Flying without a net in MDS

In this issue of Blood, Malcovati et al discuss the findings of an expert panel of the European LeukemiaNet (ELN) and their recommendations for treating myelodysplastic syndromes (MDS).¹ 

Guidance from expert panels on how to treat medical conditions abound, and it is easy to be jaded into thinking they represent no more than a “World According To Us” view of managing disease. But the ELN Expert Panel stepped up to the task of making rigorous recommendations. How did they do it? They started by identifying experts on the basis of established criteria, such as those of the National Institutes of Health Consensus Development Program²  and not on the basis of proximity to their offices. Check. They then systematically reviewed the literature for all articles guiding practice, both full manuscripts and abstracts at major conferences. Check minus, because the ELN used only English-language articles, and it did not disclose how many were identified or how many ultimately contributed to recommendations. Articles should be rated according to level of evidence, so case report findings and results from advanced phase studies are not given equal weight. Check—though note that meta-analyses garner the same score as randomized control trials. Finally, panelists are locked in a room and forced to listen to Barbra Streisand music until they come to a consensus on recommendations, which are graded according to level of evidence, consistency of results across studies, and applicability to the patient population—in this case, people with MDS. Check. And this took three consensus conferences (I suspect with music being unnecessary).

The ELN authors then took on the broad task of addressing all aspects of MDS, starting with making the diagnosis. They included standard procedures, such as the necessity for a bone marrow biopsy and cytogenetics (although including such obvious procedures in panel recommendations may seem superfluous, neither one is routinely performed, even in the United States)³  and more sophisticated approaches such as single nucleotide polymorphism arrays to detect cryptic chromosomal defects.⁴  They reaffirmed the utility of the World Health Organization classification of myeloid neoplasms⁵  and covered the broad collection of risk assessment tools available. Interestingly, while they acknowledged the shortcomings of the International Prognostic Scoring System (IPSS),⁶  they recommended its use to stratify risk for all MDS patients, given the large body of data supporting its applicability in therapeutic decisions and the relative paucity of data that have been generated for its revised successor.⁷  That will change in due time.

Rather than dividing the therapy section into treatments directed to disease severity (commonly defined as lower- vs higher-risk MDS using the IPSS and based on relative blast percentage, karyotypic abnormalities, and numbers of cytopenias), the ELN focused on each treatment modality itself. They started with watchful waiting, which may have been prescient, given the recent brouhaha over a National Cancer Institute panel’s recommendation to stop calling certain premalignant conditions “cancer.”⁸  Next, without identifying them as such, the authors introduced treatments for higher-risk MDS (stem cell transplantation, cytotoxic therapy, and hypomethylating agents), lower-risk disease (hematopoietic growth factors, immunomodulatory drugs, and immunosuppressive therapy), and ended with supportive care issues, which are germane to both.

In summary, the recommendations are rigorous, and they are comprehensive. But are they useful for those general hematologists and oncologists in practice, flying on their trapezes from patient to patient without a LeukemiaNet? In some ways no, and in some ways yes. In a patient with suspected MDS, the ELN gives equal weight to taking a good history of prior chemotherapy and radiation exposure and to obtaining a family history of Fanconi’s anemia and telomere disorders. While 10% of my patients have therapy-related MDS, I have yet to encounter someone with either of the latter conditions. In addition, for the uninitiated, while the therapy section is helpful in assigning levels of evidence to treatments being considered, it is difficult to navigate in answering the question, “for the patient sitting in my clinic with this subtype of MDS, what drug should I use?”

Impressively though, the ELN panel confirms minimum criteria for diagnosing and classifying MDS, which is more challenging than is widely appreciated.⁹  They also make clear statements regarding recommendations on controversial topics, such as remission induction therapy preceding stem cell transplantation or the use of iron chelation therapy, along with a recommendation grade. Although I may not agree with all of these recommendations, I can appreciate how they can guide physicians who do not have the time or interest to immerse themselves in the nuances of MDS literature and can keep them from falling to the floor of the Big Top.