Category Archives: Treatment

Pacritinib and Momelotinib Display Positive Real-World Impact on Anemia and Transfusion Needs in Myelofibrosis

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December 12, 2024

Author(s): Kyle Doherty

Fact checked by: Caroline Seymour

Although long-term follow-up was limited, treatment with the JAK2 inhibitors pacritinib (Vonjo) and/or momelotinib (Ojjaara) led to favorable effects on anemia and transfusion requirements among patients with myelofibrosis, according to findings from a real-world study presented in a poster during the 2024 ASH Annual Meeting.1

Patients who received momelotinib (n = 32) had a median hemoglobin count of 8.7 g/dL (range, 6.5-1.2) at the start of therapy which increased to 9.0 g/dL after 3 months of treatment (P = .021). The median platelet count at the start of therapy was 141 x 109/L (range 15 x 109-504 x 109) and increased to 116 x 109/L after 3 months (P = .317). Patients required a mean of 1.9 red blood cell (RBC) units/month at the start of therapy and 0.47 units/month after 3 months of treatment (P = .015).

Patients treated with pacritinib (n = 27) had a median hemoglobin count of 8.5 g/dL (range, 6.9-12.9) at the start of treatment and a median count of 9.1 g/dL following 3 months of therapy (P = .402). The median platelet count at the start of therapy was 65 x 109/L(range, 18 x 109-441 x 109) compared with 31 x 109/L after 3 months of treatment (P = .303). Patients required a mean of 2.4 RBC units/month at the start of therapy vs 0.75 RBC units/month after 3 months of therapy (P = .099).

“The goal of this project was to [examine] the patients who have been treated so far at Moffitt Cancer Center with either pacritinib and/or momelotinib to gain a better understanding of the hematologic responses of these therapies, the duration of treatment, and other real-world data regarding these agents after they got their approvals,” Jeremy DiGennaro, MD, said during the presentation. “Patients receiving momelotinib and pacritinib are typically older with extended disease duration, multiple prior lines of therapy, high-risk mutations, and cytopenia. Pacritinib-treated patients have more prominent baseline thrombocytopenia. [However], there were favorable impacts on anemia and transfusion requirements [with both agents], although we still do need more long-term follow-up.”

DiGennaro is an internal medicine resident physician at the University of South Florida Morsani College of Medicine in Tampa.

In February 2022, the FDA granted accelerated approval to pacritinib for the treatment of adult patients with intermediate or high-risk primary or secondary myelofibrosis with a platelet count below 50,000/µL.2 Momelotinib was approved by the FDA in September 2023 for the treatment of adult patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia.3

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Ten years of experience with ruxolitinib since approval for polycythemia vera: A review of clinical efficacy and safety

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Lucia Masarova MD1 | John Mascarenhas MD, MS2 | Raajit Rampal MD, PhD3 | Wilson Hu MD4 | Robert A. Livingston MD, MPH4 | Naveen Pemmaraju MD1

Abstract
The oral Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib was approved by the US Food and Drug Administration in 2014 for the treatment of patients with polycythemia vera (PV) who have an inadequate response to or intolerance of hydroxyurea (HU). PV is a chronic myeloproliferative neoplasm defined by primary absolute erythrocytosis, bone marrow hypercellularity, and JAK mutations such as JAK2V617F. Patients with PV experience burdensome symptoms and are at risk of thromboembolic events, in particular those with resistance to or intolerance of initial treatments such as HU. Other risks for patients with PV include progression of disease to more aggressive forms with worse prognoses, such as myelofibrosis or blast‐phase myeloproliferative neoplasms. This review summarizes the efficacy and safety of ruxolitinib from key phase 2 and 3 trials (MAJIC‐PV, RESPONSE, RESPONSE‐2, RELIEF, and Ruxo‐BEAT), large real‐world studies, and a decade of postmarketing surveillance safety data. The authors focus on improved blood count control, rates of thromboembolic events, symptom improvement, and markers of disease modification such as reduction of JAK2V617F allele burden in patients treated with ruxolitinib. They also discuss the well‐characterized safety profile of ruxolitinib regarding hematologic and other adverse events of interest. In the 10 years since its approval, ruxolitinib remains a safe and effective standard‐of‐care treatment for PV. As the treatment landscape for PV continues to evolve in the coming years, the efficacy and safety profiles of ruxolitinib suggest it will remain a
preferred treatment as monotherapy and as a potential backbone of future combination regimens.

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Luspatercept Shows Promise in Alleviating Myelofibrosis-Associated Anemia

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Ryner Lai

Luspatercept shows promise in alleviating myelofibrosis-associated anemia and has a safety profile consistent with previous research, according to a study published in Blood Advances. 

The most common therapeutics in myelofibrosis include erythropoiesis-stimulating agents, androgens, corticosteroids, and lenalidomide. However, many of these are associated with significant adverse events (AEs). Researchers are investigating therapeutic agents that are highly effective against anemia while having an acceptable safety profile.

Luspatercept is an erythropoietin maturation agent that has been approved in the United States for treating anemia in some individuals with myelodysplastic syndromes or beta-thalassemia who need red blood cell (RBC) transfusion. This therapeutic has been shown to induce transfusion independence in approximately 38% of patients. Researchers sought to explore if the success of luspatercept can be replicated in myelofibrosis and conducted a study to assess its use in patients with myelofibrosis-associated anemia, with or without transfusion dependence.

Researchers reported results from a phase 2, multicenter, open-label trial that assessed the use of luspatercept in myelofibrosis. They recruited adult patients with myeloproliferative neoplasm (MPN)-associated myelofibrosis who possessed an Eastern Cooperative Oncology Group performance status score of 2 or less and had evidence of anemia. Patients were divided according to their transfusion dependence status and whether they were on ruxolitinib therapy.

Participants received subcutaneous luspatercept at a dose of 1.0 mg/kg (with titration up to 1.75 mg/kg every 21 days for a total of 24 weeks). They were then assessed for their disease response at day 169; if they demonstrated clinical benefits, they could continue receiving luspatercept treatment for approximately 2 years longer. The primary endpoint of this study was anemia response at the end of the 24-week period.

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Update: Ruxolitinib Beats Best Available Therapy in Treating Polycythemia Vera

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October 14, 2024

Author(s): Mary Caffrey

An updated meta-analysis confirms that ruxolitinib, the Janus kinase (JAK) 1/JAK2 inhibitor sold as Jakafi, offers improvements in key measures of efficacy compared with best available therapy (BAT) for patients with polycythemia vera (PV),1 a rare, slow-progressing disorder that causes the blood to make too many red blood cells.

Caused by a genetic mutation, PV is not typically fatal on its own, but it can cause dangerous blood clots and damage to the spleen. In a small number of cases, it progresses to more aggressive forms of blood cancer.

The latest results were reported in the journal APMIS,1 formerly known as Acta Pathologica, Microbiologica, et Immunologica Scandinavica.

The analysis followed a 2020 meta-analysis involving 16 studies that appeared in Blood Advances.2 That analysis included evidence from 4 randomized controlled trials and included 663 patients; the authors estimated a thrombosis incidence of 3.09% per year for ruxolitinib vs 5.51% for BAT, but noted that globally, this did not reach significance (P = .098). “A clinical trial on selected patients at high risk of thrombosis would be warranted, but its feasibility is questionable,” the authors wrote.2

The current analysis examines ruxolitinib’s efficacy and safety compared BAT in 1061 patients with PV and in hydroxyurea-resistant and intolerant patients with PV across 6 studies, with a cutoff of November 2023. The patients included 620 on BAT and 441 on ruxolitinib. According to the investigators:

  • Those taking ruxolitinib showed higher hematocrit control (P = .015) and treatment response (P = .04) compared to BAT.
  • Patients taking ruxolitinib had significantly improved Myeloproliferative Neoplasms-Symptom Assessment Form scores (MPN-SAF), P < .01.

However, on the safety front, patients with PV treated with ruxolitinib had higher rates of nonmelanoma skin cancer (P < .01), as has been previously documented.

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Janus kinase inhibitor monotherapy and combination therapies for myelofibrosis: what’s the current standard of care?

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Mahesh Swaminathana, Akhil Jain, Sungchul Daniel Choi & Naveen Pemmaraju
Received 10 Jun 2024, Accepted 23 Sep 2024, Published online: 03 Oct 2024

ABSTRACT

Introduction

JAK inhibitors (JAKi) have changed the treatment paradigm of myelofibrosis (MF). Currently, 4 JAKis are approved in the US as monotherapy (mono) to treat patients with MF. JAKis are also being studied in combination (combo) with novel agents. Herein, we review some of the key studies that evaluated JAKi as mono and combo in MF.

Areas covered

We performed a Pubmed search for ‘JAK inhibitors’ and ‘myelofibrosis’ from 1/2010 to 12/2023. For mono, we included only the unique phase II/III studies of the approved JAKi. Selective studies that evaluated JAKi in combo with the novel agents were also included.

Expert opinion

JAKis aim to provide clinical benefit to patients via spleen size reduction and MPN symptom improvement. In order to potentially increase clinical benefit for patients with MF, several novel agents are being partnered with ruxolitinib (RUX) with the ongoing hypothesis to augment greater measures of MF disease modification. The novel agents are either ‘added-on’ to RUX or as a combo in JAKi naïve patients. Also, the mutant-targeting era of therapies is now beginning with novel CALR-mutated, novel JAK2 V617F mutation-specific and type II JAK2i in the initial stages of drug development, representing a new approach to treatment.

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Choosing the Right JAK Inhibitor for Effective Myelofibrosis Treatment

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By Jordyn Sava
Fact checked by Sabrina Serani

With 4 JAK inhibitors approved in the US and additional agents in development, it is an exciting time for the field of myeloproliferative neoplasms (MPNs). Now, experts face the challenge of determining which treatment is best for each patient.

Ruxolitinib (Jakafi), an established JAK inhibitor, was first approved by the FDA in 2011,1 showing clear survival benefits. This was followed by the FDA approvals of fedratinib (Inrebic) in 2019,2 pacritinib (Vonjo) in 2022,3 and momelotinib (Ojjaara) in 2023.4

“Each [JAK inhibitor has] their place depending on the patient’s blood counts and other clinical factors,” explained Prithviraj Bose, MD, in an interview with Targeted OncologyTM.

With multiple JAK inhibitors available to choose from, a tailored approach ensures that each patient’s specific disease characteristics and comorbidities are considered to maximize efficacy and minimize toxicity during treatment.

In the interview, Bose, professor in the Department of Leukemia at MD Anderson Cancer Center, discussed the multiple JAK inhibitors available for the treatment of patients with MPNs.

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Bose’s Guide to Ruxolitinib, Fedratinib, Pacritinib, and Momelotinib

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By Prithviraj Bose, MD

Prithviraj Bose, MD, professor in the Department of Leukemia at MD Anderson Cancer Center, provides an overview of the different JAK inhibitors currently available for patients with myeloproliferative neoplasms.

Transcription:

0:09 | We have 4 JAK inhibitors approved for the treatment of myelofibrosis in the US. Important to note, pacritinib [Vonjo] is not approved outside the US. There is obviously a lot to say on this topic, especially, ruxolitinib [Jakafi] was approved in 2011, fedratinib [Inrebic] in 2019 and then pacritinib and momelotinib [Ojjaara], more recently, 2022 and 2023. But I think I will just hit some high points.

0:36 | So for ruxolitinib, the first thing I would say about that is that it is the JAK inhibitor with the most clearly demonstrated survival benefit in myelofibrosis. Now, is that an effect just of ruxolitinib and not of the others? We do not know that. It could be a class effect, but the data are the data and the data are that ruxolitinib is the one that has a clearly shown survival benefit. I think that needs to be considered as we use it, and it is usually the most frequently used frontline drug. Now, where you can get into trouble with ruxolitinib is with cytopenias, low blood counts, and this is a drug that you need to be able to dose well in order to get the benefit that you are seeking. The dose can get compromised by cytopenias.

1:29 | That is where I will tie that into the entry of pacritinib and momelotinib. These are easier to use in the setting of cytopenias. In fact, pacritinib has a label for platelets than 50, and momelotinib is for patients with anemia in myelofibrosis. So right there, you can see that they sort of have their place more in that cytopenic population, which could be frontline, or, more commonly, second-line, after ruxolitinib. I think those are great additions in the sense that you can give them at good doses despite low blood counts, which becomes difficult with ruxolitinib, like I just said. [They are] certainly very welcome additions to the arsenal.

2:12 | I will just say 1 last thing about fedratinib, which was the second one approved. This is a good drug, perhaps as good as ruxolitinib from an efficacy stand point, but really with no clear advantage over ruxolitinib. So, I do not use it in the frontline. I do use it, however, in post-ruxolitinib settings, where the blood counts are good. In those proliferative scenarios, as opposed to the cytopenic scenarios, in second-line and beyond, I do find fedratinib to be a useful drug. It has some toxicities that one has to pay attention to. All patients should get thiamine supplementation, stuff like that, but overall, I would say those are the kind of very high level points about the 4 drugs.

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Can Vaccines Be Developed for MPNs? Study Examines the Challenges

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September 18, 2024

Author(s): Mary Caffrey

Researchers from Bulgaria conduct an analysis of the potential for therapeutic vaccines in by comparing testing results for patients from their country with an international data set.

Despite their status as myeloid malignancies, myeloproliferative neoplasms (MPNs) have drawn interest from researchers as candidates for therapeutic vaccines. Giroux et al drew attention in Science in 2022 by investigating MPNs with calreticulin (CALR) mutations, which lack T cells to target this antigen.1 Specifically, Giroux’s team pursued the major histocompatibility complex (MHC-1) allele frequences they observed and developed a heteroclitic peptide vaccine to activate T cells against tumors.

Now, a team from Bulgaria follows Giroux with a statistical approach, with results appearing in Frontiers in Immunology.2 The group first made comparisons between patients with MPNs and healthy controls within the homogenous population of Bulgaria before completing a meta-analysis involving patients and healthy controls from the 1000 Genomes Project, an international effort to collect human genome samples.3

To start, the team established that human leukocyte antigen class I (HLA-I) and class II (HLA-II) alleles alter how JAK2 V617F and CALR mutations create cancer cells in MPNs, but that the role of immune response in MPNs is not well known. Thus, the team sought to explore the role of HLA genes in MPNs with CALR mutations. They conducted analyses involving 42 patients with CALR mutations and 158 with JAK2 V6127F mutations, as well as 1083 healthy controls.2

As the authors explained, mutations in 3 genes drive all MPNs; they are JAK2, CALR, and MPL. “These mutations originate at the level of hematopoietic stem cells, but, depending on the intrinsic and extrinsic factors, can lead to differential skewing of hematopoiesis predominantly into one of the myeloid lineages presenting clinically with 1 of the 3 phenotypes,” which they noted are essential thrombocythemia, polycythemia vera, and primary myelofibrosis.2

Mutations may appear just as cancer cells form but also before symptoms appear, in a status called clonal hematopoiesis of indeterminate potential, or CHIP; it may take a long time for CHIP to convert to malignancy, and different mutations follow different paths.

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Vonjo Improves Thrombocytopenia, Anemia in Patients With Myelofibrosis

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By Jax DiEugenio
Fact checked by Chris Ryan

Improvements in thrombocytopenia and anemia were observed in patients with myelofibrosis treated with Vonjo (pacritinib) in the real-world setting, as demonstrated in findings from a retrospective study presented at the 2024 SOHO Annual Meeting.

According to the National Cancer Institute, thrombocytopenia refers to a condition in which patients have a lower-than-normal number of platelets in the blood, and this can result in excessive bleeding from wounds and easy bruising. Anemia is a condition when patients have a low count of red blood cells.

Findings showed that patients with a platelet count below 100 x 109/L (which is considered low) at baseline (74 patients) experienced an early increase in platelet count following treatment initiation that was maintained throughout the observation period. Additionally, an early increase in median hemoglobin (a protein inside red blood cells that carries oxygen from lungs to tissues and organs) was reported in all patients, and this increase was sustained throughout the observation period. Patients with hemoglobin level of less than 8 g/dL (a level that indicates anemia) at the start of treatment (35 patients) experienced a hemoglobin increase of nearly 1 g/dL by day 30.

Notably, patients who received prior treatment with Jakafi (ruxolitinib; 69 patients) experienced an increase in platelet counts and hemoglobin levels following initiation of Vonjo. At baseline, the median platelet count and median hemoglobin level in this population was 91 x 109/L and 8.7 g/dL, respectively. At day 360, the median platelet count and median hemoglobin were 97 x 109/L and 10.4 g/dL, respectively.

“In addition to spleen and symptom benefits observed in previous clinical trials, real-world outcomes demonstrate stability or improvement in thrombocytopenia and/or anemia in patients with myelofibrosis treated with [Vonjo],” lead study author Michael Marrone and colleagues, wrote in a poster presentation of the data. Marrone is an assistant professor in the College of Medicine, Department of Public Health Sciences, at the Medical University of South Carolina in Charleston.

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Allogeneic HSCT for Myelofibrosis: What to Know as More Patients Receive Treatment

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June 25, 2024

Due to new transplant approaches, allogeneic hematopoietic stem cell transplant (HSCT) is now perceived as a safer therapeutic option in patients with myelofibrosis, even among older patients. Authors of a review published in the American Journal of Hematology emphasized the crucial role of early consideration and implementation of HSCT in improving clinical outcomes in this patient population.

Despite the approval of new therapies and “various other exciting non-transplant treatments in development, allogeneic HSCT remains at present the only curative therapy for patients with myelofibrosis,” wrote coauthors Haris Ali, MD, and Andrea Bacigalupo, MD.

The challenges associated with treating myelofibrosis include transplant-related mortality and the risk for relapse after HSCT. The authors aimed to provide a comprehensive review of current clinical data, new transplant platforms, and clinical updates, which can enhance patient outcomes.

“The number of patients undergoing an allogeneic HSCT annually is steadily increasing,” Dr. Ali and Dr. Bacigalupo wrote. “This reflects the fact that HSCT has become safer with the reduction in non-relapse mortality over the years, making the choice of an HSCT more attractive among hematologists caring for [patients with myeloproliferative neoplasms].”

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