Haematologist Professor Andrew Grigg recently attended the European Haematology Association (EHA) conference in Stockholm and has kindly allowed the MPN AA to share his summary of MPN studies presented at the conference. Many thanks Professor Grigg!
Hydroxyurea (HU) is considered first line cytoreductive therapy in most parts of the world for patients
To investigate efficacy and toxicity of low-dose r-IFN? compared to HU in patients with MPN in a randomized controlled clinical phase III trial.
Patients with newly diagnosed or previously untreated (cytoreductive agents) MPN according to WHO criteria were enrolled in the DALIAH trial (NCT01387763). Patients > 60 years were randomized (I:I:I) to either r-IFN?-2a or r-IFN?-2b at a starting dose of 45 or 35 µg/week, respectively, or to HU at doses of 500 to 2000 mg/day. Patients ? 60 were randomized (I:I) to either r-IFN?-2a or r-IFN?-2b. The protocol allowed addition of HU in patients randomized to r-IFN? with major thrombosis or platelets > 1500 109/L. A planned interim analysis was performed after 18 months of therapy. The molecular and hematological response rates were assessed by the European Leukemia Net (ELN) 2009 and the EUMNET 2005 criteria. JAK2 V617F was analysed by qPCR.
205 patients were enrolled between 2012 and 2015 (Table 1). The interim analysis was performed after a median of 17.7 months (range 17.1 – 18.2). Overall response rates (ORR) were 75% (24/32) for HU and 49% (73/149) for r-IFN? among patients with ET, PV and prefibrotic myelofibrosis (pre-MF). Toxicity dependent drop-out was 5% for HU and 27% for r-IFN?. Grade 3-4 adverse events occurred in 7 (18%) HU patients and in 58 (35%) r-IFN? patients.
This planned analysis of efficacy and toxicity at 18 months shows a significant difference in the CHR rate (p=0.04) for patients treated with HU compared to low-dose r-IFN?. However, ORR was almost similar for patients still on study medication. Toxicity dependent discontinuation from r-IFN? was higher than expected (27%) even in this low-dose setting.
Comment: in patients who continued pegIFN: CHR rate comparable
Ropeginterferon alfa-2b (Ropeg) is a novel mono-pegylated IFN?, allowing convenient self-administration every 2 to 4 weeks. It is currently being developed for treatment of MPNs in particular PV. Hydroxyurea (HU) is the only licensed first-line therapy in high-risk patients with PV of all ages. Off-label IFN? as first-line therapy is primarily used in patients of younger age, partly because of the misconception that the risk-benefit ratio is not so favorable in elderly patients.
To analyse the difference in efficacy and safety of Ropeg and HU in two age cohorts (<60 years and ?60 years).
254 PV patients (WHO2008 criteria) had been randomized to receive Ropeg or HU in the PROUD Study. After 12 months of treatment, 89.6% of Ropeg treated patients and 68.5% of HU treated patients continued treatment in the CONTINUATION Study. Efficacy assessment consisted of complete hematological response (CHR) rate according ELN criteria, and the rate of CHR including symptom improvement (disease-related signs including clinically significant splenomegaly and PV-related symptoms). Secondary endpoints included JAK2V617F allelic burden assessed as rate of molecular response (modified ELN criteria). Efficacy and safety analysis was done for patients <60 years (Ropeg: n=49; HU: n=39) and ?60 years (Ropeg: n=46; HU: n=37).
After 24 months of treatment, Ropeg induced higher CHR rates compared to HU, irrespective of age: 77.6% vs. 55.9% (<60 years); 63.0% vs. 42.4% (?60 years). Higher response rates were also shown for Ropeg vs. HU for CHR including symptom improvement, similar for both age cohorts: 55.1% vs. 37.1% (<60 years); 43.5% vs. 36.1% (?60 years). CHR rate maintenance (response maintained from first occurrence to 24 months assessment) was also higher for Ropeg and age-independent for both study treatments (Ropeg <60 years: 49.0%, ?60 years: 37.0%; HU <60 years: 17.9%, ?60 years: 18.9%). A similar observation for response maintenance was shown for CHR rate including symptom improvement (Ropeg <60 years: 32.7%, ?60 years: 28.3%; HU <60 years: 15.4%, ?60 years: 18.9%). After 24 months of treatment, partial molecular response rates were higher for Ropeg compared to HU, irrespective of age: 78.1% vs. 33.3% (<60 years) and 59.5% vs 25.0% (?60 years). Regarding safety, Ropeg and HU treated patients showed comparable numbers of both, adverse events (89.8% vs. 92.3% <60 years, 93.5% vs. 91.9% ?60 years) and serious adverse events (6.1% vs. 10.3% <60 years, 21.7% vs. 24.3% ?60 years) irrespective of age. The number of adverse drug reactions (ADRs) was comparable below 60 years (77.6% vs. 74.4%) but interestingly in the cohort ?60 years, a trend towards a lower number of ADRs was evident for Ropeg (63.0%) vs. HU (89.2%). No serious ADRs were reported for Ropeg, but there were 4 serious ADRs (Acute Leukemia, Anemia, Leukopenia, Granulocytopenia) reported for HU (all patients aged ?60 years).
A high CHR, symptom improvement and molecular response (JAK2V617F) achieved by long-term treatment with Ropeg was shown, with an advantage over HU independent of age. The safety analysis in patients ?60 years also showed a positive trend regarding less ADRs and less serious ADRs for Ropeg vs. HU. These data indicate that Ropeg provides a valuable, efficacious and safe new treatment option for PV patients of all ages including elderly.