Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls

Abstract

Ruxolitinib is JAK1/JAK2 inhibitor with established clinical benefit in myelofibrosis (MF). We analyzed long-term outcomes of 107 patients with intermediate-2 or high-risk MF receiving ruxolitinib at MD Anderson Cancer Center (MDACC) on phase 1/2 trial. After a median of 32 months of follow-up, 58 patients (54%) were still receiving ruxolitinib, with overall survival (OS) of 69%. The splenomegaly and symptom reductions achieved with ruxolitinib were sustained with long-term therapy. Therapy was well tolerated; discontinuation rates at 1, 2, and 3 years were 24%, 36%, and 46%, respectively. OS of 107 MDACC patients was significantly better (P = .005) than that of 310 matched (based on trial enrollment criteria) historical control patients, primarily because of highly significant difference in OS in the high-risk subgroup (P = .006). Furthermore, among MDACC patients, those with high-risk MF experienced the same OS as those with intermediate-2 risk. Patients with ≥ 50% reduction in splenomegaly had significantly prolonged survival versus those with < 25% reduction (P < .0001). Comparison of discontinuation rates and reasons for stopping the therapy to those reported for other 51 patients in the phase 1/2 trial, and 155 ruxolitinib-treated patients in phase 3 COMFORT-I study, suggest that continued therapy with ruxolitinib at optimal doses contributes to the benefits seen, including OS benefit.

Figures

Figure 1

Dose levels for patients enrolled at MDACC in study INCB18424-251. (A) Initial doses were assigned by the clinical study protocol amendment in operation at the time of enrollment. Seventy-nine of 107 patients began dosing with twice-daily regimens ranging from 10 mg BID to 50 mg BID; the proportion of all patients starting with BID doses at a given dose group is shown. (B) Fifty-eight patients remained on study at the time of data analysis; the proportion of patients receiving the indicated BID doses is shown.

Figure 2

Effect of ruxolitinib on spleen size and myelofibrosis symptoms for patients enrolled at MDACC in study INCB18424-251. (A) Spleen length was measured at each study visit by manual palpation. Mean change from baseline (± SEM) for all 97 patients with palpable spleen at baseline and the 61 patients who demonstrated a ≥ 50% reduction in spleen length, confirmed 12 weeks later, is shown. (B) The modified Myelofibrosis Symptom Assessment Form (MFSAF) was used at serial clinic visits in 71 patients enrolled at MDACC, and a composite score corresponding to the symptoms of abdominal pain and discomfort, itching, night sweats, and bone/muscle pain was determined. The figure depicts the median percentage of change in this total symptom score over time.

Figure 3

Duration of spleen size reduction measured by palpable spleen length, or MRI/CT-imaged volume for patients enrolled at MDACC in study INCB18424-251. (A) The duration of a ≥ 50% reduction in palpable spleen length was estimated using the Kaplan-Meier method based on the 61 patients who exhibited a confirmed ≥ 50% reduction in palpable spleen length. The horizontal axis represents the time from onset of response. Patients could begin responding at any time; therefore, “weeks from onset” does not correspond to weeks in the study. Twenty-eight of 61 patients lost the response (date of first observation of spleen length reduction < 25% from baseline) before the analysis date. The median duration of response was estimated to be 166 weeks. (B) The duration of a ≥ 35% reduction in spleen volume was estimated using the Kaplan-Meier method based on the 17 patients who had a ≥ 35% reduction from baseline. The horizontal axis represents the time from onset of response. Patients could begin responding at any time; therefore, “weeks from onset” does not correspond to weeks in the study. Seven of 17 patients lost the response (defined by the first date with < 10% reduction from baseline) before the analysis date. The median duration of response was estimated to be 93 weeks, but note this estimate was based on few events in a small population.

Figure 4

Kaplan-Meier comparison of overall survival between patients at MDACC in study INCB18424-251 and the historical control population. (A) Kaplan-Meier plot of overall survival for ruxolitinib-treated and historical control patients, with HR, 95% CI, and P value, adjusted for baseline IPSS risk status. There were 33 deaths in the ruxolitinib-treated group (N = 107) and 187 deaths in the control group (N = 310). (B) Kaplan-Meier plot of overall survival for ruxolitinib-treated and historical control patients designated as high risk according to the IPSS. There were 21 deaths in the high-risk ruxolitinib-treated group (N = 63) and 111 deaths in the control group (N = 165). (C) Kaplan-Meier plot of overall survival for ruxolitinib-treated and historical control patients designated as intermediate-2 according to the IPSS. There were 10 deaths in the intermediate-2 risk ruxolitinib-treated group (N = 34) and 76 deaths in the control group (N = 145). (D) Kaplan-Meier plot of overall survival for ruxolitinib-treated patients at MDACC in study INCB18424-251 designated as high risk and intermediate-2 according to the IPSS. *Hazard ratio >1 favors intermediate-2 risk group.

Figure 5

Kaplan-Meier analysis of overall survival (in months) of patients enrolled at MDACC in study INCB18424-251 by degree of spleen length reduction. Patients were analyzed in 3 groups: patients who exhibited confirmed response of ≥ 50% reduction of palpable spleen length (n = 61), patients who exhibited confirmed response of > 25% but < 50% reduction in palpable spleen length (n = 13), and patients who exhibited confirmed < 25% reduction in palpable spleen length (n = 23). *Comparison of < 25% reduction to ≥ 50% reduction.

Figure 6

Comparison of discontinuation rates and mean ruxolitinib dosing over time in study INCB18424-251. (A) Kaplan-Meier estimates of discontinuation rates in patients enrolled from MDACC and Mayo Clinic Rochester. At 6 months, discontinuations at the Mayo Clinic Rochester were much higher than those observed at the MDACC Center. (B) Mean total daily dose of ruxolitinib at the MDACC was much higher than that for patients enrolled at the Mayo Clinic Rochester and was similar to the mean total daily dose of ruxolitinib in COMFORT-I (31 mg).