Case Report: Durable response to lenalidomide rechallenge after azacitidine failure in myelodysplastic neoplasm with del(5q)

Lower-risk myelodysplastic neoplasms (MDS) with isolated del(5q) are particularly sensitive to lenalidomide, although most patients eventually lose their response and may experience disease progression. Hypomethylating agents (HMAs) are commonly used as salvage therapy after lenalidomide failure, but treatment options following subsequent HMA failure remain limited. Evidence regarding lenalidomide rechallenge after intervening HMA therapy is scarce. We report the long-term clinical course of a woman with MDS with del(5q) and multilineage dysplasia, diagnosed after prior cytotoxic therapy for colon adenocarcinoma. Lenalidomide was started for transfusion-dependent anemia (IPSS Intermediate-1; IPSS-R Intermediate) and resulted in transfusion independence and a complete cytogenetic response after four cycles. Hematologic remission was maintained for more than three years, but lenalidomide was discontinued after 41 cycles because of progressive cytopenias and cytogenetic evolution. The patient subsequently received 36 cycles of azacitidine, achieving transient hematologic improvement before disease progression with an increase in bone marrow blasts. Because the del(5q) clone persisted and no established salvage option was available, lenalidomide was reintroduced at the original starting dose and produced a rapid erythroid response together with a reduction in bone marrow blasts, without a cytogenetic response. Hematologic benefit was sustained for approximately seven years using an individualized treatment schedule. Molecular analyses performed late during the second lenalidomide course identified two pathogenic TP53 variants, at low variant allele frequency, together with a SETBP1 mutation, corresponding to a Molecular International Prognostic Scoring System (IPSS-M) High-risk category. The response was eventually lost, and transformation to acute myeloid leukemia occurred after lenalidomide discontinuation. This case illustrates that lenalidomide rechallenge may provide prolonged clinical benefit in selected patients with persistent del(5q) after progression during HMA therapy. Further studies are required to determine the frequency and biological basis of renewed lenalidomide sensitivity in this setting.