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

Abstract

Purpose: 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).

Patients and methods: 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.

Results: 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT00104962.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

(A) Natural killer (NK; CD3−/CD16+/CD56+) subset expression at baseline and day 21 post-lenalidomide administration as determined by flow cytometry. The bar graph and the associated dot plot/histogram represent the increase in NK subset expression at baseline and at day 21. Results represent mean ± standard deviation (n = 26 pairs; P < .01). The CD3 lymphocyte gate was used as a reference to determine the percentage of NK expression at baseline and day 21 after lenalidomide administration. (B) CD3−/56+/KIR3DL1+ subset at baseline and day 21 post-lenalidomide administration. Peripheral blood (PB) NK KIR3DL1 subset increase in CD3−/56+/CD158b+ expression at day 21 post-lenalidomide administration compared with baseline (n = 7 pairs; P < .001). Representative dot plot of CD3−/56+/CD158b+ at day 21 compared with baseline. The lymphocyte population was gated and used as a reference to determine the specific subsets. (C) CD3−/56+/KIR2DS4+ subset at baseline and day 21 post-lenalidomide administration. PB NK KIR2DS4 subset increase in CD3−/56+/KIR2DS4+ expression at day 21 post-lenalidomide administration compared with baseline (n = 7 pairs; P < .001). Representative dot plot of CD3−/56+/KIR2DS4+ at day 21 compared with baseline. The lymphocyte population was gated and used as a reference to determine the specific subsets. (D) Expression of NK cells expressing the natural cytotoxicity receptor CD3−/56+/NKp46+ at baseline and day 21 post-lenalidomide administration. Increased PB CD3−/56+/Nkp46+ subset expression at day 21 post-lenalidomide administration compared with baseline (n = 7 pairs; P < .01). Representative dot plot of CD3−/56+/Nkp46+ at day 21 compared with baseline. The lymphocyte population was gated and used as a reference to determine the specific subsets.

Fig 2.

(A) Expression of granzyme B, a protease of natural killer (NK) cells, at baseline and day 21 post-lenalidomide administration. Increased granzyme B expression day 21 post-lenalidomide administration compared with baseline (P < .01). Representative dot plot of granzyme B expression compared with baseline. Results represent 26 paired patients. (B) Expression of NK activation marker, CD107a, at baseline and day 21 post-lenalidomide administration. Increased CD107a expression day 21 post-lenalidomide administration compared with baseline (P < .05). Representative dot plot of CD107a expression compared with baseline. Results represent 26 paired patients.

Fig 3.

(A) Interleukin (IL) -2 serum levels pre- and post-lenalidomide determined by enzyme-linked immunosorbent assay (ELISA) assay. Results are expressed as mean ± standard deviation (SD) and all 26 paired samples were run in triplicate. IL-2 levels were significantly increased at day 21 compared with baseline (P < .01). (B) IL-15 serum levels pre- and post-lenalidomide determined by ELISA assay. Results are expressed as mean ± SD and all 26 paired samples were run in triplicate. IL-15 levels were significantly increased at day 21 compared with baseline (P < .001). (C) Granulocyte macrophage–colony stimulating factor (GM-CSF) serum levels pre- and post-lenalidomide determined by ELISA assay. Results are expressed as mean ± SD and all 26 paired samples were run in triplicate. GM-CSF protein production was significantly increased at day 21 compared with baseline (P < .01).