Efficacy and Safety of Ruxolitinib in Regularly Transfused Patients with Thalassemia: Results from Single-Arm, Multicenter, Phase 2a Truth Study
Authors: Aydinok Yesim , Karakas Zeynep , Cassinerio Elena , Siritanaratkul Noppadol , Kattamis Antonis , Maggio Aurelio , Hollaender Norbert , Mahuzier Bruyère , Gadbaw Brian , Taher Ali T. 
Published: October 2019

Abstract

BACKGROUND: Ruxolitinib (RUX) is approved in adult patients (pts) with myelofibrosis (MF), and in pts with polycythemia vera (PV) who are resistant/intolerant to hydroxyurea. Splenomegaly, a key clinical feature in advanced MF/PV, is also common in pts with transfusion-dependent thalassemia (TDT). In pts with TDT, splenomegaly worsens anemia, leading to increased transfusion requirement (TR). Similar to murine models of MF (Ostojic A, 2012), JAK2 inhibition led to a decrease in spleen size in murine models of thalassemia (Musallam KM, 2013). Additionally, thalassemia-related ineffective erythropoiesis was associated with hyperactivation of JAK-STAT pathway in preclinical studies. These findings indicate that RUX treatment (Tx) might benefit pts with TDT and splenomegaly. Present exploratory study aims to evaluate the effect of RUX Tx on TR, spleen volume (SV), and pre-transfusion hemoglobin (Hgb) levels.
METHODS: TRUTH is a single-arm, multicenter, phase 2a study exploring the efficacy and safety of RUX in regularly transfused adult pts (N = 30) with thalassemia and splenomegaly, for 30 weeks (core study). Starting dose of RUX was 10 mg twice daily (maximum dose of 25 mg in 5 mg/10 mg increments). Pts were required to receive iron chelation (deferoxamine/deferasirox) for at least 4 week prior to screening and throughout the study. Primary end point was the percent change of red blood cells (RBCs) transfused between week 6 to 30 vs baseline period (BL; defined as period between 24 weeks prior to start of Tx and week 0). Change of SV from BL (by MRI/CT) at week 12 and week 30 was a secondary end point. Other secondary end points included safety (N = 30, safety set) and change of pre-transfusion Hgb level from BL.
RESULTS: Of the 30 pts enrolled (median age, 24 years; 60% male), 26 completed the core phase at week 30 and 4 discontinued before week 30 (adverse event [AE], N = 2; withdrew consent, N = 1; subject/guardian decision, N = 1). Of those 26 who completed core Tx, 20 pts continue to receive RUX beyond the core study via other mechanisms. The median duration of exposure during the core phase was 30.2 weeks and median actual dose intensity of RUX was 27.2 mg/day (range, 13.3-39.0 mg/day). Mean hematocrit (HCT) adjusted volume of transfused RBC per 4 weeks was 605 mL for the BL period and 560 mL for the on-Tx period (between week 6-30; N = 27, per protocol set; 3 pts received < 18 weeks of Tx). Mean percent change of transfusion rate was −5.9 (95% CI: −14.7, 2.83). Change of HCT adjusted transfused volume per 4 weeks for on-Tx period vs BL is shown in Figure 1A. The percent change from BL in SV at week 30 is represented in Figure 1B. The mean SV reduction from BL at week 12 (N = 26) and week 30 (N = 25) was −19.7% and −26.8%, respectively. A slight trend for improvement was observed in the median pre-transfusion Hgb levels over time (pre-Tx = 8.4 g/L; end of study [week 24-30] = 8.9 g/L). At BL, 77% (23/30) of pts had Hgb levels below LLN but ≥ 8 g/dL and 20% (6/30) of pts had Hgb levels < 8 g/dL. At BL, 20% (6/30) of pts had a platelet (PLT) count below LLN but > 50 × 109/L, while no pt had PLT counts < 50 × 109/L. Worst post-BL hematologic abnormalities were Hgb (< 8g/dL, [hypo] = 17 pts [57%]), and PLT counts (< 50 × 109/L [hypo] = 1 pt [3%]). The most common AEs (all grade [G], ≥ 5%, regardless of study drug relationship) were upper respiratory tract infection (27%), nausea (20%), and upper abdominal pain/anemia/diarrhea/weight increased [each = 17%]). Overall, 25 pts experienced AEs, 11 pts had G 3 or 4 AEs, and 6 pts had serious AEs (regardless of study drug relationship); while, 13 pts experienced AEs, 5 pts had G 3 or 4 AEs, and 3 pts had serious AEs that were suspected to be related to the study drug. No deaths were reported during the study. AEs led to dose reduction/study Tx interruption in 9 pts (regardless of study drug relationship [≥ 5%]: nausea [all G = 2 pts (7%); G 3 or 4 = 1 pt (3%)] and vomiting [all G = 2 pts (7%); G 3 or 4 = 1 pt (3%)]).
CONCLUSION: RUX Tx showed a trend for improvement in transfused red cells and a slight improvement in pre-transfusion Hgb; while, there was a noticeable reduction in SV over time. As per investigator assessment of clinical benefit, a majority of pts continued Tx beyond the core study. RUX was well tolerated in the study population with modest incidences of G 3 or 4 and serious AEs, with no new safety findings. Given the sustained decrease in SV, further studies could be valuable to determine if RUX Tx may be an alternative to splenectomy in pts with TDT.

Disclosures
Aydinok: Shire: Research Funding; Cerus: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Karakas:Novartis: Research Funding. Siritanaratkul:Jansen-Cilag: Research Funding; Novartis: Research Funding; Roche: Research Funding; Pfizer: Research Funding. Kattamis:Novartis: Honoraria, Research Funding; ApoPharma: Honoraria. Hollaender:Novartis: Employment. Mahuzier:Novartis: Employment. Gadbaw:Novartis: Employment. Taher:Novartis: Honoraria, Research Funding; Celgene: Research Funding.