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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

S1609

Knudsen, T. A.1; Hansen, Lund D.2; Ocias, Frans L.2; Bjerrum, Weis O.3; Brabrand, M.2; Ellervik, C.4; el Fassi, D.5; Frederiksen, M.6; Kjær, L.1; Kielsgaard, T.7; Kruse, T. A.8; Mourits-Andersen, H. T.9; Møller, P.1; Overgaard, U. M.3; Patel, Andersen D.1; Severinsen, Tang M.10; Skov, V.1; Sørensen, Lindholm A.1; Stentoft, J.11; Starklint, J.12; de Stricker, K.7; Thomassen, M.8; Larsen, Stauffer T.2; Hasselbalch, H.1

doi: 10.1097/01.HS9.0000564684.14072.fb
Simultaneous Sessions IV: Update on clinical trials in MPN
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1Department of Hematology, Zealand University Hospital, Roskilde

2Department of Hematology, Odense University Hospital, Odense

3Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

4Harvard Medical School, Boston, United States

5Department of Hematology, Herlev University Hospital, Copenhagen

6Department of Hematology, Hospital of Southern Jutland, Haderslev

7Department of Pathology

8Department of Clinical Genetics, Odense University Hospital, Odense

9Department of Hematology, Hospital of South West Jutland, Esbjerg

10Department of Hematology, Aalborg University Hospital, Aalborg

11Department of Hematology, Aarhus University Hospital, Aarhus

12Department of Hematology, Hospital of West Jutland, Holstebro, Denmark

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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.

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Aims:

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

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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.

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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.

Figure

Figure

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Summary/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).

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.