Frontline treatment of IDH1-mutated myelodysplastic syndrome with ivosidenib: clinical cases and therapeutic insights

To the Editor,

Ivosidenib is an oral, targeted inhibitor of isocitrate dehydrogenase-1 (IDH-1) that has shown efficacy in treating IDH-1 mutated relapsed or refractory myelodysplastic syndrome (MDS). We administered single-agent ivosidenib at a daily dose of 500 mg as a first-line treatment in two patients with mutated IDH-1 MDS.

Patient 1 is a 76-year-old male who presented with severe neutropenia and nontransfusion-dependent anemia. Bone marrow biopsy confirmed dysplastic features, cytogenetics, and molecular studies. He had a moderate-low Molecular International Prognostic Scoring System (IPSS-M) score. Molecular testing showed an IDH-1 mutation with a variable allele frequency of 28.5% with GNB1 and SRSF2 mutations. He was started on ivosidenib 500 mg daily. At the time of treatment initiation, his neutrophil count was 0.24 k/μL; within 10 days of treatment, his neutrophil count increased to 1.55 k/μL and continued to be within the normal range a year and 8 months later with treatment. A repeat bone marrow biopsy a year later showed molecular resolution of the IDH-1 clone.

Patient 2 is a 72-year-old male who was initially being evaluated for severe neutropenia. Bone marrow biopsy confirmed evidence of morphologic dysplasia, molecular testing revealed mutated IDH-1 with variable allelic frequency of 20.9% and DNMT3A mutation. His calculated IPSS-M score was low. He was initially treated with granulocyte-colony stimulating factor (G-CSF) for several months without significant response. However, due to worsening absolute neutrophil count to a nadir of 0.16 k/μL, the decision was made to start ivosidenib at 500 mg daily. Within 1 week of treatment, his neutrophils increased to 1.1 k/μL and continued to be within normal range 8 months later with treatment.

MDS is a heterogeneous hematological disorder. IDH1 mutations are known to be a driver in approximately 3% of MDS cases. This mutated gene leads to the production of an oncometabolite, which interferes with normal myeloid differentiation. The efficacy of ivosidenib, a potent oral inhibitor of IDH-1, in inducing hematopoietic redifferentiation in patients with IDH-1 mutated MDS may explain the positive response observed in our two patients. ¹

In a study published by DiNardo et al., which led to the drug’s approval for relapsed refractory MDS, the efficacy and safety of ivosidenib were evaluated in 18 patients primarily treated with hypomethylating agents. The primary endpoint of complete response plus partial response was achieved in 38.9% of patients, with an overall response rate of 83.3%. Interestingly, both the European Leukemia Net (ELN) and National Comprehensive Cancer Network (NCCN) incorporate genetic analysis for somatic mutations in the assessment of newly diagnosed patients, mainly to determine prognosis. However, targetable mutations have predominantly driven treatment algorithms in acute myeloid leukemia. Current management algorithms for MDS do not leverage targetable mutations for treatment. Nevertheless, we consider assessing 5q deletions in patients with transfusion-dependent anemia and utilize lenalidomide for treating MDS patients with 5q deletions. ²

Another important issue regarding the patients we treated with ivosidenib was their severe neutropenia. Severe neutropenia occurs in approximately 7%–18% of MDS patients and can lead to life-threatening infections, primarily due to functional deficiencies such as impaired migration and reduced bactericidal and fungicidal activities. According to NCCN guidelines, patients with low-risk MDS and clinically significant neutropenia are typically treated with hypomethylating agents, which are usually used for higher-risk MDS but are employed in this patient population due to a lack of better options. Historically, G-CSF has been utilized in such cases, although there are no established guidelines for its use, partly due to concerns about its efficacy in reducing infection rates. Additionally, there are worries that G-CSF may increase the risk of transformation to acute myeloid leukemia.

However, it has been applied in managing neutropenia resulting from hypomethylating agents, especially in the context of increased infections.^3,4

The benefit of using targeted mutational therapy such as ivosidenib lies in its unique mechanism of action, which allows for effective management of cytopenias associated with MDS, rather than exacerbating neutropenia as hypomethylating agents can in the initial cycles. The use of ivosidenib or olutasidenib as a first-line treatment for IDH-1 mutated MDS warrants further prospective investigation. Currently, there is an ongoing trial of ivosidenib for patients with clonal cytopenia of unknown significance and IDH-1 mutation.