Primary myelofibrosis (PMF) is a clonal stem cell disorder currently classified as myeloproliferative neoplasm (MPN). Median survival in PMF is estimated with 6 years, but can range from few months to several decades in early pre-fibrotic PMF. The disease course is almost always complicated by progressive anemia, symptomatic splenomegaly and severe constitutional symptoms. Causes of death include leukemic transformation with marrow failure and complications from bleeding, thrombosis, portal hypertension or infections. While PMF patients in advanced stages benefit from a JAK2 inhibitor therapy, there is no evidence for prevention of disease progression to overt MF by an early therapeutic intervention. Interferon alpha has been shown to reduce white cell counts, elevated platelet counts and improve splenomegaly and there are some observations of its disease modifying capability in the earlier phase of PMF.

The aim of the present phase II study was to test the capability of a novel pegylated interferon compound (Ropeginterferon-alfa-2b) to improve hematologic parameters, splenomegaly and to monitor the course of the disease concerning clinical symptoms in a homogeneous cohort of early pre-fibrotic PMF patients. The endpoints of the study were hematological response, maintenance or improvement of quality of life and the symptom scales during a period of 2 years interferon treatment, and interferon tolerability.

Twenty-five patients were included in the study. Nine patients were pretreated with pegylated interferon alfa 2b (PegIntron or Pegasys) during at least 3 years and 16 patients were interferon naïve. At start of therapy the median red blood cell count was 4.3 T/l (3.3 - 5.2); median hemoglobin level was 12.5 g/dl (9.6 - 14.7 g/dl), median WBC count was 7.7 G/l (2.44 - 27.55 G/l) and the median platelet count was 435 G/l (124 - 1161 G/l). Median LDH-level was 263.5 U/l (163 - 538 U/l) and the median spleen size was 11.2 cm (8 - 22 cm). 13 patients were JAK2 positive, and 12 patients were CALR positive. Detailed patient characteristics in 6-month intervals for pretreated and interferon naïve patients are given in Table 1.

At study entry, 12 patients presented with anemia, 12 with thrombocytosis, 9 with leukocytosis, 14 with elevated LDH levels and 7 with splenomegaly. After 24 months of treatment, 6 patients improved their anemia (N=2 pretreated, 4 treatment-naïve), 6 their thrombocytosis (N=6 treatment-naïve), 7 their leukocytosis (N=7 treatment-naïve), 6 normalized LDH levels (N=1 pretreated, 5 treatment-naïve) but none showed response in the form of significant spleen size reduction. The fact that no patient showed disease progression in any single parameter after 2 years of treatment can already be considered a success.

The most common side effects observed during this study include flu-like symptoms (N=7 pretreated, 15 treatment-naïve), lack of concentration (N=3 pretreated, 8 treatment-naïve), pruritus (N=2 pretreated, 7 treatment-naïve), infections (N=2 pretreated, 5 treatment-naïve) and bleeding (N=2 pretreated, 4 treatment-naïve). Generally, pretreated patients suffered from fewer side effects than treatment-naïve patients in every category. This may be due to the fact that those patients had already been exposed to an interferon in previous treatment regimen. Two patients had to be withdrawn from the study after approximately 12 months due to psychological side effects, both from the treatment-naïve group.

Additionally to conventional symptom screening, the EORTC-QLQ-C30 questionnaire was used to assess therapy-response. With this tool, function scales, symptom scales and quality-of-life were recorded. After 24 months of treatment, almost every category showed improvement for both pretreated and treatment-naïve patients. Detailed results about symptom scales are shown in Figure 1.

In conclusion, the data demonstrate that Ropeginterferon-alfa-2b is able not only to induce hematologic responses but also to improve constitutional symptoms and overall quality of life in prefibrotic PMF. Thus ropeginterferon-alfa-2b warrant further investigation as a treatment option in prefibrotic PMF, where only very limited alternatives exist.


Gisslinger:Shire: Consultancy, Honoraria; Janssen Cilag: Consultancy, Honoraria; Novartis: Honoraria, Research Funding; AOP Orphan Pharmaceuticals AG: Consultancy, Honoraria, Research Funding. Krejcy:AOP Orphan Pharmaceuticals: Employment. Widmann:AOP Orphan Pharmaceuticals: Employment. Kralovics:MyeloPro Diagnostics and Research GmbH: Equity Ownership. Krauth:Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Author notes


Asterisk with author names denotes non-ASH members.