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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 - PowerPoint PPT Presentation
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MDS: Classification and Advances in TherapyBTG2013
S. VarmaPGIMER, ChandigarhIndia
MDS•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
McNally RJQ et al. Hematological Oncology 1997. 15:173-189
MalesFemales
0 10 20 30 40 50 60 70 800.01
0.1
1
10
100
Rat
e
Disease of elderly
Age, years
Classification
Historical Perspective•Pseudo-aplastic anemia
•Refractory Anemia
•Pre-leukemia
•Myelodysplastic syndrome
Luzzatto AM. anemia pseudoaplastica Riv Ven 1907;47:193.Bomford RR, Rhodes CP. Refractory anemia. Q J Med 1941;10:175-281.
MDS: FAB Classification 1982
FAB subtype
Blast % RS% Monocytes >1x109/l
Survival (months)PB BM
RA <1 <5 <15 - 50RARS <1 <5 >15 - 75RAEB <5 5-20 variable - 11CMML <5 <20 variable + 11RAEB-T >5;
Auer rods20-30;
Auer rodsvariable +/- 5
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
Comparison of MDS ClassificationsFAB
classificationWHO Classsification
2001WHO Classification 2008
RA RA Refractory cytopenia with unilineage dyplasia• Refractory anemia• Refractory neutropenia• Refractory thrombocytopenia
RARS RARS Refractory anemia with ring sideroblasts (RARS)
RCMD RCMD
RCMD-RS RCMD-RS
RAEB RAEB I and 2 RAEB I and 2
RAEB-T RAEB II/ AML RAEB II/ AML
CMML MDS-UC MDS-UC
MDS associated with isolated del(5q)
MDS associated with isolated del(5q)
Childhood myelodysplastic syndrome• Refractory cytopenia of childhood
WHO 2008Bone Marrow Blood SubtypeDysplasia: ≥10% cells Single cell line
Mostly erythroidRCUD
Erythroid dysplasia>15% ringed sideroblasts
Anemia RARS
>10%Dysplasia: ≥2 cell lineage<5%blasts
Bi/pancytopenia RCMD
Uni-multi lineage dysplasia5-9% blasts, No Auer rods
Cytopenia<5% blast
RAEB-1
Uni-multi lineage dysplasia10-19% blasts or Auer rods
Cytopenia, 5-19% blasts or Auer rods
RAEB-2
Uni / multilineage/ no dysplasiaCharacteristic MDS CG +
Cytopenia MDS-U
Unilineage erythroid dysplasia, isolated del 5q, <5%blast
Anemia,normal or ↑Platelets
MDS with 5q
Cazzola M. Hemaologica 2011
Outcomes in MDS in Different WHO Subtypes
Advances in ManagementImproved prognostic scores
Disease related variablesHost factors
Appropriate clinical decisionDisease eradication/ controlProlonging overall survivalManaging complications of disease and therapyImproving quality of life
Prognostic scores Most widely used
There are
benefits and
limitations of all these scores
IPSS: Prognostic Variables0 0.5 1.0 1.5 2.0
Marrow blasts % <5 5-10 — 11-20 21-30
Karyotype Good Intermediate Poor
Cytopenias 0/1 2/3 - - -
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.
Risk group Overall score Median survival (years)Low 0 5.7Intermediate 1 0.5 or 1.0 3.5Intermediate 2 1.5 or 2.0 1.2Poor >/= 2.5 0.4
Greenberg P et al. Blood 1997;89:2079-2088.
Prediction of survival by IPSS
IPSSPros•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
Cons• 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
WPSSPros• 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
Cons• Not applicable for
secondary MDS
Comparison of IPSS and WPSS (258 MDS Patients)
MDACC Prognostic Scoring System (MPSS)Variable Score 1 Score 2 Score 3Performance Status ≥ 2Age in years 60-64 ≥ 65Platelets x 109/L 50-199 30-49 <30Hemoglobin gm% <12Bone marrow blasts 5-10 11-29WBC x 109/L >20Karyotyping Chromosome 7 abnormality
Complex karyotype (>2 abn)Prior transfusion Yes
MPSS risk group ScoreLow 0-4Intermediate 1 5-6Intermediate 2 7-8High ≥9
Kantarjian et alCancer 2008
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 Median OS, Mos
Median Time to
AML, Mos
Very good del(11q), -Y 60.8 NR
Good Normal, del(20q), del(5q) alone or double, del(12p) 48.6 NR
Intermediate +8, del(7q), i(17q), +19, any other single or double, independent clones 26.0 78.0
Poor inv(3)/t(3q)/del(eq), -7, double including del(7q), complex (3) 15.8 21.0
Very poor complex (≥ 3) 5.9 8.2
Fine tune the prognostic impact of •Cytogenetic abnormalities•Depth of cytopenia
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 4Cytogenetics V. good - Good - Int Poor V. poorBM blast% ≤2 - >2 - <5 - 5-10 >10 -Hgb ≥10 - 8-<10 <8 - - -Platelets ≥100 50-100 <50 - - - -ANC ≥0.8 <0.8 - - - - -
Advances in therapy of MDS
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
• 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
• 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
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: 500/750mcg 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%, ?OS/PFS/ QOL, durability:2 years
– 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%)
Newer approaches- Immunosuppressants
Immunologic suppression of normal BM function, similar to the situation in aplastic anemia, has been postulated to account for cytopenias in some MDS patients
Specific candidates- Refractory anemia with relatively hypoplastic marrow
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%
ATG
•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).
Jonasova A, Br J Haematol. 1998;100:304-309.Molldrem JJ, Br J Haematol. 1997;99:699-705.
Stadler M, Leukemia 2004;18:460-5
Chromosomal Abnormality: del13q
Only del (13 q ) Del (13q) plus other abnormalities
number 16 6GPI def clone 16 3Response to IST 100% (14/14) 40% (2/5)10 yr OSR 83% 63%Progression to AML None 2
22 patients with bone marrow failureMDS U
•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 modifiersspecial case of Del 5q syndrome
Eligibility: •del(5q)•IPSS low or Int-1•platelets > 50K/mm3
•neutrophils > 500/mm3
• transfusion dependent
Study Design
Dose Reduction5 mg qd
5 mg qod
Week: 0 4 8 12 16 20 24
EligiblePatients
Register
Response
10 mg po x 21
NO Off study
YES Continue
Results Frequency of Cytogenetic Response According to Karyotype Complexity
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
Raza et al. Blood 2008“Revlimid restores erythropoietic activity to the MDS clone”
Hypomethylating agents
Hypomethylating agents
•
• Azacytidine and decitabine are potent DNMT inhibitors
• This leads to hypomethylation of CpG dinucleotides 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
AZA ControlsMedian survival 24.5 months 15 monthsProgression to AML 27 months 13 monthsTransfusion independence 45% 11%
Fennaux et al. Lancet Oncol 2009
Decitabine
DAC Controls
Overall survival 10 months 8.5 months
Progression to AML at 1 yr 22% 33%
CR/ PR/ HI 13/6/5% 0/0/2%
Lubbert et al . JCO 2011
Hypomethylating agentsWhen 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) outpatientDuration
– 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
Predictive Factors for Achieving Response to Hypomethylating Agents
Positive• 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
MDSLow risk
(low or Int 1, BM blasts <10%)
Any age
Iron ChelationGrowth factorsDMT InhibitorsLenolidamideImmunomodulationClinical trial
Progression/ failure
HSCT
High Risk(Int 2, High risk, blasts>10%)
Age <60 Age≥60
Intensive chemoDMTIClinical trial
DMTIClinical trialIntensive Chemo
Failure
Attallah: Cancer Therap 2008;26:208-16
Failure
Unconventional and upcoming agents
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, Semin Hematol ,2012; 49:350-60
Agent Action Current statusErlotinib Oral TKI tageting EGFR Phase 2,
hypomethylating agent failed MDS casesORR 15%Stable disease 32%
Tosedostat Aminopeptidase inhibitor
Phase 1/ 2, ORR 28% in AML/MDS patients >60 years
Ezatiostat Glutathione analogue Phase 2 , 40 % efficacy in lenalidomide treated MDS patients
Siltuximab Chimaric monoclonal Ab neutralising IL6
Phase 2 for Anemia related to MDS
Kulasekararaj AG, Semin Hematol ,2012; 49:350-60
Agent Action Current statusBMN673 PARP inhibiotrs Phase 1 , open label
trial for AML, MDS, MCL, CLL
MLN4924 Small molecule inhibitor of Neddylation activating enzyme
Phase 1, AML and MDS
PF-04449913 Hedgehog pathway inhibitor
Phase 1/ 2, for myelofibrosis, AML, MDS
SCIO496 MAP kinase inhibitors Phase 1/ 2 for low and intermediate risk MDS
Kulasekararaj AG, Semin Hematol ,2012; 49:350-60
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