Presentation on theme: "Epidemiology of Chronic Myeloid Leukemia Tom Radivoyevitch, PhD Assistant Professor Epidemiology and Biostatistics Case Western Reserve University."— Presentation transcript:
Epidemiology of Chronic Myeloid Leukemia Tom Radivoyevitch, PhD Assistant Professor Epidemiology and Biostatistics Case Western Reserve University
Two CML-ogens: Radiation and Age Not exponential => use additive risk model Sv = gamma ray dose (Gy) + 10 neutron dose (Gy)
Radiation-induced CML is Multi-scale Figure by R.K. Sachs. For a 500 keV incoming photon J = 6.2e18eV Gy = 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 22 49.2 Mb From 1KG browser
Dose Response 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 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 4x10 8 10 12 nucleated marrow cells per adult and one LTC-IC per 10 5 marrow cells suggests 10 7 CML target cells P(ba|T) = 2T abl T bcr / 2 may not hold
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 G 0 /G 1 cell given a dose D t D (r)dr = expected energy at r given an ionization event at the origin = intra-track component + inter-track component S ba (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 T BCR = 5.8 kbp; T ABL = 140 kbp
Total Translocations → g(r) estimate G=25 DSB/Gy 6.25 kev/ m 3 = 1 Gy R = 3.7 m r 0 = 0.24 m, p 0 = 0.12 d in [.01,.025], dx in [.04,.05], d in [.05,.06]
Risk and Target Cell Numbers 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 to 3.64/.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 M/F=1.42 tf-tm=6.3y M/F=1.6 tf-tm=10 yrs
Age at Exposure Dependence
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)
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
HSC Reserve Loss Trend? Ave last 7 ratios 0.70 0.49 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 0.80 0.54
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=.555 Prevalence 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?
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 CML=ICD9 205.1 includes 20% CMML
Retinoic Acid and Imatinib Cures found for cancers that are molecularly homogeneous: simpler cancers are being solved first
AML and CLL More typically progress is slower
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.
All Cancer Incidence
Nagasaki HSC Reserve Loss? Hiroshima Nagasaki 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)