Tag Archives: polycythemia vera

Ropeginterferon alfa-2b shows anti-polycythaemia vera activity without causing clinically significant anaemia

Posted on by

Keita Kirito, Albert Qin, Shanshan Suo, Rongfeng Fu, Daoxiang Wu, Toshiaki Sato, Oleh Zagrijtschuk, Kazuya Shimoda, Norio Komatsu & Jie Jin

July 11, 2o24

Polycythaemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) that, in most cases, harbour the Janus kinase 2 gene (JAK2) driver mutation JAK2V617F [1]. PV is characterised by an over-production of blood cells with increased haematocrit levels, which is a risk factor for thrombotic events (TEs) and cardiovascular mortality [1, 2]. Low-dose aspirin and phlebotomy are usually recommended for patients with low-risk PV (i.e., no history of thrombosis and age ≤60 years). The National Comprehensive Cancer Network (NCCN) recommends ropeginterferon alfa-2b (BESREMi®) as a preferred cytoreductive treatment for patients with low- or high-risk PV [3].

Ropeginterferon alfa-2b is a novel polyethylene glycol (PEG)-conjugated recombinant proline-interferon alpha (IFN-a) with a favourable in vivo pharmacokinetic (PK) profile [4, 5]. Ropeginterferon alfa-2b has demonstrated substantial anti-PV clinical activity, including complete haematologic response (CHR; defined as a haematocrit <45% without phlebotomy, a platelet count ≤ 400 × 109/L, and a white blood cell count ≤10 × 109/L) and a reduction in the JAK2V617F allele burden [6,7,8,9]. Ropeginterferon alfa-2b injection is approved for adult patients with PV at an initial dose of 100 µg (or 50 µg for patients already receiving cytoreductive therapy) with 50 µg incremental intrapatient increases in the dose up to a maximum recommended dose of 500 µg every two weeks. It can take several months to reach the plateau dose level [6]. An alternative dosing regimen with a higher starting dose of 250 µg and simpler intrapatient dose escalation to 500 µg every two weeks with flexible dose adjustment according to tolerability was explored as a treatment option. This regimen controlled PV effectively, as defined by the CHR, and was associated with a shorter time to achieve a CHR [8, 9]. In this report, we aimed to examine the data from the approved slow-dose titration and exploratory higher starting dose regimens focusing on the dynamics of haemoglobin (Hgb) and the occurrence of anaemia. Anaemia is important in the context of PV treatment for several reasons. First, patients who undergo frequent phlebotomy may suffer from symptomatic iron deficiency, leading to anaemia [10]. Anaemia and symptoms can negatively affect the patient well-being and should be avoided in patients with PV and MPNs. The symptoms include headache, insomnia, concentration difficulties, dizziness, restless legs and may coincide and potentiate the disease-related symptoms of the underlying MPN [11,12,13]. Commonly used agents in the PV treatment cause anaemia in substantial numbers of cases ranging from 18% with hydroxyurea (HU) [14] to 72% with ruxolitinib [11, 15]. Anaemia is symptomatic in many cases and may limit the treatment dose or lead to treatment interruption if uncontrolled or severe cases are present. Association between venous thromboembolism and iron-deficiency anaemia has also been shown [16]. Thus, having an agent that can effectively control the elevated haematocrit without excessively suppressing the normal erythropoiesis is a major therapeutic advantage.

An important question regarding ropeginterferon alfa-2b in this context is whether the control of haematocrit is commonly accompanied by clinically significant anaemia, i.e., at the ≥grade 3 level or at the moderate, grade 2 level, but the anaemia is persistent and unmanageable. We therefore performed a retrospective analysis of the effect of ropeginterferon alfa-2b on Hgb levels at various time points or on the occurrence of anaemia with the data available from our two prospective clinical studies in patients with PV.

Read more

 

Disease Duration, Elevated WBC Count, and VAF Predict Disease Progression in Polycythemia Vera

Posted on by

June 14, 2024

Author(s): Megan Hollasch

Time from diagnosis to enrollment, elevated white blood cell (WBC) count, and variant allele frequency (VAF) were significantly associated with an increased risk of disease progression among patients with polycythemia vera (PV), according to data from the phase 4 prospective, observational REVEAL study (NCT02252159) presented at the 2024 EHA Congress by Michael R. Grunwald, MD.

“Five predictors of PV progression were identified: disease duration, thrombotic event [TE] history, WBC count of greater than 11 × 109/L, hematocrit [HCT] level of 0.45 L/L or lower, and VAF. However, HCT [level] of 0.45 L/L or lower may be confounded by disease duration and cytoreductive treatment covariates. These results provide additional support for the use of disease duration and elevated WBC and VAF as risk factors for disease progression, and identify history of TEs as a potential novel risk factor,” Grunwald and coauthors wrote in a poster presentation of the findings. Grunwald is chief of the Leukemia Division at Atrium Health’s Levine Cancer Institute and director of the Transplantation and Cellular Therapy Program at Levine Cancer Institute in Charlotte, North Carolina.

At a median follow-up of 3.7 years, findings from REVEAL, the largest prospective, observational clinical study in patients with PV to date (n = 2023), showed that 6.7% of patients progressed to myelofibrosis (MF). Results from a univariate analysis of patients with vs without progression revealed that significant covariates consisted of time from PV diagnosis to enrollment (OR, 1.065; 95% CI, 1.040-1.090; P < .0001), history of TEs (yes vs no; OR, 1.722; 95% CI, 1.170-2.534; P = .0059), HCT levels of 0.45 L/L or lower (>0.45 vs ≤0.45 L/L; OR, 0.593; 95% CI, 0.410-0.858; P = .0056), and white blood cell (WBC) count of greater than 11 × 109/L at enrollment (>11 vs ≤11 × 109/L; OR, 2.053; 95% CI, 1.445-2.918; P < .0001).

Read more

Predictors of symptom scores in myeloproliferative neoplasms: A real-world retrospective cohort study

Posted on by

Muhammad Ali Khan, Syed Arsalan Ahmed Naqvi, Irbaz Bin Riaz, and Jeanne M. Palmer

Abstract

Background: Although high symptom burden indicates poor survival and informs treatment decisions, little is known about the impact of demographic, clinical, and laboratory features on total symptom score (TSS) in patients with myeloproliferative neoplasms (MPN).
Methods: Patients with MPN (polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF)) were identified from the retrospective chart review. TSS, individual symptom scores (fatigue, early satiety, abdominal discomfort, inactivity, concentration problems, fever, night sweats, itching, bone pain, weight loss), demographic characteristics (race, ethnicity, age, gender), clinical features (time since diagnosis, depression status, obesity status, spleen size), laboratory results and season at the time of visit were recorded from the clinical encounter when index assessment of TSS was performed for each patient. Normality was assessed using visual inspection of data distribution, whereas multicollinearity was assessed using various inflation factors. A univariable regression followed by a multivariable regression analysis was conducted using a backward selection approach. A p-value <0.05 indicated a statistically significant association of a given feature with TSS.
Results: The chart review identified 252 patients (PV: 78; ET: 81; MF: 93). Mean age was 59 (SD: 17.7), 67 (SD: 13.0), and 68 (SD: 10.9) years for ET, PV, and MF respectively. Most patients were white (PV, MF: 92%; ET: 83%) and females (ET: 75%; PV: 60%; MF: 53%). The TSS of patients was highest with PV (mean: 18.5; SD: 16.9) followed by MF (mean: 18.1; SD: 15.4) and ET (mean: 14.3; SD: 15.9). Fatigue was the most reported symptom whereas the least reported symptoms were fever and weight loss. Univariable regression analyses showed depression (B: 17.7; p=0.02), female gender (B: 10.6; p=0.01), platelet count (B: 0.03; p=0.03), and hemoglobin (Hb) (B: -2.6; p=0.01) in PV patients, depression (B: 19.8, p=2×10-5) in ET patients and depression (B: 11.0, p=0.03), white blood cell (WBC) count (B: 0.2; p=0.01), neutrophil count (B: 0.3, p=0.01), and non-neutrophil WBC count (B: 0.6; p=0.02) in MF patients to have significant association with TSS. Multivariable regression analyses (Table) showed Hb (B: -2.5; p=0.01) and platelet count (B: 0.02; p=0.03) in PV patients, depression (B: 19.7; p=2×10-5) in ET patients and depression (B: 12.3, p=0.01) and WBC count (B: 0.3; p=0.002) in MF patients to have a significant association with TSS.
Conclusions: Depression in ET and MF and low Hb in PV were identified as significant drivers of symptom burden. Identifying and managing patients with these comorbidities could improve their quality of life with a potential survival benefit.

Pooled Analysis Shows Cytoreduction to Be Safe, Tolerable in Younger Patients With PV

Posted on by

Ashling Wahner

Cytoreductive therapy with interferon alfa (rIFNα) or hydroxyurea is safe and well tolerated in patients with polycythemia vera (PV) under the age of 60 years and induces annualized discontinuation rates comparable to those reported with these agents in older patients with PV, for whom cytoreductive therapy is routinely used, according to findings from a meta-analysis that were published in Blood Advances.1

Across the 14 studies included in this analysis, rIFNα discontinuation rates ranged from 4.6% to 37% over median durations of 0.4 to 6.3 years. Hydroxyurea discontinuation rates ranged from 2.6% to 17% over median durations of 0.5 to 14 years.

Although the use of cytoreductive agents, such as rIFNα and hydroxyurea, is associated with reduced thrombosis risk in PV, these agents are not routinely recommended by the European LeukemiaNet (ELN) or the National Comprehensive Cancer Network (NCCN) for patients with PV under the age of 60 years. The ELN recommends cytoreductive therapy for patients with PV who are younger than 60 years of age and have not had prior thrombotic events provided that they have strictly defined phlebotomy intolerance, symptomatic progressive splenomegaly, persistent or progressive leukocytosis, extreme thrombocytosis, persistently high cardiovascular risk, inadequate hematocrit control requiring phlebotomies, and/or persistently high symptom burden.2 The NCCN does not recommend cytoreductive therapy as initial treatment for patients with low-risk disease.3

“Unfortunately, effective and potentially life-prolonging cytoreductive therapy is often deferred in younger patients who are considered ‘low-risk’ because of their age and lack of thrombosis history,” senior study author Ghaith Abu-Zeinah, MD, an instructor in medicine at Weill Cornell Medical College and an assistant attending physician at the NewYork Presbyterian Hospital in New York, New York, and coauthors, wrote in the paper.1 “The rationale for withholding cytoreductive therapy is data-sparse and driven by theoretical concerns for toxicity and unknown benefits from early treatment. Yet, there is some evidence that early treatment is both well tolerated and potentially useful.”

Read more

A Grand Time in Grand Rapids

Posted on by

MPN Advocacy & Education International held an in-person patient/caregiver event in Grand Rapids, Michigan on April 25th. The room buzzed with excitement and camaraderie as patients and caregivers had the opportunity to engage with each other and MPN experts on a wide range of topics. 

Dr. Anas Al-Janadi gave an overview of the history of MPNs and defined where we are in our current understanding of the disease and what the future may hold. While exciting discoveries were made that supported the development of drug therapies for MPN patients; such as the JAK2 mutation in 2005 and later the MPL and CALR mutations, the MPN community is still working to better understand the reasons for disease progression and ways to reduce symptom burden.

Dr. Kristin Pettit, on the heels of her wedding (Congrats, Dr. Pettit), discussed the challenges MPN patients have flying, having elective or emergency surgeries, symptom management, and some critical women’s issues. Each topic had the following take-aways: check with your doctor and practice good self-care. Dr. Pettit emphasized hydration, healthy eating, exercise and reducing stress.

Dr. Aaron Gerds shared a play-by-play of diagnosing and treating MPNs. He began by situating ET, PV, and MF on the greater spectrum of Myeloid Neoplasms. Dr. Gerds, along with the other experts that presented, stressed the importance of a good clinical examination including a thorough history and a hands-on physical examination. Gerds went on to describe the testing required to make a proper MPN diagnosis, such as; blood counts, chemistries, infectious disease, bone marrow biopsy, and molecular testing. Afterwards, he walked us through the process of navigating individual risk and treatment options using the National Comprehensive Cancer Network (NCCN) Guidelines for Myelofibrosis. 

Justin Grinell, owner and head trainer of State of Fitness, reminded us that our health is not our fault, but it is our responsibility. He shared some ways to move toward a healthy lifestyle by incorporating an 11 min movement break in our day. To take just 11 minutes each day doing something active at your own Zone 2 (when your heart rate is 180 minus your age) can have an accumulative positive effect on not just your body but on your brain as well. Be sure to look for Justin this summer during our Healthy Summer Series webinars where you can join Justin for a quick lunch-time workout. 

Finally, Dr. Craig Kessler implored patients to ask questions. Ask your doctor questions about the treatment plan they create for you. Ask what component of MPN symptoms they are focusing on, and how the treatment they recommend will address that component (anemia, blood counts, spleen reduction, etc.). He stressed getting your COVID-19 vaccine and boosters. He also made clear that your questions matter and not to be afraid to ask.

We want to thank the specialists for sharing their valuable information and spending their time away from their respective institutions. We also want to thank our patients and their family members and friends for joining us and asking such thought-provoking questions. We hope that you will have a chance to join us at our next MPN Advocacy and Education International in-person event in Asheville, NC on Thursday August 22nd. To learn more, please visit www.mpnadvocacy.com/events-list.

Dr Raajit Rampal Discusses Disease Modification and Emerging Therapies in Polycythemia Vera

Posted on by

Laura Joszt, MA

Achieving a disease-modifying therapy for polycythemia vera might require adjusting the end points in a study needed for a drug to be approved, said Raajit Rampal, MD, PhD, hematologic oncologist, associate attending physician, Memorial Sloan Kettering Cancer Center.

Transcript

Currently, there are no disease-modifying treatments in polycythemia vera, but it is being explored. What might such a therapy look like?

If we talk about disease modification, the first question is, what do you mean by disease modification? I think, what we would want is for our patients to live the longest and fullest life, free of the symptoms or burdens of their disease. To me, that is the sort of working definition of disease modification. From there, one can try to come up with biological definitions of things like depleting the stem cell, which are important things. But keeping this on a patient level, what we want for our patients [is a life free of disease burden]. How do we think about therapies that address those issues?

Part of it is a regulatory conundrum in the sense that studies have to meet certain end points for drugs to get approved, but the way we study the drugs is relative to the definitions of the end points that make the drugs successful. In many cases, [the end point is asking] are you controlling the hematocrit adequately? That’s one of the major things in polycythemia vera. But in order to really try to get at the question of disease modification, we’ve got to think about changing the end points of our studies to reflect that.

What are the things that are going to best correlate with the idea that you aren’t keeping patients free of the catastrophic consequences of their disease, like blood clots, like [disease] turning into leukemia or myelofibrosis? Are you controlling the patient’s symptoms to an adequate degree? Those are the things that I think are fundamental. But we’ve got to change the end points of our studies to really get at that.

Read more

Younger Patients With PV May Benefit From Earlier Treatment With Cytoreductive Therapies

Posted on by

Laura Joszt, MA

Although patients younger than age 60 with polycythemia vera (PV) are typically not treated with cytoreductive therapy due to treatment toxicity concerns, this may result in an undertreatment of patients as there is no clear evidence that the risk of toxicity exceeds the potential benefit of treatment, according to a study published in Blood Advances.1

PV causes an overproduction of blood cells in the bone marrow, which leads to high numbers of circulating red blood cells.2 This thickens the blood, which may not flow through smaller blood vessels properly. Although PV can be diagnosed at any age, it most often occurs in people over the age of 60 years.2

For most patients, phlebotomy is the standard treatment, and it may be the only treatment needed for years. However, additional treatment to suppress the formation of blood cells in the bone marrow may be needed. Cytoreductive therapies, such as interferons, hydroxyurea, ruxolitinib, and anagrelide, may be needed, particularly for high-risk patients.3

Currently, cytoreductive therapies are not routinely recommended by the European LeukemiaNet or National Comprehensive Cancer Network for patients with PV younger than 60 years who don’t have a history of thrombosis, a high symptom burden, or an intolerance to phlebotomy.

Read more

Rusfertide Treatment Strengthens Response and Decreases Erythrocytosis Among Patients With Polycythemia Vera

Posted on by

Jordan Kadish

03/22/2024

According to findings from the international phase 2 REVIVE trial published in The New England Journal of Medicine, treatment with rusfertide, a peptide mimetic of the master iron regulatory hormone hepcidin, strengthened responses and decreased erythrocytosis among patients with polycythemia vera (PV). Patients who received rusfertide demonstrated a mean hematocrit of less than 45% during the dose-finding period.

Marina Kremyanskaya, MD, PhD, Icahn School of Medicine at Mount Sinai, New York, New York, and coauthors stated, “Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis,” or a high concentration of red blood cells in the blood. “The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown,” they added.

To expand on the available research, the study authors aimed to assess the efficacy of rusfertide among patients with polycythemia vera. The primary end point was a response, which was characterized by the hematocrit control, absence of phlebotomy, and finishing the trial regimen during part 2. The modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary was utilized to assess patient-reported outcomes of symptoms.

Read more

Disease-, Age-, Genomic-Specific Factors Increase Risk of ET, PV, PrePMF Developing Into Overt MF

Posted on by

Laura Joszt, MA

The risk of essential thrombocytopenia (ET), polycythemia vera (PV), and prefibrotic primary myelofibrosis (PrePMF) developing into overt myelofibrosis (MF) increases with age, the accumulation of mutations, and the activation of proliferative pathways, which identifies new targets for therapeutic intervention.

The findings, based on an analysis of the mutational landscape of more than 1700 genes and the gene expression of various cells from patients with myeloproliferative neoplasms (MPNs), was published in Clinical Cancer Research.1

ET, PV, PMF, and MF are all part of a group of diseases MPNs, in which a mutation in the bone marrow causes too many red blood cells, white blood cells, or platelets.2 In addition to being the most common MPNs, ET, PV, and PMF share the presence of mutations in either Janus kinase 2 (JAK2), calreticulin (CALR), and/or MPL.3 ET and PV are less aggressive forms of MPN, but they still can progress to MF. According to the Leukemia & Lymphoma Society, Pre-PMF will likely progress to PMF, “suggesting that more regular observations for pre-fibrotic PMF patients is warranted.”3

Read more

Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera

Posted on by

Marina Kremyanskaya, M.D., Ph.D., Andrew T. Kuykendall, M.D., Naveen Pemmaraju, M.D., Ellen K. Ritchie, M.D., Jason Gotlib, M.D., Aaron Gerds, M.D., Jeanne Palmer, M.D., Kristen Pettit, M.D., Uttam K. Nath, M.D., Abdulraheem Yacoub, M.D., Arturo Molina, M.D., Samuel R. Saks, M.D., et al., for the REVIVE Trial Investigators*

Abstract

BACKGROUND

Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory hormone hepcidin, restricts the availability of iron for erythropoiesis. The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown.

METHODS

 

In part 1 of the international, phase 2 REVIVE trial, we enrolled patients in a 28-week dose-finding assessment of rusfertide. Part 2 was a double-blind, randomized withdrawal period in which we assigned patients, in a 1:1 ratio, to receive rusfertide or placebo for 12 weeks. The primary efficacy end point was a response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Patient-reported outcomes were assessed by means of the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (scores range from 0 to 10, with higher scores indicating greater severity of symptoms).

RESULTS

Seventy patients were enrolled in part 1 of the trial, and 59 were assigned to receive rusfertide (30 patients) or placebo (29 patients) in part 2. The estimated mean (±SD) number of phlebotomies per year was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was 44.5±2.2% during part 1 as compared with 50.0±5.8% during the 28 weeks before the first dose of rusfertide. During part 2, a response was observed in 60% of the patients who received rusfertide as compared with 17% of those who received placebo (P=0.002). Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF in patients with moderate or severe symptoms at baseline. During parts 1 and 2, grade 3 adverse events occurred in 13% of the patients, and none of the patients had a grade 4 or 5 event. Injection-site reactions of grade 1 or 2 in severity were common.

CONCLUSIONS

In patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo. (Funded by Protagonist Therapeutics; REVIVE ClinicalTrials.gov number, NCT04057040. opens in new tab.)

Read more