Skip to main content
NCBI home page
Clinical Hematology International logoLink to Clinical Hematology International
. 2024 Feb 2;6(1):26–38. doi: 10.46989/001c.92525

Human herpesvirus type 6 reactivation after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide and antithymocyte globulin: risk factors and clinical impact

Annalisa Paviglianiti 1,2,3,4,#, Tânia Maia 1,4,5,#, Joël-Meyer Gozlan 6,7, Eolia Brissot 1,4,8, Florent Malard 1,4,8, Anne Banet 1,4, Zoé Van de Wyngaert 1,4, Tounes Ledraa 1,4, Ramdane Belhocine 1,4, Simona Sestili 1,4, Antoine Capes 1,4, Nicolas Stocker 1,4,8, Agnès Bonnin 1,4, Anne Vekhoff 1,4, Ollivier Legrand 1,4, Mohamad Mohty 1,4,8, Rémy Duléry 1,4,8,✉
PMCID: PMC11087003  PMID: 38817703

Abstract

Human herpesvirus type 6 (HHV6) reactivation after haploidentical hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PT-Cy) has been scarcely studied, especially when antithymocyte globulin (ATG) is added to the graft-versus-host disease (GvHD) prophylaxis. We conducted a retrospective cohort study in 100 consecutive patients receiving haploidentical HCT with PT-Cy. We systematically monitored HHV6 DNA loads in blood samples on a weekly basis using quantitative PCR until day +100. The 100-day cumulative incidence of HHV6 reactivation was 54%. Clinically significant HHV6 infections were rare (7%), associated with higher HHV6 DNA loads, and had favorable outcomes after antiviral therapy. The main risk factor for HHV6 reactivation was a low absolute lymphocyte count (ALC) < 290/µL on day +30 (68% versus 40%, p = 0.003). Adding ATG to PT-Cy did not increase the incidence of HHV6 reactivation (52% with ATG versus 79% without ATG, p = 0.12). Patients experiencing HHV6 reactivation demonstrated delayed platelet recovery (HR 1.81, 95% CI 1.07-3.05, p = 0.026), higher risk of acute grade II-IV GvHD (39% versus 9%, p < 0.001) but similar overall survival and non-relapse mortality to the other patients. In conclusion, our findings endorse the safety of combining ATG and PT-Cy in terms of the risk of HHV6 reactivation and infection in patients undergoing haploidentical HCT. Patients with a low ALC on day +30 face a higher risk of HHV6 reactivation and may require careful monitoring.

Keywords: Human herpesvirus type 6, Haploidentical hematopoietic cell transplantation, Antithymocyte globulin, Graft-versus-host disease, Immune reconstitution

INTRODUCTION

Human herpesvirus type 6 (HHV6) is a common virus, with a seroprevalence of around 95% in the general population. Two variants of the virus, type A and type B, have been identified, which exhibit distinct biological characteristics and are associated with different diseases. Infection typically occurs in early childhood.1,2 While HHV6 primarily infects CD4+ T-cells, it can also establish a persistent infection in various other cell types, including mononuclear cells, salivary glands, brain tissue, lymph nodes, and endothelial cells. In rare cases, the virus is also capable of chromosomal integration, which is a unique mechanism of viral latency, a phenomenon observed in approximately 1% of the population.3 HHV6, particularly variant B, can reactivate and cause opportunistic diseases in patients under immunosuppressive treatment.4 In the context of allogeneic hematopoietic cell transplantation (HCT), HHV6 reactivation arises in 47% to 72% of patients, posing a significant risk of morbidity and mortality.5–9 In particular, HHV6 stands as the foremost cause for viral encephalitis in this population.10,11

Previous studies have evaluated risk factors and subsequent effects of HHV6 reactivation in HCT recipients, especially in umbilical cord blood transplant (UCBT), where HHV6 reactivation can reach an incidence of 80% to 97%, due to the naive status of infused T-cells and delayed hematopoietic and immune reconstitution.12,13 However, data on HHV6 reactivation after haploidentical (HAPLO) HCT are limited, especially in the case of high-dose post-transplant cyclophosphamide (PT-Cy) administration.14–18 Furthermore, most studies have involved small series and did not include rabbit antithymocyte globulin (ATG) as part of the graft-versus-host disease (GvHD) prophylaxis. Indeed, combining PT-Cy with ATG has recently emerged as a promising strategy to further reduce the risk of GvHD in HAPLO HCT with a peripheral blood stem cell (PBSC) graft.19–23 Retrospective studies suggest that this combination may result in a lower incidence of chronic GvHD without increasing the risks of relapse, when compared to PT-Cy without ATG. However, there are concerns that adding ATG might increase the risk of viral reactivations, especially cytomegalovirus (CMV), or lead to an increase in Epstein-Barr virus (EBV) viral loads.24 To date, no study has specifically assessed the impact of adding ATG to PT-Cy on HHV6 reactivation. Therefore, we aimed to evaluate the cumulative incidence and the risk factors of HHV6 reactivation, as well as its impact on clinical outcomes in a HAPLO setting when PT-Cy is combined with low-dose ATG.

MATERIALS AND METHODS

Study Population and Transplantation Modalities

This is a retrospective study evaluating all consecutive adult patients who underwent HAPLO HCT with PT-Cy at Saint-Antoine Hospital in Paris, France, between January 2013 and December 2017. HHV6 monitoring was conducted systematically during this period at our center. All patients who proceeded to transplantation provided written informed consent for the use of their data in clinical research, in accordance with the modified guidelines of the Declaration of Helsinki and the local institutional review board.

Conditioning regimens, GvHD prophylaxis, and transplantation modalities

The majority of patients received a conditioning regimen including thiotepa, as previously published.25,26 A total busulfan dose of 9.6 mg/kg was considered as myeloablative conditioning (MAC). Sequential conditioning consisted of a short course of intensive chemotherapy followed by a reduced intensity conditioning (RIC) regimen. Other conditioning regimens were considered as RIC. Stem cell sources included PBSC or bone marrow (BM).

GvHD prophylaxis consisted of cyclosporine A, mycophenolate mofetil (MMF), and PT-Cy for all patients. Cyclosporine A was initiated at a dose of 3 mg/kg/day and gradually tapered, starting from days +60 to +90 (depending on disease risk and GvHD history), while MMF was given at a dose of 30 mg/kg/day until day +35. Patients could receive rabbit ATG (Thymoglobulin, Sanofi, Paris, France) at a dose of 2.5 mg/kg/day on day -2 (in MAC or RIC) or on days -3 and -2 (mostly in sequential conditioning). High-dose PT-Cy was administered at a dose of 50 mg/kg/day on days +3 and +5 in PBSC recipients. BM recipients were scheduled to receive a single PT-Cy dose of 50 mg/kg on day +3.

Infection prophylaxis consisted of amoxicillin, trimethoprim-sulfamethoxazole (or atovaquone), and valacyclovir (or acyclovir). Patients were systematically monitored for CMV and aspergillosis twice a week, and for HHV6, EBV, BK virus, and Toxoplasma gondii once a week until at least day +100 , as previously reported.17,27,28

Detection of HHV6

Blood samples from patients were collected and subjected to HHV6 real-time polymerase chain reaction (PCR) weekly during the first 100 days after HAPLO HCT. After day +100, the frequency of blood collections depended on the patient´s clinical status, biological signs, and previous HHV6 PCR results. In the event of HHV6 reactivation, HHV6 DNA loads were monitored until they became lower than 500 international units (IU) per mL, as recommended.29 HHV6 PCR was systematically performed on gut biopsies in case of colitis and/or suspicion of GvHD. Using the automatized Qiagen (Les Ulis, France) platform, a commercially available real-time PCR kit (Altona Real-Star HHV6 PCR Kit, Jouay-lès-Tours, France) was used to simultaneously detect, discriminate, and quantify the 2 HHV6 subtypes (A and B). The test uses two standard curves generated with four quantitation standards containing 500,000, 50,000, 5,000, and 500 IU of viral DNA per reaction, respectively. DNA was extracted automatically from 200 μL of EDTA-treated whole blood on the Qiasymphony SP automat, using the Qiasymphony DSP DNA Mini Kit (Qiagen). Results are expressed as HHV6 IU/mL of whole blood, with a sensitivity threshold of 50 IU/mL and a quantitation threshold of 500 IU/mL. CMV DNA quantitation was systematically performed in parallel, using the Artus CMV QS-RGQ kit (Qiagen), on the same real-time PCR platform.

Definitions and Statistical Analysis

HHV6 reactivation was defined as the detection of at least 500 IU/mL HHV6 DNA in peripheral blood in two consecutive samples. According to the European Conference on Infections in Leukaemia (ECIL) guidelines,29 a clinically significant HHV6 infection was defined as the presence of HHV6-related end-organ disease (such as encephalitis, pneumonitis, hepatitis, and myelosuppression/allograft failure) or colitis (when biopsy-proven detection of HHV6 DNA was present), in cases where no other causes could explain the symptoms. CMV reactivation was defined as the detection of at least 1,000 IU/mL CMV DNA on peripheral blood in two consecutive samples, which systematically led to preemptive antiviral therapy. Neutrophil engraftment was defined as an absolute neutrophil count > 0.5 x 109/L for three consecutive days (the first of which was considered the engraftment day) and platelet engraftment as a platelet count > 50 x 109/L for seven consecutive days (the first of which was considered engraftment day).30 Disease type and disease status at the time of transplantation were classified according to disease risk index (DRI).31 Overall survival (OS) was defined as time from HCT until death from any cause, disease free survival (DFS) as the probability of being alive and free of disease at any point in time, relapse incidence (RI) as the time from HCT to relapse of the underlying disease, and non-relapse mortality (NRM) as the time from HCT to death without relapse. GvHD was diagnosed and graded according to standard criteria.32–34

Patients’ characteristics were compared using the Mann-Whitney test for continuous variables, and the chi-squared or Fisher’s exact test for categorical variables. Absolute lymphocyte counts (ALC) were compared at days +30, + 100, and +180 after HAPLO HCT according to HHV6 reactivation using the Wilcoxon-Mann-Whitney test. Cumulative incidence was used to estimate the occurrence rates of various endpoints, including HHV6 and CMV reactivations, neutrophil and platelet engraftment, GvHD, relapse, and NRM, to accommodate competing risks. The competing events considered were relapse and death for GvHD, relapse for NRM, and death for infectious complications. Probabilities of OS and DFS were calculated using the Kaplan–Meier method. Univariate analyses were performed using Gray’s test for cumulative incidence functions and the log-rank test to compare survival. Variables with a p value < 0.10 were introduced into a multivariate model. Multivariate analyses were performed using Cox’s proportional-hazards regression model for DFS and OS, and Fine and Gray’s proportional-hazards regression model for GvHD, NRM, and RI. On multivariate analysis, the impact of HHV6 reactivation was studied as a time-dependent variable. P values were two-sided, and differences were considered to be significant when the p value was < 0.05. The confidence interval (CI) was set at 95%. Analyses were performed with SPSS 20 (IBM SPSS Statistics for Windows, Version 20.0. IBM Corp, Armonk, NY) and R 3.5.0 (R Foundation for Statistical Computing, Vienna, Austria) software packages.

RESULTS

Patient Characteristics and HHV6 reactivation

Patient and disease characteristics are summarized in Table 1. Overall, 1,679 HHV6 PCR tests were performed on blood samples, with a median of 13 HHV6 tests per patient (range, 2-72). HHV6 reactivation, primarily variant B, occurred in 56% of the patients, with a median onset time of 20 days (range, 8-122) after HAPLO HCT (Figure 1). The cumulative incidence of HHV6 reactivation at days +30, +60, +100, and +180 after HCT was 48%, 52%, 54%, and 56%, respectively. The median highest HHV6 DNA load was 6,797 IU/mL (range, 524-1,658,173). Among the group of patients with positive HHV6 PCR results, the majority (49 out of 56, 88%) showed no evidence of HHV6-related disease, although mild symptoms such as fever or rash could occur. Seven patients were considered to have clinically significant HHV6 infection, presenting with HHV6-related end-organ disease, including colitis (n=3), encephalitis (n=2), hepatitis (n=1), and myelosuppression with secondary graft failure (n=1). One of the patients with encephalitis also had a concurrent pneumonitis. In cases of clinically significant HHV6 infection, the median highest HHV6 DNA load was 468,447 IU/mL (range, 10,400-1,658,173) compared to 6,135 IU/mL (range, 524-505,945) IU/mL in patients with no signs of infection (p < 0.001). We did not observe any cases of chromosomal integration of HHV6.

Table 1. Patient and transplant characteristics.

Characteristics HHV6 reactivation
n (%)		 No HHV6 reactivation
n (%)		 p-⁠value
Patient age (years) 0.22
≤ 51 31 (55) 19 (43)
> 51 25 (45) 25 (57)
Gender 0.11
Male 38 (68) 23 (52)
Female 18 (32) 21 (48)
Disease 0.38
Acute myeloid leukemia 29 (52) 21 (48)
Acute lymphoblastic leukemia 6 (11) 7 (16)
MDS/MPN 10 (18) 6 (14)
Lymphoma 8 (14) 10 (23)
Multiple myeloma 3 (5) 0 (0)
Disease status 0.76
Complete remission 25 (45) 21 (48)
No complete remission 31 (55) 23 (52)
Disease risk index 0.05
Low - Intermediate 42 (75) 25 (57)
High - Very High 14 (25) 19 (43)
Number of previous treatment lines 0.72
0 - 1 26 (46) 22 (50)
≥ 2 30 (54) 22 (50)
Previous transplantation 0.31
No 37 (66) 35 (80)
Autologous 10 (18) 4 (9)
Allogeneic 9 (16) 5 (11)
Conditioning regimen 0.7
Myeloablative 17 (30) 10 (23)
Reduced intensity 16 (29) 14 (32)
Sequential 23 (41) 20 (45)
Stem cell source 0.23
Bone marrow 16 (29) 8 (18)
Peripheral blood 40 (71) 36 (82)
Patient CMV serostatus 0.39
Negative 17 (30) 17 (39)
Positive 39 (70) 27 (61)
PT-Cy total dose 0.92
50 mg/kg 16 (29) 13 (30)
100 mg/kg 40 (71) 31 (70)
Antithymocyte globulin 0.12
Yes 45 (80) 41 (93)
No 11 (20) 3 (7)
Open in a new tab

Abbreviations: HHV6: human herpesvirus type 6, MDS: myelodysplastic syndrome, MPN: myeloproliferative neoplasm, CMV: cytomegalovirus, PT-Cy: post-transplant cyclophosphamide.

Figure 1. Cumulative incidence of HHV6 reactivation after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide (at day +30: 48%, at day +100: 54%).

Figure 1.

Open in a new tab

Risk Factors for HHV6 Reactivation

At day +30, the median ALC was 290/µL (0-670). Patients with an ALC < 290/µL at day +30 had a higher cumulative incidence of HHV6 reactivation than those with an ALC ≥ 290/µL (63% versus 35%, respectively, p = 0.003) (Figure 2). The use of ATG had no significant impact on HHV6 reactivation (52% with ATG versus 79% without ATG, p = 0.12). No other factors such as age, gender, underlying disease, CMV serological status, number of previous treatments, conditioning regimen, or stem cell source were associated with the incidence of HHV6 reactivation.

Figure 2. Cumulative incidence of HHV6 reactivation according to the median absolute lymphocyte count (ALC) at day +30 after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide (black continuous line: ALC < 290/µL, dashed line ALC ≥ 290/µL). The cumulative incidence of HHV6 reactivation at day +30 was 63% versus 35% (p = 0.003) and, at day + 100, 68% versus 40% (p = 0.003).

Figure 2.

Open in a new tab

Impact on Hematological Engraftment and T-cell Reconstitution

At day +30, the cumulative incidence of neutrophil engraftment was 94% (95% CI 88-99). Three patients failed to achieve it. The median time to neutrophil engraftment was 17 days (range, 5-88), and there was no difference according to HHV6 reactivation. Multivariate analysis showed no association between HHV6 reactivation and the cumulative incidence of neutrophil engraftment at day +30 (Table 2). At day +180, the cumulative incidence of platelet engraftment > 50 x 109/L was 77% (95% CI 92-100). The median time to platelet engraftment was 33 days (range, 11-373) in cases of HHV6 reactivation and 27 days (range, 13-167) in the absence of HHV6 reactivation. Patients who experienced HHV6 reactivation had a poorer platelet recovery (hazard ratio [HR] 1.81, 95% CI 1.07-3.05, p=0.026) (Table 2). Finally, HHV6 reactivation was not significantly associated with the kinetics of lymphocyte reconstitution (Figure 3).

Table 2. Multivariate analysis of risk factors for HHV6 reactivation.

Cumulative incidence of neutrophil engraftment HR 95% CI p value
HHV6 reactivation* (yes versus no) 1.08 0.60-1.94 0.805
DRI (very high-high versus intermediate-low) 1 0.60-1.56 0.997
Number of previous treatment lines (≥ 2 versus 0-1) 1.11 0.76-1.68 0.631
Patient CMV serostatus (positive versus negative) 0.78 0.51-1.20 0.262
Cumulative incidence of platelet engraftment
HHV6 reactivation* (yes versus no) 1.81 1.07-3.05 0.026
DRI (very high-high versus intermediate-low) 1.68 1.02-2.78 0.043
Number of previous treatment lines (≥ 2 versus 0-1) 0.93 0.59-1.44 0.737
Patient CMV serostatus (positive versus negative) 0.88 0.56-1.44 0.600
Acute grade II-IV GvHD
HHV6 reactivation* (yes versus no) 2.29 0.99-5.27 0.052
DRI (very high-high versus intermediate-low) 1.56 0.69-3.51 0.286
Number of previous treatment lines (≥ 2 versus 0-1) 1.04 0.49-2.22 0.922
Patient CMV serostatus (positive versus negative) 0.95 0.42-2.13 0.891
Relapse incidence
HHV6 reactivation* (yes versus no) 1.44 0.14-14-5 0.759
DRI (very high-high versus intermediate-low) 3.23 1.53-6.79 0.002
Number of previous treatment lines (≥ 2 versus 0-1) 1.66 0.77-3.57 0.195
Patient CMV serostatus (positive versus negative) 1.44 0.67-3.13 0.354
Non-relapse mortality
HHV6 reactivation* (yes versus no) 1.45 0.09-22.5 0.792
DRI (very high-high versus intermediate-low) 1.72 0.77-3.86 0.188
Number of previous treatment lines (≥ 2 versus 0-1) 1.65 0.75-3.63 0.217
Patient CMV serostatus (positive versus negative) 3.13 1.18-8.32 0.022
Disease-free survival
HHV6 reactivation* (yes versus no) 1.52 0.26-8.69 0.641
DRI (very high-high versus intermediate-low) 2.41 1.40-4.15 0.001
Number of previous treatment lines (≥ 2 versus 0-1) 1.64 0.95-2.84 0.079
Patient CMV serostatus (positive versus negative) 2 1.10-3.63 0.02
Overall survival
HHV6 PCR (positive versus negative) 0.69 0.13-3.66 0.665
DRI (very high-high versus intermediate-low) 2.09 1.16-3.76 0.014
Number of previous treatment lines (≥ 2 versus 0-1) 1.81 0.99-3.30 0.054
Patient CMV serostatus (positive versus negative) 2.03 1.05-3.93 0.035
Open in a new tab

Abbreviations: HHV6: human herpesvirus type 6, DRI: disease risk index, CMV: cytomegalovirus, GvHD: graft-versus-host disease, PCR: polymerase chain reaction, HR: hazard ratio.

*HHV6 reactivation was included as a time-dependent risk factor.

Figure 3. Lymphocyte reconstitution according to HHV6 reactivation at days +30, +90, and +180 after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide (grid pattern boxes: HHV6 reactivation, white boxes: no HHV6 reactivation).

Figure 3.

Open in a new tab

CMV Reactivation

CMV reactivation was observed in 53% of the patients, with a median time of 28 days (range, 3-168) after HCT. The cumulative incidence of CMV reactivation at days +30, +60, +100, and +180 was 29%, 51%, 52%, and 53%, respectively. Co-occurrence of CMV and HHV6 reactivations was observed in 32% of patients (57% of patients with HHV6 reactivation). In only five patients, CMV reactivation preceded HHV6 reactivation. However, a history of HHV6 reactivation was not correlated with a higher incidence of CMV reactivation (p = 0.59). The median time of CMV reactivation occurrence did not significantly differ between patients who experienced HHV6 reactivation and those who did not.

Impact of Antiviral Treatment on HHV6 Reactivation

Antiviral therapies, including foscarnet, ganciclovir, or cidofovir, were administered to a total of 59 patients, with 37 out of 56 (66%) having HHV6 reactivation. It is important to note that in most patients (31 out of 37), the initiation of antiviral therapy was prompted by concomitant CMV reactivation. Additionally, six patients received antiviral therapy specifically for clinically significant HHV6 infection, such as colitis (n=3), encephalitis (n=2), and hepatitis (n=1). All of these patients had a favorable outcome after undergoing antiviral therapy.

Graft-versus-Host Disease

The cumulative incidence of acute grade II-IV GvHD at day +100 was 26% (95% CI 19-37). In univariate analysis, patients who experienced HHV6 reactivation had a higher cumulative incidence of grade II-IV acute GvHD compared to those who did not (39% versus 9%, p < 0.001) (Figure 4, Supplementary Table S1). HHV6 reactivation was more frequently observed in patients who experienced acute grade III-IV GvHD, with 12 out of 13 having HHV6 reactivation (p = 0.005). There was an association between a higher HHV6 DNA load and the development of acute grade II-IV GvHD (p = 0.02). However, when HHV6 was analyzed as a time-dependent covariate on multivariate analysis, the association did not reach statistical significance (HR 2.29, 95% CI 0.99-5.27; p=0.05). No association was observed between HHV6 reactivation and the cumulative incidence of chronic GvHD at 1 year (36% in cases of HHV6 reactivation versus 27%, p= 0.36).

Figure 4. Cumulative incidence of acute grade II-IV GvHD according to HHV6 reactivation within 100 days after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide (dashed line: HHV6 reactivation, continuous line: no HHV6 reactivation). The cumulative incidence of acute grade II-IV GvHD at day +100 was 39% versus 9% (p < 0.001).

Figure 4.

Open in a new tab

OS, DFS, Relapse, and NRM

After a median follow-up of 36 months (range, 11-76), 48 patients had died. The causes of death included relapse of the underlying hematologic disease (48%), infection (31%), GvHD (10%), hepatic veno-occlusive disease (7%), and miscellaneous (4%). The cumulative incidence of NRM was 12% (95% CI 7-21) at day + 100 and 27% (95% CI 20-38) at 3 years. RI was 29% (95% CI 21-40), OS 51% (95% CI 41-61%), and DFS 44% (95% CI 34-54) at 3 years. On multivariate analysis (Table 2), a high or very-high DRI was associated with a higher risk of relapse (HR 3.23, 95% CI 1.53-6.79, p = 0.002), lower OS (HR 2.09, 95% CI 1.16-3.76, p = 0.014), and lower DFS (HR 2.41, 95% CI 1.40-4.15, p = 0.001). A positive CMV serostatus was associated with an increased NRM (HR 3.13, 95% CI 1.18-8.32, p = 0.02), lower OS (HR 2.03, 95% CI 1.05-3.92, p = 0.035), and lower DFS (HR 2.00, 95% CI 1.10-3.63, p=0.02). HHV6 reactivation was not significantly associated with RI, NRM, OS, and DFS (Table2 and Supplementary Table S1).

DISCUSSION

This is one of the largest studies reporting HHV6 reactivation in adult patients undergoing unmanipulated T-cell replete HAPLO HCT with PT-Cy. It is also the first study to assess the incidence, risk factors, and consequences of HHV6 reactivation when pre-transplant low-dose rabbit ATG is added to PT-Cy. Our findings confirm that HHV6 reactivation (mainly variant B) is common in a HAPLO setting with PT-Cy, with a cumulative incidence of 54%. Notably, this incidence is similar to what has been reported with matched related or unrelated donors, and lower than the incidence with UCBT or ex vivo T-cell depleted HAPLO HCT. Importantly, the addition of ATG to PT-Cy did not increase the risk of HHV6 reactivation. A key strength of our study is the systematic weekly monitory of HHV6 DNA in blood, a practice which was only implemented in one other study involving HAPLO HCT with PT-Cy.18 In the latter, HHV6 reactivation occurred in 112 out of 145 (77%) patients undergoing HAPLO HCT with PT-Cy but without ATG.18 In contrast to our study, other reports evaluating HHV6 in this setting have primarily focused on symptomatic reactivations.14–16 The lack of systematic monitoring in those studies may underestimate the true incidence of HHV6 reactivation, especially in cases where symptoms were either absent or mild. Regarding clinically significant HHV6 infections, our study demonstrates a low incidence (7%), whereas one study on HAPLO HCT with PT-Cy reported a rate of 16%,18 and another analysis of PT-Cy with non-HAPLO donors reported a rate of 24%.35 Taken together, our findings suggest the combination of ATG and PT-Cy does not present a higher risk of HHV6 reactivation or clinically significant HHV6 infections compared to PT-Cy without ATG in the HAPLO HCT setting.

Lymphocyte reconstitution is known to be delayed following PT-Cy in HAPLO HCT, and a delay in lymphocyte reconstitution has been associated with a higher incidence of viral reactivations and related diseases, particularly CMV.36,37 Combining ATG with PT-Cy can induce a significant reduction in early gamma-delta (γδ) T-cell proliferation, and is associated with a higher risk of increase in EBV viral loads.38 However, the impact of such a delayed lymphocyte reconstitution on HHV6 reactivation has scarcely been studied. Two previous studies have reported a protective effect of higher lymphocyte counts (CD3+ lymphocytes ≥ 200/µL) against HHV6 reactivation.35,39 Consistent with these results, our analysis revealed that patients with a low ALC on day +30 (< 290/µL) had a higher incidence of HHV6 reactivation. This finding may serve as a valuable tool to help clinicians identify patients at higher risk of HHV6 reactivation, for whom a closer monitoring of HHV6 by PCR might be considered. The low incidence of clinically significant HHV6 infection, the favorable outcome of these infections, and the absence of significant impact of HHV6 reactivation on survival outcomes in our study do not warrant the routine weekly monitoring of HHV6 in all patients undergoing HAPLO HCT, even when ATG is added to the GvHD prophylaxis. In accordance with the ECIL guidelines,29 HHV6 PCR is recommended for the diagnosis of infection. Routine screening and repeated HHV6 PCR may be performed in high-risk patients, such as those with low ALC. Interestingly, HHV6 reactivation in our study was not associated with an increased risk of CMV reactivation, in contrast to findings from other studies in non-HAPLO HCT settings.5,8,40–42 The cumulative incidence (53%) was not higher than that reported by others on HAPLO HCT without ATG or allogeneic HCT with non-HAPLO donors during the pre-letermovir era.43–45 These results confirm that low-dose (≤ 5 mg/kg) pre-transplant ATG can be safely added to PT-Cy in HAPLO PBSC transplantation, with respect to the risk of viral infections.

The precise impact of HHV6 reactivation on morbidity, quality of life, and mortality after HCT remains unclear. While some studies have reported an increased post-transplant mortality associated with HHV6 reactivation,12,41,42 others have found no detrimental effect on NRM.8,35,39 We did not observe any significant impact of HHV6 reactivation on RI, NRM, OS, or DFS. Additionally, the correlation between HHV6 DNA loads and clinical outcomes has yielded conflicting results. While higher HHV6 DNA loads have been associated with development of encephalitis,46 other authors have found no correlation with clinical signs,47 prediction of CMV reactivation,16 or patient outcomes such as OS.8,35,39 Interestingly, in our cohort, HHV6 DNA loads were higher in the case of clinically significant HHV6 infections (always above 10,000 IU/mL, with a median of 468,447 IU/mL). However, the level of HHV6 DNA loads was not associated with patient outcomes in terms of RI and NRM.

Our study provides deeper insights into the benefit of treating HHV6 reactivation with antiviral therapies. While ganciclovir, foscarnet, and cidofovir have demonstrated inhibitory effects on HHV6 replication in vitro, there are insufficient data to guide curative treatment approaches for HHV6 reactivation and clinically significant HHV6 infection, with the exception of HHV6 encephalitis.29 Although prophylactic or preemptive treatment approaches for HHV6 reactivation are not recommended in HCT recipients, the curative use of ganciclovir or foscarnet is probably useful in HHV6-related disease, especially in the case of encephalitis.29,46 In our study, a majority of patients (66%) with HHV6 reactivation received antiviral therapy, primarily due to concomitant CMV reactivation. This high proportion of patients receiving antiviral therapy might have contributed to the low incidence of clinically significant HHV6 infections. Although patients with clinically significant HHV6 infection had favorable outcomes after antiviral therapy, our study was not designed to assess the efficacy of curative antiviral approaches. It remains unknown how symptomatic patients, especially those with HHV6-related colitis or hepatitis, would have fared without any antiviral therapy. A prospective, randomized, placebo-controlled trial would be needed to address this critical question, considering the substantial toxicities associated with antiviral agents.

Other findings include a delayed platelet engraftment and an increased risk of acute GvHD in patients experiencing HHV6 reactivation. These are consistent with those from most previous studies, although the causative role of HHV6 reactivation as a trigger for acute GvHD remains a subject of debate.5–9,12,35,39,42,48–50 The main limitations of our study are related to its retrospective nature, despite the systematic monitoring of HHV6 with PCR. Our cohort consisted of patients with heterogenous underlying diseases and conditioning regimens, which may introduce confounding factors affecting the incidence of HHV6 reactivation and patient outcomes. Immune reconstitution is influenced not only by donor type (HAPLO or non-HAPLO), source of hematopoietic cells (PBSC, BM, or UCBT), and GvHD prophylaxis (PT-Cy, ATG), but also by pre-transplant factors such as hematologic disease, treatments administered, conditioning regimens, and post-transplant factors including GvHD, infections, status of the gut microbiota, and the therapies used to manage post-transplant complications.

In conclusion, HHV6 reactivation is common after HAPLO HCT with PT-Cy, although the incidence is lower compared to UCBT or HAPLO HCT with ex-vivo T-cell depleted grafts. Importantly, the incidence of clinically significant HHV6 infections remained low, even with the addition of ATG to PT-Cy. The main risk factor for HHV6 reactivation was a low ALC at day +30 after HCT. While HHV6 reactivation did not significantly impact survival outcomes, it was associated with delayed platelet recovery and an increased incidence of acute GvHD, as described in non-HAPLO HCT. Overall, our findings show that combining ATG and PT-Cy in unmanipulated HAPLO PBSC transplantation is a safe and valid approach that does not increase the risk of HHV6 reactivation or infection.

Authorship statement

AP provided clinical care, recruited patients, performed statistical analyses, and wrote the manuscript. TM provided clinical care, collected, assembled, and analyzed data, and wrote the manuscript. JGM performed biological analyses and provided virologic expertise and support in the manuscript writing. FM, EB, AB, ZVW, TL, RB, SS, AC, NS, AB, AV, OL, and MM provided clinical care and commented on the manuscript. All authors approved the submission of the final version of the manuscript for publication purposes.

Competing Interests

FM reports lecture honoraria from Therakos/Mallinckrodt, Sanofi, JAZZ Pharmaceuticals, Gilead, Novartis, and Bristol Myers Squibb, all outside the submitted work. MM reports grants and lecture honoraria from Janssen, Sanofi, Maat Pharma and JAZZ Pharmaceuticals, lecture honoraria from Celgene, Amgen, BMS, Takeda, and Pfizer, grants from Roche, all outside the submitted work. RD reports research funding from Ligue contre le Cancer, Arthur Sachs, Monahan Foundation, Servier Foundation, Philippe Foundation, DCP AP-HP, honoraria from Novartis and Takeda, non-financial support from Kite Pharma / Gilead, all outside the submitted work. The other authors declare no competing financial interests.

Supplementary Material

Supplementary Material
chi_2024_6_1_92525_193179.docx (25.7KB, docx)

Acknowledgments

Acknowledgments

The authors thank the Association for Training, Education and Research in Hematology, Immunology and Transplantation for their generous and continuous support.

Funding Statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

References

  1. Summary of the 10th International Conference on Human Herpesviruses-6 and -7 (HHV-6A, -6B, and HHV-7) Komaroff Anthony L., Boeckh Michael, Eliason Eva, Phan Tuan, Kaufer Benedikt B. Jan 4;2018 Journal of Medical Virology. 90(4):625–630. doi: 10.1002/jmv.25004. doi: 10.1002/jmv.25004. [DOI] [PubMed] [Google Scholar]
  2. Latency, Integration, and Reactivation of Human Herpesvirus-6. Pantry Shara N, Medveczky Peter G. Jul 24;2017 Viruses. 9(7):194. doi: 10.3390/v9070194. doi: 10.3390/v9070194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Inherited Chromosomally Integrated Human Herpesvirus 6 Genomes Are Ancient, Intact, and Potentially Able To Reactivate from Telomeres. Zhang Enjie, Bell Adam J., Wilkie Gavin S., Suárez Nicolás M., Batini Chiara, Veal Colin D., Armendáriz-Castillo Isaac, Neumann Rita, Cotton Victoria E., Huang Yan, Porteous David J., Jarrett Ruth F., Davison Andrew J., Royle Nicola J. Nov 15;2017 Journal of Virology. 91(22):e01137–1154. doi: 10.1128/jvi.01137-17. doi: 10.1128/jvi.01137-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Detection of Human Herpesvirus 6B (HHV-6B) Reactivation in Hematopoietic Cell Transplant Recipients with Inherited Chromosomally Integrated HHV-6A by Droplet Digital PCR. Sedlak Ruth Hall, Hill Joshua A., Nguyen Thuy, Cho Michelle, Levin Greg, Cook Linda, Huang Meei-Li, Flamand Louis, Zerr Danielle M., Boeckh Michael, Jerome Keith R. May;2016 Journal of Clinical Microbiology. 54(5):1223–1227. doi: 10.1128/jcm.03275-15. doi: 10.1128/jcm.03275-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation. Zerr Danielle M., Corey Lawrence, Kim Hyung W., Huang Meei-Li, Nguy Long, Boeckh Michael. Apr;2005 Clinical Infectious Diseases. 40(7):932–940. doi: 10.1086/428060. doi: 10.1086/428060. [DOI] [PubMed] [Google Scholar]
  6. Human herpesvirus 6 DNA in plasma after allogeneic stem cell transplantation: incidence and clinical significance. Ogata Masao, Kikuchi Hiroshi, Satou Takako, Kawano Rie, Ikewaki Junji, Kohno Kazuhiro, Kashima Kenji, Ohtsuka Eiichi, Kadota Jun-ichi. Jan;2006 The Journal of Infectious Diseases. 193(1):68–79. doi: 10.1086/498531. doi: 10.1086/498531. [DOI] [PubMed] [Google Scholar]
  7. Risk factors for developing human herpesvirus 6 (HHV-6) reactivation after allogeneic hematopoietic stem cell transplantation and its association with central nervous system disorders. Yamane Akiko, Mori Takehiko, Suzuki Shigeaki, Mihara Ai, Yamazaki Rie, Aisa Yoshinobu, Nakazato Tomonori, Shimizu Takayuki, Ikeda Yasuo, Okamoto Shinichiro. Jan;2007 Biology of Blood and Marrow Transplantation. 13(1):100–106. doi: 10.1016/j.bbmt.2006.09.003. doi: 10.1016/j.bbmt.2006.09.003. [DOI] [PubMed] [Google Scholar]
  8. Early human herpesvirus type 6 reactivation after allogeneic stem cell transplantation: a large-scale clinical study. Dulery Rémy, Salleron Julia, Dewilde Anny, Rossignol Julien, Boyle Eileen M., Gay Julie, de Berranger Eva, Coiteux Valerie, Jouet Jean-Pierre, Duhamel Alain, Yakoub-Agha Ibrahim. Jul;2012 Biology of Blood and Marrow Transplantation. 18(7):1080–1089. doi: 10.1016/j.bbmt.2011.12.579. doi: 10.1016/j.bbmt.2011.12.579. [DOI] [PubMed] [Google Scholar]
  9. Human herpesvirus 6 (HHV-6) reactivation and HHV-6 encephalitis after allogeneic hematopoietic cell transplantation: a multicenter, prospective study. Ogata Masao, Satou Takako, Kadota Jun-ichi, Saito Noriyuki, Yoshida Takashi, Okumura Hirokazu, Ueki Toshimitsu, Nagafuji Koji, Kako Shinichi, Uoshima Nobuhiko, Tsudo Mitsuru, Itamura Hidekazu, Fukuda Takahiro. May 30;2013 Clinical Infectious Diseases. 57(5):671–681. doi: 10.1093/cid/cit358. doi: 10.1093/cid/cit358. [DOI] [PubMed] [Google Scholar]
  10. Risk factors of human herpesvirus 6 encephalitis/myelitis after allogeneic hematopoietic stem cell transplantation. Miyashita Naohiro, Endo Tomoyuki, Onozawa Masahiro, Hashimoto Daigo, Kondo Takeshi, Fujimoto Katsuya, Kahata Kaoru, Sugita Junichi, Goto Hideki, Matsukawa Toshihiro, Hashino Satoshi, Teshima Takanori. Apr 12;2017 Transplant Infectious Disease. 19(3) doi: 10.1111/tid.12682. doi: 10.1111/tid.12682. [DOI] [PubMed] [Google Scholar]
  11. Ogata M, Oshima K, Ikebe T, Takano K, Kanamori H, Kondo T, Ueda Y, Mori T, Hashimoto H, Ogawa H, Eto T, Ueki T, Miyamoto T, Ichinohe T, Atsuta Y, Fukuda T, on behalf of the Complication Working Group of the Japan Society for Hematopoietic Cell Transplantation . Bone Marrow Transplantation. 11. Vol. 52. Springer Science and Business Media LLC; Clinical characteristics and outcome of human herpesvirus-6 encephalitis after allogeneic hematopoietic stem cell transplantation; pp. 1563–1570. [DOI] [PubMed] [Google Scholar]
  12. Human herpes virus 6 infection is a hallmark of cord blood transplant in adults and may participate to delayed engraftment: a comparison with matched unrelated donors as stem cell source. Chevallier P, Hebia-Fellah I, Planche L, Guillaume T, Bressolette-Bodin C, Coste-Burel M, Rialland F, Mohty M, Imbert-Marcille B-M. 2010Bone Marrow Transplantation. 45(7):1204–1211. doi: 10.1038/bmt.2009.326. doi: 10.1038/bmt.2009.326. [DOI] [PubMed] [Google Scholar]
  13. Impact of stem cell graft on early viral infections and immune reconstitution after allogeneic transplantation in adults. Illiaquer Marina, Imbert-Marcille Berthe-Marie, Guillaume Thierry, Planche Lucie, Rimbert Marie, Bressollette-Bodin Céline, Le Bourgeois Amandine, Peterlin Pierre, Garnier Alice, Le Houerou Claire, Moreau Philippe, Mohty Mohamad, Chevallier Patrice. Aug;2017 Journal of Clinical Virology. 93:30–36. doi: 10.1016/j.jcv.2017.05.019. doi: 10.1016/j.jcv.2017.05.019. [DOI] [PubMed] [Google Scholar]
  14. Tischer Johanna, Engel Nicole, Fritsch Susanne, Prevalsek Dusan, Hubmann Max, Schulz Christoph, Zoellner Anna-K., Bücklein Veit, Reibke Roland, Mumm Friederike, Rieger Christina T., Hill Wolfgang, Ledderose Georg, Stemmler Hans Joachim, Köhnke Thomas, Jäger Gundula, Kolb Hans Jochem, Schmid Christoph, Moosmann Andreas, Hausmann Andreas. Annals of Hematology. 10. Vol. 94. Springer Science and Business Media LLC; Virus infection in HLA-haploidentical hematopoietic stem cell transplantation: incidence in the context of immune recovery in two different transplantation settings; pp. 1677–1688. [DOI] [PubMed] [Google Scholar]
  15. Human Herpesvirus 6 Infection Following Haploidentical Transplantation: Immune Recovery and Outcome. Greco Raffaella, Crucitti Lara, Noviello Maddalena, Racca Sara, Mannina Daniele, Forcina Alessandra, Lorentino Francesca, Valtolina Veronica, Rolla Serena, Dvir Roee, Morelli Mara, Giglio Fabio, Barbanti Maria Chiara, Lupo Stanghellini Maria Teresa, Oltolini Chiara, Vago Luca, Scarpellini Paolo, Assanelli Andrea, Carrabba Matteo G., Marktel Sarah, Bernardi Massimo, Corti Consuelo, Clementi Massimo, Peccatori Jacopo, Bonini Chiara, Ciceri Fabio. Dec;2016 Biology of Blood and Marrow Transplantation. 22(12):2250–2255. doi: 10.1016/j.bbmt.2016.09.018. doi: 10.1016/j.bbmt.2016.09.018. [DOI] [PubMed] [Google Scholar]
  16. Human Herpesvirus 6 replication predicts Cytomegalovirus reactivation after allogeneic stem cell transplantation from haploidentical donor. Crocchiolo Roberto, Giordano Laura, Rimondo Andrea, Bologna Muriel, Sarina Barbara, Morabito Lucio, Bramanti Stefania, Castagna Luca, Mineri Rossana. Nov;2016 Journal of Clinical Virology. 84:24–26. doi: 10.1016/j.jcv.2016.09.008. doi: 10.1016/j.jcv.2016.09.008. [DOI] [PubMed] [Google Scholar]
  17. Mohty Razan, Brissot Eolia, Battipaglia Giorgia, Ruggeri Annalisa, Dulery Rémy, Bonnin Agnès, Médiavilla Clémence, Sestili Simona, Belhocine Ramdane, Vekhoff Anne, Ledraa Tounes, Lapusan Camelia Simona, Adaeva Rosa, Isnard Françoise, Legrand Olivier, Mohty Mohamad, Malard Florent. British Journal of Haematology. 3. Vol. 187. Wiley; Infectious complications after post-transplantation cyclophosphamide and anti-thymocyte globulin-based haploidentical stem cell transplantation; pp. e64–68. [DOI] [PubMed] [Google Scholar]
  18. Infections after Allogenic Transplant with Post-Transplant Cyclophosphamide: Impact of Donor HLA Matching. Oltolini Chiara, Greco Raffaella, Galli Laura, Clerici Daniela, Lorentino Francesca, Xue Elisabetta, Lupo Stanghellini Maria Teresa, Giglio Fabio, Uhr Lina, Ripa Marco, Scarpellini Paolo, Bernardi Massimo, Corti Consuelo, Peccatori Jacopo, Castagna Antonella, Ciceri Fabio. Jun;2020 Biology of Blood and Marrow Transplantation. 26(6):1179–1188. doi: 10.1016/j.bbmt.2020.01.013. doi: 10.1016/j.bbmt.2020.01.013. [DOI] [PubMed] [Google Scholar]
  19. Rabbit anti-T cell globulin in allogeneic hematopoietic cell transplantation. Storek Jan, Mohty Mohamad, Boelens Jaap Jan. Jun;2015 Biology of Blood and Marrow Transplantation. 21(6):959–970. doi: 10.1016/j.bbmt.2014.11.676. doi: 10.1016/j.bbmt.2014.11.676. [DOI] [PubMed] [Google Scholar]
  20. Impact of Adding Antithymocyte Globulin to Posttransplantation Cyclophosphamide in Haploidentical Stem-Cell Transplantation. El-Cheikh Jean, Devillier Raynier, Dulery Remy, Massoud Radwan, Al Chami Farouk, Ghaoui Nohra, Moukalled Nour, Pagliardini Thomas, Marino Fabrizio, Malard Florent, Bazarbachi Abdul Hamid, Mohty Razan, Bazarbachi Ali, Castagna Luca, Mohty Mohamad, Blaise Didier. Sep;2020 Clinical Lymphoma Myeloma and Leukemia. 20(9):617–623. doi: 10.1016/j.clml.2020.04.003. doi: 10.1016/j.clml.2020.04.003. [DOI] [PubMed] [Google Scholar]
  21. Thiotepa and antithymocyte globulin-based conditioning prior to haploidentical transplantation with posttransplant cyclophosphamide in high-risk hematological malignancies. Peric Zinaida, Mohty Razan, Bastos Juliana, Brissot Eolia, Battipaglia Giorgia, Belhocine Ramdane, Sestili Simona, Giannotti Federica, Vekhoff Anne, Ledraa Tounes, Legrand Ollivier, Lapusan Simona, Isnard Francoise, Labopin Myriam, Bonnin Agnes, Mediavilla Clemence, Rubio Marie-Thérèse, Ruggeri Annalisa, Duléry Rémy, Malard Florent, Mohty Mohamad. 2020Bone Marrow Transplantation. 55(4):763–772. doi: 10.1038/s41409-019-0726-7. doi: 10.1038/s41409-019-0726-7. [DOI] [PubMed] [Google Scholar]
  22. Duléry Rémy, Malard Florent, Brissot Eolia, Banet Anne, Sestili Simona, Belhocine Ramdane, Calabro Martina, Van de Wyngaert Zoé, Bonnin Agnès, Ledraa Tounes, Legrand Ollivier, Labopin Myriam, Capderou Elodie, Cohen Ariel, Ederhy Stéphane, Mohty Mohamad. Bone Marrow Transplantation. 11. Vol. 58. Springer Science and Business Media LLC; Reduced post-transplant cyclophosphamide dose with antithymocyte globulin in peripheral blood stem cell haploidentical transplantation; pp. 1215–1222. [DOI] [PubMed] [Google Scholar]
  23. Combining post-transplant cyclophosphamide with antithymocyte globulin for graft-versus-host disease prophylaxis in hematological malignancies. Duléry Rémy, Brissot Eolia, Mohty Mohamad. Nov;2023 Blood Reviews. 62:101080. doi: 10.1016/j.blre.2023.101080. doi: 10.1016/j.blre.2023.101080. [DOI] [PubMed] [Google Scholar]
  24. Bonifazi Francesca, Rubio Marie-Thérèse, Bacigalupo Andrea, Boelens Jaap Jan, Finke Jürgen, Greinix Hildegard, Mohty Mohamad, Nagler Arnon, Passweg Jakob, Rambaldi Alessandro, Socie Gérard, Solano Carlos, Walker Irwin, Barosi Giovanni, Kröger Nicolaus. Bone Marrow Transplantation. 6. Vol. 55. Springer Science and Business Media LLC; Rabbit ATG/ATLG in preventing graft-versus-host disease after allogeneic stem cell transplantation: consensus-based recommendations by an international expert panel; pp. 1093–1102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Thiotepa, Busulfan, and Fludarabine Conditioning Regimen in T Cell-Replete HLA-Haploidentical Hematopoietic Stem Cell Transplantation. Duléry Rémy, Bastos Juliana, Paviglianiti Annalisa, Malard Florent, Brissot Eolia, Battipaglia Giorgia, Médiavilla Clémence, Giannotti Federica, Banet Anne, de Wyngaert Zoé Van, Ledraa Tounes, Belhocine Ramdane, Sestili Simona, Adaeva Rosa, Lapusan Simona, Isnard Françoise, Legrand Ollivier, Vekhoff Anne, Rubio Marie-Thérèse, Ruggeri Annalisa, Mohty Mohamad. Jul;2019 Biology of Blood and Marrow Transplantation. 25(7):1407–1415. doi: 10.1016/j.bbmt.2019.02.025. doi: 10.1016/j.bbmt.2019.02.025. [DOI] [PubMed] [Google Scholar]
  26. Sequential Conditioning with Thiotepa in T Cell- Replete Hematopoietic Stem Cell Transplantation for the Treatment of Refractory Hematologic Malignancies: Comparison with Matched Related, Haplo-Mismatched, and Unrelated Donors. Duléry Rémy, Ménard Anne-Lise, Chantepie Sylvain, El-Cheikh Jean, François Sylvie, Delage Jérémy, Giannotti Federica, Ruggeri Annalisa, Brissot Eolia, Battipaglia Giorgia, Malard Florent, Belhocine Ramdane, Sestili Simona, Vekhoff Anne, Delhommeau François, Reman Oumédaly, Legrand Ollivier, Labopin Myriam, Rubio Marie-Thérèse, Mohty Mohamad. May;2018 Biology of Blood and Marrow Transplantation. 24(5):1013–1021. doi: 10.1016/j.bbmt.2018.01.005. doi: 10.1016/j.bbmt.2018.01.005. [DOI] [PubMed] [Google Scholar]
  27. Incidence and risk factors for hemorrhagic cystitis in unmanipulated haploidentical transplant recipients. Ruggeri A., Roth-Guepin G., Battipaglia G., Mamez A.-C., Malard F., Gomez A., Brissot E., Belhocine R., Vekhoff A., Lapusan S., Isnard F., Legrand O., Gozlan J., Boutolleau D., Ledraa T., Labopin M., Rubio M.-T., Mohty M. Nov 25;2015 Transplant Infectious Disease. 17(6):822–830. doi: 10.1111/tid.12455. doi: 10.1111/tid.12455. [DOI] [PubMed] [Google Scholar]
  28. Features of Toxoplasma gondii reactivation after allogeneic hematopoietic stem-cell transplantation in a high seroprevalence setting. Paccoud Olivier, Guitard Juliette, Labopin Myriam, Surgers Laure, Malard Florent, Battipaglia Giorgia, Duléry Rémy, Hennequin Christophe, Mohty Mohamad, Brissot Eolia. 2020Bone Marrow Transplantation. 55(1):93–99. doi: 10.1038/s41409-019-0641-y. doi: 10.1038/s41409-019-0641-y. [DOI] [PubMed] [Google Scholar]
  29. Ward Katherine N, Hill Joshua A, Hubacek Petr, de la Camara Rafael, Crocchiolo Roberto, Einsele Hermann, Navarro David, Robin Christine, Cordonnier Catherine, Ljungman Per. Haematologica. 11. Vol. 104. Ferrata Storti Foundation (Haematologica); Guidelines from the 2017 European Conference on Infections in Leukaemia for management of HHV-6 infection in patients with hematologic malignancies and after hematopoietic stem cell transplantation; pp. 2155–2163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Summary of Scientific and Statistical Methods, Study Endpoints and Definitions for Observational and Registry-Based Studies in Hematopoietic Cell Transplantation. Kanate Abraham S., Nagler Arnon, Savani Bipin. 2019Clinical Hematology International. 2(1):2–4. doi: 10.2991/chi.d.191207.001. doi: 10.2991/chi.d.191207.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Armand Philippe, Kim Haesook T., Logan Brent R., Wang Zhiwei, Alyea Edwin P., Kalaycio Matt E., Maziarz Richard T., Antin Joseph H., Soiffer Robert J., Weisdorf Daniel J., Rizzo J. Douglas, Horowitz Mary M., Saber Wael. Blood. 23. Vol. 123. American Society of Hematology; Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation; pp. 3664–3671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. 1994 Consensus Conference on Acute GVHD Grading. Przepiorka D., Weisdorf D., Martin P., Klingemann H.G., Beatty P., Hows J.., et al. 1995Bone Marrow Transplant. 15(6):825–828. [PubMed] [Google Scholar]
  33. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Jagasia Madan H., Greinix Hildegard T., Arora Mukta, Williams Kirsten M., Wolff Daniel, Cowen Edward W., Palmer Jeanne, Weisdorf Daniel, Treister Nathaniel S., Cheng Guang-Shing, Kerr Holly, Stratton Pamela, Duarte Rafael F., McDonald George B., Inamoto Yoshihiro, Vigorito Afonso, Arai Sally, Datiles Manuel B., Jacobsohn David, Heller Theo, Kitko Carrie L., Mitchell Sandra A., Martin Paul J., Shulman Howard, Wu Roy S., Cutler Corey S., Vogelsang Georgia B., Lee Stephanie J., Pavletic Steven Z., Flowers Mary E.D. Mar;2015 Biology of Blood and Marrow Transplantation. 21(3):389–401.e1. doi: 10.1016/j.bbmt.2014.12.001. doi: 10.1016/j.bbmt.2014.12.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IIa. The 2020 Clinical Implementation and Early Diagnosis Working Group Report. Kitko Carrie L., Pidala Joseph, Schoemans Hélène M., Lawitschka Anita, Flowers Mary E., Cowen Edward W., Tkaczyk Eric, Farhadfar Nosha, Jain Sandeep, Steven Philipp, Luo Zhonghui K., Ogawa Yoko, Stern Michael, Yanik Greg A., Cuvelier Geoffrey D.E., Cheng Guang-Shing, Holtan Shernan G., Schultz Kirk R., Martin Paul J., Lee Stephanie J., Pavletic Steven Z., Wolff Daniel, Paczesny Sophie, Blazar Bruce R., Sarantopoulos Stephanie, Socie Gerard, Greinix Hildegard, Cutler Corey. Jul;2021 Transplantation and Cellular Therapy. 27(7):545–557. doi: 10.1016/j.jtct.2021.03.033. doi: 10.1016/j.jtct.2021.03.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Noviello Maddalena, Lorentino Francesca, Xue Elisabetta, Racca Sara, Furnari Giulia, Valtolina Veronica, Campodonico Edoardo, Dvir Roee, Lupo-Stanghellini Maria Teresa, Giglio Fabio, Piemontese Simona, Clerici Daniela, Oltolini Chiara, Tassi Elena, Beretta Valeria, Farina Francesca, Mannina Daniele, Ardemagni Anna, Vago Luca, Bernardi Massimo, Corti Consuelo, Peccatori Jacopo, Clementi Massimo, Ciceri Fabio, Bonini Chiara, Greco Raffaella. Blood Advances. 18. Vol. 7. American Society of Hematology; Human herpesvirus 6–specific T-cell immunity in allogeneic hematopoietic stem cell transplant recipients; pp. 5446–5457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Increased Infections and Delayed CD4+ T Cell but Faster B Cell Immune Reconstitution after Post-Transplantation Cyclophosphamide Compared to Conventional GVHD Prophylaxis in Allogeneic Transplantation. Khimani Farhad, Ranspach Peter, Elmariah Hany, Kim Jongphil, Whiting Junmin, Nishihori Taiga, Locke Frederick L., Perez Perez Ariel, Dean Erin, Mishra Asmita, Perez Lia, Lazaryan Aleksandr, Jain Michael D., Nieder Michael, Liu Hein, Faramand Rawan, Hansen Doris, Alsina Melissa, Ochoa Leonel, Davila Marco, Anasetti Claudio, Pidala Joseph, Bejanyan Nelli. Nov;2021 Transplantation and Cellular Therapy. 27(11):940–948. doi: 10.1016/j.jtct.2021.07.023. doi: 10.1016/j.jtct.2021.07.023. [DOI] [PubMed] [Google Scholar]
  37. Post-Transplantation Cyclophosphamide Is Associated with an Increase in Non-Cytomegalovirus Herpesvirus Infections in Patients with Acute Leukemia and Myelodysplastic Syndrome. Singh Anurag, Dandoy Christopher E., Chen Min, Kim Soyoung, Mulroney Carolyn M., Kharfan-Dabaja Mohamed A., Ganguly Siddhartha, Maziarz Richard T., Kanakry Christopher G., Kanakry Jennifer A., Patel Sagar S., Hill Joshua A., De Oliveir Satiro, Taplitz Randy, Hematti Peiman, Lazarus Hillard M., Abid Muhammad Bilal, Goldsmith Scott R., Romee Rizwan, Komanduri Krishna V., Badawy Sherif M., Friend Brian D., Beitinjaneh Amer, Politikos Ioannis, Perales Miguel-Angel, Riches Marcie. Jan;2022 Transplantation and Cellular Therapy. 28(1):48.e1–48.e10. doi: 10.1016/j.jtct.2021.09.015. doi: 10.1016/j.jtct.2021.09.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. High-dose post-transplant cyclophosphamide impairs γδ T-cell reconstitution after haploidentical haematopoietic stem cell transplantation using low-dose antithymocyte globulin and peripheral blood stem cell graft. Stocker Nicolas, Gaugler Béatrice, Labopin Myriam, Farge Agathe, Ye Yishan, Ricard Laure, Brissot Eolia, Duléry Remy, Sestili Simona, Battipaglia Giorgia, Médiavilla Clémence, Paviglianiti Annalisa, Banet Anne, Van De Wyngaert Zoe, Ledraa Tounes, Mohty Mohamad, Malard Florent. Jan;2020 Clinical & Translational Immunology. 9(9):e1171. doi: 10.1002/cti2.1171. doi: 10.1002/cti2.1171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Human Herpesvirus 6 Infection Following Haploidentical Transplantation: Immune Recovery and Outcome. Greco Raffaella, Crucitti Lara, Noviello Maddalena, Racca Sara, Mannina Daniele, Forcina Alessandra, Lorentino Francesca, Valtolina Veronica, Rolla Serena, Dvir Roee, Morelli Mara, Giglio Fabio, Barbanti Maria Chiara, Lupo Stanghellini Maria Teresa, Oltolini Chiara, Vago Luca, Scarpellini Paolo, Assanelli Andrea, Carrabba Matteo G., Marktel Sarah, Bernardi Massimo, Corti Consuelo, Clementi Massimo, Peccatori Jacopo, Bonini Chiara, Ciceri Fabio. Dec;2016 Biology of Blood and Marrow Transplantation. 22(12):2250–2255. doi: 10.1016/j.bbmt.2016.09.018. doi: 10.1016/j.bbmt.2016.09.018. [DOI] [PubMed] [Google Scholar]
  40. Ljungman P., Wang F.-Z., Clark D. A., Emery V. C., Remberger M., Ringdén O., Linde A. British Journal of Haematology. 3. Vol. 111. Wiley; High levels of human herpesvirus 6 DNA in peripheral blood leucocytes are correlated to platelet engraftment and disease in allogeneic stem cell transplant patients; pp. 774–781. [DOI] [PubMed] [Google Scholar]
  41. Impact of Human Herpesvirus-6 Reactivation on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation. Aoki Jun, Numata Ayumi, Yamamoto Eri, Fujii Eriko, Tanaka Masatsugu, Kanamori Heiwa. Nov;2015 Biology of Blood and Marrow Transplantation. 21(11):2017–2022. doi: 10.1016/j.bbmt.2015.07.022. doi: 10.1016/j.bbmt.2015.07.022. [DOI] [PubMed] [Google Scholar]
  42. HHV-6 reactivation and associated sequelae after hematopoietic cell transplantation. Zerr Danielle M., Boeckh Michael, Delaney Colleen, Martin Paul J., Xie Hu, Adler Amanda L., Huang Meei-Li, Corey Lawrence, Leisenring Wendy M. Nov;2012 Biology of Blood and Marrow Transplantation. 18(11):1700–1708. doi: 10.1016/j.bbmt.2012.05.012. doi: 10.1016/j.bbmt.2012.05.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7) Ljungman Per, de la Camara Rafael, Robin Christine, Crocchiolo Roberto, Einsele Hermann, Hill Joshua A, Hubacek Petr, Navarro David, Cordonnier Catherine, Ward Katherine N. Aug;2019 The Lancet Infectious Diseases. 19(8):e260–e272. doi: 10.1016/s1473-3099(19)30107-0. doi: 10.1016/s1473-3099(19)30107-0. [DOI] [PubMed] [Google Scholar]
  44. Goldsmith Scott R., Abid Muhammad Bilal, Auletta Jeffery J., Bashey Asad, Beitinjaneh Amer, Castillo Paul, Chemaly Roy F., Chen Min, Ciurea Stefan, Dandoy Christopher E., Díaz Miguel Ángel, Fuchs Ephraim, Ganguly Siddhartha, Kanakry Christopher G., Kanakry Jennifer A., Kim Soyoung, Komanduri Krishna V., Krem Maxwell M., Lazarus Hillard M., Liu Hongtao, Ljungman Per, Masiarz Richard, Mulroney Carolyn, Nathan Sunita, Nishihori Taiga, Page Kristin M., Perales Miguel-Angel, Taplitz Randy, Romee Rizwan, Riches Marcie. Blood. 23. Vol. 137. American Society of Hematology; Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis; pp. 3291–3305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Marty Francisco M., Ljungman Per, Chemaly Roy F., Maertens Johan, Dadwal Sanjeet S., Duarte Rafael F., Haider Shariq, Ullmann Andrew J., Katayama Yuta, Brown Janice, Mullane Kathleen M., Boeckh Michael, Blumberg Emily A., Einsele Hermann, Snydman David R., Kanda Yoshinobu, DiNubile Mark J., Teal Valerie L., Wan Hong, Murata Yoshihiko, Kartsonis Nicholas A., Leavitt Randi Y., Badshah Cyrus. New England Journal of Medicine. 25. Vol. 377. Massachusetts Medical Society; Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation; pp. 2433–2444. [DOI] [PubMed] [Google Scholar]
  46. Human herpesvirus 6 (HHV-6) reactivation and HHV-6 encephalitis after allogeneic hematopoietic cell transplantation: a multicenter, prospective study. Ogata Masao, Satou Takako, Kadota Jun-ichi, Saito Noriyuki, Yoshida Takashi, Okumura Hirokazu, Ueki Toshimitsu, Nagafuji Koji, Kako Shinichi, Uoshima Nobuhiko, Tsudo Mitsuru, Itamura Hidekazu, Fukuda Takahiro. May 30;2013 Clinical Infectious Diseases. 57(5):671–681. doi: 10.1093/cid/cit358. doi: 10.1093/cid/cit358. [DOI] [PubMed] [Google Scholar]
  47. Jeulin Helene, Agrinier Nelly, Guery Matthieu, Salmon Alexandra, Clément Laurence, Bordigoni Pierre, Venard Véronique. Transplantation. 10. Vol. 95. Ovid Technologies (Wolters Kluwer Health); Human herpesvirus 6 infection after allogeneic stem cell transplantation: incidence, outcome, and factors associated with HHV-6 reactivation; pp. 1292–1298. [DOI] [PubMed] [Google Scholar]
  48. Effects of Prophylactic Foscarnet on Human Herpesvirus-6 Reactivation and Encephalitis in Cord Blood Transplant Recipients: A Prospective Multicenter Trial with an Historical Control Group. Ogata Masao, Takano Kuniko, Moriuchi Yukiyoshi, Kondo Tadakazu, Ueki Toshimitsu, Nakano Nobuaki, Mori Takehiko, Uoshima Nobuhiko, Nagafuji Koji, Yamasaki Satoshi, Shibasaki Yasuhiko, Sakai Rika, Kato Koji, Choi Ilseung, Jo Yumi, Eto Tetsuya, Kako Shinichi, Oshima Kumi, Fukuda Takahiro. Jun;2018 Biology of Blood and Marrow Transplantation. 24(6):1264–1273. doi: 10.1016/j.bbmt.2018.02.008. doi: 10.1016/j.bbmt.2018.02.008. [DOI] [PubMed] [Google Scholar]
  49. The complex relationship between human herpesvirus 6 and acute graft-versus-host disease. Pichereau Claire, Desseaux Kristell, Janin Anne, Scieux Catherine, Peffault de Latour Régis, Xhaard Aliénor, Robin Marie, Ribaud Patricia, Agbalika Félix, Chevret Sylvie, Socié Gérard. Jan;2012 Biology of Blood and Marrow Transplantation. 18(1):141–144. doi: 10.1016/j.bbmt.2011.07.018. doi: 10.1016/j.bbmt.2011.07.018. [DOI] [PubMed] [Google Scholar]
  50. Human Herpesvirus-6B Reactivation Is a Risk Factor for Grades II to IV Acute Graft-versus-Host Disease after Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis. Phan Tuan L., Carlin Kristen, Ljungman Per, Politikos Ioannis, Boussiotis Vicki, Boeckh Michael, Shaffer Michele L., Zerr Danielle M. Nov;2018 Biology of Blood and Marrow Transplantation. 24(11):2324–2336. doi: 10.1016/j.bbmt.2018.04.021. doi: 10.1016/j.bbmt.2018.04.021. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material
chi_2024_6_1_92525_193179.docx (25.7KB, docx)

Articles from Clinical Hematology International are provided here courtesy of International Academy for Clinical Hematology

RESOURCES