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Refractory anemia case report mds
1. With case report of MDS
presenting as anemia
Approach to Myelodysplastic Syndrome
(MDS) & Overview of Treatment
Dr. Jaykumar Sejpal,
Medical Advisor, Oncology.
2. Scope of presentation
Clinical presentation
Diagnostic workup
Management approach
Choosing agent for treatment
3. Clinical presentation
64 year-old male
Presented with new-onset decreased exercise
tolerance of two months duration
Also complaint of fatigue, weakness & occasional
dizziness
Past Medical History:
Hypertension
Negative previous hematologic disorder
Treated with iron supplements
Physical Examination:
No hepatosplenomegaly
4. Complete Blood Count
Macrocytic anemia
Peripheral Smear:
RBC: Ansisocytosis and
macrocytosis
No poikilocytosis
WBC:
Predominantly mature
neutrophils and
lymphocytes
No dyspoiesis
No blasts
WBC 2 x 103 /μL
RBC 1.84 x 10 6 /μL
Hgb 5.1 g/dL
Hct 19.5 %
MCV 127 fL
Platelet 1,10,000 /μL
Differential:
55% PMN, 32% Lymph,
12% Mono, 1% Eos
5. No aspirate smear
Bone marrow biopsy-
Touch Prep:
Dyserythropoiesis
Two possible
megakaryoblasts
Blast count about 4%
Flow:
Mixed population,
slightly abnormal
myeloid maturation, no
increase in blasts.
Iron Stain:
Increased stores
without ringed
sideroblasts
6. Immunohistochemistry (IHC)
CD34 IHC stains of bone marrow (BM) aspirates helps to
distinguish between hypocellular myelodysplastic
syndrome (hMDS) and aplastic anemia (AA)
8. Cytogenetics
Multiple Complex Abnormalities:
Monosomy 2,5,7 and 15
Trisomy 8
Unbalanced translocation b/t 17p and 2q
Additional chromosomic material of unknown origin
replacing 7q (of the remaining 7) and on 17q and
12p
10. MDS
FAB Classification
RA: Refractory anemia
RARS: refractory anemia with ringed sideroblasts
RAEB: refractory anemia with excess blasts
CMML: Chronic myelomonocytic leukemia
RAEB-T: refractory anemia with excess blasts in
transformation
11.
12. MDS Type Blood Marrow
Refractory cytopenia with unilineage
dysplasia (RCUD)
Refractory anemia (RA)
Refractory neutropenia (RN)
Refractory thrombocytopenia (RT)
Uni- or bicytopenia
<1% blasts
Unilineage dysplasia
<5% blasts
<15% sideroblasts
Refractory anemia with ring
sideroblasts (RARS)
Anemia
No blasts
Erythroid dysplasia
<5% blasts
≥15% sideroblasts
Refractory cytopenia with multilineage
dysplasia (RCMD)
Cytopenia(s)
<1% blasts
<1 × 109/L monocytes
Dysplasia in ≥2 lineages
<5% blasts
<15% sideroblasts
Refractory anemia with excess blasts-1
(RAEB-1)
Cytopenia(s)
<5% blasts
<1 × 109/L monocytes
Dysplasia
5%–9% blasts
Refractory anemia with excess blasts-2
(RAEB-2)
Cytopenia(s)
5%–19% blasts
<1 × 109/L monocytes
Dysplasia
10%–19% blasts
Myelodysplastic syndrome -
unclassified (MDS-U)
Cytopenias
≤1% blasts
Dysplasia
<5% blasts
MDS associated with isolated del(5q) Anemia, normal or elevated
platelets
<1% blasts
<5% blasts
Isolated del(5q)
WHO classification 2008
13. Signs and symptoms
Non-specific presentation
Many patients are asymptomatic
Diagnosis on finding abnormalities found on routine blood counts
(e.g., anemia, neutropenia, and thrombocytopenia)
Symptoms or complications resulting from cytopenia (eg,
infection, fatigue, bleeding, easy bruising)
Anemia:
Most common cytopenia
Fatigue, weakness, exercise intolerance, angina, dizziness
Infection:
Bacterial infections, skin infections
Fungal, viral, mycobacterial infection
Thrombocytopenia:
Petechiae and/or purpura, bleeding
Autoimmune abnormalities
14. Evaluation
Myelodysplastic syndrome (MDS) is characterized by abnormal
cell morphology (dysplasia) and quantitative changes in one or
more of the blood and bone marrow elements (ie, red cells,
granulocytes, platelets)
Complete blood count
Anemia
Leukopenia
Thrombocytopenia
Periphreral blood smear
Dysplastic blood cells
Bone marrow aspirate/ biopsy
Evaluation of the blasts and other cells
Fibrosis of marrow
Genetic features [del(7q), del(5q), del(13q),del(11q),
del(12p),del(9q)]
Distinguishes between MDS and acute myeloid leukemia (AML)
Prognostic
15. International Prognostic Scoring System
(IPSS):most widely used prognostic system
Variable
Score
0 0.5 1.0 1.5 2.0
Bone marrow
blasts (percent)
<5 5 to 10 - 11 to 20 21 to 30
Karyotype* Good
Inter-
mediate
Poor - -
Cytopenias• 0/1 2/3 - - -
Risk group IPSS score
Median Survival
(years) without
therapy
Low 0 5.7
Intermediate-1 0.5 to 1.0 3.5
Intermediate-2 1.5 to 2.0 1.2
High 2.5 to 3.5 0.4
* Karytope definitions:
Good: Normal;-Y; del (5q); del (20q)
Poor: Complex (≥3 abnormalities);
abnormal chromosome 7
Intermediate: All others
• Cytopenia definitions:
Red blood cells: Hemoglobin <10 g/dL
(100 g/L)
White blood cells: Absolute neutrophil
count <1800/microL
Platelets: Platelet count <100,000/microL
Greenberg et al. Blood 1997;89(6):2079–88.
16. Revised International Prognostic Scoring
System (IPSS-R) in MDS
Prognostic Variable Scores
0 0.5 1.0 1.5 2.0 3.0 4.0
Cytogenetics Very
Good
Good Intermedi
ate
Poor Very
Poor
Bone marrow blast (%) ≤2 >2 to <5 5 to 10 >10
Hb (g/dL) ≥10 8 to <10 <8
Platelets (cells/uL) ≥100 50 to 100 <50
Absolute Neutrophil
Count (cell/uL)
≥0.8 <0.8
Risk Group IPSS-R
Score
Median
Survival (years)
Very Low ≤1.5 8.8
Low >1.5 to 3.0 5.3
Intermediate >3 to 4.5 3.0
High >4.5 to 6 1.6
Very High >6 0.8
Greenberg et al. Blood. 2012;120(12):2454–65.
* Cytogenetic definitions:
Very good: -Y, del(11q).
Good: Normal, del(5q), del(12p), del(20q),
double including del(5q).
Intermediate: del(7q), +8, +19, i(17q), any
other single or double independent clones.
Poor: -7, inv(3)/t(3q)/del(3q), double
including -7/del(7q), complex: 3
abnormalities.
Very poor: Complex: >3 abnormalities.
17. Overview of Treatment
1. Supportive Care
Important adjunct to the management of all patients
with MDS
Red cell transfusions
Antibiotics for infection
Platelet transfusion
Erythropoiesis stimulating agents (ESAs)
Iron chelation therapy (ICT)
18. Overview of Treatment
2. Disease-Modifying Agents
Lenalidomide: only for del(5q) MDS
Immunosuppressive therapy
Antithymocyte globulin (ATG)
Alemtuzumab
Low-dose cytarabine, Intensive chemotherpy like
daunorubicine+ cytarabine
DNA methyltransferase inhibitors:Azacitidine, Decitabine
3. Allogeneic Hematopoietic Stem Cell Transplantation
(HSCT)
Only potentially curative treatment for MDS
Cure rates in selected patients ranging from 30%-60%
19. Treatment: Changing paradigms
Earlier it was believed that , apart from supportive
treatment with transfusion and antibiotic, there
was no other possible therapeutic strategy.
But with availability of hypomethylating agents
(Deciabine, Azacitidine); therapy for MDS has
evolved and changed at rapid pace
22. Disease burden in India
Higher number of Indian patients in intermediate to
high-risk group1
Higher frequency of disease observed in young age
(<45 years), unlike global scenario1
With improved awareness & more thorough clinical
workups, it is likely that the number of new patients
diagnosed with MDS each year will increase in the
future
1. Indian J. Med. Res. 2009 Aug;130(2):155–9.
23. Limitations of currently available treatment
in India
Supportive care & most of the medical therapies do not
prolong survival in MDS
Allogeneic HSCT
Only treatment for MDS with the potential for cure
Limitations
Possible in ~5% patients only
Lack of donor availability
High costs
Co morbidities in elderly, poor performance status-
ineligible for transplant
24. DNA methyltransferase inhibitors
Also called hypomethylating agents
Azacitidine
Decitabine
Constitute an essential tool in the treatment of
myelodysplastic syndrome (MDS)
Allowed the treatment of higher-risk elderly and frail
patients, who in the past were treated exclusively with
the best supportive care
Although do not achieves final cure,
Induce an improvement in hematopoiesis &
Azacitidine, a demonstrated prolonged overall survival
26. Comparison between Decitabine and Azacitidine for
MDS: A Meta-analysis with 1,392 Subjects
Clinical choice between HMAs is not clear
One more meta-analysis was performed to
compare survival advantage of decitabine and
azacitidine in patients with MDS.
Eleven trials with a total of 1392 patients with
MDS (decitabine, n = 768; azacitidine, n = 624)
were included for analysis.
Mixue et al Clinical Lymphoma,Myeloma and Leukemia (2014).
27. Comparison between Decitabine and
Azacitidine for MDS: A Meta-analysis with
1,392 Subjects
Azacitidine vs BSC
Significantly improved overall survival (hazard ratio [HR],
0.69; 95% CI, 0.54-0.87)
Significantly delayed and time to acute myeloid leukemia
transformation (HR, 0.51; 95% CI, 0.35-0.74).
But these benefits were not found with decitabine.
Among patients with higher risk (IPSS >=3) or older >75
years, treatment with azacitidine was a favorable factor,
whereas decitabine showed no advantage.
Therefore, with higher overall response rates and better
survival benefits, azacitidine is recommended as the
first-line hypomethylating agent for MDS, especially in
elderly patients or those with high risk.
Mixue et al Clinical Lymphoma,Myeloma and Leukemia (2014).
28. Key Comparison: Azacitidine vs
Decitabine
Parameter Azacitidine Decitabine
MOA • Azacitidine is incorporated
into both RNA and DNA
• Direct cytotoxicity on bone
marrow blasts (Additional
MOA)
• Decitabine is primarily
incorporated into DNA
• No direct cytotoxic effect
Route of
administration
Preferred route of
administration: SC
Can be given IV also
Should be administered by
IV only
Storage for delayed
use
Reconstituted solution using
refrigerated (2° -8°C) water
for injection can be stored up
to 22 hours at 2˚C - 8˚C
Diluted solution for infusion
prepared using cold (2˚C -
8˚C) infusion fluids can be
preserved for maximum of 4
hours at 2˚C - 8˚C
Survival advantage in
MDS over BSC
(months)
9.5 months (AZA-001)
(p<0.0001)
1.6 months (Lubbert et al,
2011)
(p=0.38)
29. Key Comparison: Azacitidine vs
Decitabine
Parameter Azacitidine Decitabine
Indirect meta-
analysis
Favors Azacitidine for
survival benefit
Do not favour decitabine
Study in AML Azacitidine vs Decitabine showed
• Superior survival
• Less hospitalization
NCCN
recommendation
Category 1 agent in
Higher risk MDS
Category 2A
EHA 2014
recommendation
Azacitidine is standard of
care for high risk MDS
Less preferred
NICE guidelines Recommends
Azacitidine
Doesn’t recommend
Decitabine
30. Guidelines recommendations
NCCN Guidelines
NCCN recommends azacitidine for…
Low/Intermediate-1 risk MDS with clinically relevant
thrombocytopenia or neutropenia or increased marrow
blasts
Intermediate-2, High risk MDS patients who are not
transplant candidates or donor is not available. (category 1)
(While the response rates are similar for both drugs
azacitidine & deciatabine, survival benefit from a Phase
lll randomized trial is reported for azacitidine and not
for decitabine)
ESMO Guidelines
Randomized comparisons of 5-azacytidine against low-
dose cytarabine or BSC have shown survival benefit
31. NICE Guidelines
Azacitidine is a clinically effective treatment for
myelodysplastic syndrome.
Compared with other treatment options, azacitidine was
associated with
Relief from fatigue
Fewer hospitalisations because of infections
Decreased need for blood and platelet transfusion, &
Increased ability to perform day-to-day activities
Azacitidine is licensed as first-line treatment for
myelodysplastic syndromes or acute myeloid leukaemia
and would replace best supportive care, low-dose and
standard-dose chemotherapy.
Guidelines recommendations
32. Summary
HMAs are most essential group for treatment of myelodysplastic
syndrome (MDS)
For MDS patients who are not eligible for transplant; NCCN
recommends azacitidine as prefrred category 1 agent
Only chemotherapeutic agent showing survival benefits in MDS
Azacitidine vs supportive care or coventional care
Significant survival benefit
Delays progression to AML
Reduces transfusion burden
Improves Quality of Life parameters
Convenient administration by SC route
Fewer infection-related hospitalizations, decreases need for blood
and platelet transfusion
Superior choice over decitabine
Strong recommendations for azacitidine by guidelines like NCCN,
NICE, ESMO
Ring sideroblasts are named so because of the arrangement of the iron granules in a ring form in mitochondria around the nucleus
Auer rods are clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of leukemic blasts.
autoimmune conditions in patients with MDS were chronic rheumatic heart disease (7 percent), rheumatoid arthritis (6 percent), pernicious anemia (6 percent), psoriasis (2 percent), and polymyalgia rheumatica (2 percent)
A minute red or purple spot on the surface of the skin as the result of tiny hemorrhages of blood vessels in the skin
Any of several blood diseases causing subcutaneous bleeding
Shown is the strategy for treatment choices for patients with IPSS lower-risk MDS according to type of cytopenias and with sequential treatment in case of relapse/resistance after first-line therapy. EPO indicates erythropoietin; ICT, iron chelation therapy; HSCT, hematopoietic stem cell transplant; ESA, erythropoietic stimulating agents; and BSC, best supportive care.