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Validation of a Post-Transplant Lymphoproliferative Disorder Risk Prediction Score and Derivation of a New Prediction Score Using a National Bone Marrow Transplant Registry Database
Lee, C. C., Hsu, T. C., Kuo, C. C., Liu, M. A., Abdelfattah, A. M., Chang, C. N., Yao, M., Li, C. C., Wu, K. H., Chen, T. C., et al
The oncologist. 2021
Abstract
BACKGROUND We externally validated Fujimoto's Post-Transplant Lymphoproliferative Disorder (PTLD) scoring system for risk prediction by using the Taiwan Blood and Marrow Transplant Registry Database (TBMTRD), and aimed to create a superior scoring system using machine learning methods. MATERIALS AND METHODS Consecutive allogeneic hematopoietic cell transplant (HCT) recipients registered in the TBMTRD from 2009 to 2018 were included in this study. The Fujimoto PTLD score was calculated for each patient. The machine learning algorithm, LASSO, was used to construct a new score system, which was validated using the 5-fold cross validation method. RESULTS We identified 2,148 allogeneic HCT recipients, of which 57 (2.65%) developed PTLD in the TBMTRD. In this population, the probability for PTLD development by Fujimoto score at five years for patients in the low, intermediate, high and very high-risk groups were 1.15%, 3.06%, 4.09%, 8.97%, respectively. The score model had acceptable discrimination with a C-statistic of 0.65 and a near-perfect moderate calibration curve (HL test P of 0.81). Using LASSO regression analysis, a four-risk-group model was constructed and the new model showed better discrimination in the validation cohort when compared with The Fujimoto PTLD score (C-statistic: 0.75 vs. 0.65). CONCLUSION Our study demonstrated a more comprehensive model when compared with Fujimoto's PTLD scoring system, which included additional predictors identified through machine learning that may have enhanced discrimination. The widespread use of this promising tool for risk stratification of patients receiving HCT allows identification of high-risk patients that may benefit from preemptive treatment for PTLD. IMPLICATIONS FOR PRACTICE We validated the Fujimoto score for the prediction of PTLD development following HSCT in an external, independent, and nationally representative population. We also developed a more comprehensive model with enhanced discrimination for better risk stratification of patients receiving HSCT, potentially changing clinical managements in certain risk groups. Previously unreported risk factors associated with the development of PTLD after HSCT were identified using the machine learning algorithm, LASSO, including pre-HSCT medical history of mechanical ventilation, and the chemotherapy agents used in conditioning regimen.
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Low incidence of post-transplant lymphoproliferative disorder after allogeneic stem cell transplantation in patients with lymphoma treated with rituximab
Fujimoto, A., Hiramoto, N., Yamasaki, S., Inamoto, Y., Ogata, M., Sugio, Y., Fukuda, T., Uchida, N., Ikegame, K., Matsuoka, K. I., et al
Hematological oncology. 2020
Abstract
Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after hematopoietic stem cell transplantation (HSCT). Several studies of risk factors for PTLD have been reported; however, the probability of, and risk factors for, PTLD in patients with lymphoma are unknown. Japanese nationwide transplant registry data from 5270 patients with lymphoma after allogeneic HSCT were analyzed. Mature B-cell, T/NK-cell, and T-cell lymphoblastic subtypes accounted for 49%, 26%, and 9.6% of lymphoma cases, respectively. Rituximab was used in 1678 lymphoma patients, most of whom (89%) received HSCT for mature B-cell lymphoma. Thirty-one patients with lymphoma developed PTLD, representing a probability of 0.77% at 2 years post-HSCT, which did not differ significantly from that in patients with other diseases (P = 0.98). Year of HSCT after 2010 [hazard ratio (HR) = 5.6, 95% confidence interval (CI), 1.48-21.3], anti-thymocyte globulin (ATG) use in the conditioning regimen (HR = 4.5, 95% CI, 1.61-12.5), and no rituximab use before HSCT (HR = 3.2, 95% CI, 1.26-7.90) were identified as risk factors for PTLD. Probabilities of PTLD at 1 year post-HSCT according to rituximab and ATG use were 0.23% (rituximab+, ATG-), 0.75% (rituximab-, ATG-), 1.25% (rituximab+, ATG+), and 3.53% (rituximab-, ATG+). Regarding lymphoma subtypes, patients with mature B-cell lymphoma had the lowest incidence of PTLD (0.35% at 2 years). Among high-risk patients receiving ATG, the mortality rate due to infection was elevated in those previously treated with rituximab (22%) relative to those without (14%); however, the difference was not significant (P = 0.10). Rituximab use before HSCT significantly reduces the risk of PTLD. Adding rituximab to the conditioning regimen is potentially a good strategy to prevent the development of PTLD in high-risk patients. This article is protected by copyright. All rights reserved.
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Survival Outcomes of Allogeneic Hematopoietic Cell Transplants with EBV positive or EBV negative Post Transplant Lymphoproliferative Disorder (PTLD), A CIBMTR Study
Naik, S., Riches, M., Hari, P., Soyoung, K., Chen, M., Bachier, C., Shaughnessy, P., Hill, J., Ljungman, P., Battiwalla, M., et al
Transplant infectious disease : an official journal of the Transplantation Society. 2019;:e13145
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Abstract
BACKGROUND Post-transplant lymphoproliferative disorders (PTLD) are associated with significant morbidity and mortality following allogeneic hematopoietic cell transplant (alloHCT). Although most PTLD is EBV-positive (EBVpos), EBV-negative (EBVneg) PTLD is reported; yet its incidence and clinical impact remain largely undefined. Furthermore, factors at the time of transplant impacting survival following PTLD are not well described. METHODS Between 2002 and 2014, 432 cases of PTLD following alloHCT were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). After exclusions, 267 cases (EBVpos = 222, 83%; EBVneg = 45, 17%) were analyzed. RESULTS Two-hundred and eight patients (78%) received in vivo T-cell depletion (TCD) with either anti-thymocyte globulin (ATG) or alemtuzumab. Incidence of PTLD was highest using umbilical cord donors (UCB, 1.60%) and lowest using matched related donors (MRD, 0.40%). Clinical features and histology did not significantly differ among EBVpos or EBVneg PTLD cases except that absolute lymphocyte count recovery was slower and CMV reactivation was later in EBVneg PTLD [EBVpos 32 (5 - 95) days versus EBVneg 47 (10 - 70) days, p=0.016]. There was no impact on survival by EBV-status in multivariable analysis [EBVneg RR 1.42, 95% CI 0.94-2.15, p = 0.097]. CONCLUSIONS There is no difference in survival outcomes for patients with EBVpos or EBVneg PTLD occurring following alloHCT and 1-year survival is poor. Features of conditioning and use of serotherapy remain important. This article is protected by copyright. All rights reserved.
PICO Summary
Population
Cases of Post-transplant lymphoproliferative disorder (PTLD) following alloHCT reported to the Center for International Blood and Marrow Transplant Research (n=267).
Intervention
EBV positive cases (n=222).
Comparison
EBV negative cases (n=45).
Outcome
Incidence of PTLD was highest using umbilical cord donors (UCB, 1.60%) and lowest using matched related donors (MRD, 0.40%). Clinical features and histology did not significantly differ among EBVpos or EBVneg PTLD cases except that absolute lymphocyte count recovery was slower and CMV reactivation was later in EBVneg PTLD [EBVpos 32 (5 - 95) days versus EBVneg 47 (10 - 70) days]. There was no impact on survival by EBV-status in multivariable analysis.
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Risk factors and predictive scoring system for post-transplant lymphoproliferative disorder after hematopoietic stem cell transplantation
Fujimoto, A., Hiramoto, N., Yamasaki, S., Inamoto, Y., Uchida, N., Maeda, T., Mori, T., Kanda, Y., Kondo, T., Shiratori, S., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
We analyzed data of 64,539 consecutive patients in the national Japanese transplant registry, including 40,195 after allogeneic stem cell transplantation, 24,215 after autologous stem cell transplantation, and 129 after syngeneic stem cell transplantation, and 299 developed Epstein-Barr virus positive post-transplant lymphoproliferative disorder. The probability at 2 years was 0.79% after allogeneic transplantation, 0.78% after syngeneic transplantation, and 0.11% after autologous transplantation. The following variables were identified as risk factors after allogeneic transplantation in multivariate analysis: antithymocyte globulin use in a conditioning regimen, antithymocyte globulin use for acute graft-versus-host disease treatment, donors other than HLA-matched related donors, aplastic anemia, second or subsequent allogeneic transplantation, the recent year of transplantation, and acute graft-versus-host disease. The probability at 2 years increased particularly after 2009 (1.24%) than before (0.45%). To stratify the risk of post-transplant lymphoproliferative disorder before allogeneic transplantation, a novel 5-point scoring system was generated based on three pre-transplant risk factors: antithymocyte globulin use in a conditioning regimen (high-dose, 2 points; low-dose, 1 point), donor type (HLA-mismatched related donor, 1 point; unrelated donor, 1 point; cord blood, 2 points), and aplastic anemia (1 point). Patients were classified into 4 risk groups according to the summed points: low- (0 or 1 point), intermediate- (2 points), high- (3 points), and very high-risk (4 or 5 points) groups with probabilities at 2 years of 0.3, 1.3, 4.6, and 11.5%, respectively. Our scoring system is useful for predicting patients at high risk of post-transplant lymphoproliferative disorder. Careful observation and close monitoring of Epstein-Barr virus reactivation are warranted for these high-risk patients.
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Posttransplant monomorphic Burkitt's lymphoma: clinical characteristics and outcome of a multicenter series
Bobillo, S., Abrisqueta, P., Sanchez-Gonzalez, B., Gine, E., Romero, S., Alcoceba, M., Gonzalez-Barca, E., Gonzalez de Villambrosia, S., Sancho, J. M., Gomez, P., et al
Annals of hematology. 2018
Abstract
Burkitt's monomorphic posttransplant lymphoproliferative disorder (B-PTLD) is an uncommon subtype of PTLD. Owing to the paucity of this complication, clinical characteristics and outcome has not been fully described. Clinical characteristics and outcomes of 20 patients diagnosed with B-PTLD from 10 transplant centers belonging to the GEL/TAMO group were reviewed. Median time from transplant to B-PTLD was 7.2 years. All the cases fulfill the morphologic and genetic criteria of B-PTLD, whereas Epstein-Barr virus (EBV) was detected in 70% of cases. Patients were treated with different chemotherapy combinations, and three patients received upfront rituximab monotherapy. The great majority of patients receiving CHOP-like regimens attained a complete response (CR) (73%), similar to that obtained with dose-intensive chemotherapy (83% CR). In contrast, patients receiving upfront rituximab monotherapy required subsequent chemotherapy. Two patients (10%) died during treatment due to infection. The median progression-free survival and overall survival (OS) were 16 months and 139 months, respectively. When analyzing variables predicting for OS, we found that patients with bone marrow involvement had an adverse prognosis, with a median OS of 6 months (p = 0.008). In conclusion, B-PTLD is an uncommon complication usually associated with EBV infection and with an aggressive clinical course, particularly in patients with bone marrow involvement. High-dose chemoimmunotherapy obtained similar responses to R-CHOP, suggesting that R-CHOP could be an adequate alternative for these patients. In contrast, rituximab monotherapy does not seem to be effective enough to control the disease.