Diagnosing Myelodysplastic Syndromes With David Steensma, MD, FACP; Reza Nejati, MD; and Ilene Galinsky, BSN, MSN, ANP-C

Dr. David Steensma, Dr. Reza Nejati, and Ms. Ilene Galinsky.

A complex group of heterogenous hematopoietic disorders, myelodysplastic syndromes (MDS) often go unrecognized and undiagnosed. Accurate diagnosis and risk assessment for this condition require a myriad of tests and an in-depth evaluation of symptoms. In this excerpt from their continuing medical education (CME)/nursing continuing professional development (NCPD) virtual tumor board entitled Diagnosis and Management of Myelodysplastic Syndromes, Dr. David Steensma, Dr. Reza Nejati, and Ms. Irene Galinsky discuss tumor characteristics, pathologic findings, and symptom assessment to aid the diagnosis and treatment of patients with MDS.

David Steensma, MD, FACP: Myelodysplastic syndromes represent a group of hematopoietic neoplasms that result in marrow failure. The marrow becomes incapable of producing normal numbers of healthy red cells, white cells, or platelets. These are clonal disorders that are characterized by cytopenias, and morphologic dysplasia is characteristic. Ineffective hematopoiesis explains the paradox between a marrow that’s usually cellular and a blood that is usually hypocellular. At least half of the patients have an abnormal karyotype, and almost all have abnormalities on molecular genetic profiling. Finally, these diseases are unstable, and there is a risk of clonal progression from lower- or higher-risk MDS into acute myeloid leukemia (AML), which happens in about 25% to 30% of cases overall.

The median age at diagnosis is approximately 70 years. There is a male predominance, except for the deletion(5q) subtype. The incidence increases significantly with age. Approximately 30,000 to 45,000 new cases are diagnosed each year in the US, based on Medicare claims data. Therapy-related MDS can be seen at any age, including in children who have received radiation or chemotherapy for another disease. There is also an increase in the recognition of germline marrow failure syndromes, such as Fanconi anemia or telomere disorders, and this not only predisposes to MDS, but it often leads to MDS that’s diagnosed at a relatively young age. Cytopenias are essential for the diagnosis of MDS. However, a diagnosis can be made really at any degree of cytopenia if definitive morphologic or karyotypic findings are present. In some cases, especially those with isolated deletion(5q) or abnormalities with chromosome 3, an elevated platelet count can be seen.

Reza Nejati, MD: The recommended required percentage of erythroid, megakaryocytic, and granulocytic cells showing dysplasia must be greater than or equal to 10% in order to be considered significant. In practice, this is often difficult to assess and is subject to significant interobserver variability, especially for megakaryocytic dysplasia. Significant megakaryocytic dysplasia is defined as greater than or equal to 10% dysplastic megakaryocytes, based on the evaluation of at least 30 megakaryocytes in aspirate smears or bone marrow sections. Marked increasing fibrosis is seen in approximately 10% of MDS cases, more often in therapy-related MDS. A mild increase in fibrosis does not change the clinical course; however, marked fibrosis is associated with an aggressive clinical course in MDS regardless of blast count.

The MDS category includes several distinct subtypes, which are defined by the number of cytopenias at presentation, the number of myeloid lineages manifesting dysplasia, the presence of ring sideroblasts, and the blast percentage in the peripheral blood and bone marrow. It is worth mentioning that the myeloid lineages affected by cytopenias are not necessarily those that manifest dysplasia. In the current classification, only one cytogenetic abnormality, deletion(5q), is used in the definition of specific MDS subtype. The subtypes of MDS included in this classification can be generally categorized into three groups on the basis of survival time and incidence of evolution to AML. The first group is the low-risk group. This group contains MDS with single lineage dysplasia, MDS with ring sideroblasts and single lineage dysplasia, and MDS with isolated deletion(5q). The intermediate risk group contains MDS with multilineage dysplasia and MDS with ring sideroblasts and multilineage dysplasia. The high-risk group consists of MDS with excess blasts based on blast count in peripheral blood and bone marrow.

Dr. Steensma: When we see patients with MDS, once we have received this pathologic information, we can risk stratify them into different subgroups using tools such as the International Prognostic Scoring System (IPSS), which was developed in 1997. The IPSS incorporates prognostic information from the marrow blast proportion, the karyotype, and the number of cytopenias and stratifies patients into four risk groups. Because the IPSS did not take into account the severity of cytopenias and accounted for weighted blasts more heavily than karyotype—when karyotype actually probably has more of an influence on the outlook—the IPSS was revised in 2012. It includes five categories: very low, low, intermediate, high, and very high. In general, patients with low or intermediate-1 IPSS are lumped together as lower-risk MDS, whereas those with intermediate-2 and high are considered higher-risk MDS. In the revised IPSS, the intermediate category can go either way, and we often distinguish lower-and higher-risk patients in this group using molecular genetics.

Our first case study is a patient with lower-risk MDS, a 61-year-old woman who presents with dyspnea on exertion and fatigue, two of the most common symptoms that bring patients with MDS to the doctor. Her medical history includes hyperlipidemia and hypertension, and her blood counts show normocytic anemia and no other cytopenias. A chemistry group was unremarkable, and the ferritin was normal. The serum erythropoietin was 214 units per liter. The patient was treated with darbepoetin for four doses, but there was no improvement in the hemoglobin. The patient continued to receive red cell transfusions on a regular basis. Now the ferritin is up to 1,720 ng/mL, but the other counts remain stable.

Ilene Galinsky, BSN, MSN, ANP-C: Based on all this information, we’re getting an idea of what our treatment plan should be and what characteristics this patient is going to have with her MDS. I think it’s important to always look at all the lab results. What are all the symptoms the patient is presenting with? Before you have a diagnosis of MDS, you also have to rule out other sources for the symptoms. While MDS is not the most common diagnosis, fatigue and dyspnea are some of the major symptoms that bring a patient in, as Dr. Steensma mentioned. The most common symptoms associated with MDS are fatigue, shortness of breath, infection, and bleeding. Lab tests should be performed at baseline to help with the diagnosis. Is someone’s thyroid abnormal? Are their iron studies normal? Is the B12 level acceptable? Check methylmalonic acid, ferritin folate, reticulocyte count, and erythropoietin level at baseline.

When you’re looking at the bone marrow, it’s important—especially if you’re the one doing the bone marrow—to make sure you’re sending it off for morphology, flow cytometry, chromosome analysis, and molecular analysis. Looking at the number of blasts and the chromosome and molecular results will help guide us in our treatment plan and help in our discussion about prognosis. You should always be thinking that the only known cure is a stem cell transplant. Obviously, not everyone, based on age, can have a stem cell transplant, but always keep it in the back of your mind to think about what future treatment should be. If it’s someone who’s young, think about human leukocyte antigen (HLA) typing the patient and getting the family information, and also look at the spleen. If they have an enlarged spleen on exam, this could be another potential diagnosis other than MDS.

Dr. Steensma: As we assess the patient’s risk, we not only consider their IPSS score, revised IPSS score, and molecular genetics features, but also the other things that we want to know about the patient: their age, their performance status, and their comorbid conditions. These are all important considerations when designing a treatment plan for the patient.

Ms. Galinsky: Always take into consideration the patient’s quality of life and what’s important to them and their families, and always think in mind of clinical trials, as we need to continue getting therapies for this disease.

About Dr. Steensma, Dr. Nejati, and Ms. Galinsky

David Steensma, MD, FACP, is an Associate Professor of Medicine at Harvard Medical School and an attending physician at Dana-Farber Cancer Institute and Brigham and Women’s Hospital. He is also a member of the Leukemia Program and the Cancer Genetics and Epigenetics Program at Dana-Farber/Harvard Cancer Center. Dr. Steensma’s research focuses on the development of novel therapies for MDS, the identification of new somatic genetic mutations, the intersection of clonal hematopoiesis and marrow failure, and the non-hematologic effects of clonal hematopoiesis.

Reza Nejati, MD, is an Assistant Professor in the Department of Pathology at Fox Chase Cancer Center in Philadelphia. He specializes in the treatment of patients with hematologic malignancies, including MDS, acute and chronic leukemias, lymphomas, and blastic plasmacytoid dendritic cell neoplasms, with particular expertise in the use of flow cytometry. Dr. Nejati has authored or coauthored several peer-reviewed publications focusing on genetic and pathologic characteristics of hematologic malignancies.

Ilene Galinsky, BSN, MSN, ANP-C, is a Senior Program Research Nurse Practitioner in the Leukemia Program at Dana-Farber Cancer Institute. She specializes in the treatment and management of patients with MDS, myelofibrosis, acute and chronic leukemias, and other bone marrow failure disorders. Ms. Galinsky has contributed to over 40 presentations and abstracts in peer-reviewed publications, and she has been instrumental in the development and implementation of treatment protocols for patients with hematologic malignancies.

Edits have been made to this excerpt for the sake of clarity and brevity. Any views expressed above are the speaker’s own and do not necessarily reflect those of Oncology Data Advisor. Gain additional expert perspectives from Dr. Steensma, Dr. Nejati, and Ms. Galinsky by completing the full complimentary CME/NCPD activity. 

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