EVALUATION OF A PROTOTYPE CLL RISK MODEL

FOR POTENTIAL INCLUSION IN THE COMPUTER PROGRAM NIOSH-IREP

September, 2009

Lydia B. Zablotska, M.D., Ph.D. Assistant Professor Department of Epidemiology & Biostatistics School of Medicine University of California San Francisco
Mailing Address and Contact Information: 3333 California St., Suite #280 San Francisco, CA 94118 Ph: (415) 476-4673 Fax: (415) 563-4602 E-mail: lydia.zablotska@ucsf.eduINTRODUCTION

Trabalka and Apostoaei present an important and well-organized report (1) that provides a background, back-up data and rationale for a me thodology to develop a prot otype risk model for chronic lymphocytic leukemia (CLL) to be used with the NIOSH-IREP computer program. The following review of this report is broken down into two categories. First, the key points of the model development are addressed, technical questions regarding th e specific elements of the
model are raised and tentative solutions offered which may help refine the CLL risk model. Second, minor editorial changes/ suggestions are introduced.

KEY POINTS OF THE CL L MODEL DEVELOPMENT

A starting point for CLL risk model developmen t described in the Trabalka and Apostoaei report (1) was a model currently in use by the Vete ran’s Administration (VA). In the VA model, risk of CLL is thought to be similar to the risk estimated for a lymphoma and multiple myeloma grouping. The highest of the reconstructe d doses to the red bone marrow, spleen or thymus are used to estimate the probability of causation of CLL occurring in military personnel exposed to radiation.

In their report, Trabalka and Apostoaei went through several steps to develop a CLL risk
model.
1. Review of the latest epidemiological, mol ecular and clinical literature on radiationrelated risks of CLL. 2. Analysis of incidence rates of CLL in the U. S. and in Japan as a whole and for Hiroshima and Nagasaki separately. 3. Evaluation of the NIOSH model for lymphoma and multiple myeloma in terms of its relevance to the proposed CLL risk model. 4. Creation of a “Version 1” protot ype model based on Land et al. 2003 (2) by extending a latency period for CLL.
These steps are reviewed in more detail below.

21. Review of the latest epidemiological, mol ecular and clinical literature on radiationrelated risks of CLL. Trabalka and Apostoaei (1) have thoroughly reviewed the key papers from the NIOSH Annotated Bibliography for CLL from 2004, as well as additional papers cited by several reviewers of the arguments advanced by the EEOIC PA stakeholders. Sections 3.0 and 4.0 of the report contain a wide review of th e recent developments in CLL rese arch. In particular, some of
the issues raised are as follows:

• Developmental characteristics of CLL as a form of NHL.

• Description of radiation target organs for CLL.

• Use of historical ICD codes for CLL and potential implications for research.

• New areas of CLL research, including genetic and molecular studies.
The report under review wa s issued in January 2009 (1) . In this reviewer’s opinion, it would be essential to augment it with several recent re ferences, which potentially could have an effect on the CLL risk model development. It is und erstood that recent attempts at developing
radiation risk models (2-4) necessarily had to rely on the data from the Life Span Study (LSS) of survivors of atomic bombings in Japan to deve lop various radiation cance r risk models. While the data from the studies of occupationally exposed nuclear workers (5) were considered important to predict risks from low-dose low dos e-rate exposures, it could not be used for quantitative risk assessment “principally becau se of the imprecision of the risk estimates obtained” (p. 268, (4) ). However, since the pub lication of the NIOSH-CDC (2) , UNSCEAR
2000 (3) , and BEIR-VII (4) reports, the results of a much larg er pooled analysis of mortality of more than 400,000 nuclear work ers have been published (6) . Several reports based on this study provide much more precise estimates of cancer and non-cancer risks due to radiation exposure with narrower confidence intervals compar ed to the pooled study of nuclear workers (5) available at the time the three reports discussed above were issued.

The following recent references are considered pa rticularly important for the development of
a CLL risk model:

- Vrijheid et al. 2008 (7) analysis of mortality from CLL in a pooled cohort of 295,963
nuclear workers from 15 count ries. After an average lifetime cumulative dose of 15 mSv, the study found little evidence of radiation-rela ted risks of mortality from CLL. Small
number of deaths in the c ohort ascribed to CLL (n cas es=65), high probability of

3misclassification of CLL on death certificates, and low doses decreased the power of the study. NHL mortality in this cohort (n cas es=248), however, was increased with an ERR=0.44 per Gy, 90% CI: <0, 4.78.

- Muirhead at al. 2009 (8) presented the results of an ex tended follow-up of the cohort of 174,541 workers from the National Registry for Ra diation Workers in the U.K. After an average cumulative dose of 25 mSv, no increase d risk of CLL incidence (n cases=128) or mortality (n cases=69) was obs erved, although confidence inte rvals were wide and were compatible with risks estimated for other types of leukemia. In contrast, incidence risk of NHL was border-line significant with an ERR=1.28 per Sv, 95% CI: -0.38, 4.06, p onesided=0.081 (n cases=305). A similar, al beit smaller and non-si gnificant, increasing
trend of death from NHL with dose was observed.

- Richardson et al. 2009 (9) recently reported a positive si gnificant association between ionizing radiation and NHL in a cohort of U.S. nuclear workers from the Savannah River Site (SRS), significantly larger in size than the one observed in the age- and sexcomparable LSS cohort (ERRs of 7.62 and 1.12 per Sv, respectively). The analysis was based on 51 deaths from NHL in a cohort of 20,940 SRS workers exposed to comparatively high average cumulative doses of 44 mSv (10) . An earlier study (11) did not find any increase in risk for CLL based on 22 deaths.

- Two additional recent incidence-based studies of radiation workers have shown an
association between CLL and o ccupational radiation exposure (12, 13) , with one study (12) reporting a significant increase in CLL am ong Czech uranium miners presumably due to a gamma-radiation component of exposure in the mines and the other study (13) reporting an elevated risk among radiologic technologists who worked during the early years, when occupational dos es were presumably high.

- Finally, two case-control st udies of leukemia among C hornobyl (Chernobyl) clean-up workers have been published recently. Kesminiene et al. 2009 (14) reported on the incidence of hematological malignancies am ong clean-up workers from Belarus, Russia

4and Baltic countries. The majority of worker s were from Belarus and had little exposure to actual clean-up work. Ne vertheless, doses experienced by the clean-up workers (median 13 mGy) were comparable to the dos es received by the oc cupationally exposed nuclear power industry workers from th e recent 15-country study (mean=19 mSv) (6)

. Radiation-related risk of C LL was similar to that of non-CLL leukemia, ERR=4.7 and 5.0 per Gy, respectively. However, the dose-response was not st atistically significant, in no small part due to a small number of cases (40 cases of leukemia, including 19 CLL).

A second case-control study of Chornobyl cl eanup workers from Ukraine utilized essentially the same method to estimate radiation doses from detailed dosimetric questionnaires, but used a much more rigor ous case ascertainment protocol and case verification and confirmation procedures (15) . The study was based on leukemia cases confirmed by the Internationa l Hematology and Pathology Panel (15, 16) . As a disclosure, I am a senior and co rresponding author of this study (17) and have performed all data analyses fo r the publication.

In Romanenko et al. 2008 (17) , workers were exposed to re latively high doses, although still in the low-dose range (mean dose=76 mGy). A significant dose-response was reported for all leukemia with an ERR= 3.44 per Gy, 95% CI: 0.47, 9.78. There was no significant difference in risk of CLL (n cases=39) and non-CLL (n cases=32) leukemia (p=0.75) and the risk of CLL was estimated at 4.09 per Gy, 95% CI: <0, 14.41. To further clarify these issues, the study has been extended to ascertai n cases for another 6 years (2001–2006) and its results ar e expected at the end of 2010.

In summary, a new evidence that came into light in the year since the re port has been issued, provides evidence for the hypothesis advo cated by Trabalka and Apostoaei (1) that CLL may be radiogenic and that its risk profile may be simila r to that previously observed for other types of
leukemia and/ or NHL. These studies are of particular importance because they provide evidence from the low-dose studies, a dose range of primary interest for occupationally exposed
workers in the U.S.

52. Analysis of incidence rates of CLL in the U.S. and in Japan as a whole and for Hiroshima and Nagasaki separately Trabalka and Apostoaei used 2005 SEER database (18) to estimate sex- and age-specific
incidence rates of CLL in the United States. Th is database contains information on new cancers diagnosed in the 13 U.S. metropolitan cancer re gistries in 1992-2002. The methodology used to estimate the rates in Table A.1 and Figure A.1 is not entirely clear and should be explained in
more detail. It should also be noted that a much more detailed and up-to-date information about incidence rates in the U.S. popul ation has been quoted in a re cent article by Dores et al. 2007 (19) . Relevant to the current re port, the article pr ovides incidence rates of CLL and small lymphocytic lymphoma (SLL), a type of NHL clos ely related to CLL, es timated from the SEER
database for 1993-2004 (20) . Dores et al. 2007 (19) showed that there were significant delays in reporting of CLL but not SLL in SEER. They es timated underreporting of CLL to be as high as 24% and suggested that 9-12 year s were needed to capture dela yed reporting. Zent et al. 2001 (21) suggested that, due to the rath er indolent nature of CLL, tumo r registries may be missing as much as 38% of CLL compared with the inci dence of CLL detected using sophisticated measures such as flow cytometric immunophenotypic analysis.

The incidence rates of combined CLL/SLL in Dores et al. 2007 (19) are twice as high as those reported by Trabalka and Apostoaei in Table A.1 (1) , 7.04 and 3.72 per 100,000 per year for males and females, respectively. Approximately twenty-five percent of cases are attributed to SLL. Thus, there is still a big discrepancy between the numbers in Table A.1 and the numbers
cited in Dores et al. 2007 (19) . The discrepancy is important because it provides evidence about incidence rates of CLL in the U.S. population in the absence of occupatio nal radiation exposures.

Tables A.2 and A.3 present estimates of inci dence rates of CLL in the Japanese population and for the Hiroshima and Nagasaki population se parately. Trabalka an d Apostoaei used IARC
Publication No. 143 to estimate these rates (22) . It should be noted that a more recent edition of
the Cancer Incidence on Five Continents (CI5) is now available (detailed CI5-VIII (23) and CI5-
IX (24) ). In addition, Table A.2 does not specify the years that were used to estimate incidence rates. Finally, incidence rates of CLL in Nagasa ki are very unstable due to a small number of observed cases. For example, upon quick review of the detailed CI5-VIII (23) , this reviewer

6observed that incidence rates of CLL varied wi dely from year to year in 1973-1997 in the Nagasaki Tumor Registry, with th e majority of annual rates being zero, but some rates being as high as 0.93 and 0.81 per 100,000 per year for males and females, respectively. Thus, the calculation of expected number of CLL cases on page 5 is subject to great uncertainty.

In summary, this section would benefit from a more detailed description of the methods used to estimate average incidence rates of CLL in the U.S. and in the Japanese population. Provisions should be made to account for delayed reporting of CLL cases in the SEER database. In view of the main argument of this report that CLL and SLL are the same diagnostic entity,
efforts should be made to include SLL incidence ra tes in the calculations. The more up-to-date
datasets should be used in the calculations. Caution should be exercised while predicting an expected number of CLL cases in the absence of radiation in the Japane se population due to high variability of incidence rate s of CLL in this population.

3. Evaluation of the NIOSH model for lymphoma and multiple myeloma in terms of its relevance to the proposed CLL risk model. Trabalka and Apostoaei (1) reviewed a lymphoma model deve loped for the previous iteration of NIH Radioepidemiological tabl es and presented a justificat ion for its use in predicting
radiation-related risks of CLL. It is hard to agree with their argument to use a risk model for a combined grouping including multiple myeloma cases simply because ‘it too is a disease of old age’ (p.15, (1) ). So far, there are very few studies whic h have explicitly eval uated the biological processes underlying radiation-related multiple myeloma and its origins. CLL and multiple myeloma are both B-cell hematological ma lignancies, but are entirely “distinct lymphoproliferative neoplasms with different clin ical presentations and clinical courses” (p.561, (25) ). In addition, keeping a combined group estima te would necessarily lo wer the risk estimate to be used for CLL. In fact, average excess relative risk estimate for multiple myeloma among men in the LSS study is 0.17 per 1 Sv, i.e. five -fold lower than a risk estimate for NHL among men, ERR=0.91 per Sv. Since The Principles & Practice of Oncology textbook by DeVita et al. (26) notes that 25% of CLL are SLL cases, it make s sense to use the higher estimate for NHL
cases in the new CLL risk model.

7Another argument advanced to use a comb ined estimate for NHL, multiple myeloma and Hodgkin’s lymphoma is that NHL may include bo th indolent lymphomas (of which CLL/SLL is a part) and more aggressive lymphomas. The no tion of CLL being indolent has been disputed recently. Several studies have demonstrated ma rked differences in th e clinical course and morphological features of CLL diagnosed in Chornobyl cleanup workers exposed to gamma
radiation and the general population (27-29) . Chornobyl-associated CLL cases were characterized by younger age, more advanced st age of disease at presentation, and faster progression. Cleanup workers with comparatively large radiation doses had CLL characterized by high mutation rates in several genes a ssociated with poor disease prognosis (27, 28) . Thus, it is possible that CLL among workers occupationally exposed to radiation could differ from the CLL in the general populati on unexposed to radiation.

A careful consideration should be given to existing risk models for development of a new CLL risk model. For example, recent studies showed that risks of incident CLL among Chornobyl clean-up workers are comparable to th e risks of non-CLL leukemia. Both studies (14, 17) showed that CLL risks are at the level of risks observed for leukemia in the LSS study, i.e. average excess relative risk of 3.91 at 1 Sv for men (3) . These studies, thus, show that further consideration should be given to using current leukemia models to predict risks of CLL.

This reviewer understands that the most recen t updates of leukemia and lymphoma incidence
in the LSS cohort based on DS02 have not been published, but would strongly advocate waiting for them and asking Dr. Land to develop a new CLL risk model based on the combination of NHL and CLL cases along with careful cons ideration of the recently published Chornobyl
studies. If this choice is enti rely not possible, then the NHL-a lone model is more appropriate than a combined lymphoma and multiple myeloma risk model.

4. Creation of a “Version 1” prototype model based on Land et al. by extending the latency period for CLL. The three most important assumptions of the new prototype model proposed by Trabalka and Apostoaei (1) are as follows:

• A latency period for CLL has a point estimate of 15 years

8• Bone marrow is not an appropriate ta rget organ for CLL risk estimation

• A dose and dose-rate effectiveness f actor (DDREF) should be used for fractionated exposures

• A multiplicative model, in which an excess relative risk per unit of dose multiplies the background risk, is not appropriate for CLL

A choice of a 15-year lag in the incident CLL ri sk model is not completely justified as it is
based on neither real observationa l studies nor biological models, but solely on the mathematical projections. At the time when a ll solid cancers are assigne d a 10-year latency pe riod, it is hard to
defend a notion that CLL is somehow different from other cancers. A strategy of separating
CLL from other radiation-related leukemias ha s been challenged recently and one should be cautious about introducing new ‘exceptional’ ap proaches to modeling CLL risks. A quick
review of the most recent CLL/NHL studies showed that a 10-year lag has become a standard in
the last decade. Richardson et al. 2009 (9) found significant increases in risk of NHL mortality in the SRS cohort both under 5-year and 10-year lag assumptions. In our study of Chornobyl clean-up workers (17) , we assessed lag time in 1-year in crements between 0 and 10 years. The deviance, was minimized for both CLL and non-CLL analyses when we the lag interval was set to 2 years.

A discussion regarding target organs for C LL on page 18 is not entirely clear to this reviewer. The great majority of occupationally exposed workers in the U.S. would have been exposed to external gamma radiation. Their e xposures are usually reco rded as whole-body doses and stored either by employing f acilities, the Nuclear Regulatory Commission or the Department of Energy. The majority of recent studies of U.S. nuclear workers used whole-body or bone marrow doses for analysis of leukemia, CLL, NHL or combination thereof (9, 30, 31) . A proposal to develop a “surr ogate for a whole-body dose ... { by way of} combination of the esophageal, colon, and bone marrow doses” as desc ribed on p. 18 is, therefore, questionable.

Land et al. 2003 (2) report applied the DDREF factor to all chronic exposures. However, a notion that the risk per unit dose decreases with decrea sing dose and dose-rate is not supported in any of the low-dose low-dose-rate studies publis hed in the last decade. The 15-country study (6) showed that the risk of solid cancer among occ upational exposed workers was similar or higher

910 per unit of dose exposure compared to the L SS study. Thus, a continued use of the DDREF factor should be carefully evaluated.

An argument about handling of risk transport between populati on advanced in paragraph 2 on page 19 is not convincing. The reason that so far we have limited data about CLL risks from epidemiological studies of radiation workers an d medically exposed groups is not because the
interaction between CLL and radiation is not multiplicative but because most occupational
studies to date were based on mortality rather than inciden ce and mortality data usually underestimate, possibly substantia lly, the occurrence of CLL. Ca se in point is a recent study from the U.K. by Muirhead et al. 2009 (8) which showed that approximately 50% of CLL incident cases did not have a corresponding death from CLL. Not surprisingly then, recent mortality studies that evaluated dose response fo r CLL separately had either negative findings (6, 32) or positive findings with a negative dose–response trend (31, 33, 34) . In view of this underreporting of deaths from CLL, more attent ion should be paid to the recent results with respect to radiation-related risks of NHL. As mentioned on page 2 of this report, Muirhead et al.
2009 (8) reported a border-line significant risk of incident NHL in their study.

Furthermore, the reason that high-dose studies of populations treated w ith radiotherapy for a first primary cancer showed no increase in the inci dence of CLL, whereas a significant increase
was demonstrated for all other types of leukemia (35, 36) , is because of the short follow-up after radiation treatment and young age of cancer survivors.

In summary, the four main assumptions used to develop a prototype CLL risk model are questioned by this reviewer. A model assuming a standard 10-year latency period based on the whole-body doses seems the most appropriate at this time. Further analysis of the LSS incidence data and its comparison with the recent studie s of incident CLL in occupationally exposed
workers (14, 17) should shed light on the appropri ateness of the DDREF at low doses.MINOR EDITORIAL CHANGES/ SUGGESTIONS.

• A statement on page 5 that “If the estima ted number of CLL cases in the absence of radiation exposure had been greater than 4, then we might have been able to conclude that the dose-response for CLL in the LSS cohort should be negative” is incorrect. The relationship between exp ected and observed cases of CLL is not related to the dose-response due to radiation.

• There are several mistakes in refere ncing various tables on pages 14-15:

• Tables 18, 19 and 20 in UNSCEAR 2000 (3)

• Table IV.C.2 in Land et al. 2003 (2)

• Several direct quotes from Land et al. 2003 (2) on p.15 are not properly
referenced

• Section 5.0 would benefit from a more struct ured approach with separate subtitles for separate topics

• Figure 1 is missing Boivin et al. 1986 (36) with 166 CLL cases

• A discussion of the application of weight s to different target organs on p.18 is highly speculative and should be carefully re-evaluated

• In view of the recently published studies, th is reviewer disagrees with a statement on page 19 about ‘week radiogenicity’ of CLL. Improved study methods and diagnostic procedures in recent studies pr ovide substantial ev idence of radiationrelated risks of CLLREFERENCES

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