MDS represents a challenge to the hematologists because of the heterogeneous nature of the disease, and the presence of diversity of conditions across the entire spectrum of MDS as well as the vague boundaries between MDS and other related myeloid disorders. The overall outcome of MDS are very heterogeneous with an overall survival ranges from few months to years in some patients.
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell neoplasms characterized by ineffective hematopoiesis, dysplasia of the myeloid cells, cytopenias  and increased risk of progression to acute leukemia . It occurs more frequently in older individuals  with a median age at presentation of 70-75 years. The incidence of MDS is estimated at 5-13/100,000/year  but rises to >20/100,000/year in the ageing population . Unexplained anemia associated with a high MCV in the very old should trigger the suspicion of underlying MDS .
MDS is a complex multistep process comprising severe disturbance within the hematopoietic cell compartment and in the bone marrow microenvironment and the complex interactions between both compartments . Activation of the innate immune signaling (i.e. myeloid derived suppressor cells) and the activation of NLRP3 inflammasome in hematopoietic stem/ progenitor cells play a central role in the biology of MDS  by producing an inflammatory lytic form of cell death termed pyroptosis and clonal expansion .
Several prognostic scorings systems risk-stratify MDS patients, including the International Prognostic Scoring System (IPSS), the revised IPSS (IPSS-R), the WHO Prognostic Scoring System (WPSS), and the Global MD Anderson Prognostic Scoring System (MDAPSS).All use mainly 3 categories:
i. cytogenetic analysis,
ii. bone marrow blast percentage (except for WPSS), and
iii. cytopenias (WPSS uses transfusion dependency, the revised [WPSSR] included hemoglobin level instead of transfusion dependency).
Age was included as an independent prognostic factor in MDAPSS and IPSS-R–age only. The IPSS and IPSS-R are the most commonly used prognostic models in clinical practice. Application of these models in practice has several shortcomings .
Current therapeutics for MDS is primarily based on stratification of patients into lower- and higher-risk disease using clinical prognostic scoring systems . In lower risk MDS, therapy aims at improving cytopenia(s), preventing complications like bleeding or severe infections and to decrease transfusion burden. In higher risk MDS, the principal aim of treatment is to modify the natural course of disease limiting disease progression and improving survival rates .
Allo-HSCT remains the only treatment option for possible
cure. Non-intensive and risk adapted treatment ranging from
iron chelation to lenalidomide and hypomethylating agents
(HMA) are appropriate for the majority of MDS patients .
Lenalidomide and the HMA (azacitidine and decitabine) have
been FDA approved for use in MDS-related indications . Once
an HMA fails via intolerance, resistance or relapse after favorable
response, the patient outlook is poor . MDS in patients
over 85 years is not actively managed with pharmacological
intervention or chemotherapy . Molecular drivers have
profound implications in future clinical investigations, prognosis
and treatment decisions . Comprehensive molecular
characterization has identified novel therapeutic strategies
that offer significant promise . Novel agents in development
for MDS include luspatercept, rigosertib, immune checkpoint
inhibitors and venetoclax .
a. Observation is appropriate for asymptomatic patients
until their cytopenias worsen or become more symptomatic
b. Patients with anemia and a sEPO < 100 U/L have a
greater than 70% chance of responding to ESA .
c. Lenalidomide: an immunomodulatory drug that
selectively suppresses del(5q) clones through induction
of ubiquitination of casein kinase 1A1 (CK1) resulting
in CK1 degradation. CK1a is encoded by a gene within
a commonly deleted region for del(5q) MDS . The
“targeted” use of lenalidomide in del5q MDS yielded a 50%
or greater reduction in transfusions in 76% of patients,
whereas 67% achieved transfusion independence lasting for
a median duration of >2.7 years , and 30–40% achieved
cytogenetic remission . P53 mutations do less well
compared with del5q patients without TP53. There is a
27% response rate to lenalidomide in non del5q patients
. Lesser response to lenalidomide treatment occurs with
a complex karyotype that includes del5q and with excess
marrow blasts .
d. Anti-T cell immunosuppressive therapy (IST, e.g.,
antithymocyte globulin, corticosteroids, and cyclosporine or
tacrolimus) is reasonable in patients who lacks excess blasts
or a complex karyotype and who has either (i) anemia not
responding to ESA or lenalidomide or has (ii) another severe
cytopenia not responding to growth factors.
e. IST is a particularly attractive consideration if the
marrow is hypocellular for age. The presence of a PNH clone
or HLA DR15 status did not predict IST response .
f. Treatment with HMA or enrollment in clinical trials is
recommended in low-risk MDS patients with anemia who
lose response to ESA, danazol, or lenalidomide .
A specific activin receptor fusion proteins that act as a
ligand trap to neutralize negative regulators of late-stage
erythropoiesis . It results in RBC transfusion independence in
10% to 50% of lower risk MDSs resistant to available treatments
. Luspatercept has a substantial potential to target anemia
of lower-risk MDS with ring sideroblasts and presence of splice
factor SF3B1 mutations  who are refractory or not eligible to
ESA (NCT02631070, MEDALIST trial) .
An oral hypoxia inducible factor prolyl hydroxylase inhibitor.
It promotes erythropoiesis through increasing endogenous
erythropoietin levels and improves iron regulation by
modulation of hepcidin levels. Its efficacy and safety for treating
anemia in lower-risk MDS patients with low RBC transfusion
burden is in phase 3 study (NCT03263091) .
A telomerase inhibitor that targets cells with short telomere
lengths and active telomerase . MDS patients with significantly
shorter telomeres compared to healthy controls and higher
telomerase activity exhibited significantly inferior survival .
Imetelstat has encouraging activity in lower risk, treatment
naïve MDS patients that are RBC-TD . Single center has
shown activity of imetelstat in MDS with RS phenotype. Phase
2/3 study is ongoing in RBC-TD and ESA-relapsed or refractory
lower-risk MDS patients. Preliminary results demonstrated
that 38% of patients achieved RBC transfusion-independence.
Its activity was higher in patients without del(5q) and without
prior exposure to either lenalidomide or HMA .
Allo-HSCT remains the only potentially curative option but
is accessible to only a small number of fit patients  and is
fraught with complications such as acute and chronic graft vs
host disease and non-relapse mortality . HMA therapy is
used as pre-transplant bridging therapy to cytoreduce disease,
especially for those patients who will get reduced intensity
conditioning (RIC) approaches and those who have more than
10% marrow blasts. Outcomes are at least as good with HMA
as with intensive chemotherapy . Upfront allo-HSCT has
shown no benefit for lower-risk MDS patients, regardless of a
myeloablative or RIC strategy .
HMA are the standards of care in HR-MDS not eligible for allo-
HSCT . Azacitidine and decitabine are two nucleoside analogs that are DNA hypomethylating agents . The mechanism
of action of HMA is unclear and may result from a combination
of conventional cytotoxic DNA hypomethylation (no specific signature)
and immune related mechanisms including changes in
interferon signaling and presentation of neoantigens as epitopes
to the immune system . HMA can decrease clonal burden and
may therefore result in improved hematopoiesis . Response
to HMAs cannot be predicted . Available molecular genetic
assays do not differentiate responders versus non responders
HMAs dampen immune response by up-regulating inhibitory
immune-checkpoint molecule expression such as programmed
cell death protein-1 (PD-1), PD-L1, and PD-L2 while enhancing
antitumor immune response, resulting in HMA resistance .
HMA do not eradicate transformed stem cells, so relapse is
inevitable . Patients with HR-MDS and those who fail to
respond to or to relapse/ progress after HMA treatment have
limited therapeutic options and poor prognosis . The median
overall survival of HMA refractory MDS with IPSS intermediate-
2/ high risk MDS was ~6 months . There is no approved
second-line therapy .
Three new HMAs are in late phase in clinical trials:
guadecitabine (a parenterally administered dinucleotide
nucleoside analog), CC486 (an orally bioavailable form of
azacitidine) and cedazurine (an orally administered fixed-dose
combination of decitabine and a cytidine deaminase inhibitor)
Current developments include combination of HMA with
novel drugs targeting epigenetic or immunomodulatory
pathways or prevent resistance by using checkpoint inhibitors
to enhance immune attack .
i. Immune checkpoint inhibitors (ICPIs): PD-L1 expression
is upregulated in HR-MDS compared with lower-risk
MDS patients and in those who fail HMA therapy . ICPIs
including PD-1 inhibitor nivolumab and cytotoxic T lymphocyte
associated antigen 4 (CTLA4) inhibitor ipilimumab
have demonstrated activity in the treatment of MDS including
those who failed prior HMA therapy . Combining inhibition
of the PD-L1/PD-1 pathway with azacytidine may
improve outcome . ICPIs toxicities result from overactivation
of the immune system .
ii. BCL2 inhibitor, venetoclax with azacytidine in HRMDS
patients after HMA failure is currently recruiting
iii. Isocitrate dehydrogenase (IDH) inhibitors: IDH inhibitors
target mechanism in epigenetic regulation. Potential
synergistic effects with HMA are assumed and are under investigation
iv. Rigosertib, an inhibitor of Ras effector pathways,
is in a phase 3 study in patients failing HMA treatment
(NCT02562443) and demonstrated some benefit in a subset
of patients .
TP53 mutations are considered a universally poor prognostic
factor. TP53 Mutations have been reported in 5% to 18% of MDS
patients and are generally associated with higher-risk disease,
including MDS with excess blasts, therapy-related myeloid
neoplasms, complex cytogenetics and a small subset of patients
with 5q minus syndrome . Patients with HR-MDS carrying
TP53 mutations may have clinical response and significant
mutation clearance with decitabine treatment . p53 activators
restore the wild-type conformation of mutant p53 and thereby
rescue p53 function. APR-246 is a p53 reactivator in phase 1b/2
study in combination with azacitidine (NCT03072043) for MDS
patients with up to 30% blasts. Given the poor outcomes in TP53
patient groups, this could be a promising therapeutic agent if the
trial yields favorable results .
New treatments such as hypomethylating agents and lenalidomide
have been approved with a limited benefit to patients’
outcome. There is a demand for a complex and personalized variety
of therapeutic approaches.
Taylor J, Coleman M, Alvarez K, Pichardo J, Sen F, et al. (2018) Elinexor, a first-in-class XPO1 inhibitor, is efficacious and tolerable in patients with myelodysplastic syndromes refractory to hypomethylating agents. Blood 132:233.