Five-Year Trial Shows Interferon Outperforms Hydroxyurea Molecularly in Myeloproliferative Neoplasms

For decades, patients newly diagnosed with Philadelphia chromosome-negative myeloproliferative neoplasms have begun treatment with hydroxyurea, an oral chemotherapy agent that suppresses blood cell production and lowers the risk of thrombosis. Now, results from the DALIAH trial, a multicentre, randomised, open-label, phase 3 study conducted across nine centres in Denmark, offer the most comprehensive head-to-head comparison to date between hydroxyurea and low-dose pegylated interferon alpha in this diverse group of blood cancers. The five-year findings, published in eClinicalMedicine, reveal a nuanced picture in which both drugs achieve comparable clinicohaematological control, but interferon demonstrates a clear edge in dismantling the molecular machinery of the disease among patients who can tolerate it.

The myeloproliferative neoplasms encompass essential thrombocythaemia, polycythaemia vera, prefibrotic primary myelofibrosis, and overt primary myelofibrosis, all disorders driven by mutated haematopoietic stem cells, most commonly carrying the JAK2V617F mutation. These conditions predispose patients to life-threatening blood clots and bleeding, and conventional cytoreductive therapy has primarily aimed at reducing this thrombotic risk. Hydroxyurea has long served as the default first-line option, yet it leaves 10 to 40 percent of patients intolerant or resistant, and lingering concerns about its long-term leukemogenic potential have fuelled the search for alternatives.

Interferon alpha occupies a fundamentally different therapeutic niche. Rather than simply poisoning dividing cells, this immunomodulating agent acts directly on haematopoietic stem and progenitor cells. Animal studies have shown that interferon alpha rouses quiescent malignant stem cells from dormancy, with a striking preference for cells carrying the JAK2V617F mutation, ultimately driving the malignant clone toward functional exhaustion. This disease-modifying potential, combined with the improved tolerability conferred by pegylation, prompted Danish investigators to design DALIAH as the earliest and largest randomised trial of long-term pegylated interferon in newly diagnosed patients across all myeloproliferative neoplasm subtypes.

Between February 2012 and July 2015, the trial enrolled 206 patients, of whom 203 formed the modified intention-to-treat population. Adults with newly diagnosed or treatment-naive disease were eligible regardless of risk score, a deliberate design choice that broadened the trial beyond the high-risk patients targeted by most prior studies. Older patients, aged over sixty, were randomised among hydroxyurea, pegylated interferon alpha-2a, or pegylated interferon alpha-2b, while younger patients avoided hydroxyurea owing to its theoretical leukemogenic risk and were randomised between the two interferon formulations. The cohort comprised 73 patients with essential thrombocythaemia, 89 with polycythaemia vera, 16 with prefibrotic myelofibrosis, and 25 with overt primary myelofibrosis. The median age was 62 years, and JAK2V617F was the dominant driver mutation, present in 74 percent of participants with a median baseline variant allele frequency of 34 percent.

The primary endpoint was the rate of molecular response, defined by European LeukemiaNet criteria as a substantial or complete reduction in the JAK2V617F variant allele frequency, measured serially by quantitative polymerase chain reaction at eight time points up to 60 months. By intention-to-treat analysis, which counted patients who discontinued treatment as non-responders, molecular response rates were statistically indistinguishable between the two drugs: 23 percent in the hydroxyurea arm versus 24 percent in the interferon arm at 60 months. This apparent parity, however, masks a profound divergence revealed when the analysis was restricted to patients who remained on their assigned therapy.

Among those who stayed the course, pegylated interferon proved decisively superior from 36 months onward. At that juncture, 56 percent of interferon-treated patients had achieved a molecular response, compared with just 23 percent of those on hydroxyurea, a gap that widened to 67 percent versus 35 percent by 60 months. Three interferon-treated patients reached complete molecular remission, with the JAK2V617F mutation rendered undetectable by an assay sensitive to 0.1 percent. Moreover, patients on hydroxyurea lost their responses far more frequently, with 62 percent losing molecular response versus only 13 percent of interferon patients, a difference that proved highly significant. The kinetics told a parallel story: the median relative reduction in variant allele frequency from baseline to 60 months was 75 percent with interferon compared with only 20 percent under hydroxyurea.

On secondary endpoints, the two drugs traded advantages. Complete clinicohaematological response at 12 months was similar between groups, and by intention-to-treat analysis hydroxyurea held a modest edge at 18 months, 58 percent versus 38 percent, though per-protocol analysis later favoured interferon at 36 and 60 months. Hydroxyurea normalised blood counts faster, with haematological response reached in a median of 1.6 months versus 3.8 months for interferon, a predictable consequence of its direct cytorepressive action. Conversely, more hydroxyurea patients lost their haematological responses over time, 86 percent compared with 44 percent on interferon. Bone marrow histopathology delivered an unexpected finding: by intention-to-treat analysis, histopathological remission at 60 months favoured hydroxyurea, 18 percent versus 5 percent, though paired analyses and per-protocol comparisons blurred this difference, and the investigators caution that fibrosis grading was inconclusive in significantly more hydroxyurea patients.

Safety data underscored the trial’s central challenge. At 60 months, 60 percent of all patients had discontinued study treatment, and discontinuation was significantly more frequent with interferon at 65 percent than with hydroxyurea at 37 percent. Toxicity drove the disparity: 45 percent of interferon patients stopped treatment for adverse events, most commonly flu-like illness, injection-site irritation, fatigue, and neuropsychiatric symptoms, while only 13 percent of hydroxyurea patients discontinued for that reason. Notably, discontinuation for toxicity clustered among younger and female patients and varied dramatically between study sites, from 30 to 69 percent, leading the authors to speculate that investigator enthusiasm may have shaped dosing decisions. Yet a subgroup of patients tolerated interferon long-term, and no treatment-related events of grade 3 or higher occurred beyond 24 months among those continuing therapy.

Thrombosis, the cardinal clinical concern in these diseases, was not prevented by interferon. Nineteen major thrombotic events occurred during treatment, with a rate of 5.5 events per 100 patient-years among older interferon patients versus 2.8 per 100 patient-years with hydroxyurea, a difference lacking statistical significance but clinically noteworthy. Importantly, 68 percent of thrombotic events occurred while blood counts remained normalised and before any substantial molecular reduction, reinforcing the multifactorial nature of clotting risk in myeloproliferative neoplasms. No patient progressed to myelofibrosis, acute myeloid leukaemia, or myelodysplastic syndrome, and five deaths were recorded across the cohort without an evident treatment-related pattern.

The DALIAH results arrive amid converging evidence that molecular response is not merely a laboratory curiosity. Data from the CONTINUATION-PV and MAJIC-PV trials link deepening JAK2V617F depletion with prolonged event-free survival, suggesting that eradicating the malignant clone may genuinely alter disease course. Within this framework, interferon’s slow but sustained molecular advantage, even as hydroxyurea’s responses eroded, positions low-dose pegylated interferon alpha-2a as a viable first-line option for carefully selected patients, particularly younger individuals in whom decades of cytoreductive therapy loom ahead. The trial’s authors call for biomarkers capable of predicting both response and tolerability at diagnosis, noting that mutated DNMT3A may confer interferon resistance. They also propose an intriguing strategy: an initial six to twelve months of combination therapy using hydroxyurea to rapidly normalise counts while interferon gradually strips away the malignant clone, followed by interferon monotherapy. With pegylated interferon alpha-2b withdrawn from the European market but alpha-2a still available and mono-pegylated ropeginterferon expanding the armamentarium, the era of disease-modifying first-line therapy for myeloproliferative neoplasms may finally be within reach.

Subject of Research: A five-year randomised phase 3 trial comparing pegylated interferon alpha with hydroxyurea as first-line cytoreductive therapy in myeloproliferative neoplasms.

Article Title: Interferon-α vs hydroxyurea in patients with myeloproliferative neoplasms (DALIAH): a multicentre, randomised, open-label, phase 3 trial in Denmark

Article References: Knudsen, T. A., Hansen, D. L., Ocias, L. F., Bjerrum, O. W., Brabrand, M., Christensen, S. F., Eickhardt-Dalbøge, C. S., Ellervik, C., El Fassi, D., Frederiksen, M., Kjær, L., Kristensen, T. K., Kruse, T. A., Larsen, M. K., Mourits-Andersen, T., Möller, S., Overgaard, U. M., Severinsen, M. T., Skov, V., … Hasselbalch, H. C. (2026). Interferon-α vs hydroxyurea in patients with myeloproliferative neoplasms (DALIAH): a multicentre, randomised, open-label, phase 3 trial in Denmark. eClinicalMedicine, 100, Article 104193. https://doi.org/10.1016/j.eclinm.2026.104193

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104193

Keywords: myeloproliferative neoplasms, pegylated interferon alpha, hydroxyurea, JAK2V617F, molecular response, DALIAH trial, polycythaemia vera, essential thrombocythaemia, primary myelofibrosis, phase 3 trial, cytoreductive therapy, haematology