mds classification and advances in therapy n.
Skip this Video
Loading SlideShow in 5 Seconds..
MDS: Classification and Advances in Therapy PowerPoint Presentation
Download Presentation
MDS: Classification and Advances in Therapy

Loading in 2 Seconds...

play fullscreen
1 / 46

MDS: Classification and Advances in Therapy - PowerPoint PPT Presentation

  • Uploaded on

MDS: Classification and Advances in Therapy. BTG2013. S. Varma PGIMER, Chandigarh India. MDS. Highly heterogeneous group of disorders Variable natural history Variable mortality rate Variable response to therapy Commonest cause of death Progressive bone marrow failure

I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
Download Presentation

PowerPoint Slideshow about 'MDS: Classification and Advances in Therapy' - joben

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
mds classification and advances in therapy

MDS: Classification and Advances in Therapy


S. Varma

PGIMER, Chandigarh


  • Highly heterogeneous group of disorders
    • Variable natural history
    • Variable mortality rate
    • Variable response to therapy
  • Commonest cause of death
    • Progressive bone marrow failure
    • Conversion to AML






Age-related Incidence of MDS


Disease of elderly



0 10 20 30 40 50 60 70 80

Age, years

McNally RJQ et al. Hematological Oncology 1997. 15:173-189

historical perspective
Historical Perspective
  • Pseudo-aplasticanemia
  • Refractory Anemia
  • Pre-leukemia
  • Myelodysplastic syndrome

Luzzatto AM. anemiapseudoaplasticaRivVen 1907;47:193.

Bomford RR, Rhodes CP. Refractoryanemia. Q J Med 1941;10:175-281.

mds limitations of fab classification
MDS: Limitations of FAB Classification
  • Multilineage cytopenia with <5% BM blasts
  • Rough prediction of prognosis
  • Cytogenetics not given importance
  • Ill defined entities: childhood MDS, T-MDS & other secondary MDS
  • Immunophenotyping and genetic techniques not included
advances in management
Advances in Management

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


Prognostic scores

Most widely used

There are benefits and limitations of all these scores


Overall score is the sum of the scores for following parameters:

BM blasts %: score 0 =< 5%; 0.5=5-10%; 1.5=11-19%; 2.0=20-30%.

Cytopenias: score 0 = no/ one cytopenia; 0.5 = 2 or 3 cytopenias.

Cytogenetics: score 0 (good)= Normal karyotype, -Y, 5q- or 20q-;

score 1.0 (poor)= 7q- or -7, complex translocations;

score 0.5 (intermediate)= all others.

Greenberg P et al. Blood 1997;89:2079-2088.



  • Simplicity:
    • Use of only 3 variables
  • Applicable at centers with limited lab support
  • Widely used in clinical practice and research
    • Bulk of scientific data on MDS is based of IPSS


  • Includes patients with
    • 20-30% blasts
    • CMML
  • Does not consider severity of cytopenias
    • Strong predictor of outcome
  • Can not be applied in pre-treated patients

WHO Prognostic Scoring System

*BM fibrosis grade 2-3 shifts risk group by one step



  • Simplicity: use of only 3 variables
  • Accurate prediction of survival and risk of leukemic evolution at any time during the course of their disease
  • Useful in predicting post transplant outcome


  • Not applicable for secondary MDS
mdacc prognostic scoring system mpss
MDACC Prognostic Scoring System (MPSS)

MPSS risk group Score

Low 0-4

Intermediate 1 5-6

Intermediate 2 7-8

High ≥9

Kantarjian et al

Cancer 2008

2012 revised ipss
2012 Revised IPSS
  • Fine tune the prognostic impact of
  • Cytogenetic abnormalities
  • Depth of cytopenia

Schanz J, et al. J Clin Oncol. 2012;30:820-829. Greenberg PL, et al. Blood. 2012;120:2454-2465.

treatment considerations
Treatment considerations
  • Myelodysplasia are incurable without HSCT
  • Highly variable natural history
  • Treatment considerations must take into account many factors, including the
    • Pathologic diagnosis
    • The prognosis based on the IPSS or WPSS
    • Cell line /s affected
    • Feasibility of performing a clinical trial
tools to treat mds
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
to trick or treat
To Trick or Treat
  • Treatment should be reserved and potentially diagnosis to be transmitted to the patient and family, only if there are symptoms resulting from anemia or other cytopenias or perhaps pre-symptomatic anemia or severe thrombocytopenia.
  • Old and frail patients or those who have equivocal diagnostic features, benefit from a period of observation.
  • Neutropenia without infection is a poor justification for initiation of therapy.

Stone RM. Blood 2009

role of growth factors
Role of Growth Factors

Most widely prescribed class of medications for MDS (55%)

newer approaches immunosuppressants
Newer approaches- Immunosuppressants

Immunologic suppression of normal BM function, similar to the situation in aplasticanemia, has been postulated to account for cytopenias in some MDS patients

Specific candidates- Refractory anemia with relatively hypoplastic marrow

predictor of response to immunosuppressant
Predictor of Response to Immunosuppressant
  • HLA-DR-15-positivity
  • RA (<5% blasts)
  • IPSS Low/Int-1
  • Age <60 years
  • Brief transfusion history
  • Trisomy 8 abnormality
  • Normal cytogenetics
  • Marrow cellularity <30%
  • Phase II study (N=35) on MDS-RA
  • Both equine and rabbit ATG were found to be active
  • Response to
    • Equine ATG: 29% (34/115)
    • Rabbit ATG: RR 42%.
    • 75% responders durable response (median 31.5 months).

Stadler M, Leukemia 2004;18:460-5

Jonasova A, Br J Haematol. 1998;100:304-309.

Molldrem JJ, Br J Haematol. 1997;99:699-705.

chromosomal abnormality del13q
Chromosomal Abnormality: del13q

22 patients with bone marrow failure


  • MDS-U with del (13q) is a benign disorder with good response to IST
  • Del (13q) should not be considered intermediate risk abnormality

Hosokawa et al, Haematologica 2012;97:1845

biological response modifiers special case of del 5q syndrome
Biological response modifiersspecial case of Del 5q syndrome


  • del(5q)
  • IPSS low or Int-1
  • platelets > 50K/mm3
  • neutrophils > 500/mm3
  • transfusion dependent
study design







10 mg po x 21

Dose Reduction

5 mg qd

5 mg qod


Off study

Week: 0 4 8 12 16 20 24

Study Design

Frequency of Cytogenetic Response According to Karyotype Complexity

len in non del 5q mds
Len in non del(5q) MDS
  • Can be considered for low risk, adequate ANC and platelet counts
  • Expected response rates are similar to other treatment alternatives
  • Use in high risk MDS remains investigational

“Revlimid restores erythropoietic activity to the MDS clone”

Raza et al. Blood 2008

hypomethylating agents1
Hypomethylating agents
  • Azacytidine and decitabine are potent DNMT inhibitors
  • This leads to hypomethylation of CpGdinucleotides in gene promoters and reactivation of previously silent genes
  • Cytotoxic activity similar to cytarabine
5 azacytidine

AZA001: Euro study despite CALGB 9221

Primary endpoint: survival

5 Azacytidine

Fennaux et al. Lancet Oncol 2009


Lubbert et al . JCO 2011

hypomethylating agents2
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
  • Aza vs Decitabine head to head trial results awaited

Optimal dose, schedule, route

  • Azacitidine:
    • 7 day 75mg/m2/d sc q 28 days (5-2-2 or 50mg/m2 5-2-5 schedule)
  • Decitabine:
    • 3 day 15mg/m2/dose IV 8 hrly (total dose 135mg/m2) inpatient
    • 5 day 20mg/m2 /d over 1 hr (total dose 100mg/m2) outpatient


  • 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. HematolOncolclin N Am 2010

predictive factors for achieving response to hypomethylating agents
Predictive Factors for Achieving Response to Hypomethylating Agents


  • Mol/ Cyto:
    • Mutated TET2
    • Mutated EZH2
    • Phosphoinositase – Phospholipase C beta 1 hypomethylation
  • Clinical Variable
    • Doubling of Platelets
  • Negative
  • Mutated P 53
  • Abnormal/ complex karyotype
  • BM Blasts >15%
  • Previous therapy
  • Transfusion dependency
  • BM fibrosis grade 3

Santini V, ASH 2012



High Risk

(Int 2, High risk, blasts>10%)

Low risk (low or Int 1, BM blasts <10%)

Any age

Age <60


Iron Chelation

Growth factors

DMT Inhibitors



Clinical trial

Intensive chemo


Clinical trial


Clinical trial

Intensive Chemo



Progression/ failure


Attallah: Cancer Therap 2008;26:208-16

what s on the horizon
What’s on the Horizon?
  • In the quest of effective therapy, currently there are approximately 200 clinical trials are ongoing and numerous agents are at various stages of drug development
  • The need for a novel agent is particularly noted in patients failing hypomethylating agents who are ineligible for stem cell transplant

Kulasekararaj AG, SeminHematol ,2012; 49:350-60

take home message
Take Home Message
  • Myelo-dysplastic syndromes are heterogeneous disorders
  • Prognostic scores are evolving with use of cyto-genetics and molecular markers
  • Treatment depends upon the prognostic and host factors
  • MTI and IMIDs are being increasingly used
  • HSCT is the only curative treatment
  • Treatment paradigms are evolving