Introduction: In the phase 3 MDS-005 study, LEN treatment was associated with a significant increase in transfusion independence (TI) vs placebo (26.9% vs 2.5%; P < 0.001) (Santini et al. J Clin Oncol. 2016;pii:JCO.2015.66.0118) and greater clinical benefit vs placebo (31.9% vs 3.8%) (Garcia-Manero et al. Haematologica. 2016;101:abstract P252) in red blood cell (RBC) transfusion-dependent (TD) pts with lower-risk non-del(5q) MDS who were ineligible for or refractory to erythropoiesis-stimulating agents (ESAs). For pts with lower-risk del(5q) MDS, a starting dose of LEN 10 mg is recommended, followed by subsequent dose modifications in response to adverse events (AEs), in order to maximize duration of treatment and thereby improve pt outcomes. This study evaluated the relationship between LEN exposure, including dose reductions, and duration of treatment, and the clinical benefit to pts with lower-risk, non-del(5q) MDS in the multicenter, randomized, double-blind, phase 3 MDS-005 study.

Methods: Eligible pts were age ≥ 18 years, had TD anemia due to International Prognostic Scoring System (IPSS)-defined Low- or Intermediate-1-risk MDS, lacked the del(5q) mutation, and were ineligible for or refractory to ESAs. Pts were randomized 2:1 to receive LEN 10 mg (n = 160) or placebo (n = 79) once daily (both in 28-day cycles). Pts randomized to LEN with creatinine clearance ≥ 40 to < 60 mL/min (n = 57) received LEN 5 mg. Cumulative dose, dose reductions, and discontinuations were recorded; association between these parameters and clinical benefit or RBC-TI was evaluated. Clinical benefit ≥ 8 weeks was defined as the composite endpoint of RBC-TI ≥ 8 weeks, or transfusion reduction of ≥ 4 units packed RBCs (pRBCs) ≥ 8 weeks, or hemoglobin (Hb) increase ≥ 1.5 g/dL ≥ 8 weeks (International Working Group 2006), or cytogenetic response (CyR). Rate of transfusion reduction was calculated using data collected during a 112-day assessment period to account for on-study differences in transfusion burden. LEN dose modifications due to AEs were defined in the study protocol. The analysis included all pts receiving LEN.

Results: Of 160 LEN-treated pts included in the analysis, 77 (48.1%) underwent ≥ 1 LEN dose reduction. A total of 73 pts experienced ≥ 1 dose reduction due to AEs, amounting to 102 dose reductions overall. Of these AE-related dose reductions, 47 were due to neutropenia, 33 due to thrombocytopenia, and 2 due to other hematologic conditions. Median time to first dose reduction was 85 days (interquartile range [IQR] 50-114 days). A total of 145 LEN-treated pts discontinued therapy: 52 discontinued due to AEs; 32 discontinued before the end of cycle 3, of which 23 were due to AEs.

Of the 77 pts who had ≥ 1 dose reduction, 6 (7.8%) pts had a dose reduction in the first cycle; 37 (48.1%) pts had dose reductions during cycles 1-3. During the first 3 cycles of LEN, pts with ≥ 1 dose reduction received a lower median dose than those with no dose reductions (385 mg [IQR 318-520 mg] vs 660 mg [IQR 415-840 mg]). However, when analyzed over the course of the entire study, pts undergoing ≥ 1 dose reduction received a higher median cumulative dose than those with no dose reductions (950 mg [IQR 595-1,435 mg] vs 715 mg [IQR 370-1,660 mg]). Duration of treatment was also longer for pts with ≥ 1 dose reduction vs those with no dose reductions (172 days [IQR 140-391 days] vs 92 days [IQR 46-168 days]).

Pts with ≥ 1 dose reduction were more likely to achieve RBC-TI ≥ 8 weeks than pts with no dose reductions (39% vs 16%; odds ratio [OR] 3.44 [95% confidence interval {CI} 1.63-7.26]). Pts with ≥ 1 dose reduction were also more likely to achieve clinical benefit ≥ 8 weeks vs pts with no dose reductions (47% vs 18%; OR 3.98 [95% CI 1.94-8.15]).

Conclusions: In this post hoc analysis of the MDS-005 study, pts undergoing ≥ 1 LEN dose reduction had a longer duration of treatment, and were more likely to achieve RBC-TI and the composite endpoint of clinical benefit (RBC-TI ≥ 8 weeks, transfusion reduction ≥ 4 units pRBCs ≥ 8 weeks, Hb increase ≥ 1.5 g/dL ≥ 8 weeks, or CyR) than pts with no dose reductions.


Santini:Novartis: Consultancy, Honoraria; Onconova: Other: advisory board; Amgen: Other: advisory board; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Astex: Other: advisory board. Almeida:BMS: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Shire: Speakers Bureau. Fenaux:Celgene, Novartis, Teva: Honoraria; Celgene, Janssen, Novartis, Astex, Teva: Research Funding. Gatterman:Celgene Corporation: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Heinrich-Heine-Universitat Dusseldorf: Employment. Ozawa:Sumitomo Dainippon Pharma Co. Ltd: Research Funding; JCR Pharmaceutical Inc: Consultancy; Celgene Japan: Consultancy; Takara Bio Inc: Research Funding. Goldberg:COTA Inc: Employment; Novartis: Consultancy; Pfizer: Honoraria; Bristol Myers Squibb, Novartis: Speakers Bureau; Neostem: Equity Ownership. Weaver:Celgene Corporation: Employment, Equity Ownership. Sugrue:Celgene Corporation: Employment, Equity Ownership.

Author notes


Asterisk with author names denotes non-ASH members.

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