Ruxolitinib Efficacy and Safety in Myelofibrosis: A Multicenter Observational Study

PATIENTS AND METHODS

A multicenter observational study was conducted in patients with myelofibrosis receiving ruxolitinib. Data regarding disease characteristics, dosage, safety and efficacy of ruxolitinib were collected retrospectively.

A total of 73 patients, diagnosed between 2002 and 2014 in 10 clinical sites, were included in the analysis. The male:female ratio was 2:1, median age at diagnosis was 64 years (range 27 to 82) and median duration of ruxolitinib therapy was 14 months. The study expands over 376.7 patient-years of observation, including 94.4 patient-years while on ruxolitinib.

RESULTS

The diagnosis, revisited according to the WHO 2008 criteria, was primary myelofibrosis in 61%, post-essential thrombocythemia myelofibrosis in 21% and post-polycythemia vera myelofibrosis in 17% of patients. Median time from diagnosis till onset of ruxolitinib was 2.97 years. At the beginning of ruxolitinib treatment, the international prognostic scoring system (IPSS) risk category was low (3%), intermediate-1 (30%), intermediate-2 (42%), high (25%). Ruxolitinib starting dose was 5mg (18%), 10mg (20%), 15mg (30%), 20mg (32%) twice daily (BID).

Response was defined as reduction in spleen size and disappearance of constitutional symptoms. The mean spleen size -measured in centimeters below left costal margin- was reduced from 10.8cm ± 1.6 (95% CI - confidence interval) at the beginning of ruxolitinib, to 6.6cm ±1.5 after 3 months and further to 4.5cm ±3.0 after 12 months of treatment. The reduction in spleen size after 3 months of treatment, expressed as percentage change from baseline tends to be higher with higher starting dose: 33% with 5mg BID, 29% with 10mg BID, 54% with 15mg BID and 59% with 20mg BID. At the onset of ruxolitinib, 77% of patients experienced constitutional symptoms. At 1 and 3 months of treatment the percentage fell to 30% and 15.5% respectively. On ruxolitinib dose of 20mg BID, the presence of constitutional symptoms rapidly declined from 84% to 18% after the first month of treatment. On the lower dose of 5mg BID, 67% of patients remained with symptoms after one month (p=0.02), but that proportion fell down to 18% by the third month of treatment with the same dose.

Ruxolitinib was well tolerated without any non-hematological adverse events in 85.1% of patients at the beginning of therapy and in 90.2% after 3 months. Gastro-intestinal symptoms were the main complain in 6% of patients at the beginning of therapy, which disappeared by the third month of treatment. Any other non-hematological adverse event accounted for less than 2% each.

Hematological parameters were affected by ruxolitinib therapy. Thrombocytopenia of all grades was present in 30% of patients at the beginning of treatment, in 52% at 3 months, and 59% at 12 months of treatment. Grade 3 and 4 thrombocytopenia was present in 7%, 14% and 18% respectively. The respective median platelet counts were 201000/μL, 125000/μL and 115000/μL.

The dose of ruxolitinib remained stable in half the patients and was modified in the rest. Of those starting with 5mg BID, 60% remained in that dose, and 20% had their dose increased. Of those starting with 10mg BID, 67% remained stable, and 25% had their dose increased. Of those on 15mg BID, 53% remained in the same dose and 32% had their dose decreased. The majority (68%) of patients starting with 20mg BID, had their dose decreased. Dose modifications of ruxolinitib at 1, 3, 6, 12 months of treatment were not correlated with statistically significant changes in spleen size at the same time points (p-values: 0.4, 0.8, 0.8, 0.6 respectively).

Permanent discontinuation of ruxolitinib occured in 16.7% of patients for the following reasons: side effects (including anemia, thrombocytopenia, investigator decision, patient preference) in 8.3%, progressive disease (including one death) in 5% and no response in 3.3% of the patients.

CONCLUSIONS

Ruxolitinib can effectively improve splenomegaly and alleviate constitutional symptoms in patients with myelofibrosis. The symptoms are relieved slower with the low dosage, whereas the main side effect is thrombocytopenia. It can however be maintained within safety limits (grade < 3), with dose modifications without hampering efficacy.