Pomalidomide In Sickle Cell Disease: Phase I Study Of a Novel Anti-Switching Agent

Thalidomide (THAL), lenalidomide (LEN), and pomalidomide (POM) have been used successfully in the treatment of several inflammatory and neoplastic disorders (e.g. erythema nodosum leprosum, multiple myeloma, and myelodysplastic syndromes) over the past two decades. THAL, LEN, and POM use is strictly regulated as they are teratogenic, although LEN and POM are considered less teratogenic than THAL. The anti-neoplastic effects of these agents include anti-VEGF action, in addition to anti-inflammatory, immunomodulatory, and antiproliferative properties. POM has up to a >50,000 fold more potent anti-TNFα effect than THAL. These effects are suggestive of a potential benefit of these drugs as anti-inflammatory agents in sickle cell disease (SCD). Moutouh de Parseval et al (JCI, 2008) showed that POM induced fetal hemoglobin (HbF) production more potently than hydroxyurea (HU) in a dose-dependent manner in CD34+ cell cultures from peripheral blood in patients with SCD. Furthermore, while increasing concentrations of HU resulted in cytotoxicity and a sharp decline in cell viability, POM had no such effect. This was followed by the study of POM in a mouse model by our group; Meiler et al showed that POM induced HbF in a manner comparable with HU (Blood, 2011). Additionally, POM led to an increase in erythropoiesis in the marrow of sickle cell mice, an effect which was not observed with HU.

We conducted a Phase I trial of POM in SCD at 2 centers (GRU Sickle Cell Center and Wayne State University) and enrolled a total of 15 patients with 3 patients for each dose level (0.5, 1.0, 2.0, 3.0, and 4.0 mg/day). Inclusion criteria included: age 18-60 years, SS or Sβ0 thal genotype, severe SCD as defined by 1 or more of the following: > 1 pain episode/year, history of acute chest syndrome, leg ulcers, or priapism in the past 3 years. Women were eligible if they were post-menopausal or had a hysterectomy. Patients had to be intolerant, unresponsive, or unwilling to undergo HU therapy and had to be off HU for at least 90 days. Dose limiting toxicities (DLT) were graded on the following scale: grade 1 (mild), grade 2 (moderate), and grade 3 (severe). Anemia grades 1, 2, 3, and 4 were based on 11−-24%, 25−-49%, 50-74%, and ≥ 75% decrease compared with baseline, respectively; grade 4 could also be < 4.5 g/dL.

The median age of enrolled patients was 31.2 years (mean 33.7, range 20-52), 14 were male and all but 1 were African-American. The treatment period was 12 weeks. Most patients (14/15) completed 12 weeks of study drug; 1 subject was lost to follow-up after 10 weeks. Overall, the drug was well tolerated; there were no DLTs observed in any of the 5 dose cohorts. None of the adverse events (AEs) or serious adverse events (SAEs) were thought to be study-drug related. The most common AEs and SAEs were vaso-occlusive episodes. Three patients developed acute chest syndrome while they were on the study drug. No significant change was observed in laboratory parameters (CBC, retics, chemistries, HbF, F-cells, inflammatory markers) in patients enrolled into the 0.5, 1.0, 2.0, and 3.0 mg/day cohorts. Two of the 3 patients in the 4 mg/day cohort showed an increase in HbF, F cells, and total Hb (Table). One patient enrolled in the extended phase (3 mg/day based upon clinical benefit while on 1 mg/day; healing of chronic leg ulcer) showed a consistent increase in HbF and F cells, which became evident after 6 months of POM.

In summary, the results of this Phase I study of POM in SCD show that the drug is well tolerated up to a daily dose of 4 mg. An increase in HbF, F-cells, and total Hb was evident only with 4 mg/day dosing or at longer periods (> 6 months) of exposure to POM at lower doses (3 mg/day). Based upon these encouraging results, a Phase II study of ≥ 3 mg/day of POM for an extended duration is planned.