Genetic Links to High Altitude Found to Reduce Inflammation, Speed Response to PV Therapy

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December 10, 2024

Author(s): Mary Caffrey

Questions about why an indigenous population living the Andes Mountains of South American had elevated hemoglobin led to the discovery that a variant linked to living at high altitude is also tied to reduced inflammation, as well as improved response to a therapy used to treat myeloproliferative neoplasms (MPNs).1

Jihyun Song, PhD | Image credit: University of Utah

The research to be presented today at the 66th American Society of Hematology Annual Meeting & Exposition in San Diego, California, could lead to more precise treatments for polycythemia Vera (PV) and essential thrombocythemia (ET). Today, these 2 are treated with ropeginterferon-α (Besremi), and the work led by Jihyun Song, PhD, of Huntsman Cancer Institute at the University of Utah, now shows that populations with Andean enriched NFKB1 haplotype respond better to ropeginterferon-α.

The study has been accepted for publication in Nature Communications.

PV and ET are both associated with overproduction of blood cells; PV causes the bone marrow to produce too many red blood cells, while ET produces too many platelets. Both PV and ET can lead to chronic inflammation, increase the risk of blood clots, and progress to leukemia. These conditions also increase hypoxia-inducible factors (HIFs), which can impact the survival of cancer cells in low-oxygen environments.

At a press briefing prior to Song’s presentation today, senior author Josef T. Prchal, MD, a physician scientist who holds the Charles A. Nugent, MD, and Margaret Nugent Endowed Professorship in Medicine/Hematology at the University of Utah, explained that the genetic variants that developed over time to allow the Aymara people survive in the Andes can be seen in some other populations—and they correlate with some differences in MPN phenotypes.

Josef Prchal, MD | Image credit: Photo supplied by ASH

“Our study suggests that with genotyping, the NFKB1 variant can be used as a biomarker for determining which patients may be more or less responsive to ropeginterferon-α treatment,” Prchal said.

He opened his remarks with an overview of how populations evolve with their environments; not only the Aymara but also Tibetans and Ethiopians have adapted to altitude in different ways, which he explored in earlier papers in Science2 and Nature Genetics,3 among others.

It is known that when humans spend time high altitude, their bodies adapt to reduced oxygen levels by increasing hemoglobin concentrations in the blood. This allows the body to carry more oxygen. Prchal explained how Song took this knowledge further. “We set up to try to find the gene which explains the hemoglobin,” he said.

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Navtemadlin Reduces Markers of Disease Burden in Relapsed/Refractory Myelofibrosis

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December 9, 2024

Author(s): Morgan Bayer

Treatment with navtemadlin (KRT-232) lowered the levels of biomarkers of disease burden in patients with relapsed/refractory myelofibrosis, according to findings from the phase 3 BOREAS trial (NCT03930732) that were presented at the 2024 ASH Annual Meeting.1

“I want to emphasize the biology that drives this approach. MDM2 is a negative regulator of wild-type p53, which is a master determinant of cell fate, and this becomes very critical when you consider its influence over the 4 hallmarks of myelofibrosis: CD34-positive myelofibrosis cell proliferation, myelofibrosis driver gene variant allele frequency (VAF), bone marrow fibrosis, and pro-inflammatory cytokines,” said John O. Mascarenhas, MD, during a presentation of the data.

Mascarenhas is professor of medicine, hematology and medical oncology, director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and director of the Adult Leukemia Program at the Mount Sinai Tisch Cancer Center in New York, New York.

In the randomized, multicenter, global phase 3 BOREAS trial, navtemadlin monotherapy was compared with best available therapy (BAT) that included hydroxyurea, peginterferon, immunomodulatory drugs, or supportive care. Patients included in the trial had TP53 wild-type myelofibrosis and were refractory or had relapsed on prior therapy with a JAK inhibitor. The data cutoff date was September 30, 2024.

In the study, 183 patients were randomly assigned 2:1 to receive navtemadlin (n =1 23) at 240 mg 7 days in a row for a 28-day cycle (with 21 days of drug holiday) or 1 cycle of BAT (n = 60) for 28 days. “The patients who were on a JAK inhibitor at the time had a 28-day washout period so that from a spleen and symptom perspective they were clear on day 1 of navtemadlin dosing,” Mascarenhas explained.

“What we saw in terms of biomarkers was a very significant potent, rapid reduction in circulating CD34 cells as a hallmark of myelofibrosis even within 12 weeks and sustained over 24 and 36 weeks,” Mascarenhas stated. At 12 weeks, CD34-positive cells showed a median reduction of 68% from baseline in 50 patients in the navtemadlin arm and 52% in 25 patients in the BAT arm. This trend continued at 24 weeks (n = 48, 70% reduction vs n = 19, 38% reduction) and at 36 weeks (n = 21, 76% reduction vs n = 9, 33% reduction).

The reduction in driver gene VAF by 50% or greater was observed in 21% (n = 17/82) of patients in the navtemadlin arm and 12% (n = 4/33) of patients in the BAT arm at 24 weeks, “nearly doubling the molecular response at 24 weeks,” Mascarenhas noted.

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Prognostic Implications of Pulmonary Hypertension in Myeloproliferative Neoplasms and Predictors of Hematologic Progression

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Orly Leiva, MD, Steve Soo, MD, Nathanial Smilowitz, Harmony Reynolds, Binita Shah, Samuel Bernard, Michelle Hyunju Lee, MD, Chi-Joan How, MD, and Gabriela S. Hobbs, MD

Introduction:
Myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are a group of disorders of clonal hematopoiesis associated with increased risk of cardiovascular disease (CVD), including pulmonary hypertension (PH). In a prior study of patients with MPN and established CVD, PH was associated with increased risk of hematologic progression to secondary MF or acute leukemia and major adverse cardiovascular events (MACE). However, the prognostic implication of PH among patients with MPN regardless of prior CVD status is unclear. Furthermore, transthoracic echocardiographic (TTE) characterization of risk of hematologic progression among those with PH has not been well studied.
Methods:
This was a multicenter retrospective cohort study of MPN patients with ≥ 1 TTE after diagnosis of MPN at New York University Langone Health and Massachusetts General Hospital from 2010 to 2023. PH was defined as estimated pulmonary artery systolic pressure (PASP) ≥ 40 mmHg on first TTE after MPN diagnosis. The primary outcome was a composite hematologic outcome of progression to secondary MF, acute leukemia, or death from MPN. Secondary outcome was MACE, a composite of arterial or venous thrombosis, heart failure (HF) hospitalization, or CV death. Given the competing risk of death, multivariable Fine-Gray competing-risk regression was used to estimate subhazard ratio (SHR) of the primary and secondary outcomes, and were adjusted for age at first TTE, MPN type, driver mutation, any non-driver mutation status, time from MPN to TTE, hemoglobin and WBC concentration, and spleen size. The association between PH and MACE was further adjusted for treatment for the MPN, left ventricular ejection fraction (LVEF), prior CVD, indication/setting of TTE, diastolic dysfunction, anti-thrombotic use, statin use, and creatinine. Hemodynamic predictors of the composite hematologic outcome among patients with PH was assessed using univariate competing-risk regression. Variables that were significantly different between groups (p < 0.05) were adjusted for age, time from MPN to TTE, driver and non-driver mutations, and spleen size.
Results:
Of the 555 patients included, 42.7% had PV, 41.1% ET, and 16.2% had MF at time of TTE, 48.5% were male and 86.8% were White race. PH was diagnosed in 195 patients (35.1%). The median time from MPN diagnosis to TTE was 39 months. Patients with PH were older (median age 71 vs 66 years, p <0.001), more likely to have MF (25.6% vs 11.1%, p <0.001), and higher VAF of driver MPN mutation (median 50% vs 40%, p = 0.002) and larger spleen sizes at time of TTE (median 13.7 vs 12.0 cm, p <0.001). Patients with PH had a higher rate of prior HF (15.4% vs 3.3%, p <0.001), hypertension (69.7% vs 56.7%, p= 0.003), and AF (29.7% vs 15.6%, p <0.001). After a median follow-up of 51 months, the composite hematologic outcome (23.6% vs 10.3%, p <0.001) and MACE (41.5% vs 19.2%, p <0.001) were more common among patients with PH. After multivariable competing-risk regression, PH was associated with increased risk of hematologic outcome (aSHR 1.79, 95% CI 1.10-2.92) and MACE (aSHR 1.67, 95% CI 1.10-2.56). Among patients with PH, 46 (23.6%) had hematologic outcome. After adjustment, atrial enlargement (aSHR 0.42, 95% CI 0.20-0.90) and valvular regurgitation (aSHR 0.30, 95% CI 0.16-0.57) were associated with decreased risk of hematologic outcome. Tricuspid annular plane systolic excursion (TAPSE, aSHR 2.44, 95% CI 1.27-4.69), a marker of right ventricular (RV) function, and estimated cardiac output (CO, aSHR 1.33, 95% CI 1.40-1.70) were associated with increased risk of hematologic outcome.
Conclusions:
Among patients with MPN, PH was associated with increased risk of hematologic progression and MACE. Our study also sheds some light on the pathophysiology behind PH and MPN progression given the association between preserved RV function and higher CO and MPN progression. MPN progression may lead to increased catabolic demand and cell turnover that may increase CO and may in part explain the association of preserved RV function and increased CO among patients with PH and MPN progression. However, further studies are needed to better understand the physiology of PH in MPN, characterize PH phenotypes and their associations with outcomes, and to assess the utility of TTE for screening for PH and surveillance of MPN progression.

 

Clinical Characteristics Defined in Adolescents and Young Adults With MPNs in Japan

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Vicki Moore, PhD

An analysis based in Japan identified differences in clinical characteristics between adolescents and young adults (AYA) and the non-AYA population among those with polycythemia vera (PV) or essential thrombocytopenia (ET). Findings were reported in the International Journal of Hematology.

The study was a large-scale retrospective analysis of AYA patients (aged 20 to 39 years) in the Japanese JSH-MPN-R18 registry who had been seen for an initial visit for PV or ET between April 2005 and March 2018. The study investigators evaluated clinical characteristics associated with PV or ET in this AYA cohort to increase understanding of myeloproliferative neoplasms (MPNS) in this population, in comparison with non-AYA patients from the registry.

In the registry, a total of 596 patients with PV and 1152 patients with ET were identified. There were 31 AYA patients among those with PV and 141 AYA patients among those with ET, corresponding to 5.2% of the total patients with PV and 12.2% of those with ET. In the AYA cohort, the median age at diagnosis was 33 years with PV and 32 years with ET.

AYA patients with PV had a lower median neutrophil ratio (71%) than non-AYA patients with PV did (78%; P <.01). Their median neutrophil count (6.5 x 109/L) was also lower than in the non-AYA population with PV (9.238 x 109/L; P =.03).

Among patients with ET, the AYA cohort showed lower values than non-AYA patients did for numerous parameters, such as median leukocyte count, neutrophil ratio, neutrophil count, lactate dehydrogenase level, and D-dimer level (P <.01 each). Palpable splenomegaly was also more common among AYA than non-AYA patients in the ET group (6.3% vs 2.3%, respectively; P =.02).

In patients with ET, the 5-year rate of hemorrhage-free survival (HFS) was higher for AYA patients (100%) than for non-AYA patients (93.9%; P <.01). For patients with PV, HFS did not significantly differ between AYA and non-AYA patients.

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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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Drug Offers New Option for Patients With Rare Blood Disorders in ‘No Man’s Land’

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By Sara Bondell – 

Myelodysplastic/myeloproliferative neoplasms are a group of diseases that occur when bone marrow produces too many blood cells while also demonstrating evidence of dysfunctional blood cell production, thereby having characteristics of both myelodysplastic syndromes and myeloproliferative neoplasms. Consensus for treating patients with these diseases is lacking, and patients are often excluded from clinical trials.

This puts patients with myelodysplastic/myeloproliferative neoplasms in a “no man’s land,” says Andrew Kuykendall, MD, a hematologist at Moffitt Cancer Center.

Since the syndromes can present with symptoms similar to those seen in myelofibrosis, a rare type of bone marrow cancer, Kuykendall decided to investigate if a myelofibrosis treatment could be effective in myelodysplastic/myeloproliferative neoplasms.

A phase 2 trial presented at the American Society of Hematology annual meeting assessed the efficacy of a JAK inhibitor called fedratinib in patients with myelodysplastic/myeloproliferative neoplasms or chronic neutrophilic leukemia. A JAK inhibitor is a type of medication that treats inflammation driven by malignant or inflammatory disorders by blocking the body’s production of cytokines, or proteins that cause inflammation.

Andrew Kuykendall, MD

Andrew Kuykendall, MD

“Fedratinib, interestingly, is also caught in ‘no man’s land’ within the treatment paradigm of myelofibrosis despite demonstrating significant potency. It was the second of four approved JAK inhibitors but has failed to establish a clear niche,” Kuykendall said.

Twenty-four patients on the trial received fedratinib daily. After 24 weeks, 53% of patients responded to the treatment. Half of patients had a symptom response, and 37.5% had a spleen response.

“This is a very high-risk group of patients who frequently harbor clinical characteristics that would suggest less likelihood of responding to treatment, so it is encouraging that fedratinib was able to achieve response rates of this magnitude,” Kuykendall said. “This data suggests that this is a very reasonable treatment option for these patients.”

Kuykendall says that while the results are promising, fedratinib does not replace allogeneic stem cell transplants, which should be the goal for eligible patients with these diseases. The drug, however, can be used to bridge patients to transplant.

“I also think one of the biggest takeaways from this study for me is that you can enroll a trial with a very rare disease,” Kuykendall said. “One of the reasons people don’t necessarily put resources behind these rare diseases is because they fear they can’t enroll, and I think we proved that’s not the case.”

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Authors Identify Monoclonal Antibody to Selectively Target CALR Mutations in MPNs

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November 29, 2024

Author(s): Mary Caffrey

A monoclonal antibody that selectively targets mutations in calreticulin (CALR), the second most common driver of myeloproliferative neoplasms (MPNs), showed promising results in tests with engineered cell lines and in a mouse model, according to findings published yesterday in Blood.1

A decade after the discovery of CALR, the results are the first for a possible therapy for CALR-mutated MPNs to reach the clinic, according to an accompanying commentary,2 which described the discovery of CALR mutations as the activator in most cases of JAK2V617F-negative essential thrombocythemia (ET) and myelofibrosis (MF) cases “as a surprise, because a major role for CALR had not been previously described.”2

Incyte logo | Image: Incyte

The monoclonal antibody, INCA033989, being developed by investigators from Incyte with collaborators from the University of York and hospitals in France, was described by study authors as having “antagonized mutated CALR-driven signaling and proliferation in engineered cell lines and primary CD34+ cells from patients with MPN. ”At the same time, the novel antibody showed no binding activity with other cells.

Finally, in an experiment with mouse model of mutated CALR-driven MPN, treatment with an antibody surrogate designed for the mouse model “effectively prevented the development of thrombocytosis and accumulation of megakaryocytes in the bone marrow.”

The investigational antibody reduced replication of disease-initiating cells in both primary and secondary transplantations, the authors said, “illustrating its disease-modifying potential.”

There are 3 main types of MPN disorders, with most driven by mutations in Janus kinase (JAK2); this mutation accounts for 90% of patients with polycythemia vera (PV), 60% of patients with ET, and 55% of patients with MF. Next, CALR mutations are found in 25% of patients with ET and 35% of patients with MF. Mutations in CALR are not responsible for PV, the authors state.

They note that the mutant CALR protein is oncogenic; patients with ET and MF show clonal proliferation of hematopoietic stem cells. Patients with ET in particular are at risk of thrombosis and hemorrhage while those with MF may develop anemia or leukopenia, splenomegaly, bone marrow fibrosis, or see their disease transform into leukemia. A 2021 study appearing in Blood found that the 10-year mortality risk for patients younger than age 60 was 13% for those with ET, 18% for PV, and 49% for MF, compared with 6% for a control group.3

The investigators note that there has been great progress understanding mutated CALR in the 10 years after its discovery, including how it interacts with the thrombopoietin receptor (TPOR) and the resulting behavior of the mutated CALR protein with TPOR on the cell surface.

“Such findings fueled interest in targeted therapeutics,” they wrote, with both vaccines and antibodies being pursued.1 The cell surface of mutated CALR makes it an obvious target for antibodies, and the authors outlined results from earlier preclinical studies involving the mechanisms that contributed to development of the investigational antibody.

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Study Reveals Prognostic Implications of Pulmonary Hypertension in Myeloproliferative Neoplasms

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January 25, 2024

Lara C. Pullen, PhD

An analysis of patients with myeloproliferative neoplasms (MPN) has revealed that pulmonary hypertension (PH) is associated with an increased risk of hematologic progression and major adverse cardiovascular events (MACE). Orly Leiva, MD, an advanced heart failure and transplantation fellow at the University of Chicago, will present results that shed light on the pathophysiology behind PH and MPN progression, including an association between preserved right ventricular (RV) function and higher MPN progression, during the 66th American Society of Hematology (ASH) Annual Meeting and Exposition.

Dr. Leiva and colleagues designed the retrospective study to examine the connection between cardiology and MPN and determine whether the relatively common transthoracic echocardiographic (TTE) procedure can predict MPN progression. The study included 555 patients, 42.7% of whom had polycythemia vera, 41.1% had essential thrombocythemia, and 16.2% had myelofibrosis at the time of TTE. The cohort was 48.5% male and 86.8% white.

Thirty-five percent of the patients had a diagnosis of PH at the time of their first TTE; PH was defined as a pulmonary artery systolic pressure (PASP) of at least 40 mm Hg. The median time from MPN diagnosis to TTE was 39 months. Patients with PH were a median age of 71 years compared with 66 years for those without PH (p<0.001), and patients with PH were more likely to have myelofibrosis than those without. Patients with PH were also more likely than patients without PH to have a higher variant allele frequency of driver MPN mutation and larger spleen sizes at the time of TTE. They also had a higher rate of prior heart failure, hypertension, and atrial fibrillation than patients without PH.

Dr. Leiva’s team followed the patients for a median of 51 months and noted that composite hematologic outcome and MACE were more common among patients with PH than those without PH. When they performed a multivariable competing-risk regression on the data, the investigators found that PH was associated with an increased risk of hematologic outcome and MACE, such that 23.6% of patients with PH experienced a hematologic outcome. After adjusting for variables that varied significantly between groups, they found that atrial enlargement and valvular regurgitation were associated with decreased risk of hematologic outcome. In contrast, a marker of RV function, tricuspid annular plane systolic excursion, and estimated cardiac output were both associated with an increased risk of hematologic outcome.

“MPNs are a chronic disease,” Dr. Leiva told ASH Clinical News. “Some patients have the potential to live for decades.” Although thrombotic events are a classic cause of mortality in patients with MPN, many die from cardiovascular causes, and the results from this study highlight the non-thrombotic complications of MPN. Dr. Leiva proposed that MPN progression leads to increased catabolic demand and cell turnover, which might lead to increased cardiac output. Such a connection would explain the association between preserved RV function and increased cardiac output among patients with PH and MPN progression.

Dr. Leiva acknowledged that the study was primarily hypothesis-generating, and he called for a prospective study to further investigate the physiology of PH in MPN, characterize PH phenotypes and their associations with outcomes, and assess the utility of TTE screening for PH and surveillance of MPN progression. Until then, he explained that as a cardiologist, when treating a patient with MPN, he looks immediately at the patient’s TTE results. He suggested that all cardiologists and hematologists look for signs of MPN progression if a patient’s PASP exceeds 40 mm Hg or they have other signs of PH on their TTE.

The full study is scheduled to be presented on Saturday, December 7, 2024, at 3:15 p.m. at the 66th ASH Annual Meeting and Exposition in San Diego. This article will be replaced with a summary of the presentation after the session has concluded. Check back later this month for updates!

Any conflicts of interest declared by the authors can be found in the original abstract.

Reference

Leiva O, Soo S, Smilowitz N, et al. Prognostic implications of pulmonary hypertension in myeloproliferative neoplasms and predictors of hematologic progression. Abstract 246. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 7, 2024; San Diego, California.

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Myelofibrosis symptom assessment form total symptom score version 4.0: measurement properties from the MOMENTUM phase 3 study

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November 25, 2024

Christina Daskalopoulou, Boris Gorsh, Gerasimos Dumi, Samineh Deheshi, Chad Gwaltney, Jean Paty, Catherine Ellis, Jun Kawashima & Ruben Mesa

Abstract

Purpose

The Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) comprises 7 common MF symptom items (fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, bone pain) and is the first patient-reported outcome (PRO) instrument designed to assess MF symptom burden. Given that information on the psychometric properties of this instrument has been limited, we sought to evaluate its measurement properties and validate its use in the phase 3 MOMENTUM trial.

Methods

Data were pooled to assess MFSAF item distribution, structural validity, reliability (test-retest and internal consistency), construct validity (convergent, divergent, and known-groups), and sensitivity to change. Other PRO measures included Patient Global Impression of Severity/Change (PGIS/PGIC), EORTC QLQ-C30, PROMIS Physical Function Short Form 10b, and ECOG performance status.

Results

Participants (N = 195) showed high completion rates (> 93%) across 24 weeks. Moderate to strong Spearman correlation coefficients among items were mostly observed at baseline (range, 0.289–0.772) and week 24 (range, 0.391–0.829), which supported combining items into a multi-item scale and total score. Internal consistency (Cronbach’s α, 0.877 at baseline and 0.903 at week 24) and test-retest reliability (intraclass correlation coefficient, > 0.829) were satisfactory across selected time intervals. Reliability was also supported by McDonald’s omega (ω) coefficient (> 0.875). MFSAF moderately correlated with PRO measures of similar content, differentiated between PGIS and ECOG groups (P < .001), and was able to detect change over time.

Conclusions

The MFSAF v4.0 is a valid tool to assess MF symptom burden, supporting its use in future trials in similar populations.

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A robust tool for complex time-to-event data analysis in the context of myeloproliferative neoplasms

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November 25, 2024

by Gunilla Sonnebring, Karolinska Institutet

A new thesis from Karolinska Institutet shows the effectiveness of flexible parametric survival models in modeling multiple time-scales, providing a robust tool for complex time-to-event data analysis. The models were tested in the context of myeloproliferative neoplasms, a group of chronic hematologic malignancies in which the bone marrow makes too many red blood cells, white blood cells, or platelets.

This overproduction can lead to various complications, including blood clots (thrombosis), bleeding problems, transformation to acute myeloid leukemia and myelodysplastic syndromes.

In her thesis, doctoral student Nurgul Batyrbekova at the Department of Medical Epidemiology and Biostatistics, describes a novel method to modeling multiple time-scales in time-to-event analysis by using flexible parametric survival models (FPM) that can seamlessly incorporate multiple time-scales without requiring data splitting. She also explores whether traditional survival models that rely on a single time-scale lead to bias and inaccuracies in certain scenarios.

In two of her studies, using the novel method, Nürgul investigates clinically relevant questions for MPN, specifically, how the rate of thrombosis and the rate of transformation to AML/MDS are affected by age and duration of MPN disease.

Overall, her thesis could show that the new way to use multiple time-scales in survival models was better and provides answers to clinically relevant research questions in the field of MPN.

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