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A.L. Sørensen et al.
out rate was comparable with that in previous studies of PEG-IFNa2 in interferon-naïve patients.4-8,10,11 The prelimi- nary results from the phase I/II RUXOPEG study (ClinicalTrials.gov NCT02742324) in patients with more advanced MF support our findings.36 In that study, a decrease in spleen size, improvement in blood counts, and a reduction in JAK2 V617F allele burden were observed in ten evaluable patients.
In total, 19% of PV patients and 33% of MF patients ful- filled the criteria for BMHR. These findings suggest a dis- ease-modifying effect of the combination treatment.34,35 Profound effects of PEG-IFNa2 on bone marrow histology have been observed before, but usually after longer peri- ods of treatment.28,29,37,38 Long-term treatment with ruxoli- tinib in patients with MF seems to decrease bone marrow fibrosis in only a small subset of patients.39 In a study investigating PEG-IFNa2 treatment in 30 patients with low- or intermediate-1 risk MF, two (7%) had CR, nine (30%) had PR, and four (13%) had clinical improvement after a median of 80.3 months.37 In our study, 28%, 17%, and 12% of MF patients achieved CR, PR, and clinical improvement, respectively, within 2 years.
Normalization of blood cell counts may be critical in reducing the risk of thrombosis and improving sur- vival.1,40,41 Therefore, a key finding of this study is the fast and sustained normalization of elevated blood cell counts. Similar high rates of hematologic response were observed previously with a starting dose of PEG-IFNa2 90 μg/week in patients with PV.5-7 In two phase II studies on PV patients, the median time to complete hematologic response was 2 and 3 months, respectively.5,6 In our study, the median time to PBCR was 1 month for PV patients. Similar to our study, most patients in one of those studies had received previous cytoreductive treatment.6 In the phase II study of ropeginterferon-a2b for PV patients, the median time to complete hematologic resposne was more than 1 year.42 Notably, baseline cell counts were higher in these studies than in ours, and fewer patients had received cytoreductive treatment before inclusion in two of the studies, which may explain the shorter time to response for PV patients in our study. Importantly, the response cri- teria are not identical in the studies, and comparisons between the studies should, therefore, be interpreted with caution. Ropeginterferon-a2b induced higher rates of blood cell count and spleen responses than did hydroxy- urea after 2 years in an ongoing randomized controlled trial.43 Ruxolitinib monotherapy in patients with PV previ- ously treated with hydroxyurea, in the RESPONSE I and II studies, resulted in PBCR rates of only 24% and 17% after 6 months.15,17 In comparison, 80% of PV patients in our study achieved PBCR within 6 months.
The MPN-SAF TSS decreased significantly during com- bination treatment. Ruxolitinib has previously been shown to reduce symptom burden in patients with MF or PV with relatively few side-effects.14,15,17,19 In contrast, in a study comparing hydroxyurea with PEG-IFNa2, no reduc- tion in TSS was observed in either group.44
The marked reduction in the JAK2 V617F allele burden and a 41% MR rate add further evidence of a selective effect of combination treatment on the malignant clone. Similar findings were made in patients treated with PEG- IFNa2, and in the RESPONSE I study in which 34% achieved MR after a median of 25 months of ruxolitinib treatment.5,6,23,30 Notably, the baseline median JAK2 V617F allele burden was 83% in the RESPONSE I study com-
pared with 47% in our study. It is likely that a higher pro- portion of patients in RESPONSE I was evaluable for PMR than in our study. Ruxolitinib treatment in patients with MF has resulted in markedly lower rates of MR.45 Importantly, most previous studies assessing the JAK2 V617F allele burden have a limit of detection of ≥1%.5,6.30,42,45 The assay used in our study has a sensitivity of ≤0.1% mutated alleles; this is important for compar- isons of CMR and the total rate of MR.
We found an association between MR and both remis- sion and PBCR. Similarly, during ropeginterferon-a2b treatment, an association between MR and hematologic response was observed.42,43 Likewise, in a phase II study of PEG-IFNa2, 94% of patients with MR also had a hemato- logic response, and ten of 13 patients with complete bone marrow response, also achieved MR; seven had CMR.11,29 The clinical benefit of MR is still unclear, but higher JAK2 V617F allele burden may be associated with a higher risk of thrombotic events and progression to MF.41,46
The drop-out rate in our study was 16%; 8% stopped due to adverse events. Notably, the drop-out rate was 6% in PV patients and 32% in MF patients, respectively. In total, 31% of PV patients and 37% of MF patients discon- tinued PEG-IFNa2 when including patients who contin- ued ruxolitinib monotherapy and drop-outs. This propor- tion was similar in the two groups. Similar rates were reported in previous studies on PEG-IFNa2 treatment.4- 8,10,11 However, in our study, 94% had previously been treated with PEG-IFNa2; we therefore expected a high rate of PEG-IFNa2 discontinuation. Moreover, in an ongo- ing Danish study, the rate of PEG-IFNa2 discontinuation in treatment-naïve patients was approximately 50%.12 Consequently, our findings are still very encouraging. Ruxolitinib has been shown to increase the risk of infec- tions, particularly in patients with MF.13,15,17,19,47 We observed a relatively high infection rate, with six patients (12%) developing grade 3 pneumonia. Importantly, patients with fever were hospitalized and treated with intravenous antibiotics, immediately for safety precau- tions, and thereby fulfilled the criteria for grade 3 or 4 adverse events. This may have led to an overestimation of grade 3 or 4 infectious adverse events. Indeed, only three of the six grade 3 or 4 cases of pneumonia registered were radiologically or microbiologically verified. Grade 1 or 2 anemia was recorded in 71.9% of PV patients. A high ini- tial dose of ruxolitinib may account for this. The initial ruxolitinib dose used in this study was 20 mg BID for most patients compared with 10 mg BID in the RESPONSE studies, since the phase II study dose-finding study was published after preparation of the protocol.15,17 Accordingly, dosage reduction was frequent.
The inclusion criteria used in this trial do not directly reflect the European LeukemiaNet guidelines for the initi- ation of cytoreductive treatment.3 Indeed, both high- and low-risk PV patients were included. This is similar to other clinical trials investigating PEG-IFNa2 treatment.5,6,42 The indications for administering PEG-IFNa2 are wider in Denmark than internationally, and a strategy of an early intervention targeting the malignant clone has previously been described.48 Indeed, combination treatment as an early intervention may induce deep clinical, histological and molecular remission more frequently than PEG-IFNa2 monotherapy.5,6,23,27-29 Achieving deep remission could lead to periods of observation without treatment or mainte- nance treatment with a low dose of PEG-IFNa2, which
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