2. DISEASE OVERVIEW
• The myelodysplastic syndromes (MDS) are a very
heterogeneous group of clonal haematopoietic stem cell
diseases characterized by
Cytopenia
Dysplasia in one or more of the major myeloid lineages
Ineffective haematopoiesis
Recurrent genetic abnormalities
&
Increased risk of developing AML
3. • MDS occurs in 3 to 4 individuals per 105 in the US population
• Prevalence increases with age. In individuals age 60 and above,
prevalence is 7 to 35 per 105
• MDS affects more frequently males than females
• Exposure to prior chemo or radiation therapy is a risk for the
development of MDS
4. • MDS is usually suspected by the presence of cytopenia on a routine analysis of
peripheral blood
• This prompts evaluation of bone marrow cell morphology (aspirate) and
cellularity (biopsy)
• A manual count of bone marrow blasts is fundamental for risk assessment
• Cytogenetic analysis helps in predicting risk and in selecting therapy
• The International Prognostic Scoring System (IPSS) is still commonly used for
risk calculation & to decide therapy
• The revised IPSS score (IPSS-R) was published in 2012
• At present IPSS-R is used to calculate prognosis but IPSS is still used to decide
therapy
5. • Natural history and therapeutic decisions are different for
patients with lower risk disease (low and INT-1) versus those
with higher (INT-2 and high)
• In lower risk disease interventions have been traditionally
developed to improve transfusion needs
• Whereas higher risk options were initially modeled following
therapy of AML with remission induction being the goal
• This concept was modified by the better understanding of the
natural history of MDS and the development of new therapies,
in particular the hypomethylating agents
6. DIAGNOSIS
• The diagnosis of MDS is generally suspected based on the presence of an
abnormal CBC
• Diagnosis is confirmed by performing a bone marrow aspiration and biopsy
• The bone marrow aspirate allows for detailed evaluation of cellular
morphology and evaluation of percent of blasts
• The bone marrow biopsy allows for determination of bone marrow
cellularity and architecture
• Diagnosis is established by the presence of dysplasia
• Biopsy helps in diagnosis and potentially in selecting therapy. For instance,
in our practice we only use immunotherapy (ATG, cyclosporine, steroids) in
hypocellular MDS (marrow cellularity less than 20 to 30% depending on
age)
7. • Bone marrow cytogenetics are of importance to calculate prognosis of
patients and in some subsets of patients to select the most effective form of
therapy
• A number of other assays can be used to help in the diagnosis of MDS.
These include the use of flow cytometry, fluorescent in situ hybridization
(FISH) and genomic sequencing techniques
• Flow cytometry can help in the identification of abnormal phenotypic
patterns and can be of help in cases of minimal dysplasia
• Because the significant heterogeneity of cytogenetic alterations in MDS,
there is no evidence that a panel of FISH probes could replace routine 20
metaphase cytogenetic analysis. Thus, opinion is FISH and flow cytometry
should not be considered part of the standard work up evaluation procedure
and should be used in specific situations
9. Diagnostic problems in MDS: CHIP, ICUS, and CCUS
• Because diagnosis of MDS is based on morphological assessment it can be
subjective particularly in patients with early low risk disease
• It is calculated that diagnostic discrepancy can occur at the time of initial
presentation in close to 20% of patients
• Clinical assessment is needed in patients with minimal or not diagnostic evidence
of dysplasia. In these cases, it is recommended that other causes of cytopenia be
excluded
• Routine tests include the analysis of anemia and thrombocytopenia, and exclusion
of cause of blood loss or inflammatory processes
• When suspected, evaluation of GI tract needs to be considered
• Once other potential causes of cytopenia are excluded, additional diagnostic tools
including cytogenetic evaluation, flow cytometry and, more recently, DNA
sequencing, can help define the diagnosis and predict patient outcomes
10. • Patients with cytopenia but no dysplasia are considered in the subset of idiopathic
cytopenia of undetermined significance (ICUS)
• The presence of a somatic mutation in the context of cytopenias with no diagnostic
criteria for MDS is now considered a clonal cytopenia of undetermined
significance (CCUS)
• The presence of clonal somatic mutations have been reported in hematopoietic
cells from older individuals without evidence of hematological disorder as part of
age-related clonal hematopoiesis of undetermined potential (CHIP)
• A subset of patients of importance are those with MDS/MPN features. At the
present time, with the exception of chronic myelomonocytic leukemia, we do not
fully understand the natural history of patients with MDS/MPN. They are currently
treated as MDS but studies are ongoing to clarify this issue. Of note, specific
MDS/MPN subtypes have particular mutational profiles and may benefit from
specific therapeutic approaches
14. Both the IPSS and IPSS-R were developed
in a very specific subset of patients: newly
diagnosed patients at the time of initial
presentation. Patients with proliferative
features and CMML or that have received
prior therapy were excluded. To overcome
these limitations, the global MDACC
model was developed
• Patients with 0 to 4 points had a
median survival of 54 months and a 3
year 63% survival
• Patients with 5 and 6 points had a
median survival of 23 to 30 months
and 3-year survival of 30 to 40%
• Patients with 7 to 8 points had a
median survival of 13 months and a
3-year survival rate of 13 to 19%
• Patients with 9 or more points had a
median survival of 5 to 10 months
and a 2% 3-year survival
15. CYTOGENETIC AND MOLECULAR ALTERATIONS
The most recent cytogenetic risk classification in MDS includes 5 different
subgroups including 20 different alterations
16. • Mutations in genes such as RUNX1, TP53
or EZH2 have consistently been associated
with adverse prognosis
• Mutations in the splicing factor SF3B1 are
associated with very favorable outcomes
and prolonged survival
• Patients with TET2 mutations may have
higher response rates to azacitidine than
those without mutation
• Presence of TP53 mutations was recently
associated with high response rates to a 10-
day schedule of decitabine
• The results of molecular mutations is aiding
in the development of clinical trials
• Some of these targeted therapies have been
recently approved by the FDA for AML and
similar approvals will likely follow for
patients with MDS in the near future
• Mutations in TP53, RUNX1, ASXL1,
JAK2, and RAS pathway genes are
associated with significantly shorter overall
survival or relapse free survival after
allogeneic stem cell transplantation, with
TP53 mutations being particularly adverse
17. RISK ADAPTED THERAPY
At the present time, IPSS is still used to decide the choice of therapy for an
individual patient
18. Options for newly diagnosed patients with lower risk MDS
Erythroid growth factor support:
• A course of ESA with or without G-CSF is not contraindicated in most
patients with low risk MDS with significant anemia without other cytopenia
• Data indicates that early incorporation of these agents is more effective
• Maintain therapy for at least 3 months to judge efficacy
• In responding patients, continue therapy until transfusion effect is lost
Lenalidomide:
• The degree of response with lenalidomide in patients with lower risk MDS,
anemia, good platelets and del5q makes it the standard of care for this subset
of patients
• Do not consider this agent in patients with thrombocytopenia
• Based on the results of the recent phase III randomized study, lenalidomide
can be considered an option for selected red cell-transfusion-dependent
patients with non-del5q MDS
• Evaluation of TP53 mutation status could be advisable in patients with del5q
MDS prior to starting therapy with lenalidomide (inadequate response)
19. Azanucleosides:
• Both 5-azacitidine and decitabine are used in patients with lower risk disease
that are transfusion dependent
• Most patients treated with these agents have failed or were not candidates for
growth factor support or lenalidomide
• Results from the ongoing randomized phase II study will be needed to
determine whether these agents can modify the natural history of lower-risk
disease and be considered standard of care in the frontline setting or after
growth factor support
Immune therapy:
• A majority of older patients with hypoplastic MDS cannot tolerate ATG and
most patients are treated with some form of supportive care that could
include cyclosporine, growth factors and steroid
• In younger patientswith severe hypoplastic MDS, alloSCT should be
considered as soon as possible. For those that are not candidates, a
combination with horse ATG is recommended
20. Allogeneic stem cell transplantation:
• AlloSCT is generally not recommend in patients with lower risk disease at
initial presentation
• Patients that are candidates for alloSCT and that had been exposed to
multiple therapies (growth factors, lenalidomide, azanuclesoides, etc.)
should be considered for transplantation
• Patients with hypoplastic MDS that are young should be considered for
alloSCT up front
Supportive care measures in MDS:
• Antibiotics is not routinely recommend in patients with isolated neutropenia
and MDS that are not receiving some form of cytotoxic or
immunosuppressive therapy
• Prophylactic antibiotics is used in patients receiving active therapy
• Iron chelation is used in patients with ferritin levels in excess of 2500 ng/mL
21. Options for patients with relapsed or refractory lower risk MDS:
• Treatment of patients with lower risk MDS is sequential
• A common practice is to start growth factor support and then consider
lenalidomide or an azanucleoside
• Patients that fail either lenalidomide or azanucleoside are candidates for
clinical trials or alloSCT
• There is no drug approved in the US for patients with MDS and HMA
failure
• A number of agents are being studied for lower risk MDS. These include
oral azacitidine
oral decitabine
agents that modulate TGF-B pathway such as luspatercept and
sotatercept
proteasome inhibitors and antagonists of Toll-like receptor signaling
immune checkpoint regulators
22. Options for newly diagnosed patients with higher risk MDS
Azanucleosides:
• The azanucleosides are the standard of care for most patients with higher risk
disease
• No study has compared 5-azacitidine vs decitabine
• Although response rates appear to be similar, only 5-azacitidine has been
associated with improvement of survival in a randomized trial
• Based on this, 5-azacitidine is considered as standard therapy for front line
treatment in higher risk MDS
AML-like chemotherapy:
• The randomized AZA-001 study was not powered to demonstrate the
superiority of 5-azacitidine versus AML-like therapy
• This is restricted to younger patients with a high likelihood of response to
the therapy or candidates for alloSCT
• AML therapy is rarely used in older patients or in those with poor risk
cytogenetics or TP53 mutation
23. AlloSCT:
• All patients potential candidates for alloSCT should be counseled regarding
the possibilities of undergoing alloSCT
• Although alloSCT should be considered for patients with higher-risk MDS
this may not be the case in patients with high risk mutations such as TP53, in
whom, transplant may have to be considered only if an optimal donor is
available, optimal pretransplant response has been obtained and if lower
doses of post-transplant 5-azacitidine or decitabine are considered
• Lower doses of 5-azacitidine can also be considered in patients at high risk
for relapse post transplantation
24. Investigational new options for patients with higher risk
MDS, including HMA failures
• At the present time there is no therapy approved for patients with higher risk
MDS that fail hypomethylating agents or relapsed after AML-like therapy or
alloSCT. They should be considered for an investigational clinical trial and
potentially alloSCT
• Investigational agents:
Histone deacetylase inhibitors: Pracinostat, Vorinostat and Panobinostat
A second generation HMA: Guadecitabine
Very low dose Clofarabine
Immune checkpoint inhibitors
Enasidenib, a small molecule inhibitor of mutant IDH2
BCL-2 inhibitors such as Venetoclax