Array BioPharma, Novartis.

No abstract

Sickle-cell disease (SCD) and β thalassemia constitute worldwide public health problems. New therapies, including hydroxyurea, have attempted to augment the synthesis of fetal hemoglobin (HbF) and improve current treatment. Lenalidomide and pomalidomide are members of a class of immunomodulators used as anticancer agents. Because clinical trials have demonstrated that lenalidomide reduces or eliminates the need for transfusions in some patients with disrupted blood cell production, we investigated the effects of lenalidomide and pomalidomide on erythropoiesis and hemoglobin synthesis. We used an in vitro erythropoiesis model derived from human CD34 + progenitor cells from normal and SCD donors. We found that both compounds slowed erythroid maturation, increased proliferation of immature erythroid cells, and regulated hemoglobin transcription, resulting in potent induction of HbF without the cytotoxicity associated with other HbF inducers. When combined with hydroxyurea, pomalidomide and, to a lesser extent, lenalidomide were found to have synergistic effects on HbF upregulation. Our results elucidate what we believe to be a new mechanism of action of pomalidomide and lenalidomide and support the hypothesis that pomalidomide, used alone or in combination with hydroxyurea, may improve erythropoiesis and increase the ratio of fetal to adult hemoglobin. These findings support the evaluation of pomalidomide as an innovative new therapy for β-hemoglobinopathies.

No abstract

TO THE EDITOR: Lenalidomide is a novel immune modulating drug (IMiD) that has demonstrated impressive antitumor activity in previously treated multiple myeloma and International Prognostic Scoring System low-risk and intermediate-1 risk deletion 5q myelodysplastic syndromes. The antileukemic effects of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) were recently reported in two ongoing phase II studies. 1,2 In the first study by Chanan-Khan et al, lenalidomide was given orally with a cyclic 25-mg regimen (day 1 to 21 of a 28-day cycle) in 45 patients with relapsed or refractory CLL; the overall response rate (ORR) was 47% with 9% of the patients attaining complete remission. In the other study by Ferrajoli et al, oral lenalidomide was administered at 10 mg daily for 28 days and dose escalated up to a maximum of 25 mg daily, in 45 patients with relapsed CLL who had received at least one purineanalog based regimen. The first 35 patients assessable for response had an ORR of 38% with 9% attaining complete remission. In both studies notable adverse reactions included tumor flare reaction (TFR) and tumor lysis syndrome (TLS). In the study by Chanan-Khan et al, TFR occurred in 58% (grade Յ 2, 50% and grade Ն 3, 8%) and TLS in 5% (all grade 3) of the patients. Ferrajoli et al reported 37% of TFR (grade Յ 2, 30% and grade Ն 3, 7%) and no TLS.We summarize here the development of TLS and TFR during lenalidomide therapy in CLL. TFR during lenalidomide therapy has been observed in CLL and small lymphocytic lymphoma (SLL). TFR occurs in the majority of lenalidomide-treated CLL patients, and is usually not severe and generally well managed with nonsteroidal antiinflammatory agents or steroids.Seven TLS episodes were observed among 260 CLL patients treated with lenalidomide to date. All seven patients had onset of TLS of varying severity during the first 15 days of treatment. Two patients also had concomitant TFR characterized by severe back and bone pain. TLS was complicated by acute renal failure and/or cardiac arrhythmia in three patients. Metabolic abnormalities and renal dysfunction resolved with supportive therapy in five patients; however, two patients died. Bulky disease, moderate renal insufficiency, and increased uric acid levels before therapy distinguished these seven patients from those who did not have TLS.Due to these findings, Celgene Corporation (Summit, NJ) temporarily suspended enrollment to its sponsored CLL trial (CC-5013-CLL-001) and an independent data monitoring committee (DMC) reviewed the data. The DMC recommended that, given the evidence of lenalidomide's significant activity in CLL in this and other trials, 1,2,5 the CLL-001 study should continue, but with modifications to define a better-tolerated lenalidomide dosing regimen. The DMC noted that similar reactions occurred with other immune modulating agents in CLL. 3,4 The use of low-dose-intensity regimens at the initiation of therapy and aggressive TLS prophylaxis and monitoring decreased the incidence of TL...