Polycythemia vera and essential thrombocythemia in children, still a challenge for pediatricians

Posted on February 7, 2025February 7, 2025 by MPN Advocacy & Education

February 4, 2025

Agathe Picard, Sophie Bayart, Marianna Deparis, Cécile Dumesnil De Maricourt, Sophie Haro, Anne Jourdain, Coralie Mallebranche, Fanny Rialland, Damien Luque Paz, Cedric Pastoret, Virginie Gandemer & Elie Cousin

Abstract

Polycythemia vera (PV) and essential thrombocythemia (ET) are rare myeloproliferative neoplasms (MPN) in children, adolescents and young adults. No recommendations are available concerning these patients’ management. Transposing to children the knowledge established in adult patients is not acceptable. For a better understanding of difficulties encountered by pediatricians and adult hematologists, we conducted a national practice analysis concerning follow-up of patients under 18 diagnosed with ET or PV, in France. Then, we present data from a multicentric, descriptive, retrospective study, including 17 patients with ET or PV, diagnosed under 18, coming from 7 hematopediatric departments in France. Interviewed physicians reported a lack of expertise and theoretical training in the hematological field to diagnose and follow children with MPNs. Data from 17 patients (15 ET, 2 PV) confirmed a high proportion of asymptomatic patients at the time of diagnosis (41%). Proportion of “triple-negative” patients (59%) was higher than in adult cohorts. 60% of patients underwent a bone marrow biopsy and 31% of cases were discussed during a multi-disciplinary staff meeting. 76.5% patients were treated, with a high frequency of antithrombotic and cytoreductive drugs. No complications were observed during the 45 months of median follow-up.
Conclusion: Physicians insisted on the need for training. Only the accumulation of descriptions of MPNs in children will lead to a better management of these diseases. Considering the small proportion of pediatric patients with complications after diagnosis, rapid therapeutic de-escalation seems essential to consider during the follow-up in a close collaboration with adult hematologists.

Second-Line Fedratinib Produces Early Platelet Count Improvements in Myelofibrosis

Posted on February 7, 2025February 7, 2025 by MPN Advocacy & Education

February 5, 2025

Author(s): Jax DiEugenio

Fact checked by: Chris Ryan

Patients with myelofibrosis who received second-line fedratinib (Inrebic) experienced early increases in platelet count compared with those given best available therapy (BAT), and a higher magnitude of benefit was observed in patients with a low platelet count at baseline, according to findings from the phase 3 FREEDOM2 trial (NCT03952039) presented at the 2024 ASH Annual Meeting.

Findings showed that in the overall safety population, fedratinib generated improvements in mean platelet count and mean change from baseline platelet count, most noticeably in early treatment cycles.

In patients with a low platelet count at baseline, defined as at least 50 to less than 100 x 10⁹/L, patients treated with fedratinib (n = 34) experienced a mean increase in platelet count of 45% on day 15 of cycle 1 compared with 11% for those given BAT (n = 21). Among patients with a high platelet count at baseline of at least 100 x 109/L, these rates were 27% for fedratinib (n = 85) and –6% for BAT (n = 39).

During a presentation of the data, lead study author Haifa Kathrin Al-Ali, MD, explained that increased platelet count was not correlated with changes in spleen size, pointing to a potential benefit for fedratinib on thrombopoiesis.

“These data suggest a platelet-sparing effect of second-line fedratinib vs BAT, and support fedratinib as a promising second-line treatment option for patient with myelofibrosis with low or high baseline platelet count,” said Al-Ali, who is a professor of translational oncology and head of the Krukenberg Cancer Center at the University Hospital of Halle (Saale) in Germany.

Calreticulin Mutations Can Worsen Survival Outcomes in Ruxolitinib-Treated Patients With Myelofibrosis

Posted on February 3, 2025February 3, 2025 by mpn_admin

January 31, 2025

Author(s): Luke Halpern, Assistant Editor

Patients with myelofibrosis (MF) who harbor calreticulin (CALR) mutations begin treatment with ruxolitinib presenting severe disease with a longer median time from diagnosis, with inferior spleen responses and lower rates of symptom responses observed at 6-months, according to study results published in Annals of Hematology.¹

CALR mutations in patients with myelofibrosis being treated with ruxolitinib can lead to worsened outcomes. | Image Credit: © rost9 | stock.adobe.com

CALR mutations can be found in around 20% of patients with primary and post-essential thrombocythemia (ET) MF. Patients who harbor CALR mutations often present with distinct clinical features compared with Janus kinase (JAK)2-mutated patients. Typically, they feature lower levels of hemoglobin and white blood cells, present at younger age, and are associated with better survival rates.^1,2

Ruxolitinib (Jakfafi; Incyte) is a targeted therapeutic option for patients with MF that has shown efficacy regardless of the driver mutation in patients. However, new therapies continue to be developed that specifically target CALR, necessitating further research on therapies that are currently standard in CALR-positive patients, according to the investigators.^1,3

The study authors reported the outcomes of a sub-analysis of the RUX-MF clinical trial, documenting 135 patients with CALR mutation who received ruxolitinib in a real-world setting. The analysis was performed with major considerations, including that the younger age of CALR-mutated patients compared with JAK2-mutated patients may influence survival outcomes, and that younger patients are eligible for allogeneic stem cell transplantation, which the investigators noted could meaningfully impact the treatment algorithm.¹

In total, 786 patients from the RUX-MF trial were JAK2-mutated, while 135 had a CALR mutation. Only 78 CALR-mutated patients were evaluable, in which their mutation was type 1-like in 66.7% of the population, while 30.8% had type 2-like mutation. At the beginning of ruxolitinib initiation, CALR-mutated patients were younger, had higher percentages of peripheral blasts, and lower median hemoglobin levels compared with JAK2-mutated patients.¹

Responses to ruxolitinib and patient outcomes according to mutation type were reported at 6 months. There were no major differences in spleen responses (CALR: 21.4%; JAK2: 25.7%), and there were comparable rates of treatment-emergent anemia (CALR: 35.7%; JAK2: 30.4%) and both overall and treatment-emergent thrombocytopenia. However, symptoms response was significantly lower in CALR-mutated patients (56.1% vs 66.7%), and overall anemia rates (60.3% vs 50.3%) were higher in this population compared with JAK2-mutated participants.¹

Across the 135 patients with CALR mutation, there were no factors associated with spleen or symptom response. Notably, factors correlated with worse survival included hemoglobin below 10 g/dL and a high burden of symptoms. In the subgroup of 72 CALR-mutated patients who began ruxolitinib over 2 years following diagnosis, anemia (HR: 1.92; 95% CI, 1.02-3.79) and the use of a reduced ruxolitinib initiation dose (HR: 2.29; 95% CI, 1.15-4.56) were associated with poor overall survival.¹

Real-world treatment patterns and health outcomes for patients with myelofibrosis treated with fedratinib

Posted on January 30, 2025January 30, 2025 by mpn_admin

January 14, 2025

Francesco Passamonti Shalon Jones e , a,b , Siddhi Korgaonkar c Dorothy Zissler e , , Keith L Davis Rohan C Parikh c c , Manoj Chevli d , and Samantha Slaff

ABSTRACT

Aim: Assess real-world fedratinib (FEDR) treatment patterns and clinical outcomes in patients with primary or secondary myelofibrosis following discontinuation of ruxolitinib (RUX). Patients & Methods: This study was a retrospective, noninterventional medical record review of patients in Canada, Germany, and the United Kingdom (UK). A total of 70 physicians (primarily hematologist-oncologists [78.6%]) provided data for 196 eligible patients.

Results: Patients were mostly male (62.8%) with primary myelofibrosis (76.5%) and initiated FEDR at a mean age of 67.7 years. Median treatment duration was 11.5 months (median follow-up, 13.8 months), and nearly half (49.5%) of patients initiated FEDR at the label-indicated dose of 400 mg daily. Six months post-initiation, 77.7% and 66.8% of patients experienced symptom and spleen response, respectively. Kaplan-Meier estimates of median progression-free and overall survival from initiation were 23.8 months (95% CI, 21.1–27.6) and 29.8 months (95% CI, 23.9-NE), respectively.

Conclusion: These findings demonstrate real-world FEDR effectiveness among patients with myelofibrosis who discontinued RUX.

PLAIN LANGUAGE SUMMARY

What is this summary about?

Myelofibrosis (MF) is a rare blood cancer that can cause unhealthy spleen growth and symptoms, such as feeling tired, loss of appetite, bone pain, and fever. This is a summary of an article that reviewed medical records of patients with MF from treatment centers in Canada, Germany, and the United Kingdom (UK). The study looked at people who had been taking a medication called fedratinib (FEDR) for their MF after they had stopped taking a different medication called ruxolitinib (RUX). Many of the people stopped taking RUX because their MF got worse within a few years. The study wanted to see if taking FEDR reduced symptoms and spleen size for people with MF after they stopped taking RUX.

What were the results?

After at least 6 months of taking FEDR, 77.7% of the people in the study had fewer symptoms, and 66.8% of people in the study had a decrease in spleen size or no spleen growth. Additionally, most people taking FEDR after discontinuing RUX went nearly 2 years without their MF symptoms or illness getting worse.

What do the results mean?

These results suggest that FEDR is an effective treatment for people with MF who have stopped taking RUX.

Essential Thrombocythemia A Review

Posted on January 30, 2025January 30, 2025 by mpn_admin

January 27, 2025

Ayalew Tefferi, MD¹; Naseema Gangat, MD¹; Giuseppe Gaetano Loscocco, MD²; et al

Abstract

Importance Essential thrombocythemia, a clonal myeloproliferative neoplasm with excessive platelet production, is associated with an increased risk of thrombosis and bleeding. The annual incidence rate of essential thrombocythemia in the US is 1.5/100 000 persons.

Observations Patients with essential thrombocythemia have a persistent platelet count of 450 × 10⁹/L or greater. The differential diagnosis includes myeloproliferative neoplasms (polycythemia vera, primary myelofibrosis, chronic myeloid leukemia); inflammatory conditions such as rheumatoid arthritis and systemic lupus erythematosus; infections; splenectomy; iron deficiency anemia; and solid tumors such as lung cancer. Approximately 90% of individuals with essential thrombocythemia have genetic variants that upregulate the JAK-STAT (signal transducer and activator of transcription 5) signaling pathway, including Janus kinase 2 (JAK2, 64%), calreticulin (CALR, 23%), and myeloproliferative leukemia virus oncogene (MPL, 4%). The median age at diagnosis of essential thrombocythemia is 59 years. The median overall survival exceeds 35 years in those diagnosed at 40 years or younger. Patients with essential thrombocythemia are at increased risk of arterial thrombosis (11%), venous thrombosis (7%), and hemorrhagic complications (8%). Thrombosis risk is increased among those with a history of thrombosis, age older than 60 years, a JAK2 gene variant, and cardiovascular risk factors (eg, hypertension, diabetes mellitus, hyperlipidemias, tobacco use). Use of aspirin (81-100 mg/d) is suggested for most patients with essential thrombocythemia to lower thrombosis risk. In a retrospective study of 300 affected patients with a low thrombosis risk (younger than 60 years with no prior thrombosis), those not taking aspirin (100 mg/d) had a risk of arterial thrombosis of 9.4/1000 patient-years and a venous thrombosis risk of 8.2/1000 patient years; cardiovascular risk factors were associated with a higher risk of arterial thrombi (incidence rate ratio, 2.5 [95% CI, 1.02-6.1]), and a JAK2 gene variant was associated with increased risk of venous thrombosis (incidence rate ratio, 4.0 [95% CI, 1.2-12.9]). In a randomized trial of 114 patients at higher risk for thrombosis (age older than 60 years or a prior thrombotic event), cytoreduction with hydroxyurea significantly lowered the risk of arterial or venous thrombotic events compared with no cytoreductive therapy (3.6% vs 24%; P < .01). At a median of 8.5 years from diagnosis, approximately 10% of patients with essential thrombocythemia develop myelofibrosis and about 3% develop acute myeloid leukemia.

Conclusions Essential thrombocythemia is a rare clonal myeloproliferative neoplasm associated with an increased risk of venous and arterial thrombosis, hemorrhage, myelofibrosis, and acute myeloid leukemia. Based on individual risk factors for thrombosis, persons with essential thrombocythemia may be treated with low-dose aspirin, either alone or in combination with a cytoreductive drug such as hydroxyurea.

Cardiovascular Risk Factors Increase Thrombosis, Mortality in Patients With Myelofibrosis, Other MPNs

Posted on January 28, 2025January 28, 2025 by mpn_admin

January 27, 2025

Author(s): Luke Halpern, Assistant Editor

Cardiovascular risk factors (CVRFs) that increase thrombosis and overall mortality are more prevalent in patients with myeloproliferative neoplasms (MPNs), and especially those with myelofibrosis (MF), who have increased rates of hyperlipidemia and hypertension compared with patients with essential thrombocythemia (ET) or polycythemia vera (PV), according to study results published in Blood: Vessels, Thrombosis, and Hemostasis.¹

Thrombosis is a potentially serious complication of myelofibrosis. | Image Credit: © Artur | stock.adobe.com

Managing thrombosis risk in patients with MF are pillars of optimal treatment, along with controlling bleeding. Studies have indicated that thrombosis is common across a variety of MPNs, including MF, ET, and PV, and more common in those patients when compared with the general population. CVRFs such as hypertension, hyperlipidemia, type 2 diabetes, and obesity have known effects on thrombosis in the general population, but data is unclear on the impact of CVRFs on patients with MF or other MPNs.^2,3

For patients with MF, it is critical for pharmacists and treatment providers to recognize the prevalence of thrombosis and its potential risk factors, including CVRFs. In this current study, the investigators conducted a retrospective cohort analysis of 1005 patients with MPNs to evaluate the impact of CVRFs on real-world patient outcomes. Additionally, study authors investigated the likelihood of MPN transition to conditions such as MF or acute leukemia.^1,2,3

Across the study sample, 215 patients had MF, 28 had pre-MF, 415 had ET, and 313 had PV. Patients with MF were found to be more likely to harbor at least 1 CVRF compared with those with ET, PV, and the general patient population (46% vs 34% in the general MPN population), according to the investigators. The most common CVRFs observed in the overall patient population were hypertension (21%), hyperlipidemia (16%), and having a body mass index (BMI) greater than or equal to 30 (12%). For patients with MF, these incidences were 31%, 22%, and 11% respectively.¹

Spleen volume assessment in Ph-negative chronic myeloproliferative neoplasms: a real-life study comparing ultrasonography vs. magnetic resonance imaging scans

Posted on January 27, 2025January 27, 2025 by MPN Advocacy & Education

January 21, 2025

Novella Pugliese, Carlo Cavaliere, Luca Basso, Laura De Fazio, Rosalia Malafronte, Claudia Giordano, Annamaria Vincenzi, Silvia Varricchio, Massimo Mascolo, Vincenzo Martinelli, Marco Picardi, Marco Salvatore & Fabrizio Pane

Abstract

Splenomegaly is a quite common clinical feature of Philadelphia (Ph) negative chronic myeloproliferative neoplasms (MPNs) and its presence may, in some cases, drives treatment decision. Most importantly, palpable splenomegaly is a minor criterion for both pre-fibrotic/early primary myelofibrosis and primary myelofibrosis (PMF) diagnosis, even if clinical assessment by physical examination is poorly reliable and accurate. On the other hand, despite the International Working Group-Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet guidelines defined spleen response criteria by palpation, they also recognized the highly subjective nature of spleen size assessment by physical examination, and recommended objective confirmation of volume reduction via computed tomography or magnetic resonance imaging (MRI). In particular, spleen volume (SV) reduction of at least 35% via MRI is typically the primary endpoint in PMF and in some polycythemia vera clinical trials. Nevertheless, this technique seems inconvenient in routine clinical practice. To simplify serial monitoring of spleen size by using ultrasonography (US), we retrospectively analyzed medical records of 39 newly diagnosed MPN patients who underwent spleen ultrasonography as well as MRI. The median SV assessed by US was 600 ml (range 200–5000 ml) while median SV evaluated by MRI was 553.1 ml (range 172–5140 ml), revealing a strong linear relationship between methods, with a correlation coefficient of r = 0.96 (95% CI 0.92–0.98, P < 0.0001). Our findings support the role of US into pre-screening assessments for clinical trials and practice, offering a pragmatic solution for evaluating SV in MPN patients and ultimately improving patient care and clinical decision-making in this complex disease landscape.

Basophilia at Diagnosis Associated With Worse Outcomes in Several MPNs

Posted on January 21, 2025January 21, 2025 by mpn_admin

January 20, 2025

The significance of basophilia across essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) has not been previously characterized. This led Lisa Yuen, MD, and colleagues to conduct a retrospective study examining a broad cohort of myeloproliferative neoplasms (MPNs) to determine basophilia’s associations with clinical and molecular features and patient outcomes. The researchers found that a more aggressive disease phenotype and poorer clinical outcomes were associated with higher levels among patients with MPNs. The findings were reported in the American Journal of Hematology.

The investigators analyzed data from 195 patients who were diagnosed with an MPN between 2008 and 2019. All cases were classified according to the revised 4th edition World Health Organization classification.

The researchers defined basophilia as a relative or absolute increase in peripheral blood or bone marrow aspirate within 6 months of the patient’s first diagnostic biopsy.

Basophilia was present in 22% of patients. The investigators noted a lower incidence of basophilia in patients with ET and PV compared with patients with pre-fibrotic PMF, fibrotic PMF, post-ET MF, post-PV MF, or MPN-unclassifiable (8% vs 35%; P<0.001). Among the patients without basophilia at baseline, the researchers found that 12% subsequently developed basophilia within a median of 19.6 months after the initial MPN diagnosis. Patients with basophilia were also significantly older (P<0.001) and had higher white blood cell count (P<0.001) and reticulin grade (P<0.001), lower hemoglobin levels (P=0.01), and lower platelet counts (P<0.001) than patients without basophilia.

Basophilia was also associated with more frequent abnormal cytogenetics (P<0.001), higher mean total of mutations detected by next-generation sequencing (P<0.001), and more frequent JAK2 (P<0.001), SF3B1 (P=0.0083), and SRSF2 (P=0.0159) mutations, but less frequent calreticulin mutations (P=0.0018). At a median follow-up of 63 months, overall survival (OS) and leukemia-free survival (LFS) were significantly shorter in the basophilia group (54 months and 46 months, respectively; P<0.001). The median OS and LFS remained shorter in the basophilia group when patients with ET and PV were excluded (P=0.003 and P=0.002, respectively).

“These results suggest that basophilia could represent an additional prognostic marker in patients with MPNs, by highlighting patients who may have shorter survival and higher risk of progression to blast phase than would be predicted by current risk modeling,” the researchers concluded.

Impact of Recent Translational and Therapeutic Developments on Clinical Course of BCR::ABL1-Positive and -Negative Myeloproliferative Neoplasms

Posted on January 20, 2025January 20, 2025 by mpn_admin

January 2025

Tariq I Mughal, John Mascarenhas, Raajit K Rampal, Prithviraj Bose, Thomas Lion, Helen Ajufo, Abdulraheem Yacoub, Soheil Meshinchi, Lucia Masarova, Ruben Mesa, Catriona Jamieson, Tiziano Barbui, Giuseppe Saglio, Richard A Van Etten

Abstract

Despite the study of BCR::ABL1-positive and -negative myeloproliferative neoplasms (MPNs) providing seminal insights into cancer biology, tumor evolution and precision oncology over the past half century, significant challenges remain. MPNs are clonal hematopoietic stem cell-derived neoplasms with heterogenous clinical phenotypes and a clonal architecture which impacts the often-complex underlying genetics and microenvironment. The major driving molecular abnormalities have been well characterized, but debate on their role as disease-initiating molecular lesions continues. The introduction of the ABL1 tyrosine kinase inhibitors have been extremely successful in the treatment of chronic myeloid leukemia with most patients having a near-normal life expectancy. Similar success has, however, not been achieved for BCR::ABL1-negative MPNs in terms of disease course modification and most patients remain incurable. In both disease categories, genomic instability seems to increase the risk of disease progression to accelerated/blast phase, which is resistant/refractory to conventional treatment and associated with a poor prognosis. To address some of these issues, the late John Goldman and Tariq Mughal founded a scientific and clinical platform in 2006, the Post-American Society of Hematology (ASH) MPN workshop, to appraise novel cancer biology, candidate therapeutic targets, treatments and other clinical challenges and pay tribute to all the many scientists and clinicians around the world instrumental to the progress made and continuing advances being made. This paper summarizes some of the recent data discussed at the 18^th edition of the workshop and includes reference to some data presented or published after the workshop, including the 26^th John Goldman CML conference.

N-acetylcysteine inhibits thrombosis in a murine model of myeloproliferative neoplasm

Posted on January 20, 2025January 20, 2025 by mpn_admin

Brianna M Craver ¹, Gajalakshmi Ramanathan ¹, Summer Hoang ¹, Xinyue Chang ¹, Laura F Mendez Luque ¹, Stefan Brooks ¹, Hew Yeng Lai ¹, Angela G Fleischman

January 2020

Abstract

Thrombosis is a major cause of mortality in patients with myeloproliferative neoplasms (MPNs), though there is currently little to offer patients with MPN beyond aspirin and cytoreductive therapies such as hydroxyurea for primary prevention. Thrombogenesis in MPN involves multiple cellular mechanisms, including platelet activation and neutrophil-extracellular trap formation; therefore, an antithrombotic agent that targets one or more of these processes would be of therapeutic benefit in MPN. Here, we treated the JAK2^V617F knockin mouse model of polycythemia vera with N-acetylcysteine (NAC), a sulfhydryl-containing compound with broad effects on glutathione replenishment, free radical scavenging, and reducing disulfide bonds, to investigate its antithrombotic effects in the context of MPN. Strikingly, NAC treatment extended the lifespan of JAK2^V617F mice without impacting blood counts or splenomegaly. Using an acute pulmonary thrombosis model in vivo, we found that NAC reduced thrombus formation to a similar extent as the irreversible platelet inhibitor aspirin. In vitro analysis of platelet activation revealed that NAC reduced thrombin-induced platelet-leukocyte aggregate formation in JAK2^V617F mice. Furthermore, NAC reduced neutrophil extracellular trap formation in primary human neutrophils from patients with MPN as well as healthy controls. These results provide evidence that N-acetylcysteine inhibits thrombosis in JAK2^V617F mice and provide a pre-clinical rationale for investigating NAC as a therapeutic to reduce thrombotic risk in MPN.