Lenalidomide and Risk of Acute Myeloid Leukemia (AML) Transformation Among Myelodysplastic Syndrome (MDS) Patients
Authors: Rollison Dana E , Shain Kenneth H. , Lee Ji-Hyun , Hampras Shalaka S , Fulp William , Fisher Kate , Al Ali Najla H , Padron Eric , Lancet Jeffrey , Xu Qiang , Knight Robert D. , List Alan F. , Dalton William , Komrokji Rami 
Published: October 2019

Abstract
Introduction: Lenalidomide is currently approved by the FDA for treatment of transfusion-dependent, lower risk, deletion 5q (del(5q)) MDS patients. In practice, lenalidomide is often used for treatment of non-del(5q) anemic, lower risk MDS patients as endorsed by national guidelines. The risk of AML transformation among non-del(5q) MDS patients treated with lenalidomide has not been well studied, nor among del(5q) MDS patients outside the context of original clinical trials. We conducted a retrospective cohort study of 1,248 MDS patients treated with or without lenalidomide at the Moffitt Cancer Center (MCC) to investigate the association between lenalidomide and AML transformation.
Methods: Patients treated for MDS at MCC in 2004-2012 were identified through MCC's data warehouse, including data from the Cancer Registry, electronic medical records and disease-specific databases. A total of 1,248 MDS patients, ages 18+ years, were identified, corresponding to International Classification of Diseases for Oncology Third Edition (ICD-O-3) codes 99801, 99803, 99833, 99843, 99853, 99863, 99873, 99891 and 99893. A total of 150 cases of AML transformation were verified by two hematologists confirming the MDS diagnosis and AML transformation. Incidence rates and 95% confidence intervals (CI) for AML transformation were estimated based on the Poisson distribution. Cox proportional hazards ratios (HR) and 95% CIs were calculated to estimate age-adjusted associations between lenalidomide treatment and AML transformation in the overall cohort, and stratified by lower (low and intermediate-1) risk versus higher (intermediate-2 and high) risk IPSS. To obtain additional details on lenalidomide treatment and potential confounders, medical chart abstraction was conducted for all AML cases and a sample of MDS patients from the baseline cohort who had not developed AML; these controls were matched to cases 1:1 on age at MDS diagnosis (<60 versus 60+ years), gender, follow-up time (+/- 6 months), date of diagnosis, (+/- 1 year), lower versus higher risk IPSS, and presence or absence of del (5q). Based on the abstracted data for the nested case-control sample, associations between lenalidomide and AML transformation were adjusted for cytogenetic risk, use of erythroid-stimulating agents (ESA), percent bone marrow myeloblasts, and MDS histology.
Results: Overall, 1,248 MDS patients were followed for an average of 30 months, including patients treated with (n=210) or without (n=1,038) lenalidomide. AML transformation was observed among 16 patients treated with lenalidomide (2.4 per 100 person-years) and 134 patients treated without lenalidomide (5.5 per 100 person-years), corresponding to an age-adjusted HR of 0.44 (95% CI=0.26-0.74). Only two of the 150 MDS patients who transformed to AML had MDS del(5q). When stratified by IPSS, there was no increased risk of AML transformation associated with lenalidomide among patients with lower risk IPSS (HR=0.27, 95% CI=0.12-0.64) or patients with higher risk IPSS (HR=0.99, 95% CI=0.51-1.93). Based on the nested case-control analysis, 16.0% and 20.7% of MDS-AML cases and matched MDS controls who did not develop AML were treated with lenalidomide, respectively, corresponding to an adjusted odds ratio (OR) of 1.16 (95% CI=0.52-2.56). Although a significant interaction was noted between lenalidomide and IPSS in relation to AML in the cohort analysis (Figure 1), lenalidomide was not associated with AML transformation among lower risk (OR=0.44, 95% CI=0.10-1.94) or higher risk (OR=2.06, 95% CI=0.69-6.18) MDS patients after adjustment for prognostic factors in the case-control analysis.
Conclusion: To our knowledge, this study represents the largest cohort investigated outside the context of clinical trials for the rate of AML transformation among MDS patients treated with lenalidomide and the first to specifically examine non-del(5q) patients. Lenalidomide treatment was not associated with an increased risk of AML transformation among this large cohort of MDS patients.
Figure 1: Incidence of acute myelogenous leukemia (AML) among myelodysplastic syndrome (MDS) patients treated with or without lenalidomide (Lena) and stratified by lower risk IPSS (low risk or intermediate-1 [0,1]) versus higher risk IPSS (intermediate-2 or high risk [2,3]), Moffitt Cancer Center, 2004-2012 Figure 1:. Incidence of acute myelogenous leukemia (AML) among myelodysplastic syndrome (MDS) patients treated with or without lenalidomide (Lena) and stratified by lower risk IPSS (low risk or intermediate-1 [0,1]) versus higher risk IPSS (intermediate-2 or high risk [2,3]), Moffitt Cancer Center, 2004-2012

Disclosures
Rollison: Celgene, Inc.: Research Funding. Off Label Use: Lenalidomide given as treatment for non-del(5q) MDS and/or multiple myeloma . Shain:L&M Healthcare/Onyx/Amgen: Research Funding, Speakers Bureau; Envision/Celgene: Research Funding, Speakers Bureau. Lee:Celgene, Inc.: Research Funding. Hampras:Celgene, Inc: Research Funding. Fulp:Celgene, Inc.: Research Funding. Fisher:Celgene, Inc: Research Funding. Al Ali:Celgene, Inc: Research Funding. Padron:Icyte: Speakers Bureau; Novartis: Speakers Bureau. Lancet:Celgene, Inc: Consultancy, Research Funding. Xu:Celgene, Inc.: Employment, stock options Other. Knight:Celgene, Inc: Employment, stock options Other. List:Celgene, Inc.: Consultancy. Dalton:Genentech: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene, Inc.: Research Funding. Komrokji:Celgene: Consultancy, Research Funding.