CLL / MBL Epidemiology - University of Manitoba · ©2014 MFMER | slide-1 CLL / MBL Epidemiology...

©2014 MFMER | slide-1

CLL / MBL EpidemiologyTim [email protected]

Canadian CLL ConferenceSeptember 18, 2014


Background


2008 CLL/MBL Diagnostic Criteria• Absolute B lymphs >5000 =CLL

• Absolute B lymphs <5000• Cytopenias with marrow infiltration=CLL• No cytopenias, nodes or

hepatosplenomegaly by exam/CT=MBL• No cytopenias, but either nodes or

hepatosplenomegaly by exam/CT=SLL

Hallek, Blood, 15 June 2008, Vol. 111, No. 12, pp. 5446-5456


Evolution of CLL/SLL Classification

Diagnostic IndicatorsNational Cancer

Institute-Working Group 1996 Guidelines1

CLL immunophenotype necessary (Clonality confirmed by flow cytometry) X

Absolute Lymphocyte Count (ALC) ≥5 x 109/L X

B Lymphocyte Count ≥ 5 x 109/L

1Cheson, Blood; 87: 4990-4997 (1996)2Hallek, Blood; 111: 5446-5456 (2008)

2008 International Workshop on

Chronic Lymphocytic Leukemia2

X

X


Effect of IWCLL 2008 Classification on CLL/MBL Distribution

CLLMBL

NCI-WG 1996

IWCLL-2008


Two Categories of MBL

Rawstron Clin Cytometry 78B:S19-23

Median 0.001x109/L clonal B-cell Median 2.9x109/L clonal B-cells


What type of MBL are we talking about??

©2013 MFMER |

slide-7MBL, Rawstron, NEJM 359:6, Aug 7, 2008, 575-583; Vardi, et.al, Blood Vol 121, #5, 4521-4528

What MBL phenotype?

1. CLL like (Rawstron 5.1%, ages 62-80)2. Non-CLL like (Rawstron 1.8%, ages 62-80)

Extent of detected lymphocytosis?

1. Low-count (LC-MBL)a. 0.5 x 109/L or less clonal B-cellsb. rate of conversion to CLL unknown (low)

2. High-count (HC-MBL)a. >0.5 x 109/L clonal B-cellsb. Rate of conversion to CLL requiring Rx is 1.1% per year


Leukemia & Lymphoma Society, Facts Spring 2014, www.LLS.org


Prior Incidence Studies of CLL/SLL

Incidencerate by 100,000 people

OlmstedCounty

Minnesota 1975-19891

Netherlands Cancer

Registry 1989-20083

SEER 2005-2009

(Caucasian)4

Overall5.8 3.8 4.2

Males 7.7 5.1 5.8 (6.1)

Females 4.4 2.3 - 2.5 3.0 (3.2)

1Call, Mayo Clinic Proceedings; 69:315-322 (1994)2Wu, Blood; 116:4430-4435 (2010)3van den Broek, European Journal of Cancer; 48:889-895 (2012)4Howlader, SEER Cancer Statistics Review; National Cancer Institute (2012)

Taiwan National Cancer Registry

1986-20052

-

0.47

0.24


CLL Olmsted County 1975-1989

• Increased ascertainment due to automated hematology

• More utilization of medical services by elderly

• Shifting patterns @ Dx• Lowering Rai Stage• Lowering ALC• Longer time to first Rx

• 1985-1989 @ 6.2 per 100,000, age and sex adjusted

Call, Mayo Clinic Proceedings 1994: 69:315-328


Olmsted County, Minnesota Update 2014


Olmsted County, Minnesota

DemographicsPopulation: 144,248i

Race: 86% CaucasianLargest city: Rochester

Mayo Clinic / Mayo Medical Laboratories • Provides the sole hematology practice and

hematopathology testing within the county

i. 2010 U.S. Census Bureau


Rochester Epidemiology Project

• Research infrastructure• Links together medical records of Olmsted County, MN residents

from multiple sources of health care• Facilitates access to medical records from multiple institutions• Archives historical medical records

• 1.8 million patient records

• 50+ health care sources from 1935-present

• 926,069 unique people

Rocca, Mayo Clinic Proceedings; 87:1202-1213 (2012)

St Sauver, American Journal of Epidemiology; 173:1059-1068 (2011)


Aims• Determine the incidence of CLL/SLL and clinically

identified MBL in Olmsted County 2000-2010

• Compare the effects of reclassification on the incidence of clinically identified MBL and CLL/SLL within Olmsted County

• Compare demographic, staging & prognostic factors in this population between both classifications

• Identify Olmsted County residents with CLL/SLL and clinically identified MBL using the Rochester Epidemiology Project and Mayo Clinic records

• Verify all cases

Methods


Definitions used in study

• CLL=CLL/SLL• MBL=High count MBL,

• i.e. “clinically identified”


CLL Descriptive Factors 2000-2010

1996 Criteria 2008 Criteria

Number 115 79

Male 66 (57%) 49 (62%)

Female 49 (43%) 30 (34%)

Median age (range) 71.7 (46.9 – 92.9) 73.7 (47.4 - 92.9)

Median ALC (range) 7.6 (1.0 - 98.1) 8.1 (1.0 - 98.1)

Median B-cell count (range) 4.6 (0.1 – 93.5) 7.1 (0.1 - 93.5)

Call,Cancer. 2014 Jul 1;120(13):2000-5


Clinical MBL Descriptive Factors 2000-2010


Number 8 40

Male 5 (62.5) 20 (50)

Female 3 (37.5) 20 (50)

Median age (range) 74.6 (47.7 – 88.9) 71.5 (47.7 – 88.9)

Median ALC (range) 3.3 (2.1 – 4.2) 5.9 (2.1 – 15.6)

Median B-cell count (range) 1.4 (0.6 – 2.1) 2.8 (0.6 – 4.9)

Call,Cancer. 2014 Jul 1;120(13):2000-5


Incidence 2000-2010

Incidence per 100,000 1996 Criteria 2008 Criteria

Age adjusted 0.65 3.5

Age and sexadjusted

0.66 3.5

Age adjusted - Male 0.95 3.9

Age adjusted - Female 0.45 3.3

Adjusted to 2010 US white population


9.9 6.7

10.0 6.8

13.2 9.8

7.6 4.5

Clinically Identified MBL CLL

Call,Cancer. 2014 Jul 1;120(13):2000-5


CLL/SLL Incidence (All Rai Stages)

No trend seen towards an increase in CLL/SLL

Call,Cancer. 2014 Jul 1;120(13):2000-5


CLL/SLL Incidence (Rai Stage 0)

No trend seen towards an increase in CLL/SLL

Call,Cancer. 2014 Jul 1;120(13):2000-5


1996 Criteria (N) 2008 Criteria (N)

CD38+ 25.2% (29) 26.6%

Rai Staging• Rai 0 60.9% (70) 43.0% (34)

• Rai 1-2 33.9% (39) 49.4% (39)

• Rai 3-4 5.2% (6) 7.6% (6)

Totals N=115 N=79

CLL Prognostic Factors 2000-2010

Note: Prognostic indicators not available for MBL due to the low number of clinically identified MBL cases that met the 1996 criteria

Call,Cancer. 2014 Jul 1;120(13):2000-5


MBL Incidence

No trend seen towards an increase in MBL


Time to First Treatment (TTT)for CLL/SLL (All Stages)

Median TTT1996= 9.2 years2008= 6.5 years

Call,Cancer. 2014 Jul 1;120(13):2000-5


Time to First Treatment Comparison for CLL/SLL (Rai Stage 0)


How does the data compare?


Incidence Comparisons• SEER 2010 5.04 per 100,000• UK 2011 3.7 per 100,000• Czech (Lower Moravian Region), 2007 6.2 per

100,000• Manitoba 2009

SEER; Cancer Research UK cancerstats; Seftel, Leukemia Research 33 (2009) 1463–1468; Panovska, ClinicaLymphoma, Myeloma and Leukemia August 2010 297-300


Italian Study, Molica

• 2006-2010• 414 Binet A patients registered prospectively at

a national database• Reclassified Rai 0 vs. MBL

• Resulted in a 31% decrease in Rai 0 patients

• Shifted CLL patients to a higher Rai stage distribution

• 3 year time to first treatment• 77.2% to 69.9%

Molica, Expert Review of Hematology, ePub October 2014, Vol. 7, No. 5 , Pages 691-695 (doi:10.1586/17474086.2014.954542)


What about CLL Prevalence?


CLL prevalence data--sparse

• CDC• 2001 the CLL prevalence in the US was

58,574 cases • US population 285 million

• ??? ~20.5 per 100,000

• Czech (South Moravian Region) 2010• Population 1,127,718

• Incidence: 6.2 per 100,000 inhabitants

• Prevalence: 48 per 100/000

NIOSH Public meeting Report Jul7 21, 2004; Panovska, ClinicaLymphoma, Myeloma and Leukemia August 2010 297-300


SEER Cancer Statistics Review 1975-2011


Stage and Clinical Outcome

Rai Stage

Characteristic Median Survival

0 Lymphocytosis only 150I Lymphadenopathy 101II Organomegaly 71III Anemia (Hg<11) 19IV Thrombocytopenia (<100) 19

2009* N=2397

168

120

120

60

76

*Mayo Clinic CLL Database 2009

Rai Blood 46:219 (1975)


Estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy

CancerVolume 118, Issue 12, pages 3123-3127, 31 JAN 2012 DOI: 10.1002/cncr.26679http://onlinelibrary.wiley.com/doi/10.1002/cncr.26679/full#fig1


Therapeutic advances

• Chemoimmunotherapy• Higher CR rate• MRD achieveable in a

higher %• Longer Progression

free survival.• ASH 2012 #3959

Keating, • 222 pts. (median

age=57)• @ 10 years• 35% alive/disease free

• Targeted Therapy• Ibrutinib

• Idelalisib, ABT-199, etc.


One can only postulate that prevalence will rise significantly

• This data could• Have impact on health policy• Incentivize drug development• Alter practice patterns• etc.


How does this effect practice?


MBL• Develop practice guidelines/models• Recognize risks of

• Disease progression• Increased infection risks• Secondary cancer risks

• Establish an ICD code• Currently it can coded as:

• CLL• Lymphocytosis• Atypical lymphocytosis• Lymphoproliferative disorder


CLL

•It’s not as “good” a leukemia as it used to be.


Projected increase in CLL prevalence

• Increasing numbers of CLL patients in practices• Many requiring long term monitoring

• There is no indication at this time that targeted Rx will alter the rate of certain complications such as:

• Autoimmune cytopenias• Richter’s transformation• Infection risk• Hypogammaglobulinemia• 2nd malignancy

• Recognizing and treating the unique complications of targeted Rx.

• Costs… more to come….


“Studies such as these are not glamorous in the current medical climate, but are of considerable interest to investigators who are attempting to establish relationships between disease and etiologic factors and are seeking ways to improve the public health.

The medical profession can only hope that the process of monitoring the incidence of various diseases in studies such as these will continue and be expanded. In trying to conquer leukemia, we must seek clues from every avenue and provide accurate data ….for comparison with those being gathered elsewhere.”

Leukemia, Whither Goest thou?Michael J KeatingMayo Clinic Proceedings 1994, 69:4 397-398

Acknowledgements

• Susan Slager, Ph.D

• Kari Rabe, M.S.

• Jim Cerhan, M.D., Ph.D.

• Susan Schwager

• Asher Chanan-Khan MD

• Curt Hanson, M.D.

• Joe Leis, M.D., Ph.D.

• Tait Shanafelt, M.D.• Neil Kay, M.D. • Wei Ding, MBBS, Ph.D.• Sameer Parikh, MBBS• Debbie Bowen, CNP• Michael Conte, PA-C.


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