Patients who do get them often stop early or do not get the recommended dose.
More than half of patients with high-risk myelodysplastic syndrome may not be receiving guideline-recommended treatment with hypomethylating agents.
Additionally, about half of patients who do get those treatments stop before completing the recommended six cycles, and up to 40% are not getting the required doses.
"This is a perfect storm," Sudipto Mukherjee, MD, PhD, MPH, physician in the department of hematology and medical oncology at Cleveland Clinic, told Healio. "With these three things that we saw, it may explain why we are not seeing significant survival benefit in this patient population in the U.S."
Hypomethylating agents azacitidine and decitabine have both been FDA approved for high-risk myelodysplastic syndrome (MDS) about 20 years, Mukherjee said.
Clinical trials showed azacitidine extended OS over other conventional therapies by approximately 9 months.
However, real-world survival data of high-risk MDS over the past 2 decades have not significantly changed despite availability of these drugs, according to study background.
"Why is it that we are almost 20 years out from the time these drugs were approved and we are not seeing any impressive survival benefit for people with high-risk MDS in this country?" Mukherjee asked. "This is important because for higher risk, newly-diagnosed MDS, these are currently the only two FDA-approved drugs available in the market."
Mukherjee and colleagues specifically used national Medicare data to investigate this question, as approximately 83% of patients diagnosed with MDS are aged 65 years and older and therefore, likely to be captured in the dataset.
The retrospective analysis included 49,154 individuals (42.4% aged 75-84 years; 53.9% men; 88.4% white) diagnosed with MDS between 2012 and 2013.
Receipt of hypomethylating agents served as the primary endpoint. Patterns and duration of use served as secondary endpoints.
In all, 16.1% of patients received hypomethylating agents. Of those, 73% got azacitidine.
"When you diagnose 100 patients with MDS, based on the available data, anywhere from 30% to 40% are usually high-risk MDS," Mukherjee said. "They all should be getting either azacitidine or decitabine as per the recommended treatment guidelines. In our study, only 16% were getting the recommended treatment. That is a really low number. A lot of people who have the diagnosis are not getting treated, and clearly that will not improve outcomes."
Compared with individuals aged 65 to 74 years, those aged 85 years and older had significantly lower odds of receiving hypomethylating agents (adjusted OR = 0.41; 95% CI, 0.38-0.44), as did those aged 75 to 84 years (aOR = 0.81; 95% CI, 0.76-0.86).
Additionally, women had a lower likelihood of getting hypomethylating agents than men (aOR = 0.81; 95% CI, 0.77-0.86). Black individuals also had reduced odds compared with white individuals (aOR = 0.7; 95% CI, 0.62-0.8), as did those who identified as "other" race or ethnicity (aOR = 0.78; 95% CI, 0.68-0.9).
Patients with no or one cytopenia had greater odds of receiving hypomethylating agents compared with those who had two or three cytopenias (aOR = 2.08; 95% CI, 1.96-2.2), and those who had a bone marrow biopsy had more than 12 times the likelihood of receiving treatment (aOR = 12.61; 95% CI, 10.78-14.74).
Among individuals who received azacitidine, 34% stopped treatment at cycle 4 (the minimum recommended duration), and about 50% stopped before finishing cycle 6.
"If you start any patient on either azacitidine or decitabine, you have to patiently wait for at least 4 to 6 months before you will see the full therapeutic benefit or effect of the drugs," Mukherjee said. "There is a small number of patients who may need a longer time, sometimes 9 months or longer. What did we see in our study? Just after one cycle, already a quarter of patients have discontinued the treatment. By the time you reach six treatment cycles, anywhere from 40% to 50% have discontinued treatment. If you do not give the treatment for the recommended duration, you are sub-optimally treating those patients."
Additionally, 31% of participants did not have a complete first treatment cycle and that number increased to 40% by cycle 6.
"We used a rather a loose criteria," Mukherjee said. "We said if somebody got at least more than 50% of the recommended doses in a treatment cycle, we considered that a completed treatment cycle. For azacitidine, we wanted them to get at least four of the seven daily doses. For decitabine, we considered three out of the five recommended daily doses in that 28-day period.
"This is very inadequate treatment," he continued after seeing how many patients did not meet those criteria. "You will never get the results you desire with this approach because this is not how it should be done. It is contrary to the clinical guidelines, and this is not how it was done in the clinical trial that led to the approval of these drugs."
Researchers acknowledged study limitations, including lack of cytogenic and molecular data.
Most individuals with high-risk MDS get treated in their communities, Mukherjee said.
Knowledge gaps in these settings may explain the disparities and infrequent treatment use.
Women and Black individuals usually have less high-risk disease features, and it is unclear whether this introduces a perception bias against use of hypomethylating agents in these groups. .
"If patients are high risk, it does not matter whether they are white, Black, Asian or Pacific Islander, or if they're a male or a female," Mukherjee said. "If they have high-risk MDS, there is an FDA-approved drug for that indication, and it should be used."
Ideally, azacitidine should be given for 7 consecutive days, but some community clinics may not be open on weekends, which could hinder use.
During treatments, patients likely will need to visit a doctor's office or hospital at least a couple of times a week for the entire treatment cycle to either receive hypomethylating agents or blood count assessments to determine transfusion needs.
"That's a big burden on a lot of patients," Mukherjee said.
Additionally, treatment tends to lower blood counts initially, and these individuals often have low counts to start.
"In the first two cycles, when your counts are dropping lower than where you started, you may see an increase in the need for blood transfusions," Mukherjee said. "That is how the nature of the treatment flows. Things tend to get worse before they get better. That is where a lot of things can go wrong. Patients may experience that and think, 'Maybe I should not be on this treatment.' That is where physicians or health care providers need to jump in and have detailed conversations, saying that this is expected before things start getting better."
But sometimes physicians may prematurely stop the treatment because they do not think it is working, as shown in a study where the patients' and physicians' perception of treatment benefits differed widely.
"Treatments are really being driven by the physicians. The question is, how much are they on board?" Mukherjee asked. "Do they have any knowledge gaps? Do they have the necessary resources -- the pathologic backing that they need, the access to and interpretation of genomic results? Are they aware of the fact that the counts are expected to drop in the first few cycles and that should not be a reason to discontinue the treatment? You may hold the treatment to allow the counts to recover or delay it a little bit, but to prematurely discontinue the treatment is completely going to deprive the patient of any benefit from these drugs."
Mukherjee suggested that there might be a benefit for patients with MDS to have a one-time consultation at a major academic center or a center for excellence. That will ensure a comprehensive treatment plan and possibly shared care with community oncologists, and that might address some of the treatment discrepancies identified in this study.
"If you look across the cancer literature for rare and complicated cancers, it has been shown that if patients had access to or if they had a one-time consultation at a center of excellence or a major academic center for that disease, they have improved survival outcomes," Mukherjee said. "Why? Because of the expertise [these centers] have. They can formulate a treatment plan.
"This is a low-hanging fruit for me," he added. "It should be done in most patients with MDS, if possible. It will give the treating community physician an entire plan on how to approach this patient, and all they need to do is execute it. It takes the burden of getting familiarized with the disease and all the latest advances in pathology and genomic technologies off their shoulders."