7/24/2012 1 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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7/24/2012
1
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
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)
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