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Challenges in Personalizing the Management of Myelodysplastic Syndromes: Case Studies

Rami Komrokji, MD

Department of Oncologic Sciences
University of South Florida
Vice Chair
Malignant Hematology Department
Moffitt Cancer Center
Tampa, Florida

Dr Rami Komrokji presents 3 patient cases to illustrate the challenges of personalizing therapy for patients with MDS, from Clinical Care Options (CCO)

View ClinicalThoughts from this Author

Released: November 16, 2022

Key Takeaways

  • The management of myelodysplastic syndromes is challenging, and additional therapies are needed, especially for higher-risk disease.
  • Recent updates to 2 different classification systems have the potential to impact clinical practice.
  • To learn more about personalizing therapy for patients with MDS and gain expert insight on the latest classification updates and management strategies, register now for our symposium at the 2022 American Society of Hematology Annual Meeting and Exposition. 

The field of myelodysplastic syndromes (MDS) is evolving, particularly in terms of diagnosis, new classifications, and risk stratification. The therapeutic landscape is evolving, as well. At the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition, I will be chairing a satellite symposium on MDS with Amer Zeidan, MBBS, MPH, and Maria Díez Campelo, MD, PhD, where we will discuss the latest guideline changes and how to optimally integrate the latest clinical evidence. To highlight some of the topics we will discuss during the symposium, I will describe 3 patient cases that illustrate what healthcare professionals encounter on a daily basis when caring for their patients with MDS.

Patient Case Scenarios

  • Patient Case 1: The patient is a 71‑year‑old female presenting with pancytopenia. A bone marrow biopsy was performed and showed ring sideroblasts. The patient was treated in a community setting with erythroid‑stimulating agents for 3 months, then azacitidine for 6 months. However, she remained red blood cell transfusion dependent, so she was referred to a tertiary academic center.

    At our center, we repeated the bone marrow biopsy, which showed the presence of ring sideroblasts >15%, but the karyotype was normal, and no somatic mutations were detected by next-generation sequencing. When ring sideroblasts are present in the context of dysplasia, cytopenia, and no mutation, that always raises a flag to rule out copper deficiency. A test of copper levels revealed that the patient had a severe copper deficiency and not MDS.
  • Patient Case 2: The patient is a 71-year-old female with a similar presentation to patient 1, and the workup does not show any evidence of bleeding or nutritional deficiencies.

    The patient underwent a bone marrow aspirate and biopsy that confirmed the presence of ring sideroblasts ≥15% and erythroid dysplasia. The karyotype was normal. Next-generation sequencing revealed a SF3B1 K700E mutation with a variant allele frequency of 30%.
  • Patient Case 3: The patient is a 71-year-old female with a similar presentation to patient 1, and the workup does not show any evidence of bleeding or nutritional deficiencies.

    In this patient, the bone marrow biopsy showed ≥15% ring sideroblasts and 10% to 15% myeloblasts. The cytogenetics revealed a complex karyotype, including deletion 5q, and next-generation sequencing revealed a TP53 mutation with variant allele frequency of 65%.

These cases really highlight the heterogeneity of MDS and that a common presentation could have totally different underlying causes. The first patient had a nutritional deficiency that mimics MDS. There are diseases that can mimic MDS, including nutritional deficiencies, other myeloid diseases, and large granular lymphocyte leukemia, and it is not uncommon to encounter these in practice.

The second patient has classical MDS with ring sideroblasts. Because this patient has an SF3B1 mutation, her disease would now be classified as MDS-SF3B1 under the new classification systems vs MDS with ring sideroblasts.

The third patient, unfortunately, has higher‑risk disease with excess blasts and a TP53 mutation. Therapeutic options for this patient are limited, and better therapies for higher‑risk patients remain the most challenging unmet need in MDS.

New Classification Systems for MDS
We also will highlight the newer classification systems for MDS. There is a new classification proposed by the WHO, as well as one from the International Consensus Classification group. There are similarities and differences between these classifications, emphasizing the importance of molecular features in some areas and redrawing the line between MDS and acute myeloid leukemia, which may have therapeutic implications.

I think one of the more important recent advances is the International Prognostic Scoring System (IPSS) molecular risk stratification model, which is starting to be used in practice. This model, in addition to the common clinical variables that we use for risk stratification, now integrates molecular data. I anticipate that we will see several presentations highlighting the use of the newer classification systems, as well as the IPSS molecular risk stratification, at ASH 2022.

Latest Evidence on Personalizing Therapy for MDS
Part of the session then will be dedicated to lower‑risk MDS, as demonstrated in the second case I presented, where treatment options include erythroid‑stimulating agents, luspatercept, lenalidomide, and hypomethylating agents, which are now available as an oral formulation. In addition, newer investigational agents are being tested.

There are planned trials in MDS precursor conditions such as clonal hematopoiesis of indeterminate potential (CHIP) or clinical cytopenia of unknown significance (CCUS) to examine if the progression of disease to MDS can be slowed. In lower‑risk MDS, there are efforts to move to earlier treatment or perhaps prevent MDS. Colleagues from Spain have led trials on the introduction of lenalidomide early in the disease course in patients with deletion 5q that showed better transfusion‑free survival and really challenged the dogma in lower-risk MDS that transfusion‑free survival could be an endpoint for those patients. Luspatercept is the most recent drug approved by the FDA for the management of anemia, and we will highlight the role of luspatercept, patient selection, and appropriate usage, as well as whether luspatercept has a role outside its current indication. In addition, oral hypomethylating agents are being tested in lower-risk MDS, as are novel agents.

In higher-risk MDS, we will discuss the current treatment landscape, the role of transplant, use of hypomethylating agents, and updates on ongoing trials. Transplant remains the backbone and main therapeutic strategy, along with hypomethylating agents. There are ongoing efforts to examine the efficacy of combinations of hypomethylating agents with other therapies, with a few contenders being magrolimab, venetoclax, and sabatolimab, as well as possible triplet therapies. Strategies to tackle the unmet need for patients with TP53-mutant disease also will be discussed.

To Learn More, Attend Our Symposium at ASH 2022!
Please join me and my colleagues, Amer Zeidan, MBBS, MPH, and Maria Díez Campelo, MD, PhD, live or online on Friday, December 9, for our CME-certified symposium titled, “An Expert Discussion on MDS: Current and Future Personalized Management Approaches,” where we will summarize state‑of‑the‑art advances in diagnosis and risk stratification, as well as the ongoing evolution of the landscape of managing both lower- and higher‑risk MDS. I hope we will see you in New Orleans!

Click here to register!

Your Thoughts?
What challenges do you face in personalizing therapy for your patients with MDS? Answer the question below and join the discussion.

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