Efficacy of Lenalidomide and Bortezomib for Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) Relapsing after Allogeneic Stem Cell Transplantation
Authors: Brunner Andrew M. , Blonquist Traci M. , McMasters Malgorzata , Hobbs Gabriela S. , McAfee Steven L , Rosenblatt Jacalyn , Amrein Philip C. , Connolly Christine , Ramos Aura Y. , Mikami Kaleb , Logan Emma , Dey Bimalangshu R , Spitzer Thomas , Avigan David E. , Chen Yi-Bin , Ballen Karen K. , El-Jawahri Areej , Fathi Amir T. 
Published: October 2019

Abstract
Introduction: AML and MDS are advanced myeloid malignancies more common among older adults and generally associated with poor outcomes. Allogeneic hematopoietic cell transplantation (HCT) may cure a proportion of affected patients, but disease relapse remains common and is associated with dismal survival. High doses of lenalidomide may modulate graft-vs-leukemia (GvL) effects, and have shown encouraging responses for relapsed AML. Bortezomib may also augment GvL and potentiate the effect of other chemotherapeutics. We conducted a phase I study of escalating doses of bortezomib added to high-dose lenalidomide in patients with AML and MDS, who had relapsed following HCT.
Methods: We enrolled patients aged ≥ 18 years, with AML or MDS, relapsing after HCT in a '3+3' dose-escalation study. Patients with grade ≥3 GVHD, or chronic GVHD requiring >20mg/d of prednisone were excluded. Patients otherwise had to be off immunosuppressive therapy for 2 weeks. Lenalidomide 50mg/d was administered on days 1-21 of 28-day induction cycles. On days 2, 5, 9, and 12, subcutaneous bortezomib was administered at escalating dose levels: 0.7mg/m2, 1.0mg/m2, and 1.3mg/m2. Patients could receive up to two cycles of induction. After reaching the maximally tolerated dose (MTD), 9 patients were enrolled at the recommended phase II dose (RP2D) of bortezomib 1.3mg/m2.
Dose limiting toxicities (DLTs) included G4 peripheral neuropathy, G3+ aGVHD, moderate/severe cGVHD, non-resolving G3/4 non-hematologic toxicities, and the inability to receive at least 50% of both drugs during induction. The DLT period spanned up to 2 induction cycles, but could be 1 cycle if a patient entered complete remission (CR) or complete remission with incomplete count recovery (CRi) after the first cycle. Response to induction was the best response after up to two cycles of induction and was assessed in those patients treated at the MTD/RP2D. Donor lymphocyte infusions (DLI) were allowed after induction per the treating physician.
Results: A total of 21 patients were enrolled, with a median age of 66 years at study entry (range 23-74). The patients were predominately male (62%) and white (86%), while 2 patients (10%) identified as of Hispanic ethnicity. The majority had AML (19/21), with 10 of the AML patients having disease arising from prior CMML (1), MDS (7), or MPN (2). Three patients had del(5q); 2 patients had loss of 17p and 2 patients had complex cytogenetics. Three patients were enrolled at bortezomib dose levels of 0.7mg/m2 and 1.0mg/m2; at dose level 3, one patient experienced a DLT for receiving < 50% of doses and the cohort was expanded to 6 total patients. An additional 9 expansion patients were then treated at this dose level for a total of 15 patients treated with lenalidomide 50mg and bortezomib 1.3mg/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), consistent with what was seen during dose escalation. Across all cohorts (n=21), 4 patients achieved CR/CRi.
Of the 15 patients treated at the MTD/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, 3 achieved a CR/CRi (20%, 90%CI 5.7-44.0%). Another 2 patients had stable disease. One additional patient achieved a CR in the first dose cohort (Figure 1). Chimerism during treatment tracked with disease response; one patient with persistent low chimerism achieved CRi and received DLI as well (patient 3, who also harbored a TP53 mutation). A total of 3/13 patients tested harbored TP53 mutations; 2/3 achieved CRi while the third (patient 2) came off treatment during induction.
Conclusions: Lenalidomide may be safely combined with bortezomib in patients with AML and MDS relapsing after HCT, with an encouraging rate of complete remission (20%) in this poor risk population. Overall toxicities with this regimen were manageable, and largely related to cytopenias. Of note, 2 of the 4 CR/CRi responses on the trial were in patients with TP53-mutated disease, suggesting that this regimen should be further evaluated in this high-risk population, and combination with donor lymphocyte infusion may also merit investigation in larger studies.
Figure 1. Figure 1.

Disclosures
Brunner: Takeda: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding. Rosenblatt:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Amrein:Takeda: Research Funding. Chen:Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy. Fathi:Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria; Astellas: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Agios: Honoraria, Research Funding.