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Risk stratification of CMV recurrence after HSCT
Results
Patients’ characteristics
One hundred and seventy-five allogeneic HSCT recipi- ents were enrolled. Twenty-one patients were excluded from the analysis, due to either protocol violation (n=8) or the absence of valid T-Track® CMV test results (n=13). The study flow diagram is shown in Online Supplementary Figure S2. Of the 154 HSCT recipients included in the final analysis, 101 (65.5%) experienced at least one treatment- requiring CMV reactivation (hereafter designated as “CMV reactivation”) up to day 225 after transplantation (Table 1). Eight patients (4.6%) were diagnosed with CMV disease and 69 (44.8%) with GvHD (Table 1 and Online Supplementary Table S2). The majority of patients with GvHD (50/69 [72.5%] of all patients and 33/40 [82.5%] of D-/R+ patients) experienced at least one episode of CMV reactivation. This is in line with the strong immunosuppressive effect of steroids used for the treatment of GvHD.31,32 Of the 101 patients who had a CMV reactivation, 65 (64.4%) belonged to the D-/R+ high-risk group (Table 2). Sixty-one (60.4%) patients experienced only one CMV reactivation while 40 patients developed either two (n=24) or three (n=16) CMV reacti-
vations (hereafter referred to as “recurrent CMV reactiva- tion”) (Table 2). Most of the HSCT recipients who had recurrent CMV reactivation were high-risk patients (37/40 [92.5%]) (Table 2). Therefore, we focused on high- risk patients as the clinically relevant population with regards to the risk of CMV recurrence after HSCT. The median (range) time to CMV reactivation in D-/R+ patients for the first, second and third CMV reactivation was 37 (19-58), 109 (63-188) and 174 (119-219) days after transplantation, respectively (Online Supplementary Figure S3B). The respective median (range) CMV viral load is presented in Figure 1.
Table 1. Patients’ characteristics. Study population, N (%)
Gender, n (%) Male
Female
Age in years, median (range)
Underlying disease, n (%) Acute myeloid leukemia Myelodysplastic syndrome Acute lymphoid leukemia Non-Hodgkin lymphoma Multiple myeloma Osteomyelofibrosis Chronic myeloid leukemia Chronic lymphoid leukemia Severe aplastic anemia
Donor (D) / recipient (R) CMV serostatus, n (%) D+/R+
D+/R-
D-/R+
Stem cell source, n (%) Bone marrow Peripheral blood
Donor source, n (%)
Matched sibling
Matched unrelated donor Mismatched unrelated donor
Conditioning regimen, n (%) Non-myeloablative Myeloablative, standard Myeloablative, toxicity-reduced
At least one treatment-requiring CMV reactivation, n (%) CMV disease, n (%)
Graft-versus-host disease, n (%)
Infections other than CMV (after day 45), n (%)
Death, n (%)
CMV: cytomegalovirus.
154 (100%)
88 (57.1) 66 (42.9)
58 (20-75)
79 (51.3) 24 (15.6) 17 (11.0) 12 (7.8) 10 (6.5) 4 (2.6)
3 (1.95) 3 (1.95) 2 (1.3)
53 (34.4) 19 (12.3) 82 (53.3)
9 (5.8) 145 (94.2)
31 (20.1) 92 (59.8) 31 (20.1)
41 (26.6) 75 (48.7) 38 (24.7)
101 (65.6) 8 (4.6) 69 (44.8) 52 (33.8) 21 (13.6)
CMV-CMI was evaluated using a standardized IFN-γ ELISpot-based assay (T-Track® CMV).26,27,30 A total of 647 valid test results were included in the analysis. The distri- bution of spot-forming cells (SFC) was analyzed over time after transplantation in response to the CMV proteins IE- 1 and pp65 (Online Supplementary Figure S4A). Overall, the response to IE-1 antigen was lower than that to pp65 throughout the study, especially in D-/R+ patients. A sig- nificant increase in the response to pp65 was apparent in D-/R+ patients over time (Online Supplementary Figure S4A). Accordingly, while the proportion of IE-1-positive tests remained low (up to 33.3% around day 145), that of pp65-positive tests increased to 64.5% in D-/R+ patients (Online Supplementary Figure S4B). Interestingly, the per- centage of T-Track® CMV-positive tests (considering both IE-1 and pp65 markers) was consistently higher than that of pp65 alone, reaching 77.4% of positive tests around day 145 in D-/R+ patients (Online Supplementary Figure S4B). Thus, although generating lower spot counts, IE-1 antigen contributes significantly to T-Track® CMV test positivity.
Measurement of CMV-specific cell-mediated immunity over time after hematopoietic stem cell transplantation
The patterns of SFC distribution relative to the start of the first CMV reactivation were comparable (Online Supplementary Figure S4C).
CMV-specific cell-mediated immunity measured after the end of treatment of a first CMV reactivation can predict recurrence of CMV reactivation
The primary aim of the study was to evaluate the suit- ability of measuring CMV-CMI after the end of treatment of a first-occurring CMV reactivation to predict freedom from or occurrence of a subsequent CMV reactivation (Figure 2A). CMV-CMI was measured on the day of dis- continuation of antiviral treatment (day 0), and on days 7
Table 2. Cytomegalovirus reactivation according to the patients’ cytomegalovirus serostatus.
Study population, n
No documented CMV reactivation, n
At least one CMV reactivation, n
One CMV reactivation only, n Recurrent CMV reactivation, n
Two CMV reactivations, n
Three CMV reactivations, n
154 82
53 17
101 65
61 28 40 37
24 21
16 16
53 19
20 16
33 3
30 3 3 0
3 0
0 0
All D-/R+ D+/R+ D+/R-
CMV: cytomegalovirus; D-: CMV-negative donor; R+: CMV-positive recipient; D+: CMV- positive donor; R-: CMV-negative recipient.
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