Epstein–Barr Virus Monitoring after an Allogeneic Hematopoietic Stem Cell Transplant: Review of the Recent Data and Current Practices in Canada
Abstract
1. Introduction
2. Methods
2.1. Review of Literature
2.2. Survey on Current Practices in Canada
3. Results
3.1. Literature Review
3.1.1. Incidence of EBV-DNAemia after Allogeneic HSCT
3.1.2. Incidence of EBV-Related PTLD after Allogeneic HSCT
3.1.3. Optimal Biomarkers for PTLD Detection
3.1.4. Overall Efficacy of EBV-DNAemia-Based Pre-Emptive Strategy with Rituximab
3.1.5. Optimal Threshold for EBV-DNAemia-Driven Therapy
3.1.6. Efficacy of Universal Primary Prophylaxis Strategy
3.1.7. Alternative Therapies for EBV-DNAemia
3.2. Current Practices in Canadian Transplant Centers
4. Conclusions and Future Directions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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N Patients Studied | Type of Transplant | Conditioning | GvHD Prophylaxis | % of EBV Reactivation | % PTLD | Median Day of EBV-DNA Detection | Identified EBV-DNAemia Risk Factors after Multivariate Analysis | References |
---|---|---|---|---|---|---|---|---|
186 Adults | MUD MSD MMUD MMRD | MAC, RIC | CyA +/− MTX or MMF | 48% ≥ 500 genomes/mL 18% ≥ 20,000 genomes/mL | 4.3% | N/A | N/A | Burns [12] (2016) |
28 Pediatric | MUD MRD | MAC, RIC | CyA, CyA + MTX Rabbit ATG (2–5 mg/kg) | 46.4% | N/A | 47 | MUD, MAC | Chiereghin [8] (2016) |
30 Adults Adolescents > 14 | MUD MSD HID | MAC | CyA + MTX CyA + MTX + MMF Rabbit ATG (10 mg/kg) | 47% | 6.7% | 31 | N/A | Fu [13] (2016) |
332 Adults | N/A | TBI, Flu, Other (NP) | ATG (NP) | 69.6% ≥ 1000 copies/mL | N/A | 98 | D-EBV status, ATG, Flu, TBI MUD, GvHD | Raberahona [14] (2016) |
182 Pediatric | MUD HID | MAC, RIC, NMA | Rabbit ATG (5 mg/kg) or horse ATG (100 mg/kg), T depletion, other | 33% | 0.5% | 94.5 | Acute GvHD grade II to IV, Horse ATG EBV serostatus D+ R−, | Laberko [9] (2017) |
306 Adults | MUD MSD MMUD CB | MAC | CyA, MTX | 82% | 14% | 33 | EBV serostatus D+ R− | Kalra [15] (2018) |
50 Adults | HID | RIC | PTCy CyA Rabbit ATG (5 mg/kg) | 64% | 8% | N/A | N/A | Law [16] (2018) |
15 Adults (6) Pediatric (9) | MRD MMUD CB | MAC, RIC | ATG (NP) Tacrolimus + MTX CyA + MTX, Tacrolimus | 100% | 50% (Adult) 25% (Pediatric) | N/A | N/A | Marinho-Dias [32] (2018) |
199 Adults | MUD MSD, HID, CB | MAC, RIC | ATG (NP) | 50% | 0.5% | N/A | N/A | Delapierre [17] (2019) |
266 Pediatric | MUD MRD | MAC, NMA | CyA + MTX, CyA + other MMF, ATG (NP) Alemtuzumab | 30% | 3% | N/A | N/A | Althubaiti [10] (2019) |
123 Adults | MUD MRD | MAC, RIC, NMA | Rabbit ATG (4 mg/kg) Tacrolimus + MMF Tacrolimus + MTX | 24% | N/A | N/A | MUD with ATG | Figgins [18] (2019) |
200 Adults | MRD HID | MAC | Rabbit ATG (2.5 mg/kg), MTX + MMF + CyA | 44% | 11.9% | 42 | For MRD: ATG, male D, CMV-DNAemia, For HID: donor age > 40, CR at transplant, CMV-DNAemia, | Gao [19] (2019) |
408 Adults | HID | MAC, RIC | MTX+ CyA + MMF Rabbit ATG (7.5 or 10 mg/kg) | 20.7% (ATG 7.5 mg) 40% (ATG 10 mg) | N/A | N/A | ATG dose | Lin [20] (2019) |
40 Adults | MRD MMUD CB | MAC, RIC | ATG (NP)/none | 70% | 0% | N/A | Female R, UD, HLA-MM, PBSCs, MAC, ATG, acute GvHD | Marinho-Dias [21] (2019) |
63 Adults | HID | MAC, RIC | PTCy/Tacrolimus/MMF | 28.5% | 0% | 99 | N/A | Mohyuddin [22] (2019) |
186 Adults | MRD MUD HID | MAC, RIC | CyA + MTX CyA + MTX + MMF Rabbit ATG (6–10 mg/kg) | 18.8% | 0% | 53 | BM graft | Wang [23] (2019) |
890 Adults | MRD HID CB? | MAC, RIC | CyA + MTX ± MMF + ATG (NP) | 19.7% | 0.2% | 57 | ATG, HLA-MM, chronic GvHD | Ru [24] (2020) |
270 Adults | MRD MUD MMUD HID | RIC, TBI | Rabbit ATG (4.5 mg/kg), PTCy, CyA | 63.7% | 12% | 68 | MRD | Salas [25] (2020) |
156 Pediatric | MRD MMRD CB | MAC, Other | ATG (NP) Alemtuzumab, CyA, MTX, MMF, Tacrolimus | 42.3% | 3.2% | N/A | R EBV+, D EBV+, ATG, female R | Enok Bonong [11] (2021) |
296 Adults | MUD MMUD HID | MAC | CyA + MTX + MMF Rabbit ATG (10 mg/kg) | 42.6% | 0.67% | 48 | N/A | Ke [26] (2021) |
382 Adults | MRD MMRD MUD | MAC, RIC | CyA + MMF, CyA + MTX ATG (NP) | 56.5% | 1.3% | 35 | HLA-MM, TBI, UD, EBV IgG donor serology, CyA/MTX and ATG use of GvHD prophylaxis | Macy [27] (2021) |
405 Adults | MRD, MUD, HID, CB | MAC, RIC | ATG (4.5 mg/kg), CyA + MTX | 54.8% | 5.4% | N/A | ATG | Lindsay [28] (2021) |
515 Adults | MRD MUD MMUD | RIC, MAC | Alemtuzumab CyA | 35.8% | 3.9% | 89.5 | MRD | Marzolini [29] (2021) |
61 Adults | HID | MAC, RIC | PTCy +/− Rabbit ATG (4.5 mg/kg) CyA + MMF Sirolimus + MMF | 55.8% (ATG) vs. 12.5% (no ATG) | N/A | N/A | ATG | Chen [30] (2022) |
56 Pediatric | MRD MUD MMR MMUD | MAC, MIC, RIC | ATG (NP) Alemtuzumab | 67.9% | 1.8% | 40 | R EBV+, ATG | Kania [4] (2022) |
1184 Adults | MRD MUD MSD | RIC, Other | ATG (4.5 mg/kg) + MTX + CyA | 86% | 9% | 35 | For PTLD: EBV D+/R−, TBI, non-MRD (sibling) | Kinzel [31] (2022) |
N Patients Treated with Rituximab | Donor Type | EBV-DNAemia Threshold | Rituximab Dosage and # of Doses | % of Patients with Clearance | Time of Clearance Assessment | % Relapse of EBV | % PTLD | References |
---|---|---|---|---|---|---|---|---|
30 (EBV) 8 (PTLD) Adults | MSD MUD MMRD MMUD | >20,000 copies/mL | 375 mg/m2 up to 4 weekly doses | 100 (EBV) 63 (PTLD) | UK | 0 | N/A | Burns [12] (2016) |
19 Pediatric | HID | >1000 copies/106 PBMCs | 375 mg/m2 single dose | 89 (1 dose only) | UK | 0 | 0 | Kobayashi [57] (2017) |
61 Adults | MRD MUD MMRD MMUD | Copies > 2.5 limit of detection OR sustained rising levels of viral load | 375 mg/m2 weekly until viremia clearance | 52 (1 dose) 97 (1–4 doses) | Median of 5 days post-RTX Median (range) of 9 days (1–41) post-RTX initiation | 1.4 | 1.4 | Jain [59] (2017) |
28 (EBV) 6 (PTLD) Adult and pediatric patients | RD UD | 1000 gE/mL × 2 occasions OR 10,000 gE/mL in one sample | 375 mg/m2 weekly until viremia <1000 gE/mL and resolution of clinical signs | 89 (1–6 doses) 83 * (4–6 doses) | UK | 12 | 18 | Kinch [34] (2018) |
16 Adults | MSD MUD HID CB | >1000 IU/mL OR without possibility of IS reduction | 100 mg/m2 weekly until viremia decreased of 1 log10 and below 1000 IU/mL | 93 (1–4 doses) | After 4 doses | N/A | 6.3 | Delapierre [17] (2019) |
19 Pediatric | RD UD HID | 40,000 copies/mL | 375 mg/m2 single dose | 100 (1 dose only) | Median (range) of 9 days (3–20) from RTX | 0 | 0 | Kim [58] (2019) |
107 Adults | MRD MUD HID | 2 consecutive viral loads in whole blood >5000 IU/mL | 375 mg/m2 weekly until viremia clearance | 95 (1–8 doses) | UK | N/A | 5 | Stocker [56] (2020) |
20 Adults | MRD UD CB HID | 11 treated >1000–10,000 IU/mL 3 treated >10,000–100,000 IU/mL 6 treated >100,000 IU/mL | 375 mg/m2 weekly until viremia clearance | 85 (1–4 doses) | UK | N/A | 15 | Lindsay [28] (2021) |
Questions | Answers | Pediatric Centers n = 4 | Adult Centers n = 8 |
---|---|---|---|
1. Is there a systematic EBV monitoring strategy at your center? | Yes No | 4 NA | 6 2 |
2. What ASCT patients are considered for systematic EBV monitoring? | All High-risk only No answer | 4 NA NA | 3 3 2 |
2a. If you have selected “only patients at high risk” at the previous question, please specify. | AC 1: EBV serology mismatch/Use of ATG for GvHD prophylaxis/use of Alemtuzumab/MUD/MMUD/HID/Grade III-IV acute GvHD/Steroid-refractory acute GvHD. AC 2: EBV serology mismatch/Use of ATG for GvHD prophylaxis/MUD/MMUD/HID/CB/Any acute GvHD treated with oral prednisone or IV solumedrol. AC 3: Use of ATG for GvHD prophylaxis/HID/CB/any acute GvHD | ||
3. Where is EBV detection assay performed? | At our center No answer | 4 NA | 6 2 |
4. What technique is used for EBV monitoring? | Quantitative PCR Quantitative/Qualitative PCR No answer | 3 1 NA | 6 NA 2 |
5. What specimen is utilized? | Whole blood Plasma No answer | 2 2 NA | 4 2 2 |
6. What type of assay is used? | Commercial assay LDT No answer | 2 2 NA | 2 2 4 |
7. When is EBV monitoring ended after transplantation? | D + 100–120 D + 180 2 years D + 180/when IS are stopped D + 100–120/extend if prolonged IS When IS are stopped No answer | 1 1 1 1 NA NA NA | 1 1 NA 1 1 2 2 |
8. At what frequency is EBV monitored? | Weekly Every 2 weeks Weekly until D + 100 then less frequently No answer | 3 NA 1 NA | 5 1 NA 2 |
9. Do you modify this frequency in certain circumstances? | Yes No Rarely No answer | 2 1 1 NA | 5 1 NA 2 |
9a. If you have selected “yes” at the previous question, please specify. | PC 1: Spread out as the patient further from HSCT and less seen, and there is no concern with clinical or laboratory EBV related problems AC1/2: Rising EBV PCR AC3: Q2 weeks once started tapering of IS AC 4: When >3 months and on prolonged IS, may be less frequent if not being seen in clinic weekly AC 5: If positive result weekly analysis can be used instead every 2 weeks | ||
10. Do you perform preemptive treatment strategy for EBV reactivation/PTLD? | Yes No No answer | 3 1 NA | 6 NA 2 |
11. Regarding preemptive strategy, what threshold is used to start therapy? | Specific number of copies/mL No fixed threshold, physician decision No answer | 1 2 1 | 5 1 2 |
11a. For “specific number of copies/mL”, please specify the number. | PC 1: 10,000 AC 1: >300,000 to treat; >30,000 PTLD investigation AC 2: 300,000 without symptoms, 30,000 with symptoms (fever, rash, lymphocytosis, lymph node enlargement) AC3: 5000 AC4/5: 10,000 | ||
12. What is your 1st line of therapy for asymptomatic EBV-DNAemia? | Reduction of IS Rituximab Rituximab + Reduction of IS No answer | 1 1 1 1 | 2 NA 4 2 |
13. What is your 2nd line of therapy for refractory asymptomatic EBV-DNAemia (no PTLD)? | Reduction of IS Rituximab Rituximab + Reduction of IS Further IS reduction Donor lymphocyte infusion No answer | 1 1 NA 1 NA NA | NA 2 1 NA 1 4 |
14. What is your 3rd line of therapy for refractory asymptomatic EBV-DNAemia (no PTLD)? | Anti-virus specific T cells No answer No patient has really made it to third line | 1 3 NA | 2 5 1 |
15. How long after an intervention for EBV-DNAemia do you continue surveillance? | 2–3 months 3–6 months ~3 Months At least 3 months Until 2 years Clearance of virus (2 measurements) Depends on outcome, severity, response Weekly until IS discontinued or 4 weeks No answer | 1 NA NA NA 1 1 NA NA 1 | NA 1 1 2 NA NA 1 1 2 |
16. Do you have a systematic surveillance strategy for late-onset PTLD? | Yes No No answer | 1 3 NA | 2 4 2 |
16a. If you have selected “yes” at the previous question, please specify. | PC 1: Virus Monitoring until 2 years post ASCT AC 1: Patients who had previous reactivation can be monitored longer AC 2: Weekly for the first 3 months or if GvHD. Bi-weekly once tapering IS and not previous activation. Stop once IS off |
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Ratiu, C.; Dufresne, S.F.; Thiant, S.; Roy, J. Epstein–Barr Virus Monitoring after an Allogeneic Hematopoietic Stem Cell Transplant: Review of the Recent Data and Current Practices in Canada. Curr. Oncol. 2024, 31, 2780-2795. https://doi.org/10.3390/curroncol31050211
Ratiu C, Dufresne SF, Thiant S, Roy J. Epstein–Barr Virus Monitoring after an Allogeneic Hematopoietic Stem Cell Transplant: Review of the Recent Data and Current Practices in Canada. Current Oncology. 2024; 31(5):2780-2795. https://doi.org/10.3390/curroncol31050211
Chicago/Turabian StyleRatiu, Claire, Simon F. Dufresne, Stéphanie Thiant, and Jean Roy. 2024. "Epstein–Barr Virus Monitoring after an Allogeneic Hematopoietic Stem Cell Transplant: Review of the Recent Data and Current Practices in Canada" Current Oncology 31, no. 5: 2780-2795. https://doi.org/10.3390/curroncol31050211
APA StyleRatiu, C., Dufresne, S. F., Thiant, S., & Roy, J. (2024). Epstein–Barr Virus Monitoring after an Allogeneic Hematopoietic Stem Cell Transplant: Review of the Recent Data and Current Practices in Canada. Current Oncology, 31(5), 2780-2795. https://doi.org/10.3390/curroncol31050211