Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: the HOVON-SAKK-132 trial

Abstract

Lenalidomide, an antineoplastic and immunomodulatory drug, has therapeutic activity in acute myeloid leukemia (AML), but definitive studies about its therapeutic utility have been lacking. In a phase 3 study, we compared 2 induction regimens in newly diagnosed patients age 18 to 65 years with AML: idarubicine-cytarabine (cycle 1) and daunorubicin and intermediate-dose cytarabine (cycle 2) without or with lenalidomide (15 mg orally on days 1-21). One final consolidation cycle of chemotherapy or autologous stem cell transplantation (auto-SCT) or allogeneic SCT (allo-SCT) was provided according to a prognostic risk and minimal residual disease (MRD)-adapted approach. Event-free survival (EFS; primary end point) and other clinical end points were assessed. A second random assignment in patients in complete response or in complete response with incomplete hematologic recovery after cycle 3 or auto-SCT involved 6 cycles of maintenance with lenalidomide (10 mg on days 1-21) or observation. In all, 392 patients were randomly assigned to the control group, and 388 patients were randomly assigned to lenalidomide induction. At a median follow-up of 41 months, the study revealed no differences in outcome between the treatments (EFS, 44% ± 2% standard error and overall survival, 54% ± 2% at 4 years for both arms) although in an exploratory post hoc analysis, a lenalidomide benefit was suggested in SRSF2-mutant AML. In relation to the previous Dutch-Belgian Hemato-Oncology Cooperative Group and Swiss Group for Clinical Cancer Research (HOVON-SAKK) studies that used a similar 3-cycle regimen but did not pursue an MRD-guided approach, these survival estimates compare markedly more favorably. MRD status after cycle 2 lost prognostic value in intermediate-risk AML in the risk-adjusted treatment context. Maintenance with lenalidomide showed no apparent effect on relapse probability in 88 patients randomly assigned for this part of the study.

Graphical abstract

Figure 1.

Study schema. Ara-C, cytarabine; bid, twice per day; c.i., continuous infusion; d, day; hr, hour; iv, intravenous; R, random assignment.

Figure 2.

EFS and OS following lenalidomide remission induction therapy vs control induction treatment. EFS (A) and OS (B) for patients receiving remission induction therapy (control group vs lenalidomide [Lena] therapy group). Patients were randomly assigned for their first and second induction cycles of combination chemotherapy without additional lenalidomide (control treatment) or with lenalidomide at 15 mg on days 1 to 21 of both cycles. F, failure (or event).

Figure 3.

Relapse-free survival of complete responders after remission induction therapy according to MRD-negative/positive status. RFS according to attainment of MRD negativity for all patients (A), in the subgroup of patients with persistent positive MRD (B), and in those attaining a status of MRD negativity according to remission induction therapy (control group vs lenalidomide therapy group) (C). The unfavorable effect of MRD positivity is evident, but there is no apparent effect of lenalidomide treatment on outcome in patients attaining a status of MRD negativity or in patients with persistent MRD.

Figure 4.

Prognostic value of MRD status after remission induction in distinct AML risk groups in context of MRD-guided consolidation treatment choice. RFS by MRD status after induction cycle 2 in favorable risk (A), intermediate risk (B), and adverse risk (C) 2017 ELN risk classification groups. The prognostic significance of MRD positivity is lost in intermediate-risk AML in the context of MRD-guided treatment choice.

Figure 5.

Relapse probability and OS of complete responders following maintenance treatment with lenalidomide or observation. CIR (A) and OS (B) in patients in CR/CRi randomly assigned between lenalidomide maintenance treatment and observation.