Epstein-Barr virus (EBV)-induced post-transplant lymphoproliferative disorder (PTLD)occurs frequently when rabbit antithymocyte globulin (ATG) is used in hematopoietic cell transplant (HCT) conditioning. We retrospectively studied 554 patients undergoing ATG-conditioned myeloablative HCT. Strategies used to minimize mortality due to PTLD were either therapy of biopsy-diagnosed PTLD in the absence of EBV DNAemia monitoring (n = 266) or prompt therapy of presumed PTLD (based on clinical/radiologic signs and high EBV DNAemia, in the setting of weekly EBV DNAemia monitoring) (n = 199). Both strategies resulted in similar mortality due to PTLD (0.7% vs 1% at 2 years, P = .43) and similar overall survival (63% vs 67% at 2 years, P = .23) even though there was a trend toward higher PTLD incidence with the prompt therapy.Donor positive with recipient negative EBV (D+R−) serostatus was a risk factor for developing PTLD. Older patient age, HLA-mismatched donor, and graft-versus-host disease were not associated with increased risk of PTLD. In summary, in ATGconditioned HCT, D+R− serostatus, but not older age, mismatched donor or GVHD is a risk factor for developing PTLD. EBV DNAemia monitoring may be a weak risk factor for developing/diagnosing PTLD; the monitoring coupled with prompt therapy does not improve survival. K E Y W O R D SEpstein-Barr virus, post-transplant lymphoproliferative disorder, prompt therapy, rituximab
Introduction: Sickle cell disease (SCD) is associated with major morbidity and mortality and yet many of our patients are not using the available disease modifying medication, hydroxyurea (HU). Furthermore, dose-titration of HU is required in order to achieve the maximum therapeutic benefit. Certain challenges can limit HU acceptance, such as misconceptions about safety, frequency of monitoring, and ease of access (i.e. insurance). Incorporating a pharmacist-managed HU hydroxyurea prescribing protocol into the SARBBD Comprehensive Care Program will help to address many of the barriers responsible for poor HU uptake among SCD patients and improve HU utilization. Objectives: To improve the uptake and optimization of HU among patients with Sickle Cell Disease within the SARBBD Comprehensive Care Program. Methods: Commencing in January 2020, clinic pharmacist support of 0.2 full-time equivalents (FTEs) was made available to the SARBBD program, and a pharmacist-led comprehensive HU prescribing protocol was adapted from the current CanHaem and National Heart, Lung, and Blood Institute guidelines. The clinical pharmacist was available for all Sickle Cell Disease clinic appointments, and was responsible for all aspects of HU management, including educating, counselling, and prescribing (titrating and monitoring as outlined in the prescribing protocol). It is worth noting that independent pharmacist prescribing is permitted in Alberta (Alberta College of Pharmacists, 2021). Patients were initiated on HU at a low dose of 500 mg daily to limit gastrointestinal sensitivities, and then increased to 1000 mg daily after one week. Thereafter the dose was titrated every 2-4 weeks as permitted by the patient's tolerance and laboratory parameters (i.e., CBC, liver and renal function, reticulocyte count) up to their maximum tolerated dose (MTD), defined as the maximum dose that maintains neutrophils ≥ 1.5 x 10 9/L, platelets > 80 x 10 9/L, and hemoglobin > 50 x 10 9/L. Following HU initiation and after every laboratory visit, the clinical pharmacist followed-up with patients via telephone to discuss HU tolerance, adherence, and dosing. Perceived benefits (i.e., pain episodes), medication supply, drug access (insurance), and planning for future follow-ups were also addressed as necessary. Results: As of January 2020, the SARBBD program provided care to 119 patients with SCD. Of those patients, 7 patients were managed with a transfusion exchange protocol, and therefore were not considered HU candidates. Of the 112 eligible SCD patients, 39 (34.8%) were already on HU therapy, 15 of whom were at MTD (38.4% of HU patients, 13.4% of 112 eligible SCD population). By June 2021 (18 months of pharmacist managed HU), there were 123 eligible SCD patients, of whom 71 were on HU (57.7%), with 37 at MTD (52.1% of HU patients, 30.1% of total eligible SCD population). Every month on average the pharmacist; has 27 interactions (phone, email) with SCD patients, reviews 18 lab reports, initiates HU for 2 patients, and will make over 4 dose adjustments. A majority of patient interactions involved educating patients on HU, and addressing common misconceptions about HU adverse effects and risks. Further, a significant proportion of HU initiations required pharmacist assistance with insurance authorization. Overall, patient acceptance of the pharmacist-managed HU prescribing was positive. One patient commented, "Working with [the pharmacist] has been great as he diligently has been able to keep a close eye on my blood results while making adjustments to my dosage of HU, without requiring a visit to the doctor. This was great as it didn't tie the doctors up, but also I was able to communicate with [the pharmacist] and get the same information at a convenient time. [The pharmacist] has also been extremely supportive, open and positive while answering questions". Conclusion: Incorporating a pharmacist into the SARBBD program, as well as implementing a pharmacist-managed HU prescribing protocol has led to improved HU uptake and optimization. In addition, a greater proportion of patients have been able to reach MTD. The most common barriers to HU utilization, such as miseducation, frequency of laboratory monitoring, and medication access, can be overcome with dedicated pharmacist involvement. Funding: Sickle Cell Disease Association of Canada (SCDAC) grant and Novo Nordisk Investigator Initiated Grant Disclosures Poon: University of Calgary: Current Employment; Bayer: Honoraria, Research Funding; CSL-Behring: Honoraria, Research Funding; Bioverativ/Sanofi: Honoraria; Novo Nordisk: Honoraria; Pfizer: Honoraria; Roche: Honoraria; Takeda: Honoraria. Lee: Bayer: Research Funding, Speakers Bureau; Biovertiv/Sanofi: Honoraria, Research Funding; CSL Behring: Honoraria; Novo Nordisk: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Roche: Honoraria; Takeda: Honoraria.
Introduction: Epstein-Barr virus (EBV)-induced posttransplant lymphoproliferative disorder (PTLD) incidence is particularly high when using graft versus host disease (GVHD) prophylaxis with rabbit antithymocyte globulin (ATG). Preemptive therapy with rituximab given when EBV DNAemia exceeds a threshold has been adopted by some centers. However, this exposes a large fraction of patients to rituximab, which is costly and toxic (neutropenia). Wagner et al suggested a high efficacy of prompt therapy (monitoring EBV DNAemia, having a high index of suspicion for PTLD in patients with high DNAemia, and treating PTLD with rituximab at a presumed early stage)(Blood 103:3979, 2004). In Alberta, we adopted the prompt therapy in 2012. Here we report our experience. Methods: We retrospectively studied 511 patients undergoing myeloablative allogenic hematopoietic stem cell transplant (HCT). ATG (4.5 mg/kg) was used for GVHD prophylaxis in addition to methotrexate and cyclosporine. Between 1/2007 and 1/2011, no EBV monitoring was done and PTLD (usually histologically diagnosed, including Epstein-Barr encoding RNA [EBER] in situ hybridization) was treated with rituximab (period "No EBV Monitoring", 267 patients). Between 2/2011 and 4/2012, EBV monitoring (weekly till day 100) was done, but PTLD was treated with rituximab only when histologically diagnosed ("Transition" period, 88 patients). We noted that histologically proven PTLD occurred only with EBV DNAemia >40,000 genome copies/mL blood. Between 5/2012 and 12/2014, EBV monitoring was done, PTLD was diagnosed as clinical/radiological manifestation of PTLD with EBV DNAemia >40,000 and was treated with rituximab promptly (period "Prompt Therapy", 156 patients). We compared the "No EBV Monitoring" period with the "Prompt Therapy" period, using Fine-Gray analysis for cumulative incidence of PTLD, mortality due to PTLD or mortality associated with PTLD (death due to any cause after PTLD has been diagnosed) and Cox analysis for overall survival. Results: In all 3 periods combined, a total of 48 PTLDs developed at a median day 55 after HCT. 81% PTLDs occurred before day 100. Comparison of the "No EBV Monitoring" and the "Prompt Therapy" periods showed a non-significant trend toward a higher cumulative incidence of PTLD in the latter period (possibly due to the increased index of suspicion for PTLD in patients with high DNAemia), and no difference in mortality due to PTLD, mortality associated with PTLD, or overall survival (Figure 1). After rituximab, clinical/radiological regression of PTLD occurred in 15/21 (71%) patients in the No EBV Monitoring period and in 13/17 (76%) patients in the Prompt Therapy period (not significant). Next, we evaluated whether PTLD regression is associated with DNAemia becoming undetectable and progression with persistently detectable DNAemia. This was evaluated in patients from the "Transition" and the "Prompt Therapy" periods. As shown in Figure 2, all (7/7) patients with PTLD progression had persistently detectable DNAemia. Among patients with PTLD regression, DNAemia became undetectable in most (15/20) patients. 0/15 (0%) patients with persistently undetectable DNAemia developed PTLD progression, whereas 7/12 (58 %) patients with persistently detectable DNAemia developed PTLD progression. This suggests high negative predictive value but low positive predictive value of persistently detectable DNAemia for PTLD progression. Conclusion: Prompt therapy of presumed early PTLD in the setting of EBV monitoring did not result in better outcomes than therapy of presumed advanced PTLD (without EBV monitoring). Even with the prompt therapy, rituximab was only 76% efficacious. After rituximab, undetectable EBV DNAemia indicates PTLD regression, whereas persistently detectable EBV DNAemia is associated with 58% risk of PTLD progression. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.