MDS AND MPS

1. MYELODYSPLASTIC
SYNDROME(MDS)
&
MYELOPROLIFERATIVE
DISORDERS
Dr ANIL KUMAR G
ASST PROF
DEPT OF MEDICINE

2. MDS
• Disorders of multipotent hemopoietic stem cell
• Heterogenous group
• Hemopoiesis is ineffective and morphological
dysplastic ( Blood/ BM)
• Tendency to evolve into acute leukemia
• Elderly patient

3. Definition:
• A group of clonal bone marrow stem cell
disorders, characterized by hypercellular
marrows, peripheral cytopenias, and cell
functional abnormalities
–Ineffective hematopoiesis
• Highly variable natural history
• High mortality rate
• Unless permanent control achieved (by
alloBMT) death due to bone marrow failure,
with or without conversion to AML

4. FAB (1982)
• Refractory anemia (RA)
• Refractory anemia with ring sideroblast (RARS)
• Refractory anemia with excess blast (RAEB)
• Refractory anemia with excess blast in
• transformation (RAEBt)
• Chronic myelomonocytic leukemia (CMML)

5. MDS: Limitations of FAB Classification
• Multilineage cytopenia with <5% BM blasts
• Rough prediction of prognosis
• Cytogenetics not given importance
• Immunophenotyping and genetic techniques not
included

6. Comparison of MDS Classifications
FAB classification
1982
WHO Classification 2008
RA Refractory cytopenia with unilineage dyplasia
• Refractory anemia
• Refractory neutropenia
• Refractory thrombocytopenia
RARS Refractory anemia with ring sideroblasts (RARS)
RCMD(Refractory cytopenia with multilineage dysplasia)
RCMD-RS
RAEB RAEB I and 2(excess blast)
RAEB-T RAEB II/ AML
CMML MDS-UC
MDS associated with isolated del(5q)
Childhood myelodysplastic syndrome
• Refractory cytopenia of childhood

7. Predisposition:
Acquired:
Mutagen/Genotoxic Stress
 Therapeutic
alkylators, Topo-II agents,
-emitters (32P), autoSCT
 Environmental/occupational
(benzene)
 Tobacco
Aplastic anemia
PNH
List AF, et al. The Myelodysplastic Syndromes. In: Wintrobe’s Hematology 2003.
Heritable:
Constitutional genetic disorders
 Trisomy 8 mosaicism
 Familial monosomy 7
Neurofibromatosis 1
Embryonal dysgenesis (del12p)
Congenital Neutropenia
 Kostmann, Schwachman-Diamond
DNA repair deficiencies
 Fanconi anemia, AT, Bloom syndrome
Pharmacogenomic polymorphisms
(GSTq1-null)

8. Clinical Overlap / Associations:
• AML
• Aplastic anemia
• Myeloproliferative disease
• leukemia
• Autoimmune diseases
AML
PRCA
PNH
MDS
AA
LGL MPD
With Permission of J Maciejewski,M.D. Taussig Cancer Center/ Cleveland Clinic Foundation
With Permission of American College of Physicians from Young NS. Ann Intern Med. 2002 Apr 2;136(7):534-46
(ACP not responsible for accuracy of figure translation).

9. Diagnosis and
Classification

10. Basic Diagnostic Evaluation:
• Peripheral blood counts + reticulocyte count
• Bone marrow biopsy and aspiration
– Cytogenetics
• Auxiliary tests
– FISH
– Flow cytometry in indeterminate cases
– Iron saturation, ferritin
– B12, folate levels
– EPO level
Establish diagnosis
Assess
– FAB/WHO classification
– IPSS score (if applicable)
http:// www.NCCN.org MDS Guidelines
http://www.hmds.org.uk/mds.html

11. Epling-Burnett and List. Curr Opin Hematol 2009;16:70

13. Improved prognostic scores
Disease related variables
Host factors
Appropriate clinical decision
Disease eradication/ control
Prolonging overall survival
Managing complications of disease and therapy
Improving quality of life

14. 2012 Revised IPSS
Schanz J, et al. J Clin Oncol. 2012;30:820-829. Greenberg PL, et al. Blood. 2012;120:2454-2465.
Prognostic
Subgroup
Cytogenetic Abnormality
Very good del(11q), -Y
Good Normal, del(20q), del(5q) alone or double, del(12p)
Intermediate +8, del(7q), i(17q), +19, any other single or double, independent clones
Poor inv(3)/t(3q)/del(eq), -7, double including del(7q), complex (3)
Very poor complex (≥ 3)
Fine tune the prognostic impact of
•Cytogenetic abnormalities
•Depth of cytopenia

15. IPSS-R
Risk Category Risk Score
Very low ≤ 1.5
Low >1.5 - 3
Intermediate >3 – 4.5
High >4.5 - 6
Very High >6
Variable 0 0.5 1 1.5 2 3 4
Cytogenetics V. good - Good - Int Poor V. poor
BM blast% ≤2 - >2 - <5 - 5-10 >10 -
Hgb ≥10 - 8-<10 <8 - - -
Platelets ≥100 50-100 <50 - - - -
ANC ≥0.8 <0.8 - - - - -

16. Tools to treat MDS
• Observation
• Supportive therapy (Transfusions)
• Hematopoietic growth factors
• Iron chelation
• Lenalidomide (Revlimid 2005)
• Hypomethylating agents
▫ Azacitidine (Vidaza 2004)
▫ Decitabine (Dacogen 2006)
• Immunosuppression
• Allogeneic stem cell transplantation
• Newer agents

17. Role of Growth Factors
GCSF Support improves ANC (75% patients)
Has no impact on overall survival.
Not recommended for routine infection prophylaxis
Thrombopoietic
agents
Most have no significant impact on transfusion needs:
Main utility
–Fewer dose modifications of disease modifying agents
–Romiplostim: weekly
–Eltrombopag: under study
Erythropoiesis
stimulating agents
(ESA)
–First line therapy for IPSS low or Int-1 risk MDS with
EPO <500U/L (NCCN guidelines)
–Response rates; 20-30%,
–Epoeitin alpha: 60,000-80,000 U once per week
–Darbopoietin alpha: 500mcg once 3 weekly
Most widely prescribed class of medications for MDS (55%)

18. Biological response modifiers
special case of Del 5q syndrome
Eligibility:
•del(5q)
•IPSS low or Int-1
•platelets > 50K/mm3
•neutrophils > 500/mm3
•transfusion dependent

20. Hypomethylating agents
•
• Azacytidine and decitabine are potent DNMT
inhibitors
• This leads to hypomethylation of dinucleotides in
gene promoters and reactivation of previously
silent genes

21. Hypomethylating agents
When to start
– Int/ high risk MDS (IPSS)
– Transfusion dependent/ EPO failure
– Not yet known if early treatment is better than late treatment in MDS
Which drug
– NCCN recommends Azacitidine preference over Decitabine
– EORTC study failed to show survival benefit.
– MDACC regimen (5 day 20mg/m2/d) highest CR
Duration
– Optimal duration- not known
– To treat responding pts till disease progression, as long as tolerated
– At least 4 cycles recommended for adequate response
Steensma et al. Hematol Oncol clin N Am 2010

22. MDS
Low risk
(low or Int 1, BM blasts <10%)
Any age
Iron Chelation
Growth factors
DMT Inhibitors
Lenolidamide
Progression/ failure
HSCT
High Risk
(Int 2, High risk, blasts>10%)
Age <60 Age≥60
Intensive chemo
DMTI
DMTI
Intensive Chemo
Failure
Failure

23. MYELOPROLIFERATIVE
DISORDERS

24. The myeloproliferative diseases (MPDs) are
clonal stem cell disorders characterised by
leukocytosis, thrombocytosis, erythrocytosis,
splenomegaly, and bone marrow
hypercelularity

25. Myeloproliferative Disorders
(old classification)
a group of disease characterized by overgrowth of one or
more hematologic cell lines in BM
1. chronic myelogenous leukemia (CML)
2. polycythemia vera (PV)
3. essential thrombocythemia
4. agnogenic myeloid metaplasia/myelofibrosis
www.freelivedoctor.com

26. Myeloproliferative Disorders
(2008 WHO classification)
1. polycythemia vera
2. chronic idiopathic myelofibrosis
3. essential thrombocytosis
4. chronic myeloid leukemia (CML)
5. [chronic neutrophilic leukemia]
6. [chronic eosinophilic leukemia]
7. [hypereosinophilic syndrome]
8.Mast cell disease
“myelodysplastic/myeloproliferative diseases”
juvenile myelomonocytic leukemia
atypical chronic myeloid leukemia (lacking t(9;22))
chronic myelomocytic leukemia
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27. Polycythemia Vera
(lots of red cells - for real)
An uncommon disorder - distinguish from
other causes of erythrocytosis
Diagnosis depends on knowledge of
erythropoeisis
Complications most commonly from
thrombosis and vascular incidents
Long natural history with treatment

28. Definition of Erythrocytosis
Normal hematocrit :
 Male 47  5 percent
 Female 42  5 percent
Normal hemoglobin :
 Male 15  2 gm/dl
 Female 13.5  1.5 gm/dl

29. Absolute vs. Relative
Erythrocytosis
Normal Spurious Polycythemia
Plasma Vol
RBC

30. Pathophysiology of
Polycythemia

31. Secondary Polycythemia
Inappropriate EPO (ectopic production)
 Tumors (hepatoma, renal carcinoma,
leiomyoma, hamartoma)
 Renal disorders (transplantation, cysts)
 hemangiomas
 Androgen abuse
 EPO abuse
 Familial polycythemia

32. Polycythemia Vera
P. vera is a rare disease
Median age 60 - 65 years
Clinical features
 Attributed to increased blood viscosity and
poor oxygen delivery to organs (brain)
 Poor O2 delivery leads to ischemia and
thrombosis
 Expanded blood volume and viscosity
leads to increased cardiac work load

33. P. Vera - Symptoms & Signs
Symptoms
 Headache
 Weakness
 Pruritis (aquagenic)
 Dizziness
 Diaphoresis
 Visual disturbance
 Weight loss
Signs
 Splenomegaly 70%
 Skin plethora 67%
 Hepatomegaly 40%
 Conjunctival plethora
59%
 Systolic Hypertension
72%

34. P. Vera - Diagnosis
(PVSG criteria)
Criteria
 RBC mass elevated
 SaO2 > 92%
 Splenomegaly (or)
thrombocytosis
Leukocytosis
high LAP
high B12
Significance
 True vs. spurious
 R/O most 2 causes
 Evidence for MPD
False Positive 0.5%
 smokers, drinkers

36. Diagnosis of Polycythemia Vera
Major Criteria
1. Hgb level > 18.5 g/dL in men, >16.5 g/dL in women
2. Presence of the JAK2V617F mutation (in 95% of patients)
Minor Criteria
1. Bone marrow biopsy showing hypercellularity
2. Serum Epo level below normal range
3. Endogenous erythroid colony formation in vitro
PV is likely if:
A. Both major criteria and at least 1 minor criterion are met, or
B. First major criterion and at least 2 minor criteria are met

37. Treatment of Polycythemia Vera (PV)
Control and maintain Hct levels <45%
Manage disease-related complications of PV
Phlebotomy to maintain Hct levels <45%
Low-dose aspirin in appropriate patients
Hydroxyurea or IFNα as first-line cytoreductive therapy at any
age
Patients with inadequate response to or intolerance of HU use
Ruxolitinib (Jakifi) JAK2 inhibitor
Anagrelide (0.5 mg qds/d) is used mainly to manage
thrombocytosis in patients refractory to other treatments.

38. Essential
Thrombocythemia

39. Essential Thrombocythemia
Rare disorder (1.5 per 100,000)
proliferation of megakaryocytes causing marked increase in
circulating platelets (>1 million)
morphologically abnormal platelets
splenomegaly, mucosal hemorrhage, thromboses
arrow:
macrothrombocyte
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40. Essential Thrombocythemia
Incidence: 1.5 per 100,000
Age at Dx: 60 y/o (~20% <40 y/o)
F to M ratio: 1.6 : 1
Social risk factor: 1. long-term use of dark hair dyes
2. living in tuff house
3. electrician
Clinical features: - near normal life expectancy
- frequent vasomotor and thrombo-
hemorrhagic episodes
Treatment: low-dose acetylsalicylic acid
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41. Myelofibrosis
Bone marrow fibrosis
• fibroblasts may be “innocent bystanders”
• fibrosis probably driven by neoplastic megakaryocytes
Middle aged adults (50-60 y/o)
extramedullary hematopoiesis (spleen, liver)
May occur as an extension of CML or PV
Abnormal peripheral RBCs (“tear-drop” & nucleated RBCs)
Immature WBC and abnormal platelets
Infection, thrombosis and hemorrhage as a major
complicationwww.freelivedoctor.com

42. Myelofibrosis
LARGE AND BIZARRE PLATELETS,
LEUKOCYTOSIS
“naked” nuclear
fragments
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44. CHRONIC MYELOID
LEUKEMIA

45. Definition
• Chronic myelogenous leukemia is a pluripotent
stem cell disease characterized by
anaemia,extreme blood granulocytosis with
immaturity ,basophilia,thrombocytosis and
splenomegaly.
• Occurs more often in men.
• Disease of firsts.
• High doses of ionising radiation can increase the
occurrence of CML.

46. Pathophysiology
• Genetic hallmark of CML is the presence of
BCR-ABLfusion gene product.
• The fusion protein is a result of reciprocal
translocation between the abelson oncogene on
chromosome 9 and break point cluster region on
chromosome 22.
• Fusion genes are generated that encode
190,210,or 230 kda forms of the BCR-ABL
tyrosine kinase.
Other genetic abnormalities
• Trisomy 8,p53 loss.
• Interleukin 1 b involved in the progression of
CML to the blastic phase.

47. CML Pathogenesis:
Philadelphia (Ph)
Chromosome
47
 CML first cancer demonstrated to have underlying
genetic abnormality
• Associated with Ph chromosome
 Result of translocation between chromosomes 9
and 22

49. Clinical presentation
Symptoms
• Fatigue,malaise
• Weight loss
• Early satiety
• Left upper quadrant pain or mass
• Easy bruising ,bleeding
• Fever
Uncommon presentation
• Acute gouty arthritis,priapism,myocardial
infarction,venous thrombosis,visual
disturbances,sweet syndrome..

50. Signs
• pallor
• Splenomegaly
• Sternal tenderness
• Lymhadenopathy
• Hepatomegaly
• Purpura
• Retinal haemorrhage

51. Diagnostic approach to CML
Peripheral blood
• Granulocytic leukocytosis>50*10p9/l
• Predominance of neutrophils and increased %of
myelocytes.
• Absolute basophilia.
• Platelets are normal or increased in number.
Bone marrow
• Marrow is hypercellular with granulocytic
predominance.
• Megakaryocytes are increased in number with
abnormal morphology.
• Increase in reticulin fibrosis.
• Blasts less than 5%.

52. Band
forms
promyelo
cyte
myelocyte
meta
myelo
cyte

53. Diagnosis of accelarated phase
• Blasts 10-20% in peripheral blood and or
bone marrow.
• Basophils >20% in peripheral blood.
• Persistent thrombocytopenia.
• Increasing spleen size and white blood
count despite therapy.
• Cytogenetic evidence of clonal evolution.

54. ACCELERATED PHASE
MYELOB
LAST

55. Blast crisis phase
• Blast > 20%
• Extramedullary blast proliferation.
• Large aggregates or clusters of blast in
bone marrow.

56. Clinical Presentation of Ph+ CML
56

57. Other abnormalities
There is increase in
• uric acid level
• vitamin B12 level.
• lactate dehydrogenase.
• Increase in the level of angiogenic factors.
• Decrease level of leukocyte alkaline
phosphatase.
• Increase in histamine levels.

58. • Identification of philadelphia chromosome
• Can be done by conventional cytogenetic
karyotyping,FISH,RT-PCR.
Conventional cytogenetics
• Entire chromosomal complement is
evaluated to identify philadelphia
chromosome and other abnormalities.
• Can be done on both peripheral blood and
bone marrow.
Disadvantage
• Presence of cryptic or submicroscopic
BCR-ABL arrangement cannot be
identified

59. Fluorescent insitu hybridisation
Advantage
• Fast results,greater sensitivity than
conventional cytogenetics.
• cryptic molecular alteration can be
detected.
Reverse transciptase-PCR
• Detects different length products
corresponding to chimeric BCR-ABL
proteins of 190,210 and 230 kda.
• So helps in distinguishing CML from ALL.

60. Fluorescent insitu hybridisation

61. Prognostic factors
Sokal index
• Percentage of circulating blast,spleen
size,platelet count,age and cytogenetic clonal
evolution.
• Was developed based on chemotherapy treated
patients.
Hassford system
• Developed on interferon alpha treated patients.
• Includes% of circulating blast,spleen
size,platelet count,age,% of eosinophils and
basophils.

62. Treatment
• Drugs
• Stem cell transplant.
• Leukaphresis and splenectomy.
drugs
• Imatinib mesylate,dasatinib,nilotinib
• Hydroxyurea
• busulphan
• Interferon-alpha
• Homoharringtonine
• Anagrelide.
• Cytarabin.

63. Imatinib
• It is an ABL specific tyrosine kinase
inhibitor.
• Imatinib induces apoptosis in cells
expressing BCR/ABL.
• Dose is 400mg/day.
• It should achieve cytogenetic remission
by 6months and molecular remission by
18 months.
• Side effects-edema,pleural and pericardial
effusion,nausea,vomiting,diarrhoea,muscl
e cramps,skin rash,bone pain and
arthralgia.myelosuppression.

64. Imatinib Mechanism of Action
64

65. Criteria for Extent of Imatinib Treatment
. Hematologic response -White cell count <10x109(platelet
count <450 x 109/L, no immature myeloid cells in the
blood, and disappearance of all signs and symptoms
related to leukemia (including palpable splenomegaly)
lasting for at least 4 weeks.
•
Major cytogenetic response-Less than 35% of cells
containing the Ph chromosome by cytogenetic analysis of
marrow cells.
• Complete cytogenetic response-No cells containing the
Ph chromosome by cytogenetic analysis of marrow cells.
• Major molecular response-Blood cell BCR-ABL ratio
<0.05% (3-log reduction in PCR signal from mean
pretreatment baseline value)
• .Complete molecular response-Blood cell BCR-ABL levels
undetectable (usually by nested RT-PCR method).

66. Guidelines for response to imatinib
treatment
Time of
observation
unsatisfact
ory
Suboptimal
response
Optimal
response
3 MONTHS NoHR pHR CHR
6 No mcyR mcyR McyR
12 noMCYR McyR CcyR
18 noCcyR CcyR MMR

72. Newer tyrosine kinase inhibitors
Dasatinib
• Structurally unrelated to imatinib binds to
the ABL kinase domain.
• Side effect-myelosuppression,pleural
effusion,prolongation of QT interval.
Nilotinib
• Structural derivative of imatinib binds to
ABL kinase domain.
• Side effects-rashes,transient elevation of
indirect bilirubin levels and
myelosuppression.

73. Hydroxy urea
• Inhibitor of ribonucleotide reductase.
• Lower the blood counts in 1-2 days.
• Dose is 500-3000 mg/day.
• Side effect-nausea and skin rash.
• Given for patients intolerant to imatinib.
Busulphan
• Gradually lowers the blood counts.
• Dose-6-10 mg/day.
• Should not be used in patients expected to
undergo bonemarrow transplantation.

74. Interferon alpha
• Causes complete haemotologic response
in >70% of patients.
• Dose is 5 million units daily by
subcutaneous administration.
• Hasford score was developed to predict
the survival of patients treated with
interferon alpha.
Homoharringtonine
• it is a plant alkaloid causes cytogenetic
response in patients in late chronic phase.

75. Anagrelide
• It is used for treating elevated platelet
count in CML.especially in presence of
thrombosis and bleeding
Leukapheresis
• Control CMLonly temporarily.
• Used in hyperleucocytic patients where
rapid cytoreduction can reverse the
symptoms.
• Pregnant patient with CML can be
controlled by leukaphresis.

76. Allogenic stem cell transplant
• Outcome depends on patients age,phaseof
disease,type of donor,preparative regimen,graft
vs host disease,post transplantation treatment.
• Patients age should be less than 70
years.transplantation from donor should be HLA
matched.
• Peripheral blood can be used a source of
haemotopoietic progenitor cells.preoperative
regimen like cyclophosphamideplus total body
irradiationis used.
• Complications-graft vs host disease.

77. Differential diagnosis
• Chronic myelomonocytic leukemia
• Juvenile myelomonocytic leukemia
• Chronic neutophilic leukemia
• Atypical CML
• Diseases associated with
hypereosinophilia.

78. Chronic myelomonocytic leukemia
• Anemia, monocytosis >1000/l; blood blasts <10%;
increased plasma and urine lysozyme; BCR
rearrangement absent; uncommon cases with PDGFR-
mutation respond to imatinib.
• Chronic eosinophilic leukemia
• Blood eosinophil count >1500/l; cardiac and neurologic
manifestations common; a proportion of cases have
PDGFR- mutations and are responsive to imatinib
mesylate.
Chronic monocytic leukemia
• Proportion of monocytes elevated; very rare form of
leukemia.
Juvenile myelomonocytic leukemia
• Infants and children <4 years; eczematoid or
maculopapular rash; anemia and thrombocytopenia;
increased HgF in 70% of cases; neurofibromatosis in
10% of cases; BCR rearrangement absent .

80. Most CML Patients Are Diagnosed in
the Chronic Phase
80
Chronic Phase 80% Blast Phase 10%

81. CML Pathogenesis:
Philadelphia (Ph) Chromosome
81
 CML first cancer demonstrated to have underlying genetic
abnormality
• Associated with Ph chromosome
 Result of translocation between chromosomes 9 and 22
 Detected in approx. 95% of patients with CML

83. Clinical Presentation of Ph+ CML
83

84. Treatment of CML
• Imatinib (Gleevec), developed by Dr. Brian Druker at
Oregon Health & Sciences University and Novartis
pharmaceutical company in mid-1990.
• Also found to be effective in other blood cancers and
GIST by inhibiting different TK proteins.
• World-wide sales now $28 billion in the 10 years from
2001-2011.
• Now 4 drugs, second generation tyrosine kinase
inhibitors available to treat CML.
• Drugs continue throughout life.
84

85. Imatinib Mechanism of Action
85

86. Treatment of CML
• 4 Targeted drugs which block the action of tyrosine
kinase (TKIs):
– Imatinib (Gleevec)
– Dastinib (Sprycel)
– Nilotinib (Tasigna)
– Bosutinib (Bosulif)
• Side Effects
– Skin rash
– Fluid retention
– Diarrhea
– Vascular thrombosis
• Omacetaxine (Synribo) or Homoharringtonine
(alkaloid) approved use when 2 TKIs have failed 86

87. Event-Free Survival and Survival
Without AP/BC on First-Line Imatinib
87

88. Survival Rates for Stem Cell
Transplantation
88

89. ‘Inverted Iceberg’ Schematic of CML burden
and reduction over time.
89

90. CML Treatment Cessation of TKIs
• If relapse occurs, it develops within the first 6 months
after the treatment stopped
• About 40%—50% of patients have no recurrence if
their initial leukemic burden was low and they had
been on treatment for a long duration (> 10 years)
• Ongoing studies investigating second generation TKIs
e.g. nilotinib and achieving more rapid MMR > 4 – 5
logs
• Current recommendation is to continue with TKI
treatment for life
• Patients may not be able to tolerate TKI and alternative
drug chosen
90