Phase 2 Study of Lenalidomide Maintenance for Patients with High-Risk Acute Myeloid Leukemia in Remission
Authors: Aboudalle Iman , Kantarjian Hagop M. , Ravandi Farhad , Jabbour Elias J. , Daver Naval G. , Estrov Zeev E. , Andreeff Michael , Ferrajoli Alessandra , DiNardo Courtney D. , Pemmaraju Naveen , Naqvi Kiran , Jain Nitin , Pelletier Sarah Gwen , Garcia-Manero Guillermo , Cortes Jorge E. , Kadia Tapan M. 
Published: October 2019

Abstract
Background: New drug combinations and higher intensity therapy have led to significant improvements in complete remission (CR) rates for patients (pts) with acute myeloid leukemia (AML). However, many pts with high-risk AML who respond to initial induction/consolidation chemotherapy and are not candidates for allogeneic stem cell transplantation (ASCT) will eventually relapse with very poor outcomes. With the exception of ASCT, long-term maintenance treatment in AML is still not part of the standard treatment approach. NK cells as part of the immune microenvironment are important mediators of immune surveillance in AML. Lenalidomide can enhance NK cell activity and immune synapse formation, and has anti-leukemia activity in AML. Here, we evaluated the efficacy of low intensity, continuous dosing of lenalidomide in pts with high-risk AML in remission.
Methods: Adult pts with high-risk AML who have achieved first or second CR after induction chemotherapy and at least one consolidation cycle within 12 months of enrollment and who are not candidates for immediate ASCT were enrolled in this phase 2 trial. High-risk features for AML included adverse cytogenetics, FLT3 mutation, prior myeloid neoplasm or dysplasia (secondary AML, s-AML), therapy related AML, primary refractory AML, or minimal residual disease (MRD) persistence at any point after initial induction chemotherapy. Pts were treated continuously with lenalidomide 10 mg orally daily on days 1-28 of a 28-day cycle for up to 24 cycles. After cycle 1, stepwise dose escalations were allowed to 20 mg daily in pts who were tolerating their dose and have presence of minimal residual or morphologically detectable disease. The primary objective is to assess relapse free survival (RFS). Secondary objectives are duration of remission, overall survival (OS) and safety profile.
Results: A total of 28 pts were enrolled in this study with a median age of 61 years (range, 24-87). Baseline characteristics of all pts are summarized in Table 1. All pts were in CR at the time of enrollment, with 22 (79%) pts in CR1 and 6 (21%) in CR2. Patient started lenalidomide maintenance after a median of 8.8 months (range, 4-19.3) from the start of induction chemotherapy. High-risk features at the time of enrollment were as follows (some are overlapping): 7 (25%) pts with history of prior myeloid neoplasm, 15 (54%) persistent MRD, 7 (25%) adverse mutational profile, 6 (21%) adverse cytogenetics, 3 (11%) CR2 status, 2 (7%) therapy related AML and 2 (7%) primary refractory disease.
The median number of cycles was 6 (range, 1-24). Six (21%) pts completed 24 months of maintenance treatment, and 8 pts are still receiving lenalidomide on study. Overall, lenalidomide was well tolerated; Serious adverse events of grade 3 or 4 were observed in 11 (39%) pts including rash (n=6), thrombocytopenia (n=4), neutropenia (n=4), fatigue (n=2), febrile neutropenia (n=1), nausea (n=1), vomiting (n=1). Nine (32%) pts continued on 10 mg dosing, 2 (7%) had successfully increased the dose to 15 mg daily, 15 (54%) had dose reduction to 5 mg daily mainly due to rash (n=6), thrombocytopenia (n=3), neutropenia (n=2), nausea (n=1), fatigue (n=2), and diarrhea (n=1). Two pts discontinued treatment because of recurrent rash despite dose reduction. At the time of lenalidomide initiation, 5 (18%) pts had detectable MRD with a median of 0.1% of aberrant blasts (range, 0.02-1.6%) detected by flow cytometry. Of them, four pts relapsed within 3.7 months (range, 1.2-5.7), and one received ASCT due to persistent MRD and continues in remission. With a median follow-up of 12.1 months (range, 3-39), 11 (39%) pts relapsed after a median of 2.9 months (range, 0.7-23); of them, 7 pts had a prior myeloid neoplasm (n=6) or therapy related AML (n=1). The median duration of remission for all pts was 8.9 months (range, 0.7-38). The 1-year OS and RFS from time of enrollment were 67% and 52%, respectively (figure 1). The median RFS in pts with prior myeloid neoplasm (n=7) or therapy related AML (n=2) was only 10 months versus not yet reached in pts with other high-risk categories (p=0.01) (figure 1).
Conclusion: Lenalidomide is a safe and feasible maintenance strategy in high-risk AML pts who are not candidates for ASCT. This trial continues to surpass the pre-specified expected rate of RFS of high-risk pts based on a historical cohort. Pts with secondary treated or therapy related AML remain with poor outcomes.

Disclosures
Ravandi: Xencor: Research Funding; Jazz: Honoraria; Jazz: Honoraria; Abbvie: Research Funding; Sunesis: Honoraria; Orsenix: Honoraria; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding. Jabbour:Takeda: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Daver:Alexion: Consultancy; Novartis: Research Funding; Karyopharm: Consultancy; ImmunoGen: Consultancy; Pfizer: Consultancy; Incyte: Research Funding; Incyte: Consultancy; Sunesis: Consultancy; Daiichi-Sankyo: Research Funding; Sunesis: Research Funding; BMS: Research Funding; Novartis: Consultancy; ARIAD: Research Funding; Otsuka: Consultancy; Pfizer: Research Funding; Karyopharm: Research Funding; Kiromic: Research Funding. Andreeff:Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy; Oncolyze: Equity Ownership; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; Reata: Equity Ownership; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Reata: Equity Ownership; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; Oncolyze: Equity Ownership; SentiBio: Equity Ownership; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding. DiNardo:Bayer: Honoraria; Abbvie: Honoraria; Karyopharm: Honoraria; Medimmune: Honoraria; Agios: Consultancy; Celgene: Honoraria. Pemmaraju:stemline: Consultancy, Honoraria, Research Funding; Affymetrix: Research Funding; cellectis: Research Funding; samus: Research Funding; novartis: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; SagerStrong Foundation: Research Funding. Jain:Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Seattle Genetics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Pfizer: Research Funding; Infinity: Research Funding; Incyte: Research Funding; Infinity: Research Funding; ADC Therapeutics: Research Funding; BMS: Research Funding; Astra Zeneca: Research Funding; Genentech: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Abbvie: Research Funding; Pharmacyclics: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Servier: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Cellectis: Research Funding; Astra Zeneca: Research Funding; Adaptive Biotechnologioes: Research Funding; Servier: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cortes:Astellas Pharma: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kadia:Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; BMS: Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Novartis: Consultancy.