Data‐driven analysis of JAK2V617F kinetics during interferon‐alpha2 treatment of patients with polycythemia vera and related neoplasms

Abstract

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.

Mathematical Modeling of MPNs Offers Understanding and Decision Support for Personalized Treatment

“…The model predicts the time of relapse to increase with an increasing treatment period. In health economy, such a prediction may also be of interest, since cost and gains could be anticipated [12]. Furthermore, the mechanism-based model can be used for estimating the patient-specific and dose-independent threshold value for dosing, separating a good responder from a poor responder-see Figure 7.…”

“…The Cancitis model described in Section 4.2.1 is first calibrated such that the growth of the JAK2V617F allele burden of the model agreed with the growth found in [12] for the initial exponential disease development from 0 to 50%. Patients having less than four longitudinal observations are excluded, reducing the number of patients available for analysis from 113 to 63.…”

“…Data were obtained from the DALIAH trial (#EudraCT 2011-001919-31), as described in [12] and encompassing 113 patients being treated with IFN. DALIAH is an ongoing Danish multicenter prospective randomized open label phase III clinical trial comparing IFN (Pegasys and PegIntron) with hydroxyurea.…”

“…In Denmark and a few other places, off-label pegylated interferon-α2, mostly interferon-α-2b (PegIntron) and interferon-α-2a (Pegasys), have been used for the treatment of patients with MPNs with success for years, as demonstrated in the Danish DALIAH trial (see Material and Method). A statistical data-driven analysis of this study has most recently been reported [12].…”

Anti-Glucosylsphingosine Autoimmunity, JAK2V617F-Dependent Interleukin-1β and JAK2V617F-Independent Cytokines in Myeloproliferative Neoplasms

“…Unfortunately, suppression of the MPN clone and significant reduction in the mutation load are typically not obtained with JAK inhibitors [ 17 , 18 , 19 ]. In contrast, IFN-α therapy frequently leads to clinical and molecular remission, in PV and also in JAK2 - and CALR -mutated ET [ 20 , 21 , 22 , 23 ]. One explanation is that the actions exerted by JAK inhibitors and IFN-α on inflammation are quite different.…”