The higher initial dose and accelerated titration regimen of ropeginterferon as a treatment option for certain patients with polycythaemia vera

We agree with the insights and comments in the Letter to the Editor by Drs. Barbui, Tefferi and Vannucchi in response to our report of the 2‐year results with ropeginterferon alpha‐2b (ropeg) for the treatment of polycythaemia vera (PV) by using a higher initial dose and accelerated titration (HIDAT) regimen. ¹ , ² We believe that the HIDAT regimen of ropeg represents an appropriate treatment option for certain patients with PV based on clinical and haematological parameters, and Janus kinase 2 (JAK2) mutant allele burden. ³ Using the standard approved dosing regimen of ropeg in the management of PV, the PROUD‐PV/CONTINUATION‐PV study has demonstrated the durable complete haematological response (CHR), reduction of JAK2V617F allele burden and long‐term clinical benefits including event‐free survival attainable with ropeg. ⁴ , ⁵

While ethnic sensitivity analyses have shown that ropeg is effective across diverse patient populations, ⁶ the management of PV should be individualized according to disease and patient characteristics as well as desired treatment outcomes. PV is a neoplasm with heterogeneous clinical manifestations and disease course. ⁷ Patients present with a wide range of clinical signs and symptoms including different degrees of splenomegaly. ⁸ The clinical course for neoplastic transformation to myelofibrosis (MF) or acute myeloid leukaemia (AML), and haematological disease progression as defined by Barbui et al., ⁹ also differs among patients. Evidence‐based alternative dosing options allow physicians to make informed decisions in the flexibility to individualize ropeg dose and schedule. While PV is almost universally associated with a JAK2 mutation, a JAK2 mutation alone does not appear to be sufficient to confer the PV phenotype. Rather, the occurrence and progression of PV results from clonal expansion of cells harbouring a driver JAK2 mutation, coexisting or passenger mutations and perhaps epigenetic changes. Therefore, a logical treatment approach is one that suppresses neoplastic cell‐intrinsic growth regulatory signals, and not just the JAK2 kinase alone. ¹⁰ Ropeg is an interferon (IFN)‐based therapy which could activate a network of tumour suppressor and cell cycle regulatory proteins. ¹⁰ , ¹¹ , ¹² Given its anti‐clonal activities directly on neoplastic cells and immunomodulatory effect on the immune system, ropeg has the potential to eradicate the neoplastic clones associated with PV.

JAK2V617F allele burden or variant allele frequency (VAF) in peripheral blood is a reliable marker of disease burden, and treatment effect associated with in vivo exposure to ropeg. ¹⁰ , ¹³ Available data suggest that elevated JAK2V617F VAF is associated with increased thrombotic risk and disease progression, while JAK2V617F VAF reduction is associated with improved event‐free survival and overall survival. ¹⁴ The HIDAT regimen of ropeg achieved a maximal reduction of JAK2V617F VAF, with a complete molecular response (CMR, defined as a reduction in JAK2V617F VAF to undetectable levels) achieved by 25% (11/44) of patients at 24 months. ² A CMR rate of 19.6% (18/92) was observed at 60 months in PROUD‐PV/CONTINUATION‐PV. ⁵ With the HIDAT regimen of ropeg, the reduction in JAK2V617F VAF continued while the CHR rate plateaued consistent with continued eradication of the neoplastic clones. ²

While the benefit of slow dose titrations of ropeg based on haematological responses and tolerability has been established as the standard, it is useful to evaluate additional dosing options for certain patient groups with PV. We fully agree with Dr. Barbui et al. that ropeg dose and treatment need to be individualized, balancing efficacy, safety, tolerability and affordability. ¹ We think that the HIDAT regimen could serve as an option for patients who carry a high JAK2V617F VAF, high thrombotic risk with a prior history of notable thromboembolism and a high probability of disease transformation to MF or AML based on clinical, haematological and molecular assessment. This group of patients might benefit from a more rapid response to ropeg. As noted previously, PV is also heterogenous with respect to JAK2V617F VAF and even patients with low‐risk PV can harbour a very high JAK2V617F VAF. ¹⁵ Therefore, the rapid response strategy may also be beneficial for these patients. One possible solution for maintaining maximal efficacy while balancing the safety and tolerability is to reduce the dosing interval from biweekly to monthly after the maximal response is achieved and stabilized as shown in our report by Suo et al. ² We found that adverse events were notably decreased during the second year of the ropeg treatment, in which the dosing schedule was changed from biweekly to monthly. ² In conclusion, we fully agree with Dr. Barbui et al. that the management of PV needs to be individualized. Given the heterogenous nature of PV and varying needs of patients, we believe that having an alternative option for patients who might benefit from a HIDAT regimen of ropeg is consistent with this notion.

AUTHOR CONTRIBUTIONS

All authors contributed to the work and approved the manuscript for publication.

FUNDING INFORMATION

This paper was supported by PharmaEssentia Corporation.

CONFLICT OF INTEREST STATEMENT

L Zhang and J Jin declare no conflict of interest. A Qin serves as the chief medical officer of the PharmaEssentia Corporation.

ETHICS STATEMENT

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DATA AVAILABILITY STATEMENT

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