Speaker
Description
The Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs) are slowly developing haematological malignancies characterised by an overproduction of blood cells. Chronic inflammation is associated with the diseases and suggested to play an important role in disease initiation and progression as well as being a consequence of the diseases.
In the DALIAH trial, treatment-naïve MPN patients were treated with either Hydroxyurea (HU) or low dose interferon-$\alpha$ (IFN-$\alpha$) and followed for up to five years\cite{knudsen_final_2023}. Both HU and IFN-$\alpha$ are commonly used treatments for MPN. On top of their cytoreductive effects, IFN-$\alpha$ is a potent immunostimulatory cytokine, while HU has been shown to decrease the level of pro-inflammatory cytokines and the neutrophil-to-lymphocyte ratio in sickle cell disease patients\cite{zahran_effect_2020}.
With a mechanism-based, nonlinear ordinary differential equation model, we investigate the role of inflammation in MPN disease progression and response to treatment. The model includes stem cell, progenitor cell, and mature cell
compartments of wild-type and mutated hematological cells with a nonlinear
negative feedback from the mature to the stem cell compartments.
By comparing the mechanism-based model to longitudinal measurements of mature blood cell counts, variant allele frequency of the MPN driver mutation \textit{JAK2}V617F, and cytokines of the patients enrolled in the DALIAH trial, we aim to identify a signature of inflammatory mediators with prognostic impact.
Bibliography
@article{zahran_effect_2020,
title = {Effect of {Hydroxyurea} {Treatment} on the {Inflammatory} {Markers} {Among} {Children} {With} {Sickle} {Cell} {Disease}},
volume = {26},
issn = {1076-0296, 1938-2723},
url = {https://journals.sagepub.com/doi/10.1177/1076029619895111},
doi = {10.1177/1076029619895111},
abstract = {Background:
Neutrophil-to-lymphocyte ratio (NLR) was introduced as a potential inflammatory marker in sickle cell disease (SCD). This study aimed to evaluate the impact of hydroxyurea (HU) treatment on the value of NLR and some inflammatory mediators in SCD.
Methods:
The hematological parameters and clinical events were analyzed in 35 children with SCD under HU treatment and followed up for 1 year and in 20 healthy controls. Enzyme-linked immunosorbent assay was performed for the evaluation of proinflammatory cytokines, including interleukin (IL) 6, IL-8, high-sensitivity C-reactive protein (hs-CRP), and tumor necrosis factor α (TNF-α).
Results:
Hydroxyurea significantly improves most of the hematological parameters in children with SCD. The percentages of hemoglobin fraction S, serum levels of TNF-α and IL-6 were significantly decreased when compared to baseline value but did not reach the value of the healthy control. The HU treatment led to a significant decrease in NLR compared to the baseline values and reached healthy control values. Neutrophil-to-lymphocyte ratio was positively correlated with hs-CRP, TNF-α, and IL-8 serum levels and negatively correlated with percentage of fetal hemoglobin and hematocrit values. The cutoff value of NLR to expect a response to HU among SCD was 3.0, with 76\% specificity and 85\% sensitivity (area under the curve: 0.85, P {\textless} .0001). In conclusion, hydroxyurea induced a decrease in NLR and inflammatory cytokines, which represent a biomarker of inflammation in SCD. The calculation of NLR is a straightforward and cheap method for SCD outcome prediction in young children.},
language = {en},
urldate = {2026-03-12},
journal = {Clinical and Applied Thrombosis/Hemostasis},
author = {Zahran, Asmaa M. and Nafady, Asmaa and Saad, Khaled and Hetta, Helal F. and Abdallah, Alam-Eldin M. and Abdel-Aziz, Safwat M. and Embaby, Mostafa M. and Abo Elgheet, Amir M. and Darwish, Sanaa F. and Abo-Elela, Mohamed Gamil M. and Elhoufey, Amira and Elsayh, Khalid I.},
month = jan,
year = {2020},
pages = {1076029619895111},
}
@article{knudsen_final_2023,
title = {Final {Analysis} of the {Daliah} {Trial}: {A} {Randomized} {Phase} {III} {Trial} of {Interferon}-α {Versus} {Hydroxyurea} in {Patients} with {MPN}},
volume = {142},
issn = {0006-4971, 1528-0020},
shorttitle = {Final {Analysis} of the {Daliah} {Trial}},
url = {https://ashpublications.org/blood/article/142/Supplement%201/746/502286/Final-Analysis-of-the-Daliah-Trial-A-Randomized},
doi = {10.1182/blood-2023-173127},
abstract = {Background: Hydroxyurea (HU) is the most commonly used first-line cytoreductive treatment option for patients with myeloproliferative neoplasms (MPN) worldwide. However, increasing evidence on the efficacy and safety of pegylated interferon-alpha2 (IFNα) is emerging, and optimal first-line treatment is to be established.
Aims: To compare the efficacy and safety of HU vs. low-dose IFNα in patients with MPN over five years.
Methods: DALIAH (NCT01387763) was a randomized phase III trial of HU vs. IFNα in newly diagnosed or untreated patients with MPN (essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic myelofibrosis (PreMF), and primary myelofibrosis (PMF)). Patients \> age 60 were randomized (1:1:1) to HU, IFNα-2a, or IFNα-2b whereas patients ≤ age 60 were randomized to IFNα-2a or IFNα-2b. The primary outcome was the JAK2V617F molecular response (MR) rate at 18, 36, and 60 months per 2009 European LeukemiaNetwork (ELN) (ET, PV, PreMF) or 2005 European Myelofibrosis Network (EUMNET) (PMF) criteria. Secondary outcomes included the complete clinicohematologic response (CHR) rate at 12 months. The JAK2V617F allele burden was measured using quantitative polymerase chain reaction (qPCR) on peripheral blood (assay sensitivity: 0.1\%). Primary and secondary outcomes were compared between groups (HU vs. IFNα or HU vs. IFNα \> 60 years) using Fisher's exact test (categorical variables) or Wilcoxon rank-sum test (continuous variables). Paired comparisons (within groups) were made using Wilcoxon signed-rank test. Serial JAK2V617F measurements were compared by unadjusted mixed-effects linear regression analysis.
Results: We included 203 patients (ET: 73 (36\%), PV: 89 (44\%), PreMF: 16 (8\%), and PMF: 25 (12\%)) in the modified intention-to-treat (ITT) population. Baseline characteristics were well balanced except for median age (HU: 68 years vs. IFNα: 59 years, p\<0.0001) ( Table 1). The MR rate by ITT analysis was similar between HU and IFNα (18 months: 19\% vs. 21\%, p=1.00; 36 months: 19\% vs. 26\%, p=0.64; 60 months: 23\% vs. 24\%, p=1.00) (Figure 1A). However, the JAK2V617F allele burden was significantly lower in the IFNα group at month 36 and beyond (Figure 1B) and the absolute median (IQR) change in JAK2V617F allele burden (baseline to 60 months) was greater with IFNα (-20\% (-9;-49) vs. -7\% (3;-15), p=0.0053) (Figure 1C). Two patients (IFNα: n=2) were in complete molecular remission (undetectable JAK2V617F) at 60 months. The CHR rate by ITT analysis was higher with HU at 18 months (58\% vs. 38\%, p=0.03) but similar at all other time points (12 months: 50\% vs. 36\%, p=0.21; 60 months: 24\% vs. 22\%, p=0.83) ( Figure 1D). A post hoc subgroup analysis comparing HU with IFNα \> age 60 showed comparable efficacy results. Among patients remaining on treatment (per-protocol analysis), the MR and CHR rates were superior in the IFNα group compared to the HU group at 36 months and beyond. The MR and CHR rates (HU vs. IFNα) by per-protocol analysis were: MR at 36 months: 23\% vs. 56\%, p=0.01; MR at 48 months: 27\% vs. 59\%, p=0.02; MR at 60 months: 35\% vs. 67\%, p=0.03; CHR at 36 months: 33\% vs. 67\%, p=0.002; CHR at 60 months: 38\% vs. 62\%, p=0.05.
Overall treatment discontinuation at 60 months was 60\% (HU: 37\% vs. IFNα: 65\%, p=0.0019). The most common cause of treatment discontinuation was adverse events (HU: 6/38 (16\%); IFNα: 71/165 (43\%)). Adverse events ≥ grade 3 occurred in 46\% (HU: 58\% vs. IFNα: 45\%, p=0.15). Nineteen major thrombotic events were reported in 16 patients (HU: 4 events in 4 patients; IFNα\>60: 12 events in 10 patients; IFNα≤60: 3 events in 2 patients), corresponding to an incidence rate of 2.6 per 100 person-years for HU and 3.4 per 100 person-years for IFNα (IFNα\>60: 6.2; IFNα≤60: 1.2). None of the patients transformed into secondary acute myeloid leukemia. Five patients died during follow-up (HU: 2; IFNα: 3).
Bone marrow histologic remission rates at 36 and 60 months will be presented at the meeting.
Conclusion: ITT analysis detected no significant difference in the MR or CHR rates between HU and IFNα with long-term treatment (5 years) among patients with MPN, reflecting a higher treatment discontinuation rate in the IFNα group (65\%). Thus, using the per-protocol principle, the MR and CHR rates were superior in the IFNα group at 36 months and beyond.},
language = {en},
number = {Supplement 1},
urldate = {2026-03-12},
journal = {Blood},
author = {Knudsen, Trine Alma and Hansen, Dennis Lund and Ocias, Lukas Frans and Bjerrum, Ole and Brabrand, Mette and Christensen, Sarah Friis and Eickhardt-Dalbøge, Christina Schjellerup and Ellervik, Christina and El Fassi, Daniel and Frederiksen, Mikael and Kjær, Lasse and Kristensen, Thomas Kielsgaard and Kruse, Torben A. and Larsen, Morten Kranker and Mourits-Andersen, Torben and Möller, Sören and Overgaard, Ulrik Malthe and Severinsen, Marianne Tang and Skov, Vibe and Sørensen, Anders Lindholm and Stentoft, Jesper and Starklint, Jørn and De Stricker, Karin and Thomassen, Mads and Larsen, Thomas S. and Hasselbalch, Hans C.},
month = nov,
year = {2023},
pages = {746--746},
}
