Iatrogenic immunosuppression and risk of non‐Hodgkin lymphoma in solid organ transplantation: A population‐based cohort study in Australia

Na, Renhua; Laaksonen, Maarit A.; Grulich, Andrew E.; Meagher, Nicola S.; McCaughan, Geoffrey W.; Keogh, Anne; Vajdic, Claire M.

doi:10.1111/bjh.14083

Cited by 24 publications

(16 citation statements)

References 44 publications

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“…Both of these key characteristics of human carcinogens [43] may contribute mechanistically to the development of NHL. For example, immunosuppression is strongly associated with the development of NHL [44,45]. Furthermore, increased risk of NHL has been associated with common genetic variants in the oxidative stress pathway, including NADPH oxidase, which plays an important role in signaling for the proliferation of lymphocytes and tumor cells [46].…”

Section: Discussionmentioning

confidence: 99%

2,4-dichlorophenoxyacetic acid (2,4-D) and risk of non-Hodgkin lymphoma: a meta-analysis accounting for exposure levels

Smith¹,

Smith²,

Merrill³

et al. 2017

Annals of Epidemiology

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2,4-Dichlorophenoxyacetic acid (2,4-D) is one of the most commonly used selective herbicides in the world. A number of epidemiology studies have found an association between 2,4-D exposure and non-Hodgkin lymphoma (NHL) but these results are inconsistent and controversial. A previous meta-analysis found no clear association overall but did not specifically examine high-exposure groups. We conducted a systematic review and meta-analysis of the peer-reviewed epidemiologic studies of the associations between 2,4-D and NHL, with a particular focus on high-exposure groups, and evaluations of heterogeneity, dose-response, and bias. A total of 12 observational studies, 11 case-control studies, and one cohort study, were included. The summary relative risk for NHL using study results comparing subjects who were ever versus never exposed to 2,4-D was 1.38 (95% confidence interval (CI), 1.07-1.77). However, in analyses focusing on results from highly exposed groups, the summary relative risk for NHL was 1.73 (95% CI, 1.10-2.72). No clear bias based on study design, exposure assessment methodology, or outcome misclassification was seen. Overall, these findings provide new evidence for an association between NHL and exposure to the herbicide 2,4-D.

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Section: Discussionmentioning

confidence: 99%

2,4-dichlorophenoxyacetic acid (2,4-D) and risk of non-Hodgkin lymphoma: a meta-analysis accounting for exposure levels

Smith¹,

Smith²,

Merrill³

et al. 2017

Annals of Epidemiology

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“…early lesions) to aggressive lymphoma (i.e. The incidence of PTLD in adult SOT is highest in multivisceral and intestinal (3-7%) and lowest in renal transplants (1-3%), mainly attributed to lymphocyte load in the allograft and intensity of immunosuppression (5)(6)(7)(8)(9)(10)(11)(12). Epstein-Barr virus (EBV) infection tends to drive the pathogenesis of early PTLD, via primary infection or reactivation of quiescent virus, but the role of EBV in PTLD occurring late posttransplantation and in monomorphic PTLD is less clear (2,4).…”

Section: Introductionmentioning

confidence: 99%

“…Epstein-Barr virus (EBV) infection tends to drive the pathogenesis of early PTLD, via primary infection or reactivation of quiescent virus, but the role of EBV in PTLD occurring late posttransplantation and in monomorphic PTLD is less clear (2,4). The incidence of PTLD in adult SOT is highest in multivisceral and intestinal (3-7%) and lowest in renal transplants (1-3%), mainly attributed to lymphocyte load in the allograft and intensity of immunosuppression (5)(6)(7)(8)(9)(10)(11)(12). In contrast to SOT and HSCT, no cases of PTLD have been reported to date after clinical islet transplantation despite the prolonged immunosuppression required.…”

Section: Introductionmentioning

confidence: 99%

Posttransplant Lymphoproliferative Disorder After Clinical Islet Transplantation: Report of the First Two Cases

Peters

Olateju

Deschênes

et al. 2017

American Journal of Transplantation

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We report the first two cases of posttransplant lymphoproliferative disorder (PTLD) in recipients of islet transplants worldwide. First, a 44-year-old recipient of three islet infusions developed PTLD 80 months after his initial transplantation, presenting with abdominal pain and diffuse terminal ileum thickening on imaging. He was treated with surgical excision, reduction of immunosuppression, and rituximab. Seven months later, he developed central nervous system PTLD, presenting with vertigo and diplopia; immunosuppression was discontinued, resulting in graft loss, and he was given high-dose methotrexate and underwent consolidative autologous stem cell transplantation. He remains in remission 37 months after the initial diagnosis. Second, a 58-year-old female recipient of two islet infusions developed PTLD 24 months after initial islet infusion, presenting with pancytopenia secondary to extensive bone marrow involvement. Immunosuppression was discontinued, resulting in graft loss, and she received rituximab and chemotherapy, achieving complete remission. Both patients were monomorphic B cell PTLD subtype by histology and negative for Epstein-Barr virus in tissue or blood. These cases document the first occurrences of this rare complication in islet transplantation, likely secondary to prolonged, intensive immunosuppression, and highlight the varying clinical manifestations of PTLD. Further studies are needed to determine incidence rate and risk factors in islet transplantation.

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“…We defined follow-up as the time from transplantation until re-transplantation, 80 years of age, death, or the end of follow-up (December 31, 2006), whichever occurred first. 11,12 We assessed the changes in maintenance immunosuppressive drugs prescribed at discharge by 1, tion]), that is, whether they remained on the drugs they were prescribed at discharge during follow-up or whether they were changed.…”

Section: Discussionmentioning

confidence: 99%

“…Record linkage was performed by the Australian Institute of Health and Welfare utilizing an established probabilistic record linkage algorithm. 10 We obtained ethical approval from the Australian Institute of Health and Welfare Institutional Review Board (IRB) (EC2008- [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] and all other relevant IRBs.…”

Section: Data Linkagementioning

confidence: 99%

Longitudinal immunosuppression data can minimize misclassification bias in solid organ transplantation cohorts

Laaksonen

Webster

McCaughan

et al. 2019

Clinical Transplantation

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Background: Most cohort studies investigating the effect of immunosuppression on transplant outcomes use drugs at first hospital discharge. We evaluated the extent of drug exposure misclassification and its impact on outcome prediction. Methods:We retrospectively collected longitudinal immunosuppression data, at discharge and at 1, 5, 10, and 15 years after transplantation, and outcomes for solid organ transplant recipients 1984-2006 (n = 3133). We compared the risk of death from exposure to individual immunosuppressive drugs (cyclosporine, tacrolimus, azathioprine, and mycophenolate) and dual therapies, as defined by discharge only vs longitudinal immunosuppression data, using adjusted Cox proportional hazards models. Results: During a median follow-up of 5.2 years, immunosuppressive drugs were altered for 947 (30%) recipients and 955 recipients died. Longitudinal receipt of cyclosporine and azathioprine were associated with an increased risk (HR 1.41, 95% CI 1.07-1.89, and HR 1.34, 95% CI 1.00-1.80), and mycophenolate with a reduced risk (HR 0.35, 0.16-0.78), of death. Recipients on mycophenolate and tacrolimus dual therapy had a lower risk of death compared to those on azathioprine and cyclosporine dual therapy (HR 0.30, 0.10-0.93). The increased risk of death associated with the receipt of cyclosporine or azathioprine was not shown in the analyses based on drugs allocated at discharge, and all of the associations between immunosuppressive regimens and death were strengthened in the analyses based on longitudinal immunosuppression data. Conclusions: Cohort findings based on immunosuppressive drugs allocated at discharge should be interpreted with caution due to potential exposure misclassification. The use of granular, longitudinal data on immunosuppressive regimens could improve prediction. K E Y W O R D S cohort, immunosuppression, longitudinal, misclassification, prediction, transplantation S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Laaksonen MA, Webster AC, McCaughan GW, Keogh AM, Grulich AE, Vajdic CM. Longitudinal immunosuppression data can minimize misclassification bias in solid organ transplantation cohorts.

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Iatrogenic immunosuppression and risk of non‐Hodgkin lymphoma in solid organ transplantation: A population‐based cohort study in Australia

Cited by 24 publications

References 44 publications

2,4-dichlorophenoxyacetic acid (2,4-D) and risk of non-Hodgkin lymphoma: a meta-analysis accounting for exposure levels

2,4-dichlorophenoxyacetic acid (2,4-D) and risk of non-Hodgkin lymphoma: a meta-analysis accounting for exposure levels

Posttransplant Lymphoproliferative Disorder After Clinical Islet Transplantation: Report of the First Two Cases

Longitudinal immunosuppression data can minimize misclassification bias in solid organ transplantation cohorts

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