Background

Relapse in elderly AML remains a significant challenge. In VIALE-A, 52% and 74% of participants (age >75) with previously untreated AML in the venetoclax (VEN)+azacitidine (AZA) and AZA+placebo arms developed progressive disease (PD) or morphologic relapse (MR) after a median follow-up of 43.2 months, respectively. The prognosis of relapsed/refractory (R/R) AML post-VEN-based regimens is poor with limited treatment options in patients ineligible for intensive therapy.

Methods

A case report and literature review.

Result

A 70-year-old male was diagnosed with Myelodysplastic syndrome (MDS), subtype Refractory cytopenia with multilineage dysplasia in 2016.(WHO classification, 2008) The karyotype was normal, next-generation sequencing (NGS) not performed, and the IPSS score was 0.5. Eight months later, bone marrow evaluation (BME) for progressive cytopenia diagnosed AML with NPM1 mutation.(WHO classification, 2022) Karyotype was normal, with associated SRSF2 and TET2 variants. He received eight cycles of low-dose cytarabine (LDAC; 20 mg/m2) with VEN 100 mg daily added after the first five cycles. Complete remission with incomplete hematologic recovery was attained. The NPM1 and SRSF2 variants became undetectable at 2% variant allele frequency. Infective complications and worsening cardiac failure necessitated treatment cessation. He remained in remission for 19 months.

Re-treatment commenced in 2019 for relapsed AML. New FLT3 and IDH2 variants were identified, in addition to the known NPM1 and SRSF2 variants. Daily VEN 100 mg and LDAC 40 mg were initiated, and after three cycles, LDAC was reduced to 20 mg daily for a further three cycles secondary to ocular toxicity and worsening neuropathy related to pre-existing CIDP. He attained CRi, and the NPM1, FLT3, and IDH2 variants became undetectable with persistence of SRSF2 variant on NGS. Transfusion-independent cytopenia persisted without evidence of relapse on repeat BMEs.

In 2021, repeat BME for worsening neutropenia diagnosed MDS with multi-lineage dysplasia. The karyotype showed del(20)(q13.1) in 20% of cellls. NPM1 measurable residual disease (MRD) was negative with a sensitivity of 10-5. The IPSS was 0.5. Azacitidine 75 mg/m2 was commenced, and to date, the patient has received 33 cycles. The AML and MDS remain in remission nine years after initial diagnosis, with persistent NPM1 MRD negativity.

Discussion

There is limited data regarding re-treatment of R/R AML with VEN-based regimens. In a retrospective single-centre study, 33% (5/15) of patients with AML responded to re-treatment with VEN and HMA at relapse, and all achieved CR/CRi. The median age was 66 (19–81) years, 11 (73%) patients had de novo AML, and 8 (53%) patients had high-risk disease according to 2017 ELN risk stratification. Fourteen patients were initially treated with decitabine, and one with azacitidine.(Othman et al.,2020)

We hypothesise that the time-limited initial treatment may have reduced the risk of resistance and enabled disease sensitivity in re-treatment. Given that retreatment was effective in this case, it raises the question of whether treatment in the elderly should be time-limited if CR/CRi is achieved to limit toxicity and prevent the development of treatment resistance. Othman et al., 2024 demonstrated that transplant-ineligible patients treated with VEN and LDAC or azacitidine achieved prolonged treatment-free remission after cessation of therapy if MRD is achieved within four cycles of treatment. To the authors' knowledge, VEN and LDAC time-limited re-treatment for relapsed AML, including NPM1-mutated cases, and the MRD responses have not been reported. Prospective studies are needed to determine the efficacy of time-limited therapy and the re-initiation of VEN-based therapy at relapse.

Conclusion

This case contributes to the limited literature on the efficacy of re-treatment with VEN-based therapy in elderly patients with relapsed AML, the clonal evolution of disease recurrence, and long-term outcomes in re-treatment. Further data from prospective studies assessing the efficacy and safety of VEN re-treatment and establishing the role of molecular monitoring are required. The role of time-limited VEN therapy as a method of preventing treatment resistance and limiting treatment-related toxicity remains an important question in the transplant-ineligible cohort, given the poor prognosis and limited options of R/R AML post-VEN and HMA therapy.

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2025
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