Anemia and the Use of Erythropoietic-Stimulating Agents with Ruxolitinib in the COMFORT-II Study

Ruxolitinib (INC424), a potent and selective oral JAK1 and JAK2 inhibitor, has demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms, role functioning, and quality of life in 2 phase 3 studies (the COMFORT studies) in patients with primary myelofibrosis (PMF), post-polycythemia vera-MF (PPV-MF), and post-essential thrombocythemia-MF (PET-MF). Consistent with ruxolitinib's known mechanism of action, anemia was one of the most frequently reported adverse events (AEs) and was generally transient and manageable and led to discontinuation in only one patient. In clinical practice, anemia can be managed with erythropoietic-stimulating agents (ESAs), which promote red blood cell proliferation via cytokine receptors that signal through the JAK pathway. Because these agents act upstream of ruxolitinib in the JAK2 pathway, it is important to determine the effects of these medications on the safety and efficacy of ruxolitinib.

COMFORT-II is an open-label, randomized, multicenter study in patients with MF. Patients were randomized (2:1) to receive ruxolitinib 15 or 20 mg twice daily or best available therapy (BAT; as selected by the investigator). Use of ESAs (eg, darbepoetin alfa, epoetin alfa), although not prohibited, was discouraged for patients randomized to ruxolitinib because they can increase spleen size, which could confound the efficacy analyses. This post hoc analysis evaluates the safety and efficacy of ruxolitinib in patients receiving concomitant ESAs in the COMFORT-II study.

Use of ESAs was reported for 9 (PMF, n=6; PET-MF, n=2; PPV-MF, n=1) of the 146 patients who were treated with ruxolitinib (darbepoetin alfa, 1.4% [n=2]; epoetin alfa, 4.8% [n=7]), with a median duration of exposure to ESAs of 22.1 weeks. The median dose intensity of ruxolitinib was numerically higher for patients who received ESAs (+ESA group; 39.2 mg/day) compared with those who did not receive ESAs (–ESA group; 30.0 mg/day). The mean change from baseline in spleen volume at week 48 was similar in both groups (+ESA, –29.8%; –ESA, –30.1%); 44.4% of the +ESA group (4 of 9 patients) and 27.0% of the –ESA group (37 of 137 patients) achieved ≥ 35% reduction in spleen volume from baseline at week 48. The mean number of packed red blood cell units received per month while on treatment was similar in both groups (+ESA, 0.78; –ESA, 0.86). The AEs reported in the +ESA group were similar to those reported in the –ESA group; serious AEs (SAEs) were reported for 4 patients in the +ESA group (patient 1: fracture of the distal radius after a fall; patient 2: urinary tract infection, abdominal pain, and anemia; patient 3: herpes zoster; patient 4: respiratory infection, decrease in general condition, and acute renal insufficiency). SAEs determined to be possibly related to study medication (respiratory infection and decrease in general condition) occurred in 1 patient who discontinued the study; this patient died from respiratory infection. At baseline, patients in the +ESA and –ESA groups had median creatinine levels of 70.2 and 75.4 μmol/L, respectively. Median changes from baseline at week 48 were similar for reticulocytes (+ESA, –13.6%; –ESA, –9.1%) and hemoglobin (+ESA, –5.8%; –ESA, –5.7%). The +ESA group had higher median levels of erythropoietin (39.0 and 7.0 pg/mL) at baseline and a larger increase at week 48 (485.0% and 185.2%).

In the COMFORT-II study, ruxolitinib resulted in significant reduction in spleen size compared with BAT in patients with PMF, PPV-MF, or PET-MF. In these analyses, although the sample size is small, the use of ESAs did not appear to affect the efficacy of ruxolitinib concerning spleen size reduction, and no substantially different AEs were reported between patients receiving ESAs and those who did not. Additionally, concomitant use of ESAs may have allowed for an increased dose of ruxolitinib. The use of ESAs for the treatment of anemia is common in clinical practice, and further analyses in combination with ruxolitinib in this patient population are warranted.

McMullin:Novartis: Honoraria; Amgen: Honoraria; Bristol Myers: Honoraria. Harrison:Novartis: Honoraria; Incyte: Honoraria; S*Bio: Honoraria; Celgene: Honoraria; Sanofi Aventis: Honoraria. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment. Wearver:Novartis Pharma AG: Employment. Stalbovskaya:Novartis Pharma AG: Employment. Kiladjian:Novartis: Honoraria; Celgene: Honoraria.