ROPEGINTERFERON ALPHA-2B IS EFFICACIOUS AND REDUCES VARIANT TET2 ALLELE BURDEN IN PATIENTS WITH POLYCYTHAEMIA VERA AND TET2 MUTATION: GENETIC ANALYSIS OF PHASE III PROUD-PV/CONTINUATION-PV STUDIES
Author(s): ,
Robert Kralovics
Affiliations:
Department of Laboratory Medicine,Medical University of Vienna,Vienna,Austria
,
Christoph Klade
Affiliations:
AOP Orphan Pharmaceuticals,Vienna,Austria
,
Pencho Georgiev
Affiliations:
Clinic of Haematology,University Multiprofile Hospital,Plovdiv,Bulgaria
,
Dorota Krochmalczyk
Affiliations:
Teaching Unit of the Haematology Department,University Hospital Krakow,Krakow,Poland
,
Liana Gercheva-Kyuchukova
Affiliations:
Clinical Haematology Clinic,Multiprofile Hospital for Active Treatment,Varna,Bulgaria
,
Miklos Egyed
Affiliations:
Department of Internal Medicine II,Kaposi More Country Teaching Hospital,Kaposvar,Hungary
,
Viktor Rossiev
Affiliations:
Department of Internal Medicine,Samara Kalinin Regional Clinical Hospital,Samara,Russian Federation
,
Petr Dulicek
Affiliations:
Department of Clinical Haematology,University Hospital Kralove,Hradec Kralove,Czech Republic
,
Arpad Illes
Affiliations:
Department of Haematology,Faculty of Medicine, University of Debrecen,Debrecen,Hungary
,
Halyana Pylypenko
Affiliations:
Regional Treatment and Diagnostics Haematology Centre,Cherkasy Regional Oncology Centre,Cherkasy,Ukraine
,
Lylia Sivcheva
Affiliations:
First Department for Internal Medicine,Multiprofile Hospital for Active Treatment,Vratsa,Bulgaria
,
Jiri Mayer
Affiliations:
Clinic of Internal Medicine - Haematology and Oncology,University Hospital Brno,Brno,Czech Republic
,
Vera Yablokova
Affiliations:
Department of Haematology,Yaroslavl Regional Clinical Hospital,Yaroslavl,Russian Federation
,
Kurt Krejcy
Affiliations:
AOP Orphan Pharmaceuticals,Vienna,Austria
,
Hans Hasselbalch
Affiliations:
Department of Haematology,Zealand University Hospital,Roskilde,Denmark
,
Jean-Jacques Kiladjian
Affiliations:
Clinical Investigation Centre,St. Louis Hospital and Paris Diderot University,Paris,France
Heinz Gisslinger
Affiliations:
Department of Internal Medicine I, Division of Haematology and Blood Coagulation,Medical University Vienna,Vienna,Austria
EHA Library. Kralovics R. 06/12/20; 293574; EP1085
Robert Kralovics
Robert Kralovics
Contributions
Abstract

Abstract: EP1085

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

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

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

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

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