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Rusfertide Improves Responses, Meets Primary End Point of REVIVE Trial in Polycythemia Vera

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Caroline Seymour

Treatment with rusfertide led to a higher response rate of 69.2% vs 18.5% with placebo in patients with polycythemia vera, meeting the primary end point of the phase 2 REVIVE trial.

Treatment with rusfertide (PTG-300), a subcutaneous injectable hepcidin mimetic, led to a higher response rate of 69.2% vs 18.5% with placebo in patients with polycythemia vera (PV), meeting the primary end point of the phase 2 REVIVE trial (NCT04057040; P = .0003).1

Responders included those who completed 12 weeks of double-blind treatment while maintaining hematocrit control without meeting criteria for phlebotomy or undergoing phlebotomy.

“Participants in our studies who required frequent phlebotomy, with or without cytoreductives, have now been treated with rusfertide for more than two years, remaining largely phlebotomy free,” Arturo Molina, MD, MS, chief medical officer of Protagonist, said in a press release. “Data from the REVIVE study suggest that rusfertide treatment results in a highly statistically significant reduction in the need for therapeutic phlebotomy in phlebotomy-dependent patients, leading to rapid, sustained, and durable control of hematocrit levels below 45%. Part 2 of REVIVE, the randomized withdrawal study, yielded no new safety findings while confirming previously reported efficacy and safety findings observed in the open-label portion of REVIVE [part 1].”

“These randomized withdrawal data from the REVIVE study indicate a dramatic difference in the experience of the treatment group versus the placebo group,” Ronald Hoffman, MD, the Albert A. and Vera G. List Professor of Medicine (Hematology and Oncology), director of the Myeloproliferative Research Program at the Icahn School of Medicine at Mount Sinai, and principal investigator of the study, said. “With robust and strongly positive results observed across a diverse set of patients, we now have further confirmation of rusfertide’s potential to serve as an important future treatment option for patients with PV.”

Patients with PV who have hematocrit levels above 45% are at a greater risk of thrombosis. Standard therapy for these patients includes therapeutic phlebotomy alone or in combination with cytoreductive agents. However, current therapies are not effective in reducing hematocrit levels below 45% and are not all well tolerated. Rusfertide is a hepcidin mimetic being developed as a non-cytoreductive option to maintain hematocrit levels below 45% in patients with PV.2

The phase 2 study enrolled patients with excessive erythrocytosis despite therapeutic phlebotomy (3 or more in the 6 months prior to enrolling) with or without cytoreductive therapy with a hematocrit level below 45% at study entry.

Eligible participants were first treated in a 28-week, open-label, dose-titration and efficacy evaluation phase (part 1).1 Patients administered rusfertide in doses ranging from 10 mg to 120 mg weekly. Doses were adjusted each month to maintain hematocrit levels below 45%.2

Afterward, patients (n = 53) were randomly assigned 1:1 to rusfertide or placebo for another 12 weeks as part of the double-blind, placebo-controlled phase (part 2). Patients in this cohort had frequent phlebotomy requirements. Notably, 92.3% (n = 24/26) of patients in this cohort treated with rusfertide remained free from phlebotomy (P = .0003).

Additionally, the change from moderate or severe Myeloproliferative Neoplasm-Symptom Assessment Form (MPN-SAF) symptom scores at baseline was statistically significant in fatigue, problems with concentration, inactivity, and itching during the 28-week, open-label portion of part 1 of the study.

A comparison of symptom assessments in part 2 was not made because most patients administered placebo had discontinued treatment prior to the 12-week MPN-SAF symptom assessment.

“All study subjects who participated in the REVIVE clinical trial had been previously unsuccessful in controlling their hematocrit using standard-of-care therapies alone,” Andrew Kuykendall, MD, Department of Malignant Hematology, Moffit Cancer Center, added. “These new data from REVIVE provide important insights into the role that rusfertide can potentially have within a future PV treatment paradigm, supporting patients and their physicians in achieving the treatment goal of hematocrit below 45%, in step with current National Comprehensive Cancer Network Clinical Practice Guidelines.”

Regarding safety, the agent was well tolerated, and no new adverse effects (AEs) were reported since the safety analysis was presented at the 2022 ASH Annual Meeting and Exposition. The most common AEs were localized injection site reactions.

Rusfertide is also under study in the ongoing, phase 3 VERIFY trial (NCT05210790) vs placebo in patients with PV maintaining hematocrit control and in improving symptoms of disease.3

“The new randomized withdrawal data confirm our previous efficacy and safety findings of rusfertide in PV and support our strong conviction that rusfertide can be a potentially transformational therapeutic option for polycythemia vera,” Dinesh V. Patel, PhD, president and chief executive officer of Protagonist, said. “With the completion of the REVIVE study, the company’s topmost priority continues to be execution of the 250-patient global, pivotal, phase 3 VERIFY study in PV. The Protagonist team continues to work with full dedication alongside investigators, site staff and other partners with the shared aim of bringing this important potential therapy to PV patients.”

References

  1. Protagonist Therapeutics announces highly statistically significant results from the randomized withdrawal portion of the REVIVE study of rusfertide in polycythemia vera. News release. Protagonist Therapeutics. March 15, 2023. Accessed April 3, 2023. https://www.yahoo.com/lifestyle/protagonist-therapeutics-announces-highly-statistically-113000427.html
  2. Hoffman R, Ginzburg Y, Kremyanskaya M, et al. Rusfertide (PTG-300) treatment in phlebotomy-dependent polycythemia vera patients. J Clin Oncol. 2022;40(suppl 16):7003. doi:10.1200/JCO.2022.40.16_suppl.7003
  3. A phase 3 study of rusfertide in patients with polycythemia vera (VERIFY). ClinicalTrials.gov. Updated March 28, 2023. Accessed April 3, 2023. https://clinicaltrials.gov/ct2/show/NCT05210790

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Secreted Mutant Calreticulins Act as Cytokines in Myeloproliferative Neoplasms

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March 29, 2023

Lauren Dembeck, PhD

Mutant calreticulin (CALR) resulting from a frameshift mutation becomes a “rogue cytokine,” pathologically activating the thrombopoietin receptor (TpoR), driving proliferation of hematopoietic cells in patients with myeloproliferative neoplasms (MPNs), according to research published in Blood. The findings suggest the level of circulating mutant CALR proteins could potentially be used as a biomarker for risk stratification of CALR-mutated MPNs.

The researchers used a combination of molecular and cell-based assays as well as microscopy studies to evaluate whether secreted mutant CALRs act in a paracrine or autocrine manner to activate the TpoR of adjacent cells and whether this “rogue cytokine” effect is relevant to MPN pathogenesis.

Using 159 plasma samples from patients with MPN, the researchers discovered that mutant CALR proteins are secreted. They detected soluble mutant CALR in 106 of 111 (95%) patients at levels up to 160 ng/mL in patient plasma, with a mean level of 25.64 ng/mL.

In cases where mutational CALR burden and clinical diagnosis data were available (n=57), the team demonstrated that plasma levels of soluble mutant CALR were directly correlated with the allele burdens in the patients’ blood (r2=0.43; P <.0001).

To study the functional relevance of extracellular mutant CALR, the researchers immunoprecipitated the plasma from 5 patients with MPN and 5 control participants without MPN and analyzed the precipitating proteins using mass spectrometry. They found that plasma mutant CALR is found in complex with soluble transferrin receptor 1 (sTFR1), and that this carrier protein complex increases mutant CALR half-life.

They went on to demonstrate that recombinant mutant CALR proteins are able to bind and activate the TpoR in cell lines and primary megakaryocytic progenitors from patients with mutated CALR in which they drive thrombopoietin-independent colony formation.

Using an assay able to assess protein interactions in cultured cells (HEK293), the researchers demonstrated that mutant CALR proteins produced in 1 cell specifically interact with the TpoR on different target cell. Compared with cells that only carry TpoR, they found that cells carrying both TpoR and mutant CALR are hypersensitive to exogenous mutant CALR and respond to levels of mutant CALR that are similar to those found in patient plasma.

To test the cytokine effect of CALR, the team treated primary cells from patients with MPN carrying CALR mutations or JAK2 V617F or from healthy control participants with mutant or wildtype CALR. They demonstrated that the secreted mutant CALR induces a significant increase in megakaryocyte colony formation for patients with CALR mutations but not for patients with JAK2 V617F or healthy control participants.

“To our knowledge, this work is the first to demonstrate that circulating mutant CALR proteins can exert a rogue cytokine activity on cells that express the TpoR,” the authors wrote in their report. “Our finding that mutant CALR proteins act as rogue cytokines could open new perspectives for treating patients with CALR-mutated MPNs.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Pecquet C, Papadopoulos N, Balligand T, et al. Secreted mutant calreticulins as rogue cytokines in myeloproliferative neoplasms. Blood. 2023;141(8):917-929. doi:10.1182/blood.2022016846

Discussing the Ever-Changing MPN Treatment Landscape

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Andrew Kuykendall, MD

Andrew Kuykendall, MD, an assistant member at the H. Lee Moffitt Cancer Center of University of South Florida in Tampa, FL, discusses some of the most recent approvals seen in the myeloproliferative neoplasm (MPN) space.

Ruxolitinib (Jakafi) was the first JAK1/2 inhibitor to receive FDA approval for the treatment of MPNs. Others, including fedratinib (Inrebic) and pacritinib (Vonjo), have since gained FDA approval, and are showing benefit for this patient population.

Transcription:

0:08 | 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.

0:42 | 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.

1:40 | 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.

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Hydroxyurea Does Not Appear to Increase Second Malignancy Risk in Myeloproliferative Neoplasms

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March 28, 2023

Jonathan Goodman, MPhil

Patients with myeloproliferative neoplasms (MPNs) treated with hydroxyurea do not appear to have a higher risk of secondary malignancies (SMs), according to research published in Blood Advances.

Classical Philadelphia chromosome-negative MPNs, which include polycythemia vera (PV), essential thrombocythemia (ET), and primary/secondary myelofibrosis (MF), are linked with an annual risk of transformation into acute myeloid leukemia (AML) of up to 20%.

Previous research has suggested, furthermore, that the use of hydroxyurea — a myelosuppressive agent used as a cytoreductive therapy in the MPN setting — may increase the risk of SMs through interference with DNA synthesis.

For this population-based study, researchers evaluated data from patients with MPNs including PV, ET, and MF to determine whether a link exists between hydroxyurea and SM development, whether hematologic or solid.

Overall, data from 4023 patients with an MPN were included, of whom 2683 had received hydroxyurea. The most common diagnosis was ET (49.1%), while 42% of patients had PV and 8.9% of patients had MF. The median age in the cohort was 77 years, 61.3% of patients were female sex, and 24% of patients had had a previous cancer. All data were obtained from the Surveillance, Epidemiology, and End Results Medicare-linked database.

The median follow-up was 3.25 years. At this point, 489 patients in the overall cohort had developed an SM, which included solid (346 cases), lymphoid (73 cases), and myeloid (70 cases) malignancies.

Analysis showed that, among those treated with hydroxyurea, the cumulative incidence of SM was 19.88%, compared with 22.31% not treated with hydroxyurea (P <.01 on a Gray’s test). No differences, furthermore, were noted in the incidence of solid or specific hematologic SMs (P =.3) between the 2 groups.

“[Hydroxyurea] use in older patients with MPN was not associated with an increased incidence of SM overall or AML…specifically, supporting [hydroxyurea] as the preferred cytoreductive option for this patient population,” the authors wrote in their report. “However, a longer follow-up may be necessary to confirm these findings.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Wang R, Shallis RM, Stempel JM, et al. Second malignancies among older patients with classical myeloproliferative neoplasms treated with hydroxyurea. Blood Adv. 2023;7(5):734-743. doi:10.1182/bloodadvances.2022008259

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Immunosuppressive Therapies, Comorbidities Heighten COVID-19 Risk in People With MPNs

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Jared Kaltwasser

Older age was also a risk factor for hospitalization and death in patients with myeloproliferative neoplasms (MPN) who contract COVID-19, the investigators found.

People with myeloproliferative neoplasms (MPN) who contract COVID-19 have particularly poor outcomes, according to a new study, especially if they have a history of taking immunotherapies or are older than 70 years of age.

The report, published in Therapeutic Advances in Hematology, suggests better strategies are needed to help protect this patient group if they are exposed to viruses such as SARS-CoV-2.

Corresponding author Jon Salmanton-García, of the University of Cologne, and colleagues, noted that people with Philadelphia-negative MPN face a higher risk of infections generally, but they said factors such as medications and comorbidities can affect a patient’s level of risk.

Previous research has suggested that people with MPN face 3 times the risk of infection compared to the general population, and the investigators said that data point alone suggests patients with MPN could be more likely to experience severe cases of COVID-19.

In the new study, Salmanton-García and colleagues wanted to better understand how a patient’s previous therapies and other clinical characteristics might affect their disease course when they were diagnosed with COVID-19. To find out, they turned to an international cooperative registry, dubbed EPICOVIDEHA, which was launched in February 2020 by a working group of the European Hematology Association.

The team identified a total of 398 patients with MPN who were diagnosed with COVID-19 since the start of the database. Those patients had a median age of 69 years, and they were followed for a median follow-up period of 76 days.

The largest proportion of the cohort was diagnosed with myelofibrosis (MF; 46%), while 28.4% had essential thrombocythemia (ET), and 25.6% of patients had a diagnosis of polycythemia vera (PV).

In terms of medication history, 37.2% of patients had most recently received hydroxyurea as therapy for their cancer, and 27.9% had most recently taken Janus kinase (JAK) inhibitors. Other types of therapies reported by patients included immunomodulating agents and steroids.

A majority of patients in the cohort eventually required hospitalization for their COVID-19 (54%). Of those hospitalized, one quarter were admitted to the intensive care unit, and 29 patients required mechanical ventilation, the investigators said.

Patients with exposure to immunosuppressive therapies prior to COVID-19 onset had a higher risk of hospitalization (odds ratio [OR], 2.186; 95% CI, 1.357-3.519), as did people who were over the age of 70 years (OR, 2.636; 95% CI, 1.683-4.129).

Nearly one-quarter (22.4%) of the cohort died during the follow-up period. Again, older age and exposure to immunosuppressive therapies increased the risk to patients, as did previous comorbidities.

Turning toward potential strategies to improve outcomes for these patients, Salmanton-García and colleagues noted that COVID-19 vaccines have helped to reduce the risk of severe disease, but they said the risks remain high in patients with blood cancers.

The authors said they believe their study to be the first to find that previous exposure to immunosuppressive agents are an independent risk factor for hospitalization and death in patients with COVID-19.

“Specific preventative strategies need, thus, to be tailored for these individuals at risk, including application of potentially protective preventative antibody cocktails as well as meaningful tapering strategies for MPN patients pretreated with JAK inhibitors,” they wrote.

The authors said more data will be needed to more fully understand the interplay of certain therapies, MPNs, and COVID-19 risk, including data on how vaccination might affect risk.

In the meantime, they said clinicians should carefully consider these factors when making therapeutic decisions related to patients with MPNs.

Reference

Marchetti M, Salmanton-García J, El-Ashwah S, et al. Outcomes of SARS-CoV-2 infection in Ph-neg chronic myeloproliferative neoplasms: results from the EPICOVIDEHA registry. Ther Adv Hematol. Published online March 11, 2023. doi:10.1177/20406207231154706

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Abbas Assesses the Use of Allogenic Transplant In MPNs

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Targeted Oncology Staff

During a Targeted Oncology™ Case-Based Roundtable™ event, Jonathan Abbas, MD, discussed with his fellow clinicians the use of allogeneic hematopoietic stem cell transplant in patients with myeloproliferative neoplasms and how ruxolitinib fits into their care.

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 unexplained weight loss​. Her spleen was palpable 8 cm below the left costal margin. Genetic testing showed she was negative for a JAK2 V617F or CALR mutation. Her karyotype was 46XX​ and a bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis.

A blood smear revealed leukoerythroblastosis and she was diagnosed with primary myelofibrosis​ with a DIPSS (Dynamic International Prognostic Scoring System) risk score of intermediate-2 and also had an intermediate MIPSS70 risk score.

DISCUSSION QUESTIONS

  • In your experience with myelofibrosis, which symptoms/presentations have the most negative impact on patients’ quality of life?​
  • What are the treatment goals for a patient like this? ​

In your practice:​

  • What is the trigger to initiate therapy for a patient with myelofibrosis?​
  • What is the timing to start JAK (Janus kinase) inhibitor therapy, and how do you choose?​
  • How does the nature and burden of symptoms influence your decision to initiate JAK inhibitor therapy? ​
  • How important is it to initiate therapy early?​

JONATHAN ABBAS, MD: Is this a patient where from day 1 you’re talking about an allogeneic [hematopoietic stem cell] transplant [HSCT] referral? Is this a patient that a transplanter would want to see early in the disease course or is this something that you might want to hold off on a HSCT consult until something isn’t behaving as well as it could?

JEREMY PANTIN, MD: The [patient is] approaching the age limit where things are going to start getting [difficult] and not somebody that we’ll take straight to allogeneic HSCT transplant, but you probably want to consider therapy to reduce that spleen size. If the patient appears to not have comorbidities and may be a good candidate for HSCT, the intermediate-2 or greater risk will certainly allow them to move forward, in terms of the favorable risk-to-benefit ration, if everything is aligned.

MICHAEL T. BYRNE, MD: I think we used to argue about this, not argue [necessarily], but these were the hard patients because nobody knows what to do with them. She’s the right age for transplant, but also, transplant is not without risk. Quality of life is probably worse after an allogeneic HSCT than it could be without, so I don’t know. I think you plug her in then you see what her donor search looks like, and regardless of whether she goes to treatment, I think this is somebody that you probably treat if for no other reason than to try and improve her quality of life.

OLALEKAN O. OLUWOLE, MBBS, MD: I completely agree with what my colleague just said. We have several targeted therapies in this area, and we can just find 1 to give them to control their symptoms.1 If that fails, there will be another. There are many in development, so for those who are not keen on getting transplanted, there is a viable pathway to just keep treating them. Now for the patient who says, “I want to see what the odds are,” like what [Dr. Bryne] said, find out if they have a donor, talk about the risk-benefit, and go for it.

ABBAS: From my HSCT days, I would totally agree with you. I think this is a patient I would want to see early, to explain that you might not need me now, but you might need me one day. You’ve potentially got years left of transplant eligibility, and we don’t have a crystal ball about how your response to treatment is going to be and where this disease is going.

Then just to be the devil’s advocate for the case, this is a lucky one where we had intermediate risk with 1% blasts. If this [patient] had 6% or 7% of 8% blasts and we were now nudging closer to high risk, that might sway all of us to maybe think initially therapy might be more of a bridge to HSCT, because there might be a little bit less stable disease.

[This] is a symptomatic patient. Is there anybody out there who would watch and wait with this patient regardless of whether they are seeing the allogeneic HSCT team or not? Or does everyone feel this patient warrants some therapy?

RYAN CARR, MD: Yes, based on her symptoms, if you tried to watch and wait, so [the patient] might end up seeing somebody else.

ABBAS: I agree with you. She will certainly be finding another group in town if you said, “You have [myelofibrosis], but it’s not that big a deal. Let’s just see you back in 3 months.” I think it’s unanimous this is a [patient] who’s not a watch-and-wait case. They are out there, but this is not her.

CASE UPDATE

Additional lab values showed the following counts:

  1. Red blood cells: 3.40 × 1012/L
  2. Hemoglobin: 13.2 g/dL
  3. Hematocrit: 36%
  4. Mean corpuscular volume: 94 fL
  5. White blood cells: 23.0 × 109/L
  6. Platelets: 450 × 109/L
  7. Peripheral blood blasts: 1%

DISCUSSION QUESTIONS

  • How do you use platelet count?
  • What if a patient had thrombocytopenia at baseline? ​
  • How does age/frailty factor in?

ABBAS: [If there is] thrombocytopenia at baseline, I guess we have 2 options for this. One would be; are we comfortable still sticking with ruxolitinib [Jakafi], which we all agree on [in a patient case like this], but dose modifying potentially for thrombocytopenia or would just any thrombocytopenia necessarily make us think about another agent, if anybody wants to weigh in on it?

BRYNE: I think a thrombocytopenia of 140 × 109/L is different than thrombocytopenia of 30 × 109/L. That’s quite a difference [between the level where a patient should receive] ruxolitinib vs pacritinib [Vonjo].

ABBAS: Yes, I would agree with you. Without the specific measurements, it’s hard to say. Just also remember you certainly can, and we’ve been doing for years is dose decreasing the ruxolitinib with a lot of benefit.2 Unless you’re in that extreme situation like down below 50 × 109/L platelet count, I still think there’s a window to go with the tried and true [method here].

How about frailty? How about if this woman, let’s say she was extremely frail and it wasn’t necessarily a disease-related frailty, just other comorbidities? Would that sway us? Do we feel that JAK inhibitors are particularly tough on patients? Would this factor in at all if she were 78 years old or if she was 88 years old?

JACK ERTER, MD: No. I think this drug is, all things considered, quite on target and easy to take for most patients. I would certainly have no hesitation to give an 88-year-old a trial at a dose-modified start of ruxolitinib.

References

1. Li B, Rampal RK, Xiao Z. Targeted therapies for myeloproliferative neoplasms. Biomark Res. 2019 Jul 16;7:15. doi: 10.1186/s40364-019-0166-y

2. Mesa RA, Cortes J. Optimizing management of ruxolitinib in patients with myelofibrosis: the need for individualized dosing. J Hematol Oncol. 2013 Oct 22;6:79. doi: 10.1186/1756-8722-6-79

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Patient Outcomes in the Myeloproliferative Neoplasm Treatment Landscape

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Prithviraj Bose, MD
Prithviraj Bose: The outcomes for patients with PV and ET overall are good. So, these are, of course, the indolent ones among the classic myeloproliferative neoplasms. And so when you compare to myelofibrosis, for example, the outcomes are much better. And for that reason, we’re not transplanting anybody with ET and PV, for example, because their median survival is fairly long. At least compared to myelofibrosis. So, in ET, we generally think that the median survival is not different from an age and gender matched population. In PV, it’s been reported to be between 14 and 19 years. And PV definitely is a worse disease than ET. That’s well known. Both of them can, of course, progress to myelofibrosis and rates have been published at 10 years, at 15 years, you definitely have a reasonable chance around 10% in PV, although there are ranges, of course, across different studies of progression to myelofibrosis and smaller risk, thankfully, of transformation to AML. So, generally, these are diseases that people live with for many years. And obviously, because of that, day to day symptoms become an issue. It’s not just about controlling the counts and preventing blood clots, which continues to be goal number one. But I think there’s a lot of other things that we need to pay attention to. In fact, there have been studies like the MPN landmark study, which have shown that there is some discordance between patients’ priorities and physicians’ priorities. So, for example, patients are very keen to modify their underlying biology to sort of stop or halt or slow this inexorable disease progression that may otherwise occur. So that is more important to them sometimes than preventing a blood clot. That’s not to say that a blood clot couldn’t be bad. It could be a stroke or a heart attack, but in patients with these chronic diseases, it’s really important to them to try and do something to the root cause, so to speak, and its natural course. So this is where I think the increasing interest in getting this allele burden of JAK2 down, regardless whether that’s with an interferon or with ruxolitinib, is gaining ground. And the hope is that that would translate to improved myelofibrosis-free survival, improved overall survival, and increased leukemia-free survival, all of that. Now, symptoms is another whole different and important domain. Symptoms, many studies have shown that MPN patients, PV, ET, MF, all of them, MF usually more symptomatic than PV, but PV more symptomatic than ET, have a wide range of symptoms. And they can be debilitating, disabling sometimes, or at least bad enough that they impair quality of life, work productivity, etc. There’s been many surveys of patients that have shown these. And so certainly, this is important to elicit from patients. As I said earlier, using that MPN SAFTSS form is very helpful, because it allows you to objectify it and follow it over time. And we do have drugs, for example, ruxolitinib that comes to mind first, as a drug that addresses symptoms really more effectively than any other drug right now with PV. And so, it certainly draws attention to the fact that we need to be cognizant of symptoms and always elicit those and see how well we’re doing with that aspect, beyond the more traditional aspects of treating patients with PV.

Researchers identify cell type that could be key to preventing marrow transplant complication

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March 24, 2023

A bone marrow transplant can be a lifesaving treatment for people with relapsed blood cancers, but a potentially lethal complication known as graft-versus-host disease put limitations on this procedure. New research from the University of Wisconsin–Madison is helping to change that by identifying the cell population that causes GVHD, a target that may make bone marrow transplants safer and more effective.

An allogenic (from a donor) bone marrow transplant is a common treatment for blood cancers and other diseases of the immune system. During the transplant, the patient’s immune cells are replaced with the donor’s healthy cells. While the donor cells can help cure the patient’s blood cancer, they can also cause GVHD—in which donor T cells, a specialized immune cell in the blood, attack the patient’s healthy cells. This causes complications similar to an autoimmune disease that can be lethal.

“Graft versus host disease is one of the most common complications after an allogeneic hematopoietic cell transplantation procedure, and the field knows quite well that the T cells from the donor are the ones mediating the disease,” says the study’s lead author Nicholas Hess, a scientist at UW–Madison’s Carbone Cancer Center. “Before this study, there was no finite T cell population that we’ve been able to identify as the cause of GVHD, so all our treatment regimens generally impacted the entire T cell population. But targeting all the T cells is not ideal, as they don’t just cause this detrimental disease, they also have a beneficial impact on the ability to prevent relapses.”

Today in Science Advances, Hess and collaborators including Stem Cell and Regenerative Medicine Center members Christian Capitini, professor of pediatrics, and Peiman Hematti, professor of medicine, published their findings, identifying cells called CD4/CD8 double positive T cells (DPT) causing GVHD in immunodeficient mice. To further confirm their findings, the researchers directly investigated human patient samples.

“We looked at over 400 clinical samples from 35 patients as a part of this study and found double positive T cells to be predictive of GVHD. We also found four other biomarkers which are predictive of not just GVHD, but also relapse in general,” says Hess. “Based on that, our next step is to merge the biomarkers into a machine learning algorithm that can output a risk prediction model. Clinicians could then use this model to understand a patient’s risk of relapse and GVHD.”

A team of physicians and scientists at UW–Madison is working on ways to address the problematic cells in patients while leaving healthy and helpful T cells to flourish. Hess says that while the team is very confident the double positive T cells are directly involved in GVHD, the key step in bringing this discovery to the clinic will be developing a targeted depletion strategy and this prediction model.

“When we can gain confidence in this biomarker research and our ability to identify patients at risk, then we will potentially be able to treat them before they have all the detrimental effects of this disease,” Hess says.

The study won a Best Abstracts Award from the American Society for Transplantation and Cellular Therapy and was presented at the American Association of Immunologists (AAI) and ECOG-ACRIN conferences, creating excitement based on the findings’ potential impact beyond blood cancer and transplantation.

“I’ve learned that DPTs have been found in a variety of chronic human inflammatory diseases, which goes to show that this is not a specific thing to graft-versus-host disease. It’s probably a wider phenomenon that these human T cells are doing that we’ve never really appreciated before,” says Hess. “It’s very exciting because it gives us something to study further. I’ve always been interested in taking something you discover in the lab and translating it to the clinic. I think it’s what gets me up every day. It is kind of the ultimate goal in my life to be able to say I participated in something that helped patients in some way.”

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Incyte Provides Regulatory Update On Ruxolitinib Extended-Release Tablets

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WILMINGTON, Del.–(BUSINESS WIRE)–Mar. 23, 2023– Incyte (Nasdaq:INCY) today announced that the U.S. Food and Drug Administration (FDA) has issued a complete response letter for ruxolitinib extended-release (XR) tablets, a JAK1/JAK2 inhibitor, for once-daily (QD) use in the treatment of certain types of myelofibrosis (MF), polycythemia vera (PV) and graft-versus-host disease (GVHD).

The complete response letter states that the FDA cannot approve the application in its present form. The FDA acknowledged that the study submitted in the New Drug Application (NDA) met its objective of bioequivalence based on area under the curve (AUC) parameters but identified additional requirements for approval. Incyte intends to meet with the FDA to determine appropriate next steps.

“While we are disappointed that the FDA issued a complete response letter for ruxolitinib extended-release tablets, we remain committed to advancing care for people with myeloproliferative neoplasms and GVHD,” said Hervé Hoppenot, Chief Executive Officer, Incyte. “We will work closely with the FDA on the appropriate next steps to address their comments.”

The NDA was based on two studies designed to show that ruxolitinib XR tablets are dosage strength proportional and bioequivalent to Jakafi® (ruxolitinib) tablets. The first study was designed to determine the relative bioavailability of ruxolitinib XR tablets to Jakafi tablets and to demonstrate that ruxolitinib XR tablets are dosage strength proportional to Jakafi tablets. The second study was an open-label, randomized, two-period, two-way crossover study in 63 healthy adults evaluating the bioequivalence of the highest strength of ruxolitinib XR tablets (50 mg) dosed once-daily (QD) to the highest strength of Jakafi tablets (25 mg) dosed twice-daily (BID), following a single dose and at steady-state. Study results demonstrated that ruxolitinib XR 50 mg tablets dosed QD is bioequivalent to Jakafi 25 mg tablets dosed BID, based on AUC parameters.

About Jakafi® (ruxolitinib)
Jakafi® (ruxolitinib) is a JAK1/JAK2 inhibitor approved by the U.S. FDA for treatment of polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea; intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF in adults; steroid-refractory acute GVHD in adult and pediatric patients 12 years and older; and chronic GVHD after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older1.

Jakafi is a registered trademark of Incyte.

Important Safety Information

Jakafi can cause serious side effects, including:

Low blood counts: Jakafi® (ruxolitinib) may cause low platelet, red blood cell, and white blood cell counts. If you develop bleeding, stop taking Jakafi and call your healthcare provider. Your healthcare provider will do a blood test to check your blood counts before you start Jakafi and regularly during your treatment. Your healthcare provider may change your dose of Jakafi or stop your treatment based on the results of your blood tests. Tell your healthcare provider right away if you develop or have worsening symptoms such as unusual bleeding, bruising, tiredness, shortness of breath, or a fever.

Infection: You may be at risk for developing a serious infection during treatment with Jakafi. Tell your healthcare provider if you develop any of the following symptoms of infection: chills, nausea, vomiting, aches, weakness, fever, painful skin rash or blisters.

Cancer: Some people have had certain types of non-melanoma skin cancers during treatment with Jakafi. Your healthcare provider will regularly check your skin during your treatment with Jakafi. Tell your healthcare provider if you develop any new or changing skin lesions during treatment with Jakafi.

Increases in cholesterol: You may have changes in your blood cholesterol levels during treatment with Jakafi. Your healthcare provider will do blood tests to check your cholesterol levels about every 8 to 12 weeks after you start taking Jakafi, and as needed.

Increased risk of major cardiovascular events such as heart attack, stroke or death in people who have cardiovascular risk factors and who are current or past smokers while using another JAK inhibitor to treat rheumatoid arthritis: Get emergency help right away if you have any symptoms of a heart attack or stroke while taking Jakafi, including: discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back, severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw, pain or discomfort in your arms, back, neck, jaw, or stomach, shortness of breath with or without chest discomfort, breaking out in a cold sweat, nausea or vomiting, feeling lightheaded, weakness in one part or on one side of your body, slurred speech

Increased risk of blood clots: Blood clots in the veins of your legs (deep vein thrombosis, DVT) or lungs (pulmonary embolism, PE) have happened in people taking another JAK inhibitor for rheumatoid arthritis and may be life-threatening. Tell your healthcare provider right away if you have any signs and symptoms of blood clots during treatment with Jakafi, including: swelling, pain, or tenderness in one or both legs, sudden, unexplained chest or upper back pain, shortness of breath or difficulty breathing

Possible increased risk of new (secondary) cancers: People who take another JAK inhibitor for rheumatoid arthritis have an increased risk of new (secondary) cancers, including lymphoma and other cancers. People who smoke or who smoked in the past have an added risk of new cancers.

The most common side effects of Jakafi include: for certain types of myelofibrosis (MF) and polycythemia vera (PV) – low platelet or red blood cell counts, bruising, dizziness, headache, and diarrhea; for acute GVHD – low platelet counts, low red or white blood cell counts, infections, and swelling; and for chronic GVHD – low red blood cell or platelet counts and infections including viral infections.

These are not all the possible side effects of Jakafi. Ask your pharmacist or healthcare provider for more information. Call your doctor for medical advice about side effects.

Before taking Jakafi, tell your healthcare provider about: all the medications, vitamins, and herbal supplements you are taking and all your medical conditions, including if you have an infection, have or had low white or red blood cell counts, have or had tuberculosis (TB) or have been in close contact with someone who has TB, had shingles (herpes zoster), have or had hepatitis B, have or had liver or kidney problems, are on dialysis, have high cholesterol or triglycerides, had cancer, are a current or past smoker, had a blood clot, heart attack, other heart problems or stroke, or have any other medical condition. Take Jakafi exactly as your healthcare provider tells you. Do not change your dose or stop taking Jakafi without first talking to your healthcare provider.

Women should not take Jakafi while pregnant or planning to become pregnant. Do not breastfeed during treatment with Jakafi and for 2 weeks after the final dose.

Please see the Full Prescribing Information, which includes a more complete discussion of the risks associated with Jakafi.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

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Parsaclisib Myelofibrosis Trial Discontinues; Likely To Miss Primary End Point

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Nicholas Wrigley

The phase 3 LIMBER-304 trial examining parsaclisib with ruxolitinib vs matched placebo will be discontinued after an interim analysis concluded it would likely miss the primary end point.

Investigators will discontinue treatment with parsaclisib plus ruxolitinib (Jakafi) for patients with myelofibrosis after an interim analysis concluded the regimen was unlikely to meet its primary end point, according to a press release on the phase 3 LIMBER-304 trial (NCT04551053).

Investigators will present data from the phase 3 LIMBER-304 trial evaluating parsaclisib plus ruxolitinib in myelofibrosis at a future medical meeting.

LIMBER-304 examined the experimental regimen vs ruxolitinib monotherapy in patients with myelofibrosis who had an inadequate response to said monotherapy. In the interim analysis, an independent data monitoring committee assessed the intent-to-treat patient population.

Investigators will present data from this trial at a future medical meeting.

The randomized, double-blind phase 3 LIMBTER-304 study evaluated the combination regimen in an estimated 212 patients. Patients needed to be on stable doses of ruxolitinib ranging from 5 mg to 25 mg twice daily for at least 8 weeks prior to the first day of study treatment. They must also have received at least 3 months of prior ruxolitinib therapy overall.

Eligible patients were then randomly assigned 1:1 to receive either oral parsaclisib or matched placebo once daily in addition to continued ruxolitinib.

The primary end point was the incidence of targeted reductions in spleen volume as assessed by MRI or CT imaging. Secondary end points included the incidence of targeted reductions in total symptom score (TSS), overall changes in TSS, time to the first 50% or greater reduction in TSS, overall survival, the incidence of treatment-related adverse effects, the time of onset of spleen volume reductions, and the duration of maintenance of spleen volume reduction.

Stratification factors included platelet count and Dynamic International Prognostic Scoring System (DIPSS) risk category.

Patients needed to have disease which fell in the intermediate-1, intermediate-2, or high DIPSS risk categories to be included in the study. A palpable spleen of 5 cm or larger below the left costal margin on physical examination at the screening visit and an ECOG score no greater than 2 were also required for enrollment.

Available bone marrow biopsy specimens and pathology reports from 2 months prior or a bone marrow biopsy at screening were also required for inclusion. Patients also needed to have a life expectancy of at least 24 weeks.

Exclusion criteria included any prior therapy involving PI3K inhibition, as well as a recent history of inadequate bone marrow reserve or inadequate liver and renal function at screening. An active invasive malignancy in the preceding 2 years and splenic irradiation in the preceding 6 months before the first dose of the study drug were also grounds for exclusion.

Reference

Incyte provides update on interim analysis of phase 3 LIMBER-304 study of parsaclisib and ruxolitinib in patients with myelofibrosis. News Release. Incyte. March 3, 2023. Accessed March 6, 2023. https://bit.ly/3ydeqU7

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