Dr Pettit Highlights Whether Low-Risk MDS Is Really Low Risk

Kristen Pettit, MD, University of Michigan, discusses myelodysplastic syndromes (MDS) and specifically highlights if low-risk MDS is really low risk. These data were presented at the virtual 2021 Lymphoma, Leukemia & Myeloma (LL&M) Congress.

“We know that MDS is a very heterogeneous disease with a wide range of potential outcomes for patients, ranging from very indolent asymptomatic disease to an aggressive phenotype with severe cytopenias and risk of progression to AML,” Dr Pettit said.

Dr Pettit said the clinical spectrum of MDS follows the genomic evolution of the malignant clone. Disease-initiating mutations usually include splicing, chromatic modification, or DNA methylation, Dr Pettit said. Patients with a sole mutation in 1 gene tend to have only mild disease pathologies, such as CHIP or early lower-risk MDS, she said. Over time, additional mutations involving transcription factors, signaling pathways, or DNA methylating led to an increase in genomic complexity, aggressive disease behavior with more severe cytopenias, and eventual progression to secondary acute myeloid leukemia (AML).

In terms of defining low-risk MDS, Dr Pettit said there are tools to predict when a patient may experience more aggressive disease behavior, including IPSS, WPSS, MDA LR-PSS³, and IPSS-R⁴. The IPPS-R⁴ score is the most used today, she said. The IPPS-R⁴ focuses on age, bone marrow blasts, cytogenetics, and number and depth of cytopenias to group patients into 5 risk groups (very low, low, intermediate, high, very high).

“I'd like to point out that this was developed based on conventional karyotyping, and an MDS FISH panel should not take the place of conventional karyotyping for the purpose of risk stratification,” Dr Pettit said.

Generally, patients with an IPPS-R⁴ score of less than 3 and who are in the very low, low-risk, or low-intermediate risk groups are considered “lower-risk,” Dr Pettit said. Those in the high or very-high risk groups are considered “higher-risk.”

“When we look at all patients with MDS, two-thirds of those with MDS will fall into a lower-risk disease category,” Dr Pettit said.

Dr Pettit then highlighted the outcomes within each risk group.

The median survival time duration for patients varies from 9 years for patients with very low-risk MDS to less than a year for patients with very high-risk (low: 5.3 years; intermediate: 3 years; high: 1.6 years.) The risk of AML progression, which is measured by the time it takes to 25 percent of the patients in that risk group to develop AML, ranges from 10.8 years for lower-risk MDS to less than a year for higher-risk MDS. Among patients with lower-risk MDS, 25 percent die within 2 years, she said.

“Still, these prognostic systems are not perfect and the outcomes within each risk group are somewhat heterogeneous,” Dr Pettit said.

Thus, Dr Pettit aimed to determine how to better predict who those patients might be, and what to make of the intermediate risk group. She said molecular findings help.

There are 5 high-risk gene mutations that predict a worse prognosis, independent of the IPSS-R⁴ score, for lower-risk MDS, Dr Pettit said. Patients with very low IPSS risk, low risk, or intermediate risk, and have a high molecular risk mutation, will experience worsening overall survival (OS) compared to those without those mutations.

“These are certainly groups of patients with technically lower-risk IPSS-R scores, who you would definitely want to identify early and perhaps be ready to approach more aggressively,” Dr Pettit said. “This is the reason that next-generation sequencing (NGS) for patients with MDS is so important and should be incorporated into the initial workup.”

There are other clinical and pathologic features that indicate higher-risk disease among lower-risk cases, Dr Pettit said, referring to the depth and kinetics of cytopenias, as well as therapy-related disease after prior chemotherapy or radiation, inherited predisposition factors, bone marrow fibrosis of grade 2 or higher, and a lack of response to treatment.

“For example, a platelet decrease by more than 25 percent in the first 6 months after diagnosis is a higher-risk feature,” she said.

In terms of managing this group of patients, the goals of treatment for lower-risk MDS are generally different than those with higher-risk MDS, she said.

With lower-risk disease, clinicians tend to focus on improving symptoms and quality of life while lessening cytopenias, Dr Pettit said. This is different from higher-risk disease because earlier interventions, such as hypomethylating agents or allogenic transplant, have not been shown to improve OS, prevent clonal evolution, or prevent transformation to acute leukemia in those with lower-risk MDS, she said. The standard approach to treat lower-risk MDS, Dr Pettit said, starts by determining if a patient is asymptomatic without significant cytopenias. If so, close observation is appropriate as well as watching for signs of disease progression.

“In general, treatment for MDS should be based on both disease risk and individual symptoms and lab findings,” Dr Pettit said.

For low-risk MDS patients with anemia, supportive measures can be used, she said, including transfusions, lenalidomide if there's an isolated del(5q), or erythropoiesis-stimulating agents (ESAs) if the endogenous EPO level is low. Anemia responses can occur in 20 to 40 percent of patients, and the response duration ranges from 18 to 24 months.

For MDS patients with ring sideroblasts who either don't or are unlikely to respond to ESA, luspatercept is an option. For those with thrombocytopenia, supportive care for bleeding or super low platelet counts includes transfusions or thrombopoietin agonists. For those with neutropenia or recurring infections, antimicrobial prophylactics can be utilized. If multiple lineages are involved, a more aggressive approach might be needed, such as hypomethylating agents, transplant consultations.

“ESAs are a cornerstone of therapy for those of lower-risk MDS that's complicated by anemia, especially those with an endogenous serum EPO level of less than 500,” Dr Pettit said.

There are factors that can predict a favorable response to ESAs, including a lower serum EPO level at the start of treatment and lower red blood cell transfusion requirement.

Dr Pettit said immune dysregulation is a key feature of MDS, referring to a phase 3 study on lenalidomide in lower-risk MDS. In this study, MDS patients with an isolated del(5q) were randomized to receive 2 doses of lenalidomide versus placebo. Findings showed that treatment with lenalidomide resulted in transfusion independence in 56 percent and 42 percent of patients in the 2-dosing cohort versus 5 percent in the placebo cohort. Responses for MDS patients without a del(5q) were less robust, Dr Pettit said, with response rates around 25% and a duration of response of less than a year.  

“The use of lenalidomide may be able to restore sensitivities to ESAs in some patients, so this combination can be considered in select situations where other options don't exist.

Luspatercept, a recombinant fusion protein, was FDA-approved last year for patients with lower-risk MDS with ring sideroblasts and/or an SF3B1 mutation, and who are transfusion-dependent and not eligible for ESAs, Dr Pettit said.

“Luspatercept was the first new FDA approval of a therapy for MDS in 16 years, which is definitely cause for some excitement,” Dr Pettit said.

The FDA approval was based on data from the MEDALIST trial, which is a randomized phase 3 study of luspatercept versus placebo. Patients with lower-risk MDS with more than 15 percent ring sideroblasts, or those with a SF3B1 mutation with more than 5 percent ring sideroblasts, were enrolled. These patients were transfusion-dependent and either refractory or unlikely to respond to ESAs. The treatment plan included a luspatercept injection given every 3 weeks subcutaneously, starting at 1 mg/kg, and escalating to 1.33mg/kg, and if needed, up to 1.75mg/kg. The primary end point was transfusion independence for 8 weeks or more, which was reached in 38 percent of patients on luspatercept versus 13 percent on placebo.

“In this select patient population, luspatercept has a real potential to make a difference in terms of transfusion needs and symptoms of anemia,” Dr Pettit said.

Concerning DNA hypomethylating agents, Dr Pettit said azacitidine and decitabine are both options for lower-risk MDS that requires treatment due to cytopenias not responding to supportive measures. However, neither has been shown to prologue survival in lower-risk MDS, unlike higher-risk disease, and head-to-head studies have not demonstrated superiority of either one.

An enzyme called cytidine deaminase (CDA) is another choice, Dr Pettit said. It was FDA-approved in July 2020 for intermediate- or high-risk MDS and CMML, with the caveat that more studies are needed to confirm the endpoints. The addition of cedazuradine inhibits CDA and improves the bioavailability of HMAs. This oral agent was given for 5 days of a 28-day cycle. The drug exposure is very similar between the IV and oral formulations. The response rate is similar to historical controls, and toxicity is similar to IV, with cytopenias being the major thing to monitor, Dr Pettit said.

A newer oral agent under investigation for lower-risk MDS, she said, is imetelstat, a telomerase inhibitor. The enzyme in telomerase, according to Dr Pettit, helps to maintain telomere length and is upregulated in MDS cells as well as some other cancers. In a phase 2 study of 57 patients with lower-risk transfusion-dependent MDS, 37 percent of patients achieved transfusion independence for 8 weeks, and 23 percent achieved it for even longer at 24 weeks. The median duration of transfusion independence was 65 weeks. There was also evidence of reduction of the malignant clone. Cytopenias were observed in the first month, but improved over time.

There are several novel therapies for MDS worth mentioning, Dr Pettit said, including venetoclax, an oral BCL2 inhibitor that was approved for AML, as well as IDH1 and 2 inhibitors, which occur in 4 to 12 percent of MDS cases. For MDS, studies of venetoclax alone or in combination with HMAs are currently underway for patients with higher-risk and relapsed or refractory (R/R) disease. Early responses are encouraging, Dr Pettit said, but cytopenias are common and may limit its use in this MDS setting.

Pevonedistat is another novel NEDD8-activating enzyme inhibitor. A phase 2 study of pevonedistat plus azacitidine versus azacitidine alone in higher-risk MDS patients showed improvements in OS and event-free survival (EFS). However, a phase 3 study in higher-risk MDS and CMML failed to meet its primary endpoint of EFS.

“To come back to the title of the session, is low-risk MDS really low risk? Well, molecular studies can help identify high-risk cases hiding among lower-risk IPSS-R categories,” Dr Pettit said. She also emphasized that low risk of death does not equal a low symptom burden.

Dr Pettit concluded: “Still, major areas of unmet need for this population include ways to improve cytopenias, improve symptoms and quality of life, prevent leukemic transformation, improve survival, and lessen the burdensome schedules and toxicities with our available treatments.”—Emily Bader