Hetty E. Carraway, MD, MBA
In an interview with OncLive®, Hetty E. Carraway, MD, MBA, outlined changes and challenges in the classification, risk stratification, and management of myelodysplastic syndromes (MDS), which were discussed during the inaugural Bridging the Gaps in Leukemia, Lymphoma, and Multiple Myeloma Meeting.
This includes the incorporation of molecular mutation data into classification systems and the need for a more consolidated set of criteria; current approaches to management of clonal hematopoiesis, particularly for patients with high-risk features; the roles of the newly approved agents imetelstat (Rytelo) and luspatercept-aamt (Reblozyl) in lower-risk MDS; and lessons learned from phase 3 studies of hypomethylating agents (HMAs) in higher-risk MDS.
“[Classification] tools are important for us to use, and it’s important to know when to use them in a patient’s treatment—whether at the time of initial diagnosis or potentially later on at [the time of] relapse,” Carraway, a staff associate professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University; vice chair of Strategy and Enterprise Development at the Taussig Cancer Institute in the Division of Hematologic Oncology and Blood Disorders at the Cleveland Clinic; and member of the Immune Oncology Program at Case Comprehensive Cancer Center in Ohio, emphasized. “[Although] we have these tools, in reality, there can be challenges in applying them based on the [molecular] data [available] for the patient in front of us.”
Carraway also highlighted current challenges and ongoing innovations in the management of acute myeloid leukemia (AML) in a concurrent article.
OncLive: What tools are currently used for disease classification criteria and risk stratification in MDS?
Carraway: Risk stratification for patients with a diagnosis of MDS is [done] through a scoring system called the International Prognostic Scoring System [IPSS], which has existed for some time. [It was] initially called the IPSS, then revised as the IPSS-R, and is now further refined with the addition of molecular data as the IPSS-M. These risk assessments or tools help us identify [whether a] patient is at low risk or high risk for progression of their MDS to a higher-risk disease, such as AML. If [a patient is at] higher risk, [progression] may occur within the next 6 months to 1 year, and treatment options and recommendations will differ for that patient compared with someone at lower risk.
Many of us have appreciated the IPSS-M because it refines the prognostic scoring system for patients with MDS in ways that the prior IPSS and IPSS-R do not. We also need to have access to molecular data for our patients, which not everyone has. That’s part of why there may be a gap.
What are some of the limitations associated with these classification systems, and how might they be addressed?
One of the current challenges we have, specifically in MDS, is that there is the International Consensus Classification criteria and World Health Organization criteria. We have worked hard as a community to acknowledge that having 2 classification systems is not ideal for our patient population. It is very confusing for patients and can also create challenges when enrolling patients into clinical trials, [as we strive] to unify and establish best practices in terms of requesting and/or requiring one system.
[Another key change] in the classification [of MDS] that is important to highlight is the incorporation of molecular mutation data, which allows us to classify disease based on [the presence of] mutations such as SF3B1 or TP53…rather than relying [solely on] morphology as a tool to define diagnoses. The incorporation of molecular mutations has refined our ability to classify these diseases. We still have not perfectly aligned our classification criteria, but that’s one place where we know and aspire to have momentum.
The same is true in the AML space, [where] determine whether a leukemia is favorable risk, intermediate risk, or poor risk based on the presence or absence of specific mutations and/or cytogenetic features. Again, it is important for the field to move forward using the most up-to-date tools—by identifying mutations with next-generation sequencing and by a multitude of newer technologies.
Finally, because we now have these tools, [we are also better able] to identify measurable residual disease, which has significant implications. [However, this also raises] questions about [how to treat] patients when disease is detectable even at very low levels.
How is clonal hematopoiesis typically managed, particularly for patients with high-risk features?
We’ve learned [a lot] from some of the work led by Zoey Xie, MD, MS, of Moffitt Cancer Center, [in which she] deliberately and extensively annotated patients with clonal hematopoiesis of indeterminate potential [CHIP] and clonal cytopenia of undetermined significance [CCUS], such that there are scoring systems that we use for patients with CHIP and CCUS.
[Through this] robust, retrospective work, they’ve been able to demonstrate that patients with high-risk CCUS [have a malignancy that] can clinically behave similarly to those with low-risk MDS.
This finding has important implications, particularly because these patients with [high-risk CCUS] are not currently included in ongoing clinical trials. For example, studies in low-risk MDS typically do not include patients with high-risk CCUS in their eligibility criteria. That landscape will likely need to change in the future because of these data.
What still needs to be learned to better determine the risk of clonal hemopoiesis in select patient populations?
We have a close eye on the fact that there are specific mutations that matter, as well as the number of mutations that matter and the degree of cytopenias for patients. As we follow them, we also care deeply about prior exposures. If patients have had prior chemotherapy and/or significant family history, we’re learning about specific mutations [being associated with] better responses to specific drugs. In this space, we also need to make sure that we’re paying attention to cardiovascular risk management for patients. Those themes [will continue to] emerge as we think about therapeutic interventions.
What does the FDA approval of imetelstat for the treatment of patients with lower-risk MDS mean for clinical practice?
Imetelstat is a very important agent for patients who have anemia and/or are transfusion dependent. This agent is impressive in the way patients respond to it in terms of achieving transfusion independence. Some of the challenges with imetelstat involve monitoring patients closely for transfusion dependence initially, as they can develop cytopenias during the early cycles of therapy. [However], patients may later become transfusion independent. [It is important to provide] adequate information to patients so they are aware of this, are adhering to follow-up, and are appropriately supported throughout treatment.
What has been most notable with imetelstat is the degree of transfusion independence that happens and how meaningful the rise in hemoglobin is for patients. It is exciting to have a new agent that we can use. For any community physicians with questions about using this drug, [I’d advise them] to reach out to colleagues who are adept and have used it before.
What questions remain regarding the role of luspatercept in ring sideroblast (RS)–negative, lower-risk MDS?
Based on findings from the [phase 3] COMMANDS study [NCT03682536], luspatercept was FDA approved for patients with anemia [stemming from lower-risk] MDS. In that study, the majority of enrolled patients had SF3B1 mutations and/or the presence of RS. We know that this subset of patients tends to respond well to luspatercept, which is encouraging, and the overall data were impressive.
However, questions remain about the subset of patients who are RS-negative and/or SF3B1-negative, [as fewer] of these patients were enrolled in the trial. Clinicians are [uncertain about] whether they should be using luspatercept or erythropoiesis-stimulating agent [ESA]–based therapy in the frontline setting [for this subgroup]. We just need more patients to be treated.
[Although] a subset analysis from COMMANDS suggested [comparable] responses between luspatercept and ESAs in this [RS-negative] patient population, the [amount] of patient [data collected] was small, so we don’t have the answer to this quite yet.
The other important consideration is dosing. Many patients in the study ultimately required the higher dose of luspatercept at 1.75 mg/kg. The trial protocol mandated a dose escalation from 1.0 mg/kg to 1.33 mg/kg and then up to 1.75 mg/kg, based on hemoglobin response. It is important to ramp up that dose, particularly if the hemoglobin has not reached 11 or 11.5 g/dL. There are remaining questions about whether dose escalation [is necessary] or if we could initiate therapy at 1.75 mg/kg, given that the higher dose was well tolerated and required for many patients. Those are going to be emerging questions that we hope to answer in the future.
In your clinical practice, what are the most important considerations when utilizing HMAs for patients with high-risk MDS?
It is important for patients with high-risk MDS to embark on therapy to delay progression to higher-risk disease, such as AML. All these patients, if they are transplant eligible, need to obtain a transplant consult quickly so that, if appropriate, we can quickly work in conjunction with the transplant team. For some patients with high-risk disease, we also begin to consider [whether there is] a role for HMAs in the post-transplant setting. [There are] unanswered questions in that space, and we are eager to address them through ongoing and future studies of HMAs.
In terms of lessons learned, we know that HMAs are important for [patients with] high-risk MDS to stay on. From some of the recent phase 3 studies, even those that ultimately failed [to meet their primary end points], we learned that maintaining patients on a 28-day treatment cycle is critical. Supporting patients adequately so that they can remain on treatment, whether through transfusions or prophylactic antibiotics, better serves them, particularly if they’re able to tolerate and be supported through their cytopenias.
What is one key action item regarding clinical outcomes associated with HMAs?
One of the key areas of ongoing refinement in the management of patients with high-risk MDS is the definition and requirements of complete remission [CR]. In patients with acute leukemias with CRs, there aren’t as robust hemoglobin requirements, so moving the needle with regard to remissions there is important. With regard to HMA-based therapy, we do want to have control of the blast percentage in our patients with high-risk MDS. [The therapeutic goal] remains to reduce bone marrow blast percentage and restore normal hematopoiesis, including neutrophil, hemoglobin, and platelet production. Making sure that our patients are supported [enough to] remain on therapy in a consistent manner, and that they are given the transfusion support that they need, helps them get through the therapy to optimize their quality of life and decrease their toxicities.