Efficacy and safety of ruxolitinib in patients with myelofibrosis and low platelet count (50 × 10⁹/L to <100 × 10⁹/L) at baseline: the final analysis of EXPAND

Abstract

Background: Thrombocytopenia is a common feature of myelofibrosis (MF), a myeloproliferative neoplasm driven by dysregulated JAK/STAT signaling; however, pivotal trials assessing the efficacy of ruxolitinib (a JAK1/2 inhibitor) excluded MF patients with low platelet counts (&lt;100 × 109/L). Objectives: Determination of the maximum safe starting dose (MSSD) of ruxolitinib was the primary endpoint, with long-term safety and efficacy as secondary and exploratory endpoints, respectively. Design: EXPAND (NCT01317875) was a phase 1b, open-label, ruxolitinib dose-finding study in patients with MF and low platelet counts (50 to &lt;100 × 109/L). Methods: Patients were stratified according to baseline platelet count into stratum 1 (S1, 75 to &lt;100 × 109/L) or stratum 2 (S2, 50 to &lt;75 × 109/L). Previous analyses established the MSSD at 10 mg twice daily (bid); long-term results are reported here. Results: Of 69 enrolled patients, 38 received ruxolitinib at the MSSD (S1, n = 20; S2, n = 18) and are the focus of this analysis. The incidence of adverse events was consistent with the known safety profile of ruxolitinib, with thrombocytopenia (S1, 50%; S2, 78%) and anemia (S1, 55%; S2, 44%) the most frequently reported adverse events and no new or unexpected safety signals. Substantial clinical benefits were observed for patients in both strata: 50% (10/20) and 67% (12/18) of patients in S1 and S2, respectively, achieved a spleen response (defined as ⩾50% reduction in spleen length from baseline) at any time during the study. Conclusion: The final safety and efficacy results from EXPAND support the use of a 10 mg bid starting dose of ruxolitinib in patients with MF and platelet counts 50 to &lt;100 × 109/L. Registration: ClinicalTrials.gov NCT01317875.

Pharmacokinetics and Pharmacodynamics of Ruxolitinib: A Review

“…Ruxolitinib AEs are mostly treated by dose reductions, supportive care or with concomitant medication such as corticosteroids, antibiotics or blood transfusions [ 13 , 38 , 53 , 54 ]. In the EXPAND study, similar results were found [ 55 ]. This study was performed with MF patients with low platelet count divided into two strata (75 to < 100 × 10 9 /L and 50 to < 75 × 10 9 /L).…”

“…This study was performed with MF patients with low platelet count divided into two strata (75 to < 100 × 10 9 /L and 50 to < 75 × 10 9 /L). All 69 patients experienced at least one AE such as anemia, thrombocytopenia, decreased platelet count and fatigue, where thrombocytopenia was the most common reason to discontinue the treatment with ruxolitinib [ 55 ].…”

The management of myelofibrosis: A British Society for Haematology Guideline

“…Regarding JAK inhibitors, both ruxolitinib and fedratinib are safe and effective in patients with baseline platelet counts ≥50 × 10 9 /L. 12,40 The SPC do not support institution of therapy below this level, although both drugs are frequently used in real-world practice outside strict SPC recommendations with dose modification and close monitoring. Pacritinib, as described above, is specifically targeted at MF patients with platelet counts <50 × 10 9 /L.…”

“…A suggested algorithm for these patients is shown in Figure 3, including where more recent JAK inhibitors, if/ when approved, may fit best. Regarding JAK inhibitors, both ruxolitinib and fedratinib are safe and effective in patients with baseline platelet counts ≥50 × 10 9 /L 12,40 . The SPC do not support institution of therapy below this level, although both drugs are frequently used in real‐world practice outside strict SPC recommendations with dose modification and close monitoring.…”

Toxicity of targeted anticancer treatments on the liver in myeloproliferative neoplasms

“…In this investigation, a total of 5 cases of elevations in bilirubin values were noticed: 1 of the 18 patients who had platelets < 75000/mmc but > 50000/mmc and 4 of the 20 patients who had platelets < 100000/mmc but > 75000/mmc. However, of these, only two grade 3 or more increases in bilirubin levels were highlighted, all were reported in patients with thrombocyte counts < 100000/mmc but > 75000/mmc[ 56 ].…”