Dr. Mascarenhas on the Evolution of JAK Inhibitors in Myelofibrosis

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John O. Mascarenhas, MD

John O. Mascarenhas, MD, professor of medicine, hematology, and medical oncology, Icahn School of Medicine at Mount Sinai, director, the Center of Excellence for Blood Cancers and Myeloid Disorders, member, the Tisch Cancer Institute, discusses evolution of JAK inhibitors in the treatment landscape of myelofibrosis.

For nearly a decade, ruxolitinib (Jakafi) was the only JAK inhibitor approved for the treatment of patients with myelofibrosis after the FDA approved ruxolitinib as the first drug to specifically treat patients with myelofibrosis in November 2011. However, fedratinib (Inrebic) and pacritinib (Vono) joined the treatment paradigm in recent years. In 2019, the FDA approved fedratinib for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis and, most recently, in 2022, the FDA granted an accelerated approval to pacritinib for the treatment of adult patients with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L. It is anticipated that momelotinib will be approved at some point in 2023, Mascarenhas notes.

Due to the expanding options for JAK inhibitors in the treatment of myelofibrosis, it is critical that practitioners be aware of the different niches that a JAK inhibitor may be applicable, Mascarenhas says.

Because ruxolitinib has been a part of the treatment landscape for nearly a decade and has an established role in the treatment of myelofibrosis, clinicians may be more comfortable with the drug due to a wealth of experience with that particular JAK inhibitor, and it will likely remain the mainstay of JAK inhibitor therapy for patients with myelofibrosis, Mascarenhas continues.

The other JAK inhibitor options can fill needs in specific subsets of patients. Pacritinib represents a treatment option for patients with platelet count of less than 50 x 109/L, and, notably, it can be utilized, irrespective of platelet count, as a second-line JAK inhibitor, Mascarenhas says. Moreover, fedratinib has broader label and can be utilized in the up-front or second-line settings, Mascarenhas says. As a second-line treatment, fedratinib represents a potential option specifically in patients who experience progression or a lack of spleen response with ruxolitinib, Mascarenhas adds. However, neither ruxolitinib nor fedratinib are good drugs for improving anemia and can be associated with myelosuppression, Mascarenhas concludes.

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Incyte Reports 2022 Fourth Quarter and Year-end Financial Results, Provides 2023 Financial Guidance and Updates on Key Clinical Programs

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– Total FY’22 net product revenues grew 18% to $2.75 billion; total FY’22 revenues of $3.4 billion (+14% Y/Y)

– Jakafi® (ruxolitinib) net revenues of $647 million (+9% Y/Y) in Q4’22 and $2.41 billion (+13%) in FY’22; Jakafi net revenues guidance range of $2.53 – $2.63 billion for FY 2023

– Opzelura™ (ruxolitinib) Cream net revenues of $61 million in Q4’22 and $129 million in FY’22, driven by strong demand in atopic dermatitis, a successful launch in vitiligo and broadening formulary access

Conference Call and Webcast Scheduled Today at 8:00 a.m. ET

WILMINGTON, Del.–(BUSINESS WIRE)–Incyte (Nasdaq:INCY) today reports 2022 fourth quarter financial results, provides 2023 financial guidance and provides a status update on the Company’s clinical development portfolio.

“We are well positioned for strong growth with our current product portfolio and we expect to deliver many important updates this year as we continue to execute on our growth and diversification strategy.”

“We are entering 2023 with significant momentum, following a year of strong commercial performance and progress of several important mid-to-late stage programs across our pipeline. Opzelura has now become the market share leader among branded agents for new atopic dermatitis patients and the adoption in vitiligo has been strong,” said Hervé Hoppenot, Chief Executive Officer, Incyte. “We are well positioned for strong growth with our current product portfolio and we expect to deliver many important updates this year as we continue to execute on our growth and diversification strategy.”

Portfolio Updates

MPNs and GVHD – key highlights

LIMBER (Leadership In MPNs and GVHD BEyond Ruxolitinib) program: Important LIMBER updates were presented at the American Society of Hematology (ASH) Annual Meeting in December 2022:

  • Parsaclisib + ruxolitinib in myelofibrosis (MF): Final results from the Phase 2 trial in MF patients with a suboptimal response to ruxolitinib demonstrated additional spleen volume response and symptom improvement with the addition of parsaclisib. Add-on parsaclisib was generally well-tolerated. A Phase 3 trial evaluating parsaclisib as an add-on to ruxolitinib in suboptimal responders is ongoing with results expected at the end of 2023.
  • Zilurgisertib (ALK2) ± ruxolitinib in MF: Initial results from the Phase 1 study evaluating zilurgisertib as monotherapy or in combination with ruxolitinib in patients with anemia due to MF were presented, establishing proof of mechanism in improving anemia. Updated combination data with ruxolitinib are expected later this year.
  • INCA33989 (mCALR) in MF and essential thrombocythemia (ET): A novel anti-mutant calreticulin (mCALR) monoclonal antibody was unveiled during the ASH plenary session. These data highlight Incyte’s discovery capabilities and research progress in MF and ET; two patient populations where 25-35% of patients have a CALR mutation. INCA33989 is expected to enter the clinic later this year.

Ruxolitinib extended release (XR) formulation: The New Drug Application (NDA) was accepted by the U.S. Food and Drug Administration (FDA) with a Prescription Drug User Fee Act (PDUFA) target action date of March 23, 2023.

Axatilimab in chronic graft-versus-host disease (GVHD): In December, Syndax and Incyte announced that results from the Phase 1/2 trial of axatilimab in patients with recurrent or refractory chronic GVHD following two or more prior lines of therapy were published in the Journal of Clinical Oncology. The data demonstrate that treatment with axatilimab resulted in an overall response rate (ORR) by cycle 7, day 1 of 67% across all patients. AGAVE-201, a global pivotal Phase 2 trial of axatilimab in patients with cGVHD, is ongoing with results expected mid-2023. A Phase 1/2 combination trial of axatilimab with ruxolitinib in patients with newly-diagnosed cGVHD is expected to initiate later this year.

Jakafi patent extension: Incyte was granted pediatric exclusivity which adds six months to the expiration for all ruxolitinib patents, thereby extending the patent expiry for Jakafi through December 2028.

Indication and status

Ruxolitinib XR (QD)

(JAK1/JAK2)

Myelofibrosis, polycythemia vera and GVHD: NDA under review

Ruxolitinib + parsaclisib

(JAK1/JAK2 + PI3Kδ)

Myelofibrosis: Phase 3 (first-line therapy) (LIMBER-313)

Myelofibrosis: Phase 3 (suboptimal responders to ruxolitinib) (LIMBER-304)

Ruxolitinib + INCB57643

(JAK1/JAK2 + BET)

Myelofibrosis: Phase 2

Ruxolitinib + zilurgisertib

(JAK1/JAK2 + ALK2)

Myelofibrosis: Phase 2

Ruxolitinib + CK08041

(JAK1/JAK2 + CB-Tregs)

Myelofibrosis: Phase 1 (LIMBER-TREG108)

Axatilimab (anti-CSF-1R)2

Chronic GVHD: Pivotal Phase 2 (third-line plus therapy) (AGAVE-201)

Ruxolitinib + axatilimab2

(JAK1/JAK2 + anti-CSF-1R)

Chronic GVHD (newly diagnosed): Phase 1/2 in preparation

1

Development collaboration with Cellenkos, Inc.

2

Clinical development of axatilimab in GVHD conducted in collaboration with Syndax Pharmaceuticals.

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Exploring Available and Anticipated Therapies for MPNs

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Jordyn Sava

In an interview with Targeted Oncology, Andrew Kuykendall, MD, discussed the most recent approvals for MPNs, practice changing abstracts presented at ASH 2022, and what he expects to see in 2023.

In recent years, the field of myeloproliferative neoplasms (MPNs) has had several clinical developments, including the novel treatments ruxolitinib (Jakafi), fedratinib (Inrebic), and pacritinib (Vonjo).1-2

Ruxolitinib was the first JAK1/2 inhibitor to receive FDA approval and has made tremendous strides for patients with myelofibrosis (MF). Then, fedratinib, another JAK2 inhibitor, received regulatory approval in 2019. This option has shown promise in the second-line for patients who are ruxolitinib-resistant with intermediate-2 and high-risk MF.

However, there was an unmet need of severely thrombocytopenic patients with intermediate- or high-risk MF. This was addressed with the regulatory approval of the JAK2/IRAK1 inhibitor, pacritinib, in February 2022.

Now, clinical trials are ongoing to evaluate a new JAK1/2 option, momelotinib, for patients with JAK-inhibitor treated, symptomatic, and anemic patients with MF. Momelotinib is being evaluated in the ongoing phase 3 MOMENTUM trial (NCT04173494). Findings from the study have already shown there to be significant improvements in anemia measures, spleen size, and symptoms for this patient population.

According to Andrew Kuykendall, MD, if the FDA grants an approval for momelotinib in 2023, this will be practice changing for patients with MPNs.

“The main thing that will shake up treatment in 2023 is the anticipated approval of momelotinib. We’ve seen the positive data from the MOMENTUM study, and we are looking at an approval sometime during the summer of 2023. This is an agent that has been studied in the SIMPLIFY-1 and -2 trials [NCT01969838; NCT02101268] as well as the recently completed MOMENTUM study. This agent is another JAK inhibitor, but it has a little bit of a different niche. It seems to be a little more favorable, and its impact on anemia induces some transfusion independence, and it still has some good effect on spleen and symptoms,” Kuykendall, MD, an assistant member at the H. Lee Moffitt Cancer Center of University of South Florida in Tampa, FL, told Targeted OncologyTM, in an interview.

In the interview, Kuykendall discussed the most recent approvals for MPNs, practice changing abstracts presented at the 2022 American Society of Hematology Annual Meeting (ASH 2022), and what he expects to see in 2023.

What exciting changes have been seen in the MPN space over the past year?

Things with MPNs are changing relatively fast. Going back to November of [2021], we had the approval of ropeginterferon alfa-2b-nj for polycythemia vera, which was kind of the second approval we’ve had of a polycythemia vera medication, and certainly has transformed how we think about treating that disease with an idea of potential for disease modification. In February [2022], we had the accelerated approval of pacritinib for the treatment of myelofibrosis for patients that have severe thrombocytopenia. It was very exciting to get 2 drugs approved within the context of a year. Then, we have the continued enrollment of many phase 3 clinical trials that are potentially practice changing and may bring new therapeutic options to the table.

Can you discuss some of the new approvals?

With ropeginterferon, for a long time, we’ve been using interferon formulations within polycythemia vera and essential thrombocythemia, maybe to a lesser extent within myelofibrosis. This is going back to the 90s. We know that it’s effective, it can help control counts, and we have seen in small numbers of patients that it may be able to decrease the JAK2 allele burden and potentially could correlate with delayed disease progression and potential disease modification. That’s something that has been exciting to patients.

Historically, interferon has been challenged by toxicity, especially the short acting forms. As we got pegylated interferon, we had longer acting, better tolerated, and lower doses, and patients stayed on for a longer period of time, did better, could appreciate some of those durable responses that you get when you’re on long term therapy. With ropeginterferon, we’ve now got an approved agent as opposed to using something off-label. It’s given less frequently, so every 2 weeks, and we have seen good long-term data with more robust datasets that have shown the ability to decrease allele fractions and JAK2 mutations. What that’s brought to the table is something not completely new, because we’ve been using interferons, but something that has stronger data to support it. It’s something that we can use as an approved on-label medication for many patients. I think it’s gotten patients very excited about potentially having something that can alter the natural history of disease.

Pacritinib on the other hand is something that was approved for an unmet need. It’s an accelerated approval for patients with thrombocytopenia with less than 50,000 platelets, and for those patients, we don’t have many great options. We have ruxolitinib and fedratinib that are approved, but typically, they’ve been given in patients with over 50,000 platelets. We have struggled to treat these patients with lower platelet counts. Pacritinib has great data in the PERSIST-1 trial and PERSIST-2 trials [NCT01773187; NCT02055781], and in the ongoing PACIFICA study [NCT03165734]. It shows that it can be safely leveraged in these patients with lower platelet counts. We were happy to get the accelerated approval because now, we have an option for those patients, and we’re not having to do things off-label or give modified doses. Now, we have something we can fully dose and bring an effective treatment for these patients that have an unmet need.

What abstracts presented at ASH 2022 do you think are practice changing or show potential for patients with MPNs?

There [were] 24 oral abstracts for MPNs this year [at ASH]. One [we saw was] the final dataset from the RUXOpeg study [​​NCT02742324]. It was a combination of ruxolitinib and peg-interferon. This could be immediately changed as both drugs are available to us right now. The question has always been, can we meaningfully combine these 2 agents in MPNs and is there a benefit to doing that? Ruxolitinib is thought of as something that helps with symptoms of the disease, spleen symptoms, and has a survival benefit in myelofibrosis for more of the advanced stages.

Then we have interferon, which is thought of in earlier stages of MPNs and something that has this potential for disease modification that maybe we don’t see with ruxolitinib. The idea of reusing them together is something we’ve talked about for a long time, we’ve seen early datasets, and we have the final results of the RUXOpeg study, which is an upfront combination of the 2 in intermediate-1 risk patients. We can get some support if we were to leverage this combination. Is that something that we get benefit out of? With the presentation [at ASH], we were able to see some of the impact that interferon has on stem cell populations and see if there is a rationale for leveraging this combination in early phase patients.

Looking ahead, what do anticipate the treatment landscape for MPNs to look like?

I think that we’re still going to be kind of gaining data from these phase 2 clinical trials. The main thing that will shake up treatment in 2023 is the anticipated approval of momelotinib. We’ve seen the positive data from the MOMENTUM study, and we are looking at an approval sometime during the summer of 2023. This is an agent that has been studied in the SIMPLIFY-1 and -2 trials as well as the recently completed MOMENTUM study. This agent is another JAK inhibitor, but it has a little bit of a different niche. It seems to be a little more favorable, and its impact on anemia induces some transfusion independence, and it still has some good effect on spleen and symptoms. We know that anemia is inherent to myelofibrosis, it’s going to be a part of everyone’s disease course over time. Unfortunately, with ruxolitinib and fedratinib, we’ve had to often punt that. Patients have had a worsening of their anemia, at least temporarily with those agents. We’ve said that we will accept that for the spleen and symptom benefits. With momelotinib, maybe we don’t have to do that, and this anemic patient population may have an alternative option that could treat multiple aspects of the disease and we won’t have to kind of ignore 1 aspect while treating the others. That will probably be the biggest thing that shakes things up.

The other question that we have in polycythemia that was supported with abstracts presented at [ASH 2022] is, where do we leverage interferon vs hydroxyurea vs ruxolitinib. All 3 are approved and utilized within the realm of MPNs, especially polycythemia vera. We have used ropeginterferon more so for this allele fraction, this disease modification aspect, but more data presented on ruxolitinib suggests patients on long-term ruxolitinib who have [polycythemia vera] or [essential thrombocytopenia] may be able to get similar VAF or allele fraction reductions. That may shake things up a bit because we haven’t thought of that or seen that. Seeing that this occurs over the long-term is what we think about with ropeginterferon. These allele fractions, this disease burden, and reductions typically take a long time to happen. If we can see that and if we do believe this data coming out with ruxolitinib, that may shake things up as far as how we talk to patients and how we leverage these agents in clinical practice.

REFERENCES:
Masarova L, Bose P, Pemmaraju N, et al. Improved survival of patients with myelofibrosis in the last decade: single-center experience. Cancer. 2022;128(8):1658-1665. doi:10.1002/cncr.34103
Verstovsek S, Parasuraman S, Yu J, et al. Real-world survival of US patients with intermediate- to high-risk myelofibrosis: impact of ruxolitinib approval. Ann Hematol. 2022;101(1):131-137. doi:10.1007/s00277-021-04682-x

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Clinical Review of ropeginterferon alfa-2b Suggests Amended Dosing Schedule May Support Improved Clinical Outcomes in Polycythemia Vera

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Review of studies published in Frontiers in Oncology highlights dosing considerations that may help more patients achieve earlier complete hematological response

BURLINGTON, Mass.–(BUSINESS WIRE)–PharmaEssentia USA Corporation, a subsidiary of PharmaEssentia Corporation (TPEx:6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology and oncology, today announced the publication of a review of clinical literature in the journal, Frontiers in Oncology. The research indicates that an amended dosing schedule, with higher initial dose and faster dose titration of ropeginterferon alfa-2b (marketed as BESREMi®), may correlate to earlier complete hematological response (CHR) in polycythemia vera (PV) in adults. The analysis titled, “An alternative dosing strategy for ropeginterferon alfa-2b may help improve outcomes in myeloproliferative neoplasms: An overview of previous and ongoing studies with perspectives on the future,” was co-authored by PharmaEssentia researchers.

“This latest research will help support more informed dialogue among physicians regarding their patients with PV.”

“This publication delves into the critical connection between an accelerated dosing regimen for ropeginterferon alfa-2b and the key efficacy, safety and tolerability outcomes we aim to achieve for our patients,” said John Mascarenhas, M.D., Director of the Adult Leukemia Program and Leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai and study author. “The data from these clinical and investigational studies suggest that a higher starting dose and faster titration could be an appropriate approach to attain clinical outcomes earlier while minimizing the risk of thrombosis and hemorrhage in patients with PV.”

PV is the most common myeloproliferative neoplasm (MPN) and a long-term, potentially life-threatening disease with limited treatment options. Recent clinical investigations suggest the potential for rapid titration and higher starting doses to benefit those with PV.1

The publication highlights the findings from multiple studies supporting the efficacy, safety and tolerability of a 250-350-500 mcg titration dosing regimen of ropeginterferon alfa-2b:

  • A compassionate use program (CUP) study in Taiwan (n=14; hydroxyurea and/or anagrelide resistance or intolerance patients) resulted in a CHR rate of 73% at 52 weeks vs 51% observed in a study with a slower titration method. No new safety signals were detected.
  • Interim results from an ongoing, Phase 2, single-arm study in Chinese PV patients (n=49; resistant or intolerant to hydroxyurea) showed that amended dosing achieved a CHR rate of 52% at Week 24 compared to 43% at Week 52 observed in PROUD-PV. Treatment-related Grade >3 adverse events (AEs) were reported in five patients (10.2%).
  • Data from an investigator-initiated trial in Korea (n=45; hydroxyurea naïve or pre-treated PV patients) indicated higher hematologic and molecular responses at 6 months. Dose reductions were required in 4.4% of patients and the majority of AEs were Grade 1 or 2 with no treatment-related serious AEs reported.

Across the studies, ropeginterferon alfa-2b was generally well-tolerated. No thromboembolic complications have been reported with the accelerated titration regimen in PV. Rather, the review authors indicate that it is reasonable to believe that the accelerated dosing regimen may potentially minimize the risk of thrombosis and hemorrhage associated with an under-dosing during dose titrations.

“As more clinicians gain familiarity with BESREMi®, we want to support treatment goals by ensuring patients can effectively achieve and maintain their target clinical and molecular responses, as this may help reduce the risk of disease progression over time,” said Raymond Urbanski, M.D., Ph.D., Senior Vice President and U.S. Head of Clinical Development and Medical Affairs. “This latest research will help support more informed dialogue among physicians regarding their patients with PV.”

PharmaEssentia is interested in the attributes of the amended dosing approach with ropeginterferon alfa-2b that may extend into related MPNs with unmet needs such as essential thrombocythemia (ET) and pre-fibrotic primary myelofibrosis (pMF). Several planned or ongoing Phase 3 clinical trials will further evaluate this regimen of ropeginterferon alfa-2b in ET (SURPASS and EXCEED trials) and PV (ECLIPSE trial). Plans for a Phase 3 clinical trial in pMF are also underway.

Follow PharmaEssentia USA on Twitter and LinkedIn for news and updates.

About Polycythemia Vera (PV)

Polycythemia vera (PV) is a cancer originating from a disease-initiating stem cell in the bone marrow resulting in a chronic increase of red blood cells, white blood cells, and platelets. PV may result in cardiovascular complications such as thrombosis and embolism, and often transforms to secondary myelofibrosis or leukemia. While the molecular mechanism underlying PV is still subject of intense research, current results point to a set of acquired mutations, the most important being a mutant form of JAK2.2

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

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

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

Indication

BESREMi is indicated for the treatment of adults with polycythemia vera.

Important Safety Information

WARNING: RISK OF SERIOUS DISORDERS

Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping therapy.

CONTRAINDICATIONS

  • Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation, or suicide attempt
  • Hypersensitivity to interferons including interferon alfa-2b or any of the inactive ingredients of BESREMi.
  • Moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment
  • History or presence of active serious or untreated autoimmune disease
  • Immunosuppressed transplant recipients

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Myeloproliferative Neoplasm Management: Future Directions in Care

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Feb 2, 2023

Naveen Pemmaraju, MD
John Mascarenhas, MD

 

Closing out their discussion on myeloproliferative neoplasms, key opinion leaders share excitement for future evolutions in the treatment paradigm.

Transcript:

Naveen Pemmaraju, MD: So team, what I want to do is, I’m going to go to each of you and get some final comments, and ask you to give me 2 or 3 things. Maybe 1 is something that you learned, maybe at ASH [American Society of Hematology meeting] or in the last few months leading up to ASH, and then 2 and 3 is what’s your wish list? What do you want us as the field to think about and focus on in 2023, either in the setting of clinical trials, transplant symptom burden, to give folks out there a sense of what you are thinking about and what you’re excited about? Dr Palmer, we’ll start with you, and we’ll go down the panel.

Jeanne M. Palmer, MD: This year at ASH, it was great to hear some of the updated information and to try to understand the new drugs that are coming out and have discussions with people about where we think they’re going to fall into the landscape of the therapy. I look forward to exploring that further. Although I recognize it’s certainly going to be a goal for the next 5 years, probably more than the next year, I’m hopeful that we’ll be able to do that. One of the things that’s on my wish list is I think we need to better understand the response criteria we’re looking at, so what is the meaningful response that we have for a patient? Right now, we’ve been using spleen size, reduction, and symptom burden, which are very important factors that contribute to it, but what are the markers that are going to predict survival? Because it takes a long time to see survival. We must figure that out. What are the markers that are most meaningful to patients? What can we anchor with something like the Global Impression of Change that tells us this makes the patient feel a lot better. It doesn’t just make me feel better to look at their numbers or look at different things, but it makes them feel better also, more importantly, associated with survival. That’s my wish list is to come up with the best way to figure out what works.

Naveen Pemmaraju, MD: Wonderful. Dr Oh, your final thoughts?

Stephen Oh, MD, PhD: We are at a very exciting time for this field with more new agents becoming available, and many are now in phase 3 that may soon become approved. It continues to be an extremely exciting time for the field. In terms of specific things that I will highlight, I’ll be the broken record and keep coming back to inflammation and anemia, and more recognition that this is something important in terms of the clinical features of patients with mild fibrosis, anemia related to inflammation, targeting these pathways, hepcidin. It’s also something as far as updates on the lab side that is increasingly being investigated. What I continue to say as far as that’s concerned is, we all ask, can we more potently target the abnormal inflammation? But I think there is an opportunity to leverage these abnormal inflammatory signaling pathways in a way that not just reduces symptoms and improves bone marrow function, but can turn it on its head to target the malignant cone as well in a more effective way. That’s what I would highlight. The last thing I would say, we talked about this new monoclonal antibody for mutant calreticulin. The other obvious approach, and along those lines, is something specific for mutant JAK2 [Janus kinase 2]. We still don’t have that. There are obvious reasons why that has not been the case over the years, but I think there is a growing hope, maybe it’s the best way to say it, that a truly mutant selective JAK2 inhibitor may be here in the coming years.

Naveen Pemmaraju, MD:Wow. That’s exciting. I’ll share my thoughts with the panel. At this year’s ASH, the exciting thing for me was mainly in our myelofibrosis sessions, the emphasis on what all of you discussed here, which was the elucidation and understanding of disease biology and biomarkers that you can hang your hat on, or at least have a sense of what’s going on. The one that really captured that for me was what Dr Oh presented, which was the ACVR1 [activin A receptor type I] story in pacritinib [Vonjo], our third approved JAK inhibitor. We now have several JAK inhibitors, momelotinib and pacritinib, which can be not only delivered in the setting of cytopenias, but actually improving the cytopenias, including the holy grail of anemia. I want to see how the combination therapies do, not only in terms of overall survival, spleen and symptoms, but how they do with the anemia, and how durable that is. I thought that was an exciting finding. For the future, as you all know in our own discussions, I hope you’ll allow me to say a unified theory of disease modification, what we’ve all talked about, and I still think it’s an aspirational goal. It can be something like overall survival as the top most important thing for our patients and for us, coupled with the traditional factors that Ruben and Serge pioneered of spleen size reduction symptoms, and then coupled with some of the newer markers that Steve, Dr Angela Fleischman [University of California, Irvine] and our colleagues are working on, including VAF, variant allele fraction, cytokine state, and maybe even bone marrow fibrosis. Can we couple all those into something meaningful for our patients? John, let me turn it to you, and then Ruben for your final thoughts.

John Mascarenhas, MD:It’s difficult to be the fourth person in a row to do this. I thought that’d be Ruben, because he set all the right things you said all the top line.

Naveen Pemmaraju, MD:It’s all supervised here, OK.

John Mascarenhas, MD:I agree with you all, and I know you share this enthusiasm. As a clinician investigator in this field, this is a great time to be in it because the science is driving the medicine and translating directly into the clinic. What we learned in the clinic feeds back and then helps us understand how to refine and go about it the right way. I’m most impressed with beyond the things I’ve been talking about, is how we sit down and listen carefully to a lot of the scientific sessions. You start to realize that there’s so much interconnectivity here between the pathways, seemingly redundancy here, and what we end up often doing is trying to target 1 pathway that we think is relevant, not understanding that there’s so many other pathways that are activated, and that compensate and sometimes overcompensate for shutting down 1 pathway. There’s a lot of examples of this, one clear example is if you shut down BET [bromodomain and extraterminal] regulated transcription, you have a consequence of down regulating NF-kappaB [nuclear factor-kappa B] activity, and down regulating BCL-2 [B-cell lymphoma 2] expression, c-MYC expression, all relevant nodes in the pathobiology of myelofibrosis. It begs the question, is there 1 specific target? Or is what we’re looking at such a complex interplay that we need to be approaching this from various angles at the same time? Which I think reinforces the theme that we’ve been discussing, which is rational combination, mechanism-based combination. I’m excited that a lot of the scientific abstracts that were presented today will in 2 years, 3 years, translate into the next wave of clinical trials. I think that’s fabulous. That’s why we’re here.

Naveen Pemmaraju, MD:That’s fantastic. Ruben, take us home and give us your final thoughts.

Ruben Mesa, MD:One thing I’ve learned this year is don’t let the perfect be the enemy of the good. Meaning, when ruxolitinib [Jakafi] was first approved, there were many detractors saying, “This is supportive care. I could just give patients 10 milligrams of prednisone, and they’d be the same.” That is just pure nonsense. The rate at which patients pass away from myelofibrosis is clearly decreased significantly over the years. Is it perfect? No. I think the expansion we’ve had now to hopefully have 4 JAK inhibitors is important. These drugs make an important difference. They each have their own role. I still agree with John, I want to look at novel combinations, but a combo that includes a JAK inhibitor probably is logical, based on several things that we have learned. Although these are not perfect, these are good drugs that make a real impact on patients both in terms of length of life and quality of life. Now my wish list is, I envisioned the situation where we’re 18 months from now, and we have 6 phase 3 clinical trials that have data that looks similar, we improve spleen and symptoms more than singulation ruxolitinib, and we have a toxicity profile that includes diarrhea, nausea, and vomiting. That’s what we’re going to be stuck with. So how do we sort through which patient goes on which drug because they’re going to be patients that have a fabulous response to rux [ruxolitinib] and pelabresib, rux [ruxolitinib] and parsaclisib, rux [ruxolitinib] and navitoclax, rux [ruxolitinib] and HDM2 inhibitor, on and on, but not everyone. How do we sort through that? I think the correlative studies are going to be important. How do we sort through so that we have any science behind I’m going to give which drug just comes to top of mind because they have very different mechanisms of action, and the patients are different? Those that develop these trials hope that the patients are going to be eligible, of course, but we realize that a drug has a 20% response rate. It means it has 100% response rate for 20% of the patients and has a 0% response rate for the other 80%. That’s my wish list. Our work is not done when we have the top line data on those phase 3 studies, but a tremendous sense of progress and hope. As Naveen and I were talking earlier at ASH, when you think about what ASH looked like in MF [myelofibrosis] in 2002. In 2002, I gave the oral presentation on thalidomide [Thalomid] and prednisone, and it was like the Super Bowl. There were so many people there because we showed some improvement in anemia, but that was it, no spleen, no symptoms, no disease modification. There was a bouncer outside keeping people out, so the progress we’ve made is unbelievable.

Naveen Pemmaraju, MD:Well, I must tell you, team, we have lovely discussions. This was one of the best yet. On behalf of my colleagues Ruben, John, Steve, and Jeanne, I want to thank you all for this very rich and informative discussion. I want to thank our audience for taking time to view this, and we hope that you found this OncLive Peer Exchange discussion to be useful and informative for your practices. With that, I’m Naveen Pemmaraju. We will sign off for now and see you next time. Thank you all so much.

Transcript edited for clarity.

 

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A Phase 1 Study of Ruxolitinib plus Abemaciclib to Treat Myelofibrosis

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Purpose

In this study, researchers want to find the highest dose of the drug abemaciclib that can be given safely with ruxolitinib in people with myelofibrosis that has developed on its own (primary myelofibrosis) or as a complication of the blood diseases polycythemia vera or essential thrombocythemia. In people with myelofibrosis, the bone marrow is not able to make enough blood cells. The spleen is bigger than normal, making the stomach feel very full. Patients may also have fever and night sweats.

Doctors think that giving ruxolitinib, a standard medication for myelofibrosis, in combination with abemaciclib (a breast cancer medication that is investigational in this study) may be a useful treatment. Both ruxolitinib and abemaciclib block specific proteins that play a role in cancer growth. By blocking these proteins, the drugs may cause myelofibrosis to stop growing.

Participants in this study will receive one of three doses of abemaciclib in combination with ruxolitinib. Both medications are taken orally (by mouth).

Eligibility

To be eligible for this study, patients must meet several requirements, including:

  • Participants must have intermediate-risk or high-risk primary myelofibrosis or myelofibrosis associated with polycythemia vera or essential thrombocythemia.
  • Patients must have been taking ruxolitinib for at least 12 weeks and had an inadequate response, such as a persistently enlarged spleen or other symptoms.
  • Patients must be able to walk and do routine activities for more than half of their normal waking hours.
  • This study is for people age 18 and older.

Contact

For more information and to ask about eligibility for this study, please contact the office of Dr. Raajit Rampal at 646-608-3746.

Protocol

22-075

Phase

I

Disease Status

Newly Diagnosed & Relapsed/Refractory

Investigator
Raajit K. Rampal

Co-Investigators
Michael J. Mauro

Momelotinib May Effectively Reduce Anemia and Other Symptoms for Patients With Myelofibrosis

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Posted: 1/31/2023 10:49:00 AM
Last Updated: 2/2/2023 2:43:15 PM

 

The targeted therapy momelotinib may offer clinically significant improvement in disease-related symptoms, including anemia and spleen enlargement, for patients with myelofibrosis, according to a novel study published by Srdan Verstovsek, MD, PhD, and colleagues in The Lancet.

The findings support the use of momelotinib—a potent ACVR1/ALK2 and JAK1/2 inhibitor—over the standard therapy danazol in treating patients with myelofibrosis who were resistant, refractory, or intolerant to first-line therapy—especially patients who were symptomatic and those with anemia.

Srdan Verstovsek, MD, PhD

Srdan Verstovsek, MD, PhD

Background

Myelofibrosis, a type of myeloproliferative neoplasm, is characterized by dysregulated JAK signaling—which can disrupt the body’s normal production of blood cells and can lead to common symptoms such as an enlarged spleen and anemia. Chronic anemia in these patients is associated with poor prognoses.

Currently approved JAK inhibitors can improve spleen responses and other disease-related symptoms, but they also can worsen anemia. In this trial, momelotinib improved anemia and reduced transfusion dependency in patients with myelofibrosis who were previously treated with JAK inhibitors. Momelotinib can be administered and maintained at full dosage because it does not suppress bone marrow activity like other JAK inhibitors.

“Current options for managing anemia in our patients [with myelofibrosis] provide only modest and temporary benefits, so we are excited about these findings,” explained lead study author Dr. Verstovsek, the United Energy Resources, Inc, Professor of Medicine and Director of the Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. “The trial results suggest that momelotinib is safe, well-tolerated, and can improve one of the most common and debilitating clinical problems for this patient population,” he highlighted.

MOMENTUM: Study Methods and Results

The new study—one of the first of its kind to evaluate JAK1/2 and ACVR1/ALK2 inhibition in patients with myelofibrosis and anemia—was designed to compare the clinical benefits of momelotinib with those of danazol, a synthetic androgen currently used to treat anemia in patients with symptomatic myelofibrosis.

In the international, randomized phase III MOMENTUM trial, researchers randomly assigned 195 adult patients to receive either momelotinib plus placebo (n = 130) or danazol plus placebo (n = 65). Among the trial participants, 63% of them identified as male and 37% identified as female. The participants for both groups had a median age of 71 to 72 years.

The trial’s primary endpoint was symptom reduction after 24 weeks of treatment, defined as a 50% or greater reduction in the Myelofibrosis Symptom Assessment Form Total Symptom Score. The researchers discovered that 25% of patients who received momelotinib saw benefits in their disease symptoms compared with 9% of those who received danazol.

Patients treated with momelotinib also experienced a significant reduction in their spleen size, with 25% responding after 24 weeks of therapy. Additionally, these patients required fewer blood transfusions compared with those receiving danazol.

Conclusions

The safety profile of momelotinib was comparable to the safety observed in previous clinical trials. The most common nonhematologic side effects experienced by trial participants in the momelotinib group included diarrhea, nausea, weakness, and itchy or irritated skin.

“If approved, momelotinib could offer an effective option for patients with myelofibrosis to improve anemia, splenomegaly, and other disease-related symptoms over other approved medications so far,” Dr. Verstovsek emphasized. “Momelotinib may also be an ideal partner for combinations with other investigational agents in development to further control myelofibrosis symptoms,” he concluded.

The researchers noted that they continue to monitor the effectiveness of momelotinib through ongoing patient follow-ups and long-term survival.

Disclosures: The research in this study was supported by Sierra Oncology. For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

 

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Accelerated Phase of MPN: What It Is and What to Do About It

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Anand Patel, Olatoyosi Odenike

 

Abstract

Progression of Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) to the accelerated phase (AP) or blast phase (BP) is associated with poor outcomes. As our understanding of the molecular drivers of MPN progression has grown, there has been increasing investigation into the use of novel targeted approaches in the treatment of these diseases. In this review we summarize the clinical and molecular risk factors for progression to MPN-AP/BP followed by discussion of treatment approach. We also highlight outcomes using conventional approaches such as intensive chemotherapy and hypomethylating agents along with considerations around allogeneic hematopoietic stem cell transplant. We then focus on novel targeted approaches in MPN-AP/BP including venetoclax-based regimens, IDH inhibition, and ongoing prospective clinical trials.

Introduction

The classic Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) are hematopoietic stem cell diseases characterized by activated JAK/STAT signaling pathways and a variable propensity to evolve toward accelerated or blast phase disease (MPN AP/BP). Outcomes are poor in MPN AP/BP and have not changed substantially in the past decade. Our increasing understanding of the molecular-genomic factors and pathways that drive MPN progression have the potential to lead to meaningful targeted therapeutic approaches. This argues for consideration of a personalized approach that takes the mutational spectrum of the individual patient into account, in addition to clinical factors, when fashioning a therapeutic strategy1. For example, emerging retrospective data with IDH inhibitors in MPN AP/BP lend credence to this approach and are now informing prospective early phase clinical investigation2,3.

By consensus definition, MPN-AP refers to the presence of peripheral circulating or bone marrow blasts in the 10-19% range and MPN-BP refers to 20% ≥ blasts in the peripheral blood or marrow, in an individual with a pre-existing MPN4,5. Overall survival (OS) in both MPN-AP and MPN-BP is limited particularly in the absence of allogeneic hematopoietic stem cell transplantation (allo-HCT). Even in the current era of myeloid therapies, outcomes for MPN-AP/BP are quite poor with median OS of 9 months reported in a multicenter retrospective study6.

The median survival in MPN-AP is in the 16- to 18-month range. Of note however, a relatively large series from the Mayo clinic shows that patients with primary myelofibrosis (PMF) with peripheral or marrow blasts in the 5-9% range have a survival outcome that is indistinguishable from that of patients with 10 to 19% blasts7. Similarly, data reported by MD Anderson demonstrates that a blast range of 5-9% in PMF has similarly poor outcomes when compared to 10-19% even in the era of ruxolitinib8,9. Overall, patients with 5% or more circulating or marrow blasts can therefore be viewed as being on a continuum towards progression to MPN-BP, which has a particularly dismal survival outcome measured in the 3-5 month range. Therefore, it is reasonable to propose that therapeutic strategies designed for particularly high risk populations such as MPN-BP should similarly be applied to MPN-AP, including those with blasts in the 5% or greater range. For those who are fit enough to undergo allo-HCT, this should be entertained early on, with a view to bridging patients to allo-HCT as soon as there is effective disease control.

Risk factors for progression to MPN AP/BP include MPN subtype and is highest for PMF. In a large contemporary series, the 20-year cumulative estimate of blast phase transformation was 3.8%, 6.2% and 14.2% for essential thrombocythemia (ET), polycythemia vera (PV) and PMF, respectively10. Other risk factors for progression to MPN-BP include clinicopathologic features, previous treatment, laboratory values, genetic features of disease, and prognostic scoring systems (Table 1). The mutational landscape of MPN -AP/BP is complex, and in addition to the canonical driver mutations in JAK2, MPL and CALR, includes acquisition of co-mutations (Table 2) which segregate along various pathways including DNA methylation, chromatin modification, DNA repair and RNA splicing11, 12, 13. The evolutionary pathway to MPN-BP is far from linear however, and in some instances, evidence has pointed towards bi-clonal disease or the existence of a pre-JAK2 ancestral clone14, 15, 16. Acquisition of high molecular risk mutations including ASXL1, EZH2, IDH1/2, SRSF2, and TP53 coupled with worsening clinical parameters including increasing circulating blasts and worsening thrombocytopenia can point towards those patients with advanced MPNs, who are on a trajectory toward MPN-AP/ BP. Early consideration of potentially curative approaches such as allo-HCT is important in these scenarios while in the chronic phase, given the paucity of effective interventions once the disease progresses to MPN AP/BP17.

Therapeutic interventions range from intensive induction chemotherapy to less intensive approaches such as hypomethylating agent (HMA) based therapies. Much of the experience regarding outcomes with these approaches are retrospective in nature and are largely derived from the treatment of patients in the blast phase. It is likely however, that the general principles and lessons learned in this regard would also be applicable to MPN-AP1. Outcomes across a number of targeted therapy approaches are summarized in Table 3.

Given the relative chemoresistance of MPN AP/BP, with response rates in the 35-45% range and short remission durations, the benefit of intensive chemotherapy as a therapeutic strategy is limited to those situations where allo-HCT can be utilized for consolidation1,11,18,19. HMA-based approaches are associated with CR rates in approximately 25% range in most series, with overall response rates in the 40-50% range1,19. In reported retrospective comparisons, there has been no survival advantage to an intensive chemotherapy approach over a less intensive one, in the absence of consolidative allo-HCT11,12. Of note, there are no randomized studies comparing these approaches. While JAK inhibition has a well-established role in the management of chronic-phase MPNs, JAK inhibitor monotherapy is largely ineffective for MPN-AP/BP20 and there is no evidence yet that JAK inhibition significantly changes natural history with regard to likelihood of evolution to AP/BP21. There have also been several prospective studies evaluating ruxolitinib in combination with HMAs in MPN-AP/BP. Response rates have ranged from 26-45% with median OS of less than one year22, 23, 24. In the absence of randomized trials or a matched historical population, it remains unclear if the addition of ruxolitinib to an HMA offers additional benefit beyond HMA monotherapy.

While allo-HCT is considered the only curative approach for MPN-AP/BP, considerations around the appropriate time for transplantation and which patients may derive the most benefit from allo-HCT continue to evolve. Blast percentage certainly has prognostic implications in the setting of survival outcomes in MPNs, however the impact of blast burden on patients undergoing allo-HCT is less clear. A clinical/molecular score in patients with MF undergoing allo-HCT found no impact of blast percentage on post-transplant outcomes25. In addition, a recent analysis of 35 patients with AP MF that underwent reduced-intensity conditioning (RIC) allo-HCT reported a 5-year OS of 65% which compared favorably to the chronic-phase MF group (n=314) that also underwent RIC allo-HCT26. This suggests that in patients with MPN-AP that are eligible for transplant consideration should be given to proceeding with allo-HCT even if blast burden is not reduced. The impact of blast reduction in MPN-BP prior to allo-HCT is also not well defined1,17. Some studies have demonstrated that while achievement of a CR prior to allo-HCT may offer some benefit, overall survival is still poor27, 28, 29, 30. Furthermore, the ability to achieve a deep remission prior to allo-HCT with current therapies is quite limited. Molecular factors also have an impact on outcomes after allo-HCT in MPN-BP; in particular the presence of TP53 mutation is associated with poor survival even in patients with blast reduction prior to allo-HCT31. These findings starkly highlight the need for prospective novel therapies in this patient population.

The B-cell lymphoma 2 (BCL-2) family of proteins are involved in the regulation of mitochondrial outer membrane permeability and the resultant apoptosis of cells. The family is comprised of BCL-2 along with other proteins such as BCL-xL and MCL-132. Pre-clinical studies established the reliance of AML cells on BCL-2 for survival and mitochondrial dependence on BCL-2 as an anti-apoptotic mechanism; inhibition of BCL-2, on the other hand, was found to drive apoptosis of AML cells and inhibit growth of AML progenitor cells33, 34, 35. Pre-clinical studies of JAK2-driven hematologic malignancies have demonstrated overexpression of the BCL-2 family of proteins and that resistance to JAK inhibition can be overcome with addition of a BCL-2/BCL-xL inhibitor36. The clinical benefit of the BCL-2 inhibitor venetoclax in combination with azacitidine has been confirmed in AML and the use of venetoclax in combination with intensive chemotherapy is under investigation37,38. In addition, the use of the BCL-2/BCL-xL inhibitor navitoclax in combination with ruxolitinib for patients with myelofibrosis and lack of response to ruxolitinib has demonstrated promising results in the Phase II setting39. There is much interest in ascertaining the role of venetoclax in MPN-AP/BP; the majority of data is based in retrospective analysis at this time.

There are several retrospective analyses that have investigated venetoclax-based combination therapies in MPN-AP/BP. The initial experience reported by Tremblay et al analyzed 9 patients with MPN-AP/BP (8 MPN-BP, 1 MPN-AP) that received HMA+Venetoclax. CR/CRi rate was 33% and 3 patients proceeded to allo-HCT. The median OS was 4.2 months for this cohort40. Masarova et al reported on 31 patients with MPN-BP that received venetoclax-containing regimens at a single center. Fourteen patients were treated in the frontline setting and 17 had R/R disease; 18 patients received an HMA, 5 patients received cladribine and low-dose cytarabine (LDAC), 6 patients received intensive chemotherapy, and 2 patients received an IDH inhibitor in combination with venetoclax. CR/CRi rate was 19% with all responses occurring in the frontline population and 2 patients received an allo-HCT; median OS for the cohort was 4 months. Of note, 83% of patients developed a Grade 3+ infection and the 8-week mortality of the 32-patient cohort was 32%41. Gangat et al reported on 32 patients with MPN-BP treated with HMA+Venetoclax across 3 centers; 23 received HMA+Venetoclax in the frontline setting and 9 received HMA-Venetoclax in the relapsed/refractory (R/R setting). CR/CRi rate in the frontline patient cohort (n=23) was 44% and 6 patients went onto receive allo-HCT. There was no significant difference in median OS when comparing patients treated with HMA+Venetoclax to a historical population treated with HMA monotherapy (n=26) or intensive chemotherapy (n=69) (8 months vs 5.5 months vs 8 months, respectively; p=0.13)42. A multi-center retrospective analysis by King et al analyzed outcomes of 27 patients with MPN-AP/BP treated with venetoclax-containing combination therapies. Twenty-one patients had MPN-BP while 6 patients had MPN-AP at time of treatment; 24 patients received an HMA combined with venetoclax while 3 patients received LDAC. The acute leukemia response-complete (ALR-C) rate was 30% and 5 patients received an allo-HCT; the median OS was 6 months for patients with MPN-BP and median OS of 3.6 patients for those with MPN-AP43.

While BCL-2 inhibition in MPN-AP/BP may hold promise, its current role in management is unclear. An analysis of 80 patients with MPN-AP/BP diagnosed and treated from 2017 onwards found no significant difference in overall survival between patients treated with HMA-Venetoclax in the frontline setting (median OS 0.59 years) when compared to those treated with other HMA-based regimens (median OS 1.1 years)6. Given pre-clinical work elucidating the role of BCL-xL and MCL-1 dependency in MPNs and erythroid/megakaryocytic AML, prospective evaluation of navitoclax in MPN-AP/BP is underway (NCT05455294, NCT05222984) and may provide a means of overcoming the resistance to venetoclax seen in MPN-AP/BP36,44, 45, 46.

Isocitrate dehydrogenase (IDH)1 and 2 are essential enzymes within the tricarboxylic acid (TCA) cycle and catalyze the formation of alpha-ketoglutarate, which is necessary for appropriate epigenetic regulation. Mutations in IDH1 and IDH2 are seen across a variety of malignancies and lead to accumulation of the oncometabolite R-2-hydroxyglutarate (R-2HG)47. Accumulation of R-2-HG inhibits alpha-ketoglutarate dependent dioxygenases such as Jumonji C-domain lysine demethylases and ten-11 translocation (TET) enzymes. In myeloid malignancies this promotes leukemogenesis via proliferation and differentiation block of immature hematopoietic cells. In MPNs, both IDH1 and IDH2 mutations are associated with inferior OS and increased risk of progression to MPN-BP17. Pre-clinical work has demonstrated the efficacy of IDH inhibition as monotherapy and in combination with JAK inhibition in the treatment of IDH-mutated MPNs48. The incidence of IDH1/2 mutations is enriched in MPN-AP/BP and ranges from 19-26%, making IDH inhibition an intriguing targeted therapy approach11, 12, 13. Ivosidenib and enasidenib, inhibitors of the IDH1 and IDH2 mutant enzymes respectively, have provided a novel lower-intensity approach in the treatment for IDH-mutated AML49, 50, 51, 52, 53. The efficacy of this approach in AML has spurred investigation in MPN-AP/BP as well. In our single-center analysis of 8 patients with IDH2-mutated MPN-AP/BP treated with enasidenib-based regimens; 7 patients had MPN-BP while 1 had MPN-AP. Six patients were treated in the frontline setting while 2 received treatment in the R/R setting; 7 of these patients received enasidenib monotherapy while one received enasidenib in combination with azacitidine. Using 2012 MPN-BP consensus criteria54 the response rate was 75% with an ALR-C rate of 25%. The 1-year OS was 50% and the longest response surpassed 4 years. Differentiation syndrome was seen in 25% of patients. Of note, even in patients with durable responses, there were molecular and histopathologic findings of chronic-phase MPN that persisted, which suggests that IDH inhibition did not address the underlying chronic-phase MPN2. Chifotides et al retrospectively analyzed 12 patients with IDH-mutated MPN-BP at their institution (7 IDH1 mutated, 5 IDH2 mutated) that received IDH inhibitor-based therapy. A variety of IDH inhibitor-including approaches were employed including IDH inhibitor monotherapy or in combination with ruxolitinib, venetoclax, HMA therapy, or intensive chemotherapy. Seven patients were treated in the frontline setting while 5 were treated in the R/R setting; 25% of patients achieved a CR and the median OS of the entire cohort was 10 months3. A prospective study of ruxolitinib combined with enasidenib for patients with IDH2-mutated MPN-AP/BP and MF is ongoing (NCT04281498); amongst the 5 patients with MPN-AP/BP treated the CR rate was 40% with the longest duration of treatment being 13 cycles and ongoing55. Other prospective efforts investigating IDH inhibition are include utilization of a novel IDH1/2 inhibitor (NCT04603001).

Section snippets

Conclusions

MPN-AP remains an ongoing therapeutic challenge. There is no standard treatment approach. Our current knowledge of molecular pathogenesis, and the emerging promise of select targeted therapeutics dictates consideration of a personalized approach (Figure 1). Given the relative chemo-resistance of this group of diseases, approaches that have the potential to be tolerable and to bridge transplant eligible individuals to an allo-HCT should be considered whenever possible. For those who are

COI

AAP: Research Funding (Institutional) from Pfizer, Kronos Bio, Celgene/BMS; honoraria from Abbvie and Bristol-Myers Squibb

OO: advisory board of Bristol-Myers Squibb, Celgene, Novartis, Taiho and Kymera Therapeutics; DSMB for Threadwell Therapeutics; research funding (institutional) from ABBVIE, Agios, Aprea, Astex, Astra Zeneca, Bristol Myers Squibb, Celgene, CTI, Daiichi, Incyte, Janssen, Kartos, Loxo, Novartis, NS-Pharma and Oncotherapy Sciences.

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Crizotinib Has Preclinical Efficacy in Philadelphia-Negative Myeloproliferative Neoplasms

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TRANSLATIONAL CANCER MECHANISMS AND THERAPY| JANUARY 20 2023
Lindsay M. Gurska; Rachel Okabe; Alexandra Schurer; Meng Maxine Tong; Mark Soto; Daniel Choi; Kristina Ames; Shira Glushakow-Smith; Allison Montoya; Ellen Tein; Linde A. Miles; Haiying Cheng; Pamela Hankey-Giblin; Ross L. Levine; Swati Goel; Balazs Halmos; Kira Gritsman
Abstract
Purpose:

The Philadelphia chromosome–negative myeloproliferative neoplasms (MPN) polycythemia vera, essential thrombocythemia, and primary myelofibrosis are characterized by JAK/STAT pathway activation. JAK inhibitors are approved for MPN treatment, but persistence has been observed, due to JAK/STAT reactivation.

Experimental Design:

Using MPN patient samples, JAK2-mutated cell lines, and MPN mouse models, we examined both the efficacy and mechanism by which crizotinib, the ALK/MET/RON/ROS1 inhibitor approved for the treatment of non–small cell lung cancer, alters MPN cell proliferation and JAK/STAT activation.

Results:

We found that crizotinib suppresses proliferation and activation of JAK/STAT signaling, and decreases the disease burden in the JAK2V617F mouse model of MPN. Furthermore, we found that crizotinib could overcome JAK inhibitor persistence to ruxolitinib. Interestingly, phosphorylation of the crizotinib target RON kinase was enhanced in ruxolitinib-persistent cells. We show that phospho-JAK2 and phospho-RON can physically interact to sustain JAK/STAT signaling, and that the combination of crizotinib and ruxolitinib disrupts this interaction. Furthermore, RON knockdown suppresses proliferation and activation of JAK/STAT signaling in JAK2-mutated cells, and RON deletion in a JAK2V617F mouse MPN model decreases the disease burden. We also observed RON hyperactivation in MPN patient cells, suggesting that RON may be an important target of crizotinib in MPN.

Conclusions:

In summary, we demonstrate that crizotinib has preclinical efficacy in MPN patient cells, JAK2-mutated cell lines, and a JAK2-mutated mouse model, and that the combination of crizotinib with JAK inhibitors suppresses JAK inhibitor persistence. Our work suggests that crizotinib should be investigated for the treatment of patients with MPN.

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