Contributions
Abstract: EP1085
Type: e-Poster
Background
Ropeginterferon alpha-2b is a causative treatment in polycythaemia vera (PV): its targeted action on JAK2V617F mutated hematopoietic stem cells (HSC) diminishes the tumour burden. However, up to 50% of patients with PV acquire additional non-driver mutations that promote disease progression, and which could affect responses to interferon.
Aims
We aimed to investigate the influence of non-driver mutations on the efficacy of ropeginterferon alpha-2b.
Methods
Patients with PV diagnosed by WHO 2008 criteria who were cytoreduction-naïve or HU pre-treated without resistance were randomised 1:1 to receive ropeginterferon alpha-2b or hydroxyurea (HU) in PROUD-PV. After one year, patients rolled over into CONTINUATION-PV. Treatment arms remained as allocated in PROUD-PV, but patients in the HU arm could switch to best-available therapy (BAT). Efficacy assessments included complete haematological response (CHR) and molecular response using modified ELN criteria, and JAK2V617F allele burden. Next generation sequencing (NGS; TruSight™ Myeloid Panel, Illumina) was performed to detect non-driver mutations. All patients enrolled in CONTINUATION-PV were included in an interim efficacy analysis over 36 months by non-driver baseline mutational status.
Results
A total of 257 patients were treated in PROUD-PV and 171 rolled over into CONTINUATION-PV. NGS data at baseline (in PROUD-PV) were available for 163/171 patients. TET2 was the most frequently identified non-driver mutation at baseline (in 14.1% of patients); other non-driver mutations observed were DNMT3A (3.7%) and ASXL1 (1.2%). Comparing to patients with wild-type TET2, baseline characteristics of TET2+ patients showed a significantly higher mean age (65.3 years versus 56.1 years; p=0.0003) and proportion of women (78.3% versus 47.1%; p=0.007). Mean JAK2V617F allele burden at baseline was higher in TET2+ patients (51.2%, versus 42.3% in TET2- patients). Dosing was comparable between the TET2+ and TET2- subgroups throughout treatment.
High haematological responses were achieved during long-term ropeginterferon alpha-2b therapy in both TET2+ and TET2- patients. At 24 and 36 months, CHR was achieved by 60.0% and 70.0% of TET2+ patients, respectively (n=10) and 72.0% and 70.7% of TET2- patients, respectively (n=82).
JAK2V617F molecular response rates to ropeginterferon alpha-2b showed no significant difference (p>0.05) between TET2+ and TET2- patients (50.0% at 24 and 36 months for TET2+; 70.7% and 68.3%, respectively for TET2-). Furthermore, there was no significant difference between the subgroups regarding the absolute JAK2V617F allele burden or the relative change in allele burden.
Among TET2+ patients receiving ropeginterferon alpha-2b, the mean TET2 variant allele burden decreased steadily from 32.4% at baseline to 24.2%, 20.0% and 17.3% at months 12, 24 and 36, respectively, although only 3 TET2+ patients had available NGS data at month 36. The reduction in TET2 variant allele burden was statistically significant at month 24 (p=0.047).
Conclusion
Ropeginterferon alpha-2b induces high haematological and molecular responses in patients with PV regardless of TET2 mutational status. Ropeginterferon significantly reduces the mutational burden of both JAK and TET2, thus reducing the mutated HSC pool, underscoring the disease-modifying capability of this stem-cell targeting agent.
Session topic: 16. Myeloproliferative neoplasms - Clinical
Keyword(s): Clinical trial, Interferon alpha, Mutation status, Polycythemia vera
Abstract: EP1085
Type: e-Poster
Background
Ropeginterferon alpha-2b is a causative treatment in polycythaemia vera (PV): its targeted action on JAK2V617F mutated hematopoietic stem cells (HSC) diminishes the tumour burden. However, up to 50% of patients with PV acquire additional non-driver mutations that promote disease progression, and which could affect responses to interferon.
Aims
We aimed to investigate the influence of non-driver mutations on the efficacy of ropeginterferon alpha-2b.
Methods
Patients with PV diagnosed by WHO 2008 criteria who were cytoreduction-naïve or HU pre-treated without resistance were randomised 1:1 to receive ropeginterferon alpha-2b or hydroxyurea (HU) in PROUD-PV. After one year, patients rolled over into CONTINUATION-PV. Treatment arms remained as allocated in PROUD-PV, but patients in the HU arm could switch to best-available therapy (BAT). Efficacy assessments included complete haematological response (CHR) and molecular response using modified ELN criteria, and JAK2V617F allele burden. Next generation sequencing (NGS; TruSight™ Myeloid Panel, Illumina) was performed to detect non-driver mutations. All patients enrolled in CONTINUATION-PV were included in an interim efficacy analysis over 36 months by non-driver baseline mutational status.
Results
A total of 257 patients were treated in PROUD-PV and 171 rolled over into CONTINUATION-PV. NGS data at baseline (in PROUD-PV) were available for 163/171 patients. TET2 was the most frequently identified non-driver mutation at baseline (in 14.1% of patients); other non-driver mutations observed were DNMT3A (3.7%) and ASXL1 (1.2%). Comparing to patients with wild-type TET2, baseline characteristics of TET2+ patients showed a significantly higher mean age (65.3 years versus 56.1 years; p=0.0003) and proportion of women (78.3% versus 47.1%; p=0.007). Mean JAK2V617F allele burden at baseline was higher in TET2+ patients (51.2%, versus 42.3% in TET2- patients). Dosing was comparable between the TET2+ and TET2- subgroups throughout treatment.
High haematological responses were achieved during long-term ropeginterferon alpha-2b therapy in both TET2+ and TET2- patients. At 24 and 36 months, CHR was achieved by 60.0% and 70.0% of TET2+ patients, respectively (n=10) and 72.0% and 70.7% of TET2- patients, respectively (n=82).
JAK2V617F molecular response rates to ropeginterferon alpha-2b showed no significant difference (p>0.05) between TET2+ and TET2- patients (50.0% at 24 and 36 months for TET2+; 70.7% and 68.3%, respectively for TET2-). Furthermore, there was no significant difference between the subgroups regarding the absolute JAK2V617F allele burden or the relative change in allele burden.
Among TET2+ patients receiving ropeginterferon alpha-2b, the mean TET2 variant allele burden decreased steadily from 32.4% at baseline to 24.2%, 20.0% and 17.3% at months 12, 24 and 36, respectively, although only 3 TET2+ patients had available NGS data at month 36. The reduction in TET2 variant allele burden was statistically significant at month 24 (p=0.047).
Conclusion
Ropeginterferon alpha-2b induces high haematological and molecular responses in patients with PV regardless of TET2 mutational status. Ropeginterferon significantly reduces the mutational burden of both JAK and TET2, thus reducing the mutated HSC pool, underscoring the disease-modifying capability of this stem-cell targeting agent.
Session topic: 16. Myeloproliferative neoplasms - Clinical
Keyword(s): Clinical trial, Interferon alpha, Mutation status, Polycythemia vera