Abstract
The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis in recipients of haploidentical and fully matched transplantations is on the increase. Published studies have reported an increased incidence of cytomegalovirus (CMV) infection with the use of PTCy. Limited data exist on the incidence and outcomes of infection with non-CMV herpesviruses (NCHV) in this setting. The aim of this study was to evaluate the cumulative incidence of NCHV infections and the association of NCHV infections with transplantation-specific outcomes in recipients of haploidentical transplantation with PTCy (HaploCy), matched sibling donor transplantation with PTCy (SibCy), and matched sibling donor transplantation with calcineurin inhibitor-based prophylaxis (SibCNI). We hypothesized that, like CMV infection, HaploCy recipients of also will have a higher risk of NCHV infections. Using the Center for International Blood and Marrow Transplantation Research database, we analyzed 2765 patients (HaploCy, n = 757; SibCNI, n = 1605; SibCy, n = 403) who had undergone their first hematopoietic stem cell transplantation (HCT) between 2012 and 2017 for acute myelogenous leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. The cumulative incidence of NCHV at 6 months post-NCT was 13.9% (99% confidence interval], 10.8% to 17.3%) in the HaploCy group, 10.7% (99% CI, 7.1% to 15%) in the SibCy group, and 5.7% (99% CI, 4.3% to 7.3%) in the Sib CNI group (P < .001). This was due primarily to a higher frequency of human herpesvirus 6 viremia reported in patients receiving PTCy. The incidence of Epstein-Barr viremia was low in all groups, and no cases of post-transplantation lymphoproliferative disorder were seen in either PTCy group. The incidence of NCHV organ disease was low in all 3 cohorts. The development of NCHV infection was associated with increased treatment-related mortality, particularly in the HaploCy group. There was no association with the development of GVHD, relapse, or disease-free survival. Patients in PTCy cohorts who did not develop NCHV infection had lower rates of cGVHD. This study demonstrates that the use of PTCy is associated with an increased risk of NCHV infection. The development of NCHV infection was associated with increased nonrelapse mortality, especially in the HaploCy group. Prospective trials should consider viral surveillance strategies in conjunction with assessment of immune reconstitution for a better understanding of the clinical relevance of viral reactivation in different HCT settings.
Keywords: Non-CMV herpesvirus, Post-transplantation, cyclophosphamide, Haploidentical, HHV-6, Epstein-Barr virus
INTRODUCTION
Allogeneic hematopoietic cell transplantation (HCT) has curative potential for several hematologic malignancies. There has been a considerable increase in the number of partially matched (haploidentical) transplantations performed worldwide [1]. Traditionally, haploidentical HCT has been associated with substantial bidirectional alloreactivity, which often results in graft failure or severe graft-versus-host disease (GVHD). However, the use of post-transplantation cyclophosphamide (PTCy) in the haploidentical HCT platform has resulted in improved GVHD rates and overall outcomes comparable to those in fully matched donor HCT; thus, the PTCy platform is being increasingly applied in the matched donor setting [2]. With the increased use of this platform has come the identification of changes in of post-transplantation complications, including hemorrhagic cystitis, relapse, and infections [3].
Before widespread adoption of the T cell-replete graft with PTCy platform, haploidentical HCT regimens often used in vivo (antithymocyte globulin [ATG] or alemtuzumab) or ex vivo depletion of T cells (CD34 selection) from the graft, which likely contributed to poor immune reconstitution and increased risk of infections [4]. The patterns of immune reconstitution after haploidentical HCT remain poorly characterized in the PTCy era, but recent studies suggest impaired T cell and natural killer cell recovery compared with matched donor HCT [5,6].
Infection with viruses from the human herpesvirus family—herpes simplex virus (HSV)-1 and 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpes virus-6 (HHV-6)—is a well-established cause of morbidity and mortality after HCT, especially with HLA-mismatched transplants [7]. CMV in particular is associated with an increased risk of transplantation-related mortality with all transplantation platforms [8]. Data from the Center for International Blood and Marrow Transplantation Research (CIBMTR) demonstrate that both PTCy and haploidentical donors contribute to this risk [9]. In addition, limited available data suggest a possible increased risk of non-CMV herpesvirus (NCHV) infections after haploidentical transplants with PTCy [10,11].
To address this, we designed a retrospective observational study using the large multi-institutional database of the CIBMTR to compare the incidence and outcomes of NCHV in 3 different HCT settings: haploidentical HCT using PTCy (HaploCy), matched sibling donor HCT using PTCy (SibCy), and matched sibling donor HCT using standard GVHD prophylaxis with a calcineurin inhibitor (CNI) plus methotrexate/mycophenolate mofetil (SibCNI). We hypothesized that, like CMV infection, patients receiving HaploCy will have higher risks of NCHV infections.
METHODS
Data Source
The CIBMTR is a large working group of more than 500 transplant centers worldwide that collects data on autologous transplantations, allogeneic transplantations, and other immune effector cell therapies. These data are reported to a statistical center located at the Medical College of Wisconsin in Milwaukee and the National Marrow Donor Program coordinating center in Minneapolis. Participating centers are required to report all transplantations consecutively with longitudinal follow-up. Onsite audits monitor data and reporting compliance. Automated checks for discrepancies, physicians’ reviews of submitted data, and onsite audits of participating centers ensure data quality. Observational studies conducted by the CIBMTR are performed in compliance with all applicable federal regulations pertaining to the protection of human research participants. The CIBMTR collects data at 2 levels: Transplant Essential Data (TED) and Comprehensive Report Form (CRF) data. Detailed disease and pretransplantation and post-transplantation clinical information, including infection-related data, are collected on a subset of registered patients selected for CRF data by a weighted randomization scheme. TED and CRF level data are collected pre-HCT, at 100 days and 6 months post-HCT, and annually thereafter until death. Only CIBMTR CRF data are used in this analysis, and all patients provided signed consent for CIBMTR registry data collection. Infection data collected include organism, site of infection, and date of infection. Information on screening parameters, severity, diagnostic methodology, and treatment is unavailable.
Patients
This study included patients age >2 years of age with a diagnosis of acute myelogenous leukemia (AML), acute lymphoblastic leukemia, or myelodysplastic syndrome (MDS) who underwent HCT with a haploidentical donor and PTCy (HaploCy), a matched sibling donor receiving PTCy (SibCy), or a matched sibling donor treated with calcineurin inhibitor and methotrexate/mycophenolate mofetil (SibCNI) reported to the CIBMTR between 2012 and 2017. Because of the small sample size, patients who underwent matched unrelated donor HCT with PTCy were excluded. Patients receiving an umbilical cord blood transplant, single-mismatch related donor transplant, transplant with CD34 selection or ex vivo T cell depletion, antithymocyte globulin and/or alemtuzumab were also excluded. To minimize center bias for viral surveillance, patients transplanted at centers with no reported haploidentical transplants were also excluded. The data were locked on January 1, 2019, with a 2-year completeness index of 91% in the HaploCy cohort, 93% in the SibCy cohort, and 95% in the SibCNI cohort.
Statistical Analysis
Because the 3 groups were defined by the presence or absence of infection at day 180, baseline patient-, disease-, and transplantation-related factors are descriptive. Cumulative incidence estimates to account for competing risks were calculated. The day 180 cumulative incidence of NCHV (HSV, VZV, EBV, and HHV-6) by donor group was measured, with death as a competing risk. For all other analyses, as the main effect variable was time-dependent; dynamic landmark studies were used by choosing 3 landmark time points comprising the median and interquartile range (IQR) for the development of NCHV infection [12]. Owing to interactions between the donor type, GVHD prophylaxis with PTCy (or not), and variables of interest in each analysis, composite variables were used. For each of the 6 groups defined by donor, GVHD prophylaxis, and infection status, outcomes described included overall survival (OS), disease-free survival (DFS), nonrelapse mortality (NRM), relapse, and chronic GVHD at 2 years. Supplementary Table S1 lists the variables considered in the Cox proportional hazards regression models.
Acute GVHD occurring before onset of infection was included as a time-dependent variable in the Cox models. The assumption of proportional hazards for each factor in the Cox models was tested. When the proportional hazards assumption was violated, a time-dependent variable was added to the model. The stepwise variable selection method was used to identify significant risk factors associated with the outcomes. Factors significantly associated with the outcome variable at a significance level of 0.01 were kept in the final model. Interactions between the main effect and significant covariates were tested. Center effects were examined, and all reported multivariable analyses were adjusted for center effects using the score test [13]. Because infections are expected to have the greatest impact around the time of transplantation, all outcomes were examined to 2 years post-HCT.
RESULTS
Patient Demographics
This study included 757 HaploCy patients from 100 centers, 403 SibCy patients from 77 centers, and 1605 SibCNI patients from 100 centers. Table 1 describes the patient, disease, and transplantation characteristics classified by the development of NCHV infection by day 180.
Table 1.
Characteristics of Patients by Donor/PTCy Status and NCHV Type Reported to the CIBMTR, 2012 to 2017
| Variable | NCHV Infection by Day 180 | No NCHV Infection | ||||
|---|---|---|---|---|---|---|
| HaploCy (N = 105) | SibCy (N = 43) | SibCNI (N = 92) | HaploCy (N = 652) | SibCy (N = 360) | SibCNI (N = 1513) | |
| Number of centers | 38 | 25 | 35 | 95 | 69 | 100 |
| Male sex, n (%) | 75 (71) | 25 (58) | 43 (47) | 384 (59) | 218 (61) | 890 (59) |
| Age, yr, median (range) | 53 (3–75) | 43 (13–65) | 57 (5–73) | 58 (3–78) | 47 (3–75) | 57 (2–78) |
| KPS ≥ 90, n (%) | 49 (47) | 31 (72) | 51 (55) | 341 (52) | 202 (56) | 895 (59) |
| Race/ethnicity, n (%) | ||||||
| Caucasian, non-Hispanic | 60 (57) | 25 (58) | 57 (62) | 384 (59) | 214 (59) | 1052 (70) |
| African American | 25 (24) | 7 (16) | 15 (16) | 106 (16) | 49 (14) | 92 (6) |
| Others | 19 (18) | 9 (21) | 18 (20) | 115 (18) | 71 (20) | 244 (16) |
| Missing | 1 (<1) | 2 (5) | 2 (2) | 47 (7) | 26 (7) | 125 (8) |
| HCT-CI, n (%) | ||||||
| 0 | 26 (25) | 8 (19) | 22 (24) | 173 (27) | 95 (26) | 370 (24) |
| 1–2 | 20 (19) | 15 (35) | 21 (23) | 189 (29) | 109 (30) | 426 (28) |
| 3–4 | 42 (40) | 13 (30) | 31 (34) | 169 (26) | 91 (25) | 445 (29) |
| 5+ | 16 (15) | 7 (16) | 18 (20) | 121 (19) | 64 (18) | 267 (18) |
| Missing | 1 (<1) | 0 | 0 | 0 | 1 (<1) | 5 (<1) |
| Donor age, yr, median (range) | 35 (17–68) | 39 (12–63) | 53 (2–74) | 36 (9–76) | 46 (4–72) | 54 (3–82) |
| Donor/recipient sex match, n (%) | ||||||
| Male-male | 48 (46) | 15 (35) | 24 (26) | 241 (37) | 141 (39) | 483 (32) |
| Male-female | 19 (18) | 14 (33) | 22 (24) | 161 (25) | 85 (24) | 325 (21) |
| Female-male | 27 (26) | 10 (23) | 19 (21) | 143 (22) | 77 (21) | 407 (27) |
| Female-female | 11 (10) | 4 (9) | 27 (29) | 107 (16) | 57 (16) | 297 (20) |
| Missing | 0 | 0 | 0 | 0 | 0 | 1 (<1) |
| Donor/recipient CMV serostatus, n (%) | ||||||
| +/+ | 45 (43) | 16 (37) | 48 (52) | 281 (43) | 156 (43) | 636 (42) |
| +/− | 10 (10) | 4 (9) | 6 (7) | 44 (7) | 32 (9) | 157 (10) |
| −/+ | 30 (29) | 14 (33) | 18 (20) | 187 (29) | 87 (24) | 365 (24) |
| −/− | 17 (16) | 7 (16) | 16 (17) | 114 (17) | 72 (20) | 311 (21) |
| Recipient missing | 0 | 0 | 2 (2) | 3 (<1) | 2 (<1) | 13 (<1) |
| Donor missing | 3 (3) | 2 (5) | 2 (2) | 23 (4) | 11 (3) | 31 (2) |
| Disease, n (%) | ||||||
| AML | 67 (64) | 35 (81) | 61 (66) | 461 (71) | 275 (76) | 964 (64) |
| ALL | 7 (7) | 2 (5) | 1 (1) | 19 (3) | 17 (5) | 59 (4) |
| MDS | 31 (30) | 6 (14) | 30 (33) | 172 (26) | 68 (19) | 490 (32) |
| Graft type, n (%) | ||||||
| Bone marrow | 49 (47) | 21 (49) | 18 (20) | 259 (40) | 110 (31) | 182 (12) |
| Peripheral blood | 56 (53) | 22 (51) | 74 (80) | 393 (60) | 250 (69) | 1331 (88) |
| Conditioning regimen intensity, n (%) | ||||||
| Myeloablative | 60 (57) | 29 (67) | 59 (64) | 254 (39) | 193 (54) | 876 (58) |
| RIC/NMA | 45 (43) | 14 (33) | 33 (36) | 398 (61) | 167 (46) | 637 (42) |
| GVHD prophylaxis, n (%) | ||||||
| Cyclophosphamide | 105 | 43 | 0 | 652 | 360 | 0 |
| CNI + MMF ± others | 0 | 0 | 28 (30) | 0 | 0 | 334 (22) |
| CNI + MTX ± others | 0 | 0 | 64 (70) | 0 | 0 | 1179 (78) |
| TBI | 66 (63) | 24 (56) | 39 (42) | 465 (71) | 210 (58) | 397 (26) |
| Growth factors post-transplantation, n (%) | 86 (82) | 36 (84) | 23 (25) | 534 (82) | 283 (79) | 356 (24) |
| Time from diagnosis to HCT, mo, median (range) | 9 (2–165) | 8 (3–291) | 5 (1–57) | 7 (1–160) | 7 (<1–396) | 6 (1–556) |
| Year of transplantation, n (%) | ||||||
| 2012–2014 | 23 (22) | 9 (21) | 49 (53) | 147 (23) | 78 (22) | 757 (50) |
| 2015–2017 | 82 (78) | 34 (79) | 43 (47) | 505 (77) | 282 (78) | 756 (50) |
KPS indicates Karnofsky Performance Status; HCT-CI, Hematopoietic Cell Transplantation-specific Comorbidity Index; ALL, acute lymphoblastic leukemia; NMA, non-myeloablative; MMF, mycophenolate mofetil; MTX, methotrexate; TBI, total body irradiation.
Irrespective of infection occurrence, SibCy patients were younger (HaploCy: median, 58 [IQR, 3 to 78] years; SibCy: median, 46 [IQR, 3 to 75] years; SibCNI: median, 57 [IQR, 2 to 78] years; P< .001), and the HaploCy group had a greater representation of African Americans (HaploCy, 18%; SibCy, 15%, SibCNI: 7%) and a younger donor population (HaploCy: median, 36 [range, 9 to 76] years; SibCy: median, 45 [range, 4 to 72] years; SibCNI: median, 54 [range, 2 to 82]; P< .001). Most transplantations were performed in patients with AML in first complete response with intermediate cytogenetics. The HaploCy group had more bone marrow grafts, use of reduced-intensity conditioning (RIC) regimens, low-dose total body irradiation, and use of granulocyte colony-stimulating factor (G-CSF). Absolute lymphocyte count at days 100 and 180 were similar in the 3 cohorts; however, data were missing in 5% of patients at day 100 and in 20% at day 180.
Infection Outcomes
The cumulative incidence of NCHV at day 30 was 6.9% (99% CI, 5% to 9% in the HaploCy cohort, 3.2% (99% CI, 1% to 6%) in the SibCy cohort, and 1.7% (99% CI, 1% to 3%) in the SibCNI cohort. This increased to 13.9% (99% CI, 11% to 17%), 10.7% (99% CI, 7% to 15%), and 5.7% (99% CI, 4% to 7%) (P< .001) by 6 months post-HCT (Figure 1).
Figure 1.
Cumulative incidence of NCHV infection across the 3 HCT cohorts.
The cumulative incidence of NCHV at day 30 was 6.9% (99% CI, 5% to 9%) in the HaploCy cohort, 3.2% (99% CI, 1% to 6%) in the SibCy cohort, and 1.7% (99% CI, 1% to 3%) in the SibCNI cohort. This increased to 13.9% (99% CI, 11% to 17), 10.7% (99% CI, 7% to 15%), and 5.7% (99% CI, 4% to 7%), respectively (P < .001) by 6 months post-HCT.
The median onset of NCHV infections for the entire study population was 40 days (IQR, 23 to 98 days). HHV-6 viremia contributed to the majority of NCHV in both the HaploCy and SibCy arms (HaploCy, 9.3%; SibCy, 5.7%; SibCNI, 1.9%); however, the incidence of HHV6 end-organ disease was low in all 3 cohorts. The incidence of EBV viremia was low in all 3 cohorts (HaploCy, 2.9%; SibCy, 3.7%; SibCNI, 1.8%). Only 1 case of EBV-end organ disease was reported, occurring in the SibCNI cohort. The incidence of NCHV organ disease was low in all 3 cohorts (HaploCy, 2%; SibCy, 1%; SibCNI, 2%). The majority of NCHV organ disease was related to HSV and VZV infections. Table 2 presents the characteristics of NCHV infections in these cohorts.
Table 2.
NCHV Infections by 180 Days
| Variable | HaploCy (N = 757), n (%) | SibCy (N = 403), n (%) | SibCNI (N = 1605), n (%) | P Value |
|---|---|---|---|---|
| Number of viral infections (any) by day 180 | <.001 | |||
| None | 331 (44) | 201 (50) | 1035 (64) | |
| 1 | 221 (29) | 114 (28) | 383 (24) | |
| 2 | 138 (18) | 49 (12) | 128 (8) | |
| 3+ | 67 (9) | 39 (10) | 59 (4) | |
| NCHV | ||||
| Viremia | 92 (12) | 38 (9) | 60 (4) | <.001 |
| HSV | 4 (<1) | 0 | 3 (<1) | .394 |
| HHV-6 | 71 (9) | 23 (6) | 31 (2) | .004 |
| EBV | 22 (3) | 15 (4) | 30 (2) | .004 |
| NCHV organ involvement (± viremia) | 18 (2) | 6 (1) | 34 (2) | .600 |
| HSV | 11 (1) | 4 (<1) | 16 (1) | .496 |
| VZV | 3 (<1) | 2 (<1) | 11 (<1) | .458 |
| HHV-6 | 4 (<1) | 0 | 6 (<1) | .457 |
| EBV | 0 | 0 | 1 (<1) | .698 |
| Sites other than blood (not mutually exclusive) | ||||
| Gastrointestinal | 7 (<1) | 3 (<1) | 13 (<1) | .860 |
| Lung | 2 (<1) | 1 (<1) | 3 (<1) | .837 |
| Liver | 0 | 0 | 1 (<1) | .698 |
| Sinus/upper respiratory | 3 (<1) | 1 (<1) | 8 (<1) | .817 |
| Central nervous system | 1 (<1) | 0 | 4 (<1) | .547 |
| Lower genitourinary | 1 (<1) | 0 | 2 (<1) | .832 |
| Upper genitourinary | 3 (<1) | 2 (<1) | 2 (<1) | .126 |
| Skin | 4 (<1) | 2 (<1) | 10 (<1) | .813 |
| Other sites | 2 (<1) | 0 | 2 (<1) | 0.607 |
The values for the organisms in the table are for the patients with the individual infections by a specific organism. Some patients had more than 1 NCHV reported, and a patient may be included in more than 1 organism group.
NRM
For patients still alive and developing an NCHV infection before day 40 (median onset), the estimated 2-year NRM was 37.6% (99% CI, 22% to 55%) for the HaploCy cohort, 26.1% (99% CI, 3% to 61%) for the SibCy cohort, and 24% (99% CI, 8% to 46%) for the SibCNI cohort (Supplementary Figure S1).
Conversely, for those patients alive and without NCHV infection by day 40, the NRM was lower: HaploCy, 17.5% (99% CI, 14% to 22%); SibCy, 15.9% (99% CI, 1% to 21%); SibCNI, 12.4% (99% CI, 10% to 15%). Multivariable analysis for NRM performed using a group of SibCNI without NCHV infection as the reference group found that development of NCHV infection was associated with higher NRM (Figure 2).
Figure 2.
Multivariable analysis of outcomes with NCHV infection. Values are HR (99% CI) from Cox models for risk of death, relapse, NRM, and chronic GVHD. The reference group is SibCNI without NHCV infection. The highest risk is seen in the HaploCy cohort (HR, 3.21; 99% CI, 1.70 to 6.09; P < .001); however, increased NRM was also seen in the SibCy (HR, 2.50; 99% CI, 1.02 to 6.09; P = .008) and SibCNI (2.75; 99% CI, 1.39 to 5.45; P < .001) cohorts. Other factors associated with increased NRM included HCT from a female donor to a male recipient (HR, 1.46; 99% CI, 1.14 to 1.88; P < .0001), older age (P = .0021), and development of grade II-IV aGVHD (HR, 2.67; 99% CI, 1.83 to 1.91; P < .0001) (see Table 3).
GVHD
Univariate analysis at each of the landmark times for NCHV infection demonstrated no impact of NCHV infection on grade II-IV acute GVHD development by 6 months post-HCT (Supplementary Figure S2).
Multivariable analysis for cGVHD showed that patients in both PTCy cohorts who did not develop NCHV infection by day 180 had a decreased risk of developing cGVHD compared with the reference group of SibCNI without infection (HaploCy: hazard ratio [HR], 0.62 [99% CI, 0.46 to 0.82], P< .0001; SibCy: HR, 0.59 [99% CI, 0.39 to 0.88], P= .0006) (Figure 2). Notably, patients receiving PTCy regardless of donor type and who developed NCHV infection had a similar risk of developing chronic GVHD as seen in the infected and noninfected SibCNI cohorts (HaploCy: HR, 0.97 [99% CI, 0.61 to 1.55], P = .87; SibCy: HR, 0.89 (99% CI, 0.38 to 2.13], P= .74). Other factors associated with an increased risk of cGVHD include receipt of peripheral blood stem cells (HR, 2.25; 99% CI, 1.68 to 3.02; P< .0001), a female donor and male recipient (HR, 1.26; 99% CI, 1.03 to 1.53; P< .003) or a female donor and female recipient (HR, 1.25; 99% CI, 1.02 to 1.54; P = .006), and development of grade II-IV aGVHD prior to infection (HR, 1.32; 99% CI, 1.08 to 1.61; P = .0003) (Table 3).
Table 3.
Multivariable Analysis Results for Events by 2 Years Post-HCT, Adjusted for Center Effects
| Variable | N | HR (99% CI) | P Value |
|---|---|---|---|
| Overall mortality | |||
| Main effect variable | .0002 | ||
| SibCNI, no NCHV infection | 1480 | 1.00 | |
| HaploCy with NCHV infection | 101 | 1.82 (1.18–2.80) | .0004 |
| SibCy with NCHV infection | 43 | 1.20 (0.61–2.34) | .4872 |
| SibCNI with NCHV infection | 89 | 1.38 (0.87–2.20) | .0705 |
| HaploCy, no NCHV infection | 628 | 1.31 (1.02–1.67) | .0057 |
| SibCy, no NCHV infection | 352 | 1.07 (0.75–1.51) | .6405 |
| Disease/cytogenetics/stage | <.0001 | ||
| Leukemia, favorable cytogenetics, early/intermediate | 68 | 1.00 | |
| Leukemia, intermediate/normal cytogenetics, early | 667 | 1.02 (0.58–1.80) | .9287 |
| Leukemia, poor cytogenetics, early | 434 | 0.99 (0.57–1.71) | .9604 |
| Leukemia, intermediate/normal cytogenetics, intermediate | 213 | 1.10 (0.63–1.92) | .6745 |
| Leukemia, poor cytogenetics, intermediate | 124 | 1.31 (0.72–2.36) | .2429 |
| Leukemia, any cytogenetics, advanced | 291 | 1.94 (1.09–3.45) | .0030 |
| MDS, very low/low | 307 | 0.91 (0.51–1.62) | .6594 |
| MDS intermediate | 229 | 1.57 (0.89–2.75) | .0400 |
| MDS high/very high | 162 | 2.04 (1.10–3.80) | .0029 |
| Missing | 198 | 1.33 (0.70–2.53) | .2529 |
| HCT-CI | .0007 | ||
| 0 | 679 | 1.00 | |
| 1–2 | 762 | 0.94 (0.66–1.34) | .6504 |
| 3–4 | 768 | 1.08 (0.77–1.53) | .5540 |
| 5+ | 484 | 1.30 (0.92–1.84) | .0543 |
| Age at HCT, yr | <.0001 | ||
| 0–20 | 234 | 1.00 | |
| 21–40 | 479 | 0.86 (0.60–1.25) | .3001 |
| 41–60 | 945 | 1.27 (0.90–1.79) | .0800 |
| >60 | 1035 | 1.61 (1.08–2.40) | .0019 |
| Acute GVHD grade II-IV | <.0001 | ||
| No | 1797 | 1.00 | |
| Yes | 896 | 1.54 (1.25–1.89) | |
| Main effect variable | .2551 | ||
| SibCNI, no NCHV infection | 1462 | 1.00 | |
| HaploCy with NCHV infection | 100 | 1.14 (0.69–1.86) | .5031 |
| SibCy with NCHV infection | 42 | 0.58 (0.24–1.43) | .1222 |
| SibCNI with NCHV infection | 87 | 0.90 (0.50–1.63) | .6434 |
| HaploCy, no NCHV infection | 617 | 1.14 (0.89–1.47) | .1697 |
| SibCy, no NCHV infection | 348 | 1.17 (0.82–1.67) | .2664 |
| Disease/cytogenetics/stage | <.0001 | ||
| Leukemia, favorable cytogenetics, early/intermediate | 67 | 1.00 | |
| Leukemia, intermediate/normal cytogenetics, early | 658 | 0.59 (0.34–1.05) | .0180 |
| Leukemia, poor cytogenetics, early | 430 | 0.82 (0.46–1.46) | .3724 |
| Leukemia, intermediate/normal cytogenetics, intermediate | 208 | 0.86 (0.50–1.49) | .4855 |
| Leukemia, poor cytogenetics, intermediate | 124 | 1.16 (0.62–2.17) | .5502 |
| Leukemia, any cytogenetics, advanced | 289 | 1.80 (1.06–3.07) | .0043 |
| MDS, very low/low | 305 | 0.98 (0.57–1.68) | .9132 |
| MDS intermediate | 227 | 1.14 (0.63–2.06) | .5663 |
| MDS high/very high | 159 | 2.12 (1.19–3.80) | .0009 |
| Missing | 189 | 1.04 (0.58–1.88) | .8533 |
| Conditioning intensity | <.0001 | ||
| Myeloablative | 1417 | 1.00 | |
| RIC/NMA | 1239 | 1.51 (1.27–1.79) | |
| Time from diagnosis to HCT (≤ 4 months) | <.0001 | ||
| <6 mo | 325 | 1.00 | |
| 6 mo-1 yr | 149 | 0.72 (0.56–0.93) | .0008 |
| ≥1 yr | 145 | 0.47 (0.32–0.67) | <.0001 |
| Time from diagnosis to HCT (>4 months) | .2843 | ||
| <6 mo | 1339 | 1.00 | |
| 6 mo-1 yr | 637 | 1.05 (0.79–1.41) | .6460 |
| ≥1 yr | 680 | 0.88 (0.66–1.18) | .2661 |
| Acute GVHD grade II-IV | <.001 | ||
| No | 1812 | 1.00 | |
| Yes | 844 | 0.79 (0.68–0.92) | |
| NRM | |||
| Main effect variable | <.001 | ||
| SibCNI, no NCHV infection | 1473 | 1.00 | |
| HaploCy with NCHV infection | 103 | 3.21 (1.70–6.09) | <.0001 |
| SibCy with NCHV infection | 42 | 2.50 (1.02–6.09) | .0083 |
| SibCNI with NCHV infection | 88 | 2.75 (1.39–5.45) | .0001 |
| HaploCy, no NCHV infection | 634 | 1.46 (0.87–2.44) | .0579 |
| SibCy, no NCHV infection | 352 | 1.10 (0.56–2.17) | .7231 |
| Donor-recipient sex match | .0021 | ||
| Male-male | 927 | 1.00 | |
| Male-female | 616 | 0.85 (0.50–1.44) | .4153 |
| Female-male | 658 | 1.32 (0.72–2.43) | .2317 |
| Female-female | 491 | 1.89 (0.93–3.86) | .0212 |
| Age at HCT, yr | .0021 | ||
| 0–20 | 234 | 1.00 | |
| 21–40 | 477 | 0.85 (0.50–1.44) | .4153 |
| 41–60 | 946 | 1.32 (0.72–2.43) | .2317 |
| >60 | 1035 | 1.89 (0.93–3.86) | .0212 |
| Acute GVHD, grade II-IV | <.0001 | ||
| No | 1837 | 1.00 | |
| Yes | 855 | 2.67 (1.83–3.91) | |
| Chronic GVHD | |||
| Main effect variable | <.0001 | ||
| SibCNI, no NCHV infection | 1486 | 1.00 | |
| HaploCy with NCHV infection | 104 | 0.81 (0.49–1.36) | .3035 |
| SibCy with NCHV infection | 43 | 0.73 (0.30–1.78) | .3689 |
| SibCNI with NCHV infection | 90 | 0.71 (0.45–1.10) | .0419 |
| HaploCy, no NCHV infection | 644 | 0.58 (0.44–0.78) | <.0001 |
| SibCy, no NCHV infection | 354 | 0.58 (0.38–0.87) | .0005 |
| Graft type | <.0001 | ||
| Bone marrow | 635 | 1.00 | |
| Peripheral blood | 2086 | 2.26 (1.69–3.02) | |
| Donor-recipient sex match | .0006 | ||
| Male-male | 936 | 1.00 | |
| Male-female | 621 | 1.01 (0.82–1.25) | .9195 |
| Female-male | 669 | 1.26 (1.03–1.55) | .0027 |
| Female-female | 495 | 1.24 (1.00–1.54) | .0084 |
| Number of viral infections (any) by day 180 | .0063 | ||
| None | 1545 | 1.00 | |
| 1 | 699 | 1.16 (0.96–1.40) | .0412 |
| 2 | 312 | 1.16 (0.90–1.51) | .1378 |
| 3+ | 165 | 1.54 (1.06–2.25) | .0032 |
| Acute GVHD, grade II-IV | .0018 | ||
| No | 1817 | 1.00 | |
| Yes | 904 | 1.27 (1.04–1.56) | |
Relapse
There was no impact on the risk of relapse based on the main effect variable of development of a NCHV by day 180 and donor type with/without PTCy (Figure 2). As shown in Table 3, factors associated with increased risk of relapse by 2 years post-HCT included transplantation for high/very high risk MDS (HR, 2.12; 99% CI, 1.19 to 3.80; P < .001) or advanced acute leukemia (HR, 1.80; 99% CI, 1.06 to 3.07; P = .004) and nonmyeloablative/RIC conditioning (HR, 1.51; 99% CI, 1.27 to 1.79; P < .001). A longer interval from diagnosis to HCT was associated with a lower risk of relapse during the first 4 months post-transplantation, but the effect was lost beyond 4 months. The development of grade II-IV aGVHD was protective against relapse (HR, 0.80; 99% CI, 0.68 to 0.93; P= .0001).
OS
In the first 2 years post-HCT, mortality was 49.5% (n = 375) in the HaploCy cohort, 44.4% (n = 179) in the SibCy cohort, and 46.9% (n = 753) in the SibCNI cohort. Supplementary Table S2 lists the causes of death in the 3 cohorts.
Thirty-eight percent of deaths in the HaploCy cohort were due to infection of any kind, as either the primary or secondary cause, compared with 27% of the deaths in both the SibCy and SibCNI cohorts (P< .001). Compared to SibCNI patients without NCHV infection, patients in the HaploCy cohort had a higher risk of death irrespective of NCHV infection (HaploCy with infection: HR, 1.82 [99% CI, 1.18 to 2.80], P = .0004; HaploCy without infection: HR, 1.31 [99% CI, 1.02 to 1.67], P = .006) (Figure 2). Patients in the SibCy cohort did not have a higher risk of death compared with the SibCNI without NCHV infection cohort. Additional factors associated with decreased survival included HCT for high/very high-risk MDS (HR, 2.04; 99% CI, 1.10 to 3.80; P = .003), higher Hematopoietic Cell Transplantation-specific Comorbidity Index; age >60 years (HR, 1.61; 99% CI, 1.08 to 2.40; P = .002); and development of aGVHD grade II-IV prior to infection (HR, 1.54; 99% CI, 1.25 to 1.89; P < .001) (Table 3).
DISCUSSION
This is the largest study reported to date comparing the incidence and outcomes of NCHV infections in the setting of 3 different HCT platforms: HaploCy, SibCy, and SibCNI. Our data show that the incidence of NCHV infection was highest in the HaploCy cohort, followed by the SibCy and SibCNI cohorts. HHV-6 viremia was the primary contributor to this higher incidence. The development of NCHV infection was associated with increased NRM in all 3 cohorts; however, the magnitude was greatest in the HaploCy cohort and was associated with an inferior OS. We found very low rates of NCHV organ involvement in all 3 cohorts.
The most common NHCV infection reported in our analysis was HHV-6. HHV-6 has 2 distinct virus species, HHV-6A and HHV-6B, with a combined seroprevalence of >90% in adults [14]. Studies have reported incidence rates of 30% to 70% of post-transplantation HHV-6 reactivation, which has been associated with encephalitis, fever, rash, bone marrow failure, pneumonitis, acute GVHD, and CMV reactivation [15–21]. A unique feature of the HHV-6 virus is its ability for chromosomal integration in the host DNA, with resulting vertical transmission [22,23]. In a transplantation study, chromosomally integrated HHV6 was found in 1.4% of the recipients and in 0.9% of the donors and was associated with a higher incidence of acute GVHD (adjusted HR, 1.7 to 1.9; P = .004 to .001) [24]. We found a lower incidence of HHV-6 infection in all 3 study cohorts compared with some previously reported studies [21,25]. The use of prospective screening of all patients in some of these studies likely resulted in many asymptomatic viremia cases contributing to the higher incidence. Because the CIBMTR does not collect data on institutional practices for viral detection, it is not possible to confirm whether the HHV-6 testing in this population was driven by clinical concerns or more aggressive screening. Many transplant centers do not use standard screening for HHV6, because there is no documented efficacy in treatment for isolated viremia. There is no evidence that low-level HHV-6 viremia increases the risk of encephalitis, the most clearly established complication of HHV-6 reactivation [26,27].
Because of this study’s retrospective design, we cannot determine whether the association of HHV-6 infection with increased NRM is a direct association or a result of increased viral testing in otherwise sick patients. We also do not have data on the prevalence of chromosomally integrated HHV-6 in this cohort. The higher incidence of infection in both PTCy cohorts raises concerns about impaired T cell and natural killer cell reconstitution resulting from PTCy [5,28]. There is also evidence that a high level of HHV-6 viremia itself may affect T cell reconstitution [29].
The low incidence of EBV infection in the HaploCy cohort is in sharp contrast to previous reports in non-PTCy haploidentical HCT showing a high incidence of EBV infection and subsequent post-transplantation lymphoproliferative disorder [30,31]. This difference is likely related to impaired early T cell reconstitution secondary to the use of in vivo or ex vivo T cell depletion in previous haploidentical HCT platforms. A large retrospective study using PTCy as GVHD prophylaxis for both haploidentical and matched donor transplantations reported no cases of EBV-associated PTLD at 1 year [32]. The exact mechanism responsible for this protection from EBV is unclear; hypotheses include PTCy-induced destruction of EBV-infected B cells with relative sparing of EBV-specific memory T cells [32].
The cumulative incidence of HSV and VZV infection was low in all cohorts in this study. The near-universal use of acyclovir/valacyclovir prophylaxis has resulted in a low incidence of HSV and VZV in all HCT settings. This study’s infection rate may represent breakthrough infections, discontinuation of prophylaxis, or patient noncompliance with prophylaxis; however, this cannot be determined in the absence of prophylaxis data.
Even though this study’s primary objective was to assess the incidence of NCHV infections and their effect on NRM, we also analyzed the association of NCHV infection with GVHD, overall mortality, and relapse rates. We did not find an association of NCHV infection with the development of grade II-IV acute GVHD, which has been reported previously [33]. This study also found lower OS in the HaploCy cohort compared with the SibCNI cohort, irrespective of the development of NCHV infection. A recent CIBMTR publication reported similar OS in HaploCy and SibCNI groups of AML patients [34]. Our study also included patients with MDS and acute lymphoblastic leukemia, suggesting that outcomes between transplantation platforms also could be disease-dependent. There was no impact on relapse rate based on the main effect variable of developing an NCHVinfection by day 180 and donor type with or without PTCy. Interestingly, although multivariable analysis showed that patients in the PTCy cohorts with no NCHV infection by day 180 had a decreased risk of developing cGVHD, the PTCy cohorts with NCHV infection by day 180 had a similar risk of cGVHD compared with the SibCNI cohort. The exact mechanism by which PTCy is protective against cGVHD has not been established, and the role of regulatory T cells in promoting tolerance is under clinical investigation [6].
This study has several limitations, starting with the retrospective design. Even though the data were collected from a large prospective observational database, granular information on infections is not reported. The CIBMTR does not collect data on antiviral prophylaxis, institutional standards for monitoring virus levels in blood, and antiviral therapy threshold. Similarly, institutions differ regarding the definition of criteria for clinically significant infection; however, the multivariable analyses are all adjusted for center effect to minimize these differences.
We also were not able to assess the immunosuppression burden and the relationship to infections. Modifications to the current CIBMTR data collection forms should improve our understanding of viral infections and response to treatment. The CIBMTR does not collect data on the reasons for choosing PTCy over CNI for prophylaxis in sibling donor HCT. A future study also should include matched unrelated donor transplants with PTCy and conventional GVHD prophylaxis. There is an ongoing prospective clinical trial comparing outcomes including immune reconstitution and infectious complications between patients randomized to receive either CNI-based or PTCy-based GVHD prophylaxis in patients undergoing RIC allogeneic HCT [35].
In summary, in our study cohort, HaploCy HCT was associated with an increased incidence of NCHV infections, with a predominance of HHV-6 viremia. This was associated with an increase in overall mortality for the infected HaploCy cohort. This information should aid transplant physicians in selecting the donor and transplantation platform, as well as in considering risk-adapted screening and preemptive strategies. Prospective studies are needed to understand the true incidence and outcomes of clinically significant infections in relation to unique immune reconstitution with different HCT platforms.
Supplementary Material
ACKNOWLEDGMENTS
The CIBMTR is supported primarily by Public Health Service Grant U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); Grant HHSH250201700006C from the Health Resources and Services Administration (HRSA); and Awards N00014-20-12705 and N00014-20-1-2832 from the Office of Naval Research. Support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, and from the following commercial entities: AbbVie, Accenture, Actinium Pharmaceuticals, Adaptive Biotechnologies, Adienne, Allovir, Amgen, Astellas Pharma US, bluebird bio, Bristol Myers Squibb, CareDx, CSL Behring, CytoSen Therapeutics, Daiichi Sankyo, Eurofins Viracor, ExcellThera, Fate Therapeutics, Gamida-Cell, Genentech, Gilead, GlaxoSmithKline, Incyte, Janssen/Johnson & Johnson, Jasper Therapeutics, Jazz Pharmaceuticals, Karyopharm Therapeutics, Kiadis Pharma, Kite Pharma, Kyowa Kirin, Magenta Therapeutics, Medac, Merck & Co, Millennium, Miltenyi Biotec, MorphoSys, Novartis Pharmaceuticals, Omeros, Oncopeptides, Orca Biosystems, Pfizer, Pharmacyclics, Sanofi Genzyme, Seagen, Stemcyte, Takeda Pharmaceuticals, Tscan, Vertex, Vor Biopharma, and Xenikos.
Data use statement: The CIBMTR supports accessibility of research in accordance with the NIH Data Sharing Policy and the NCI Cancer Moonshot Public Access and Data Sharing Policy. The CIBMTR only releases deidentified datasets that comply with all relevant global regulations regarding privacy and confidentiality.
Financial disclosure:
The CIBMTR is supported primarily by Public Health Service U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); HHSH250201700006C from the Health Resources and Services Administration (HRSA); and N0001420-1-2705 and N00014-20-1-2832 from the Office of Naval Research; Support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, and from the following commercial entities: AbbVie; Accenture; Actinium Pharmaceuticals, Inc.; Adaptive Biotechnologies Corporation; Adienne SA; Allovir, Inc.; Amgen, Inc.; Astellas Pharma US; bluebird bio, inc.; Bristol Myers Squibb Co.; CareDx; CSL Behring; CytoSen Therapeutics, Inc.; Daiichi Sankyo Co., Ltd.; Eurofins Viracor; ExcellThera; Fate Therapeutics; Gamida-Cell, Ltd.; Genentech Inc; Gilead; GlaxoSmithKline; Incyte Corporation; Janssen/Johnson & Johnson; Jasper Therapeutics; Jazz Pharmaceuticals, Inc.; Karyopharm Therapeutics; Kiadis Pharma; Kite, a Gilead Company; Kyowa Kirin; Magenta Therapeutics; Medac GmbH; Merck & Co.; Millennium, the Takeda Oncology Co.; Miltenyi Biotec, Inc.; MorphoSys; Novartis Pharmaceuticals Corporation; Omeros Corporation; Oncopeptides, Inc.; Orca Biosystems, Inc.; Pfizer, Inc.; Pharmacyclics, LLC; Sanofi Genzyme; Seagen, Inc.; Stemcyte; Takeda Pharmaceuticals; Tscan; Vertex; Vor Biopharma; Xenikos BV.
Footnotes
SUPPLEMENTARY MATERIALS
Supplementary material associated with this article can be found in the online version at doi:10.1016/j.jtct.2021.09.015.
Conflict of interest statement: There are no conflicts of interest to report.
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