Azacitidine Combination with Lenalidomide in Treating Higher-Risk Myelodysplastic Syndromes: A Single-Center, Phase 2 Trial

Background: Azacitidine, which works through the proteosomic destruction of DNA methyltransferase and resultant chromatin decondensation, is used primarily in patients with higher-risk myelodysplastic syndromes (MDS). Lenalidomide has been approved by the US Food and Drug Administration for the treatment of MDS patients with del(5q) cytogenetic abnormality. It has also shown activity in patients with higher-risk MDS and acute myeloid leukemia. In this trial, we assessed the efficacy and safety of combining azacytidine and lenalidomide in higher-risk MDS.

Methods: This is a single-center, phase 2 trial. Aza (75mg/m²/d on days 1-7 of a 28-day cycle) was administered in combination with lenalidomide (10 mg/day on days 1 to 21 every 28 days) for patients. The primary endpoint was the overall response rate (ORR). Secondary endpoints were overall survival (OS), progression-free survival (PFS), and adverse events (AEs). An MDS targeted-exome-seq panel including 37 driver genes was used for screening.

Results: Between Oct 2020 to Apr 2023, a total of 41 MDS patients were enrolled. 32 patients were evaluable for efficacy. 23 (71.875%) responded to therapy: 7 achieved a complete response (CR) (21.875%), 12 a marrow CR (mCR) (37.5%), and 4 a hematologic improvement (HI) (12.5%), of whom 10 of the mCR patients also had a HI. The median follow-up was 5.6 months (1 to 27.4), the median overall survival (OS) was not reached, and the median progression-free survival was 12.2 months. The time to reach CR was 2 months (range, 1 to 4.5), and the median CR duration was 8+ months (range, 5 to 27.4) (Table 1). 27 patients had at least one mutation, the most common being TET2 (n = 12), ASXL1 (n = 12), TP53 (n = 7), SRSF2 (n = 6), and RUNX1 (n = 6) (Fig.1A). Compared with patients without mutations, CR/mCR rate was significantly higher for those with mutations in TP53 (100% v 48%; P =0 .025) (Fig. 1B), ORR were numerically higher for those with TP53 (100% v 64%; P = 0.149) and TET2 (85% v 63%; P = 0.422) (Fig. 1C). We also observed a reduction of VAF in TP53 and TET2 mutation after the combination treatment (Fig. 1D & 1E). Common grade 3/4 nonhematologic adverse events included thrombocytopenia (18.75%), infection (12.5%), and febrile neutropenia (9.4%).

Conclusion
This trial demonstrated that the combination of azacytidine with a lenalidomide regimen is an effective therapy for higher-risk MDS patients, with high efficacy and well-tolerance. Patients with TP53 mutation appear more likely to achieve a CR/mCR.