How do I treat an elderly patient with low-risk MDS?

This is Eric Padron, assistant professor at the H. Lee Moffitt Cancer Center in the Department of Hematologic Malignancies. The title of this activity is “How do I treat an elderly patient with low-risk MDS.” The learning objectives are number one, perform prognostic risk assessments appropriate for patients with MDS and then number two, to design treatment plans that are tailored to low-risk elderly MDS patients consistent with clinical guideline recommendations.

I would like to get started with the brief introduction on myelodysplastic syndromes, and then proceed to a representative case, and hopefully guide you through the prognostication, algorithms, as well as the initial treatment algorithms for a low-risk elderly patient. As you may know, myelodysplastic syndromes are a heterogeneous group of diseases that manifest essentially with peripheral cytopenia and a propensity for AML transformation at a rate of approximately 30%. In the bone marrow biopsy and aspirate, the diagnosis of MDS requires bone marrow dysplasia, which we will talk about further throughout the case, and could also have elevations in myeloblast count as well as chromosomal and genetic abnormalities which we will discuss in depth. The two critical points of this discussion are number one, to recognize that prognostication is the single most important clinical step for your individual patient because it improves on the estimated natural history of your particular MDS patient, but probably more important, it helps guide a practitioner’s decision in tailoring therapy, and so it allows for a more personalized approach and a more evidence-based approach. With that being said, let us go through an informative case that I hope will illustrate the importance of prognostication and how we go through initial treatment selection.

This is a 70-year-old Caucasian woman who, in retrospect, had some dyspnea on exertion and shortness of breath but just wanted to get her annual physical and was incidentally discovered to have cytopenia. A routine complete blood count was done and her hemoglobin was 10.2 g/dL. Her MCV was slightly macrocytic at 99 fL, which is obviously typical of myelodysplastic syndromes along with a whole host of macrocytic anemias. Her white blood cell count was 3.1x109/L. Her ANC was 1220/mm3 and her platelet count was 94,000/mm3. This CBC was rechecked four weeks later and the hemoglobin had dropped to 9 g/dL. The MCV was 101 fL. The white blood cell count was 4x109/L and the ANC was 2000/mm3. The platelet count was now 100,000/mm3, and the patient’s dyspnea on exertion had slightly worsened.

After a peripheral workup which included peripheral smear, reticulocyte count, vitamin levels, a bone marrow aspirate and biopsy was performed which demonstrated the following: morphologically, the bone marrow aspirate was consistent with morphologic evidence of dysplasia and all three cell lines; and pathologically for the diagnosis of MDS, what is required is that at least one of the lineages just has at least 10% of cells with dysplastic features, and that is typically after at least 200 cells are annotated on an aspirate.1,2

So in this case, all three lines had greater than 10% dysplasia. After 10% dysplasia, there is really no prognostic or diagnostic significance to the degree of dysplasia but only to make the diagnosis more straightforward. This particular bone marrow biopsy was also negative for reticulin fibrosis, which is important in myelodysplastic syndrome because emerging evidence suggests that reticulin fibrosis is graded by the international scale at greater than 2+ as independently adversely prognostic in myelodysplastic syndrome.3 There were also no ring sideroblasts which are actually favorably prognostic. So the magic number is 15%. If more than 15% ring sideroblasts are present in the erythroid precursors, then that is actually sub-classified as a different morphologic category, but it is also prognostically favorable.4,5 The myeloblasts are also counted in detail, and 3% of 200 cells are myeloblasts by morphology. This is another important point because in myelodysplastic syndromes and risk stratification and diagnosis, you want to make sure that you are looking at the aspirate smear with respect to a myeloblast percentage. This is the gold standard. So flow cytometry or immunohistochemistry should not be used unless a bone marrow aspirate is not available and a subsequent marrow biopsy cannot be done; but if you can, aspirates are the way to go because flow cytometry can underestimate blast counts and IHC can overestimate blast counts because CD34-positive cells are not only myeloblasts,1,6 other cells stain for CD34; but in this case, morphologically, there were 3% blasts. The patient’s karyotype is assessed by conventional G-banding (Giemsa banding) cytogenetics and a normal female karyotype is identified in 20 metaphases. By the World Health Organization 2008 criteria, this patient was diagnosed with myelodysplastic syndromes subtype refractory cytopenia with multilineage dysplasia.2

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After the diagnosis is confirmed, the most critical step in evaluating a patient with MDS is accurately risk stratifying them, and again that is because it helps give your patient a more accurate representation of the nature of their disease.1,7,8

Supplemental Slides (PDF)

There are some myelodysplastic syndromes that you die with in which the median survival is more than 5 years, and there are some myelodysplastic syndrome that you are likely to die of; for instance, the highest-risk myelodysplastic syndromes have a median survival of less than a year, so that difference is critically important for your patient to be aware of.8,9 Secondly, again, it helps tailor your therapy.

We will discuss in detail the treatment decision algorithm as well as the selection of therapy. When you approach a patient with mild dysplastic syndrome, historically the clinical prognostication tool of choice was known as the International Prognostic Scoring System which was developed in 1997 from a large international untreated cohort, and this is important because this scoring system was developed in the era before hypomethylating agents which have been clearly shown to impact the natural history of at least high-risk myelodysplastic syndrome.9 The International Prognostic Scoring System takes into account the number of cytopenias, the number or the percentage of myeloblast, the number of cytogenic abnormalities, yields a composite score that has a median survival and leukemia-free survival attached to it. As I said, this has been a gold standard for over a decade, but recognition that other clinical variables and refinement of the aforementioned clinical variable precipitated the revised IPSS (IPSS-R).10,11 So, the revised International Prognostic Scoring System was an updated scoring system with over 7,000 myelodysplastic syndrome, patients around world at baseline that were followed for a significant period of time, and the similar variables were included, but this time refinements were made to the cytogenetic risk groups as well as the percentage of myeloblast, and most importantly the depth of cytopenia was considered which we all knew in clinic, and it totally was prognostic.

For instance, the patient with a platelet count consistently of 100 did better than a patient with platelet counts of 20, and that was not considered in the initial IPSS. Other scoring systems that have been developed since the IPSS included WHO Prognostic Scoring System (WPSS).12 The WHO classification-based Prognostic Scoring System for MDS was developed using analysis of survival of 426 patients diagnosed with de novo MDS between 1992 and 2004, and validated using a cohort of 739 patients diagnosed between 1982 and 2003. The WPSS is a widely used system in Europe, and this system includes not only transfusion and the variables assigned in the IPSS to some degree, but most importantly, what differentiates this score from other score is the fact that it includes morphology. So the WHO morphologic classification is considered in the prognostication of patients, and another commonly used prognostic scoring system developed from MD Anderson is the Global MD Anderson Scoring System which includes things like performance status, transfusion history, elevation, and white blood cell count that were not considered in the IPSS Scoring System or the WPSS. The MD Anderson prognostic model stratified 958 study patients into four distinct prognostic groups with significantly different outcomes. Low-risk patients had a median survival of 54 months and 63% survived for three years, compared with 6 months and 4% for high-risk patients. Patients ranked at intermediate levels 1 and 2 fell between the two extremes. Results were validated in a separate test group of 957 patients. The model also was highly prognostic for 507 patients who were newly diagnosed, those to whom the IPSS model applies.13,14,15

Now, all of these prognostic scoring systems have advantages and disadvantages; and at the Moffitt Cancer Center, we would like to run all four of them to compare.

Our Patients Risk Stratification by four Prognostic Systems and Corresponding Survival Estimates

In our patients, the IPSS score turns out to be 0.5 or intermediate-I warning (median survival 3.5 years), IPSS-R 2.5 or low (median survival 3.5 years; 10.8 years. Time until 25% of patients develop AML), the WPSS score with 1 or low (median overall survival 66 months) and the MD Anderson risk model (Global MDAS) was an intermediate-1 (median overall survival 25 months). So, by convention, the intermediate-1’s, the low risks, and the intermediate scoring system groupings are all considered lower-risk myelodysplastic syndrome, where the intermediate-2’s or higher risk or higher-risk myelodysplastic syndrome.8

Limitations and Considerations for Use of the Prognostic Scoring Systems

This patient by all prognostication systems had a lower-risk designation. There are instances in which the prognostic scoring systems diverts, and so, it is important to understand the pros and cons of each. So, the IPSS as I said was the gold standard and had been used for many clinical trials and studies up until just recently. It is an important tool to understand so that you can interpret the literature and context. However, it is clear that the IPSS-R is a more refined tool in the same population; and so, at the Moffitt Cancer Center and in my practice, we essentially substitute the IPSS-R for the IPSS, and so that is the scoring system we would weigh heavily. The WPSS score is an interesting one, but the major downside here is that it requires an experienced hematopathologist for morphologic determination which is not widely available in community practices in the United States. Therefore, oftentimes, requisite data is not available to calculate this, so that is one drawback. In the MD Anderson score, especially the elderly have to be looked at very carefully because host related clinical variables are weighed heavily; for instance, age and performance status. So that if you have an 80‑year-old in relatively good performance status with the same biological disease as a 60-year-old, under the MD Anderson scoring system, the 80-year-old disease will have a higher-risk disease. Now, this may be true from the perspective of overall survival, but it is true for the biology of the disease, and so, those are the types of things that you have to weigh when considering the individual scores; but in this case, all of the scores were concordant, and so, we are confident that at least clinically the patient has lower-risk disease.

Emerging Genetic Data for Point Mutations

Lastly, the other critical point in prognostication that has become readily apparent with emerging genetic data is the point mutations that are now commercially available. As we all know, next-generation sequencing technology has really spurned a genomic revolution that has really identified point mutations, chromosomal abnormalities, and copy number changes as a central pathogenic lesion in myelodysplastic syndromes.16,17 If all of these genetic aberrations are combined, you are bound to have at least one genetic anomaly in any given myelodysplastic syndrome patient. Many groups have tried to leverage this data prognostically.16,18,19,20 So, can mutations be independently prognostic in the context of the scoring systems? I will go over the most widely used and most cited paper with respect to this. This was The New England Journal of Medicine article published in 2011.19 The first author was Rafael Bejar. This was a multi-institution study where 439 DNA samples from MDS patients were sequenced for 118 genes using a Sequenom approach. Using this, they found 953 distinct mutations. They also had clinical variables so that they could calculate the international prognostic scoring system, but it is important to note that the revised international prognostic scoring system was not calculated in this paper, and so, this paper was set in the context of the IPSS. Nonetheless, it is informative; and from this analysis, they were able to find at least one gene mutation in half, 51% of the samples; 50% of those have normal cytogenetics, so it gave us information on clonality, half of the case. It is important to note that this was also done prior to discovery of splicing mutations such that if those are included now in a panel of 30 or less genes, you can expect to identify one point mutation in approximately 70% of cases of myelodysplastic syndrome. Those were not included in this paper because they had not been discovered yet; but nonetheless, with the genes that were determined, they performed univariate analysis and later a multivariate analysis which considered the International Prognostic Scoring System NH and identified five genes that appeared to be independently prognostic of the IPSS-NH, and those five genes are: TP53, EZH2, ETV6, RUNX1, and ASXL1. How the use of these genes essentially works is that the author determined that if you calculate the IPSS and then you later identify that your patient had any one of these mutations, but the IPSS group went up one risk, and so that these mutations upstage patients from say intermediate-1 to intermediate-2 or from intermediate-2 to high risk, so they will go up the stage but never down the stage. So these mutations were all adversely prognostic.

Molecular Profiling of our Patient

So, in our patient, we did perform molecular profiling and identified a mutation in EZH2, and so, technically, under some of the models, the patient would have been upstaged. In fact, if we go    based on this paper, the risk would go up to intermediate-2. So, from a prognostic perspective, this patient did go from a lower risk to a higher risk. However, the critical question that has not been addressed yet is whether this upstaging should result in a treatment decision. In other words, does the genetic prognostication of patients drive treatment and does this picking or choosing treatment just because of this genetic mutation make sense, that is an unanswered question in the field. As it stands for now, our recommendation is that we go with the validated clinical models for treatment decisions.1

Treatment Algorithm for our Patient
Okay, so for the sake of treatment, this patient has lower risk myelodysplastic syndrome. I will now go through the treatment algorithm for lower risk myelodysplastic syndrome and very importantly lower risk myelodysplastic syndrome without the deletion 5q, which changes the assignment of treatment a little bit, and so, that is a topic for another discussion; but in this patient with symptomatic anemia, so the hemoglobin was approximately 9. The patient had shortness of breath that inhibits itself is an indication for treatment in lower-risk myelodysplastic syndrome.

Any symptomatic cytopenia should prompt at least consideration of therapy. In higher-risk disease, consideration of therapy should be that whether the symptoms are present or not such that in an attempt to reduce the rate of AML transformation, but in this lower-risk case like this case, the patient had symptomatic anemia, and so, treatment should be considered.

The first fork in the algorithm really relies on the serum erythropoietin level. One of the critical test to get is serum EPO level and to determine whether the serum EPO level is greater than 500 or less than 500, and the reason for that is data has demonstrated that if your EPO level is over 500, the chance or the likelihood that a patient will response to erythropoietin if sufficiently low such that guidelines do not recommend it, we do not do it in our practice, and we do not do it at the Moffitt Cancer Center, so the patient has EPO level greater than 500, no erythropoietin.

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Now, if the patient has serum EPO of less than 500, you certainly want to consider erythropoietin +/- G-CSF. The type of erythropoietin is not critical but erythropoietin at sufficient doses +/- G-CSF in the right population can induce response rate of up to 60% to 70% that are sustained, and so, that is a critical fork in the road. Our patient had a serum EPO level of 700, so no erythropoietin was offered.

The next fork in the road is to determine whether your patient is a candidate for immunosuppressive therapy.

Emerging evidence in the field has demonstrated that there is a subgroup of lower-risk patients that are highly sensitive, highly responsive to immunosuppressive therapy mostly in the form of ATG and cyclosporine. Now in an elderly patient or at the age of 70, this is unlikely to be a treatment strategy of choice. Retrospective studies and prospective studies have shown that the most important predictive response is age. So, age less than 60 is predictive for response to IST, elderly patient with low-risk myelodysplastic syndrome are unlikely to be candidate. The other markers to consider are HLA-DR positivity or a PNH clone. There are other less validated markers like hypocellularity in the bone marrow, CD4 to CD8 ratio in the bone marrow, but really, the triad is HLA-DR, the age and the PNH clone positivity. Again, in this case, age over 70, lack of these markers, not a candidate for immunosuppressive therapy. The next fork in the road is really a decision to either start with hypomethylating agents or consider lenalidomide or a clinical trial.

Patient Treatment Selection: Weighing the Options: Lenalidomide Vs Hypo Methylating Agents vs Clinical Trial

I will briefly go over the pros and cons and when we chose to do these.

Clinical Trial is Always Preferred if Available

In our institution if a clinical trial with a promising agent in this population is available, we do not hesitate to put patients on it, that is certainly something to consider, especially if we are in the tertiary care center.

Choosing Between Hypomethylating Agents and the IMID Lenalidomide
But assuming no clinical trial is available, the big decision is whether we should go with hypomethylating agents or whether we should go with lenalidomide. The choice of hypomethylating agents especially in lower risk is really an institutional one or a practice one. It has probably more to do with familiarity than anything else, but there are some considerations here. If you were to choose hypomethylating agent, obviously your choices are azacitidine and decitabine. Azacitidine based on pharmacologic data in lower-risk disease is given at 75 mg/m2 every 5 days out of s 28-day cycle that is different than high-risk where you give it every 7 days out of 28-day cycle.

VIDAZA (azacitidine for injection) for SC or IV use Prescribing information. Initial U.S. Approval: 2004. VIDPI.008 01/14.

Decitabine is given the same, every 5 days, [DACOGEN® (decitabine) for INJECTION PI] and so, really, the choice here is usually an institutional one; but in elderly population, the excretion of the drug is important where azacitidine is renal and decitabine is liver.
DACOGEN® (decitabine) Prescribing Information22

Randomized open-label phase II study of decitabine in patients with low- or intermediate-risk myelodysplastic syndromes23

Patients received decitabine 20 mg/m2 SC per day for 3 consecutive days on days 1, 2, and 3 every 28 days (schedule A) or 20 mg/m2 SC per day once every 7 days on days 1, 8, and 15 every 28 days (schedule B) for up to 1 year. Primary efficacy end point was overall improvement rate (OIR: complete remission [CR], partial remission [PR], marrow CR [mCR], or hematologic improvement [HI]). Secondary end points were HI, transfusion independence, cytogenetic response, overall survival (OS), and time to acute myeloid leukemia or death. Efficacy and safety populations were identical: schedule A, n = 43; schedule B, n = 22. Median time from MDS diagnosis to treatment was 3.6 months; 89% had de novo MDS. The trial was terminated early on achievement of protocol-defined OIR superiority of schedule A over schedule B; OIR was 23% for schedule A (seven CRs, three HIs) and 23% for schedule B (one mCR, one PR, three HIs). No differences were observed in secondary end points. Median OS was not reached; approximately 70% of patients were alive at 500 days. Patients in schedule A (67%) and schedule B (59%) were RBC/platelet independent on study. The most frequent drug-related adverse events overall were neutropenia (28% v 36%), anemia (23% v 18%), and thrombocytopenia (16% v 32%).

So, we have the patient with renal toxicity; for instance, in elderly patient, maybe decitabine is the way to go, but outside of those metabolisms, considerations either are appropriate. You can expect the hematologic improvement, response rate and almost 50% about 40% of patients that do get too. Just remember that the median time to response is 3 months so you have to patient, and the median duration of response is 9 months.

Lenalidomide, Immunomodulatory Drug

Lenalidomide is an oral agent that is given 21 days of 10 mg out of every 28-day cycle. [Revlimid (lenalidomide) Prescribing Information]24 This agent is highly active in patients with isolated deletion 5q who have lower risks. It also has activity in the non-deletion 5 q, so this should be considered upfront as well. [NCCN, Version 2.2.014]

Lenalidomide Efficacy and safety in non-del 5q MDS Patients (PDF)

The response rates are similar, maybe slightly lower than hypomethylating agents, but emerging data does suggest that patients who have low-risk myelodysplastic syndrome who are treated with the hypomethylating agent and then failed that hypomethylating agent have a more aggressive course, and retrospective data from our center that is presented in abstract form demonstrates that the patients who get hypomethylating agent first and then lenalidomide have a much lower response rate to lenalidomide than they would have gotten with lenalidomide upfront whereas the opposite is not true.25 If you start off with lenalidomide, the response rate of azacitidine is similar in our experience as if you gave azacitidine upfront. Again, if all things were weighted equally in my personal practice, I would start off with lenalidomide for those reasons. Now, we do not give lenalidomide in patients who have severe thrombocytopenia, and it has its own side effects which can include rash, gastrointestinal symptoms, and so side effects have to be considered in this context as well; but at the end of the day, hypomethylating agent lenalidomide or clinical trial in our particular patient would be the treatment of choice. On this patient, we started lenalidomide.

Now, the last thing I want to mention is the issue of iron chelation which in lower-risk elderly patients is certainly something that has to be at least talked about.26 These patients who are transfusion-dependent, in other words had over 20 units of packed red cells have a ferritin of over 1000. Retrospective data demonstrates that the overall survival is less, and prospective data demonstrates that end-organ damage could occur. So, if your patient’s expected survival is such that end-organ damage is possible and the patient remains transfusion-dependent, then iron chelation is certainly something that has to be considered in this patient population.

I hope this discussion was informative and helps clarify the prognostication and initial treatment of elderly lower-risk patients.


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