Epidemiology of Myelodysplastic Syndromes and ... · Epidemiology of Myelodysplastic Syndromes and Myeloproliferative Neoplasms Xiaomei Ma, Ph.D. Associate Professor of Epidemiology

Epidemiology of Myelodysplastic Syndromes and Myeloproliferative Neoplasms

Xiaomei Ma, Ph.D.Associate Professor of EpidemiologyYale School of Public Health

Co-Leader, Cancer Prevention and ControlYale Comprehensive Cancer Center

Outline• Burden of Disease• Etiology:

– Focus: factors that influence an individual’s risk to develop a disease

– Implication: primary prevention• Health Outcomes:

– Focus: factors that affect identification of disease or prognosis after disease develops

– Implication: secondary & tertiary prevention

Burden of Disease

Characterization of MDS and MPN

• In 2000, in the International Classification of Diseases for Oncology, 3rd edition (ICDO-3), the behavior code of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) changed from “1 (uncertain/borderline)” to “3 (malignant)”. 1

• In 2001, MDS and MPN became reportable to cancer registries, such as the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

1. Fritz A, ed. World Health Organization. 2000.

Age-Standardized Incidence Rate of MDS By Sex and Year of Diagnosis: SEER, 2001-2012

4.7/100,0006.3/100,0003.6/100,000

Total # of patients: ~44,500

MDS Incidence Rate By Age: SEER, 2001-2012

Median age at diagnosis: 76 years

# of New MDS Cases in the US Annually• Estimates vary substantially

– 1,500: a book published in 1995 1– ~ 10,000: two cancer registry-based studies

published in 2007 and 2008 2,3

– > 40,000: a 2010 study based on Medicare claims 4

• Registries such as SEER are usually considered an authoritative source for cancer incidence, but MDS is a challenging disease.

1. Schumacher N. MDS: Approach to diagnosis and treatment. 1995.2. Ma X et al. Cancer. 2007;109:1536-42.3. Rollison DE et al. Blood. 2008;112:45-52. 4. Goldberg SL et al. JCO. 2010;28:2847-52.

Probable Under-reporting by Cancer Registries

• Registries typically rely on inpatient surveillance for cancer incidence, but MDS is commonly diagnosed and managed outside the hospital setting.1

• During 2001-2009, SEER guidelines only required capture of the first myeloid malignancy.

• The extent to which MDS is under-reported is unclear.

1. Cogle CR et al. Blood. 2011;117:7121-5.

Studies Addressing Under-reporting

• A study using claims-based algorithms reported an annual incidence of 75 per 100,000 in persons ≥65 years, more than 3 times the SEER estimate. 1

• By reviewing electronic pathology reports, another study found that only two-thirds of true MDS cases were captured by the Florida Cancer Registry using current case-finding mechanisms. 2

1. Cogle CR et al. Blood. 2011;117:7121-5.2. Cogle CR et al. Leuk Res. 2014;38:71-5.

Prevalence of MDS• Estimated prevalence of 20.7/100,000 in Germany

– Translates to 60,000 people in the US? – Likely an underestimate due to failure to diagnose 1

• 945,000 individuals aged ≥ 65 years in the US had unexplained anemia as of 1990-1994, and MDS may be a more precise diagnosis for many of them. 2

1. Sekeres MA. Hematol Oncol Clin N Am. 2010;24:287-94. 2. Guralnik JM et al. Blood. 2004;104: 2263-8.

Observed Survival by Sex: SEER, 2001-2012

Median survival:25 months

Agents Approved for the Treatment of MDS by the US Food and Drug Administration

• Azacitidine: May 2004• Lenalidomide: December 2005• Decitabine: May 2006

SEER: Survival of MDS Patients by Year of Diagnosis

00.10.20.30.40.50.60.70.80.9

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0 0.5 1 1.5 2 2.5 3 3.5 4

Surv

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Years since MDS diagnosis

2001-20032007-2010

Log-rank p=0.08

SEER: Survival of Refractory Anemia with Excess Blasts (RAEB) Patients by Year of Diagnosis

0

0.1

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0.7

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0 0.5 1 1.5 2 2.5 3 3.5 4

Surv

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Years since MDS diagnosis

2001-20032007-2010

Log-rank p=0.01

Age-Standardized Incidence Rate of MPNBy Sex and Year of Diagnosis: SEER, 2001-2013

MPN

PV

MF

ET

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MPNPVMFET

Under-reporting of MPN by Cancer Registries(likely more severe than that of MDS)

• Substantial discrepancy in incidence rate of PV during 2001-2003 based on SEER records and Medicare claims 1– SEER-reported incidence rate: 3.5 – 4.1 per 100,000– Estimates from Medicare claims: 13.1 – 14.4 per 100,000

1. Selinger HA, Ma X. Am J Hematology. 2009;84:124-6.

Prevalence of MPN in the United States

• By using health claims data from insurance payers and conducting a validation study with patient chart review, we estimated the # of MPN patients residing in the US as of 2003: 1– PV: 65,243– ET: 71,078

• Unable to estimate prevalence of myelofibrosis due to small sample size

1. Ma X et al. Am J Hematology. 2008;83: 359-62.

Etiology of MDS and MPN

Risk Factors for MDS

• Chemotherapy and/or radiotherapy for previous cancer

• Exposure to benzene

• Tobacco smoking

• Other possible risk factors: obesity, infection

1. Strom SS et al. Leukemia. 2005;19:1912-8. 2. Strom SS et al. Semin Hematol. 2008;45:8-13.

History of Radiotherapy and MDS

• The literature is fairly consistent that radiotherapy for a previous cancer is a risk factor for MDS.

• A retrospective cohort study of 10,924 prostate cancer patients diagnosed during 1986-2011 at Cleveland Clinic found that patients who received radiotherapy and those who underwent surgery had a similar incidence of subsequent MDS, with a median follow up of 3 years.1

1. Mukherjee S et al. JNCI. 2014; 106: djt462.

Influence of Lifestyle Factors on MDS Risk 1# of

CasesPerson-yrsof follow-up

Hazard Ratio (95% CI)

p for trend

Cigarette Smoking < 0.001Never 42 1,215,608 1.0Quit, 1 pack/day 56 954,835 1.55 (1.04-2.32)Quit, >1 pack/day 53 724,524 1.87 (1.23-2.83)Current, 1 pack/day 18 252,160 2.42 (1.39-4.21)Current, >1 pack/day 18 135,193 4.70 (2.68-8.24)

Body Mass Index (kg/m2) < 0.00118.5 BMI < 25 51 1,191,019 1.025 BMI < 30 78 1,476,192 1.15 (0.81-1.64)BMI 30 64 740,187 2.18 (1.51-3.17)

1. Ma X et al. Am J Epidemiol 2009;169:1492-9..Data from the NIH-AARP Diet and Health Study, 1995 - 2003.Cohort of 600,000 50-71 year olds.

Incident MDS cases and the infection hypothesis

Location of incident MDS cases in Connecticut, 2001 - 2003

Most likely area* with high incidence ofMDS in Connecticut, 2001 - 2003

* The area included 46 census tracts and more than 214,000 individuals. Over the three-year period, there were 41 MDS cases, while the expected number was 14. O/E ratio = 2.8, p = 0.0001.

1. Ma X et al. Leuk Res. 2007;31:1683-6..

Spatial-Temporal Clustering in the Incidence of MDS in Connecticut 1

A Possible Etiologic Role for Obesity and Other Factors

• Association between obesity and MDS persisted in males and females, smokers and non-smokers, and individuals with different levels of physical activity. 1

• Spatial and space-time clustering of MDS may be consistent with hypotheses regarding infection and/or environmental chemicals. 2

• We are currently assessing exposure to traffic as a possible risk factor for MDS (R01 CA169043, PI: Ma & Guan).1. Ma X et al. Am J Epidemiol . 2009;169:1492-9. 2. Ma X et al. Leuk Res. 2007;31:1683-6..

Risk Factors for MPN

• Family history

• Exposure to benzene

• Other possible risk factors: tobacco smoking, history of autoimmune disease

• Very few existing studies

Some Recent Observations

• In the prospective Iowa Women’s Health Study cohort (n=27,370), 172 ET patients and 64 PV patients were identified.

• Risk factor profiles were mostly distinct for ET and PV. 1– ET: energy balance factors, e.g., obesity, physical activity, adult

onset diabetes; aspirin use – PV: current smoking

1. Leal AD et al. Int J Cancer. 2014;134:1741-50. .

Health Outcomes Research

Factors Influencing MDS Survival

• Older age, male gender, high blast %, # of cytopenias, transfusion dependence, and certain cytogenetic characteristics have been linked to poor survival.

• Additional patient characteristics indicated– Comorbid conditions – Socioeconomic status

Comorbid Conditions %Diabetes 21.1Congestive heart failure 20.7Chronic obstructive pulmonary disease 18.6Cerebrovascular disease 8.2Peripheral vascular disease (diagnosis) 7.0Diabetes w/ sequelae 5.6Chronic renal failure 5.6Old myocardial infarction 4.4Rheumatoid diseases 3.5Myocardial infarction 3.0Acute ulcers 2.6

Prevalence of Comorbidities in MDS Patients 1

1. Wang R,…, Ma X. Leuk Res. 2009;33:1594-8.

Data from SEER-Medicare database: incident MDS cases reported to SEER, ≥66 years

Hazard Ratio (95% CI) p for trend

Median Household Income1st quartile 1.02nd quartile 1.03 (0.89-1.18)3rd quartile 0.87 (0.75-1.01)4th quartile 0.82 (0.70-0.95) < 0.001

Charlson Comorbidity Index 0 1.01-2 1.16 (1.04-1.30) 3 1.73 (1.51-1.99) < 0.001

Adjusted Hazard Ratios of Death 1

1. Wang R, …, Ma X. Leuk Res. 2009;33:1594-8.

Comorbidity and Survival in MDS

Comorbid Conditions HR* 95% CICongestive heart failure 1.35 1.16-1.57Cerebrovascular disease 1.02 0.82-1.27Chronic obstructive pulmonary disease 1.36 1.16-1.58Diabetes 1.09 0.93-1.28*Adjusted for age, sex, median household income, MDS subtype and other comorbidities.

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0 12 24 36 48Time (months)

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Charlson index: 0

Charlson index: 1-2

Charlson index: >2

Wang R, et al. Leuk Res 2009;33:1594-1598.

1. Wang R,…, Ma X. Leuk Res. 2009;33:1594-8.

Additional Studies of Comorbidities in MDS

• Hematopoietic stem-cell transplant-specific comorbidity index vs. Charlson comorbidity index in Austrian patients (n = 419) 1

• Development and validation of MDS-specific comorbidity index in German patients ( n = 1,344) 2

• Application of MDS-specific comorbidity index to identify patients who have a greater chance of benefiting from azacitidine in Italy (n = 60) 31. Sperr WR et al. Ann Oncol. 2010;21:114-9.

2. Della Porta MG et al. Haematologica. 2011;96:441–9.3. Breccia M et al. Haematologica. 2012;97:e2.

Cost of Care for Elderly MDS Patients

• Among 6,556 MDS patients ≥ 66.5 years, the expected MDS-related 5-year cost was $63,223 (95% CI: $59,868–66,432 in 2009 dollars), higher than any of the 18 most prevalent cancers in the US. 1

• Medicare expenditure for elderly MDS patients varied considerably across SEER registries but was not associated with 2-year survival. 2

1. Wang R,…, Ma X. Leuk Res. 2012;36:1370-5.2. Zeidan A,…, Ma X. Cancer. 2016;122:1598-607.

Health Outcomes of MPN Patients

• 3-year relative survival of MPN as a group: 80% 1

• Median survival in an Italian patient cohort was 20 years for PV and 22.6 years for ET. 2

• In a SEER-Medicare population, MPN patients had significantly worse median survival than matched non-cancer “controls”. 3

– PV: 65 vs. 104 months– ET: 68 vs. 101 months– MF: 24 vs. 106 months1. Rollison DE et al. Blood. 2008;112:45-52. 2. Passamonti F et al. Am J Med. 2004; 117: 755-761.3. Price GL et al. PLoS One. 2014;9:e90299.

Impact of MPN on Health and Productivity• Of 813 MPN patients under active management in the US

(PV: 380, ET: 226, MF: 207), many had experienced MPN-related symptoms ≥ 1 year before diagnosis (PV: 61%, ET: 58%, MF: 49%). 1

• Many respondents, even those with low prognostic risk scores, reported reduced quality of life, reductions in activities of daily living, and lower work productivity.

1. Mesa R et al. BMC Cancer. 2016; 16: 167.

Summary• MDS and MPN are understudied, and the

disease burden will continue to increase.

• The etiology of both is not well understood.

• While newer treatments are available for MDS and MPN, the impact of these regimens remains to be evaluated.

Acknowledgement• Funding from the National Cancer Institute

– N01-PC-55020-20– K07 CA119108– R21 CA131927– P30 CA016359

• Collaborators– Yale University: Rong Wang, Cary Gross, Stephanie

Halene, Amy Davidoff, Steven Gore, Amer Zeidan– Columbia University: Azra Raza