Safety, Pharmacokinetics, and Immunomodulatory Effects of Lenalidomide in Children and Adolescents With Relapsed/Refractory Solid Tumors or Myelodysplastic Syndrome: A Children's Oncology Group Phase I Consortium Report

The Children's Hospital of Philadelphia, Filadelfia, Pennsylvania, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 01/2011; 29(3):316-23. DOI: 10.1200/JCO.2010.30.8387
Source: PubMed


To determine the maximum-tolerated or recommended phase II dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and immunomodulatory effects of lenalidomide in children with recurrent or refractory solid tumors or myelodysplastic syndrome (MDS).
Cohorts of children with solid tumors received lenalidomide once daily for 21 days, every 28 days at dose levels of 15 to 70 mg/m(2)/dose. Children with MDS received a fixed dose of 5 mg/m(2)/dose. Specimens for PK and immune modulation were obtained in the first cycle.
Forty-nine patients (46 solid tumor, three MDS), median age 16 years (range, 1 to 21 years), were enrolled, and 42 were fully assessable for toxicity. One patient had a cerebrovascular ischemic event of uncertain relationship to lenalidomide. DLTs included hypercalcemia at 15 mg/m(2); hypophosphatemia/hypokalemia, neutropenia, and somnolence at 40 mg/m(2); and urticaria at 55 mg/m(2). At the highest dose level evaluated (70 mg/m(2)), zero of six patients had DLT. A maximum-tolerated dose was not reached. No objective responses were observed. PK studies (n = 29) showed that clearance is faster in children younger than 12 years of age. Immunomodulatory studies (n = 26) showed a significant increase in serum interleukin (IL) -2, IL-15, granulocyte-macrophage colony-stimulating factor, natural killer (NK) cells, NK cytotoxicity, and lymphokine activated killer (LAK) cytoxicity, and a significant decrease in CD4(+)/CD25(+) regulatory T cells.
Lenalidomide is well-tolerated at doses up to 70 mg/m(2)/d for 21 days in children with solid tumors. Drug clearance in children younger than 12 years is faster than in adolescents and young adults. Lenalidomide significantly upregulates cellular immunity, including NK and LAK activity.

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    • "These drugs present anti-angiogenic and anti-proliferative activity, and their effect on the immune system, particularly on NK cells, is probably part of their mechanism of action. For instance, immunomonitoring of patients treated with immunomodulatory drugs, IMiDs have been associated with an increased expression of NKp44 and NKp46, in multiple myeloma (MM), myelodysplastic syndrome but also in solid tumors (55, 56). Interestingly, this effect of lenalidomide may not be a direct effect on NK cells because this effect was not observed in vitro on purified NK cells (57). "
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    • "The immune-modulatory drugs (IMIDs) such as thalidomide and lenalidomide are used in MM and MDS treatment and have anti-angiogenic and anti-inflammatory properties. They also act as IMIDs by cytokine release and activating effector cells by enhancing ADCC and NK-cell cytotoxicity thanks to the up-regulation of NKp46/NCR1 (75–77). "
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    • "We also show that IL-6, similar to the neuroblastoma/monocyte CM, significantly suppresses release of IFNγ by IL-2-stimulated NK cells. As with experiments testing neuroblastoma/monocyte CM, we discovered that lenalidomide, at clinically achievable concentrations [16, 32], prevented IL-6 suppression of IL-2-mediated activation of NK cell cytotoxicity, ADCC, and IFNγ secretion. "
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