3. Diagnostic Approach and Risk-Stratification
In patients with suspected MDS, previous exposure to genotoxic agents (e.g., cytotoxic chemotherapy, radiation) should be evaluated, which indicates the presence of a therapy related myeloid neoplasm (t-MN). Younger MDS patients (40 years) should be thoroughly screened for germline predispositions, which may be indicated by a family history of malignancies as well as immune or organ dysfunctions in first- and second-degree relatives. The European Leukemia Net recommendation recognizes diagnostic procedures as “mandatory” (evaluation of PB smears and BM aspirate/biopsy with cytogenetic analysis), “recommended” (fluorescence in situ hybridization (FISH) and flow cytometry), and “suggested” in specific circumstances (single-nucleotide-polymorphism (SNP), molecular diagnostics)
[13]. Process-based indicators as measurable elements for quality of care are of increasing interest to enable assessment and comparison of the impact of different health care environments on relevant MDS outcomes
[14].
4. Therapeutic Approach
Experienced physician and interdisciplinary boards should be involved in the assessment of MDS patient with symptomatic cytopenia or unexplained inflammatory conditions. This is important due to disease complexity, interfering comorbidities, and timely selection of higher-risk MDS patients being eligible for allo-HCT. Fluctuating cytopenias may be the initial manifestation of clonal hematopoiesis. However, patients with uncharacterized systemic autoinflammatory manifestations may also present with SLADMs at high VAFs, as primary manifestation of clonal hematopoiesis or even MDS
[15]. New therapeutic options and clinical trials are urgently needed, especially in elderly patients with refractory conditions
[16]. Therefore, symptomatic patients should be referred to experienced MDS centers, included in prospective registries/biobanks, and offered participation to clinical trials, whenever possible. The therapeutic approaches for lower- and higher-risk MDS are summarized in
Figure 1A,B, respectively, and an overview on the treatment landscape can be found in
Figure 2.
Figure 1. Treatment algorithm for lower- and higher-risk MDS. Yellow boxes highlight areas with an unmet clinical need in in lower (
A) and higher-risk MDS (
B). High-risk (HR) mutations comprise: ≥3 SLADMs or single mutations in
TP53,
RUNX1,
ASXL1,
ETV6,
EZH2,
SRSF2,
U2AF1,
RAS-pathway and
JAK2 with VAF ≥2%
[17][18][19]. Allo-HCT: allogeneic hematopoietic stem cell transplantation; AML-CTX: AML-based chemotherapy; ATG: antithymocyte globulin; BM: bone marrow; CSA: Cyclosporine A; CyG: cytogenetics; ESA: erythropoietin stimulating agent; HMA: hypomethylating agent; HR: high-risk mutations;
mSF3B1: mutated
SF3B1; PB: peripheral blood; PS: performance status; RBC: red blood cell concentrate; RS: ring sideroblasts; sEpo: serum erythropoietin; TPO-RA: thrombopoietin receptor agonist. Adapted from
[20].
Figure 2. Treatment landscape in MDS. Treatment can affect normal (
left) and clonal hematopoiesis (
right). SLADMs: somatic leukemia-associated driver mutations; ESA, erythropoietin stimulating agent; ICI, immune checkpoint inhibitors; G-CSF, granulocyte colony stimulating factor; HMA, hypomethylating agents; IST, immune suppressive treatment (CyA/ATG); LEN, lenalidomide; LUSPA, luspatercept; TPO-RA: thrombopoietin receptor agonists; VEN, venetoclax. Adapted from
[20].