Perspectives on Newly Diagnosed MDS
In the treatment of patients with newly diagnosed myelodysplastic syndrome (MDS), there are opportunities for risk stratification, prognostication, and treatment planning. The approach is evolving, and clinical trials have an important role.
What is the current approach to managing newly diagnosed MDS?
“For the newly diagnosed patient, the following 3 basic steps are important: establishing or verifying the diagnosis, MDS risk stratification, and tailoring the therapy based on our goals.”
For the newly diagnosed patient, the following 3 basic steps are important: establishing or verifying the diagnosis, MDS risk stratification, and tailoring the therapy based on our goals. Establishing or confirming the diagnosis up front is a crucial step. This may involve making sure that we are not missing a diagnosis such as certain nutritional deficiencies or other conditions that mimic MDS. Or, in some scenarios, we may look for other entities that can coexist with MDS, such as paroxysmal nocturnal hemoglobinuria or large granular lymphocytic leukemia. Bone marrow aspiration, biopsy, and a good hematopathology review are integral to the diagnosis of MDS, and the cytogenetics and molecular information via next-generation sequencing are a part of the evaluation nowadays as well.
For risk stratification, the Revised International Prognostic Scoring System (IPSS-R), which classifies patients into 1 of 5 MDS risk groups, is a good starting point. We are also increasingly aiming to integrate the molecular data (eg, data on somatic mutations) with the IPSS-R. Several models have been developed toward this end. Ideally, what we really need is a web-based calculator, and I think that this type of tool might emerge in the future—but we are not quite there yet. As part of the risk stratification and overall assessment of MDS, it is also important to incorporate patient-related factors, comorbidities, and functional status in a systematic way.
Once the first 2 steps have been completed, you can have discussions with the patient about treatment and tailoring therapy. The current goals of therapy for lower-risk MDS include treating cytopenias. We are largely treating the anemia, and the need for treating isolated thrombocytopenia or neutropenia is rare in the low-risk setting. In higher-risk MDS, the disease is clearly more life threatening, and we immediately entertain whether allogeneic stem cell transplantation should be considered. In patients who are not undergoing transplantation, hypomethylating agents are the standard of care. By the time of diagnosis, the majority of patients with higher-risk MDS do have profound cytopenias that will require treatment.
“I would highlight the importance of considering allogeneic stem cell transplantation early on, even at the time of diagnosis, especially in newly diagnosed patients with high-risk MDS.”
I would highlight the importance of considering allogeneic stem cell transplantation early on, even at the time of diagnosis, especially in newly diagnosed patients with high-risk MDS. For most clinicians who are caring for patients with acute myeloid leukemia (AML), the question of going to transplant once they are in remission is built into the thought process and is firmly an important component of the treatment algorithm. For some reason, patients with MDS are less likely to be considered for transplantation until later on, perhaps upon referral to a major academic center after hypomethylating agent failure. When transplantation is considered later, some patients with MDS might be missing a window of opportunity that occurs prior to disease progression.
The benefits of contemplating the possibility of transplantation early on relate not only to the disease and that window of opportunity but also to the fact that transplants require time for evaluation, planning, and preparation. We need to make sure that the patient is an appropriate candidate, is fit, and does not have underlying organ dysfunction so that the risks of transplant are mitigated. We also have to identify an optimal donor (ie, any potential HLA-identical sibling[s] or HLA-haploidentical sibling[s], as well as any unrelated donors in the registry), and this takes time.
Assistant Professor of Medicine
“There is a strong role for molecular testing up front in AML, and I believe that we are learning how to use serial molecular testing in MDS, although this is still a relatively young space in MDS compared with AML.”
My colleagues have nicely highlighted much of the evolving approach to MDS. In recent years, there have been efforts to develop a more nuanced approach—one that is similar to AML, for which several newer tools have emerged. Occasionally, in high-risk MDS, particularly for patients whose disease has AML-like features, the molecular strategies that are used in AML may come into play, but the supportive data for these strategies in MDS are less robust. There is a strong role for molecular testing up front in AML, and I believe that we are learning how to use serial molecular testing in MDS, although this is still a relatively young space in MDS compared with AML. Importantly, we want to consider allogeneic stem cell transplantation for our patients with MDS, and we want to reduce the risk of disease relapse after transplant if that is pursued. However, MDS is very heterogeneous, and further study is needed to better understand how to optimize the management of a patient's disease prior to transplant.
I completely agree that predictive models really add to our ability to set expectations with patients, but, unfortunately, we have only a few treatments at this time. We hope that our prediction models will become increasingly relevant as we add more therapeutics to our treatment armamentarium. It is important to sit down with a newly diagnosed patient and give them a sense of their journey ahead, but we are still in need of novel therapeutics. And, in that setting, it is always appropriate to consider clinical trials. Most ongoing phase 3 studies in MDS are mutation agnostic, but I think that we will all be very curious to see whether there are any subgroups that benefit from a particular investigational treatment, or whether there are any findings that might inform future clinical trials. For now, it is important to have the humility to recognize that we still have not improved upon therapies that were approved by the US Food and Drug Administration many years ago and to recognize how important it is to try to enroll more patients in clinical trials, so that we might “move the needle” in MDS treatment.
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