TOWARDS A POTENTIAL OPERATIONAL CURE IN PATIENTS WITH POLYCYTHAEMIA VERA? RESULTS FROM FIVE YEARS’ ROPEGINTERFERON ALPHA-2B THERAPY IN A RANDOMIZED SETTING
Author(s): ,
Jean-Jacques Kiladjian
Affiliations:
CIC 1427, Inserm,Université de Paris,Paris,France;Centre d’Investigations Cliniques, AP-HP,Hôpital Saint-Louis,Paris,France
,
Christoph Klade
Affiliations:
AOP Orphan Pharmaceuticals AG,Vienna,Austria
,
Pencho Georgiev
Affiliations:
Medical University of Plovdiv,Plovdiv,Bulgaria
,
Dorota Krochmalczyk
Affiliations:
Teaching Unit of the Hematology Department, University Hospital in Krakow,Krakow,Poland
,
Liana Gercheva-Kyuchukova
Affiliations:
Clinical Hematology Clinic,Multiprofile Hospital for Active Treatment 'Sveta Marina',Varna,Bulgaria
,
Miklos Egyed
Affiliations:
Department of Internal Medicine II,Kaposi Mor County Teaching Hospital,Kaposvar,Hungary
,
Petr Dulicek
Affiliations:
Department of Clinical Hematology,University Hospital Hradec Kralove,Hradec Kralove,Czech Republic
,
Arpad Illes
Affiliations:
Department of Hematology, Faculty of Medicine,University of Debrecen,Debrecen,Hungary
,
Halyna Pylypenko
Affiliations:
Department of Hematology, Regional Treatment and Diagnostics Haematology Centre,Cherkasy Regional Oncology Centre,Cherkasy,Ukraine
,
Lylia Sivcheva
Affiliations:
First Department of Internal Medicine,Multiprofile Hospital for Active Treatment - HristoBotev,Vratsa,Bulgaria
,
Jiří Mayer
Affiliations:
Clinic of Internal Medicine - Hematology and Oncology,University Hospital Brno,Brno,Czech Republic
,
Vera Yablokova
Affiliations:
Department of Hematology,Yaroslavl Regional Clinical Hospital,Yaroslavl,Russian Federation
,
Kurt Krejcy
Affiliations:
AOP Orphan Pharmaceuticals AG,Vienna,Austria
,
Victoria Empson
Affiliations:
AOP Orphan Pharmaceuticals AG,Vienna,Austria
,
Hans C. Hasselbalch
Affiliations:
Department of Hematology,Zealand University Hospital, University of Copenhagen,Roskilde,Denmark
,
Robert Kralovics
Affiliations:
Department of Laboratory Medicine,Medical University of Vienna,Vienna,Austria;CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences,Vienna,Austria
Heinz Gisslinger
Affiliations:
Department of Internal Medicine I, Division of Hematology and Blood Coagulation,Medical University of Vienna,Vienna,Austria
EHA Library. Kiladjian J. 06/09/21; 324799; EP1076
Prof. Jean-Jacques Kiladjian
Prof. Jean-Jacques Kiladjian
Contributions
Abstract
Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP1076

Type: E-Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background
Following long-term interferon-α therapy for polycythaemia vera (PV), hematologic responses persist despite treatment discontinuation in some patients, demonstrating that operational cure can be achieved. Relapse-free discontinuation is more likely in patients who achieved a JAK2V617F mutation <10% prior to stopping treatment (Daltro De Oliveira R et al., Blood 2020) but prognostic factors for deep molecular responses to interferon-α are unknown.

Aims
To explore predictive baseline factors in patients who achieved a JAK2V617F allele burden <10% after 5 years’ ropeginterferon alfa-2b (BESREMi®) therapy and to distinguish this population from patients with allele burden ≥10% regarding clinical outcome parameters.

Methods
Patients with PV diagnosed by WHO 2008 criteria who were cytoreduction-naïve or hydroxyurea (HU) pre-treated were randomised 1:1 to receive ropeginterferon alpha-2b or HU for one year in PROUD-PV. In CONTINUATION-PV, patients received long-term treatment in the study arms originally allocated. Efficacy assessments included complete haematological response (CHR) and JAK2V617F allele burden. Patients with a baseline JAK2V617F allele burden ≥10% who were treated with ropeginterferon alpha-2b for ≥5 years were analysed using univariate and multivariate logistic regression models to determine predictive baseline factors (including demographics, non-driver mutations, spleen size and PV-related symptoms) and Fisher’s or Wilcoxon test to determine other associated factors (including 4-weekly dose level, CHR, duration of maintained CHR, splenomegaly and symptoms) for achieving a JAK2V617F allele burden <10% at 5 years.

Results
In CONTINUATION-PV, 66/95 patients enrolled in the ropeginterferon alfa-2b arm had a baseline JAK2V617F allele burden ≥10% and had been treated for ≥5 years at the time of analysis, of whom 37 achieved allele burden <10% at Month 60 (last observation carried forward).

Lower age and lower JAK2V617F allele burden were identified as predictive baseline factors for achieving a JAK2V617F allele burden <10% at 5 years (median age 54.0 years for patients with allele burden <10% vs. 63.0 years in those with allele burden ≥10%; univariate and multivariate analyses p=0.005 and p=0.002; median allele burden 36.8% vs. 46.3%, p=0.03 and p=0.02 respectively). Absence of non-driver mutations was predictive only in the univariate analysis (p=0.02). Time since PV diagnosis, PV-related symptoms and spleen size were not predictive.


Allele burden <10% was associated with a higher CHR rate at Month 60 (CHR in 86.5% of patients with allele burden <10% vs. 58.6% with allele burden >10%; p=0.02) and longer maintained CHR (median: 41.8 vs. 30.3 months respectively; p=0.03).  All 37 patients with allele burden <10% had platelets <400 x 109/L and leukocytes <10 x 109/L at Month 60, but a few patients still required phlebotomy in the 5th year (n=6) or had mild splenomegaly (n=2; spleen size 14.9 cm and 13.4 cm) or pruritus (n=1). Dosing level had no impact on allele burden (p=0.9).


Operational cure defined as allele burden <10%, maintained CHR for the last ≥2 years, and no disease progression, thromboembolic events, or worsening of symptoms in the entire 5-year period was achieved in 27 patients.

Conclusion
A sizable proportion of patients with PV achieved operational cure after 5 years’ ropeginterferon alfa-2b treatment. Lower age and lower allele burden at baseline predicted allele burden <10% at 5 years, suggesting that ropeginterferon alfa-2b should be initiated early in PV to achieve the greatest long-term benefit.

Keyword(s): Clinical trial, Interferon, Molecular, Polycythemia vera

Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP1076

Type: E-Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background
Following long-term interferon-α therapy for polycythaemia vera (PV), hematologic responses persist despite treatment discontinuation in some patients, demonstrating that operational cure can be achieved. Relapse-free discontinuation is more likely in patients who achieved a JAK2V617F mutation <10% prior to stopping treatment (Daltro De Oliveira R et al., Blood 2020) but prognostic factors for deep molecular responses to interferon-α are unknown.

Aims
To explore predictive baseline factors in patients who achieved a JAK2V617F allele burden <10% after 5 years’ ropeginterferon alfa-2b (BESREMi®) therapy and to distinguish this population from patients with allele burden ≥10% regarding clinical outcome parameters.

Methods
Patients with PV diagnosed by WHO 2008 criteria who were cytoreduction-naïve or hydroxyurea (HU) pre-treated were randomised 1:1 to receive ropeginterferon alpha-2b or HU for one year in PROUD-PV. In CONTINUATION-PV, patients received long-term treatment in the study arms originally allocated. Efficacy assessments included complete haematological response (CHR) and JAK2V617F allele burden. Patients with a baseline JAK2V617F allele burden ≥10% who were treated with ropeginterferon alpha-2b for ≥5 years were analysed using univariate and multivariate logistic regression models to determine predictive baseline factors (including demographics, non-driver mutations, spleen size and PV-related symptoms) and Fisher’s or Wilcoxon test to determine other associated factors (including 4-weekly dose level, CHR, duration of maintained CHR, splenomegaly and symptoms) for achieving a JAK2V617F allele burden <10% at 5 years.

Results
In CONTINUATION-PV, 66/95 patients enrolled in the ropeginterferon alfa-2b arm had a baseline JAK2V617F allele burden ≥10% and had been treated for ≥5 years at the time of analysis, of whom 37 achieved allele burden <10% at Month 60 (last observation carried forward).

Lower age and lower JAK2V617F allele burden were identified as predictive baseline factors for achieving a JAK2V617F allele burden <10% at 5 years (median age 54.0 years for patients with allele burden <10% vs. 63.0 years in those with allele burden ≥10%; univariate and multivariate analyses p=0.005 and p=0.002; median allele burden 36.8% vs. 46.3%, p=0.03 and p=0.02 respectively). Absence of non-driver mutations was predictive only in the univariate analysis (p=0.02). Time since PV diagnosis, PV-related symptoms and spleen size were not predictive.


Allele burden <10% was associated with a higher CHR rate at Month 60 (CHR in 86.5% of patients with allele burden <10% vs. 58.6% with allele burden >10%; p=0.02) and longer maintained CHR (median: 41.8 vs. 30.3 months respectively; p=0.03).  All 37 patients with allele burden <10% had platelets <400 x 109/L and leukocytes <10 x 109/L at Month 60, but a few patients still required phlebotomy in the 5th year (n=6) or had mild splenomegaly (n=2; spleen size 14.9 cm and 13.4 cm) or pruritus (n=1). Dosing level had no impact on allele burden (p=0.9).


Operational cure defined as allele burden <10%, maintained CHR for the last ≥2 years, and no disease progression, thromboembolic events, or worsening of symptoms in the entire 5-year period was achieved in 27 patients.

Conclusion
A sizable proportion of patients with PV achieved operational cure after 5 years’ ropeginterferon alfa-2b treatment. Lower age and lower allele burden at baseline predicted allele burden <10% at 5 years, suggesting that ropeginterferon alfa-2b should be initiated early in PV to achieve the greatest long-term benefit.

Keyword(s): Clinical trial, Interferon, Molecular, Polycythemia vera

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