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This is the first clinical trial investigating combination treatment with ruxolitinib and pegylated interferon-a2 (PEG-IFNa2) for patients with chronic Philadelphia-nega- tive myeloproliferative neoplasms. Hydroxyurea is the most frequently used cytoreductive agent, but some patients are intolerant of or resistant to this drug.1-3 PEG- IFNa2 is another first-line treatment option, but its clin- ical use is limited by toxicity.3-12 Ruxolitinib reduces symp- tom burden in patients with polycythemia vera (PV) and primary or secondary myelofibrosis (MF), but the clinical benefit in patients with PV is still controversial.3,13-19 Ruxolitinib may increase the efficacy and tolerability of PEG-IFNa2,20,21 and we have reported promising results from a 1-year interim analysis, with an overall remission rate of 9% in PV patients and 39% in MF patients.22
Patients were initially treated with PEG-IFNa2a [Pegasys®; Genentech (Roche), South San Francis-co, CA, USA] 45 μg/week or PEG-IFNa2b (PegIntron®; Merck Sharp & Dohme, Hertfordshire, UK) 35 μg/week subcutaneously and ruxolitinib (Jakavi®; Novartis, Basel, Switzerland) 5-20 mg BID orally depend- ing on platelet count.
PEG-IFNa2 effectively normalizes blood cell counts and may prevent disease-related thromboembolic complica- tions in patients with essential thrombocythemia, PV, and MF.4-8,10,11,23-26 Furthermore, an anti-clonal activity of PEG- IFNa2 has been shown by reductions of the Januskinase-2 (JAK2) V617F allele burden and sustained deep molecular, hematologic, and histological remission in some patients, even several years after cessation of treatment.5,6,23,27-29 However, some patients do not respond adequately to PEG-IFNa2, and treatment is limited by frequent toxicities and high discontinuation rates, of 10–50%, due to adverse events.5-8,10-12 In particular, inflammatory side effects such as fever, flu-like symptoms, fatigue, and autoimmune thy- roiditis are troublesome.5-7,10,11
Study visits included documentation of adverse events, full- scale hematology, blood biochemistry investigations, determina- tion of the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) score,31 and assessment of compliance by research staff. Bone marrow biopsies were done at baseline and after 1 and 2 years of treatment. Spleen size was measured as the longest diameter by sonography. The proportions of JAK2 V617F and CALR-mutated alleles were quantified using a high-sensitivity real-time quantitative polymerase chain reaction method on whole blood.32,33
Endpoints
The primary outcome was efficacy, based on hematologic parameters, quality of life measurements, and the JAK2 V617F burden. The 2013 European LeukemiaNet and International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria were used to assess efficacy.34,35
In brief, for patients with PV, a complete remission (CR) required resolution of disease-related symptoms and hepatosplenomegaly, peripheral blood count remission (PBCR), no progression of the disease, no hemorrhagic or thrombotic events, and bone marrow histological remission (BMHR). A partial remis- sion (PR) required all the above except BMHR.
For patients with MF, a CR required resolution of disease-relat- ed symptoms and hepatosplenomegaly, and PBCR. A PR required resolution of disease-related symptoms and hepatosplenomegaly, and either PBCR or BMHR. Clinical improvement was defined as an anemia response or symptoms response. Progressive disease was defined as significantly increased splenomegaly or leukemic transformation.34,35
Molecular response (MR) was classified as either complete (CMR), defined as eradication of a pre-existing abnormality, or partial (PMR), defined as a ≥50% decrease in JAK2 V617F allele burden from baseline in patients with a baseline allele burden ≥20%.
Statistical analyses
We did the statistical analyses using R.3.2.3. Response rates are presented with descriptive statistics. All patients initiating the study treatment were evaluated for response, similar to the modi- fied intention-to-treat principle used for randomized, controlled trials. Statistical analyses are described in the Online Supplementary Methods section. P values <0.05 were considered statistically sig- nificant.
Results
Patients’ characteristics
In total, we included 51 patients in the study, and 50 patients initiated combination treatment; 32 had PV, and
JAK1-2 inhibitor treatment with ruxolitinib reduces dis- ease-related symptoms and splenomegaly, and it may pro- long survival in patients with MF.13,14,16,18,19 Furthermore, ruxolitinib reduces elevated blood cell counts and symp- tom burden in patients with PV.15,17 Inflammation is a crit- ical element of myeloproliferative neoplasms, and the effect of ruxolitinib seems to be mediated mainly by anti- inflammatory mechanisms.20 Moreover, a reduction in the JAK2 V617F allele burden has been observed.30 Adding ruxolitinib to PEG-IFNa2 treatment may increase the effi- cacy and tolerability of PEG-IFNa2 by reducing inflamma- tion.21,22 Combination treatment may also have a synergis- tic effect on the malignant clone, and reduced dosage of both drugs may lead to fewer side-effects compared with monotherapies.20 The rationales for the combination treat- ment have previously been described in detail.21
We report the 2-year end-of-study results from the phase II COMBI study assessing efficacy and safety of combination treatment with ruxolitinib and PEG-IFNa2.
Methods
Study design
The COMBI study (#EudraCT2013-003295-12) was an investi- gator-initiated, multicenter, open-label, single-arm phase II study; we included 50 patients: 32 with PV and 18 with MF. The study was conducted between 2014 and 2018 at three sites in Denmark and approved by the Danish Regional Science Ethics Committee and the Danish Medicines Agency. It was done under the prin- ciples of the Declaration of Helsinki. Patients gave written informed consent to their participation. For further details on the methods, see the Online Supplementary Methods section.
Patients aged ≥18 years with a diagnosis of PV or MF according
haematologica | 2020; 105(9)
Ruxolitinib and interferon-a for PV and MF
Introduction
to the 2008 World Health Organization criteria were considered eligible, if they had evidence of active disease, defined as one or more of the following: need for phlebotomy, white blood cell count ≥10x09/L, platelet count ≥400x109/L, constitutional symp- toms, pruritus, symptomatic splenomegaly, and previous throm- bosis. Key exclusion criteria were: Eastern Cooperative Oncology Group performance status ≥3, severe comorbidity, white blood cell count <1.5x109/L, and platelet count <100x109/L.
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