Risk Of Post-transplant Malignancies Research Articles

Malignancies in adult kidney transplant candidates and recipients: current status.

Posttransplant malignancies, particularly recurrent and de novo, in solid organs including kidney transplant recipients (KTRs) are a significant complication associated with substantial mortality, largely attributed to the long-term immunosuppression necessary to maintain allograft tolerance. Older age at transplantation and oncogenic virus infection along with pretransplant malignancies are among the main factors contributing to the risk of cancer in this population. As the mean age of transplant candidates rises, the rate of transplant recipients with pretransplant malignancies also increases. The eligibility criteria for transplantation in patients with prior cancer have recently changed. The overall risk of posttransplant malignancies is at least double after transplantation, including KTRs, relative to the general population, and is most pronounced for skin cancers associated with UV radiation and virally mediated tumors. The risk of renal cell carcinoma is specifically increased in the kidney transplant population. The therapy for cancer in transplant patients is associated with risk of higher toxicity, and graft rejection and/or impairment, which poses a unique challenge in its management. Reduction of immunosuppression and the use of mammalian target of rapamycin inhibitors are common after cancer diagnosis, although optimal immunosuppression for transplant recipients with cancer remains undefined. Suboptimal cancer treatment contributing to a worse prognosis has been reported for malignancies in this population. In this article, we focus on the prevalence and outcomes of posttransplant malignancies, cancer therapy including a short overview of immunotherapy, cancer screening and prevention strategies, and immunosuppression as a cancer risk factor. The 2020/2021 recommendations of the Kidney Disease: Improving Global Outcomes and the American Society of Transplantation for transplant candidates with a history of cancer are presented.

Immune Activation, Exhaustion and Senescence Profiles as Possible Predictors of Cancer in Liver Transplanted Patients

Liver transplanted (LT) patients for hepatocellular carcinoma (LT-HCC) or for other causes (LT-no-HCC) may develop post-transplantation malignancies. Although immune activation and senescence are frequently implicated in cancer development, no data is available on their possible role as biomarkers predictive of tumor onset in this setting. A total of 116 patients were investigated: the 45 LT-HCC patients were older than the 71 LT-non-HCC (p=0.011), but comparable for sex, HCV, HBV infection and immunosuppressive treatment. At baseline, the numbers of activated and senescent-like circulating cells were significantly higher in LT-HCC patients than in LT-no-HCC ones. After a median follow-up of 26.8 months, 6 post-transplant malignancies (PTM) occurred: 4 in LT-HCC (8.9%) and 2 in LT-no-HCC (2.8%) patients. Overall, subjects with high percentages of activated and exhausted T and B cells at baseline were at higher risk of PTM. Notably, within the LT-HCC group, a higher percentage of senescence-like T cells was also associated with cancer development. Moreover, patients with PTM had higher telomere erosion and higher levels of circulating PAMPs (16S rDNA) and DAMPs (mtDNA) when compared with matched patients without PTM. Overall, these findings suggest that immune activation and exhaustion may be useful to predict the risk of PTM occurrence, regardless of the cause of transplantation. In LT-HCC, T-cell senescence represents an additional risk factor for tumor onset.

Risk of malignancy in kidney transplant recipients: a nationwide population-based cohort study

BackgroundPost-transplant malignancy is major morbidity complicated in kidney transplantation (KT). In Korea, a few studies have investigated the sex- and age-dependent risk for post-transplant malignancy among KT recipients on a large scale.MethodsWe utilized a national health insurance database in Korea to investigate the relative risk of post-transplant malignancy in 12,634 KT recipients between 2007 and 2017. The same number of patients with acute appendicitis was included as a control group. The relative risk of malignancy was estimated using a multivariable-adjusted Cox model, and interaction analysis was performed to investigate age- and sex-predominant patterns.ResultsKT recipients had an overall 1.8-fold higher risk for post-transplant malignancy with an increased risk for 14 of 29 cancer types, among which Kaposi’s sarcoma, non-Hodgkin’s lymphoma, kidney, uterus, and bladder/urinary tract cancers were most prominent. Although the overall risk for post-transplant malignancy was similar between male and female KT recipients, head and neck cancer had a higher risk among male KT recipients, whereas non-Hodgkin’s lymphoma and bladder/urinary tract cancer had a higher risk among female KT recipients. Overall, the young (< 50 years) KT recipients had a higher risk for post-transplant malignancy than older ones (≥ 50 years), whose pattern was most prominent in non-Hodgkin’s lymphoma. In contrast, breast and nonmelanoma skin cancer showed a higher risk among older KT recipients.ConclusionKT recipients had an increased risk for a wide range of cancer types, some of which showed differential risk patterns with age and sex. Our result suggests that focused screening for predominant post-transplant malignancies may be an effective strategy for selected KT recipients.

Post-transplant malignancies in solid organ recipients: development mechanisms and risk factors

According to the International Agency for Research on Cancer, there were an estimated 19,292,789 new cancer cases in various localizations and 9,958,133 cancer deaths worldwide in 2020. These frightening figures clearly show that malignancies among the population is a pressing matter. The risk of post-transplant malignancy in solid organ recipients is 2–6-times higher than in the general population. Given the steadily increasing number of solid organ transplants worldwide and the gradual increase in life expectancy among organ recipients, studying the issues concerning risk factors and development mechanisms becomes a crucial task.

Incidence and Risk Factors for Second Malignancies after Transplant in Long Term Survivors of Allogeneic Haematopoietic Stem Cell Transplant: A Single Centre Experience

Second malignancies are well recognised complications of haematopoietic stem cell transplantation (HCT). The incidence increases with time after HCT with no evidence of plateau with follow up times of 15-20 years. In this study we have investigated patients over a 37-year period to include all patients transplanted at The Hammersmith hospital since 1979 who survived a minimum of two years after transplant. We aimed to describe the post-transplant malignancies (PTM) that occurred and calculate the cumulative incidence with time.MethodsData was gathered through internal databases and supplemented with case notes with all patients giving consent for their data to be used in clinical studies. Additional information on patients who had died at the time of analysis included review of death certificates for evidence of a second malignancy. If a patient had not been seen within 5 years evidence of death was sought on the NHS Spine and if apparently still alive, the date of last follow up was taken as follow up time. Second malignancies included second solid neoplasms (SSN), non-melanoma skin cancer (NMSC) and leukemias/lymphomas. These were recorded and categorised in accordance with the international classification of disease for oncology (ICD-O).Results697 patients survived a minimum of two years after HCT between 1979-2018, 60% of whom were male. Follow up was prolonged with 20% of our 2-year survivors followed up for more than 20 years. The majority of patient (80%) were aged between 20-50 at time of HCT. (median age 35.6y, range 4-69) with only 7 patients < 10 y at HCT. The most frequent diagnoses were CML (n=463) or AML (n=103). The majority of patients (n=538, 77%) had received TBI, and the most frequently used conditioning was Cyclo-TBI (479 patients, 69%). At the time of analysis, 222 patients had died and of the remaining 475, 107 were lost to follow up.We identified 97 PTM in 87 patients a median of 14.2 years post HCT (range 0.8-35.9 years). These included 58 cases of SSN, 28 cases of NMSC and 11 cases of leukemia or lymphoma. The most frequent SSN were breast (n=12), tongue (n=7), colorectal (n=6), melanoma (n=5), bladder (n=4), thyroid (n=3) and oesophagus (n=3). Of 28 patients with NMSC, 19 developed one or more BCC and 9 developed SCC.The cumulative incidence of PTMs did not plateau with time. Cumulative incidences were as follows with 95% confidence intervals (CI) in parentheses: 4.9% (3.3-7.3) at 10 years, 12.2% (9.1-16.2) at 15 years, 22.5% (17.6-28.9) at 20 years, 39% (30.3-48.4) at 25 years and 53% (41.6-64.1) at 30 years. These data reflected the substantial increases in the CI of SSN and NMSC between these time points. For SSN the cumulative incidence increased from 3% (1.8-5) at 10 years to 37.9% (27.4-49.6) at 30 years; for NMSC the cumulative incidence increased from 1.3% (0.6-2.7) at 10 years 16.6% (9.2-28.2) at 30 years.In multivariate analyses older age (>50) at time of transplant was associated with significantly increased (p<0.01) risk of PTM with a relative risk (RR) of 4.53 (2.1-9.6). On subgroup analysis this was only relevant to SSN where the RR was 5.17 (2.2-12.1). Patient/donor sex combinations other than male patient/male donor were also at increased risk of PTM, RR 1.797 (1.1-2.9), p=0.033, and again this was only significant for SSN (RR 2.11, 1.13-3.93).Discussion and conclusionsIn this predominantly adult study, the cumulative incidence of SSN and NMSC increased substantially with time after HCT beyond a 10-year follow-up period. The risk was increased in patients who were >50 at time of HCT. Prolonged expert follow-up with a high index of suspicion for second malignancy in these patients is recommended to facilitate early diagnosis. DisclosuresApperley:Novartis: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Milojkovic:Incyte: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

P156 Allelic and epitope HLA mismatch analysis in lung transplant

Aim The urgent need for donor lungs and a shortage of suitable organs requires transplantation of HLA mismatched donor:recipient pairs. Post-transplant high resolution HLA typing of the donor and recipient, if available, presents a post hoc opportunity to investigate comparative allelic and epitope mismatch strategies to predict post-transplant events and optimize immunosuppressive therapy. Methods Thirty donor-recipient lung transplant pairs with available extracted DNA were studied (De Vlaminck et al. (2015)). High resolution NGS HLA typing required targeted sequencing and was performed according to Moonsamy et al. (2013). Respective two-region HLA types were assigned using Conexio ASSIGN ATF 454 software and compared to the catalog of common and well-documented HLA alleles. Epitope mismatches were determined using HLAMatchmaker. Prior transplant studies noted the importance of HLA-A, HLA-B and DRB1 for short and long term survival and therefore were selected for this study. Results Thirty lung transplant pairs had 3 (n = 1), 4 (5), 5 (10) and 6 (14) HLA-A, HLA-B and HLA DRB1 allelic mismatches. Epitope mismatches ranged from 16–51. The epitope mismatch extremes each had 6 allelic mismatches: 16: HLA-A,-B 9; DRB1 7 and 51: HLA-A,-B 19; DRB1 32. The single 3 allelic mismatch pair had 31 epitope mismatches: HLA-A,-B 10; DRB1 21. DRB1 epitope mismatch contribution to total epitope mismatches ranged from 19% to 63%. Conclusions Allelic (antigenic) mismatches have a more limited range than epitope (immunogenic) mismatches, and mismatch burdens using these two models varied considerably in lung transplants in this study. The relative contribution of epitope mismatches in HLA-A, HLA-B and DRB1 varies in transplant donor recipient pairs. Prognostic estimates of antibody mediated rejection to inform surveillance and increased risk of post-transplant malignancies and infection to inform long term immunosuppressive therapy merit investigation using epitope mismatch burden.

Post-Transplant Malignancy after Pediatric Kidney Transplantation: Retrospective Analysis of Incidence and Risk Factors in 884 Patients Receiving Transplants Between 1963 and 2015 at the University of Minnesota

Post-transplant malignancy (PTM) remains a concern among pediatric kidney transplant (PKT) recipients. Between 1963 and 2015, 884 pediatric (age 0 to 17 years old) patients received 1,055 PKTs at our institution. Cox proportional hazards models were constructed to identify risk factors for PTM after PKT with time-to-first-PTM as a primary outcome. Secondly, the hazard of death or graft loss was calculated in patients who developed PTM. Median patient survival was 33 years (interquartile range [IQR] 18.7 to 47 years); 260 patients died during the study period and 47 had been diagnosed with PTM. There were 235 PTMs that occurred in 136 (15.4%) recipients at a median age of 29 years (IQR 17.8 to 37 years). The percentages of patients with PTM were 13% at 20 years post-PKT and 26% at 30 years post-PKT. Of PTM patients who died, 63.8% died of PTM. Among those who developed PTM, there was a higher hazard of death or graft loss (hazard ratio [HR] 1.62; 95% CI 1.11 to 2.38). In multivariable proportional hazards models, factors associated with PTM were increasing age at PKT (adjusted HR [AHR] 3.14; 95% CI 1.80 to 5.48 for 14 to 17 year-olds compared with children less than 3 years), having a living unrelated donor (LURD; AHR 3.25; 95% CI 1.27 to 8.35 compared with a living related donor), or implanting an Epstein-Barr virus (EBV)-positive allograft in an EBV-negative recipient (AHR 5.66; 95% CI 1.11 to 29.0). Compared with the general population, the cancer rate for PKT recipients was 6 times higher (126 vs 21 per 100,000 person-years). Pediatric kidney transplant recipients are at increased risk of PTM, which adversely affects survival. Children receiving transplants at an older age, from a LURD, or who receive an EBV-positive organ, should be monitored closely forthedevelopment of PTM.

Association of Pretransplant Skin Cancer With Posttransplant Malignancy, Graft Failure and Death in Kidney Transplant Recipients

Posttransplant malignancy (PTM) is one of the leading causes of late death in kidney recipients. Those with a cancer history may be more prone to develop a recurrent or a new cancer. We studied the association between pretransplant skin cancer, PTM, death, and graft failure. Primary adult kidney recipients transplanted between 2005 and 2013 were included. Malignancy information was obtained from Organ Procurement Kidney Transplant Network/United Network for Organ Sharing registration and follow-up forms. Posttransplant malignancy was classified into skin cancer, solid tumor, and posttransplant lymphoproliferative disorder (PTLD). Competing risk and survival analysis with adjustment for confounders were used to calculate risk for PTM, death and graft failure in recipients with pretransplant skin cancer compared with those without cancer. Risk was reported in hazard ratios (HR) with 95% confidence interval (CI). The cohort included 1671 recipients with and 102 961 without pretransplant skin malignancy. The 5-year cumulative incidence of PTM in patients with and without a pretransplant skin cancer history was 31.6% and 7.4%, respectively (P < 0.001). Recipients with pretransplant skin cancer had increased risk of PTM (sub-HR [SHR], 2.60; 95% CI, 2.27-2.98), and posttransplant skin cancer (SHR, 2.92; 95% CI, 2.52-3.39), PTLD (SHR, 1.93; 95% CI, 1.01-3.66), solid tumor (SHR, 1.44; 95% CI, 1.04-1.99), death (HR, 1.20; 95% CI, 1.07-1.34), and graft failure (HR, 1.17; 95% CI, 1.05-1.30) when compared with those without pretransplant malignancy. Pretransplant skin cancer was associated with an increased risk of posttransplant skin cancer, PTLD, solid organ cancer, death and graft failure.

Risk Factors for Post Transplant Malignancy After Heart Transplantation.

Background: One of the major causes of death in heart transplantation (OHT) is post transplant malignancy. Our objective is to identify risk factors for malignancy after OHT. Methods: Adult primary OHT recipients reported to the Organ Procurement and Transplantation Network/United Network for Organ Sharing from 2000-2012 were included (n=46,113). Cancer-free survival time was calculated. Multivariate Cox regression analysis was performed to characterize risk factors for post-OHT malignancy. Results: Post transplant malignancy was reported at least once in 7,427 recipients (16.1%). Median time to malignancy was 4.8 years (interquartile range: 1.4-9.0). The distribution of cancers included: skin cancer (9.2%), solid tumors (7.2%), and post transplant lymphoproliferative disease (1.6%). Pre-transplant malignancy, age 40-59 years, age ≥60 years, male gender, and white race were associated with an increased risk of post transplant malignancy (HR=1.76, 3.09, 5.44, 1.53, 2.39; all P<0.001, respectively).Figure: No Caption available.Conclusions: Our study showed that pre-transplant malignancy, older age, male recipient, and white race were associated with an increased risk of post-OHT malignancy.

Oral active vitamin d therapy as a potential chemoprevention against post-transplant malignancy

Post-transplant malignancy (PTM) is a limiting factor for both patient and allograft survival in kidney transplant recipients (KTRs). We hypothesized that active vitamin D compounds (AVDs) could reduce the development of PTM in KTRs and evaluated the effects of AVD therapy in a prospective cohort of ambulatory KTRs in a Japanese single center. We used a propensity score (PS) of having received AVDs estimated by 25 clinically relevant factors to adjust for these confounders. Among 218 participants, the mean age was 49.4 (SD, 12.1) years, 63.3% were male, the median time since transplantation was 11.2 (interquartile range [IQR], 5.2–17.1) years, and 42.2% had been treated with AVDs at baseline. The AVDs consisted of calcitriol (58.7%) and alfacalcidol (41.3%), and their median doses were 0.5 (IQR, 0.5–0.5) μg and 0.5 (IQR, 0.25–1.0) μg, respectively. During a median follow-up of 2.9 (IQR, 2.1–3.0) years, PTM was observed to have developed in 5 (5.4%) of 92 AVD users and in 11 (8.7%) of 126 non-users. Cox regression analysis with stratification by the PS tertiles showed that AVDs were significantly associated with a lower risk of PTM (hazard ratio, 0.25 [95% confidence interval, 0.07–0.82], P=0.022). The level of serum 25-hydroxyvitamin D was generally low (median, 16.6 ng/ml), and not significantly associated with PTM. Sensitivity analyses with stratification by PS quartiles, PS matching, or inverse probability weighting yielded similar results. Our results suggest a novel potential strategy to prevent PTM by using a normal dose of AVDs with a well-known safety profile. A randomized controlled trial should be performed to confirm our findings.

Post-transplant malignancy: reducing the risk in kidney transplant recipients

Introduction: The growing and aging of the end-stage kidney disease population, and improvements in short-term kidney transplant outcomes, have increased the number of patients receiving and living with kidney transplants who are at risk for the long-term complications of transplantation. Cancer has become a major cause of death following kidney transplantation, increasing the need to better understand the risk of post-transplant malignancy and to adapt patient management to minimize that risk.Areas covered: This paper reviews the scope of the problem of post-transplant malignancy, its pathogenesis, and strategies for prevention, with attention to the impact of various immunosuppressive strategies. A Medline search was conducted, reviewing English-language publications from 1948 to February 2011.Expert opinion: Post-transplant malignancy, one of the most common causes of death following transplantation, is linked to both modifiable and non-modifiable risk factors. The current armamentarium of pharmacotherapy and the possibilities for immunologic monitoring in the future hold the potential for tailoring post-transplant care to minimize the risk of post-transplant malignancy without sacrificing graft survival to optimize outcomes following transplantation.

The role of mTOR inhibition in renal transplant immune suppression

AbstractThe mammalian target of rapamycin inhibitors (mTOR‐Is) sirolimus and everolimus represent a class of proliferation signal inhibitors with a wide spectrum of activities, including suppression of T‐cell proliferation and reduction of tumor growth. In solid‐organ transplantation, mTOR inhibitors are an option for maintenance immune suppression due to their relative lack of nephrotoxicity compared with the current backbone of most regimens, the calcineurin inhibitors (CNIs). This property, in conjunction with their unique pharmacology, allows mTOR‐Is to be used as an adjunct or alternative to CNIs. Earlier studies of their use in de novo renal transplantation have delineated potential strategies for use of this class of drugs in groups of patients in whom mTOR inhibition may be useful. From recent kidney studies it appears that the time for introduction of mTOR‐I therapy may be prior to the development of proteinuria or significant graft deterioration. Consideration should also be given to the use of mTOR‐Is in patients with or at high risk of post‐transplant malignancy. Due to potential toxicities, knowledge of the adverse effects and pharmacokinetic profiles of mTOR‐Is is necessary for proper management of patients receiving these agents.

Association of Type of Induction with Posttransplant Lymphoproliferative Disorders

Association of Type of Induction with Posttransplant Lymphoproliferative Disorders

Immunosuppression and the Risk of Post-Transplant Malignancy Among Cadaveric First Kidney Transplant Recipients

The success of renal transplantation may be counterbalanced by serious adverse medical events. The effect of immunosuppression on the incidence of de novo neoplasms among kidney recipients should be monitored continuously. Using data from the Scientific Registry of Transplant Recipients, we studied the association of induction therapy by immunosuppression with antilymphocyte antibodies, with the development of de novo neoplasms. The study population included more than 41 000 recipients who received a cadaveric first kidney transplant after December 31, 1995, and were followed through February 28, 2002.Using Cox regression models, we estimated time to development of two types of malignancy: de novo solid tumors and post-transplant lymphoproliferative disorder (PTLD). We made adjustments for several patient demographic factors and comorbidities.Induction therapy was significantly associated with a higher relative risk (RR) of PTLD (RR = 1.78, p < 0.001), but not with a greater likelihood of de novo tumors (RR = 1.07, p = 0.42). Treatment with maintenance tacrolimus vs. cyclosporine showed a significantly different RR of developing de novo tumors for recipients with induction than for those not receiving induction (p = 0.024). These new estimates of the magnitude of malignancy risk associated with induction therapy may be useful for clinical practice.

New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors.

To determine the incidence and risk factors for the development of new malignancies occurring after stem-cell transplantation (SCT). Between January 1, 1974, and March 31, 2001, 3,372 patients underwent SCT at the University of Minnesota. From these transplants, 147 posttransplant malignancies (PTMs) were identified in 137 patients. Excluding nonmelanoma skin cancers (n = 19) and carcinoma-in-situ (n = 5), the remaining 123 cases represented an 8.1-fold (95% confidence interval [CI], 6.7 to 9.6) increased risk of a PTM, an excess risk of 102.7 cases/10,000 persons/yr (age and sex adjusted). This includes a significantly elevated risk for developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML; standardized incidence ratio [SIR] = 300; 95% CI, 210 to 406), non-Hodgkin's lymphoma including posttransplant lymphoproliferative disorder (PTLD; SIR = 54.3; 95% CI, 39.5 to 41.1), Hodgkin's disease (SIR = 14.8; 95% CI, 3.9 to 32.9), or solid tumors overall (SIR = 2.8; CI, 2.0 to 3.7) and in specific for melanoma, brain, and oral cavity tumors. The cumulative incidence for the development of any PTM was 6.9% (95% CI, 5.2 to 8.6) at 20 years post-SCT. For PTLD (n = 43), the cumulative incidence plateaued at 1.4% (95% CI, 1.0 to 1.8) by 10 years post-SCT. For MDS or AML, the cumulative incidence plateaued at 1.4% (95% CI, 0.9 to 1.9) by 10 years post-SCT. The cumulative incidence of developing a solid tumor did not plateau and was 3.8% (95% CI, 2.2 to 5.4) at 20 years post-SCT. These data reveal that the risk of PTMs, especially solid tumors, continues to increase even 20 years after transplant, necessitating long-term close follow-up for these patients.