ALBERT

Description: Background Recombinant Interferon Alpha-2a (r-IFNα) is a potent immunomodulating agent, which has been used off-label for the treatment of polycythemia vera (PV) for more than three decades and has been demonstrated to induce high rates of clinical, hematological and molecular responses. Only few studies have compared efficacy and safety of r-IFNα vs. hydroxyurea (HU), which is considered first line therapy for PV patients 〉 60 years in most parts of the world. However, recent studies have provided encouraging results for the treatment of PV with r-IFNα compared to HU irrespective of age (R. Hoffmann 2016; H. Gisslinger 2018). Aims To examine the difference in efficacy and safety of low-dose r-IFNα in PV patients ≤ 60 or 〉 60 years of age compared to HU 〉 60 years of age. Methods Ninety newly diagnosed or previously phlebotomized PV patients only (WHO 2008) were enrolled in the DALIAH trial (NCT01387763). All patients provided written informed consent. Patients ≤ 60 years were randomized (I:I) to r-IFNα-2a (Pegasys®) or to r-IFNα-2b (PegIntron®) whereas patients 〉 60 years were randomized (I:I:I) to either r-IFNα-2a, r-IFNα-2b or to HU. The starting dose of r-IFNα-2a and r-IFNα-2b was 45 or 35 µg/week, respectively. The HU dose was 500 to 2000 mg/day. Patients randomized to r-IFNα who presented with major thrombosis or platelets 〉 1500 109/L received HU from inclusion and until normalization of the platelet count. Efficacy assessment consisted of the clinicohematological and the molecular response rates by intention to treat analysis (ITT) using the European Leukemia Net (ELN) 2009 criteria. JAK2V617F analysis was performed by qPCR. Groups were compared by Fisher's Exact Test. Results Three-year analysis was available in all but five patients (n=85) at time of abstract submission (Table 1). The analysis was performed after a median of 36 months (range: 33-39 months). The median treatment dose was 684 mg/day (IQR: 131 - 942) for HU, 51 μg/week (IQR: 30-90 μg/week) and 54 μg/week (IQR: 30-66 μg/week) for r-IFNα-2a age ≤ 60 and 〉 60, respectively, and 41 μg/week (IQR: 29-45 μg/week) and 36 μg/week (IQR: 31-37 μg/week) for r-IFNα-2b age ≤ 60 and 〉 60. The overall clinicohematological response rate (ORR) was 68% (13/19) for HU, 42% (14/33) for r-IFNα ≤ 60 years and 39% (13/33) for r-IFNα 〉 60 years. The partial clinicohematological response rate (PHR) and the complete clinicohematological response rate (CHR) was 53% (10/19) and 16% (3/19) for HU, 9% (3/33) and 33% (11/33) for r-IFNα ≤ 60 years and 9% (3/33) and 30% (10/33) for r-IFNα 〉 60 years. Neither the ORR, CHR nor the PHR was significantly different between the three groups. Maintenance of CHR from first occurrence to data analysis after 36 months was 11% (2/19) for HU, 21% (7/33) for r-IFNα ≤ 60 years and 18% (6/33) for r-IFNα 〉 60 years. Forty-seven JAK2V617F positive patients were available for molecular response analysis after 36 months of therapy. A partial molecular response (PMR) was detected in 21% (4/19) of HU treated patients and in 24% (7/29) of r-IFNα treated patients ≤ 60 years and 18% (6/33) of r-IFNα 〉 60 years. Notably, 7% (2/29) of the r-IFNα treated patients ≤ 60 years obtained a complete molecular response (CMR). The median JAK2V617F reduction from baseline was 38% (IQR: 31-63%) for HU, 79% (IQR: 59-92%) for r-IFNα ≤ 60 years and 73% (IQR: 49-97%) for r-IFNα 〉 60 years. There was no statistically significant difference in the PMR between groups. Discontinuation of treatment for any reason after 36 months of therapy was 21% (4/19) for HU, 52% (17/33) for r-IFNα ≤ 60 years and 45% (15/33) for r-IFNα 〉 60 years. Toxicity related discontinuation was 5% (1/19) for HU and 30% (10/33) for both r-IFNα ≤ 60 and 〉 60 years. Grade 3-4 AEs occurred in 32% (6/19) of HU treated patients, 27% (9/33) in r-IFNα treated patients ≤ 60 years and in 42% (14/33) r-IFNα treated patients 〉 60 years. SAEs were reported in 21% (4/19) for HU, 9% (3/33) for r-IFNα ≤ 60 years and 24% (8/33) for r-IFNα 〉 60 years. The numbers of grade 3-4 AEs as well as SAEs were comparable between groups. Conclusion After 36 months of therapy CHR was non-significantly higher in PV patients treated with r-IFNα compared to HU by ITT, irrespective of age. Also, maintenance of CHR was longer for r-IFNα. However, ORR was non-significantly higher for HU. PMR was almost similar between the three groups but the median JAK2V617F reduction was greater for r-IFNα. Toxicity related discontinuation from study therapy was higher for r-IFNα compared to HU. Disclosures Stentoft: Bristol-Myers Squibb: Research Funding; Merck Sharp&Dohme: Research Funding. Hasselbalch:Novartis: Research Funding.

Description: Background: To investigate the role of genomics in determining response and resistance to front line treatment in MPN, we performed somatic mutational profiling of the DALIAH trial, a randomized controlled phase III trial of interferon versus hydroxyurea in newly diagnosed MPN patients. Methods: We performed genomic analyses on 202 pre-treatment primary MPN samples obtained from patients enrolled on the DALIAH trial (NCT01387763) and 135 samples obtained after 24 months of treatment. Genomic profiling comprised targeted next generation sequencing (NGS) of 100 genes, selected on the basis of their known or suspected involvement in the pathogenesis of myeloid malignancies, and 1609 informative single nucleotide polymorphisms (SNPs) on chromosome 9p. Clinicohematological response was determined by central review using ELN 2009 (ET, PV and pre-MF) and EUMNET 2005 (PMF) criteria. We evaluated the association of somatic mutations with clinical parameters and with attainment of clinicohematological complete response (CR) at 24 months. Results: Prior to treatment, 191 of 202 (95%) patients had somatic mutations, including 93% with canonical MPN phenotypic drivers: JAK2 (74%), CALR (14%), and MPL (5%). Among those with JAK2 mutations 37% had JAK2 copy-neutral loss of heterozygosity (JAK2 CN-LOH). Patients with PV were more likely to have JAK2 CN-LOH (p = 0.0001) as compared with patients with other MPN subtypes. At baseline, patients with JAK2 CN-LOH had significantly higher hemoglobin (p = 0.0001), higher white blood cell count (WBC, p = 0.002) and lower platelet count (p=0.0001) than patients without JAK2 CN-LOH. Mutations in TET2 (24%), DNMT3A (16%), and ASXL1 (10%) were the most frequent co-occurring non-MPN phenotypic driver mutations and they occurred across all MPN subtypes. In addition, 5% of patients had spliceosome gene mutations, and 6% had mutations in genes involved in RAS/MAPK signaling. Patients with TET2, DNMT3A or ASXL1 mutations were significantly older than patients without these mutations (p= 0.0001) and there was a significant association between the presence of a TET2, DNMT3A or ASXL1 mutation and prior stroke (p = 0.004). There were no other significant associations between somatic mutation status and baseline clinical characteristics. The probability of attaining clinicohematological CR at 24 months was independent of baseline somatic mutations. Among patients with JAK2 mutations who remained on interferon treatment at 24 months, those with CR had a greater reduction in mean variant allele fraction (VAF) (28% to 8%, p

Description: Background Treatment of Philadelphia chromosome negative chronic myeloproliferative neoplasms (MPNs) with recombinant pegylated interferon alpha2a/b (rIFN-alpha) has proven effective. It is well known that prolonged therapy with recombinant type 1 interferons (IFN-alpha and IFN-beta) may induce neutralizing antibodies (nAbs) against the drug leading to treatment failure. Most data on type 1 IFN immunogenicity are available from studies of patients with multiple sclerosis treated with rIFN-beta, and patients with hepatitis C treated with rIFN-alpha. A few reports have demonstrated nAbs in MPN patients not responding adequately to rIFN-alpha treatment, but the phenomenon has not been thoroughly investigated in MPNs. Patients and Methods Newly diagnosed patients with MPNs enrolled in the Danish multicenter trial - DALIAH (Low-dose rIFN-alpha versus Hydroxyurea in The Treatment of Ph-Negative MPNs) were included. Patients were randomized to treatment with either rIFN-alpha 2a or 2b at a starting dose of 45 and 35 mikrograms once weekly, respectively. The occurrence of neutralizing Abs (nAbs) against rIFN-alpha was investigated at baseline, month 12 and month 24 by reporter gene assays (iLiteTM alphabeta and iLiteTM antialpha, Biomonitor A/S, Copenhagen, Denmark). JAK2 V617F quantitative mutation analyses were performed as previously described (Larsen TS, BJH 2007). Statistical analyses were performed using STATA version 9.0. Results Ninety-two patients on sustained treatment with rIFN-alpha2a (n=48) and rIFN-alpha2b (n=44) for 12 months were analyzed for this study. Forty-five patients had ET, 39 patients had PV and 8 patients had proliferative PMF. Thirty-six out of 39 (92%) PV patients, 22 out of 45 (49%) ET patients and 4 out of 8 (50%) PMF patients were JAK2V617F mutated. Hematological responses at 12 months: ET: 67% CR, 29 % PR; PV: 64% CR, 31% PR (ELN 2009 criteria); PMF: 50% had at least a minor response (EUMNET). The median serum concentration of bioactive IFN-alpha at 12 months was 12,4 (range