Current Current Treatments in Treatments in

MDS; the MDS; the Scottish Scottish

PerspectivePerspectiveDr Dominic CulliganDr Dominic Culligan

Aberdeen Royal InfirmaryAberdeen Royal Infirmary

Age-related Incidence of Age-related Incidence of MDSMDS

0 0 2 1 2 2 49

16

26

52

59 61

34

10

10

10

20

30

40

50

60

70

20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- 80- 85- 90- 95-

Williamson PJ, et al. Williamson PJ, et al. Br J Haematol.Br J Haematol. 1994 Aug;87(4):743-5. 1994 Aug;87(4):743-5.

Age in 5-year blocksAge in 5-year blocks

(per 100,000)

Talk OutlineTalk Outline

Therapeutic OptionsTherapeutic Options Low Risk MDSLow Risk MDS

High Risk MDSHigh Risk MDS

The Scottish PerspectiveThe Scottish Perspective Scottish Medicine Consortium (SMC)Scottish Medicine Consortium (SMC)

How it worksHow it works What is good & what is bad!What is good & what is bad!

Therapeutic OptionsTherapeutic Options Low Risk MDS – Low Risk MDS –

Main problem is anaemiaMain problem is anaemia

High Risk MDS – High Risk MDS – Main problem is bone marrow Main problem is bone marrow

failure & failure & leukaemialeukaemia

Therapeutic OptionsTherapeutic Options Low Risk MDS Low Risk MDS

Supportive care/ blood transfusion /iron Supportive care/ blood transfusion /iron ChelationChelation

Erythropietic stimulating agent (ESA)Erythropietic stimulating agent (ESA) ImmunosuppressionImmunosuppression LenalidomideLenalidomide

High Risk MDS High Risk MDS Supportive careSupportive care AzacitidineAzacitidine ChemotherapyChemotherapy Stem cell transplantationStem cell transplantation

Best supportive careBest supportive care

Red cell transfusion on demandRed cell transfusion on demand

Antibiotics for treatment & Antibiotics for treatment & preventionprevention

G-CSF during infectionG-CSF during infection

Iron chelation therapyIron chelation therapy

Treatment of Anaemia in MDSTreatment of Anaemia in MDS

Symptomatic anaemia in low risk MDS

Transfusion

Growth Factors

Immunosuppression with

Antithymocyte globulin

Lenalidomide in 5q-

Treatment of Anaemia in MDSTreatment of Anaemia in MDS

Symptomatic anaemia in low risk MDS

Transfusion

Growth Factors

Immunosuppression with

Antithymocyte globulin

Lenalidomide in 5q-

Iron chelation is beneficial on survival in Iron chelation is beneficial on survival in thalassaemiathalassaemia

Age (years)0 10 20 30 40

0

0.25

0.50

0.75

1.00

1955-64 (n=21)1955-64 (n=21)1965-74 (n=39)1965-74 (n=39)

1975-97 (n=42)1975-97 (n=42)

Analysis September 2000

Davis and Porter. Adv Exp Med Biol. 2002;509:91.

Su

rviv

al p

rob

abil

ity

Thalassaemia Major treated with desferrioxamine only (N=103)

Survival by Birth Cohort: University College London Hospitals

69%

yrs

100%

Which patients if any should get iron Which patients if any should get iron chelation?chelation? IPSS score low or int-1IPSS score low or int-1

Ferritin should be 1000-2000 ng/ml or clinical Ferritin should be 1000-2000 ng/ml or clinical or radiological evidence of iron loading at the or radiological evidence of iron loading at the start of chelationstart of chelation

This would often correlate with 20-30 units of This would often correlate with 20-30 units of red cells transfusedred cells transfused

Candidates for allograft in whom there is a Candidates for allograft in whom there is a significant delay until the proceduresignificant delay until the procedure

Treatment of Anaemia in MDSTreatment of Anaemia in MDS

Symptomatic anaemia in low risk MDS

Transfusion

Growth Factors

Immunosuppression with

Antithymocyte globulin

Lenalidomide in 5q-

20 Years experience of 20 Years experience of erythropoietin erythropoietin

+/- G-CSF therapy in MDS+/- G-CSF therapy in MDS

Overall response rate ~20-40%Overall response rate ~20-40%

Best response group ~ 60-70%Best response group ~ 60-70% Refractory anaemiaRefractory anaemia Low endogenous EPO level Low endogenous EPO level

(<500mU/ml)(<500mU/ml) Low transfusion requirement Low transfusion requirement

(<2u/month)(<2u/month)

Prototype model for selecting Prototype model for selecting patients for treatment with EPO + patients for treatment with EPO +

GCSFGCSF

RA, RARS, RAEB

>+1

-1 to +1

< -1

Good response 74%

Intermediate response 23%

Poor response 7%

Score

Serum EPO <100 +2

100-500 +1

>500 -3

Unit/mth < 2 +2

= or >2 -2Hellstrom et al, BJHaem 2003, 120, 1037-46

The ‘nitty-gritty’ of EPO The ‘nitty-gritty’ of EPO therapytherapy

Is there a quality of life benefit for Is there a quality of life benefit for EPO responders?EPO responders?

Is EPO therapy cost-effective?Is EPO therapy cost-effective?

Is there a survival advantage for Is there a survival advantage for EPO responders?EPO responders?

Your doctors have still not Your doctors have still not answered two major answered two major

questions in low risk MDS!questions in low risk MDS!

Is erythropoietin therapy more Is erythropoietin therapy more beneficial than transfusion?beneficial than transfusion?

Is iron chelation therapy beneficial?:Is iron chelation therapy beneficial?:

Our drug companies are Our drug companies are trying to answer these trying to answer these

questions!questions!

Johnson & Johnson – EPOANE3021Johnson & Johnson – EPOANE3021 Erythropoietin versus PlaceboErythropoietin versus Placebo

Novartis – TELESTONovartis – TELESTO Iron chelation (Exjade) versus PlaceboIron chelation (Exjade) versus Placebo

Treatment of Anaemia in MDSTreatment of Anaemia in MDS

Symptomatic anaemia in low risk MDS

Transfusion

Growth Factors

Immunosuppression with

Antithymocyte globulin

Lenalidomide in 5q-

5q- Syndrome5q- Syndrome

del(5)(q31q33)

5q- Syndrome: Diagnostic 5q- Syndrome: Diagnostic findingsfindings

Peripheral bloodPeripheral blood

AnaemiaAnaemia Platelets normal Platelets normal

or increasedor increased

Bone marrowBone marrow Megakaryocytes with Megakaryocytes with

hypolobulated nuclei hypolobulated nuclei < 5% blasts, no Auer < 5% blasts, no Auer

rodsrods Isolated del(5)(q31)Isolated del(5)(q31)

More common in women

Median age at diagnosis 68yrs

Associated with a favourable prognosis; median survival >5yrs, AML transformation 8-16%

Phase 2 Study of Lenalidomide Phase 2 Study of Lenalidomide MDS MDS

Del 5q (MDS-003)Del 5q (MDS-003)

RREESSPPOONNSSEE

RREEGG IISSTTEERR

Wk: 0 4 8 12 16 20 24

Activation date: 7-15-03 Cohorts

10 mg × 21 days10 mg po qd

Treatment until progression/relapse

Transfusion Independence Response Transfusion Independence Response Del 5q (MDS-003)Del 5q (MDS-003)

4.6 (1 - 4.6 (1 - 49)49)

99 (67%)99 (67%)

Median time to Median time to response, wk response, wk (range)(range)

Transfusion Transfusion IndependenceIndependence

N = 148N = 148

See

BD

for

dat

a

List A et al. N Engl J Med 2006;355:1456-1465

Durable Transfusion Independence (ITT) Del 5q (MDS-003)

Median not yet reached median FU 104 wks

Case1Case1Exceptional in Exceptional in

every sense of the every sense of the word!word!

Clinical presentationClinical presentation

A 77 year old male retired farmerA 77 year old male retired farmer 2 year history:2 year history:

TiredTired LethargicLethargic Poor sleep patternPoor sleep pattern

Known three vessel coronary artery Known three vessel coronary artery diseasedisease 2 months more frequent angina2 months more frequent angina Increasing breathlessnessIncreasing breathlessness

Laboratory findingsLaboratory findings

FBC:FBC:

Hb Hb 9.1 g/dl;9.1 g/dl; MCV 96flMCV 96fl WCC WCC 2.6 x 102.6 x 1099/l/l NeutsNeuts 1.2 x 101.2 x 1099/l/l PlatsPlats 117 x 10117 x 1099/l/l

Myelodysplastic Syndrome (MDS)Myelodysplastic Syndrome (MDS)

Refractory cytopenia with multilineage Refractory cytopenia with multilineage dysplasia (WHO)dysplasia (WHO)

Follow up visitFollow up visit

Cytogenetics failed:Cytogenetics failed:

Not keen on repeat bone marrowNot keen on repeat bone marrow

Hb 8.5 g/dlHb 8.5 g/dl

ManagementManagement

Jehovah’s Witness!Jehovah’s Witness!

Case 1 Question 2Case 1 Question 2

What would you recommend?What would you recommend?

1)1) Tell him not to be so daft and have a Tell him not to be so daft and have a blood transfusion?blood transfusion?

2)2) Tell his wife and daughter (not JWs) to Tell his wife and daughter (not JWs) to persuade him to have a blood persuade him to have a blood transfusion?transfusion?

3)3) Treat him with a trial of erythropoietic Treat him with a trial of erythropoietic stimulants (EPO, Darbopoietin)?stimulants (EPO, Darbopoietin)?

4)4) Try something else?Try something else?

Case 1 Answer 2Case 1 Answer 2

What would you recommend?What would you recommend?1)1) Tell him not to be so daft and have a Tell him not to be so daft and have a

blood transfusion?blood transfusion?

2)2) Tell his wife and daughter (not JWs) to Tell his wife and daughter (not JWs) to persuade him to have a blood persuade him to have a blood transfusion?transfusion?

3)3) Treat him with a trial of erythropoietic Treat him with a trial of erythropoietic stimulants (EPO, Darbopoietin)? (high stimulants (EPO, Darbopoietin)? (high predicted response)predicted response)

4)4) Try something else?Try something else?

Initial therapyInitial therapy

Erythropoietin 30,000u once per week Erythropoietin 30,000u once per week

x 6wksx 6wks Erythropoietin 30,000u once per week Erythropoietin 30,000u once per week

+ G-CSF 105ug three times per week+ G-CSF 105ug three times per week

x 6 weeksx 6 weeks Erythropoetin 60,000u +G-CSF 2 weeksErythropoetin 60,000u +G-CSF 2 weeks No response-steady deteriorationNo response-steady deterioration

March 2009March 2009

Wheelchair- boundWheelchair- bound Angina at rest despite maximum Angina at rest despite maximum

medical therapymedical therapy Hb 5.7g/dlHb 5.7g/dl Repeat bone marrow:Repeat bone marrow:

Gross dysplasia, no increase in blastsGross dysplasia, no increase in blasts Karyotype 46XY onlyKaryotype 46XY only IPSS intermediate-1IPSS intermediate-1

Case 1 Question 3Case 1 Question 3What would you opt for?What would you opt for?

1). Palliative care with no further 1). Palliative care with no further therapy?therapy?

2). Trial of azacitidine if approved?2). Trial of azacitidine if approved?

3). Trial of lenalidomide if approved?3). Trial of lenalidomide if approved?

4).4). Trial of anti-thymocyte globulin Trial of anti-thymocyte globulin (ATG)?(ATG)?

Case 1 Answer 3Case 1 Answer 3What would you opt for?What would you opt for?

1). Palliative care with no further 1). Palliative care with no further therapy?therapy?

2). Trial of azacitidine if approved?2). Trial of azacitidine if approved?

3). 3). Trial of lenalidomide if approved?Trial of lenalidomide if approved?

4).4). Trial of anti-thymocyte globulin Trial of anti-thymocyte globulin (ATG)?(ATG)?

Exceptional Circumstances GroupExceptional Circumstances Group

Approved trial of lenalidomide based on Approved trial of lenalidomide based on fulfilling local criteria for fulfilling local criteria for exceptionality:exceptionality:

‘‘Because of his religious beliefs he is Because of his religious beliefs he is unable to receive the standard unable to receive the standard therapy-blood transfusion’therapy-blood transfusion’

Case 1 continuedCase 1 continued

22/04/09 started first cycle 22/04/09 started first cycle lenalidomidelenalidomide 10mg od for 21 days out of 28 days10mg od for 21 days out of 28 days

12/05/09 GP phoned:12/05/09 GP phoned: Bedridden, home oxygen, not coming to Bedridden, home oxygen, not coming to

hospital again, no further treatmenthospital again, no further treatment Most recent Hb 4.3g/dlMost recent Hb 4.3g/dl

Here is the really Here is the really exceptional bit!exceptional bit!

22/09/09 FBC from GP!!!22/09/09 FBC from GP!!!

Hb 13.5 g/dlHb 13.5 g/dl WCC 6.6 x 10WCC 6.6 x 1099/l/l Neuts 3.8 x 10Neuts 3.8 x 1099/l/l Platelets 166 x 10Platelets 166 x 1099/l/l

Contacted GP-It is him and repeat FBC same!Contacted GP-It is him and repeat FBC same!

Continued on lenalidomide for two years with Continued on lenalidomide for two years with normal blood counts and no symptoms of anaemianormal blood counts and no symptoms of anaemia

Case 1 Case 1 What should you display in your What should you display in your

MDS clinic?MDS clinic?

Therapeutic OptionsTherapeutic Options

High Risk MDS – Main problems are bone High Risk MDS – Main problems are bone marrow marrow failure & leukaemiafailure & leukaemia

Supportive careSupportive care AzacitidineAzacitidine ChemotherapyChemotherapy Stem cell transplantationStem cell transplantation

AzacitidineAzacitidine

It has been suggested that It has been suggested that azacitidine may switch on important azacitidine may switch on important anti-cancer genesanti-cancer genes

AZA 001:AZA 001: Study design schematicStudy design schematic

RandomisationInvestigator selection

of conventional care regimen

Azacitidine 75 mg/m2 daily for 7 days, every 28 days

Conventional care regimen•Best supportive care only•Low-dose ARA-C (20 mg/m2 daily for 14 days every 28-42 days)•Standard chemotherapy (7 + 3)

AZA-001: AZA-001: Vidaza is the only licensed drug that Vidaza is the only licensed drug that

has demonstrated a survival advantage has demonstrated a survival advantage in Int-2 and High-risk MDSin Int-2 and High-risk MDS

Vidaza – increases the median survival to 24.5 months (compared to 15 Vidaza – increases the median survival to 24.5 months (compared to 15 months with CCR) providing a months with CCR) providing a 9.4 month benefit9.4 month benefit

In a post hoc analysis Vidaza In a post hoc analysis Vidaza doubled 2-yeardoubled 2-year survivalsurvival rate compared with rate compared with CCR (p<0.001)CCR (p<0.001)

1. Fenaux P, et al. The Lancet Oncology 2009; 10: 200-01

AZA-001: AZA-001: Setting a new standard in transfusion Setting a new standard in transfusion

independenceindependence

1. Santini V. J Clin Oncol 2008 2. Fenaux P, et al. The Lancet Oncology 2009; 10: 200-013. Vidaza SmPC December 2008.

100

80

60

40

20

0

% o

f tr

ansf

usi

on

Ind

epen

den

t p

atie

nts

90

70

50

30

10

45.0

11.4

33.6% differencep<0.0001

Vidaza

CCR

Azacitidine (Vidaza)Azacitidine (Vidaza)

Standard of care for high risk MDS Standard of care for high risk MDS patients who are not candidates for patients who are not candidates for transplantationtransplantation

Approved by NICE ( Approved by NICE ( great help of great help of UKMDS Patient Forum) UKMDS Patient Forum)

Not approved by SMCNot approved by SMC

The Scottish PerspectiveThe Scottish Perspective

The Scottish Medicines ConsortiumThe Scottish Medicines Consortium

Statutory body which is part of: Statutory body which is part of: Quality Improvement Scotland (QIS)Quality Improvement Scotland (QIS)

To advice the NHS in Scotland as to To advice the NHS in Scotland as to the cost effectiveness of new the cost effectiveness of new treatmentstreatments

SMC vs. NICESMC vs. NICE

SMC decisions only apply in ScotlandSMC decisions only apply in Scotland

NICE NICE single drugsingle drug decisions only apply decisions only apply in England, Wales and Northern in England, Wales and Northern IrelandIreland

NICE NICE multiple treatmentmultiple treatment assessments assessments apply in Scotland and replace any apply in Scotland and replace any existing SMC guidanceexisting SMC guidance

New Drug CommitteePatient Access Scheme

Assessment Group(PASAG)

Main SMC Committee

Final Advice Document

The workings of the SMC

ExjadeAzacitidine

Drug Company

What about stem What about stem cell cell

transplantation?transplantation?

Current transplant activity Current transplant activity in MDSin MDS

EBMT EBMT

2008:2008: 1147 allografts for MDS ~ 10% of total 1147 allografts for MDS ~ 10% of total

1998-2006 1998-2006 1333 MDS patients > 50yrs allografted1333 MDS patients > 50yrs allografted

Considerations for all Considerations for all potential transplant potential transplant

candidatescandidates Disease characteristics Disease characteristics

Patient characteristicsPatient characteristics

AgeAge

Co morbidities (other diseases or disabilities)Co morbidities (other diseases or disabilities)

Iron status at transplantIron status at transplant

40 yr old female works in our medical illustration 40 yr old female works in our medical illustration departmentdepartment

First time blood donorFirst time blood donor

Failed the screening testFailed the screening test

Subsequent FBCSubsequent FBC Hb 12.1 g/dlHb 12.1 g/dl MCV 103 flMCV 103 fl WCC 1.9 X 10WCC 1.9 X 1099/l/l Neut 1.2 x 10Neut 1.2 x 1099/l/l Plat 258 x 10Plat 258 x 1099/l/l

Blood film: Significant dysplasiaBlood film: Significant dysplasia

Bone MarrowBone Marrow Hypercellular-confirmed on trephineHypercellular-confirmed on trephine Trilineage dysplasiaTrilineage dysplasia Blasts 1%Blasts 1%

Karyotype: 46, XX, der(21)t(1;21)Karyotype: 46, XX, der(21)t(1;21)(q11;p11)[6](q11;p11)[6]

46,XX[4]46,XX[4]

Diagnosis:Diagnosis: MDS MDS Refractory cytopenia with multilineage Refractory cytopenia with multilineage

dysplasiadysplasia Cytogenetic risk group- Standard ??Cytogenetic risk group- Standard ?? IPSS score 0.5 Intermediate 1IPSS score 0.5 Intermediate 1

What is your plan?What is your plan?

1)1) Watch and wait-no plan to Watch and wait-no plan to transplanttransplant

2)2) Proceed to transplant now?Proceed to transplant now?

3)3) Watch and wait-plan to transplant Watch and wait-plan to transplant at progression?at progression?

4)4) Something else?Something else?

Answer 1Answer 1What is your plan?What is your plan?

1)1) Watch and wait-no plan to Watch and wait-no plan to transplanttransplant

2)2) Proceed to transplant now?Proceed to transplant now?

3)3) Watch and wait-plan to transplant Watch and wait-plan to transplant at progression?at progression?

4)4) Something else?Something else?

Question 2Question 2 Would you… Would you…

Proceed to transplant as first line Proceed to transplant as first line therapy?therapy?

Give one or two cycles of Give one or two cycles of chemotherapy first?chemotherapy first?

Answer 2Answer 2 Would you… Would you…

Proceed to transplant as first line Proceed to transplant as first line therapy?therapy?

Give one or two cycles of remission Give one or two cycles of remission induction therapy prior to induction therapy prior to transplant?transplant?

Question 3Question 3She is exactly 40 yrs oldShe is exactly 40 yrs old

Would youWould you……

1)1) Perform a traditional myeloablative Perform a traditional myeloablative conditioned transplant?conditioned transplant?

2)2) Perform a Reduced Intensity Perform a Reduced Intensity conditioned transplant (RIC)?conditioned transplant (RIC)?

Answer 3Answer 3She is exactly 40 yrs oldShe is exactly 40 yrs old

Would youWould you……

1)1) Perform a traditional myeloablative Perform a traditional myeloablative conditioned transplant?conditioned transplant?

2)2) Perform a reduced intensity Perform a reduced intensity conditioned transplant (RIC)?conditioned transplant (RIC)?

Outcome?!Outcome?! RIC allograft 11/05/07RIC allograft 11/05/07

Alive and wellAlive and well

Ongoing morphologic and cytogenetic Ongoing morphologic and cytogenetic remissionremission

No GVHD and back at work full timeNo GVHD and back at work full time

Would it be otherwise given I present it to you!Would it be otherwise given I present it to you!

Thank you for listening!