Epidemiology of Chronic Myeloid Leukemia Tom Radivoyevitch, PhD Assistant Professor Epidemiology and Biostatistics Case Western Reserve University
Jan 20, 2016
Epidemiology of Chronic Myeloid Leukemia
Tom Radivoyevitch, PhDAssistant Professor
Epidemiology and BiostatisticsCase Western Reserve University
Two CML-ogens: Radiation and Age
𝑦=𝐴𝑒𝑘∗𝑎𝑔𝑒
Not exponential => use additive risk model
Sv = gamma ray dose (Gy) + 10 neutron dose (Gy)
0 20 40 60 80
Age
1
10
102
Ca
ses
pe
r 10
6 P
ers
on
-Ye
ars
U.S. CML Incidence 1973-2009
Males k = 0.047Females k = 0.046
11
1
10 20 30 40 50 60 70
Age
2
2
2 2
3
3
3
3
10
102
103
Ca
ses
pe
r 10
6 P
ers
on
-Ye
ars
Japanese A-Bomb Survivors
D < 0.02 Sv0.02 < D < 1 SvD > 1 Sv
Radiation-induced CML is Multi-scale
Figure by R.K. Sachs.
For a 500 keV incoming photon
J = 6.2e18eVGy = J/kg= 6.2e6eV/pL
Stochastic versus Deterministic
Figure by R.K. Sachs.
Why Study Radiation as the Input?
• Best carcinogen exposure assessment: A-bomb survivors remember exactly where they were, so doses can be reconstructed
• Compared to chemical carcinogen, cannot simply not use it: background, diagnostic, and therapeutic exposures are here to stay
• Physics is understood, so results across x- & γ-rays, neutrons & protons, and α- and β particles at different energies can be unified
Other CML-ogen, aging, also cannot be avoided+exposure is known
Why Study CML as the Output?
• CML is homogeneous: all have BCR-ABL• CML is prevalent: introns large => per-cell
target size for creating bcr-abl is large• leukemias have rapid onset kinetics: white
blood cells go in and out of tissues naturally so they don’t need to learn to metastasize
Chr9 = 136.3 Mb
~140 kb 139.6 Kb DNA Repair 10 (2011) 1131– 1137
~5 kb = introns between e12-e15
Chr 2249.2 Mb
From 1KG browser
PML-RARA intron sizes
~20kbSeer APL/CML 1234/10103= 12%=1/8
40/700=1/18
40%,55% Mediterr J Hematol Infect Dis. 2011;3(1)
~2kb
Dose Response
itkc
iikac
i PetDem iti )( 21 2
)(222
21 ])([ niknikikitniDDD
itkc
iniiikac
i ePetDDDem
ittkcii ettwTbaPN 22)()|(
N is the number of CML target cells in an individual P(ba|T) is the probability of BCR-ABL given a translocation
w(t)=probability density that CML arrives at t given bcr-abl at t=0
2)(
23 tkt
tetktw
30
22
22
t
ctkc
k
edtetR t
Linear R = 0.0075/Gy. LQE posterior R = 0.0022/Gy
CML Target Cell Numbers
• A comparison of age responses for CML and total translocations suggests a CML target cell number of 4x108
• 1012 nucleated marrow cells per adult and one LTC-IC per 105 marrow cells suggests 107 CML target cells
• P(ba|T) = 2TablTbcr/2 may not hold
Kozubek et al. (1999) Chromosoma 108: 426-435
BCR-to-ABL 2D distances
23
Hi-C Data
http://hic.umassmed.edu/heatmap/heatmap.php
133
chr9
chr22
K562 = bcr-abl+ CML cells
Lieberman-Aiden, et al. Science 9 October 2009: 289-293.
23
133
GM06690 = EBV-transformed lymphoblasts
Off by 2 Mb?
Theory of Dual Radiation Action
P(ba|D) = probability of a BCR-ABL translocation per G0/G1 cell given a dose D
tD(r)dr = expected energy at r given an ionization event at the origin
= intra-track component + inter-track component
Sba(r) = the BCR-to-ABL distance probability density
g(r) = probability that two DSBs misrejoin if they are created r units apart
Y = 0.004 DSBs per Mb per Gy; = mass density
TBCR = 5.8 kbp; TABL = 140 kbp
2
02
2 )()(4
)(2)|( DDdrrgrS
r
rtDYTTDbaP bababa
DABLBCR
DrrtrtD24)()(
Total Translocations → g(r) estimate
)/(0
0)( rreprg
6
5
4
3
3
2
0 )16/3()4/9(3)(R
r
R
r
R
rrS
0
)/(2
0
20 0
4
)()(
25.6
)(
4
1dre
r
rSrt
Gp rrd
0
)/(2
0
20 0
4
)()(
25.6
)(
4
1dre
r
rSrt
Gp rrxdx
0
)/(0
20
0)()(4
1drerSGp rr
d
G=25 DSB/Gy
6.25 kev/m3 = 1 Gy
R = 3.7 m r0 = 0.24 m, p0 = 0.12
d in [.01, .025], dx in [.04, .05], d in [.05, .06]
Risk and Target Cell Numbers
Dependence of R and N on the choice of fixed LQE parameters ba/ba and ban/ba
BA/BA BAn/BA R (Gy-1) N
.055/.0107 .8/.0107 .0022 (.0012, .0039)a 6.1x108 (3.3x108, 1.1x109) .055/.022 .8/.022 .0039 (.0020, .0073) 5.2x108 (2.7x108, 9.8x108) .45/3.64 .8/.022 .0094 (.0051, .0176) 7.6x106 (4.1x106, 1.4x107)
aIn parentheses are the 95% CI.
bat
ctkc N
k
edtetR t
30
22
22
ba
RN
Higher risk estimate is more biologically plausible
Linear-to-quadratic transition dose changed from [0.011-0.022]/0.055= [0.2-0.4] Gy to3.64/.45= 8.09 Gy
Linear R = 0.0075/Gy for D < 4Sv is higher here at 0.0094/Gy due to cell killing term
Bcr-Abl to CML Waiting Times
2)(
23 tkt
tetktw
ijkkjiijk PYFDAE
1950 1970 1990
IR-to-CML Latency
Year
Ca
ses
pe
r 10
4 P
ers
on
-Ye
ar-
Sv
0
2
4
6 MalesFemales
M/F=1.42tf-tm=6.3y
M/F=1.6tf-tm=10 yrs
0 20 40 60 80
Age
1
10
102
Ca
ses
pe
r 10
6 P
ers
on
-Ye
ars
U.S. CML Incidence 1973-2009
Males k = 0.047Females k = 0.046
Age at Exposure Dependence
10 20 30 40 50Age at exposure
Ca
ses
pe
r 10
5 P
ers
on
-Ye
ars
0.1
11
0
Males
mostly radiogenic
High DoseMedium DoseLow Dose
10 20 30 40 50Age at exposure
Ca
ses
pe
r 10
5 P
ers
on
-Ye
ars
0.1
11
0
Females
mostly radiogenic
High DoseMedium DoseLow Dose
Nagasaki HSC Reserve Loss?
6 Nagasaki CML vs 53 in Hiroshima Hiroshima PY=1558995 Nagasaki PY= 690084 (i.e. 2.26 lower),
53/2.26 = ~23 cases expected in Nagasaki HSC reserve permanently depleted to 25%?
Human T-cell leukemia virus (HTLV): 22 adult T-cell leukemias (ATLs) in Nagasaki compared to 1 in Hiroshima (2.26 more PY => expect ~50)
11
1
10 20 30 40 50 60 70
Age
2
2
2 2
3
3
3
3
10
102
103
Ca
ses
pe
r 10
6 P
ers
on
-Ye
ars
Japanese A-Bomb Survivors
D < 0.02 Sv0.02 < D < 1 SvD > 1 Sv
Dead-Band Control of HSC levels
• Transplant doses of 10, 100, and 1000 CRU => CRU levels 1-20% or 15-60% normal Blood (1996) 88: 2852-2858
• Broad variation in human HSC levels Stem Cells (1995) 13: 512-516
• Low levels of HSCs in BMT patients Blood (1998) 91: 1959-1965
0 20 40 60 80Age
0.1
1
10
102
Ca
ses
pe
r 10
6 P
Y
Males
1973-1984 k = 0.0581985-1996 k = 0.0481997-2009 k = 0.038
0 20 40 60 80Age
Females
0.1
1
10
102
Ca
ses
pe
r 10
6 P
Y
1973-1984 k = 0.0531985-1996 k = 0.0491997-2009 k = 0.038
HSC Reserve Loss Trend?Ave last 7 ratios0.700.49
1995 data yielded k= 0.041 [Radiat Environ Biophys (1999) 38:201–206]. 0.031 in 2006 is consistent with tlcns leading CML by 10 yrs
0.800.54
All Cancer Incidence Conclusion: Cancer therapy is not the cause of the HSC reserve depletion
Other Guesses? Does obesity increase bone marrow fat and thus squeeze out HSC? 1. Mississippi (34.4%) 51. Colorado (19.8%) 0.1*x+1(1-x)=0.5 => .5=.9x => x=.555Prevalence of cause must be greater than 55%Cancer Epidemiol Biomarkers Prev 2009;18:1501-1506 => obesity causes CML
Easier travel=> greater loads on immune system?
0 20 40 60 80
Cumulative Incidence of Cancer
age
prob
abili
ty o
f ca
ncer
10 3
10 2
0.1
0.5
malesfemales
0 20 40 60 80Age
0.1
1
10
102
Ca
ses
pe
r 10
6 P
Y
Males
1973-1984 k = 0.0581985-1996 k = 0.0481997-2009 k = 0.038
0 20 40 60 80Age
Females
0.1
1
10
102
Ca
ses
pe
r 10
6 P
Y
1973-1984 k = 0.0531985-1996 k = 0.0491997-2009 k = 0.038
Or is it CMML Misclassification?
CML = ICDO-2 9863 does not include CMML. Maybe all were called CML <1985, 50% in 1985-1995, and 0 after
0 20 40 60 80Age
0.1
1
10
102
Ca
ses
pe
r 10
6 P
Y
Males
1973-1984 k = 0.0581985-1996 k = 0.0481997-2009 k = 0.038
0 20 40 60 80Age
Females
0.1
1
10
102
Ca
ses
pe
r 10
6 P
Y
1973-1984 k = 0.0531985-1996 k = 0.0491997-2009 k = 0.038
CML=ICD9 205.1 includes 20% CMML
0 20 40 60 80Age
0.1
1
10
102
Ca
ses
pe
r 10
6 P
Y
Males
1973-1984 k = 0.0581985-1996 k = 0.0551997-2009 k = 0.053
0 20 40 60 80Age
Females
0.1
1
10
102
Ca
ses
pe
r 10
6 P
Y
1973-1984 k = 0.0531985-1996 k = 0.0541997-2009 k = 0.05
CMML rises at older ages
ICDO-2 9945 = CMML
0 20 40 60 80Age
0.1
1
10
102
Ca
ses
pe
r 10
6 P
YMales
1985-19961997-2009
0 20 40 60 80Age
Females
0.1
1
10
102
Ca
ses
pe
r 10
6 P
Y
1985-19961997-2009
Counts of CMML per year. None before 19851984 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 1 40 41 43 50 53 70 61 68 66 65 79 93 65 85 78 82 87 2003 2004 2005 2006 2007 2008 2009 93 127 84 91 104 80 123
AML
More APL or better diagnostics?
0 20 40 60 80Age
10
102
Ca
ses
pe
r 10
6 P
Y
AML Males
1973-19841985-19961997-2009
0 20 40 60 80Age
AML Females
10
102
Ca
ses
pe
r 10
6 P
Y
0 20 40 60 80Age
1
Ca
ses
pe
r 10
6 P
Y
APL Males
1973-19841985-19961997-2009
0 20 40 60 80Age
APL Females
0.1
1
Ca
ses
pe
r 10
6 P
Y
Retinoic Acid and Imatinib
Cures found for cancers that are molecularly homogeneous:simpler cancers are being solved first
0 20 40 60 80 100 1200.
00.
20.
40.
60.
81.
0
APL males
Months
Su
rviv
al
0 20 40 60 80 100 120
0.0
0.2
0.4
0.6
0.8
1.0
APL females
Months
Su
rviv
al
0 50 100 150 200 250 300
0.0
0.2
0.4
0.6
0.8
1.0
CML males
Months
Su
rviv
al
0 50 100 150 200 250 3000.
00.
20.
40.
60.
81.
0
CML females
Months
Su
rviv
al
1973-19811982-19911991-19992000-2009
AML and CLL
More typically progress is slower
0 50 100 150 200 250 300
0.0
0.2
0.4
0.6
0.8
1.0
AML males
Months
Su
rviv
al
0 50 100 150 200 250 300
0.0
0.2
0.4
0.6
0.8
1.0
AML females
Months
Su
rviv
al
0 50 100 150 200 250 300
0.0
0.2
0.4
0.6
0.8
1.0
CLL males
Months
Su
rviv
al
0 50 100 150 200 250 300
0.0
0.2
0.4
0.6
0.8
1.0
CLL females
Months
Su
rviv
al
1973-19811982-19911991-19992000-2009
Acknowledgements
• Department of Epidemiology & Biostatistics • Rainer Sachs (UC Berkeley) • Yogen Saunthararajah (Cleveland Clinic)• Thank you for listening!
SEER Underreporting Possibility
Most conservative claims-based algorithm vs. SEER. B. M. Craig et al. Cancer Epidemiol Biomarkers Prev; 21(3) March 2012
Radiation Doses Rising
AML
Assuming all CML-ogens are also AML-ogens, this implies CML decreases are NOT due to decreases in exposures to bcr-abl forming agents.
No AML trend is consistent with target cells being lineage committed and thus more tightly regulated than HSCs.
0 20 40 60 80Age
10
102
Ca
ses
pe
r 10
6 P
Y
AML Males
1973-19841985-19961997-2009
0 20 40 60 80Age
AML Females
10
102
Ca
ses
pe
r 10
6 P
Y
Others
0 20 40 60 80Age
0.1
1
10
102
Ca
ses
pe
r 10
6 P
Y
MML Males
1973-19841985-19961997-2008
0 20 40 60 80Age
MML Females
0.1
1
10
102
Ca
ses
pe
r 10
6 P
Y
0 20 40 60 80Age
0.1
1
10
102
Ca
ses
pe
r 10
6 P
Y
CLL Males
1973-19841985-19961997-2008
0 20 40 60 80Age
CLL Females
1
10
102
Ca
ses
pe
r 10
6 P
Y
All Cancer Incidence
0 20 40 60 80
Age
Cas
es p
er P
erso
n-Y
ear
10 4
10 3
10 2
Males
1973-19841985-19961997-2008
0 20 40 60 80
Age
Cas
es p
er P
erso
n-Y
ear
Females
10 4
10 3
10 2
Incidence of All Cancers
All Cancer Incidence
0 20 40 60 80
Incidence of All Cancers
age
Cas
es p
er P
erso
n-Y
ear
10 4
10 3
10 2
femalesmales
2026202 Males 2157740 Females 438616821 MalePY 454528905 FemPY
Nagasaki HSC Reserve Loss?
Hiroshima
Nagasaki10 20 30 40 50
Age at exposure
Ca
ses
pe
r 10
5 P
ers
on
-Ye
ars
0.1
11
0
mostly radiogenic
High DoseMedium DoseLow Dose
10 20 30 40 50Age at exposure
Ca
ses
pe
r 10
5 P
ers
on
-Ye
ars
0.1
11
0
High DoseMedium DoseLow Dose
6 Nagasaki CML vs 53 in Hiroshima Hiroshima PY=1558995 Nagasaki PY= 690084 (i.e. 2.26 lower),
53/2.26 = ~23 cases expected in Nagasaki HSC reserve permanently depleted to 25%? Human T-cell leukemia virus (HTLV): 22 adult T-cell leukemias (ATLs) in Nagasaki compared to 1 in Hiroshima (2.26 more PY => expect ~40)
iii
i mmO )log(