Tag Archives: myeloproliferative neoplasms

Real-World Data Shows Favorable Efficacy and Safety With Busulfan for MPNs

Posted on by
Andrea S. Blevins Primeau, PhD, MBA
Publish Date

Busulfan treatment of myeloproliferative neoplasms (MPNs) demonstrated high response rates and infrequent adverse events (AEs), according to a study of real-world data from hospitals in the United Kingdom.

“Given the lack of prospective studies on the use of busulphan, our study contributes valuable real-world data on the safety and efficacy of busulphan which clinicians should find useful in managing this challenging cohort,” the researchers wrote in their report.

In the retrospective study, researchers analyzed data from 115 patients with MPNs from 13 hospitals. The median age of the cohort was 78 years and 44% of patients were male. The majority of patients had a diagnosis of essential thrombocythemia (ET) at 67%, followed by 24% with polycythemia vera (PV), 5% with MPN not otherwise specified, and 4% with myelofibrosis. JAK2 and CALR mutations were present among 62% and 13% of patients, respectively.

There were 16% of patients with a history of malignancy, including 8% of nonmelanoma skin cancers, and 8% with cancers that included those of the breast, prostate, lung, low-grade lymphoma, and melanoma.

One previous line of therapy (LOT) had been received by 13% of patients, 63% had 2 LOTs, 19% had 3 LOTs, and 5% had 4 LOTs. The most common previous cytoreductive therapy was hydroxycarbamide (78%), followed by anagrelide (16%), pegylated interferon (8%), P32 (3%), and ruxolitinib (2%).

The dosing regimens of busulfan included repeated single doses (31%) with a median dose of 38 mg, 1- to 4-week courses (30%) with a median dose 3.5 mg, and continuous therapy lasting more than 4 weeks (35%) with a median dose of 2 mg.

Our study contributes valuable real-world data on the safety and efficacy of busulphan which clinicians should find useful in managing this challenging cohort.

The median time from busulfan initiation to last follow-up or death was 23 months. There were 14% of patients who were alive with acceptable blood count control without any other cytoreductive therapy.

Read more

Engulfment Reduces Patient Quality of Life in MPNs

Posted on by
Jonathan Goodman, MPhil
Publish Date

Engulfment is a major factor affecting patient quality of life (QoL) among individuals diagnosed with myeloproliferative neoplasms (MPNs), according to research published in the European Journal of Oncology Nursing.

Psychological guidance aiming to mitigate the feeling of being overwhelmed by disease — the notion of engulfment in clinical medicine — is essential for improving QoL, the authors noted.

Although it is recognized that MPNs can drastically and negatively affect patient QoL, there is little understanding of the ways this occurs. For this longitudinal study, researchers evaluated psychosocial adjustment to living with MPNs, including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), with a focus on 4 factors: problem-solving coping, self-management, illness identity, and resilience.

Overall, 338 patients were enrolled. The researchers evaluated measurements of the 4 key factors at baseline and 6 months thereafter using established questionnaires, including the EORTC-QLQ-C30 for QoL measurements.

At enrolment, the average age was 62.8 years, the time since diagnosis was 7.7 years, and 63.6% of patients were female sex; 38.2%, 45.3%, and 16.6% of patients had been diagnosed with ET, PV, and MF, respectively.

The findings of this study indicate that psychosocial adjustment is important for QoL in patients with MPN, especially when adjustment is not optimal.

Analysis of the collected data suggested that II-subscale engulfment most strongly and negatively affected patient QoL (beta, 0.37; P <.001); this variable remained significant after the inclusion of control variables in the model, though the signal was less pronounced (beta, 0.16; P < .05).

Moreover, baseline QoL (beta, 0.32, P <.001) a wait-and-see treatment option (beta, 0.11, P <.05), and symptom burden at the second timepoint (beta, 0.36, P < .001) were all predictive of QoL.

“The findings of this study indicate that psychosocial adjustment is important for QoL in patients with MPN, especially when adjustment is not optimal,” the study authors wrote in their report. “Furthermore, the impact of MPN symptoms on QoL should not be underestimated.”

Read more

Defective neutrophil clearance in JAK2V617F myeloproliferative neoplasms drives myelofibrosis via immune checkpoint CD24

Posted on by

May 15, 2025

Eman Khatib-Massalha, Christian Andrea Di Buduo, Agathe L Chédeville, Ya-Hsuan Ho,…Simón Méndez-Ferrer Corresponding Author
Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell-driven malignancies marked by excessive myelopoiesis and high risk of myelofibrosis, which remains therapeutically challenging. Senescent neutrophils home daily to the bone marrow (BM) to be cleared by macrophages. This avoids their accumulation, which can increase the risk of chronic inflammation or oncogenesis. Neutrophils carrying the most common oncogenic MPN driver (JAK2V617F) are protected from apoptosis, which may prolong their lifespan and enhance their pro-inflammatory activity. On the other hand, abnormal interactions of neutrophils with megakaryocytes (“emperipolesis”) have been associated with BM fibrosis in disparate hematological disorders, including MPN and grey platelet syndrome; however, the underlying pathophysiology remains unclear. We investigated neutrophil homeostasis and cellular interactions in MPN. We found that senescent neutrophils evade homeostatic clearance and accumulate in JAK2V617F MPN, but not in MPN caused by the second most prevalent mutations affecting Calreticulin (CALR) gene. This is explained by GM-CSF-JAK2-STAT5-dependent upregulation of the “don’t-eat-me” signal CD24 in neutrophils. Mechanistically, JAK2V617F CD24hi neutrophils evade efferocytosis, invade megakaryocytes and increase active TGF-b. Collectively, JAK2V617F neutrophil-megakaryocyte interactions promote platelet production in a humanized bioreactor and myelofibrosis in mouse models. Notably, chronic antibody blockade or genetic loss of CD24 restores clearance of senescent neutrophils, reduces emperipolesis and active TGF-b. Consequently, CD24 blockade improves thrombocytosis and prevents myelofibrosis in MPN mice. Taken together, these findings reveals defective neutrophil clearance as a cause of pathogenic microenvironmental interactions of inflammatory neutrophils with megakaryocytes, associated with myelofibrosis in MPN. Our study postulate CD24 as a candidate innate immune checkpoint in MPN.

Interferon Lowers Myelofibrosis Risk in Young Patients With Polycythemia Vera, Essential Thrombocytopenia

Posted on by

May 15, 2025

Author(s): Alexandra Gerlach, Associate Editor

Early treatment with interferon reduced secondary myelofibrosis (sMF) risk in adolescent and young adult (AYA) patients with polycythemia vera (PV) or essential thrombocytopenia (ET), according to study data published in Leukemia.1

Red blood cells | Image Credit: © fotogurmespb - stock.adobe.com

MF is an incurable, rare hematologic malignancy characterized by the overproduction of red blood cells. This causes bone marrow scarring, which leads to severe anemia—a key factor impacting overall survival (OS) for patients with MF. It can develop as a primary disease or secondary to ET and PV, as well as progress to acute myeloid leukemia in some cases. Although MF is primarily diagnosed in older adults, 20% of cases are in individuals under the age of 40.1,2

AYA patients with ET or PV face unique clinical challenges due to their longer life expectancy because of a lack of data on long-term outcomes and treatment strategies. Existing guidelines are specific to older populations, despite the unique clinical considerations in younger patients.1

“These patients are expected to live for several decades, and the accumulation of additional thrombotic risk factors (age, cardiovascular conditions, additional mutations) may progressively heighten this risk,” the authors wrote. “This highlights a substantial and emerging concern regarding thrombotic events in this younger demographic.”1

The study evaluates complication rates, including thrombosis and progression to sMF, and the impact of interferon (IFN) on outcomes in patients diagnosed before the age of 25. The primary outcomes of the study were thrombosis-free survival (TFS), myelofibrosis-free survival (MFS), and OS in the entire cohort and for ET and PV patients separately, and the impact of treatment on these outcomes. Secondary outcomes were identification of risk factors associated with thrombotic events and sMF.1

The study included a total of 348 patients, of whom 278 were diagnosed with ET and 70 with PV, with a median age at diagnosis of 20 years. The incidence of thrombotic events was about 1.9 per 100 patient-years, with elevated white blood cell count (≥ 11 × 109/L) and absence of splenomegaly at diagnosis identified as significant risk factors. However, cytoreductive therapy did not reduce thrombotic risk. The incidence of sMF was 0.7 per 100 patient-years, with CALR mutations and a history of thrombosis associated with higher risk.1

Read more

The evolving landscape of epigenetic target molecules and therapies in myeloid cancers: focus on acute myeloid leukemia and myeloproliferative neoplasms

Posted on by

Published May 15, 2025

Michael W. M. Kühn, Naveen Pemmaraju & Florian H. Heidel

Abstract

Research on myeloid neoplasms, a field that has been driving scientific advances in cancer for over 50 years, has yielded many discoveries that have fundamentally reshaped our understanding of cancer biology. These insights, often the product of leukemia research, have been instrumental in developing more mechanism-based treatments in the early 2000s [1]. Recognizing epigenetic dysregulation as a common disease mechanism in myeloid cancers has been groundbreaking regarding recent treatment developments that exploit chromatin-based oncogenic mechanisms. In the case of acute myeloid leukemia (AML), sequencing studies aimed at assessing the complement of genetic alterations demonstrated that more than 60% of AML cases harbored disease-driving mutations in epigenetic regulators. This high prevalence underscores the importance of epigenetic dysregulation in AML pathogenesis [2, 3]. Chromatin regulators commonly control disease-specific transcriptional programs, making them attractive therapeutic targets to manipulate neoplastic gene expression programs, particularly in myeloid neoplasms. Several drugs targeting epigenetic mechanisms and exploiting myeloid disease-specific dependencies have recently been approved for treating myeloid neoplasms. Many additional drugs are currently being investigated in clinical trials, and numerous new compound developments are being studied in preclinical studies. This manuscript will review (1) chromatin-based disease mechanisms, such as DNA methylation, chromatin regulatory complexes, and histone modifications, currently investigated for therapeutic exploitation in myeloid malignancies, and (2) therapeutic developments already approved or investigated for treating these diseases.

Read more

 

Seiter Explores Time of Initiation and Alternate Dosing of Ruxolitinib in Myelofibrosis

Posted on by

By Targeted Oncology Staff
Fact checked by Jonah Feldman

During a live event, Karen Seiter, MD, discussed the role of the JAK/STAT pathway in myeloproliferative neoplasms and the use of ruxolitinib to treat myelofibrosis.

Karen Seiter, MD

Karen Seiter, MD

Professor of Medicine
New York Medical College
Director of  the Adult Leukemia Service
Westchester Medical Center
Valhalla, NY

CASE SUMMARY

  • A 68-year-old woman presented to her physician with symptoms of mild fatigue.
  • Spleen was palpable 6 to 7 cm below the left costal margin
  • Past medical history: no known comorbidities
  • Next-generation sequencing testing: JAK2 V617F mutation
  • Karyotype: 46,XX
  • Bone marrow biopsy: megakaryocyte proliferation and atypia with evidence of reticulin fibrosis
  • Blood smear: leukoerythroblastosis
  • Diagnosis: primary myelofibrosis

Risk

  • Dynamic International Prognostic Scoring System: intermediate-1
  • Mutation-Enhanced International Prognostic Scoring System for Transplantation-Age Patients: intermediate risk

Laboratory Values

  • Red blood cell count: 3.40 ×106/μL
  • Hemoglobin level: 9.7 g/dL
  • Hematocrit: 32.3%
  • Mean corpuscular volume: 94 μm3
  • White blood cell count: 23,000/μL
  • Platelet count: 450,000/μL
  • Peripheral blood blasts: <1%

Peers & Perspectives in Oncology: What disease states are currently classified as myeloproliferative neoplasms (MPNs)?

Seiter: The latest classification is the 2022 World Health Organization [WHO] classification.1,2 As a clinician, when we have myeloproliferative diseases, we think of MPNs [as meaning the patient] has too much of something: The WBC count is too high but with maturing myeloid and not with a lot of blasts, or the hemoglobin [level] is too high, or the [platelet count is] too high. That would be potentially chronic myelocytic leukemia [CML], polycythemia vera [PV], essential thrombocytopenia [ET], and for primary myelofibrosis, the most common presentation would be somebody with either anemia, with abdominal distension or early satiety from splenomegaly. The WBC count could be high; it could be low; platelets could be high, or they could be low.

When we’re working up patients with MPN, the first step is always to make sure that they don’t have CML, because CML can look like myelofibrosis because CML can present with a high platelet count. The first step is always to [test for] the Philadelphia chromosome and perform BCR::ABL1 testing to make sure it’s not CML.

Most of these patients are going to have a bone marrow [biopsy] done. There’s always the debate about, if you have somebody with a hemoglobin level of 20 g/dL, where it looks pretty clear that they have PV, do you need a bone marrow [biopsy] in order to formally diagnose the patient? You do because that’s part of the diagnostic criteria. But sometimes, if you have a much older patient with frailty, you have to consider the goals of care. Sometimes, there may be cases of patients who don’t get the bone marrow biopsy done. The only time it would be reasonable is if the hemoglobin level is high; for anything else, there are so many other things that [it] could be that it’s important to do the bone marrow biopsy for a diagnosis.

Mastocytosis used to be [listed among the] MPNs, but [the WHO] made it its own classification. MPNs with eosinophilia are a separate category. Now we have the myelodysplastic syndrome [MDS]/MPN overlap; that’s a separate category. Then, we have MDS, secondary myeloid neoplasms, and acute myeloid leukemia.

Read more

Fedratinib Shows Promise in Rare Myeloproliferative Neoplasms

Posted on by

By 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 data from a phase 2 trial (NCT05177211) which evaluated fedratinib (Inrebic), a JAK2-selective kinase inhibitor, in patients with atypical chronic myeloid leukemia (aCML), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN)-unclassifiable, and MDS/MPN-ring sideroblasts and thrombocytosis per the 2016 WHO classification.

According to findings from this multi-institutional, investigator-initiated study presented at the 2024 American Society of Hematology (ASH) Annual Meeting, fedratinib demonstrated promising efficacy and a manageable safety profile in this patient population.

At the time of data cutoff, 24 patients were enrolled and 19 patients were evaluable. A total of 53% of patients achieved a response at 24 weeks, including 50% symptom responses and 37.5% spleen responses. Of those treated for ≥24 weeks, spleen volume decreased by an average of 32%, and 85% showed symptomatic improvement. Responses were enriched in patients with CSF3R mutations (83%) and JAK-STAT pathway mutations (70%). Further, the median overall survival (OS) was estimated at 19.7 months.

“This was a very high-risk population, as these diagnoses are associated with poor prognosis. Despite that, we observed spleen responses in approximately 35% of patients, symptom responses in 50%, and some durable responses, with the median time on treatment nearing a year. These outcomes were particularly exciting given the molecular features of this patient population, which typically predict lower response rates,” Kuykendall shares.

Safety findings showed that fedratinib was well tolerated, The majority of adverse events (AEs) were grades 1 or 2, and the most commonly seen AEs were diarrhea (37.5%), constipation (37.5%), and anemia (29%). A single grade 4 neutropenia event resolved with dose adjustments.

“Regarding the safety profile, it was consistent with prior studies of fedratinib. There were some manageable low-grade gastrointestinal [adverse events]. We implemented a more proactive approach to mitigate these, including the use of antiemetics during the first 8 weeks. Overall, the [adverse event] profile remained manageable, and the efficacy outcomes likely exceeded our initial expectations,” adds Kuykendall.

Read more

Management of common autoimmune diseases in patients with myeloproliferative neoplasms treated with pegylated interferon alfa—case report, review of the literature and multidisciplinary clinical practice recommendations

Posted on by

May 8, 2025

Axel Rüfer, Christoph Brand, […], and Sacha S. Zeerleder

Abstract

Pegylated interferons alfa are increasingly used in patients with myeloproliferative neoplasms (MPN) due to their potential disease-modifying effect. Ropeginterferon alfa-2b has been approved for patients with polycythemia vera (PV) with no symptomatic splenomegaly as first-line cytoreductive therapy, based on the results of the PROUD-PV/CONTINUATION-PV studies, documenting significantly higher rates of complete hematologic response (CHR) compared with hydroxyurea from 2-year timepoint onward. Although safety profile of pegylated interferons is overall good, interferon-related toxicities can occur. Focus of this article is on interferon-mediated autoimmune diseases. We describe two patients with PV treated with pegylated interferons alfa, one patient developed a cutaneous, paranasal sarcoidosis without any systemic symptoms and was successfully treated with topical steroids. The other patient developed widespread psoriatric skin lesions, which were treated with moderate effect with topical therapy with calcipotriene and betamethasone dipropionate foam, antidry calm lotion and in the course of the disease with ultraviolet light therapy (UVB). Only with methotrexate she achieved a nearly complete remission of the psoriasis. In both patients pegylated interferon was continued in view of the CHR and therefore the beneficial effect on MPN. We review the pertinent literature on the management of interferon-mediated autoimmune diseases in patients with MPN. As there is little published evidence on that topic, we propose multidisciplinary clinical practice recommendations based on available evidence and clinical experience in the management of patients with MPN treated with pegylated interferon alfa.

Multihit TP53 Gene Mutations May Be Detrimental in MF

Posted on by
Özge Özkaya, MSc, PhD
Publish Date

Multihit mutations in the TP53 gene (mTP53MUT) have an equally detrimental effect on long-term survival in patients with both myeloproliferative neoplasms (MPN) like myelofibrosis (MF) and those with acute myeloid leukemia (AML), according to a new study published in the American Journal of Hematology. mTP53MUT could, therefore, be used as a predictor of short-term survival in both diseases.

These findings are based on the analysis of data from 142 patients from the Mayo Clinic database with mTP53MUT-associated MPN or AML. Of these patients, 14 had accelerated phase MPN, 19 had chronic phase MPN, 28 had blast phase MPN, and 81 had AML.

Mutations in the ASXL1, EZH2, IDH1, and IDH2 genes were more common in patients with blast-phase MPN and mTP53MUT compared to those with AML and mTP53MUT.

At a median follow-up of 11.6  months, 124 patients died, and 19 patients had an allogeneic stem cell transplantation.

Overall survival, which was calculated from the time of the detection of a mTP53MUT, was similar between patients with blast-phase and accelerated-phase MPN at 4.6 and 5.6  months, respectively.

However, overall survival was longer in patients with chronic phase MPN and mTP53MUT at 11.6 months, which was similar to overall survival in patients with AML and mTP53MUT, which was 7.4 months.

Multivariable analysis showed that disease stage, allogeneic stem cell transplantation, and response to pre-transplant chemotherapy positively affected overall survival while the presence of concurrent TET2 or DNMT3A mutations affected it negatively.

Read more

Ruxolitinib Discontinuation at Conditioning Does Not Increase GVHD Risk in Myelofibrosis

Posted on by

May 7, 2025

Author(s): Alexandra Gerlach, Associate Editor

Stopping ruxolitinib (Jakafi; Incyte Corp) prior to the conditioning regimen may not influence graft-versus-host disease (GVHD) risk more than in patients with myelofibrosis (MF), according to data published in Cancer Immunology, Immunotherapy.1

MF is an incurable, rare hematologic malignancy that is part of a group of diseases called myeloproliferative neoplasms, which are characterized by the overproduction of red blood cells. This causes bone marrow scarring, leading to severe anemia—a key factor impacting overall survival for patients with MF. Other symptoms include fatigue, enlarged spleen, night sweats, bone pain, and weight loss. MF can develop as a primary disease or secondary to essential thrombocythemia and polycythemia vera. In some cases, it can progress to acute myeloid leukemia.2

Ruxolitinib is the standard of care for first-line treatment of patients with MF that was originally approved by the FDA in 2011 for the treatment of intermediate- and high-risk MF. It was also the first approved treatment for patients 12 years of age and older with steroid-refractory acute GVHD in 2019. Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor that targets the JAK/STAT pathway, a critical cellular signaling pathway that helps cells respond to cytokines. Identification of mutations within the JAK/STAT pathway paved the way for the development of agents such as ruxolitinib, fedratinib (Inrebic; Bristol Myers Squibb), momelotinib (Ojjaara; GSK), and pacritinib (Vonjo; CTI BioPharma).2,3

Read more