Prerequisites for a decision about ESA treatment in an individual patient
- A diagnosis of lower-risk MDS; IPSS low or intermediate-1; IPSS-R very low – intermediate
- An agreement between doctor and patient that stem cell transplantation is not an option at this time point
- Exclusion of rare subtypes of MDS that primarily should receive other types of treatment, e.g. immunosuppressive therapy
- Assessment of serum erythropoietin (S-Epo) level and transfusion status
How do patients feel when their hemoglobin levels decrease?
The first symptom is usually a rather diffuse decrease in physical capacity, from the level that the patient has been used to. Most MDS patients are older and usually not actively involved in sports, but surprisingly many are used to a physically active life including walking, gardening, playing golf and taking care of the household. Many patients are also reluctant to 'complain' - and many doctors are not used to ask about anemia-related symptoms. I find it important and useful to ask patients what they can do now compared to some months or years ago.
"How long are your walks with your dog? Can you walk to school and pick up your grand children? Can you walk stairs?" A former table-tennis champion told me that he no longer could stand against his grandson, although he still was a much better player.
When hemoglobin levels decrease further, patients will develop symptoms also when resting: severe tiredness (fatigue), appetite loss, dyspnea, and worsening of existing cardiac conditions, such as angina pectoris. Sometimes MDS is diagnosed in conjunction with the first blood transfusion. Professor David Bowen has in a previous blog discussed the topic of anemia and indications for blood transfusion.
Controversies
When should ESA treatment be initiated?
In many countries it is common to recommend that ESA treatment should start when the patient had developed a regular transfusion need, and in some countries this is required in order to get the drug reimbursed.
The network of investigators within the European MDS registry studied close to 1700 lower-risk MDS patients in this EUMDS Registry. Some patients were treated with ESAs and some were not according to National and local guidelines and preferences. The study showed that the onset of regular transfusion therapy was significantly delayed in patients treated with ESA at hemoglobin levels below 10 g/dl, but before the start of a regular transfusion need. The clinical effect when starting after the onset of transfusion therapy was less impressive. Therefore, we recommend that ESA treatment should be initiated before the onset of a regular transfusion need.
We know from larger clinical trials that a hemoglobin level of 10 g/dl is a common trigger level for starting ESA treatment. From my clinical practice this is usually also a level at which most patients have clear symptoms of anemia. However, many patients have symptoms already at higher Hb levels, in particular if they have other diseases such as lung or heart disease. Some years ago, the Nordic MDS group published a small study showing that quality of life increased with increasing hemoglobin levels, both when raised by ESA treatment and by blood transfusions to a Hb level higher than 12 g/dl (Nilsson-Ehle, et al, 2011). Hence, optimal trigger levels for starting ESA treatment should be studied in larger cohorts of patients, using dedicated patient-reported outcomes.
Do we have optimal tools to predict a response to ESA treatment?
The predictive model for response to ESAs published by the Nordic MDS Group in 2003 has been the basis for most International guidelines, including the EUMDS guidelines (Malcovati, et al 2013). However, the large clinical trials behind this model enrolled patients between 1990 and 2000. Many patients had a regular transfusion need at inclusion and often higher serum erythropoietin levels, as they were included later in the course of their disease. We have learnt from the EU MDS Registry that many patients are diagnosed before the onset of a regular transfusion need and that serum erythropoietin levels generally are low. It was therefore a significant contribution when Buckstein and coworkers recently published a novel predictive model, the ITACA, based on patients included in three registries mainly during the 2000s (Buckstein, et al, 2017). Based on close to 1000 patients, the ITACA score divides patients into four predictive groups based on IPSS score (low-risk vs >low-risk), transfusion need (yes vs no) and serum erythropoietin (<100 U/l vs >100 U/l). The best predictive response group has a response rate of 85%, the lowest 23%. This report thus lines up with the EU MDS Registry data, clearly demonstrating the value of initiating ESA treatment before the onset of a regular transfusion need.
What about safety and long-term efficacy?
The median duration of response to erythropoietin was 16 months in the Buckstein study, with a high proportion of patients responding for several years. The median response duration in the Nordic EPO-G-CSF studies for patients achieving a complete erythroid response was 30 months, with a proportion of patients responding for 10 years. All published studies on ESA treatment including those combining erythropoietin with G-CSF have uniformly failed to show any adverse effect on survival or leukemic transformation. On the contrary, the EUMDS study showed a tendency to improved survival in transfusion-independent patients exposed to ESAs (p=0.07).
Conclusion
Treatment with erythropoietin-stimulating agents in lower-risk MDS with symptomatic anemia is safe and effective and significantly prolongs the time to onset of a regular transfusion need. The novel MDS Right guidelines will recommend to start ESA treatment at the onset of anemia-related symptoms but before the onset of a regular transfusion need