Luspatercept in patients with

lower-risk myelodysplastic
syndromes
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01
About the
Disease
 Myelodysplastic Syndrome

-Caused by: De novo mutation, 5q- syndrome, splicing factor

mutation, IDH1 or IDH2 mutation, GATA2 deficiency, or
environmental exposure such as radiation, benzene,
chemotherapy.

-Myelodysplastic Syndrome (MDS) is a stem cell disorder

involving ineffective hematopoiesis. This results in cell
maturation defect in non-lymphoid lineages (RBCs, WBCs,
platelets, not including lymphocytes).

-Commonly found in people aged above 50 years (not

commonly found in children).

-MDS increases the risk of Acute Myeloid Leukemia.

CHIP = clonal hematopoiesis of indeterminate potential
CCUS = clonal cytopenia of undetermined significance
 Complications of MDS

- Anemia

---> Fatigue, Dizziness, irritability, pale skin.

- Neutropenia

---> Increases risk of infection.

- Thrombocytopenia

---> Causes excessive bruising and easy bleeding.

 Diagnostic criteria

The main criteria that are used to diagnose an MDS are

● At least one cytopenia (low blood cell count) in one or more of red
blood cell, white blood cell or platelet counts

And one or more of the following criteria

● Obvious changes to the structure or form of the bone marrow cells

(dysplasia) in at least 10 percent of red blood cells, white blood cells
or platelets
● Blasts making up between 5 and 19 percent of bone marrow cells
● Specific MDS-associated chromosome (cytogenetic) abnormality
 Diagnosis

● CBC:
○ Pancytopenia
■ Low RBCs, WBCs, platelets.
● Peripheral blood smear
○ Oval RBCs
○ Abnormal WBCs and platelet
● Bone marrow aspiration and biopsy
○ Increase in cell count
○ Dysplastic changes in all blood
cell types
Blood smear
 Treatment

Before the doctor start treatment, the patient’s condition must be

classified into one of two risk categories, either “lower-risk” or “higher-risk”
MDS because there are different treatment between these categories.

The risk status is determined by many factors including

● CBC
● Proportion of immature cell (blast cell) in bone marrow
● Type of chromosomal abnormality

These factors will be converted to score from The International

Prognostic Scoring System-Revised (IPSS-R)
 Treatment

This prognostic system and risk group is not used to predict the response
of MDS to the treatment but instead predicts the course of MDS without
treatment.

In Lower-risk MDS, the disease progress slowly meaning there is no severe

symptom for a long period of time, while higher-risk MDS progress fastly
and may lead to AML more quickly without treatment.

Therefore, higher-risk MDS require more intensive treatment duto rapid

progression of disease
 Treatment for Low-risk MDS

● Improve red cell count

○ Give erythropoietin (EPO) weekly
○ If patients do not response to EPO, patients are considered dependent
on red-cell transfusion
● 5q chromosomal abnormality
○ Prescribe Lenalidomide
■ Multiple mechanisms of action
● In vitro: direct anti-tumor effect, inhibition of angiogenesis, and
immunomodulation
● In vivo: induction of tumor cell apoptosis directly and indirectly by
inhibition of bone marrow stromal cell support, anti-angiogenic and
anti-osteoclastogenic effects, and by immunomodulatory activity
● Immunosuppressive therapy
○ Anti-thymocyte globulin: Antibodies against T cells and their
precursors
 Treatment for high-risk MDS

The goal is to prevent leukemia

● Hypomethylating agent
○ Azacitidine
○ Decitabine
○ Inhibit DNA methylation:
■ DNA methylation: Addition of methyl to DNA nucleotides,
decreasing their expression
■ Hypomethylating agents inhibit the methylation of tumor
suppressor genes.
● Bone marrow stem cell transplant
○ Only curative treatment
02
Phase 3 clinical trials

Double-blinded randomised controlled

About the Evaluating safety and efficacy of luspatercept

paper in patient with lower-risk myelodysplastic
syndrome with ring sideroblast + receiving
regular red-cell transfusion + disease
unresponsive to erythropoiesis-stimulating agent
or discontinued due to side effects
 Luspatercept in patients with lower-risk
myelodysplastic syndromes
Phase 3 multicenter randomized double-blind
placebo controlled study

● 65 sites in 11 countries
● Inclusion criterias
○ ≥ 18 y/o patient w/ MDS with ring sideroblasts (≥
15% RS, or ≥ RS if SF3B1 mutation present AND <
5% Bone marrow blasts)
○ IPSS-R ‘s criteria of “very low”, “low” or
“intermediate” risk MDS with RS
○ Regular recipients of red cells transfusion (≥ 2 units
per 8 weeks, 16 weeks before randomization
○ Refractory to, discontinued (due to adverse event),
or unlikely to respond to Erythropoiesis
-stimulating agents (endogenous EPO >200 U/L)
Luspatercept
- Recombinant fusion protein that binds
TGF-beta → reduce SMAD2 and
SMAD3 phosphorylation and signaling
pathway
- Allowing effective erythroid
differentiation and maturation (late
stage differentiation)
- Treatment of anemia in
beta-thalassemia and myelodysplastic
syndrome with ring sideroblasts
(who need regular transfusions)
 Serine/threonine kinase receptor-Smad Pathway
Serine/threonine kinase receptor:
● Bind to TGF-beta superfamily ligands
○ Transforming growth factor-beta (TGF-beta)
○ Activins
○ Bone Morphogenetic Proteins (BMPs)
● Two classes
○ Type I
○ Type II
● Binding of TGF-beta ligand to type II receptor cause:
○ Recruitment and phosphorylation of type I
receptor cytosolic domain
■ Formation of tetramer
● Each receptor is a homodimer,
thus their dimerization create a
tetramer.
● Phosphorylated type I receptor:
○ Recruit and phosphorylate Smad2 or Smad3
○ Trigger the Smad intracellular signaling
pathway
 Serine/threonine kinase receptor-Smad Pathway
Smad Pathway:
● Formation of type I-type II Serine/threonine kinase
receptor tetramer phosphorylate Smad2 or Smad3.
● Smad2/3 (also known as Receptor-regulated Smad, or
R-Smad), form complex with Smad4.
● The R-Smad-Smad4 complex interact with
transcription factors in different ways depending on
the stage of cancer:
○ Normal epithelium/early-stage cancer
■ Inhibition of cell growth, invasiveness,
motility
■ Promotion of apoptosis
○ Advanced cancer
■ Promotion of proliferation, invasion,
motility
■ Inhibition of apoptosis
Study design
Primary outcomes
- Transfusion independence of luspatercept for 8 weeks or
longer during week 1 through 24
Secondary outcomes

Patients in the luspatercept group had a greater

reductions from baseline than those in the
placebo group in the mean serum ferritin
level,averaged over weeks 9 through 24.
Conclusions
 Thanks!
Q & A time!

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