Introduction
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies that vary considerably with regard to life expectancy. Prognosis depends on disease-related as well as patient-related factors. Prognostic scoring systems are generally built on disease-related factors and designed to separate patients into risk groups. These risk groups are utilized by guidelines to provide risk-adapted treatment recommendations within the framework of approved drugs and procedures. Guideline-based therapeutic decision-making is enhanced by expert advice that takes patient-related factors like performance status and comorbidities into account. Widely accepted MDS guidelines that connect MDS subtypes and risk groups with a number of therapeutic options are the European LeukemiaNet (ELN) [
1] guidelines for adult patients with primary MDS, the National Comprehensive Cancer Network (NCCN) guidelines for MDS [
2], the recommendations issued by the Nordic MDS Study Group [
3], and the recommendations for allogeneic hematopoietic stem cell transplantation for MDS and chronic myelomonocytic leukemia (CMML) issued by an international expert panel [
4].
However, the survival impact of adherence to MDS guidelines and guideline-based expert advice is unknown. We addressed this question by analyzing adherence to ELN guidelines and MDS expert recommendations in the setting of the large Duesseldorf MDS Registry.
Discussion
Due to strict eligibility criteria, MDS patients enrolled in clinical trials are a selected subgroup not representative of the entire patient population. Therefore, real-life evidence of the survival impact of certain therapeutic approaches is sparse. The Duesseldorf MDS Registry approximates the characteristics of the general MDS population and thus provides robust information about the clinical value of widely used therapies.
When treating MDS patients, there are two major treatment goals: to improve the patients’ quality of life mainly with non-intensive measures and to prolong overall survival especially in high-risk MDS patients. However, low-risk patients treated with BSC only with a durable hematologic improvement tend to show superior overall survival as well, since one or more cytopenias are a primary reason for morbidity as well as mortality. As improved quality of live is closely associated to reduced mortality, we chose overall survival as our major endpoint. Furthermore, as the MDS CI adds prognostic information independently from the IPSS, we used those two prognostic scoring tools as the basis to classify our patients in both cohorts.
Our retrospective analysis of 1658 patients in cohort 1 indicates that patients eligible for a certain treatment did not gain a significant survival benefit compared with patients who did not receive it. The only exceptions were iron chelation therapy among the non-intensive BSC options, and alloSCT. When used according to the ELN guidelines, these two treatments conferred a significant survival advantage compared to the use of BSC only. The favorable effect of iron chelation in patients with lower-risk MDS may be attributable to the benefits of diminished iron-related oxidative stress, including amelioration of ineffective erythropoiesis in a minority of patients [
9]. AlloSCT is the only curative treatment, but most MDS patients are not fit enough to be eligible. As previously shown, drugs like valproic acid, low-dose Ara-C, and antithymocyte globulin (ATG) are only palliative [
10]. According to our analysis, the same is true for other therapies used these days, which can help to decrease disease-related morbidity and enhance the patients’ quality of life but fail to achieve a substantial gain in survival time.
It is therefore plausible that we failed to show a survival advantage of guideline-adherent treatment. This applies to all treatment categories examined. We found that a sizeable proportion of patients (25% on average) were indeed treated outside the guidelines. This was true for non-intensive treatment as well as alloSCT. Not being treated in strict accordance with the guidelines did not lead to inferior outcome in any of the therapeutic areas we analyzed. This observation supports the view that clinical advice should be consistent with accepted guidelines but should be free to include modifications according to patient-related risk factors, geriatric evaluation, and patient preferences.
In our prospective cohort including 381 patients seen in our outpatient clinic (cohort 2), we confirmed that adherence to guideline-based expert advice had no major impact on survival. Patients who chose to be treated differently had no inferior prognosis, as long as their treatment exceeded best supportive care. Again, the exception was alloSCT. In order to further examine the value of various therapies, we used a matched-pair procedure to compare guideline-adherent patients receiving a specific treatment with matched patients (historical controls) who received BSC only. We showed that patients following guideline-based expert advice to undergo treatment with lenalidomide, HMAs, or alloSCT did have a better prognosis than patients who would have been eligible for such treatment but received BSC only. This was true when treatment was strictly according to the guidelines, as in our analysis of cohort 1, or modified by expert advice.
Even in patients who do not derive a survival benefit from treatment with lenalidomide or HMAs, such treatment may be beneficial by improving blood counts and may even result in temporary remission. Palliative treatment should thus not be undervalued. If transfusion independency is achieved, this will greatly improve the patients’ quality of life and also decrease the risk of cardiovascular complications associated with chronic transfusion therapy in MDS [
11,
12].
It is of importance that the presence of comorbidities per se was not a criterion to exclude patients from our analyses. According to the ELN guidelines, each patient in the retrospective as well as in the prospective cohort was classified to match the respective therapeutic category. Therefore, even comorbid patients were considered to receive a suitable treatment and a selection bias on this level can be ruled out. The groups receiving treatment were not younger and fitter.
Our findings do not invalidate the ELN guidelines but emphasize that proper patient management should go beyond guidelines and should involve shared decision-making. Guidelines should be considered a useful framework rather than a dogma. Unfortunately, we were often unable to ascertain the specific reasons for non-adherence to the guidelines, mainly because many patients were managed outside our tertiary referral center. Up to now, studies of interest validating guidelines in hematology are sparse. Existing studies concerning solid tumors focus on evaluating adherence to one certain type of drug. A field of special interest is early stage breast cancer. As the work about adherence to adjuvant hormonal therapy [
13] suggests, patients’ non-adherence is associated with an increased risk of mortality. Nevertheless, studies like this are far from evaluating adherence to an entire guideline. The investigation of guideline use in other hematological entities such as acute myeloid leukemia or lymphoma would be worthwhile, to gain important information on the impact of adherence to patient related outcomes.
Altogether, our retrospective and prospective analyses imply that, with the exception of alloSCT, none of the currently available therapies is powerful enough to render deviation from guideline-based expert advice a major disadvantage in terms of prognosis. We clearly need better treatment options, which can really make a change when correctly applied by an MDS expert.
Compliance with ethical standards
Conflict of interest
A.K. has received travel support from Celgene.
K.N. has received honoraria from Jazz Pharmaceuticals and travel support from Celgene.
M.K. has no conflicts of interest to declare.
T.S. received honoraria and research funding from Celgene.
G.K. received honoraria, travel support, and research funding from Amgen and Celgene, and honoraria and travel support from Neovii, Abbvie, Roche, Biotest, Pfizer, Jazz Pharmaceuticals, Takeda, Medac, MSD, and Novartis.
A.K. received honoraria from Otsuka, Takeda, and Novartis and travel support from Takeda.
J.K. received travel support from Jazz Pharmaceuticals.
C.R. received travel support from Jazz Pharmaceuticals and travel support and honoraria from Celgene.
R.H. has no conflicts of interest to declare.
N.G. received honoraria from Novartis and research funding from Alexion and Takeda.
N.B. received travel support from Novartis, Roche, Amgen, Celgene, Sanofi Genzyme, and Janssen and research funding from Novartis, Roche, and Celgene.
U.G. received honoraria from Celgene, Novartis, Jazz Pharmaceuticals, and Amgen and research funding from Celgene and Novartis.
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