MDS: Classification and Advances in Therapy

BTG2013

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

Rate

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 - 50

RARS <1 <5 >15 - 75

RAEB <5 5-20 variable - 11

CMML <5 <20 variable + 11

RAEB-T >5; Auer rods

20-30; Auer rods

variable +/- 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 Variables

0 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 5.7

Intermediate 1 0.5 or 1.0 3.5

Intermediate 2 1.5 or 2.0 1.2

Poor >/= 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 6

GPI def clone 16 3

Response 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 Controls

Median survival 24.5 months 15 months

Progression to AML 27 months 13 months

Transfusion 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