Work

Cancer risk following post‐transplant lymphoproliferative disorders in solid organ transplant recipients

Year: 2019

Type: article

Abstract: Post-transplant lymphoproliferative disorders (PTLDs) are associated with immunosuppressive therapy administered to prevent graft rejection, leading to uncontrolled replication of Epstein–Barr virus (EBV) (Dierickx & Habermann, 2018). Solid organ transplant (SOT) recipients also have increased risks of other malignancies, particularly those with viral aetiologies (Engels et al, 2011). In the general population, lymphoma survivors have increased risk of subsequent cancers due to lymphoma treatment, underlying immune dysfunction or shared risk factors (Morton et al, 2010; Baras et al, 2017). We conducted the first assessment of cancer risk after PTLDs among SOT recipients and compared patterns to previous literature describing cancer risks after lymphoma in the general population. The Transplant Cancer Match Study links the US Scientific Registry of Transplant Recipients (SRTR) with 17 cancer registries (1987–2014), covering ~50% of the US SOT population (Table 1) (Engels et al, 2011). We excluded recipients with a cancer diagnosis before transplant (N = 19 438), a transplant before the start of cancer registry coverage (N = 7542), human immunodeficiency virus infection (N = 469), or (for liver transplants) a diagnosis of liver cancer ≤6 months after transplant (N = 1280, probably representing prevalent liver cancers). Post-transplant lymphoproliferative disorder was ascertained from: (i) linked cancer registries for lymphoid malignancies, identified using International Classification of Diseases for Oncology, edition 3 (ICD-O-3) morphology codes (Turner et al, 2010), and (ii) SRTR post-transplant follow-up files (updated at 6 and 12 months following transplantation and annually thereafter; includes both monomorphic as well as polymorphic PTLDs not reportable to cancer registries). We defined PTLD according to the World Health Organization (Swerdlow et al, 2016) plus lymphocytic leukaemias, because they are lymphoid neoplasms. We analysed PTLDs overall, as well as lymphoid malignancies and polymorphic PTLDs separately. We ascertained first malignant non-PTLD cancers from the linked cancer registries according to ICD-O-3 topography and morphology codes (Howlader et al, 2017). We analysed cancer risk overall and for specific types with ≥100 cases. Included SOT recipients (N = 235 775) were predominantly male (60·9%), non-Hispanic white (61·7%), had a median age of 48 years and more frequently received a kidney (59·8%) (Table 1). During follow-up, 3591 recipients were diagnosed with PTLD of any type (Table SI). Using Cox regression, we estimated PTLD risk with age as the time scale (Table 1). PTLD risk was elevated among males, non-Hispanic whites, recipients of induction immunosuppression with alemtuzumab or muromonab-CD3, EBV seronegative recipients at the time of transplant and recipients of organs other than kidney. We evaluated risk of non-PTLD cancer following PTLD using Cox regression (see Fig 1, footnote). Compared with recipients without PTLD, those with PTLD were more likely to be diagnosed with any subsequent non-PTLD cancer [adjusted hazard ratio (aHR) = 1·6, 95% confidence interval (CI) = 1·4–1·9; Fig 1]. Specifically, risk was elevated for cancers of the oesophagus, colon, liver, kidney, central nervous system and thyroid; non-lymphocytic leukaemia (including myelodysplasia and myeloproliferative neoplasms) and miscellaneous cancers. Overall cancer risk was elevated after lymphoid malignancies (N = 2917, aHR = 1·5, 95% CI = 1·3–1·8) and polymorphic PTLD (N = 448, aHR = 2·9, 95% CI = 1·8–4·7) (Table SII). For cancers where ≥10 PTLD cases were reported prior to diagnosis, we conducted additional exploratory analyses. Overall cancer risk following PTLD was similar irrespective of the organs transplanted, except for melanoma and kidney cancer, which were increased following PTLD only among kidney recipients (Table SIII). In analyses by time since PTLD, risk was increased ≤6 months after PTLD for cancers overall (aHR = 4·0, 95% CI = 3·0–5·2) and for most evaluated cancers (Table SIV). In contrast, cancer risks remained elevated >6 months after PTLD for kidney (aHR = 2·0; 95% CI = 1·1–3·5) and thyroid (aHR = 3·9; 95% CI = 1·7–8·8) cancers. In analyses by non-PTLD cancer stage at diagnosis, risks were more pronounced for localized/stage I cancers than regional/distant/stage II-IV cancers for kidney (aHR 2·3 vs. 0·7), thyroid (aHR 6·2 vs. 4·7) and colon cancers (aHR 3·6 vs. 1·7) (Table SV). Notably, most of the localized/stage I kidney and thyroid cancers were diagnosed >6 months after PTLD (Figure S1). In this first comprehensive assessment of cancer risk following PTLD among SOT recipients, we observed increased risk of non-PTLD cancers overall, and also for specific types. Risks were primarily increased ≤6 months after PTLD diagnosis, suggesting that diagnostic and staging investigations following PTLD (such as positron-emission/computed tomography scans) may lead to identification of some of these cancers. Notably, exceptions to this pattern were observed for kidney and thyroid cancer, for which risks persisted >6 months after PTLD diagnosis, which is consistent with the risks observed among non-Hodgkin lymphoma survivors in the general population (Baras et al, 2017). Due to the small number of PTLD cases, our results need to be replicated. Nonetheless, our results combined with general population data support a potential role for shared risk factors or lymphoid malignancy treatment in the aetiology of kidney and thyroid cancer. However, the lack of association between PTLD and lung cancer or melanoma except in some patient subgroups contrasts with results for lymphoma survivors in the general population (Morton et al, 2010; Engels et al, 2011; Baras et al, 2017). Solid organ transplant recipients have increased risk of virus-related cancers due to immunosuppressive medications, such as human papillomavirus-related anogenital cancers and hepatitis virus-related liver cancer (Engels et al, 2011). Except for liver cancer, risk of other virus-related cancers was not elevated following PTLD. Immunosuppression is an important risk factor for PTLD. However, reduction of immunosuppression is an essential part of PTLD treatment, and the subsequent partial restoration of immunity may explain the absence of increased risk of virus-related malignancies following PTLD. Our study has some limitations. Because early lesions and polymorphic PTLDs are not captured by the cancer registries and the SRTR may miss some PTLD diagnoses, we may have under-ascertained PTLDs. We may have missed some cancers due to migration of transplant recipients from outside the cancer registry catchment area, or due to matching errors. Finally, PTLD generally is managed by reduced immunosuppression and intense chemotherapy, though some patients may be cured by reduced immunosuppression and rituximab alone (Evens et al, 2010). We could not analyse the effect of PTLD treatment on the risk of subsequent cancers due to lack of data on treatment. Post-transplant lymphoproliferative disorder occurrence is a serious clinical event associated with increased risk of mortality and graft failure (Dierickx & Habermann, 2018). Our results highlight the need for awareness among clinicians regarding the increased likelihood of additional cancer diagnoses among individuals who develop PTLD. Some associations may be attributed to increased surveillance, but evidence of increased risk at longer latency intervals for kidney and thyroid cancer warrants further investigation. This research was supported in part by the Intramural Research Program of the National Cancer Institute. The authors gratefully acknowledge the support and assistance provided by individuals at the Health Resources and Services Administration (Monica Lin), the SRTR (Ajay Israni, Bertram Kasiske, Paul Newkirk, Jon Snyder), and the following cancer registries: the states of California (Tina Clarke), Colorado (Jack Finch), Connecticut (Lou Gonsalves), Florida (Brad Wohler), Georgia (Rana Bayakly), Hawaii (Brenda Hernandez), Iowa, Illinois (Lori Koch), Kentucky (Jaclyn Nee), Michigan (Glenn Copeland), New Jersey (Xiaoling Niu), New York (Amy Kahn), North Carolina (Chandrika Rao), Texas (Leticia Nogueria) and Utah (Janna Harrell), and the Seattle-Puget Sound area of Washington (Margaret Madeleine). We also thank analysts at Information Management Services for programming support (David Castenson, Matthew Chaloux, Michael Curry, Ruth Parsons). The SRTR is currently operated under contract number HHSH250201500009C (Health Resources and Services Administration) by the Minneapolis Medical Research Foundation, Minneapolis, MN. Previously, the SRTR was managed under contracts HHSH250201000018C and HHSH234200537009C. The following cancer registries were supported by the SEER Program of the National Cancer Institute: California (contracts HHSN261201000036C, HHSN261201000035C, and HHSN261201000034C), Connecticut (HHSN261201300019I), Hawaii (HHSN261201000037C, N01-PC-35137, and N01-PC-35139), Iowa (HSN261201000032C and N01-PC-35143), New Jersey (HHSN261201300021I, N01-PC-2013-00021), Seattle-Puget Sound (N01-PC-35142), and Utah (HHSN2612013000171). The following cancer registries were supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention: California (agreement 1U58 DP000807-01), Colorado (U58 DP000848-04), Georgia (5U58DP003875-01), Illinois (5U58DP003883-03), Maryland (U58DP12-1205 3919-03), Michigan (5U58DP003921-03), New Jersey (5U58/DP003931-05-00), New York (6NU58DP006309), North Carolina (U58DP000832) and Texas (5U58DP000824-04). Additional support was provided by the states of California, Colorado, Connecticut, Illinois, Iowa, Massachusetts (Massachusetts Cancer Prevention and Control Cooperative Agreement 5458DP003920), New Jersey, New York (including the Cancer Surveillance Improvement Initiative), Texas, Utah and Washington, as well as the University of Utah and Fred Hutchinson Cancer Research Center in Seattle, WA. The authors of this manuscript have no conflicts of interest to disclose. The views expressed in this paper are those of the authors and should not be interpreted to reflect the views or policies of the National Cancer Institute, Health Resources and Services Administration, SRTR, cancer registries or their contractors. PM and LMM developed the concept; PM performed statistical analyses; LMM supervised data analyses; EAE and LMM supervised the project; PM, EAE, CFL and LMM provided critical intellectual content and drafted the manuscript. All authors reviewed and approved the final manuscript. Table SI. Morphologic subtypes of PTLD included in the study. Table SII. Cancer risk following first lymphoid neoplasm or polymorphic PTLD diagnosis. Table SIII. Cancer risk following first PTLD diagnosis, stratified by transplanted organs. Table SIV. Cancer risk following first PTLD diagnosis by latency period (≤6 months, or >6 months after PTLD). Table SV. Risk of selected cancers following first PTLD diagnosis according to cancer stage. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Source: British Journal of Haematology

DOI: 10.1111/bjh.15828

Authors: Parag Mahale, Eric A. Engels, Charles F. Lynch, Lindsay M. Morton

Institutions: National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, University of Iowa

Language: English

Topic: Viral-associated cancers and disorders

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institutes of Health, National Cancer Institute, National Center for Chronic Disease Prevention and Health Promotion