Safety and Efficacy of Ruxolitinib Retreatment after Treatment Interruption in Patients Enrolled in an Open-Label, Multicenter, Expanded-Access Study in Myelofibrosis
Authors: Gupta Vikas , Tavares Renato S , Griesshammer Martin , Foltz Lynda M , Raanani Pia , Giraldo Pilar , Al-Ali Haifa Kathrin , Martino Bruno , Tannir Bayane , Ronco Julian Perez , Ghosh Jagannath , Vannucchi Alessandro M. 
Published: October 2019

Abstract
BACKGROUND:
Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated durable reductions in splenomegaly and myelofibrosis (MF)-related symptoms. Additionally, ruxolitinib proved superior to placebo and best available therapy in the phase 3 COMFORT studies and showed improved survival. In some patients (pts) receiving ruxolitinib, adverse events (AEs) may lead to treatment interruption; in such pts, AE management, dose optimization, and efficacy expectations may be balanced. This analysis provides further information about the efficacy and safety of ruxolitinib in pts who have restarted treatment after treatment interruption (cutoff date, 01 January 2014) in the JUMP (JAK Inhibitor Ruxolitinib in Myelofibrosis Patients) trial, a large, phase 3b, expanded-access program.
METHODS:
Pts with MF classified as high risk, intermediate-2 risk, or intermediate-1 risk, with a palpable spleen (≥ 5 cm from the costal margin), received starting doses of ruxolitinib based on their platelet counts at baseline (5 mg twice daily [bid; ≥ 50 to < 100 × 109/L], 15 mg bid [100 to 200 × 109/L], or 20 mg bid [> 200 × 109/L]). Endpoints included safety and tolerability, as well as changes in spleen length, symptoms, and laboratory values. This analysis included all pts who started study treatment ≥ 1 year before data cutoff and had ≥ 1 dose interruption of ≥ 7 days.
RESULTS:
This analysis included 207 pts (primary MF, 68.1%; female, 53.1%; median age, 69 years) presenting with baseline medians: spleen length, 13 cm (range, 1.0-35.0 cm); hemoglobin, 99 g/L (50.7% of pts with < 100 g/L); and platelets, 199.5 × 109/L.
At data cutoff, most pts (60.9%) remained on treatment (38.2%) or completed treatment per protocol (22.7%); the main reasons for discontinuation included AEs (18.4%), death (6.8%), disease progression (5.3%), and other (8.7%).
Overall, the median duration of exposure was 12.5 months: 1.9 months from baseline to interruption and 6.5 months after restart. The mean daily dose was 30.5 mg prior to treatment interruption and 19.4 mg after treatment restart. Dose interruptions lasted 7 to 14 days in 41.1% of pts (15 to 21 days, 26.6%; > 21 days, 32.4%) and were mostly due to AEs (92.3%). Most pts (67.1%) had only 1 dose interruption.
At weeks 12, 24, and 48, overall 45%, 53%, and 54% of pts, respectively, achieved a ≥ 50% reduction from baseline in palpable spleen length. In addition, at the same time points, 29%, 23%, and 23% achieved reductions from 25% to 50%. 68.2% (133/195) of pts experienced a ≥ 50% reduction at any time; 77 pts (58%) achieved it before interruption and 56 pts (42%) after restart. From spleen length at restart, 24% of pts achieved a further 50% reduction, 9% experienced a spleen length increase ≥ 50%, and 67% remained stable in between. Clinically meaningful improvements in symptoms (the range for the minimally important difference is 6.5 to 11.2 points), as assessed by the FACT-Lymphoma Total Score, were observed as early as week 4 (mean change from baseline, 9.6), with a trend toward improvement at week 48 (6.1).
The most common hematologic grade 3/4 AEs were anemia (43.5%) and thrombocytopenia (41.1%), leading to permanent discontinuations in 9 (4.4%) and 14 pts (6.8%), respectively. Rates of nonhematologic AEs grade ≥ 3 were low (≤ 2%), except for pneumonia (5.8%), abdominal pain (3.4%), urinary tract infection (3.4%), increased γ-glutamyltransferase (2.4%), asthenia (2.4%), and dyspnea (2.9%), but these rarely led to discontinuations (≤ 1%). Despite > 3-times longer exposure after restart, the rates of AEs before ruxolitinib interruption and after treatment restart were similar overall.
CONCLUSIONS:
In this cohort of pts, ruxolitinib provided reductions in spleen size and symptoms prior to and after treatment interruption. After restart of treatment, pts were able to stay on ruxolitinib at a median dose of ≈ 10 mg bid, and most pts did not require another interruption. Rates of AEs did not increase after treatment restart, with rates of some AEs decreasing; discontinuation rates after restart of treatment are comparable to those observed in the overall study population (Al-Ali et al. EHA 2014). Overall, ruxolitinib is generally safe and well tolerated and provides meaningful reductions in splenomegaly and symptoms in pts who have restarted ruxolitinib after treatment interruption.

Disclosures
Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Griesshammer:Shire: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria; Amgen: Honoraria. Foltz:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Janssen: Consultancy. Al-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Tannir:Novartis: Employment. Ronco:Novartis: Employment. Ghosh:Novartis: Employment. Vannucchi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding.