2 inhibitor program.”

“I am excited to join Ajax at this pivotal stage of the company’s development,” said Dr. Steensma. “Patients with MPNs continue to have major unmet clinical needs as current therapies, including approved JAK inhibitors, such as ruxolitinib, often fail to provide adequate symptomatic relief and have no effect on the course of their disease. Ajax’s Type II JAK inhibitor is a more selective and potent JAK inhibitor with the potential to significantly improve efficacy, overcome disease persistence and, more importantly, provide disease modification.”

Dr. Steensma has a more than 25-year distinguished career as a clinician, investigator and researcher in hematology-oncology. Prior to his R&D leadership role at Novartis Institutes for Biomedical Research, he was a faculty member at Harvard Medical School and Institute Physician in the Adult Leukemia Program in the Division of Hematological Malignancies at the Dana-Farber Cancer Institute, where he cared for patients with hematological malignancies and bone marrow failure and served as the Edward P. Evans Chair in Myelodysplastic Syndromes (MDS). Earlier in his career, Dr. Steensma was a fellow and then faculty member in the Division of Hematology, Department of Medicine, at the Mayo Clinic. Since 2000, he has been on numerous committees and held several editorial roles for the American Society of Hematology and served as consultant editor for the Journal of Clinical Oncology. He was also a voting member of the Oncology Drug Advisory Committee (ODAC) for the U.S. Food and Drug Administration (FDA), and member of the Board of Directors of the MDS Foundation. Dr. Steensma has published over 200 original research papers as well as numerous reviews, editorials and book chapters. He received his medical degree from the University of Chicago’s Pritzker School of Medicine.

About Ajax Therapeutics

Ajax Therapeutics, Inc. is pursuing uniquely selective approaches to develop novel next generation JAK2 therapies for myeloproliferative neoplasms (MPNs), including myelofibrosis. By combining the deep cancer and structural biology insights of our founding scientists with the industry’s most advanced computational drug discovery and protein structure platforms from our founding partner, Schrödinger, Inc., we aim to discover and develop more precisely designed therapies to address the significant unmet needs for patients with MPNs.

Please find more information at www.ajaxtherapeutics.com.

NOTE: Dr. Ross Levine serves on the board of directors of, has provided advisory services for, and has equity interests in Ajax Therapeutics. Dr. Levine also has intellectual property rights and interests that MSK has licensed to Ajax. MSK has intellectual property rights and other financial interests related to Ajax.

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

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Darlene Dobkowski, MA

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Research By: Mohammad Azam, PhD

Post Date: August 21, 2023

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

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

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

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

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

OVERCOMING DEAD ENDS

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

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

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

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

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

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

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

ZEROING IN ON DUSP1

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

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

NOVEL APPROACH FOR MPN THERAPY

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

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

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

NEXT STEPS

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

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

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