A phase I study of lenalidomide plus chemotherapy with mitoxantrone, etoposide, and cytarabine for the reinduction of patients with acute myeloid leukemia

Abstract

Patients with relapsed AML have a poor prognosis and limited responses to standard chemotherapy. Lenalidomide is an immunomodulatory drug that may modulate anti-tumor immunity. We performed a study to evaluate the safety and tolerability of lenalidomide with mitoxantrone, etoposide and cytarabine (MEC) in relapsed/refractory AML. Adult patients with relapsed/refractory AML were eligible for this phase I dose-escalation study. We enrolled 35 patients using a "3 + 3" design, with a 10 patient expansion cohort at the maximum tolerated dose (MTD). Lenalidomide was initially given days 1-14 and MEC days 4-8; due to delayed count recovery, the protocol was amended to administer lenalidomide days 1-10. The dose of lenalidomide was then escalated starting at 5 mg/d (5-10-25-50). The primary objective was tolerability and MTD determination, with secondary outcomes including overall survival (OS). The MTD of lenalidomide combined with MEC was 50 mg/d days 1-10. Among the 35 enrolled patients, 12 achieved complete remission (CR) (34%, 90%CI 21-50%); 30-day mortality was 6% and 60-day mortality 13%. The median OS for all patients was 11.5 months. Among 17 patients treated at the MTD, 7 attained CR (41%); the median OS was not reached while 12-month OS was 61%. Following therapy with MEC and lenalidomide, patient CD4+ and CD8+ T-cells demonstrated increased inflammatory responses to autologous tumor lysate. The combination of MEC and lenalidomide is tolerable with an RP2D of lenalidomide 50 mg/d days 1-10, yielding encouraging response rates. Further studies are planned to explore the potential immunomodulatory effect of lenalidomide and MEC.

A phase 1 study of the antibody‐drug conjugate brentuximab vedotin with re‐induction chemotherapy in patients with CD30‐expressing relapsed/refractory acute myeloid leukemia

“…In another phase 3 study comparing MEC alone versus MEC with valspodar, a p-glycoprotein inhibitor, using a 5-day MEC regimen, 7 the MEC-alone arm had a response rate of 25%, with a median OS of 5.4 months. The median survival observed in this study was similar to the results from recent early-phase MEC combination studies, [10][11][12]23 including those combining either sirolimus, 23 lenalidomide, 11 or decitabine 12 with MEC re-induction therapy.…”

“…[6][7][8][9] Combinations of MEC with additional agents such as lenalidomide, decitabine, or proteasome inhibitors currently are being explored. [10][11][12] Brentuximab vedotin (SGN-35; hereafter referred to as BV) is an antibody-drug conjugate (ADC) consisting of an antibody specific for human CD30 (cAC10) covalently attached to the antimicrotubule agent monomethyl auristatin E (MMAE) through a protease-cleavable linker. 13 Binding of BV to cell surface CD30 results in the internalization of the CD30-BV complex followed by MMAE release by lysosomal proteolytic cleavage.…”

Increased mitochondrial apoptotic priming with targeted therapy predicts clinical response to re‐induction chemotherapy

“…The presence of common myeloid mutations did not inform response within this small heterogenous cohort. A separate but similar study investigated LEN at varying doses on days 1‐10 and MEC on days 4‐8, and an encouraging CR rate of 41% and a 1‐year overall survival rate of 61% were observed at the MTD of 50 mg LEN (Figure B) . No correlation between genetic profile and treatment response was noted, except perhaps a slightly worse chance of response in the presence of an NRAS mutation.…”

“…Seventeen adults completed treatment on the Stanford IRB‐approved clinical trial (NCT01904643; Table S1). Viably frozen (in 10% DMSO) mononuclear cells from blood (PBMCs) and bone marrow (BMMCs) that had >70% viability and contained >5% leukemia blasts from pre‐treatment and post‐LEN stages (collected prior to MEC chemotherapy) were studied from both Stanford (n = 15) and the Dana‐Farber/Harvard Cancer Center (DF/HCC) (NCT01681537) (n = 8) phase 1 studies.…”

“…A Stanford phase 1 trial adding LEN prior to MEC chemotherapy (LEN‐MEC) led to complete remissions (CR) in 5 of 17 (29%) R/R AML patients . A separate phase 1 study of LEN‐MEC with minor differences in dosing schema has previously reported that this combination was tolerable and yielded a CR rate of 41% (7/17) at the maximum tolerated dose (MTD) …”