Low-dose ruxolitinib appears effective as treatment of patients with myelofibrosis, improving splenomegaly and symptoms with a daily dose ≤ 10 mg.
Low-dose ruxolitinib (Jakafi) appears effective as treatment of patients with myelofibrosis (MF), improving splenomegaly and symptoms with a daily dose ≤ 10 mg, according to findings from a retrospective analysis.
While the high-dose group had better outcomes to therapy, the difference in spleen length reduction between high-dose group and low-dose group was minimized. This ultimately suggests that the low-dose treatment induced slow but gradual spleen responses.
The analysis, published in Annals of Hematology, aimed to explore the treatment outcomes of patients with MF using low-dose regimens of ruxolitinib compared with high-dose treatment. The study included patients in the Department of Hematology of West China Hospital of Sichuan University between July 2017 and January 2020 who had received ruxolitinib therapy, all of whom met the 2016 World Health Organization diagnostic criteria for primary MF (PMF), post-essential thrombocythemia (ET) MF, or post-polycythemia vera (PV) MF.
The initial ruxolitinib dose for patients was determined based on the baseline platelet count and patient’s willingness. The dose was adjusted during treatment according to the changes observed in the blood cell count, as well as the therapeutic effect.
Eighty-eight patients were included in the study, of which 68 had PMF, 13 post-ET MF, and 7 post-PV MF. The median time from diagnosis to the start of treatment was 0.5 months. Forty-four patients received low-dose ruxolitinib, which was ≤ 10 mg daily. In this group, 2 patients received a 5 mg dose daily, while the remaining 42 patients had received 10 mg. The dose was individually titrated in 22 patients in order to optimize the safety and efficacy, while dose adjustments mainly occurred during weeks 10 through 16 following initiation of treatment. Final titrated doses were increased in 15 patients and decreased in 7.
Splenomegaly was improved in most patients, with 54 of 61 patients evaluated (88.5%) experienced a reduced spleen length at week 12. The average reduction was 37.4% (range, -33.3% to 100%). Thirty-eight of the patients (62.3%) had palpable spleen length reduced by ≥ 25%, and 23 (37.7%) had palpable spleen length reduced by ≥ 50%.
The palpable spleen length shrank from 5 to 10 cm to < 5 cm in 14 of 35 patients (40.0%), and 16 patients (72.8%) from > 10 cm to 5 to 10 cm.
The average spleen length reduction was 26.9% among the low-dose ruxolitinib group, which was significantly less than what was observed in the high-dose cohort (49.0%). The differences observed among the 4 different dose groups were statistically significant (P =.033), and the difference between the daily ≤ 10 mg dose cohort and the 25 to 30mg cohort was statistically significant (P = 0.007).
The overall palpable spleen length was reduced further at week 48 than what was observed at week 12, and the palpable spleen length reduction of ≥ 25% was seen in 46 of 51 patients (90.2%). Furthermore, 49 patients (96.1%) had reduced spleen length with an average reduction of 58.0% (range, -33.3% to 100%). Thirty-four patients (66.7%) had palpable spleen length reduction ≥ 50%. The palpable spleen length shrank from 5 to 10 cm to < 5 cm in 18 of 29 patients (62.1%), from 10 cm to 5 to 10 cm in 12 of 22 patients (54.5%), and from > 10 cm to < 5 cm in 8 of 22 patients in 36.4%.
At week 48, the average spleen length reduction was 46.7% among patients in the low-dose cohort, which was slightly smaller than what was observed in the high-dose cohort (64.1%) The difference in spleen reduction among the 4 dose cohorts at week 48 were not statistically significant (P =.2).
Eighty-two of 85 patients (96.5%) in the low-dose cohort had a decrease in MPN-SAF TSS compared with baseline, and the average reduction was 39.9% (range, -81.8% to 100%). Among 33 of 85 patients (38.8%), the MPN SAF TSS was decreased by more than 50%. The median MPN-SAF TSS among those with an initial daily dose ≤ 1 mg decreased by 37.8%, similar to what was observed in patients with a daily dose of 15 to 20 mg but less than those with > 20 mg dose.
Overall, the MPN-SAF TSS decrease was not statistically different among the 4 dose groups (P =.220).
The improvement in overall symptoms at week 48 was not as good as what was observed at week 12, and the ratio of patients with an MPN-SAF TSS decrease of ≥ 25% to baseline was reduced from 72.9% at week 12 to 66.6% at week 48. The MPN-SAF TSS decreased from baseline in 52 of 69 patients (75.4%) with a median of 41.5% (range, -228.6 to 100%), and it was decreased by ≥ 50% in 29 of 69 patients (42%).
The median MPN-SAF TSS of patients in the low-dose cohort decreased 35.9%, which was similar to patients with a daily dose of 15 to 20 mg but inferior to patients with a daily dose > 20 mg. The overall decrease in MPN-SAF TSS was not significantly different among the 4 groups (P =.171).
Among 17 patients whose MPN-SAF TSS increased from baseline at week 48 (24.6%), 11 were in the low-dose group (1 patient with a daily dose of 5 mg and 10 with a daily dose of 10 mg).
Overall, 30 patients underwent a bone marrow biopsy after week 48 of ruxolitinib therapy to review bone marrow pathology. Among these patients, 13 (43.3%) had improved bone marrow fibrosis, which included 4 cases with a degree changed from MF-3 to MF-2, 3 cases with the degree change from MF-3 to MF-1, 2 cases from MF-2 to MF-1, 2 cases from MF-1 to MF-0, 1 case from MF-3 to MF-0, and 1 case from MF-2 to MF-0. After treatment, the same degree of bone marrow fibrosis was seen as before treatment in 17 patients (56.7%), and none of the patients had increased bone marrow fibrosis with the low-dose treatment.
Among the 13 patients with improved bone marrow fibrosis, 5 received a final dose of 10 mg, 3 a dose of 20 mg, 2 a dose of 30 mg, and 2 a dose of ≥ 40. Among the 17 with stable bone marrow fibrosis, 5 had a final dose of 10 mg, 5 a dose of 20 mg, 6 a dose of 30 mg, and 1 a dose of 40 mg. Ruxolitinib doses had no significant effect on the bone marrow fibrosis status.
The most common adverse event (AEs) was anemia, which occurred in 80 of 88 patients (90.9%) in any grade, while grade 3/4 anemia occurred in 38 patients (43.2%). Any grade thrombocytopenia was observed in 29 patients (33.0%), of which 17 patients (19.3%) had a grade 3/4 event. Neutropenia was observed in 24 patients (27.3%), in grade 3/4 in 9 (10.2%).
In terms of treatment-emergent AEs, anemia was the most common, occurring in 37 cases (42.0%). Other treatment-emergent AEs included thrombocytopenia in 17 cases (19.3%) and neutropenia in 19 cases (21.6%).
As of March 2020, 76 of the 88 patients remained alive. Among those who had died, 5 were due to bleeding, 3 from severe infections, 2 acute leukemias, 1 renal failure, and 1 gastric cancer.
Overall, these findings demonstrate that low-dose ruxolitinib could be used to improve symptoms in patients with MF. In cases where high-dose ruxolitinib cannot be used because of low platelets or another reason, a lower dose should be considered as a valid therapeutic choice.
Yang Y, Luo H, Zheng Y, et al. Low-dose ruxolitinib shows effective in treating myelofibrosis. [Published Online January 8, 2020]. Ann Hematol. doi: 10.1007/s00277-020-04311-z