Pegylated Interferon-Alfa-2a In Clinical Responders Often Decreases JAK2 V617F Allelic Burden and/or Reverses Clonal Hematopoiesis, but These Are Not Always Parallel In PV and ET Females

Polycythemia vera (PV) and essential thrombocythemia (ET) are hematological malignancies due to clonal proliferation arising from a multilineage stem cell. Pegylated interferon-alfa-2a is a better-tolerated form of interferon shown to be effective in inducing clinical remission and reducing the JAK2V617F allelic burden in PV and ET patients. However, while the somatic JAK2V617F mutation, which is seen in the majority of PV patients, is not the PV-initiating mutation, it appears to have prognostic significance. Conventional preparations of interferon alfa have been shown in isolated instances to convert clonal to polyclonal hematopoiesis in PV patients. Our study involved 6 PV patients and 3 ET patients who achieved complete clinical remission after peg-IFN-α-2a therapy. We evaluated both the allelic burden of JAK2V617F mutation, as well as clonality of hematopoiesis by our previously developed quantitative X-chromosome-based transcriptional clonality assay.

All of the PV and ET patients had variable allelic burdens of JAK2V617F before starting the peg-IFN-α-2a therapy. The baseline allelic burden ranged from 11.8% to 93.6%, with a mean percentage of 50.9%. Peg-IFN-α-2a was administered for at least 18 months. Following peg-IFN-α-2a treatment, the allelic burden of JAK2V617F mutation decreased in all patients, with a mean of 11.37% and a range of 2.4% -31.8% (see Table); however, clonal hematopoiesis persisted in some responding patients (see Table, these results in italics). In one ET patient (not in Table), prolonged peg-IFN-α-2a therapy induced clinical remission and resumption of polyclonal hematopoiesis, with a JAK2V617F allelic burden of <1%; however, after discontinuation of peg-IFN-α-2a, the patient relapsed and her hematopoiesis reverted to clonality, yet her JAK2V617F remained at <1%.

In summary, pegylated interferon-alfa-2a induces clinical remission in a large proportion of PV and ET patients. However, at the cellular level, improvement in JAK2V617F allelic burden and resumption of normal hematopoiesis are not always parallel.

Verstovsek:Incyte Corporation: Research Funding.