Background Myelodysplastic neoplasms (MDS) are heterogeneous clonal hematopoietic neoplasms, and TP53 mutations were regarded as adverse prognostic factors in the diseases. Azacitidine (AZA) is applied primarily in patients with higher-risk MDS, and Lenalidomide (LEN) has been approved for the treatment of MDS patients with del(5q) cytogenetic abnormality. The combination of AZA and LEN has shown activity in patients with higher-risk MDS. The study aimed to evaluate the efficacy and safety of azacitidine combined with lenalidomide in patients with TP53 mutations and other high-risk myelodysplastic neoplasms (MDS).

Methods A total of 44 MDS patients who received the scheme of azacitidine (75 mg / m2on days 1–7) combined with lenalidomide (10mg on days 1-7) were enrolled in the clinical study from August 2019 to June 2025, at Zhongda Hospital, Institute of Hematology, Southeast University. This study included 14 MDS with low blast (MDS-LB),1 MDS with low blasts and SF3B1 mutation (MDS-SF3B1),11 MDS with biallelic TP53 inactivation (MDS-biTP53), 8 MDS with increased blasts type 1(MDS-IB1),10 MDS with increased blasts type 2 (MDS-IB2).

Patient samples were sequencedwith our reported targeted exome-seq for human leukemia driver genes (Jun L, Blood Cancer J. 2022).

If the VAF of the gene mutation was increased by ≥10% at the post-treatment versus pre-treatment, it was defined as clone-increased mutations. If the VAF of the gene mutation was decreased by ≥10% at the post-treatment versus pre-treatment, it was defined as clone-increased mutations. Newly-acquired mutations were defined as Mutations that were not detected at pre-treatment, while detected at post-treatment.

Results The 44 patients has a median age of 70(40～95) years, including 25 males and 19 females, and 6.8% (3/44) were classified as median low risk, 15.9% (7/44) median high risk, 25% (11/44) high risk, and 52.3%(23/44) very high risk, respectively, according to the Molecular International Prognostic Scoring System (IPSS-M).

The most frequent mutations before treatment were observed in genes TP53 (n=16, 36.4%), ASXL1 (n=10,22.7%), TET2 (n=8,18.2%), SRSF2 (n=7,15.9%), and DNMT3A (n=5,11.4%). The overall response rate (ORR) was 63.6% (28/44), including 2 complete responses (CR), 1 complete remission equivalent, 3 complete remission bilineage (CRbi), 1 complete remission unilineage (CRuni), 6 complete remission with partial hematologic recovery (CRh), 2 partial response (PR), and 13 hematologic improvement (HI) patients. The ORR was 66.7%,85.7%,54.5%, and 63.2% for IPSS-M median low risk, median high risk, high risk, and very high risk patients, respectively.

The association of gene mutation with clinical response was further analyzed in 27 paired patients who underwent the mutation analysis in both pre-treatment and post-treatment. Results showed that the response cohort had a higher number of clone-decreased mutations than the non-response cohort (1 vs 0, P=0.006), while the non-response cohort had a higher number of newly-acquired/clone-increased mutations than the response cohort (1 vs 0, P=0.035). The response rate for patients with complex karyotypes and TP53 mutations was 46.7%(7/15) and 56.3%(9/16), respectively. The variant allele frequency (VAF) of TP53 mutations dramatically decreased after treatment (65.6% vs 16.5%, P=0.017) in the response cohort. As expected, the VAF of TP53 mutations increased after treatment (56.26% vs.81.08%, P=0.285) in the non-response cohort.

Also, the most common grade 3/4 non-hematologic adverse events were pneumonia (11/44, 25%) and infections (10/44, 22.7%) in the study.

Conclusions Azacitidine combined with lenalidomide therapy was an effective and safe treatment for myelodysplastic neoplasm, with an obvious clinical efficacy in patients with complex karyotype and TP53 mutation. The clinical studies with a large patient sample will further validate the conclusion.

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2025
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