Abstract Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA) approved for treating chemotherapy-induced anemia. This phase II, double-blind, placebo-controlled study examined the efficacy of darbepoetin alfa for treating anemia of cancer (AoC) in patients not receiving chemotherapy or radiotherapy. Patients were randomized 3:1 to receive darbepoetin alfa (6.75 μg/kg) or placebo every 4 weeks; the end of the study was at week 17. The primary endpoint was the percentage of patients with a hematopoietic response. Secondary endpoints included transfusion incidence and safety parameters. Efficacy analyses were performed on 162 patients in the darbepoetin alfa group and 56 patients in the placebo group. The Kaplan–Meier percentages of patients who achieved a hematopoietic response (darbepoetin alfa, 69%; placebo, 24%) or achieved the target hemoglobin (darbepoetin alfa, 85%; placebo, 50%) differed significantly between treatment groups. The transfusion incidence did not differ between treatment groups probably because of the low baseline transfusion rates in AoC patients. The incidence of adverse events (including on-study deaths) was similar in both groups. In conclusion, darbepoetin alfa appeared to be well tolerated and significantly increased hemoglobin levels in these AoC study patients.
Abstract Momelotinib (MMB) is a JAK1/2 and ACVR1 inhibitor with demonstrated clinical activity in all 3 hallmarks of myelofibrosis (MF): anemia, constitutional symptoms, and splenomegaly. In this phase 2 open-label translational biology study (NCT02515630) of 41 transfusion-dependent patients with MF, we explored mechanisms underlying the favorable activity of MMB on MF-associated iron-restricted anemia, including its impact on serum hepcidin levels, and markers of iron storage and availability, erythropoiesis, and inflammation. A transfusion-independent response (TI-R), defined as red blood cell transfusion independence (TI) ≥12 weeks at any time on study, occurred in 17 patients (41%; 95% confidence interval [CI], 26%-58%), including 14 patients (34%; 95% CI, 20%-51%) who achieved TI-R by week 24. In addition, 78% of TI nonresponse (TI-NR) patients achieved a ≥50% decrease in transfusion requirement for ≥8 weeks. Adverse events (AEs) were consistent with previous studies of MMB in MF, with cough, diarrhea, and nausea as the most common. Twenty-one patients experienced grade ≥3 AEs, most commonly anemia and neutropenia. Consistent with preclinical data, daily MMB treatment led to an acute and persistent decrease in blood hepcidin associated with increased iron availability and markers of erythropoiesis. Baseline characteristics associated with TI-R were lower inflammation and hepcidin as well as increased markers of erythropoiesis and bone marrow function. Overall, the study demonstrates that MMB treatment decreases hepcidin in conjunction with improving iron metabolism and erythropoiesis, suggesting a mechanistic explanation for the reduced transfusion dependency observed in transfusion-dependent MF patients treated with MMB, thereby addressing the key unmet medical need in the MF population.
6605 Background: This study update assesses change in chronic LG non-heme AEs in adult Ph+ CML-CP pts switched from IM to NIL. Methods: Pts were eligible if treated with IM 400 mg/d for ≥3 mo, and had IM-related grade (G) 1/2 non-heme AEs persisting ≥2 mo or recurring ≥3 times and persisting despite best supportive care. Pts received NIL 300 mg BID. Primary endpoint is change in IM-related LG non-heme AEs at 3 mo. Disease response was monitored by RQ-PCR and pt-reported outcomes measured by 2 quality-of-life (QoL) questions and MD Anderson Symptom Inventory (MDASI)-CML. Results: 47 pts were enrolled as of data cut-off (11/14/2011). There were 168 baseline IM-related non-heme AEs: 121 G1, 47 G2. 37 pts completed 3 mo NIL, by 3 mo 103 of 154 IM-related AEs (67%) improved (92 resolved, 11 improved from G2 to G1), 47 unchanged, 4 increased in severity. 13 pts were dose reduced for NIL-related AEs; 8 pts re-escalated after AEs recovered to G1 or resolved. 34 G3 AEs occurred in 15 pts; investigators reported 19 AEs as suspected NIL-related (increased bilirubin, lipase, or blood glucose; hypokalemia; hypophosphatemia; pruritus; bronchitis; dehydration; rash; arthralgia; pleural effusion). 8 pts discontinued NIL: 6 for AEs, 2 withdrew consent. No G4 AEs were reported. 32 pts had MMR (3-log reduction of Bcr-Abl; ≤0.1% IS) at entry; 16 additional pts achieved MMR on NIL. At entry, 18 pts had 4-log reduction and 10 pts 4.5-log reduction in Bcr-Abl. 16 and 13 additional pts achieved 4- and 4.5-log reduction, respectively, on NIL. At 3 mo (n=34) 62% and 53% pts reported QoL improvement from baseline in the previous 24 h and 7 d, respectively. Reduction in MDASI-CML severity/interference scores indicates symptom improvement. Mean reductions in MDASI-CML from baseline at 3 mo: severity, 1.21 (n=34); interference, 1.55 (n=33). Conclusions: 3 mo after switching to NIL, ~70% baseline chronic LG non-heme IM-related AEs improved and ≥53% of pts reported improvement in QoL. Molecular responses were maintained or improved in all patients. Switch from IM to NIL in majority of pts reduces IM-related toxicities and preserves/induces molecular response in CML-CP.
