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The TRUTH About Ruxolitinib in Thalassemia: Lower Transfusion Burden, No Improvement in Hemoglobin

December 30, 2021

In an update from the phase IIa TRUTH study evaluating ruxolitinib in patients with transfusion-dependent thalassemia, investigators reported that treatment with the JAK1/2 inhibitor led to a reduction in red blood cell (RBC) transfusion dependence and spleen volume from baseline, though there were no clinically relevant improvements in patients' pretransfusion hemoglobin levels.

Ali T. Taher, MD, PhD, of the American University of Beirut Medical Center in Lebanon, and co-authors published their findings in a Letter to the Editor in Blood. Based on results from a preclinical study demonstrating that thalassemic erythroid cells showed upregulation of JAK2, the single-arm, open-label, multicenter TRUTH study evaluated the safety and efficacy of ruxolitinib in 30 patients (27 with ß-thalassemia and 3 with E ß-thalassemia) who required RBC transfusions.

Patients included in the study were on a regular transfusion regimen (requiring ≥2 RBC units within 4-week intervals for 24 weeks prior to enrollment) and had an enlarged spleen (≥450 cm3 confirmed by magnetic resonance imaging or computed tomography scan). Patients were excluded if they had received splenectomy prior to enrollment, had a pretransfusion hemoglobin of <65 g/L, had platelet counts <75×109/L, or had been previously treated with any JAK inhibitor.

The study included a 30-week treatment phase and an extension phase for patients who benefitted from ruxolitinib at the end of 30 weeks. Ruxolitinib was administered at a starting dose of 10 mg twice-daily; the dose could be increased by 5 mg to a maximum of 25 mg twice-daily if spleen volume was reduced by less than 50 percent from baseline by 30 weeks.

Twenty-six patients completed the 30 weeks of treatment, and four discontinued early because of adverse events (AEs; n=2), withdrawal of consent (n=1), or patient/guardian decision (n=1). Eighteen patients entered the extension phase, four of whom discontinued the study early.

The safety profile of ruxolitinib in this study was consistent with previous reports, and most AEs were grade 1 or 2 in severity. The most common all-grade AEs were upper respiratory tract infection (n=8; 27%); nausea (n=6; 20%); and diarrhea, upper abdominal pain, and weight gain (n=5; 17% for all). Five patients (17%) reported grade 3 or 4 anemia. Serious AEs deemed related to ruxolitinib included pneumonia (n=1), viral pneumonia (n=1), drug-induced hepatitis (n=1), and pyrexia (n=1).

In the primary analysis, which included the 27 patients who received at least 18 weeks of treatment, the researchers observed a mean 5.9 percent decrease in RBC transfusion requirement (95% CI –14.7-2.8) from baseline:

  • 12 patients showed a decrease in RBC volume
  • 7 showed an increase
  • 8 showed no change

At week 30, 24 patients had evaluable spleen size measurements, and there was a consistent observed reduction in spleen size from baseline, at a median of 22.5 percent by week 12 (range = –44.3-34.5%; n=26) and 26.4 percent by week 30 (range = –64.3-8.5%; n=25). "Except [for] one patient who was off study at week 30 due to AEs of anemia and upper respiratory tract infection, all patients were able to achieve at least some degree of spleen volume reduction with ruxolitinib treatment," the authors wrote. "These results show that ruxolitinib reduces splenomegaly in patients with thalassemia and suggests that targeting [the] EPO-EPOR-JAK2-STAT5 axis may limit the excessive proliferation of erythroid progenitors in [the] spleen."

The researchers also observed 1.7-fold increases in hepcidin levels from baseline to week 30 (standard deviation [SD] = 1.15; n=24), which suggest improved handling of iron absorption in the long term.  Other biomarkers (including serum iron, serum ferritin, transferrin, and transferrin saturation) experienced limited change from baseline. Though there were no significant changes in these factors, "increased levels of hepcidin may suggest that the handling of iron absorption could be improved in the long term" with ruxolitinib treatment, the researchers noted.

Also, although the investigators observed "a trend for improvement" in the median pretransfusion hemoglobin levels over time at each six-week interval, there was no clinically relevant improvement in this secondary endpoint.

"Since the major purpose of reducing spleen size in patients with transfusion-dependent thalassemia is to improve pretransfusion hemoglobin and related reduction in transfusion needs where ruxolitinib had shown a limited effect, no further phase II studies are planned," the authors concluded.

The study is limited by its small patient population and the lack of a comparator arm.

Novartis Pharmaceuticals Corporation supported the study.

The authors report receiving funding from Novartis, Celgene, Janssen-Cilag, Roche, Pfizer, ApoPharma, Ionis Pharmaceuticals, Shire, and Cerus. Novartis provided editorial support for the original manuscript.


Taher AT, Karakas Z, Cassinerio E, et al. Efficacy and safety of ruxolitinib in regularly transfused patients with thalassemia: results from a phase 2a study. Blood. 2017 November 2. [Epub ahead of print]


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