Treatment strategies for patients with myelodysplastic syndromes are built upon a foundation of supportive care, which consists of transfusions, iron chelation, and growth factor therapy.
Thomas Prebet MD, PhD
Treatment strategies for patients with myelodysplastic syndromes (MDS) are built upon a foundation of supportive care, which consists of transfusions, iron chelation, and growth factor therapy, according to a presentation by Thomas Prebet MD, PhD, at the 2015 International MDS Symposium.1
A majority of patients with MDS worldwide are treated solely with best supportive care (70%-80%), as novel therapies are generally reserved for high-risk or cytogenetically defined individuals. Traditionally, supportive care has been administered solely to ameliorate symptoms; however, contemporary research suggests that "best supportive care" could prolong survival for patients with MDS, according to Prebet, assistant director of myeloid malignancy research at the Smilow Cancer Hospital at Yale-New Haven.
For patients with low- or intermediate-risk disease, best supportive care is the standard of care. Red blood cell (RBC) transfusions are generally the first step in a supportive care treatment strategy for many patients with MDS, since up to 80% of patients will experience anemia over the course of the disease.
"Most patients with MDS are diagnosed after the age of 70, and there is strong evidence that the anemia in patients over 70 is associated with a worse outcome and morbidity, such as fatigue, poor quality of life, increased risk of hospitalization, increased risk of cardiovascular events, and eventually, an increased risk of death," Prebet explained.
Erythropoiesis Stimulating Agents Beneficial
Both short- and long-term follow-up are needed to optimize transfusion. Early detection of volume overload could help predict and prevent iron overload, Prebet explained. Additionally, frequent monitoring allows for the rapid discovery of RBC alloimmunization, which can occur in 15% to 20% of patients with MDS who receive chronic transfusions.
While transfusion optimization has utility, the administration of erythropoiesis stimulating agents (ESAs) could prevent or delay transfusion dependency, which is associated with chronic iron overload and significant economic costs, explained Prebet.
"Treatment with an ESA has been associated with improvements in quality of life in most of the studies published to date," he explained. "We also know that early introduction of ESAs improves response rate and duration."
In a study of 112 patients with de novo low or intermediate-1 IPSS risk MDS who had not undergone transfusion, outcomes were significantly improved when an ESA was administered less than 6 months from diagnosis. In patients who received an ESA within 6 months, the median interval from diagnosis to transfusion dependency was 80 months compared with 35 months when an ESA was delayed (P = .007).2
A number of factors have been identified that could be predictive of response to ESAs in patients with MDS, Prebet noted. Serum erythropoietin (EPO) levels below 200 UI/l were associated with a response rate of 69% compared with 42% in patients with higher EPO levels (P = .0001). Furthermore, patients with low or intermediate-1 risk MDS were more likely to respond to ESAs.
In addition to these factors, studies have demonstrated superior response rates with high-dose ESAs compared with traditional doses. Responses with a high-dose ESA were 20% to 50% higher, explained Prebet.
"Based on what we know, patients with lowest risk disease, lowest EPO, and a low transfusion burden need to be treated as soon as possible, based on what we know about the 6-month threshold from diagnosis," he summarized. "Or an ESA can be used later, but we need to use high-dose treatment to maximize the chances of response for these patients."
Chelation Therapy to Address Iron Overload
Patients who do not respond to standard ESA treatment could be eligible for a combination strategy. Studies have shown promise with the combination of an ESA and G-CSF, with benefits shown in response and potentially overall survival. However, the administration of this combination is controversial, Prebet added.
"Early ESA treatment failure is associated with a bad outcome for these patients, with an overall survival around 2 years, which is really low compared with the standard for low-risk disease," he said. "In these patients after a few years, they will be transfusion dependent again, and we will have to face the consequences of this dependence. One of these consequences is iron overload."
High ferritin levels from chronic iron overload are associated with liver and cardiac toxicity. Iron chelation therapy (ICT) is recommended for patients with low-risk MDS who have received ≥20 RBC transfusions with a serum ferritin above 1000, Prebet suggested.
ICT is primarily administered to prevent organ damage, which can be caused by increased ferritin levels. Improvements with chelation can be observed using MRI or liver function tests. During the first 12 months of ICT, ferritin levels decline by 500 to 700 ng/mL. However, within this same timeframe, approximately 50% of patients will discontinue treatment due to progression or adverse events (~25%).
"Compliance is a key issue for the effectiveness of these treatments," Prebet said. "Shorter durations of ICT, less than 3 months or less than 6 months, does not bring any real benefits. We really need to coach these patients to ensure compliance with this treatment is correct."
The ICT deferasirox is commonly administered for chronic iron overload. Recently, the FDA approved an oral formulation of the medication. The ease of this administration route could improve compliance rates, believes Prebet.
"This new pill limits the gastrointestinal toxicity seen with other formulations of deferasirox, and this is maybe something that will help the patients stay compliant allowing for enough exposure to the drug for a clear benefit," he said. "Close follow up with this therapy is needed in the first months of this therapy, since this is the time when you have trouble with toxicity and compliance."
In addition to declines in ferritin, ICT is associated with hematologic improvement (HI) in patients with MDS. In a 247-patient study, the HI erythroid, platelet, and neutrophil rates were 21.5%, 13%, and 22%, respectively. The median time to response was approximately 169 days.3 In addition to HI, other analyses have suggested that ICT could improve survival.
"Based on a large Medicare database analysis, there’s a survival benefit with ICT," Prebet said. "Clearly, we're talking about selected patients. We really need to be cautious about these data and our communication of this data with patients. This should not be labeled an effective treatment for survival until we have prospective results."
As larger prospective studies continue to illuminate the long-term benefits of supportive care in MDS, it remains clear that optimizing this intervention significantly improves quality of life. Best supportive care is highly dependent on each individual, and represents the most personalized therapy you can provide, Prebet concluded.