Ruxolitinib Combo Elicits Clinical Activity in Polycythemia Vera and Myelofibrosis

The combination of ruxolitinib (Jakafi) plus low-dose pegylated interferon-a2 (PEG-IFNa2; Pegasys) demonstrated an improvement in peripheral blood cell counts (PBCR), bone marrow cellularity and fibrosis, and symptom burden with acceptable toxicity in patients with polycythemia vera (PV) or proliferative myelofibrosis (MF), according to the 2-year, end-of-study results of the phase II COMBI study, which were recently published in Haematologica.

The primary end point of the study was efficacy and safety, which included response evaluations. The primary end point was determined by hematological parameters, quality of life measurements, and the JAK2 V617F burden.

Of the 32 patients with PV, 31% achieved remission (n = 10), 9% had a complete response (CR; n = 3), and 22% achieved a partial response (PR; n = 7). Another 3 patients achieved bone marrow histological remission (BMHR), but these patients did not meet the criteria for remission. An increase in the total symptom score (TSS) was observed in 1 patient. Three patients were classified as having no response to treatment after dropping out of the study. Bone marrow biopsies after 2 years were unsuccessful in 5 patients, 2 of which were in PR, and 1 patient opted out of the biopsy.

Among the 18 patients with MF, 44% reached remission (n = 8), 28% had a CR (n = 5), and 17% had a PR (n = 3). Clinical improvement was observed in 12% of the patients (n = 2), which included symptom response with a ≥50% reduction in TSS in both patients. Two patients had stable disease. One patient achieved BMHR and PBCR, but because the patient experienced grade 1 fatigue. Five patients dropped out of the study, although they did not have progressive disease.

A closer look at PBCR in the patients with PV showed that 5 patients met the requirements for PBCR at baseline. Four of these patients had PBCR at 2 years. The 27 patients who did not meet the criteria for PBCR at baseline had a median time to PBCR of 1 month. The median duration to the first PBCR was 14 months overall, with 12 out of 13 patients who lost PBCR being able to achieve it again during the study. Four out of 14 patients were deemed in need of a phlebotomy within 3 months before study inclusion, of whom only 3 required 1 phlebotomy. Two additional patients required phlebotomies during the trial.

In the MF group, 3 patients met the criteria for PBCR at baseline. Of these, 2 had PBCR at 2 years. There were 15 patients who did not have PBCR at baseline, and these individuals had a median time to PBCR of 3 months, and a 0.73 cumulative incidence of PBCR after 2 years. In the overall population of patients with MF, the median duration to the first PBCR was 5 months. Seven out of 8 patients who lost PBCR achieved it again during the trial.

After only 2 weeks, there were significant reductions in hematocrit, white blood cell count, and platelet count. However, differences in these laboratory values were not significant between patients with PV and MF.

The median TSS reduced to 15 (95% CI, 10-22) after 2 years of treatment in the study compared with 22 (95% CI, 16-29) measured at baseline. Larger TSS reductions were seen in patients who achieved remission after 2 years (P <.05). Specifically, the median TSS for patients who had a remission was reduced to 7 (95%CI, 4-13) after 2 years compared with the baseline measurement of 17 (95% CI, 10-27). In patients who did not achieve a remission, the median TSS was reduced to 25 (95% CI, 16-36) after 2 years compared with the baseline measurement of 26 (95% CI, 18-37). The TSS items that were reduced at more than half of the time points compared with baseline measurements included early satiety (P <.05), night sweats (P <.01), itching (P <.01), and weight loss (P <.001). No significant differences in TSS changes between patients with MF versus PV were found.

Spleen size was another determinant of efficacy in the study. Of 9 patients, including 5 with PV and 4 with MF, 4 patients had no palpable splenomegaly after 2 years, and 2 had reduced palpable splenomegaly. One patient had an increase in palpable splenomegaly. One out of the 2 patients who dropped out of the study, 1 had reduced palpable splenomegaly. After 2 years, a 10% reduction in spleen size occurred (95% CI, 6-15%) compared with baseline measurements (P <.001). This reduction in spleen size was statistically significant for patients with PV, but not for those with MF at 6 months and beyond.

The secondary end point of molecular response (MR) was defined as a ≥50% decrease in JAK2 V617F allele burden from baseline in patients with a baseline allele burden ≥20%. A statistically significant reduction in JAK2 V617F allele burden at all time points was observed in both groups of patients (P <.001). After 2 years of treatment in the study, the JAK2 V617F allele burden was 12% (95% CI, 6%-22%) compared with the 47% (95% CI, 33-61%) baseline measurement (P <.001). Within 2 years of treatment, the 44 patients with a JAK2 V617F mutation showed a complete MR rate of 2%, and a partial MR rate of 39%. No differences in MRs in patients with JAK2 V617F mutations between those with PV and MF were observed. One out of the 4 patients with a CALR mutation had a decrease in allele burden. Two patients with CALR-mutant disease had an increase in allele burden, and 1 patient dropped out of the study before being measured.

A statistically significant greater reduction in JAK2 V617F allele burden was seen in patients who achieved a remission after study treatment compared with those who did not achieve a remission. Of the 39 patients with JAK2 V617F-mutant disease, 15 had a MR. Eleven patients with a MR also reached remission (73%), while 5 patients did not (21%; P = .003). Fourteen patients with MR were in PBCR (93%), while only 12 patients without MR were in PBCR (50%; P = .014). Additionally, participants with a MR at 2 years had a higher rate of PBCR (P = .025) with a median time to PBCR of 1 month compared with the 6 months observed in patients who did not have a MR to therapy.

There were numerous adverse events with rate of 10% to 50%, leading to a high number of treatment discontinuations. Some of the common hematologic AEs observed in both groups of patients were anemia, thrombocytopenia, and leukopenia. In the PV group versus the MF cohort, grade 1/2 AEs included anemia (71.9% vs 83.3%), thrombocytopenia (28.1% vs 16.7%), and leukopenia (46.9% vs 38.9%), respectively. Grade 3/4 anemia occurred in 3.1% vs 33.3% of the patients with PV and MF, respectively. Additionally, 6.2% of patients with PV experienced grade 3/4 thrombocytopenia, and 3.1% had grade 3/4 leukopenia. There were no cases of grade 3/4 thrombocytopenia or leukopenia in patients with MF. Eight patients dropped out of the study due to AEs.

“In this study, we showed that a novel combination treatment with ruxolitinib and low-dose PEG-IFNα2 is an effective treatment with acceptable toxicity for patients with PV or MF. We observed remission rates of 31% for patients with PV and 44% for patients with MF. Moreover, both groups had relatively high rates of sustained PBCR,” the study authors stated. “Furthermore, we found statistically significant reductions in the MPN-SAF [Symptom Assessment Form] TSS, spleen size, and JAK2 V617F allele burden.”

COMBI was an investigator-initiated, multicenter, open-label, single-arm study. The research was done between 2014 and 2018. Patients were eligible to enroll if they were 18 years of age or older with PV or MF, which was diagnosed according to the 2008 World Health Organization criteria. The study excluded patients with an ECOG performance status ≥3, severe comorbidity, white blood cell count <1.5 × 109/L, and platelet count <100 × 109/L.

Sørensen AL, Mikkelsen SU, Knudsen TA, et al. Ruxolitinib and interferon-a2 combination therapy for patients with polycythemia vera or myelofibrosis: a phase II study [published online December 26, 2019]. Hematologica. doi: 10.3324/haematol.2019.235648.