Relationship Between Lenalidomide Dose Modification and Outcomes in Patients with Myelodysplastic Syndromes

Introduction: In clinical studies of patients (pts) with International Prognostic Scoring System (IPSS)-defined Low- to Intermediate-1-risk myelodysplastic syndromes (MDS), dose modification of lenalidomide (LEN) has been commonly used by physicians to sustain control of disease while managing toxicities. A previous real-world setting analysis has shown that dose modification of LEN in pts with multiple myeloma was associated with longer duration of therapy (DOT) and improved outcomes versus pts without dose modification (Usmani SZ, et al. Blood. 2014;124:abstract 2655). This study aimed to evaluate whether LEN dose modification in pts with MDS is associated with longer DOT and improved outcomes in a real-world setting using various measures available from claims data.

Methods: A retrospective study was conducted using a large US medical and pharmacy claims database, covering > 25 million commercial- and Medicare-insured lives annually. MDS pts with ≥ 2 outpatient claims or ≥ 1 inpatient medical claim associated with a diagnosis of MDS (ICD-9-CM codes 238.72–238.75) were identified; the first such claim was defined as the index date. A minimum of 12 months' pre-index enrollment and 6 months' post-index continuous enrollment between Jan 1, 2008 and Dec 31, 2013 was required. The inclusion criteria included pts with MDS treated with LEN who did not have claims for stem cell transplantation or high-risk disease at diagnosis. Clinically relevant metrics, including DOT, time to acute myeloid leukemia (AML), time to next therapy, time to advancement to high-risk disease (as measured by ICD-9-CM code 238.73), and time to red blood cell transfusion dependence, were compared in pts with and without LEN dose modifications (defined as: change in dose [mg/day], dose interruption of 10–60 days, or both); time-to-progression (TTP) was defined as a composite of the above. Charlson Comorbidity Index (CCI) and MDS Comorbidity Index (MDS-CI) (Della Porta MG, et al. Haematologica. 2011;96:441-9) scores were determined to compare baseline measures between groups. Adjusted hazard ratios (HRs) were calculated using a Cox proportional hazards model adjusted for age group, sex, and MDS-CI risk group at LEN initiation.

Results: Of 529 pts who met inclusion criteria, 245 (46%) had LEN dose modifications, including 135 pts with ≥ 1 dose change and 201 pts with ≥ 1 dose interruption; 91 pts had both. Overall, 54% of pts were aged ≥ 75 years; age (P = 0.647), CCI (P = 0.867), and MDS-CI (P = 0.967) did not differ between pts managed with and without LEN dose modifications. For pts without dose modifications, the rate of cytopenias within 14 days prior to discontinuation (50.7%) did not significantly differ from the rate of cytopenias within 14 days prior to first modification for pts with dose modifications (50.2%; P = 0.920). Median time to first dose modification was 1.9 months (range 0.4–23.2). Median DOT was 12.6 months for pts with LEN dose modification versus 1.9 months for pts without dose modification (P < 0.0001). The DOT benefit did not differ whether the modification was a dose change or an interruption (P = 0.115). Most pts initiated LEN at a 10 mg/day dose; the most common change for those who modified was to reduce to a 5 mg/day dose. Median TTP was 20.6 months for pts with dose modification versus 13.7 months for those without; the adjusted HR was 0.703 (95% confidence interval 0.541–0.914) (P = 0.009). Pts with dose modification had statistically significant improvements in time to AML (P = 0.018), time to next therapy (P = 0.002), and time to high-risk disease (P = 0.043) compared with pts without dose modification.

Conclusions: For pts medically managed with lenalidomide treatment for myelodysplastic syndromes in the USA, dose modifications during their treatment were associated with longer therapy duration, improvement in time to progression to AML or high-risk disease, and improved time to next therapy compared with pts without lenalidomide dose modification. Modifications were utilized in 46% of pts and the median time to modifications was similar to the DOT in those not receiving modifications, suggesting dose modifications may be worth considering for some pts who discontinue lenalidomide. This analysis supports lenalidomide dose modification in the treatment of MDS as an effective technique in the real-world setting for pts to achieve better treatment outcomes based on proxy measures available from claims data.