Treatment with PEGylated interferon‐alpha2 (IFN) of patients with essential thrombocythemia and polycythemia vera induces major molecular remissions with a reduction in the JAK2V617F allele burden to undetectable levels in a subset of patients. A favorable response to IFN has been argued to depend upon the tumor burden, implying that institution of treatment with IFN should be as early as possible after the diagnosis. However, evidence for this statement is not available. We present a thorough analysis of unique serial JAK2V617F measurements in 66 IFN‐treated patients and in 6 untreated patients. Without IFN treatment, the JAK2V617F allele burden increased exponentially with a period of doubling of 1.4 year. During monotherapy with IFN, the JAK2V617F allele burden decreased mono‐ or bi‐exponentially for 33 responders of which 28 patients satisfied both descriptions. Bi‐exponential description improved the fits in 19 cases being associated with late JAK2V617F responses. The decay of the JAK2V617F allele burden during IFN treatment was estimated to have half‐lives of 1.6 year for the monoexponential response and 1.0 year in the long term for the bi‐exponential response. In conclusion, through data‐driven analysis of the JAK2V617F allele burden, we provide novel information regarding the JAK2V617F kinetics during IFN‐treatment, arguing for early intervention.

(1) Background: myeloproliferative neoplasms (MPNs) are slowly developing hematological cancers characterized by few driver mutations, with JAK2V617F being the most prevalent. (2) Methods: using mechanism-based mathematical modeling (MM) of hematopoietic stem cells, mutated hematopoietic stem cells, differentiated blood cells, and immune response along with longitudinal data from the randomized Danish DALIAH trial, we investigate the effect of the treatment of MPNs with interferon-α2 on disease progression. (3) Results: At the population level, the JAK2V617F allele burden is halved every 25 months. At the individual level, MM describes and predicts the JAK2V617F kinetics and leukocyte- and thrombocyte counts over time. The model estimates the patient-specific treatment duration, relapse time, and threshold dose for achieving a good response to treatment. (4) Conclusions: MM in concert with clinical data is an important supplement to understand and predict the disease progression and impact of interventions at the individual level.

Background: Hydroxyurea (HU) treatment of patients with essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) (MPNs) normalizes elevated blood cell counts within weeks in the large majority of patients.Studies on the impact of HU upon the kinetics of the JAK2V617F allele burden, leukocyte, and platelet counts over time are scarce.Purpose: Using data-driven analysis as a novel tool to model the kinetics of the JAK2V617F allele burden and blood cell counts over time during treatment with HU. Material and methods:Using serial measurements of JAK2V617F and correlation analysis of routine hematological values (the Hb-concentration, leukocyte count, platelet count, and lactic dehydrogenase), we present a detailed description and analysis of the kinetics of the JAK2V617F, leukocyte, and platelet counts and lactic dehydrogenase in 27 patients (PV = 18; ET = 7; PMF = 2), who were followed in the Danish randomized trial (DALIAH). To further analyze the JAK2V617F kinetics, we use a machine learning clustering algorithm to group the response patterns.Results: Response patterns were highly heterogeneous, with clustering resulting in 3 groups and 3 outliers. In the large majority of patients, HU treatment was initially associated with a modest decline in the JAK2V617F allele burden in concert with a decline in leukocyte and platelet counts. However, HU did not induce a sustained and continuous decrease in the JAK2V617F allele burden. Conclusion:Using data-driven analysis of the JAK2V617F allele burden, leukocyte, and platelet kinetics during treatment with HU, we have shown that HU does not induce a sustained decrease in the JAK2V617F allele burden and neither induces sustained normalization of elevated cell counts in MPN patients. Our results may explain why MPN patients during treatment with HU still have a substantially increased risk of thrombosis.

Background:Interferon‐alpha2 (IFN) has been used in the treatment of the Philadelphia‐negative myeloproliferative neoplasms (MPNs) for about 30 years and several studies have convincingly demonstrated that this agent is safe and highly efficacious in normalizing elevated cell counts. Indeed, prolonged treatment (about 5 years) may be followed by normalization of the bone marrow and low‐burden JAK2V617F in a subset of patients, even being sustained for 2–3 years after discontinuation of IFN. Early treatment to reduce or eradicate the malignant clone is of paramount importance for achievement of minimal residual disease (MRD) or potentially cure in all cancers. However, in MPNs a “watch and wait” strategy is used in “low‐risk” patients allowing the malignant clone to expand with the inherent risk of increasing genomic instability, sub‐clone formation, resistance to treatment and disease progression. However, the “watch and wait” strategy has been challenged by reports demonstrating the potential of IFN to induce MRD in an increasing number of patients. Furthermore, these studies also indicate that early treatment with IFN increases the chance of sustained hematological and molecular remissions. However, the evidence for this statement is lacking.Aims:By data‐driven mathematical analysis of the JAK2V617F allele burden during IFN treatment of MPNs to deliver the proof of concept that supports early intervention with IFN to obtain the best possible treatment response.Methods:We present a thorough data driven mathematical analysis of unique serial measurements of the JAK2V617F allele burden in 66 patients most being treated with IFN in the DALIAH trial and in 7 untreated patients.Results:Without IFN treatment, the JAK2V617F allele burden increased exponentially with a period of doubling of 1.4 year. During treatment with IFN, the JAK2V617F allele burden decreased mono‐ or bi‐exponentially for 33 responders. Bi‐exponential description improved the fits in 19 cases being associated with late JAK2V617F responses. The decay of the JAK2V617F allele burden during IFN treatment was estimated to have half‐lives of 1.6 year for the mono‐exponential response and in the long term 1.0 year for the bi‐exponential response.Summary/Conclusion:In recent years, the interest of using IFN in the treatment of MPNs has been based upon studies reporting long‐term treatment with IFN to be associated with MRD in a subset of patients as defined by sustained complete hematological remissions in concert with induction of low‐burden JAK2V617F and normalization of the bone marrow. The present study delivers novel information regarding the JAK2V617F kinetics during IFN‐treatment. In untreated patients, the JAK2V617F allele burden increased exponentially with doubling time of 1.4 years. During IFN treatment, the JAK2V617F development followed either a mono‐exponential or a bi‐exponential decay for a significant proportion of patients. Analysis of the population‐level responses suggests that treatment‐schemes should extend longer than one year, as the efficacy of IFN treatment on the JAK2V617F allele burden cannot be determined after just one year.In conclusion, using data‐driven analysis of the JAK2V617F kinetics, we provide evidence for tumor burden reduction through early intervention with IFN, thereby challenging the “watch and wait” strategy commonly applied on low‐risk MPN patients.

Background Conventional cytoreductive therapy for patients with chronic Philadelphia‐negative myeloproliferative neoplasms (MPNs) includes hydroxyurea (HU), interferon‐alpha2 (IFN), and anagrelide. HU is worldwide the most used cytoreductive agent, which lowers elevated blood cell counts within days in the large majority of patients. However, some patients may experience rebound cytosis when HU is reduced due to cytopenia, thereby potentially giving rise to fluctuating cell counts during therapy. Such rapid oscillations may be harmful and potentially elicit thrombosis. Treatment with IFN gradually lowers elevated cell counts within weeks and when the dosage is reduced, the cell counts do not rapidly increase but are sustained within the normal range in the large majority of patients. Conventional hematological response criteria are among others based upon single absolute cell count values and do not take into account the relative decreases toward normal for each cell count. Materials, Methods & Results Using serial data from the Danish DALIAH trial, we herein describe a novel integrated biomarker index for the assessment of hematological and molecular (JAK2V617F) responses in patients with MPNs during treatment with IFN or HU. Discussion This novel tool convincingly displays the superiority of IFN versus HU in normalizing elevated cell counts. Our results need to be validated in larger studies but already now call for studies of the safety and efficacy of combination therapy during the initial treatment of patients with MPNs.