As certain gene mutations such as RUNX1 and ASXL1 are associated with poor prognosis in patients with myelodysplastic syndrome (MDS), the Revised International Prognostic Scoring System (IPSS-R) that have incorporated both genetic and clinical risk factors can be used as an important prognostic tool to assess whether systemic treatment or hematopoietic stem-cell transplantation (HSCT) should be given.¹ Even among patients who are not eligible for transplants, Dr. Gill, Harinder Singh Harry commented that “You still need to inform [patients] on their prognosis as MDS is not only about transplantation. In fact, these patients will need more care if they are transplant ineligible.”

For patients with very-low, low and intermediate IPSS-R risk, supportive care alone is usually sufficient. In those with symptomatic anemia with del(5q), lenalidomide can be considered and the patient should be monitored for potential treatment resistance.² For those without del(5q) and a ring sideroblasts of ≥15%, erythropoietinstimulating agents (ESA) with or without granulocyte colonystimulating factor (G-CSF) or luspatercept can be considered.² Notably, hypomethylating agents (HMA) are indicated for patients with progressive cytopenia.²

For patients with intermediate, high and very-high IPSS-R risk, HMA followed by allogeneic HSCT are given if a candidate and donor pair are available.² Otherwise, HMA will be given until disease progression and the patient may opt to enroll in clinical trials.²

As MDS patients are typically transfusion-dependent and may receive >24 units of red cells a year, Dr. Gill noted that iron overload is a common complication of MDS which is associated with increased cardiac, liver and endocrine complications, and mortality risk. To address these risks, chelating agents such as deferoxamine, deferasirox and deferiprone can be given to improve the overall survival (OS).^3,4

For MDS patients with TP53 mutation, eprenetapopt (APR-246) plus azacytidine is associated with a high objective response rate of 71%, of which 38% of patients will achieve complete molecular remission by the end of treatment.⁵ On the other hand, Dr. Gill mentioned that the triple regimen of sabatolimab plus HMA and venetoclax is currently under study and may be considered once the results are available.

When azacitidine fails, patients are considered to have secondary acute myeloid leukemia (AML) and should be given molecular targeted therapies if clinical trials are unavailable. While FLT3 inhibitor is an option for salvage therapy, the treatment is associated with a relatively short median duration of response (DOR) of 6.9 months for patients with progressive MDS.⁶ While not yet available in Hong Kong, cytarabine/daunorubicin (CPX-351) showed promise in this patient group with a superior overall remission rate when compared to the conventional 7+3 regimen (47.7% vs. 33.3%; OR=1.77; p=0.016).⁷

For relapsed/refractory AML (rrAML) patients with IDH1 and IDH2 mutations, Dr. Gill noted that ivosidenib and enasidenib are associated with good complete remission (CR) rate with improved OS based on the clinical observation. However, clinical experience also indicates that disease progression is common after treatment, suggesting that monotherapy is not an optimal treatment strategy for rrAML. While genetic predisposition to MDS and AML are rare, Dr. Gill noted that inherited predisposition may occur in both children and adults. Particularly for patients with an early onset of MDS/ AML, having MDS with any clinical or pathological features of bone marrow failure (BMF) syndrome or having familial cases of MDS or AML, they should be tested for germline predisposition for optimal disease management.