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