Clinicohematologic and Molecular Response of Essential Thrombocythemia Patients Treated with Pegylated Interferon-Alpha: A Multicenter Study on Behalf of the German Study Group-MPN (GSG-MPN)

Cytoreductive treatment with hydroxyurea (HU) or anagrelide (ANA) aims at reducing the risk of vascular complications in essential thrombocythemia (ET), while (pegylated) Interferon-α (pegIFN) may also prevent progression to secondary myelofibrosis (SMF) or acute myeloid leukemia (AML). In contrast to polycythemia vera (PV), the accessibility to pegIFN is limited in ET due to lack of approval.

To investigate the clinical benefits of pegIFN in ET, we identified within the German Study Group-Myeloproliferative Neoplasms (GSG-MPN) registry a total of 127 WHO-defined patients (pts) treated at seven University centres. In this study, we analysed clinically relevant parameters before and during pegIFN treatment and assessed the JAK2 V617F variant allele frequency (VAF) in DNA from granulocytes by droplet digital PCR (sensitivity 10^-3) in JAK2 mutated pts with available biosamples.

Baseline characteristics of the pts were: median age at diagnosis 37.0 years (yrs, range 8.2-77.4), median platelet (PLT) count 780 /nl (124-2,776), median white blood cell (WBC) count 8.2 /nl (3.0-17.3); 67% were female; 53% were JAK2 V617F-, 33% CALR-, and 5% MPL-mutated. According to the International Prognostic Score of thrombosis in ET (IPSET), 37% were low-, 31% intermediate-, and 30% high-risk (2% unknown). Median time from diagnosis to pegIFN start was 1.9 yrs (0.0-37.2); in 59% pegIFN was used as first-line drug, 20% were pre-treated with HU, 9% with ANA, and 11% with both. Main reasons for pegIFN start were high PLT count (39%), prior thrombosis (31%), ET-associated symptoms (9%), age >60 yrs (7%), and pregnancy (7%). Since 31 pts (24%) had ≥2 lines of treatment (LOT) with pegIFN, a total number of 161 LOT was recorded. PegIFN 2a was used in most LOT (54%), followed by pegIFN 2b (35%) and ropegIFN 2b (11%). Median total pegIFN treatment duration per pt was 2.3 yrs (0.1-18.1); 30/127 (24%) and 10/127 (8%) were treated for ≥5 yrs and ≥10 yrs, respectively. At last follow-up, 60% of pts were still on pegIFN. The discontinuation rate was highest in the first yr of treatment (14.3%). Adverse events (16%) and market withdrawal of pegIFN 2b (15%) were the two most frequent reasons for discontinuing a LOT. According to European LeukemiaNET response criteria (Barosi et al. Blood 2009), 89% of pts achieved clinicohematologic response at any time which was complete in 54% and partial in 35%. Median PLT and WBC counts at last follow-up (380 /nl and 5.5 /nl, respectively) were significantly lower compared to baseline (780 /nl and 8.2 /nl) (Figure). Only one pt progressed to SMF during pegIFN treatment, while no pt transformed to secondary AML. Vascular complications were rare with three arterial and five venous events in 469 pegIFN treatment yrs, resulting in an incidence of 0.6% and 1.1% per pt and yr, respectively. Flu-like symptoms were recorded in 41%, abnormal liver tests in 16%, and depression in 14% of LOT (grading and time points unknown). Quantitative assessment of the JAK2 V617F VAF on 70 samples from 14 pts with available DNA before pegIFN start and ≥2x thereafter (each at least one yr apart) revealed a reduction from median 30.5% (7.2-48.1) at baseline to 8.3% and 18.1% after 4 and 8 yrs of pegIFN treatment, respectively (n.s.); 5/14 pts (36%) achieved a ≥50% reduction (partial molecular response) and one pt showed a VAF <1%. In 10/127 pts (8%), pegIFN 2b was stopped due to market withdrawal and not immediately switched to an alternative drug as they had been treated for a median of 9.5 yrs (6-18): 3/10 pts maintained normalized blood cell counts until data cut-off (1.5-4.5 yrs after discontinuation); of these 3, one had 0.1% JAK2 V617F at the time of discontinuation, while the other two were JAK2 V617F negative (baseline VAF not available); 2/3 pts underwent bone marrow biopsy and showed histomorphological remission of ET.

Analyses of a large series of ET pts treated with pegIFN confirm a high efficacy of the drugs in achieving clinicohematologic response. Our data, including long-term treated pts with low rates of vascular complications, disease progressions, and adverse events underscore the medical benefit of pegIFN in ET. Although reduction of the JAK2 V617F VAF was not significant, molecular responses <1% and histomorphological remissions were observed in single pts. For treatment discontinuation, molecular thresholds for JAK2 V617F and CALR mutations need to be defined in the future.

FS and LLT contributed equally to this study.

Stegelmann:Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; AOP Pharma: Consultancy, Honoraria. Teichmann:Astellas: Consultancy; BMS: Consultancy, Honoraria; Pfizer: Consultancy; Sobi: Consultancy, Honoraria; AOP: Honoraria; Boehringer-Ingelheim: Honoraria; BeiGene: Other; Gilead: Other: n. Heidel:AOP: Consultancy; CTI: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Crodel:BMS: Honoraria; Novartis: Consultancy, Honoraria; AstraZeneca: Honoraria. Ernst:Janssen: Other: travel grant. Kreil:Incyte: Research Funding. Reiter:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Isfort:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; Alexion: Other: e.g. travel support; Mundipharma: Other: e.g. travel support; BMS: Honoraria; Roche: Other: e.g. travel support; Hexal: Other: e.g. travel support. Döhner:Brystol Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen Inc.: Consultancy, Honoraria, Research Funding; Berlin-Chemie: Consultancy, Honoraria; Agios Pharmaceuticals: Consultancy, Honoraria, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo Co, LTD: Consultancy, Honoraria; Gilead Sciences, Inc.: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Syndax Pharmaceuticals Inc.: Consultancy, Honoraria; Kronos Bio, Inc.: Research Funding; AstraZeneca: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Research Funding. Brümmendorf:Novartis: Consultancy, Honoraria, Other: travel grant, Research Funding; Janssen: Consultancy, Other: travel support; Merck: Consultancy, Other: travel support; Pfizer: Consultancy, Honoraria, Other: travel support, Research Funding. Döhner:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding; Astellas: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kronos: Research Funding. Koschmieder:RWTH Aachen University: Patents & Royalties: BET Inhibitor; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Karthos: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Alexion: Other: Travel support; PharmaEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; CTI Biopharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AOP Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Geron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding.

Use of pegylated interferon-alpha in essential thrombocythemia to control blood cell counts in patients at risk.