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A phase 1 study of concomitant high-dose lenalidomide and 5-azacitidine induction in the treatment of AML

Leukemia volume 27, pages 725–728 (2013)Cite this article

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Lenalidomide at a dose of 10 mg daily is approved for treatment of low risk/intermediate risk-1 myelodysplasia (MDS) patients who are red cell transfusion dependent.1, 2 We recently reported on an institutional phase 2 trial treating newly diagnosed elderly acute myeloid leukemia (AML) patients with high-dose single agent lenalidomide as an induction treatment (50 mg/day × 28 days) followed by lower dose maintenance (10 mg daily for 12 months). Thirty percent of patients achieved a complete remission (CR) or complete remission with incomplete blood count recovery (CRi) of 30%.3, 4 We and others have hypothesized that the combination of lenalidomide and azacitidine (AZA) may result in higher rates of sustained CR compared with these drugs individually. Sekeres et al.5 showed feasibility and efficacy of low-dose lenalidomide (10 mg daily) with AZA in high-risk MDS. We read the article ‘Safety, efficacy and biological predictors of response to sequential AZA and lenalidomide for elderly patients with acute myeloid leukemia’ by Pollyea et al.6 with interest. In that article, the authors report their experience with a phase 1 trial using sequential therapy with AZA and lenalidomide for elderly patients with AML. In the trial, the authors escalated the dose of lenalidomide to 50 mg/day with AZA dose fixed at 75 mg/m2. Here we report on the findings of our own institutional phase 1 prospective trial of AZA and high-dose lenalidomide (HDL) as an induction regimen followed by maintenance therapy with standard dose AZA and lower dose of lenalidomide. In contrast to Pollyea et al.,6 we (1) used escalating doses of AZA while keeping the lenalidomide dose constant, (2) used concomitant dosing of AZA and HDL and (3) chose to reduce the dose of lenalidomide after the initial two cycles of therapy.

Newly diagnosed elderly AML patients ⩾60 years of age with intermediate- or poor-risk cytogenetics, without isolated 5q abnormalities (elderly AML) and relapsed/refractory AML ⩾18 years of age (relapsed AML) were eligible for this study. Additional inclusion criteria included: Eastern Cooperative Oncology Group performance status of 0–2, and adequate renal (serum creatinine <1.5 × upper limit of normal) and hepatic function (bilirubin <2.0 mg/dl and aspartate aminotransferase/alanine transaminase <5 × upper limit of normal). Patients with acute promyelocytic leukemia, central nervous system leukemia, or prior use of lenalidomide or AZA were excluded. The treatment schedule consisted of two 28-day induction cycles with HDL, 50 mg orally for days 1–28 and AZA given intravenously for days 1–5 at three-dose cohorts (cohort 1, 25 mg/m2 (cohort 1), 50 mg/m2; cohort 2 and cohort 3, 75 mg/m2). Thereafter, patients were given maintenance cycles (every 28 days) with lenalidomide 10 mg orally for days 1–28 and AZA 75 mg/m2 intravenously for days 1–5 intravenously for up to 12 cycles. Lenalidomide and AZA were provided by the manufacturer (Celgene Corporation, Summit, NJ, USA). All patients except those with progressive disease after the two induction cycles continued with the maintenance cycles. Induction cycles were not interrupted nor were doses modified for expected hematological toxicities, but therapy could be interrupted for febrile neutropenia, grade ⩾3 nonhematological toxicities or bone marrow aplasia. During maintenance cycles, doses were delayed or reduced for febrile neutropenia, grade ⩾3 and prolonged hematological toxicities. Patients continued to receive maintenance cycles until an unacceptable adverse event or disease progression. Growth factors were not administered routinely but were allowed as clinically indicated. Response was assessed by bone marrow biopsy and complete blood count at the completion of induction cycles 1 and 2, after completion of maintenance cycles 2, 4, 6 and 12 and as clinically indicated during maintenance therapy. All adverse events were evaluated and coded using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0. Responses were assessed using the International Working Group criteria.7 The primary endpoint was to determine the maximum tolerated dose (MTD) and toxicity profile.

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  1. Section of Bone Marrow Transplant and Leukemia, Washington University in St Louis, St Louis, MO, USA

    G Ramsingh, P Westervelt, A F Cashen, G L Uy, K Stockerl-Goldstein, C N Abboud, N Bernabe, R Monahan, J F DiPersio & R Vij

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  1. G Ramsingh
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  2. P Westervelt
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  3. A F Cashen
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  4. G L Uy
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  7. N Bernabe
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  8. R Monahan
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  9. J F DiPersio
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Correspondence to R Vij.

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Ramsingh, G., Westervelt, P., Cashen, A. et al. A phase 1 study of concomitant high-dose lenalidomide and 5-azacitidine induction in the treatment of AML. Leukemia 27, 725–728 (2013). https://doi.org/10.1038/leu.2012.214

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