A phase I clinical trial of lenalidomide combined with bortezomib for acute myeloid leukemia or myelodysplastic syndrome relapsing after allogeneic stem cell transplantation

Background

Allogeneic hematopoietic cell transplantation (HCT) may improve long-term survival in patients with MDS or AML but disease relapse following HCT is common, with limited subsequent treatment options and extremely poor post-relapse outcomes. Lenalidomide and bortezomib are therapies which, in this setting, may exert antiproliferative effects, enhance graft-vs-leukemia immune responses, and potentiate chemotherapeutic drugs.

Objectives

We sought to evaluate the safety and preliminary efficacy of bortezomib in combination with high dose lenalidomide in patients with AML or MDS relapsing after HCT.

Study design

We conducted a phase I, dose-escalation, multi-center study of bortezomib added to high dose lenalidomide in patients with AML or MDS relapsing after HCT. We enrolled adult patients with recurrent or progressive AML or MDS after transplant; patients were required to be off systemic immunosuppression, with no evidence of GVHD, and with adequate organ function. Escalating doses of bortezomib were administered on days 2, 5, 9, and 12 of each cycle, while lenalidomide was given at 50 mg daily on days 1–21 of a 28-day cycle. DLTs were assessed during the first 2 cycles of induction and responses were assessed within this period. After achieving a treatment response, patients could proceed to maintenance dosing. The primary endpoint was toxicity and to establish the maximally tolerated dose (MTD) of the combination, while secondary endpoints included response rate and duration of responses.

Results

21 patients were enrolled, with a median age of 66 years (range 23–74). The majority of patients enrolled had AML (19/21). Three patients were enrolled at each bortezomib dose level of 0.7 mg/m², 1.0 mg/m² and 1.3 mg/m². One patient experienced dose-limiting toxicity at 1.3 mg/m² (received <50 % doses) and the cohort was expanded to 6 total patients, establishing this as the recommended phase two dose (RP2D); a maximum tolerated dose (MTD) was not reached. An additional 9 expansion patients were treated at this dose level for a total of 15 patients treated with lenalidomide 50 mg and bortezomib 1.3 mg/m². During dose expansion, grade 4 toxicities attributed to study drug included grade 4 neutropenia (n = 5), thrombocytopenia (n = 3), and febrile neutropenia (n = 1). Across all cohorts (n = 21), 1 patient (4.8 %) achieved CR and 3 patients (14.3 %) achieved CRi (composite CR/CRi rate of 19 %). Of the 15 patients treated at the RP2D, 4 patients had progressive disease after the first induction cycle, and 2 patients stopped therapy during induction cycle 2. A total of 9 patients completed both induction cycles. Of the 15 patients treated at the RP2D, 1 achieved CR, 2 achieved CRi (composite CR/CRi 20 %, CI 5.7–44.0 %) and 4 patients had stable disease. Chimerism during treatment generally tracked with disease response and one patient with persistent low chimerism also achieved CRi. The single patient achieving CR harbored an NPM1 gene mutation. A total of 3 out of 13 patients tested harbored a TP53 gene mutation and 2 of these patients achieved CRi on study subsequent to receiving DLI before study entry.

Conclusions

Bortezomib can be combined with lenalidomide in patients with AML and MDS relapsing after HCT with overall 19 % of patients achieving composite remission. Toxicity was manageable and primarily related to cytopenias during induction. Responding patients included 1 with NPM1-mutated AML as well as 2 harboring TP53 gene mutations, suggesting possible therapeutic benefit in very high-risk disease. Bortezomib and lenalidomide could be safely used following donor lymphocyte infusion without evidence of graft failure or immune-related toxicity.