Category Archives: Treatment

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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Pelabresib Plus Ruxolitinib Significantly Reduces Splenomegaly in Myelofibrosis

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Kristi Rosa

Pelabresib (CPI-0610) plus ruxolitinib (Jakafi) significantly reduced splenomegaly, showed a trend toward a reduction in tumor symptom score (TSS) from baseline, and improved bone marrow fibrosis and anemia at week 24 compared with ruxolitinib alone in JAK inhibitor–naive patients with myelofibrosis, according to updated data from the phase 3 MANIFEST-2 study (NCT04603495) presented at the 2024 ASCO Annual Meeting.1

As previously presented at the 2023 ASH Annual Meeting, the trial met its primary end point when a higher percentage of those who received the doublet (n = 214) experienced a 35% or greater reduction in spleen volume (SVR35) at week 24 vs those given ruxolitinib alone (n = 216), at 65.9% and 35.2%, respectively (difference, 30.4; 95% CI, 21.6-39.3; P < .001).2 The mean percentage change in spleen volume at week 24 in the pelabresib/ruxolitinib arm was -50.6% (95% CI, -53.2% to -48.0%) vs -30.6% (95% CI, -33.7% to -27.5%) in the ruxolitinib-alone arm.

When looking at all responders who achieved SVR35 response, the proportion who lost response at any point in the pelabresib/ruxolitinib arm was 13.4% and more than double in the ruxolitinib-alone arm, at 27.8%. When examining the criteria of loss of SVR35 response plus a spleen volume increase greater than 25% from nadir, this occurred in 9.3% and 14.8% of patients, respectively. Notably, SVR35 response was consistently higher with the doublet vs the monotherapy across all predefined subgroups and across hematologic subgroups.

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Advances in Interferon Therapy for Myeloproliferative Neoplasms

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Kumar Das, Dibash PhD

Oncology Times 46(6):p 1,14, June 2024. | DOI: 10.1097/01.COT.0001024068.38723.15

In the ever-evolving landscape of myeloproliferative neoplasms (MPNs), clinicians continue to explore and refine treatment strategies to improve patient outcomes. A recent review published in Therapeutic Advances in Hematology sheds light on the pivotal role of interferons, particularly pegylated formulations, in managing MPNs effectively (2024; doi: 10.1177/20406207241229588).

The advent of pegylated interferons, including peginterferon alfa-2a and ropeginterferon alfa-2b-njft, marks a significant turning point in MPN therapeutics. These agents, renowned for their potent immunomodulatory capabilities and profound impact on disease progression, have reshaped treatment paradigms outlined in the National Comprehensive Cancer Network (NCCN) Guidelines for polycythemia vera (PV), essential thrombocythemia, and primary myelofibrosis. This article delves deep into the multifaceted influence of pegylated interferons, shedding light on their efficacy, safety profiles, and future implications in MPN management.

Clinical trials, including landmark Phase II and III studies such as MPD-RC 111 and MPD-RC 112, have provided crucial insights into the efficacy of pegylated interferons. These trials meticulously assessed response rates, molecular remissions, and hematological improvements in MPN patients resistant to or intolerant of hydroxyurea. Noteworthy reductions in JAK2 V617F variant allele frequency (VAF) have underscored the molecular response achievements of pegylated interferons, highlighting their disease-modifying potential.

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

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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.”

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Direct and indirect costs for patients with myeloproliferative neoplasms

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Jingbo Yu, James Nelson, Taylor Marlin, Evan Braunstein, & Michelle Jerry

Abstract

Myeloproliferative neoplasms (MPNs) are associated with substantial healthcare resource use and productivity loss. This retrospective cohort analysis used disability leave and medical claims data to measure direct and indirect healthcare costs associated with MPNs. The analysis included 173 patients with myelofibrosis (MF), 4477 with polycythemia vera (PV), 6061 with essential thrombocythemia (ET), and matched controls (n = 519, n = 13,431, and n = 18,183, respectively). Total healthcare costs were significantly higher for cases versus controls in each cohort (mean cost difference: MF, $67,456; PV, $10,970; ET, $22,279). Cases were more likely than controls to take disability leave and incurred higher disability-related costs. Among subgroups with thrombotic events, direct and indirect costs were higher for cases versus controls. Thrombotic events substantially increased direct costs and disability leave for patients with PV or ET compared with the full PV or ET cohorts. These findings demonstrate increased economic burden for patients with MPNs.

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New Data Challenge Traditional Treatment Paradigm in MPNs, Says Dr Raajit Rampal

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Laura Joszt, MA

New data challenge the traditional thinking that low-risk patients with myeloproliferative neoplasms are largely just treated with phlebotomy and aspirin and have shown the benefits of medication, such as ropeginterferon, said Raajit Rampal, MD, PhD, hematologic oncologist, associate attending physician, Memorial Sloan Kettering Cancer Center.

Transcript

Interferons have been around for decades, but what unanswered questions remain about their use?

I think it really is about: when to start, who starts, and for how long should they be treated? Those, to me, are kind of key questions. There’s relatively recent data that looked at treating patients with polycythemia vera, who are low risk with ropeginterferon vs what we traditionally do, which is to use things like phlebotomy and aspirin. There at least seems to be some signal to suggest that those patients may derive a benefit. Our traditional thinking is we leave the patients alone except for phlebotomy and aspirin, and if they have a blood clot or symptoms or something, maybe we put them on medication. If not, we only treat them if they’re high risk. But this data was actually provocative in the sense that it said, “Well, if you take these low-risk patients, there may be some clinical benefits to them by starting early.”

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Utilization of Momelotinib for Myelofibrosis With Anemia Can Result in Small Savings

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Laura Joszt, MA

Although momelotinib to treat myelofibrosis (MF) with anemia has a higher acquisition cost, it is partially offset by savings when transfusion-related costs are reduced, according to a poster being presented at the AMCP Annual Conference, held April 15-18, 2024, in New Orleans, Louisiana.1

MF is a rare cancer in the bone marrow that disrupts the production of blood cells.2 MF causes anemia because of the extensive scarring to bone marrow. This extensive scarring also causes patients to have a low number of platelets, increasing their risk of bleeding. Patients may also have an enlarged spleen.

Momelotinib inhibits Janus kinase (JAK) 1, JAK2, and activin A receptor type 1. In September 2023, the FDA approved momelotinib to treat patients with intermediate- or high-risk MF with anemia.3

The approval of momelotinib was based on data from the phase 3 MOMENTUM trial, which found clinically significant improvements for patients treated with momelotinib vs danazol.4 A quarter of patients treated with momelotinib had a 50% or greater reduction in total symptom score compared with only 16% of patients on danazol.

Since the approval, the National Comprehensive Cancer Network (NCCN) has added momelotinib5 to its Clinical Practice Guidelines in Oncology for Myeloproliferative Neoplasms. Momelotinib was added as a category 2A treatment for patients with high-risk MF. It was also added as a 2B category treatment for patients with lower-risk MF.

Patients with MF who have anemia and are dependent on transfusions have increased medical costs and poor prognosis, the authors of the AMCP poster noted. JAK inhibitors may provide improvements in symptoms and spleen size, but they could worsen or induce anemia. However, momelotinib has been shown to reduce spleen size.4

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New study paves the way for precision drugs to treat blood cancers

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by Tampere University

April 4, 2024

The Janus kinase 2 (JAK2) protein mediates signaling from several cytokine receptors in the regulation of hematopoiesis and immune responses. Somatic mutations in human JAK2 lead to constitutive activation and cytokine-independent signaling and underlie several hematological malignancies from myeloproliferative neoplasms (MPN) to acute leukemia and lymphomas. JAK2 contains an active kinase domain and an inactive pseudokinase domain. Interestingly, pathogenic mutations mainly occur in the regulatory pseudokinase domain.

Due to its critical pathogenic role, JAK2 has become an important therapeutic target. The four currently approved JAK2 inhibitors relieve symptoms but do not heal the patient or affect survival. These drugs target the highly conserved kinase domain and affect both normal and mutated JAK2 and, due to side effects, carry a black box warning that limits their use in elderly, cardiac and cancer patients. The selective inhibition of pathogenic JAK2 is a key pending goal in drug discovery that requires a precise mechanistic understanding of the regulation of JAK2 activation.

“To understand the molecular and structural basis of the physiological and pathogenic activation of JAK2, we used single-molecule microscopy and erythropoietin receptor (EpoR) as a model system.

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