What is the new review for Myelodysplastic Syndromes (MDS)?

From the Guidelines

The current standard of care for Myelodysplastic Syndromes (MDS) involves a comprehensive approach including diagnostic classification, molecular abnormalities, therapeutic options, and recommended treatment approaches, with a focus on improving quality of life and reducing morbidity and mortality, as outlined in the 2021 ESMO clinical practice guidelines 1.

Overview of MDS Management

The management of MDS is highly individualized and depends on various factors including the patient's age, comorbidities, importance of cytopaenias, somatic mutations, and effect of first-line treatment.

• For IPSS-R very high-, high- and some intermediate-risk patients, treatment options include allogenic stem cell transplant (allo-SCT), azacitidine, and supportive care, with the choice of treatment depending on the patient's fitness, age, and availability of a donor for allo-SCT 1.
• AML-like chemotherapy has a limited indication in patients with higher-risk MDS, and is generally reserved for fit patients without unfavourable cytogenetics and >10% marrow blasts, preferably as a bridge to allo-SCT 1.

Treatment Algorithm

The treatment algorithm for higher-risk MDS is outlined in Figure 2 of the 2021 ESMO guidelines 1, and includes the following options:

• Allo-SCT for fit patients with a donor
• Azacitidine for patients without a donor or who are not candidates for allo-SCT
• Supportive care for very frail patients

New Treatments and Clinical Trials

New treatments, including IDH1 and IDH2 inhibitors, and the bcl2 inhibitor venetoclax, are being tested in clinical trials for MDS, and may offer promising options for patients who fail to respond to current treatments 1.

• The IDH1 inhibitor, ivosidenib, and IDH2 inhibitor, enasidenib, have shown significant activity in AML with the respective mutations, and are being tested in clinical trials in MDS 1.
• The bcl2 inhibitor, venetoclax, is approved by the FDA in combination with an HMA in elderly patients with AML, and is being tested in higher-risk MDS, especially in combination with azacitidine 1.

From the FDA Drug Label

14 CLINICAL STUDIES

14.1 Myelodysplastic Syndromes (MDS) Study 1 was a randomized, open-label, controlled trial carried out in 53 U. S sites compared the safety and efficacy of subcutaneous azacitidine for injection plus supportive care with supportive care alone (“observation”) in adult patients with any of the five FAB subtypes of myelodysplastic syndromes (MDS): refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL)

14 CLINICAL STUDIES

14.1 Controlled Trial in Myelodysplastic Syndrome A randomized open-label, multicenter, controlled trial evaluated 170 adult patients with myelodysplastic syndromes (MDS) meeting French-American-British (FAB) classification criteria and International Prognostic Scoring System (IPSS) High-Risk, Intermediate-2 and Intermediate-1 prognostic scores Eighty-nine patients were randomized to decitabine for injection therapy plus supportive care (only 83 received decitabine for injection), and 81 to Supportive Care (SC) alone.

The new review for Myelodysplastic Syndromes (MDS) includes two main studies:

• Azacitidine (SQ): a randomized, open-label, controlled trial comparing the safety and efficacy of subcutaneous azacitidine for injection plus supportive care with supportive care alone in adult patients with MDS 2.
• Decitabine (IV): a randomized, open-label, multicenter, controlled trial evaluating the efficacy of decitabine for injection therapy plus supportive care in adult patients with MDS meeting French-American-British (FAB) classification criteria and International Prognostic Scoring System (IPSS) High-Risk, Intermediate-2 and Intermediate-1 prognostic scores 3 and 3. Key points:
• Both studies excluded patients with Acute Myeloid Leukemia (AML).
• The studies used different treatment options and patient populations.
• The primary endpoint for the azacitidine study was response rate, while the decitabine studies focused on efficacy.

From the Research

Overview of Myelodysplastic Syndromes (MDS)

• Myelodysplastic syndromes (MDS) are heterogeneous clonal diseases characterized by cytopenias resulting from ineffective hemopoiesis 4.
• The treatment of MDS begins with risk stratification using a validated tool such as the International Prognostic Scoring System (IPSS) or its revised version (IPSS-R) 5.

Treatment Options for MDS

• Erythropoiesis-stimulating agents (ESAs) play an important role in treating anemia in lower-risk MDS patients 4, 6.
• Luspatercept was recently approved for the treatment of ESA-refractory MDS with ring sideroblasts 6, 7.
• Lenalidomide is effective in treating MDS patients with a 5q deletion 6, 8.
• Hypomethylating agents (azacitidine/decitabine) are used to improve hematopoiesis, delay disease progression, and improve survival and quality of life for a subset of patients 8, 7.
• Allogeneic hematopoietic stem cell transplantation is the only potentially curative therapy for MDS, but it is limited by the advanced age of many patients and the frequency of serious comorbid conditions 5, 8, 7.

Emerging Therapies for MDS

• Experimental agents such as venetoclax, myeloid cell leukemia 1 (MCL-1) inhibitors, eprenetapopt, CPX-351, immunotherapies, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, pevonedistat, seclidemstat, and eltanexor are being investigated for the treatment of MDS 5.
• Research into new treatment options, especially after ESA failure, is ongoing 6, 7.