This presentation offers an in-depth exploration of Myelodysplastic Syndromes (MDS), a group of bone marrow disorders. I will cover MDS basics, symptoms, diagnosis, and treatment options. Join us to uncover the complexities of MDS subtypes, their impact on patients, and the latest medical advancements. Whether you're a healthcare professional specially hematologist/oncologist or simply curious, this presentation sheds light on MDS's intricacies and the importance of early intervention

1. Myelodysplastic neoplasms
Case Based learning
Dr Mussawair hussain
SR clinical hematology and BMT
PKLI and RC Lahore

3.  55-yr-old male
presented with
fatiguability anemia
(Hb 7.0 g/dL,
platelets 490, ANC
3.4)
 No evidence of
bleeding and no
nutritional
deficiencies, no prior
radio/chemo, family
hx not significant
 Examination
unremarkable
 71-yr-old female
presenting with SOB
(Hb 8.0 g/dL, platelets
200, ANC 4)
 No evidence of
bleeding and no
nutritional
deficiencies, no prior
radio/chemo, family
hx not significant
 Examination
unremarkable
 45-yr-old male
presenting with fever
,SOB pancytopenia
(Hb 5.0 g/dL, platelets
18, ANC 0.4)
 No evidence of
bleeding and no
nutritional
deficiencies, no prior
radio/chemo, family
hx not significant
 Bruises at sample
site, febrile, no focal
signs, after
stabilization
Patient 1 Patient 2 Patient 3

4.  Bone marrow
examination
revealed trilineage
dysplasia
myeloblasts <2%
 Cytogenetics 5q
deletions ,no somatic
mutation detected
by NGS
 WHO 2022 diagnosis
 IPSS-R
 IPSS-M
 Management
 Bone marrow aspirate
and biopsy revealed
>15% RS and erythroid
dysplasia myeloblasts
<5%
 Normal karyotype,
SF3B1 detected by
NGS
 WHO 2022 diagnosis
 IPSS-RR-IPSS
 IPSS-M
 Management
 Bone marrow aspirate
and biopsy revealed
hypocellular marrow
cellularity <25% with
trilineage dysplasia
myeloblasts<5%
 Normal karyotype, no
somatic mutation
detected by NGS
 WHO 2022 diagnosis
 IPSS-R
 IPSS-M
 Management
Patient 1 Patient 2 Patient 3

5. MDS Epidemiology
More than 86% of patients were diagnosed at age ≥60 yr
Incidence Rates of MDS Increase With Age
Epidemiology of Hematologic and
Nonhematologic Malignancies in
the US (SEER Database, 2012-
2018)
Incidence*
5-Yr OS
(2012-
2018), %
Hematologic malignancies
Hodgkin’s lymphoma 2.6 89.1
MDS 4.0 36.9
Myeloma 7.1 57.9
Leukemia 14.1 65.7
Non-Hodgkin’s lymphoma 19.0 73.8
Selected nonhematologic
malignancies
Lung and bronchus 52.0 22.9
Colon and rectum 37.7 65.1
Breast 128.3 90.6
*Age-adjusted incidence rate per 100,000 men and
women per yr between 2012 and 2108.
 Overall incidence: 3.7-4.8/100,000
 In US: ≈37,000-48,000
 Median age: 70 yr
Age at Diagnosis (Yr)
Incidence
(per
100,000)
70
60
50
40
30
20
10
0
<40 40-49 50-5960-64 65-69 70-74 75-79 80-84 ≥85

6. MDS Minimal
Diagnostic Criteria
1. Persistent cytopenia(s)
 Hb <10 g/dL, or
 ANC <1800/μL, or
 Platelets <100 x 109/L
MDS major criteria
i. Morphological dysplasia (involving ≥10% of
bone marrow cells in ≥1 lineage)
ii. An increase in myeloblasts of 5%-19% in
dysplastic BM smears or 2%-19% myeloblasts
in peripheral blood smears
iii.Evidence of clonality with a typical MDS-
associated cytogenetic abnormality.
2. EXCLUDE other causes of cytopenias and
morphological changes:
 Vitamin B12/folate deficiency
 HIV or other viral infection
 Copper deficiency
 Alcohol abuse
 Medications (esp. methotrexate, azathioprine,
recent chemotherapy)
 Autoimmune conditions (ITP, Felty syndrome,
SLE, etc.)
 Hereditary BMF syndromes (Fanconi anemia,
etc)
 Other hematological disorders (aplastic
anemia, LGL disorders, MPN, etc)
Prerequisite criteria: both 1 and 2 must be fulfilled

7. ICUS

8. CHIP

9. CCUS

10. How to Investigate
• History
• Examination
• Baseline
• To confirm diagnosis and risk stratification
• To look for underlying cause
• To assess complications
• To plan further treatment

11. History
• Symptoms related to cytopenia's
• Anatomical symptoms
• Hemostatic symptoms
• Drug history
• Transfusion history
• Alcohol and tobacco consumption
• Prior exposure chemotherapy/radiotherapy
• Nutritional, environmental and occupational
• Family history
• Past hx

12. Examination
• Head to toe
• Limb abnormalities
• Skin and nail abnormalities
• Organomegaly
• Lymphadenopathy
• Congenital abnormalities

13. Baseline
• Full blood count including differential white cell count
• Blood film analysis
• Reticulocyte count
• Renal and liver function tests
• Lactate dehydrogenase
• Direct Coombs test

14. To confirm diagnosis and risk stratification
• Morphological assessment and quantification of blast population
• Iron stain of aspirate
• Cellularity assessment and reticulin stain of trephine biopsy
• Cytogenetic analysis – G-banding, FISH and/or SNP array
• Bone marrow immune-phenotyping with analysis of aberrant antigen
expression and quantification of marrow blasts
• Marrow mutational analysis/genomic studies

15. To look for underlying cause
• Haematinics – B12, folate, ferritin and iron studies
• Flow cytometric screen for paroxysmal nocturnal haemoglobinuria
• Fanconi anaemia screen
• Mutational analysis telomerase complex gene mutations
• JAK2 gene mutational analysis -myeloproliferation and/or thrombocytosis
• Copper levels where nutritional deficiency suspected in association with
dysplasia
• Tuberculosis workup if hx
• HIV, Hepatitis B, C & E, CMV, parvovirus

16. To assess complications
• The rare complications of the common diseases are more common
than the common complications of the rare diseases

17. To plan further treatment
• Erythropoietin level
• Red blood cell phenotyping
• HLA typing of patient and siblings if the patient is a candidate for
stem cell transplantation

18. Classification and defining features of myelodysplastic neoplasms (MDS)

19. Re-stratification

21. Childhood myelodysplastic neoplasms

22. MDS/MPN neoplasms

23. Recurrent somatic mutations in MDS

24. IPSS-R

26. IPSS-R cytogenetic prognostic subgroups

27. IPSS-M (IPSS-R +Age+Molecular data)
• Clinical data
• Age
• Hb,PLT,ANC
• Bone marrow blast
• Cytogenetics
• IPSS-R
• Molecular data
• IPSS-M has greater survival predictive accuracy compared with IPSS-R
in persons ≥ 60 years with myelodysplastic syndromes

28. • MDS + aplastic anemia = ???

29. • MDS
• Dysplasia
• Clonality
• Cytopenia’s
• Aplastic anemia
• Autoimmunity
• Hypocellularity

31. Patient 1
• Mds with low blast and isolated del 5q
• R-IPSS: 2 low risk
• MDT approach discussed with transplant physician
• Hematologist with special interest in MDS
• Discuss with transplant team
• Spiritual/emotional health needs
• 1st line treatment option

32. Nordic score

33. • If Nordic score 0-1
• Trial of EPO
• 30000-40000 units/week for 8 weeks
• If no response ???
• Increase dose or start lenalidomide or add GCSF

34. • Increase dose
• 60000 units/week for next 8 weeks
• If no response
• Add GCSF
• 300ug /week 2-3 divided doses
• 300ug 2-3 times /week in non responders

35. Response monitoring, criteria for response and
long-term therapy
• Complete erythroid response
• Hb.11.5gm/dl
• Transfusion independence
• Partial erythroid response
• >2gm/dl increment in HB
• Transfusion independence
• Hb <11.5g/dl

36. Darbepoetin
• 300ug every 2 weeks or 150ug every week
• Increase to 300ug/week in non responders
• If patient Hb>12gm/dl after 2 months ???
• ESA FDA approved or not

37. Adverse effects of ESA
• Studies of EPO in solid tumor patients
• Increased heart attacks
• Stroke
• Heart failure
• Blood clots
• Increased tumor growth,
• Especially when Hb >12
• In MDS risk of thrombosis 2%
• Monitor for other adverse effects

38. Iron chelation in MDS
• Patient was not responding to ESA and received 21 units RCC so far
• Serum ferritin>1000
• Iron chelation:
• Deferasirox
• Desferrioxamine
• Deferiprone
• Ophthalmological and auditory examination
• Stop if:
• Ferritin falls below 500 lg/l on deferasirox
• Ferritin falls below 1 000 lg/l on Deferoxamine
• Epic study:
• Improve erythroid response in 15-20%

39. Patient 1
• After 24 weeks of therapy patient Hb 7.5gm/dl and have SOB,
palpitation
• Next best step
• Start luspatercept
• Start lenalidomide
• Start HMAs

40. Lenalidomide in Lower Risk MDS
• MDS with del(5q): red cell transfusion independence in ~67%
• Given 10 mg/day for 21 days (28 days cycle)
• Median time to response 4-6 weeks
• Median duration of transfusion independence>104 weeks
• MDS without del(5q): red cell transfusion independence in ~26%
• Most common side effects: neutropenia and thrombocytopenia, rash

41. Dose modifications in renal impairment
Renal Impairment Dose
Mild (80 > CLcr ≥50 mL/min) 10 mg (full dose) every 24 h
Moderate (30 ≤ CLcr <50 mL/min) 5 mg every 24 h
Severe (CLcr <30 mL/min, not requiring dialysis) 5 mg every 48 h
ESRD (CLcr <30 mL/min, requiring dialysis) 5 mg three times a week after each dialysis

42. Patient 2
• MDS with low blast with SF3B1 mutation
• No response to ESA
• Transfusion dependent
• Luspatarcept

43. Luspatarcept
• Luspatercept: TGFB inhibitor
• MEDALIST Trial: Phase III randomized double blinded placebo study of
luspatercept in lower risk MDS (HMA naive)
• MDS-RS (WHO): ≥15% ringed sideroblasts or ≥5% with SF3B1 mutation
• Subcutaneously 1.0 mg/kg every 21 days (titrated to max 1.75 mg/kg)
• Primary endpoint:
• Red cell transfusion independence ≥8 weeks during first 24 weeks
• 37.9% vs 13.2%
• Most common side effects: fatigue (27%), diarrhea (22%), asthenia (20%),
nausea (20%)

44. Aplastic like
• IST
• HSCT
Patient 3
MDS like
• ESA
• Lenalidomide
• HMA
• HSCT
44
Hypoplastic MDS

45. HMA in Low risk MDS

46. Emerging therapies for low risk MDS

47. Don’t treat the number, treat the patient
• Management of neutropenia
• Recurrent infections
• Adding agent to ESA in non responders
• On hypomethylating agents to tolerate chemo
• Management of thrombocytopenia
• No prophylactic platelet transfusion
• Bleeding or fever with PLT <20
• TPO can be considered (increased progression to AML ??

48. High risk MDS
• Clinical trial
• Clinical trial
• Clinical trial

49. High risk MDS (R-IPSS>3.5)
Transplant eligible
• >10% blasts
• Induction chemotherapy or HMA pre
HSCT
• 5-10% blasts
• Individual approach
• < 5% blasts
• Upfront HSCT
Not eligible for Transplant
• Supportive care
• HMA,s
• Intensive chemotherapy
• Oral low dose melphalan

50. Hypomethylating agents
• Azacitidine
• Azacitidine : 75mg/m2 sub/int for 7 days every 28 days or 5-2-2
• Azacitidine vs conventional care
• Complete remission: 17% vs 8%
• Hematologic improvement: 49% vs 29%
• Erythroid improvement: 40% vs 11%
• Platelet improvement: 33% vs 14%
• Neutrophil improvement: 19% vs 18%
• Decreased infections requiring IV antibiotics by 33%

51. • Side effects
• Cytopenias
• Injection site reaction
• Nausea
• Vomiting
• Fatigue
• Diarrhea

52. • Real world data :Shorter OS than the clinical trial (12.4–18.9 months
compared to 24.5 months)
• Bone marrow examination before and after completion of six cycles
• Continue until progression ??
• Selected younger patients who achieve a CR with azacytidine and
have good performance status, the option of HSCT should be re-
visited.

53. Decitabine
• 15 mg/m2 IV eight-hourly for three days every six weeks
• 20 mg/m2 for five days every four weeks
• Best supportive care
• CRs 32%
• Red cell 33%
• Platelet 40% transfusion independence
• Median survival was 19.4 months

54. HMA+CDA inhibitor

55. Emerging frontline therapy for high risk MDS
AZA+VENETO

56. Intensive chemotherapy
• AML style induction chemotherapy
• D3A7
• Fit patient with no co-morbidities
• Complex karyotype, Tp53 biallelic resistant to conventional chemo

57. Low-dose chemotherapy
• Azacitidine superior over LDAC in the AZA001 study
• LDAC Obsolete in high-risk MDS
Low-dose oral melphalan
• selective use
• excess of blasts (>5%) in a hypocellular marrow
• normal karyotype
• no alternative therapy

58. Targeted developmental therapies in MDS

61. Allogeneic haematopoietic stem cell transplant
in MDS
Poor risk factors for TRM:
• High age
• Advanced disease stage
• Therapy related MDS
• Sub optimally matched unrelated donor
• Comorbidities.
Risk factors for relapse:
• High age
• Advanced disease stage
• Poor risk cytogenetics.
• Disease duration
• Severe marrow fibrosis 30.
• Somatic mutations in ASXL1, RUNX1 and TP53, EZH2 and ETV6 seem to be
independent prognostic factors

62. Allo-HSCT in Low risk MDS
Area of debate
• Intolerance to or unsuitable for lenalidomide or luspatarcept
• Lenalidomide-luspatarcept treated patients who fail to achieve transfusion
independence
• Those with TP53 mutation ???
• Those with clonal or overt progression
• Those with bone marrow fibrosis
• Hypoplastic MDS

63. Choice of conditioning regimen
MAC
• Young
• Fit patients
• Increased TRM
• Low risk of relapse
RIC
• Old
• Less fit
• Low TRM
• Increased risk of relpase

64. Higher-risk patients with >10% blasts
• Induction chemo or hypomethylating agents prior to
transplant
• Tp53 mutation resistant to conventional chemo
• Complex karyotype in absence of Tp53 clinical trial
• ALLO-HSCT not recommended in Tp 53 biallelic or with
associated complex monosomal karyotype

65. • Up-front transplant may be considered in patients with
• 5–10% blasts with slowly progressive disease
• Hypocellular or fibrotic BM

66. Low risk MDS

67. High risk MDS

69. VEXAS syndrome
• Acquired mutation in UBA1 gene
• Regulation of proteins involved in cell division, immune responses and
much more
• Bone marrow failure and autoinflammation (Skin, cartilage, lungs, joints,
vascular)
• VEXAS
• Vacuolated myeloid and erythroid precursors on BM morphology
• E1 ubiquitin activating enzyme (coded for by UBA1)
• X chromosome
• Autoinflammation
• Somatic mutation

70. CMML
MD-CMML = WBC <13
• Comparative better
• Manage like MDS
• Supportive care
• ESA
• HMA
• HSCT
• Targeted therapies
• Clinical trial
MP-CMML= WBC >13
• Adverse outcome
• Manage like MPN
• Supportive care
• Cytoreductive (hydroxycarbamide)
• HMA
• HSCT
• Targeted therapies
• Clinical trial

71. Home work
•Lenalidomide promotes the
development of TP53-mutated therapy-
related myeloid neoplasms

72. Thank you