Introduction: The Need for Upgrades in MDS Care

Speaker: Maria Diaz Campelo, University Hospital of Salmanca, Spain

Key Highlights

Challenges in Managing Low-Risk MDS (LR-MDS) Patients with Specific Mutations:

Managing LR-MDS patients can present challenges, particularly when patients exhibit specific genetic mutations like SF3B1.

The session addressed two case studies of patients newly diagnosed with MDS.

Case Details

Key Discussion Points

Recent Developments Changing the MDS Care Landscape

In the past four years, significant advancements have reshaped the management of MDS through the approval of novel therapies and the development of new prognostic tools. Four therapies have been approved—Luspatercept for lower-risk MDS, and in the metastatic setting, oral hypomethylating agents like Decitabine combined with Cedazuridine and Ivosidenib for patients with mutant EDH1. 

Additionally, two new prognostic classification systems have been introduced, adding complexity to clinical decision-making. The IPSS-M, a novel risk assessment tool incorporating molecular markers, offers improved accuracy in predicting patient prognosis. These innovations are enhancing treatment strategies and refining risk stratification in MDS care.

Can Newer Therapies Achieve the Goal of Transfusion Independence (TI) in LR-MDS?

The main goal for patients with MDS is not only to improve quality of life but also to extend overall survival, particularly by achieving TI. Transfusion dependency is linked to poorer survival rates compared to patients who maintain TI. 

Recent data from novel therapies show that reaching transfusion independence significantly increases overall survival in both the short and long term. Notably, a study presented at the last EHA meeting identified that patients who achieved TI had nearly double the expected survival rate 5-yrs post-treatment. Additionally, understanding the transfusion burden is critical, as it impacts the quality of life of patients and caregivers, including work-life challenges.

Diagnostic Criteria and Differential Diagnosis of MDS

Diagnostic Criteria

Exclude Other Causes of Cytopenias and Morphologic Changes:

Dr. Campelo mentioned that, the coexistence of multiple classifications for MDS, such as the WHO and ICC systems, poses significant challenges in clinical practice and research. While both systems aim to classify MDS based on genetic and morphological features, discrepancies in terminology and criteria complicate consistent diagnosis and treatment decisions. Efforts towards harmonization, like the recent international consortium's initiative, seek to unify classifications based on genetic signatures and blast percentages, aiming to streamline clinical trials, regulatory standards, and patient care. This harmonization effort is crucial to improve diagnostic accuracy and treatment outcomes in MDS.

Molecular Prognostication Enhances Risk Stratification in MDS

The integration of molecular data into the prognostic scoring system for MDS, particularly through the use of the molecular IPSS (IPSS-M), has shown to improve risk stratification. Genetic mutations such as TP53 and SF3B1 are key predictors of adverse outcomes. This molecular approach helps refine patient prognosis, with molecular IPSS proving valuable for patients with low to intermediate risk, enabling more tailored treatment strategies. 

In contrast, its utility in high-risk patients is less significant due to their generally poor prognosis. Overall, molecular profiling aids in identifying patients who may benefit from specific therapies, optimizing personalized care in MDS management.

Dr. Campelo talked about VALIDATE, the largest database of MDS patients with TP53 mutations treated with HMA therapy.

Rebooting LR-MDS Management: New Benchmarks and Innovative Sequential Care

Speaker: Valeria Santini, AOU Careggi, University of Florence, Italy

Key Highlights

Dr. Santini mentioned the clinical case previously discussed, focusing on transfusion-dependent MDS, highlighting unique challenges based on regional disparities.

Dr. Garcia-Manero emphasized the importance of early intervention in managing MDS, especially to reduce transfusion dependency. He highlighted that starting erythropoiesis-stimulating agents (ESAs) early in patients diagnosed in the transfusion circuit setting could potentially prevent or reduce the need for frequent transfusions. If a patient is already transfusion-dependent at the time of diagnosis, active intervention should be initiated to minimize further transfusions. 

A key discussion point was whether luspatercept should be used as a first-line therapy or whether ESAs should be attempted first before transitioning to luspatercept. Dr. Garcia-Manero supported that data from the COMMAND study which suggests broad use of luspatercept in both RS-positive and RS-negative patients. However, some questions remain regarding its initial use compared to starting with ESAs.

Dr. Campelo considered whether to start luspatercept or ESAs as first-line therapy and explored the possibility of combining both treatments. She noted that data supports combining therapies, though primarily outside clinical trials. Regarding the SF3B1 mutation, Dr. Campelo mentioned that it could impair prognosis, but the patient is likely still in a lower-risk setting. She recommended close monitoring, including bone marrow assessments, for changes in blast counts and clonal evolution. 

Luspatercept might be a more suitable choice for this patient due to the mutation's adverse impact and the fact that ESA responses are better seen in lower-risk and lower-clonal evolution patients. However, given patient’s advanced disease stage, Luspatercept may offer better therapeutic potential, especially in transfusion-dependent individuals with a limited response to ESAs.

Luspatercept is recommended as a first-line treatment for transfusion-dependent LR-MDS patients (both RS-positive and RS-negative). It works by blocking TGF-β signaling to stimulate erythropoiesis, leading to improved transfusion independence. In clinical studies, 63% of patients treated with luspatercept achieved a 1.5 g/dL increase in Hb and maintained TI for over 12 weeks, compared to 42% with ESA therapy. The drug is administered at 1 mg/kg every 3 weeks, with dose adjustments if necessary. Approved by the FDA, luspatercept is awaiting approval in other regions. It also addresses complications associated with chronic transfusions, such as iron overload.

Dr. Santini explained the COMMAND study:

Study Objective: The COMMAND study evaluates luspatercept as a first-line treatment for transfusion-dependent, LR-MDS patients compared to erythropoiesis-stimulating agents (ESAs).

Key Findings:

Safety Profile: The COMMAND study found that luspatercept has a favorable safety profile, with minimal safety concerns observed.

Key Safety Consideration:

Comparison to ESAs:

Dosing Guidance:

Dr. Santini talked about combining luspatercept with other drugs, specifically in non-RS positive MDS patients. A study by a French group, presented at an oral session, explored the combination of high-dose luspatercept and APO alpha. Although involving only a small number of patients, the study found that there was no disease progression associated with this combination. Some patients in the study were previously treated with ESA and were re-treated with this combination, highlighting an area of potential interest for further exploration.

Luspatercept in ESA Refractory Cases: 

Luspatercept is an effective second-line treatment for patients failing ESA therapy, supported by data from studies like MEDALIST, showing durable TI.

Imetelstat: 

Embracing Change in HR MDS: Modern Solutions, New Targeted Strategies, and Emerging Opportunities

Speaker: Guillermo Garcia-Manero, The University of Texas, Houston

Key Highlights

Dr. Garcia-Manero discussed the previous HR-MDS case with the panel.

He then mentioned the IPSS-M (International Prognostic Scoring System-Molecular), which is essential for evaluating high-risk situations in MDS. Dr. Campello had previously highlighted the concept of "upstaging", where patients initially classified as lower-risk based on traditional indicators like blasts or cytogenetics may be reclassified into higher-risk categories when molecular profiles are factored in. This suggests that the IPSS-M can identify subsets of patients at higher risk, allowing for better risk stratification and more tailored therapeutic strategies. Additionally, it provides insights into potential targeted therapies, particularly for mutations like IDH1, IDH2, and others.

Clinical Trials, HMA Therapy, and Targeted Agents Are Among the Recommended Options for HR-MDS:

Dr. Garcia-Manero mentioned the study which evaluated the combination of azacitidine and venetoclax for 105 HR-MDS patients. The dosage was 400 mg orally on day 14, of each 28-day cycle. Most patients enrolled with HR-MDS, 24% had TP53m. The combination achieved an overall response rate (ORR) of > 80%, with nearly 30% of patients reaching complete remission (CR).

Safety profile of Venetoclax + Azacitidine:

The Potential of “Total” Oral Therapy in MDS: Phase 1/2 Trial Findings: Oral Decitabine, Cedazuridine, and Venetoclax in Higher-Risk MDS or CMML

Three points to consider for Venetoclax dosing in MDS

Ivosidenib for IDH1m MDS: Phase 1 Study

A Phase 1 study evaluating ivosidenib in 19 patients with relapsed/refractory IDH1-mutated MDS showed promising results. ORR was 83.3%, with a complete response rate of 38.9%. While the median duration of response was not reached, the median overall survival was approximately 36 months. Notably, about 75% of red blood cell- and platelet-transfusion-dependent patients achieved TI. Ivosidenib works by targeting pathways related to R-2HG, aberrant methylation, and hematopoietic differentiation.

Olutasidenib Efficacy in IDH1m MDS

Olutasidenib has demonstrated promising efficacy in patients with IDH1-mutant MDS. In a study of 22 patients, monotherapy showed an ORR of 33%, with 27% achieving CR. When combined with other therapies, the ORR improved to 59%, with 27% achieving CR and 32% demonstrating marrow CR. The drug showed a tolerable and manageable safety profile, indicating its potential as an effective treatment option for IDH1m MDS patients.

Symposium Summary and Take-Home Thoughts

ASH Annual Meeting and Exposition, 7-10 December 2024, San Diego, California