Two-Stage Pharmacokinetic & Efficacy Study of Lenalidomide Alone or Combined with Recombinant Erythropoietin (EPO) in Lower Risk MDS EPO-Failures [PK-002].
Authors: List Alan F. , Lancet Jeffrey E. , Melchert Magda , Saba Hussein , Lush Richard , Yu Jian , Chen Nianhang , Schmidt Michele , Knight Robert 
Published: October 2019

Abstract
Background: Lenalidomide (LEN) is a myelosuppressive immunomodulatory drug that has erythropoietic activity in lower risk MDS patients who failed treatment with rhu-EPO (N Eng J Med2005; 352:549). We previously reported that LEN acts to relieve suppression of the EPO-receptor signal in MDS erythroid precursors, suggesting that the erythropoietic activity of LEN might be improved by combined treatment with rhu-EPO. To evaluate the potential benefit of the combination and the relationship between LEN pharmacokinetics (PK) and treatment-related cytopenias, we performed a PK and efficacy study using a two step design.
Methods: Eligible patients had transfusion-dependent, Low/Int-1 IPSS MDS and documented prior treatment with rhu-EPO (≥40,000 U/wk x 6, or darbepoetin equivalent). In the first phase of the study, patients received LEN monotherapy at a dose of 10mg/d [n=25] or 15 mg/d [n=15]. Single dose [n=12] and steady state [n=24] fasting PK were evaluated on days −7 and +14, respectively in subjects receiving the 10mg LEN dosage. After 16 weeks of monotherapy, erythroid non-responders (NR) and minor (MiE) responders (IWG 2000) were offered Combined Treatment in which epoetin alpha (EPO) was added at a weekly dose of 40,000 units sc for a minimum of 8 weeks. Bone marrow (BM) aspirate & biopsy were repeated within 72H of the first grade 4 cytopenia nadir.
Results: Demographics of the 39 patients treated to date include: median age, 73 years; IPSS categories, Low [n=17] and Int-1 [n=22]; deletion 5q, n=7. Among 33 patients that completed 16 weeks of monotherapy, 11 (33%) were erythroid responders [10 mg, 7/22 (32%); 15 mg, 4/11 (36%)] with 9 major [del(5q), n=6] and 2 MiE. Sixteen patients proceeded to the Combination Phase with 4 (25%) achieving an erythroid response (2 major, 2 MiE) [10 mg, 1/10; 15 mg, 3/6]. PK analyses showed no evidence of drug accumulation after 14 days of treatment. LEN AUC was highest in patients with reduced creatinine clearance (CLcr, 30–49 mL/min, n=2: 955±49; vs. CLcr ≥50 mL/min, n=22: 558±166). There was no significant difference in steady state AUC or Cmax in patients experiencing a ≥50% vs. <50% decrease in ANC or platelet count during the first 28 days of treatment. However, mean AUC inversely correlated with the interval to ≥50% reduction in platelet count (ANOVA, P = 0.04). Neutropenia [overall, 28/39 (72%); 10mg, 20/25 (80); 15mg, 8/14 (57%)] and thrombocytopenia [overall, 23/39 (59%); 10mg, 17/25 (68%); 15mg, 6/14 (43%)] were the most common ≥grade 3 adverse events (CTC v.3.0), which were accompanied by no significant change in BM cellularity or myeloid:erythroid ratio in non-del5q patients (n=10; P=0.566).
Conclusions: Inter-patient variation in systemic LEN exposure is influenced by renal function and may impact interval to development of dose-limiting cytopenias. LEN has erythropoietic activity in primary EPO-non-responders, which may be improved with the addition of EPO. The clinical benefit of the LEN+EPO combination will be investigated in a phase III intergroup study, E2905, in patients who failed primary EPO treatment or have a poor cytokine response profile.