P092 | REDUCTION IN THE ALLELIC BURDEN OF TP53 SOMATIC VARIANTS ACQUIRED DURING TREATMENT WITH LENALIDOMIDE AFTER WITHDRAWAL: DESCRIPTION OF A CASE OF MYELODISPLASTIC NEOPLASM DEL(5q)

Lenalidomide [LEN] is highly effective in treating the anemia of myelodysplastic neoplasm with del(5q) mutation [MDS-del(5q)]; however, the optimal duration of this therapy is debated due to the emergence of TP53 mutations during treatment and the prolonged maintenance of transfusion independence (TI) after discontinuation in responsive cases [Crisà E, Leukemia 2024]. Here we describe a case of a 65-year-old woman with transfusion dependent [TD] anemia due to MDS-del(5q) with molecular monitoring during and after withdrawal of LEN treatment by medical decision. Diagnosis and prognosis of the MDS were according to WHO 2017 and IPSS-R, respectively. LEN was administered according to the current schedule; during treatment and after drug withdrawal the monitoring included: monthly peripheral blood count, bone marrow [BM] cytology and cytogenetics every 6 months. BM DNA screening for TP53 somatic variants either with Sanger sequencing [SS] or Next Generation Sequencing [NGS, CMYS_R_v1 panel, Sophia Genetics] was performed at diagnosis and at least every 12 months. XL TP53/NF1 probe (MetaSystem) of 200 interphase nuclei was used for in-situ hybridization (FISH). At onset in Jul 2019 the case, defined as MDS-del(5q) IPSS-R low, presented: isolated TD anemia, isolated del(5q) in 90% methaphases, no TP53 mutations. LEN treatment started in Aug 2019, TI was reached after 6 weeks, the best BM cytogenetic response was detected after 20 cycles with del(5q) methaphases 10%. During treatment we detected these four different TP53-mutated clones in order of appearance: 1) p.(Gly279Arg); 2) p.(Arg175Gly); 3) p.(Cys275Tyr) and 4) p.(His179Gln). The clone 1 appeared after 37 cycles with a VAF of 15% (SS). Due to the detection of the TP53-mutated clone 2 with a VAF of 20% (SS) and of an increase in del(5q) metaphases (65%), LEN was discontinued in April 2023 after 44 cycles during stable complete hematological response. In the 2 subsequent NGS analyses, 12 and 18 months after withdrawal, all TP53-mutated clones showed a progressive reduction in VAF (Table). No del17p13.1 was detected by FISH analysis. At the last follow-up, two years after LEN discontinuation, the patient retained TI, stable BM and del(5q) methaphases 55%. Given the demonstration of the independent prognostic role of the allelic burden of TP53 mutations acquired during LEN in MDS-del(5q) (Montoro MJ, Blood 2024), this case encourages LEN withdrawal in responsive patients after prospective confirmation.