THREE-YEAR ANALYSIS OF THE DALIAH TRIAL - A RANDOMIZED CONTROLLED PHASE III CLINICAL TRIAL COMPARING RECOMBINANT INTERFERON ALPHA-2 VS. HYDROXYUREA IN PATIENTS WITH MYELOPROLIFERATIVE NEOPLASMS
Author(s): ,
Trine Alma Knudsen
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark
,
Dennis Lund Hansen
Affiliations:
Department of Hematology,Odense University Hospital,Odense,Denmark
,
Lucas Frans Ocias
Affiliations:
Department of Hematology,Odense University Hospital,Odense,Denmark
,
Ole Weis Bjerrum
Affiliations:
Department of Hematology,Rigshospitalet, Copenhagen University Hospital,Copenhagen,Denmark
,
Mette Brabrand
Affiliations:
Department of Hematology,Odense University Hospital,Odense,Denmark
,
Christina Ellervik
Affiliations:
Harvard Medical School,Boston,United States
,
Daniel el Fassi
Affiliations:
Department of Hematology,Herlev University Hospital,Copenhagen,Denmark
,
Mikael Frederiksen
Affiliations:
Department of Hematology,Hospital of Southern Jutland,Haderslev,Denmark
,
Lasse Kjær
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark
,
Thomas Kielsgaard
Affiliations:
Department of Pathology,Odense University Hospital,Odense,Denmark
,
Torben A. Kruse
Affiliations:
Department of Clinical Genetics,Odense University Hospital,Odense,Denmark
,
Hans Torben Mourits-Andersen
Affiliations:
Department of Hematology,Hospital of South West Jutland,Esbjerg,Denmark
,
Peter Møller
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark
,
Ulrik Malthe Overgaard
Affiliations:
Department of Hematology,Rigshospitalet, Copenhagen University Hospital,Copenhagen,Denmark
,
Dustin Andersen Patel
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark
,
Marianne Tang Severinsen
Affiliations:
Department of Hematology,Aalborg University Hospital,Aalborg,Denmark
,
Vibe Skov
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark
,
Anders Lindholm Sørensen
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark
,
Jesper Stentoft
Affiliations:
Department of Hematology,Aarhus University Hospital,Aarhus,Denmark
,
Jørn Starklint
Affiliations:
Department of Hematology,Hospital of West Jutland,Holstebro,Denmark
,
Karin de Stricker
Affiliations:
Department of Pathology,Odense University Hospital,Odense,Denmark
,
Mads Thomassen
Affiliations:
Department of Clinical Genetics,Odense University Hospital,Odense,Denmark
,
Thomas Stauffer Larsen
Affiliations:
Department of Hematology,Odense University Hospital,Odense,Denmark
Hans Hasselbalch
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark
EHA Library. Knudsen T. 06/16/19; 267363; S1609
Trine Alma Knudsen
Trine Alma Knudsen
Contributions
Abstract

Abstract: S1609

Type: Oral Presentation

Presentation during EHA24: On Sunday, June 16, 2019 from 08:30 - 08:45

Location: Elicium 2

Background

Hydroxyurea (HU) is used as first-line cytoreductive therapy for patients with myeloproliferative neoplasms (MPNs) in most parts of the world.  Recent studies have provided encouraging results for the treatment of MPN with off-label recombinant interferon alpha-2 (r-IFNα) compared with HU. However, direct comparison of HU with r-IFNα have not been conducted.

Aims

To investigate efficacy and toxicity of low-dose r-IFNα vs. HU in MPN.

Methods

The DALIAH trial is an ongoing investigator initiated Danish multicenter randomized controlled phase III clinical trial (NCT01387763). Patients (n=203) newly diagnosed with MPN according the WHO criteria and naïve to cytoreductive treatment were enrolled in the study. Patients > 60 years were randomized (1:1:1) to either r-IFNα-2a, r-IFNα-2b or HU. Patients ≤ 60 were randomized (1:1) to r-IFNα-2a or r-IFNα-2b. HU was added to treatment in patients randomized to r-IFNα presenting with major thrombosis or platelets > 1000 × 109/L until normalization of the platelet count. Starting dose was 45 µg/week for r-IFNα-2a, 35 µg/week for r-IFNα-2b and 500-2000 mg/day for HU. JAK2V617F was analyzed on whole blood by qPCR. The ELN 2009 and EUMNET 2005 criteria were used for response assessments according to the intention-to-treat principle. Fisher’s exact test was used to compare HU vs. r-IFNα > 60 years.

Results

Thirty-eight patients were randomized to HU whereas 74 patients > 60 years and 91 patients ≤ 60 years were randomized to r-IFNα (Table 1). The overall clinicohematological response rate (ORR) at 36 months among patients with essential thrombocythemia (ET), polycythemia vera (PV) and prefibrotic myelofibrosis (Pre-MF) was 22/31 (71%) for HU, 28/65 (43%) for r-IFNα > 60 years and 34/82 (41%) for r-IFNα ≤ 60 years. ORR was higher in patients treated with HU compared with r-IFNα > 60 years (p=0.02). There was no significant difference in the CHR rate. For primary myelofibrosis (PMF) the ORR was 4/7 (57%) for HU, 3/9 (33%) for r-IFNα > 60 years and 2/9 (22%) for r-IFNα ≤ 60 years.  There was no significant difference in the ORR or CHR between groups. At 36 months CHR had been achieved at some point during follow-up among all MPN diagnoses in 25/38 (66%) for HU, 43/74 (58%) for r-IFNα > 60 years and 53/91 (58%) for r-IFNα ≤ 60 years.

Seventy patients with a baseline JAK2V617F allele burden > 10% were analyzed for molecular response at 36 months. No complete responses were observed. A partial molecular response (PMR) was detected in 6/26 (23%) for HU, 16/55 (29%) for r-IFNα > 60 years and 14/50 (28%) for r-IFNα ≤ 60 years. There was no statistical difference in the PMR rate.  The median JAK2V617F reduction at 36 months was 38% (IQR: 19-63%) for HU, 70% (IQR: 46-85%) for r-IFNα > 60 years and 69% (IQR: 38-90%) for r-IFNα ≤ 60 years.

Treatment discontinuation for any reason at 36 months was 8/38 (21%) for HU, 39/74 (53%) for r-IFNα > 60 years and 51/91 (56%) for r-IFNα ≤ 60 years. Toxicity related treatment discontinuation was 5/38 (13%) for HU, 25/74 (34%) for r-IFNα > 60 and 41/91 (45%) for ≤ 60 years. Both treatment discontinuation for any reason and for toxicity was significantly higher for r-IFNα > 60 years compared with HU (p<0.05). Patients experiencing grade 3-4 AEs and SAEs were comparable.

Conclusion

At 36 months the clinicohematological ORR was higher in patients with ET, PV and Pre-MF treated with HU (p=0.02). There was no significant difference in PMR rate but the JAK2V617F reduction was higher for r-IFNα. Treatment discontinuation for any reason and for toxicity was higher in patients treated with r-IFNα compared with HU (p<0.05).

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Hydroxyurea, Myeloproliferative disorder

Abstract: S1609

Type: Oral Presentation

Presentation during EHA24: On Sunday, June 16, 2019 from 08:30 - 08:45

Location: Elicium 2

Background

Hydroxyurea (HU) is used as first-line cytoreductive therapy for patients with myeloproliferative neoplasms (MPNs) in most parts of the world.  Recent studies have provided encouraging results for the treatment of MPN with off-label recombinant interferon alpha-2 (r-IFNα) compared with HU. However, direct comparison of HU with r-IFNα have not been conducted.

Aims

To investigate efficacy and toxicity of low-dose r-IFNα vs. HU in MPN.

Methods

The DALIAH trial is an ongoing investigator initiated Danish multicenter randomized controlled phase III clinical trial (NCT01387763). Patients (n=203) newly diagnosed with MPN according the WHO criteria and naïve to cytoreductive treatment were enrolled in the study. Patients > 60 years were randomized (1:1:1) to either r-IFNα-2a, r-IFNα-2b or HU. Patients ≤ 60 were randomized (1:1) to r-IFNα-2a or r-IFNα-2b. HU was added to treatment in patients randomized to r-IFNα presenting with major thrombosis or platelets > 1000 × 109/L until normalization of the platelet count. Starting dose was 45 µg/week for r-IFNα-2a, 35 µg/week for r-IFNα-2b and 500-2000 mg/day for HU. JAK2V617F was analyzed on whole blood by qPCR. The ELN 2009 and EUMNET 2005 criteria were used for response assessments according to the intention-to-treat principle. Fisher’s exact test was used to compare HU vs. r-IFNα > 60 years.

Results

Thirty-eight patients were randomized to HU whereas 74 patients > 60 years and 91 patients ≤ 60 years were randomized to r-IFNα (Table 1). The overall clinicohematological response rate (ORR) at 36 months among patients with essential thrombocythemia (ET), polycythemia vera (PV) and prefibrotic myelofibrosis (Pre-MF) was 22/31 (71%) for HU, 28/65 (43%) for r-IFNα > 60 years and 34/82 (41%) for r-IFNα ≤ 60 years. ORR was higher in patients treated with HU compared with r-IFNα > 60 years (p=0.02). There was no significant difference in the CHR rate. For primary myelofibrosis (PMF) the ORR was 4/7 (57%) for HU, 3/9 (33%) for r-IFNα > 60 years and 2/9 (22%) for r-IFNα ≤ 60 years.  There was no significant difference in the ORR or CHR between groups. At 36 months CHR had been achieved at some point during follow-up among all MPN diagnoses in 25/38 (66%) for HU, 43/74 (58%) for r-IFNα > 60 years and 53/91 (58%) for r-IFNα ≤ 60 years.

Seventy patients with a baseline JAK2V617F allele burden > 10% were analyzed for molecular response at 36 months. No complete responses were observed. A partial molecular response (PMR) was detected in 6/26 (23%) for HU, 16/55 (29%) for r-IFNα > 60 years and 14/50 (28%) for r-IFNα ≤ 60 years. There was no statistical difference in the PMR rate.  The median JAK2V617F reduction at 36 months was 38% (IQR: 19-63%) for HU, 70% (IQR: 46-85%) for r-IFNα > 60 years and 69% (IQR: 38-90%) for r-IFNα ≤ 60 years.

Treatment discontinuation for any reason at 36 months was 8/38 (21%) for HU, 39/74 (53%) for r-IFNα > 60 years and 51/91 (56%) for r-IFNα ≤ 60 years. Toxicity related treatment discontinuation was 5/38 (13%) for HU, 25/74 (34%) for r-IFNα > 60 and 41/91 (45%) for ≤ 60 years. Both treatment discontinuation for any reason and for toxicity was significantly higher for r-IFNα > 60 years compared with HU (p<0.05). Patients experiencing grade 3-4 AEs and SAEs were comparable.

Conclusion

At 36 months the clinicohematological ORR was higher in patients with ET, PV and Pre-MF treated with HU (p=0.02). There was no significant difference in PMR rate but the JAK2V617F reduction was higher for r-IFNα. Treatment discontinuation for any reason and for toxicity was higher in patients treated with r-IFNα compared with HU (p<0.05).

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Hydroxyurea, Myeloproliferative disorder

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