Allele burden expansion in JAK2 V617F and CALR ‐mutated myeloproliferative neoplasms predicts disease progression and is associated with anagrelide treatment
Abstract
Recent prospective studies demonstrated that reductions in JAK2 V617F variant allele frequency (VAF) correlate with clinical benefit in essential thrombocythemia (ET) and polycythemia vera (PV). 1,2 However, the impact of CALR VAF dynamics with therapy on clinical outcomes remains relatively unknown. Pegylated interferon-alpha (IFN) has been shown to variably reduce CALR VAF, but changes with treatments such as hydroxycarbamide (HC), anagrelide (ANA), and ruxolitinib (RUX), a JAK inhibitor, are less well described. 3 Newer mutation-targeted therapies are demonstrating early significant reductions in VAFs, which may serve as a surrogate marker of disease modification. 4 We therefore sought to evaluate dynamics of driver mutation VAF in myeloproliferative neoplasm (MPN) patients treated with cytoreductive therapies and correlate these with clinical outcomes. Sequential cases were collated from eight international centers including the prospective MAJIC-ET study. 5 Although MAJIC-ET has been reported, inclusion enabled greater power for time-dependent outcomes. A comparator cohort of JAK2 V617F -mutated patients was included; the MAJIC-PV cohort was excluded due to substantially higher baseline VAF precluding meaningful comparison. CALR VAF was quantified using next-generation sequencing (NGS), fragment analysis, or droplet digital polymerase chain reaction (ddPCR). JAK2 V617F VAF was quantified using quantitative PCR or NGS. Serial VAF measurements within each patient were performed using the same analytical platform at the same center throughout follow-up. Molecular response (MR), comprising complete (CMR) and partial (PMR) response as defined per IWG-MRT/ELN 2013 criteria, plus an exploratory PMR20 category, is detailed in Supporting Information S2: Supplementary Methods. 6-8 Overall, 347 patients with CALR (n = 190) and JAK2 V617F (n = 157) mutations with VAF measurements at two timepoints at least 6 months apart were included (Table 1). ET was the most prevalent diagnosis (n = 235, 67.7%), followed by primary and secondary myelofibrosis (MF; n = 73, 21.1%), prefibrotic myelofibrosis (n = 17, 4.9%), PV (n = 15, 4.3%), MPN-unclassified (n = 6, 1.7%), and blast-phase MPN (n = 1, 0.3%). Treatment was defined as the predominant cytoreductive agent active between the first and second VAF measurements (Supporting Information S2: Supplementary Methods). Treatments included IFN (n = 132, 38.0%), RUX (n = 70, 20.2%), ANA (n = 29, 8.4%), HC (n = 88, 25.4%), and other therapies (n = 28, 8.0%) (Table 1). Median VAF measurement interval was 54 months (range HemaSphere.
Related
- Defining and predicting disease progression in myeloproliferative neoplasms: a proposed biomarker-driven approach
- FDX1 is associated with CALR abundance and JAK–STAT-related inflammatory signaling in myeloproliferative neoplasms
- The JAK2 V617F revolution in myeloproliferative neoplasms.
- Megakaryocytic proteomic signatures define myeloproliferative neoplasms
- Multicentric study underlining the interest of adding CD5, CD7 and CD56 expression assessment to the flow cytometric Ogata score in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms.
BibTeX
@article{ng2026allele,
title = {{Allele burden expansion in JAK2 V617F and CALR ‐mutated myeloproliferative neoplasms predicts disease progression and is associated with anagrelide treatment}},
author = {Zi Yun Ng and Laurane Cottin and Marine Demoy and Damien Luque Paz and Corentin Orvain and Wayne‐corentin Lambert and Jean‐christophe Ianotto and Eric Lippert and David M Ross and Diana Iarossi and Alesia Khan and Daniel Lock and Catherine Truong and Kamel Laribi and Yun Fan Yang and Laura Li Gagnon and Valerie Ugo and Claire N Harrison and Jennifer O'Sullivan},
journal = {HemaSphere},
year = {2026},
month = aug,
doi = {10.1002/hem3.70460},
url = {https://hal.science/hal-05753482v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Allele burden expansion in JAK2 V617F and CALR ‐mutated myeloproliferative neoplasms predicts disease progression and is associated with anagrelide treatment
AU - Zi Yun Ng
AU - Laurane Cottin
AU - Marine Demoy
AU - Damien Luque Paz
AU - Corentin Orvain
AU - Wayne‐corentin Lambert
AU - Jean‐christophe Ianotto
AU - Eric Lippert
AU - David M Ross
AU - Diana Iarossi
AU - Alesia Khan
AU - Daniel Lock
AU - Catherine Truong
AU - Kamel Laribi
AU - Yun Fan Yang
AU - Laura Li Gagnon
AU - Valerie Ugo
AU - Claire N Harrison
AU - Jennifer O'Sullivan
PY - 2026
DA - 2026/08/31
JO - HemaSphere
DO - 10.1002/hem3.70460
UR - https://hal.science/hal-05753482v1
AB - Recent prospective studies demonstrated that reductions in JAK2 V617F variant allele frequency (VAF) correlate with clinical benefit in essential thrombocythemia (ET) and polycythemia vera (PV). 1,2 However, the impact of CALR VAF dynamics with therapy on clinical outcomes remains relatively unknown. Pegylated interferon-alpha (IFN) has been shown to variably reduce CALR VAF, but changes with treatments such as hydroxycarbamide (HC), anagrelide (ANA), and ruxolitinib (RUX), a JAK inhibitor, are less well described. 3 Newer mutation-targeted therapies are demonstrating early significant reductions in VAFs, which may serve as a surrogate marker of disease modification. 4 We therefore sought to evaluate dynamics of driver mutation VAF in myeloproliferative neoplasm (MPN) patients treated with cytoreductive therapies and correlate these with clinical outcomes. Sequential cases were collated from eight international centers including the prospective MAJIC-ET study. 5 Although MAJIC-ET has been reported, inclusion enabled greater power for time-dependent outcomes. A comparator cohort of JAK2 V617F -mutated patients was included; the MAJIC-PV cohort was excluded due to substantially higher baseline VAF precluding meaningful comparison. CALR VAF was quantified using next-generation sequencing (NGS), fragment analysis, or droplet digital polymerase chain reaction (ddPCR). JAK2 V617F VAF was quantified using quantitative PCR or NGS. Serial VAF measurements within each patient were performed using the same analytical platform at the same center throughout follow-up. Molecular response (MR), comprising complete (CMR) and partial (PMR) response as defined per IWG-MRT/ELN 2013 criteria, plus an exploratory PMR20 category, is detailed in Supporting Information S2: Supplementary Methods. 6-8 Overall, 347 patients with CALR (n = 190) and JAK2 V617F (n = 157) mutations with VAF measurements at two timepoints at least 6 months apart were included (Table 1). ET was the most prevalent diagnosis (n = 235, 67.7%), followed by primary and secondary myelofibrosis (MF; n = 73, 21.1%), prefibrotic myelofibrosis (n = 17, 4.9%), PV (n = 15, 4.3%), MPN-unclassified (n = 6, 1.7%), and blast-phase MPN (n = 1, 0.3%). Treatment was defined as the predominant cytoreductive agent active between the first and second VAF measurements (Supporting Information S2: Supplementary Methods). Treatments included IFN (n = 132, 38.0%), RUX (n = 70, 20.2%), ANA (n = 29, 8.4%), HC (n = 88, 25.4%), and other therapies (n = 28, 8.0%) (Table 1). Median VAF measurement interval was 54 months (range HemaSphere.
SN - 2572-9241
ER -