What are the recent findings on Myelodysplastic Syndromes (MDS) treatment over the last 6 months?

Recent Findings on Myelodysplastic Syndromes (MDS) Treatment Over the Last 6 Months

The most significant recent advancement in MDS treatment is the development of attenuated dosing regimens of hypomethylating agents for lower-risk MDS patients, showing improved outcomes without dose-limiting side effects. 1

Key Recent Developments in MDS Treatment

Hypomethylating Agents for Lower-Risk MDS

• A randomized trial comparing low-dose decitabine (20 mg/m² daily for 3 days) versus low-dose azacitidine (75 mg/m² daily for 3 days) in lower-risk MDS showed:
  • Higher overall response rate with decitabine (67% vs 48%, p=0.042)
  • Superior transfusion independence rates with decitabine (41% vs 15%, p=0.039)
  • Median duration of transfusion independence: 22 months
  • No early deaths observed with either agent 1

Molecular Classification and Risk Stratification

• The new IPSS-M classification has been developed, incorporating genomic data into risk assessment
• This represents a significant advancement over the previous IPSS-R system by including mutational profiles for more precise prognostication 2

New Treatment Approaches

• Oral decitabine/cedazuridine has been approved for MDS treatment, offering a more convenient administration option compared to injectable formulations 2
• Luspatercept has been approved for treatment of anemia in MDS patients, particularly those with ring sideroblasts 2

Current Treatment Algorithm Based on Risk Stratification

Higher-Risk MDS (IPSS Intermediate-2 or High)

1. First-line therapy: Azacitidine (75 mg/m²/day for 7 days every 28 days)

   • Demonstrated superior median survival (24.5 vs 15.0 months) compared to conventional care regimens 3
   • Continue for at least 6 cycles to assess response 4
   • Maintenance therapy should continue if clinical benefit is observed 4

2. Allogeneic stem cell transplantation (alloSCT)

   • Only potentially curative option for higher-risk MDS 4
   • Consider for eligible patients <65-70 years (or selected fit patients >70 years) 4
   • Azacitidine may be used as a bridge to transplant 4

3. After hypomethylating agent failure

   • Poor prognosis with median survival <6 months 5
   • Switching from azacitidine to decitabine shows modest response rates (19.4%) with short response duration 5
   • Clinical trial enrollment is recommended 4

Lower-Risk MDS (IPSS Low or Intermediate-1)

1. Transfusion-dependent patients

   • Attenuated dosing of hypomethylating agents shows promise 1
   • Decitabine 20 mg/m² daily for 3 days appears superior to azacitidine at equivalent dosing 1

2. Patients with del(5q)

   • Lenalidomide remains the standard of care 4
   • Combination with azacitidine has shown clinical activity but no proven survival benefit in controlled studies 4

Pitfalls and Caveats in MDS Management

• Response assessment timing: Responses to hypomethylating agents are often delayed, typically requiring 3-6 cycles before initial response is observed 4
• Treatment duration: Premature discontinuation of therapy before adequate trial (minimum 4-6 cycles) may miss potential benefits 4
• Iron overload management: Consider chelation therapy for patients who have received >20 RBC transfusions, with serum ferritin >2500 ng/mL 4
• Monitoring patients on deferasirox: Close monitoring of serum creatinine and liver function tests is essential due to risk of renal and hepatic failure 4

Future Directions

Several targeted therapies are under investigation:

• IDH1/2 inhibitors (enasidenib, ivosidenib) for IDH-mutated MDS 4
• BCL-2 inhibitor venetoclax, particularly for TP53-mutated cases 4
• Immune checkpoint inhibitors in combination with azacitidine 4
• JAK1/2 inhibitors for patients with JAK2 mutations or MDS/MPN overlap syndromes 4

The treatment landscape for MDS continues to evolve, with molecular profiling increasingly guiding therapeutic decisions and novel targeted approaches showing promise in specific genetic subtypes.