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Treating Higher Risk

Myelodysplastic Syndromes

Stuart Goldberg MD Chief, Division of Leukemia

John Theurer Cancer Center

Hackensack NJ USA

What makes up

Blood ?

Blood is composed of 3 cellular elements and plasma:

1. Red cells carry oxygen & give energy

2. White cells fight infections

3. Platelets stop bleeding

All of these cells are made inside the bones in the Bone Marrow

What are the

Myelodysplastic Syndromes ?

A group of bone marrow failure diseases

In MDS the bone marrow “factories” become damaged and stop producing blood (red, white, platelets)

May degenerate into leukemia in 20%

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How common is MDS?

Overall incidence: 3.4 per 100,000 (roughly 10,000 people)

Age at Diagnosis (Yrs) *P for trend < .05

Rollison DE, et al. Blood. 2008;112:45-52.

0

10

20

30

40

50

< 40 40-49 50-59 60-69 70-79 ≥ 80

0.1 0.7 2.0

7.5

20.9

36.4*

Females Males Overall

Maybe MDS is even more common: 2003 US Medicare Population Study

Goldberg SL, et al. J Clin Oncol. 2010;28:2847-52.

Median age at diagnosis, yr 77

Prevalence, patients/year 76,600

Incidence by age ( ≥65; 65-69; 70-74; 75-79, >80 per

100,000)

92; 138; 199;

261

Incidence by gender, male; female, per 100,000 201; 166

Incidence by subgroup, Caucasian; African-American;

Hispanic, per 100,0000

186; 143; 147

Prior unexplained anemia

N=530 (17%)

Prior chemo- or radiotherapy

N=172 (6%)

De novo N=503 (77%)

Medicare beneficiaries in 2003 SAF 5%

N=1,713,502

Overall MDS population* SAF 5%

N=5594

• Incidence of MDS higher than previously recognized

(46,000 in 2003 ≥65 yr)

• Roughly the incidence of Lymphoma or ¼ Breast cancer

• MDS has substantial economic implications

(>$28,000/yr), before applying “low-intensity

treatments”. Much higher in transfused pts.

4 or more times cost of average elderly patient

• Organ impairment following a diagnosis of MDS is

common, with cardiac complications occurring more

frequently than in the general Medicare population

(73.2% vs 54.5%, respectively)

Conclusions From Medicare Data

Goldberg SL, et al. J Clin Oncol. 2010;28:2847-52.

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Who Gets MDS ?

• Hospital-based case control study at M. D. Anderson

(354 de novo MDS cases, 452 controls) identified the following

risk factors:

– Family history of hematopoietic cancer (OR: 1.92)

– Smoking (OR: 1.65)

– Exposure to agricultural chemicals (OR: 4.55)

– Exposure to solvents (OR: 2.05)

– Chemical exposure (solvents/agricultural chemicals) plus

history of smoking compounded MDS risk (OR: 3.22)

– Wine consumption reduced risk by almost 50% (OR: 0.54)

– Secondary MDS is when a known toxin is identified

(such as prior chemotherapy for another cancer)

Strom SS, et al. Leukemia. 2005;19:1912-1918.

What is High Risk MDS ?

• MDS is a group of bone marrow failure diseases

• Can be divided into low and high risk disease

• In low risk disease the main problem is mild/moderate lowering of blood counts leading to quality of life issues

• In high risk disease the counts may be very low or leukemia cells may be developing leading to quality and quantity of life issues

Low risk vs High risk Classification

Several methods to separate diseases:

1) Microscope review of bone marrow

– FAB naming system (French American British)

– WHO naming system (World Health Organization)

2) Scoring systems

– International Prognostic Scoring System (IPSS)

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© 2009 OptumHealth Education

Low

Risk

High

Risk

IPSS Is the Most Common Tool

for Risk Stratification

*Good = normal, -Y, del(5q), del(20q); intermediate = other karyotypic abnormalities;

poor = complex ( 3 abnormalities) or chromosome 7 abnormalities. †Hb < 10 g/dL; ANC < 1800/L; platelets < 100,000/L.

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

Score Value

Prognostic variable 0 0.5 1.0 1.5 2.0

Bone marrow blasts < 5% 5% to 10% -- 11% to 20% 21% to 30%

Karyotype* Good Intermediate Poor -- --

Cytopenias† 0/1 2/3 -- -- --

Total Score

0 0.5 1.0 1.5 2.0 2.5

Risk Low Intermediate I Intermediate II High

Figure Out Your Score (IPSS)

• Higher risk if you have multiple broken bone marrow factories leading to low blood counts

• Higher risk if there are more leukemia cells in your bone marrow

• Higher risk if you have unfavorable chromosomes (genes) in the marrow

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WHO Classification-Based

Prognostic Scoring System (WPSS)

*Good = normal, -Y, del(5q), del(20q); Intermediate = other karyotypic abnormalities;

Poor = complex (3 abnormalities) or chromosome 7 abnormalities. †RBC transfusion dependence was defined as having at least 1 RBC transfusion every 8

weeks over a period of 4 months. ‡Based on validation cohort. Malcovati L, et al. J Clin Oncol. 2007;25:3503-3510.

Score Value

Prognostic variable 0 1 2 3

WHO category RA, RARS,

del(5q)

RCMD,

RCMD-RS RAEB-1 RAEB-2

Karyotype* Good Intermediate Poor –

Transfusion requirement† No Regular – –

WPSS Risk Category‡

Very Low Low Intermediate High Very High

Median OS, mo 141 66 48 26 9

AML progression,

cumulative probability

2 years 0.03 0.06 0.21 0.38 0.80

5 years 0.03 0.14 0.33 0.54 0.84

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Common Treatment of MDS

• Low risk disease: focus on quality

– Transfusions

– Iron issues

– Growth factors

– Immunomodulatory agents (lenalidomide)

– Immune suppressants (ATG, alemtuzumab)

• High risk disease: focuses on quality & quantity

– Hypomethylating agents (5-azacytadine and decitabine)

– Conventional chemotherapy

– Bone marrow transplantation

Hypomethylating Agent Therapy

of Higher Risk MDS

• Most common treatment of higher risk MDS

• Attempts to reverse the gene damage inside the MDS cells and get the factories to produce blood again

• Also attempts to suppress the leukemia cells

• Studies have demonstrated that these medications improve quality of life compared to supportive care alone (better than just transfusions)

Hypomethylating Agent Therapy

of Higher Risk MDS

• Current NCCN guidelines recommend that these medications be offered to patients with higher risk MDS as they have been shown to improve quality and quantity of life

• More controversial when/how to use in “lower” risk MDS – In patients requiring frequent red cell transfusions

– In patients with low platelets or low white blood cells

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Hypomethylating Agent Therapy

of Higher Risk MDS

• Two approved agents in the USA

– 5-azacytadine (Vidaza)

– decitabine (Dacogen)

– Both are generally well tolerated in older individuals and both can be effective

– No age barrier to their use

– Both are covered by Medicare

5-azacytadine (Vidaza)

• A chemotherapy drug that acts by removing methyl groups from the DNA and RNA allowing silenced genes to be expressed ---- translation: restores the genes in the broken marrow factors so that they can start producing blood again

• Given one week per month indefinitely

• May be given IV or Subcutaneously

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Azacytadine vs Supportive Care

(CALBG 9221)

• Approximately 60% of patients improved their blood counts

• The time to develop leukemia was improved

• Suggestion that life-span was improved

• Quality of life surveys showed that patients receiving AZA felt better than those not

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Cum

ula

tive P

robabili

ty

Number of Subjects (N = 179)

91 34 12 6 3 1 1 1

Time (cycles)

50%, 3 cycles

81%, 6 cycles

Range: 1-22 cycles

How Long until the AZA Works? Time to First Response

90%, 9 cycles

Silverman LR, et al. ASH 2008. Abstract 227..

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Cum

ula

tive P

robabili

ty

Number of Subjects (N=179)

91 64 31 16 7 2 1 1

Time (cycles)

50%, 3 cycles

AZA-001: Time to Best Response

90%, 9 cycles 2.3 months

(95% CI: 0.3 – 3.0)

(n=21) (n=30)

3.2 months

(95% CI: 2.4 – 6.9)

43% improved response

quality after first response

Silverman LR, et al. ASH 2008. Abstract 227..

What Schedule for 5-azacytadine?

• Registration studies have used 7 day subcutaneous injections each month

• Pharmacology studies demonstrated that IV infusions can be effective

• Randomized trial in “lower risk” patients demonstrated 5 day/month similar to 7 day/month (5-2-2) but unknown benefit in “higher risk” patients

• Lyons J Clin Oncol. 2009 Apr 10;27(11):1850-6.

Decitabine (Dacogen)

• A chemotherapy drug that acts by removing methyl groups from the DNA allowing silenced genes to be expressed ---- translation: restores the genes in the broken marrow factors so that they can start producing blood again

• Given 5-days per month indefinitely

• Given IV

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Decitabine

• Open-label, multicenter, 1:1 randomized study

• IPSS: int-1, int-2, and high-risk MDS patients eligible

• Primary endpoints: response, time to AML/death

– IWG response criteria utilized for assessment

Decitabine + Supportive Care 15 mg/m2/ over 3 hrs q8h x

3 days q6w (n = 89)

Supportive Care ABX, GFs, and/or transfusions

(n = 81)

Stratification IPSS

Type of MDS (primary or

secondary)

Eligible

patients (N = 170)

R

A N

D O

M I

Z E

D

Kantarjian H, et al. Cancer. 2006;106:1794-1803.

Decitabine Phase III Trial:

Response to Decitabine (ITT)

*For patients with a confirmed date of progression.

†Best response observed after 2 cycles (median number of cycles = 3)

Kantarjian H, et al. Cancer. 2006;106:1794-1803.

IWG Response Rate,

Onset, and Duration,* n (%)

Decitabine

(n = 89)

Supportive Care

(n = 81)

Overall response rate (CR + PR) 15 (17)† 0 (0)

CR 8 (9) 0 (0)

PR 7 (8) 0 (0)

Hematologic improvement 12 (13) 6 (7)

†P value < .001 from 2-sided Fisher’s exact test

Onset and duration of response, mos

Median time to response (CR + PR)

Median duration of response (CR + PR)

3.3 (2.0-9.7)

10.3 (4.1-13.9)‡ N/A

ADOPT Decitabine Trial:

Study Design

• Patients (N = 99) with de novo or secondary MDS

of any FAB subtype and IPSS score ≥ 0.5

• Decitabine 20 mg/m2 IV daily for 5 days

• Primary endpoint: ORR by IWG 2006 criteria

• Secondary endpoints: cytogenetic response,

hematologic improvement, response duration,

survival, safety

Steensma DP, et al. J Clin Oncol. 2009;27:3842-3848.

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ADOPT Decitabine Trial:

Responses

Response (IWG 2006 Criteria), n (%) Patients (N = 99)

Overall complete response rate (CR + mCR) 32 (32)

Overall response rate (CR + mCR + PR) 32 (32)

Overall improvement rate (CR + mCR + PR +HI) 50 (51)

Rate of SD or better (CR +mCR + PR + HI +SD) 74 (75)

CR 17 (17)

mCR 15 (15)

PR 0 (0)

HI 18 (18)

SD 24 (24)

PD 10 (10)

Not assessable 15 (15)

Steensma DP, et al. J Clin Oncol. 2009;27:3842-3848.

Time to First Response with

Decitabine

Steensma DP, et al. J Clin Oncol. 2009;27:3842-3848.

0

20

10

30

50

Cycle

2 3

40

Pati

en

ts W

ith

CR

/mC

R/H

I (%

)

1 4 ≥ 5

Time to first response

Time to best response

Decitabine: Adverse Events Reported in

≥ 10% of Patients

Event, %

Patients

Grade 1-2 Grade ≥ 3

Hematologic

Neutropenia 1 31

Thrombocytopenia 2 18

Febrile neutropenia 3 14

Anemia 5 12

Nonhematologic

Fatigue 26 5

Nausea 26 1

Pyrexia 17 0

Diarrhea 12 0

Anorexia 12 0

Constipation 11 0

Pneumonia 1 11

Vomiting 10 1

Chills 10 0

Steensma DP, et al. J Clin Oncol. 2009;27:3842-3848.

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(months)

0 6 12 18 24 30 36 42

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk :

96 114 71 38 22 10 6 3

99 119 83 53 24 15 4 4

Median (months): 10.1 vs 8.5

HR = 0.88 , 95% CI (0.66, 1.17)

Logrank test: p=0.38

Decitabine

Supportive care

Overall Survival: EORTC-06011

Wijermans P, et al. ASH 2008. Abstract 226.

Potential Problems with the

Decitabine EORTC Study

• Did not demonstrate the survival benefit seen in the AZA-001 trial

• Used an outdated administration schedule (3 doses/day for 3 days compared to the 5 day schedule)

• Stopped administering decitabine after remission achieved, as compared to continuing therapy until disease progression

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Conclusions of Hypomethylating

Agent Therapy in Higher Risk MDS • Both 5-azacytadine and decitabine are generally well

tolerated in patients with MDS

• Both are outpatient treatments given one week per month

• Both raise blood counts in about half treated patients in 3-6 months

• Both suppress leukemia cells

• Both improve quality of life

• 5-azacytadine has been demonstrated to improve quantity of life in high risk disease

Stem Cell Transplantation

for MDS

• A curative approach for MDS

• However contains significant risks

• May not be applicable for older, frail patients

• Costs are covered by Medicare if performed as part of the demonstration project

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Bone Marrow Transplant

involves obtaining Marrow stem cells from

the hip of the donor in the operating room

Blood Stem Cell Transplant

involves obtaining stem cells from the donor

in the clinic (similar to donating platelets)

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“Mini” or “Reduced Intensity”

Allogeneic Transplantation

• Given age of population, full dose (“ablative”) strategies can be quite toxic

• Fully ablative strategies complicated by early mortality

• Lower dose conditioning regimens better tolerated

• Procedure is essentially the same; still requires one month hospitalization and 3-6 months intense follow up

• Less early toxicity but more late relapses

When to Transplant? Best Time with Ablative Transplant is Int-2

Cutler C, et al. Blood. 2004;104:579

Study precedes use of hypomethylating agents

Study precedes use of reduced intensity conditioning

Years

0 2 6 1 3 4 5

Probability of Survival after Allogeneic Transplants for MDS

2000-2009 - by Disease Status and Donor Type -

0

20

40

60

80

100

10

30

50

70

90

0

20

40

60

80

100

10

30

50

70

90

Pro

bability o

f Surv

ival, %

P < 0.0001

SUM-WW11_24.ppt

Early, sibling donor (N=667)

Early, unrelated donor (N=752)

Advanced, sibling donor (N=1,188)

Advanced, unrelated donor (N=1,400)

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Outcomes of Mini Transplants in MDS Age >50

Roughly 1/3 cured, 1/3 early treatment deaths, and 1/3 relapse

Lim Z et al. JCO 2010;28:405-411

Minimal Age Effect on RIC Transplant

Outcomes in AML and MDS

Kaplan-Meier estimates for disease-free survival (DFS) in (A) patients with acute myelogenous leukemia (AML) in

first complete remission (CR1) and (B) patients with myelodysplastic syndrome (MDS). Kaplan-Meier estimates for overall survival (OS) in (C) patients with AML in CR1 and (D) patients with MDS. McClune JCO 2010

Conclusions

• MDS is a group of bone marrow failure diseases

• Prognostic scoring systems exist

• Low risk patients focus on quality issues

• High risk patients have effective therapies to improve quality and quantity

• Best wishes to all of the MDS patients and their caregivers