Effect of HLA Mismatch on Post-Transplant Infections in Allogeneic Hematopoietic Stem Cell Transplantation with PTCy-Based GvHD Prophylaxis

doi:10.21203/rs.3.rs-2586425/v1

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Effect of HLA Mismatch on Post-Transplant Infections in Allogeneic Hematopoietic Stem Cell Transplantation with PTCy-Based GvHD Prophylaxis

https://doi.org/10.21203/rs.3.rs-2586425/v1

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The aim of the study was to assess the risk of infections in the first 100 days in patients grafted from haploidentical donors (HAPLO) (n=116) or HLA-matched donors (MATCHED) (Related, n=29; unrelated n=39): all patients received graft-versus-host disease (GvHD) prophylaxis with post-transplant cyclophosphamide (PTCy), mycophenolate, and cyclosporine. The two groups had comparable age, intensity of conditioning, and disease status; the stem cell source was bone marrow for HAPLO and peripheral blood for MATCHED transplants. HAPLO patients had an increased risk of bloodstream infections (BSI) (HR 2.54; 95% CI 1.39-4.62; p=0.002), in particular gram-positive BSI (HR 4.42; 95% CI 1.57-12.5; p=0.005). HAPLO patients also had increased CMV infection/reactivation (HR 3.51; 95% CI 1.79-6.87; p<0.001) and a trend for increased invasive fungal infections (HR 1.80; 95% CI 0.90-3.57; p=0.10) and EBV infection/reactivation (HR 2.07; 95% CI 0.44-9.70; p=0.35). Overall, post-transplant infections were more likely to result in infection-related mortality in HAPLO grafts (p=0.03). In this single-center study, patients with HAPLO grafts had an increased risk of BSI and CMV infection/reactivation and a trend for increased IFI and EBV infection/reactivation, compared with MATCHED grafts. These findings call for diligent monitoring of infections in patients undergoing a HAPLO transplant.

Health sciences/Diseases/Haematological diseases/Haematological cancer/Leukaemia

Health sciences/Diseases/Infectious diseases/Fungal infection

Biological sciences/Immunology/Bone marrow transplantation

Biological sciences/Immunology/Infectious diseases/Fungal infection

Biological sciences/Immunology/Transplant immunology/Allotransplantation

The use of post-transplant cyclophosphamide (PTCy)-based GvHD prophylaxis has led to increased use of haploidentical (HAPLO) donors in allogeneic transplantation for hematologic malignancies. A 2017 metanalysis including nine early retrospective studies found that transplant with a HAPLO donor is associated with similar acute GvHD, transplant-related mortality (TRM), relapse, progression-free survival, and overall survival and decreased moderate-to-severe chronic GvHD, compared with an MATCHED (MATCHED) transplant¹.

The aim of the present study, however, is not focused on main outcomes, but rather on the risk of infections after HAPLO or MATCHED transplants. One study has shown a higher incidence of early infections, especially bacterial bloodstream infections (BSI) in HAPLO grafts, compared with MATCHED grafts²; in that analysis, post-transplant cyclophosphamide (PTCy) was used only for HAPLO grafts, whereas a conventional methotrexate (MTX) cyclosporin (CSA) anti-thymocyte globulin (ATG) regimen, was given to patients with MATCHED grafts². It would be difficult to dissect the role of donor/recipient HLA matching, with the role of a different GvHD prophylaxis. A recent registry-based study compared HAPLO versus MATCHED grafts, using a uniform PTCY based GvHD prophylaxis³: there was an increased risk of fungal infections in HAPLO patients receiving a reduced-intensity regimen, and increased bacterial infections in HAPLO patients receiving a myeloablative regimen. A subset analysis limited to patients receiving peripheral blood (PB) as a stem cell source was conducted and showed no difference with the main result³. Stem cell source is indeed another variable, which needs to be considered when studying engraftment and infections.

PB transplants are thought to be associated with faster engraftment, as compared with bone marrow (BM): however, a study on HAPLO BM (n = 481) versus HAPLO PB (n = 190) grafts showed no difference in the cumulative incidence of day + 28 neutrophil engraftment (88% vs 93%) and day + 100 rate of platelet engraftment (88% vs. 85%); there was also no difference in the incidence of graft failure (9% vs. 12%)⁴. Increased risk of acute GvHD was seen in this study⁴, as well as in the European BM vs PB comparison in HAPLO transplants⁵. A randomized study in patients receiving BM or PB from unrelated donor (UD) was conducted in the United States: engraftment in PB grafts was 5 days earlier for neutrophils and 7 days earlier for platelets; the incidence of primary graft failure was 2% for PB and 6% for BM transplants⁶: nevertheless, the incidence of infectious deaths was comparable in the two groups⁶.

In the present study, all patients received the same GvHD prophylaxis, namely PTCy, CSA and mycophenolate (MMF), and we focus on the risk of bacterial, fungal and viral infections in HAPLO vs. MATCHED grafts.

Patients

The cohort in the present study includes all consecutive allogeneic transplant patients at the Policlinico Universitario Agostino Gemelli IRCCS in Rome from 2016 to 2020 who received a HAPLO or MATCHED transplant and a uniform PTCy-based GvHD prophylaxis regimen. The study of HAPLO vs. MATCHED patients was approved by ethics committee in May 2021, protocol 0019661/21. All patients provided informed consent for use of personal and clinical data for research purposes.

Patients received either a myeloablative (75%) or reduced-intensity (25%) conditioning regimen. Myeloablative regimens consisted mainly of TBF (Thiotepa 5 mg/kg x2; busulfan 3.2 mg/kg x1, x2, or x3; and fludarabine 50 mg/m² x3), FLU-TBI (Fludarabine 40 mg/m² x3 and 1200 cGy TBI), and BU-FLU (Busulfan 3.2 mg/kg x4 and fludarabine 40 mg/m² x4). Reduced-intensity regimens consisted mainly of the Baltimore regimen (Cyclophosphamide 14.5 mg/kg, fludarabine 150 mg/m², and 200 cGy TBI) and modified Baltimore regimen (Cyclophosphamide 14.5 mg/kg x2, fludarabine 30 mg/m² x5), and melphalan 30 mg/m² x1).

HAPLO transplants were performed using unmodified bone marrow as the stem cell source, while the stem cell source for MATCHED transplants was peripheral blood.

All patients received PTCy-based GvHD prophylaxis. GvHD prophylaxis for acute leukemias and myelodysplastic syndrome consisted of PTCy (50 mg/kg) on days + 3 and + 5, cyclosporine (3 mg/kg) starting on day 0, and mycophenolate mofetil (15 mg/kg bid) from day 0 to day + 36. For other diseases, GvHD prophylaxis consisted of PTCy (50 mg/kg) on days + 3 and + 4, cyclosporine (3 mg/kg) starting on day + 5, and mycophenolate mofetil (15 mg/kg bid) from day + 5 until day + 28 for transplants from MATCHED related donors and until day + 35 for transplants from other donor types.⁷ Granulocyte colony-stimulating factor (G-CSF) was used from day + 6 until neutrophil recovery in patients with HAPLO grafts.⁸

Infection prophylaxis was based on institutional protocols. Prophylactic antibacterial therapy is not used in patients with neutropenia. Prophylactic antifungal therapy is not used, though posaconazole is started in patients receiving steroids for GvHD. For patients with a positive serology for CMV (IgG), prophylaxis of CMV reactivation with letermovir (Prevymis) was started in 2019 for patients with HAPLO grafts and in 2020 for patients with MATCHED grafts.

Infections

Patient data were retrieved retrospectively from patient charts and medical records, with a follow-up period for post-transplant infections set at 100 days post-transplant.

Scoring of BSI was based on clinical findings in patient charts and records of blood cultures retrieved from medical records. Events involving common contaminants were not counted as BSI, unless the same pathogen was isolated from consecutive blood cultures.⁹ Recovery of a pathogen associated with previous colonization or infection at another site was considered secondary BSI and excluded.⁹ Positive blood cultures from a central venous catheter (CVC) accompanied by negative cultures from a peripheral vein were considered CVC colonization and not counted as a BSI. For positive blood cultures from both a central venous catheter (CVC) and peripheral vein, a differential time to positivity of ≥ 2 h was used to define the BSI as central line-related (CVC-BSI).¹⁰

Scoring of IFI was based on clinical findings in patient charts and laboratory data retrieved from medical records, with classification of IFI as proven, probable, or possible IFI based on guidelines from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium¹¹.

Scoring of CMV or EBV infection/reactivation was based on DNA count following amplification with RT-PCR, with a threshold for positivity set at > 1000 mL^–1 or > 5000 mL^–1, respectively.

Statistical analysis

To compare the incidence of infections between patients with a HAPLO vs. MATCHED donor, a competing risk analysis was performed for each infection category using cumulative incidence functions to calculate probabilities of infection and death from all causes^12–16. For cumulative incidence analysis of infections, the competing risk was death without infection. A confirmatory analysis with propensity matching was performed and included 68 HAPLO transplants and 68 MATCHED transplants. Criteria for propensity matching included donor and recipient age, disease phase, and intensity of the conditioning regimen (Myeloablative, reduced intensity).

Categorical data, including patient and transplant characteristics, were compared between HAPLO and MATCHED grafts using chi-square test.

Patient characteristics

Characteristics of the 184 patients included in the study are summarized in Table 1. Patients who received a MATCHED transplant or HAPLO transplant were similar with respect to age, sex, diagnosis, conditioning regimen, and disease status at the time of transplant. The two groups differed in terms of transplant date, with MATCHED transplants with PTCy-based GvHD prophylaxis performed at our center starting in 2019.

Engraftment

Average time to leukocyte and neutrophil engraftment was similar between patients who received a HAPLO transplant and those who received MATCHED transplants (21 days vs. 20 days). There was an increased time to platelet engraftment in HAPLO patients (24 days vs. 14 days; p < 0.001). On day + 50, absolute neutrophil count (ANC) and hemoglobin (Hb) levels were similar between the two groups (ANC: 3690/mm³ vs. 3390/mm³; Hb: 9.4 g/dL vs. 9.9 g/dL), while patients with a HAPLO graft had a lower platelet count (99000/mm³ vs. 149000/mm³; p < 0.001) and a trend for a lower lymphocyte count (870/mm³ vs. 1080/mm³; p = 0.09), as compared with MATCHED grafts.

Post-transplant infections

Bloodstream infections

Infections in both transplant groups are detailed in Table 2. In the first 100 days after transplant, a bloodstream infection (BSI) occurred in 56/116 patients (48%) with a HAPLO graft and in 14/68 patients (21%) with a MATCHED graft. In the competing risk analysis, the risk of BSI in the first 100 days post-transplant was increased in HAPLO grafts, as compared with MATCHED grafts (HR 2.54; 95% CI 1.39–4.62; p = 0.002) (Fig. 1).

To characterize the pathogenesis of bloodstream infections in HAPLO vs. MATCHED grafts, we classified BSI events according to time after transplant (Day 0 to + 20 vs. Day + 21 to + 100), characteristics of the recovered pathogens, and determination if the events were CVC-related (CVC-BSI).

During days 0 to + 20, bloodstream infections were counted in 50/116 (43%) patients with HAPLO grafts, compared with 14/68 (21%) of MATCHED grafts. During days + 21 to + 100, bloodstream infections were counted in 13/116 (11%) HAPLO grafts, compared with only 1/68 (1%) patients with MATCHED grafts.

During days 0 to + 20, a total of 75 BSI events were counted. The most frequent type of BSI was gram-negative BSI, with 30 gram-positive BSI, 43 gram-negative BSI, and 2 fungal BSI. 8/75 (11%) BSI events met the criteria for CVC-related BSI, including 5 gram-positive BSI, 2 gram-negative BSI, and 1 fungal BSI. During days + 21 to + 100, BSI were less frequent, with a total of 19 BSI events. In contrast to the first 20 days post-transplant, the most frequent type of BSI events during days + 21 to + 100 were gram-positive BSI; in total, there were 14 gram-positive BSI (2 of which were CVC-BSI), 2 gram-negative BSI (neither of which was CVC-BSI), and 3 fungal BSI (1 of which was CVC-BSI).

During the 100-day follow-up, 28/116 (24%) patients with a HAPLO graft had at least 1 gram-positive BSI, compared with 4/68 (6%) patients with a MATCHED graft. In the competing risk analysis, the risk of a gram-positive BSI was increased in HAPLO grafts, compared with MATCHED grafts (HR 4.42; 95% CI 1.57–12.5; p = 0.005). Gram-negative BSI occurred in 30/116 (26%) patients with a HAPLO graft, compared with 12/68 (18%) of patients with a MATCHED graft. In the competing risk analysis, there was a trend for increased risk of gram-negative BSI in HAPLO grafts (HR 1.44; 95% CI 0.74–2.81; p = 0.29).

Pathogens isolated in BSI are shown in Table 3. During days 0 to + 20, the most frequently isolated pathogens in HAPLO grafts were coagulase-negative Staphylococcus spp. (n = 14), Streptococcus spp. (n = 7), Escherichia coli (n = 14), and Klebsiella pneumoniae (n = 9). In MATCHED grafts, gram-positive bloodstream infections were relatively infrequent, with majority of bloodstream infections represented by Escherichia coli (n = 6) and Klebsiella pneumoniae (n = 3). During days + 21 to + 100, majority of BSI in HAPLO grafts were gram-positive bacteria, with the most frequently isolated pathogens represented by coagulase-negative Staphylococcus spp. (n = 6) and Enterococcus spp. (n = 6), while only 1 BSI occurred in MATCHED grafts and was represented by Enterococcus spp. Bloodstream infections by Viridans group Streptococcus occurred in 3 HAPLO transplants and no MATCHED transplants. 5 patients with HAPLO grafts had a fungal BSI (2 of which were CVC-BSI), while no fungal BSI occurred in MATCHED grafts.

To determine if increased BSI in patients with HAPLO grafts was influenced by immunosuppressive therapy for GvHD, we considered BSI events in the context of development of GvHD. Of the 56 HAPLO patients with a BSI in the first 100-day follow-up, only 2/56 had developed GvHD prior to the onset of the BSI; regarding MATCHED grafts, none of the 14 MATCHED patients with a BSI had developed GvHD prior to the BSI. To determine an effect of the intensity of the conditioning regimen on risk of BSI, we stratified patients who received conditioning with thiotepa-busulfan-fludarabine (TBF) according to number of days of busulfan (TBF1 vs. TBF2 vs. TBF3). Intensity of conditioning did not appear to influence risk of BSI, with BSI occurring in 45%, 63%, and 41% of HAPLO patients who received TBF1, TBF2, and TBF3, respectively, compared with 20%, 19%, and 12% of patients with MATCHED grafts.

CMV and EBV infection/reactivation

In the first 100 days post-transplant, CMV infection/reactivation occurred in 52/116 (48%) patients with a HAPLO graft and 10/68 (15%) patients with a MATCHED graft. In the competing risk analysis, CMV infection/reactivation was significantly increased in patients with a HAPLO graft (HR 3.51; 95% CI 1.79–6.87; p < 0.001) (Fig. 2).

Since the use of letermovir for CMV prophylaxis was associated with a decrease in CMV reactivation (data not shown), we looked separately at patients who received or did not receive CMV prophylaxis with letermovir. In our patient cohort, 14 patients with HAPLO grafts (12%) and 19 with MATCHED grafts (28%) were given letermovir. Of the 33 patients who received letermovir, only 1 (3%) developed CMV reactivation. Among the 151 patients who did not receive letermovir, there was a significantly increased risk of CMV infection/reactivation in patients with HAPLO grafts, as compared with MATCHED grafts (HR 3.55; 95% CI 1.77–7.12; p < 0.001).

As in BSI, the intensity of the conditioning regimen did not appear to influence the risk of CMV infection/reactivation, with CMV infection/reactivation occurring in 55%, 60%, and 19% of patients with HAPLO grafts who received conditioning with TBF1, TBF2, or TBF3, respectively, compared with 20%, 17%, and 12% of patients with MATCHED grafts.

In the 100-day follow-up, EBV infection/reactivation occurred in 8 patients with a HAPLO graft (7%) and 1 patient (2%) with a MATCHED graft. There was a similar trend toward increased EBV infection/reactivation in patients who received a HAPLO graft (HR 2.17; 95% CI 0.46–10.2; p = 0.3), which was not significant due to low incidence in either group.

Invasive fungal infections

Invasive fungal infections (IFI) were infrequent, particularly in patients with MATCHED grafts. In the first 100 days post-transplant, a proven, probable, or possible IFI occurred in 34/116 (29%) patients with a HAPLO graft and 11/68 (16%) patients with a MATCHED graft. In the competing risk analysis, there was a trend for increased risk of proven, probable, or possible IFI in patients with a HAPLO graft, compared with MATCHED graft (HR 1.80; 95% CI 0.90–3.57; p = 0.10) (Fig. 3).

In HAPLO grafts, there were 4 patients (3%) with a proven IFI, of which, 3 were due to Candida spp. and 1 due to Aspergillus terreus. Additionally, 14/116 (12%) HAPLO patients had a probable IFI, including 10 with probable candidiasis (9%) and 4 with probable aspergillosis (3%), and 16/116 (14%) HAPLO patients had a possible IFI. In MATCHED grafts, there were no proven IFI; 4/68 (6%) patients with MATCHED grafts had a probable IFI (3 with probable aspergillosis and 1 with probable candidiasis), and 7 patients (10%) had a possible IFI.

To assess the potential impact of acute GvHD (aGvHD) and antifungal prophylaxis on risk of IFI, we considered the incidence of IFI in the context of aGvHD, as patients with aGvHD are given antifungal prophylaxis along with immunosuppressive therapy as per our institutional protocol. Of the 34 HAPLO patients with a proven, probable, or possible IFI, 7 (20%) had developed aGvHD prior to IFI (1 patient with grade 1 aGvHD and 6 with aGvHD of grade 2–4). Of the 4 HAPLO patients with a proven IFI, 3/4 were negative for aGvHD, while 1/4 had aGvHD of grade 3. Of the 11 MATCHED patients with a proven, probable, or possible IFI, 2 (18%) had developed aGvHD prior to IFI (1 with grade 1 aGvHD and 1 with grade 2 aGvHD).

The intensity of the conditioning regimen (TBF1 vs. TBF2 vs. TBF3) did not appear to influence the risk of IFI (data not shown).

Infection-related mortality

To determine the clinical impact of post-transplant infections in HAPLO vs. MATCHED grafts, we looked at infection-related mortality. In patients with a HAPLO graft, there were 11 deaths due to infections acquired in the first 100 days post-transplant (9% of patients with HAPLO grafts), while in patients with a MATCHED graft, there was only 1 death to infections acquired in the first 100 days post-transplant (1% of MATCHED grafts) (p = 0.03).

The most frequent infections associated with infection-related mortality in patients with HAPLO grafts were gram-negative BSI, in particular bloodstream infection by Klebsiella pneumoniae. Infection-related mortality in HAPLO grafts included 6 gram-negative BSI, 2 gram-positive BSI, 3 IFI (of which 1 CVC-BSI), and 1 infection at another site (pulmonary infection). The only infection-related mortality in MATCHED grafts was a gram-negative BSI, which was catheter-related (CVC-BSI).

We confirm that, in patients with a hematologic malignancy receiving the same GvHD prophylaxis with PTCy, CSA and MMF, transplants from HAPLO donors have an increased incidence of post-transplant infections, as compared with transplants from MATCHED donors. Specifically, HAPLO grafts were associated with significantly increased BSI as well as significantly increased CMV infection/reactivation in patients who did not receive CMV prophylaxis with letermovir. Similar trends for increased risk of IFI and EBV infection/reactivation were observed in patients with HAPLO grafts. These findings are consistent with data from Mikulska and colleagues who found an increased risk of BSI with HAPLO grafts in a cohort of patients with hematologic malignancies in which only patients with HAPLO grafts received PTCy-based GvHD prophylaxis². In the present study, the increased incidence of BSI in the first 100 days post-transplant in HAPLO vs. MATCHED grafts was mostly related to an increased frequency of gram-positive BSI and IFI. While gram-positive BSI are associated with lower mortality rates compared with gram-negative BSI, 2/9 (22%) infection-related mortalities in patients with a HAPLO graft were due to gram-positive BSI, underscoring the clinical significance of gram-positive BSI in patients receiving a HAPLO transplant with PTCy-based GvHD prophylaxis; notably, neither of the patients with gram-positive BSI-related mortality had developed GvHD during their clinical course. While gram-negative BSI occurred with similar frequency in patients HAPLO and MATCHED grafts, gram-negative BSI appeared to be more fatal in HAPLO grafts, with 6/30 (20%) of HAPLO patients with gram-negative BSI succumbing to their BSI, compared with 1/12 (8%) of patients with MATCHED grafts. Overall, the data suggest a more marked impairment in immune function after an allotransplant with PTCy-based GvHD prophylaxis in patients with a HAPLO graft.

While it was suggested that a higher incidence of BSI in HAPLO transplants may be related to the mucosal injury induced by high-dose PTCy², the findings in the present study suggest that HLA mismatch conferred by HAPLO donor in itself may influence infection risk and that impaired immune reconstitution following HAPLO transplantation may lead to increased susceptibility to invasive infections resulting from PTCy-mediated mucosal injury². This model would be supported by data on immune reconstitution following HAPLO vs. MATCHED transplants, which showed that HAPLO transplant leads to impaired reconstitution of NK cells and T cells in the early post-transplant period¹⁷. While our data indicate similar time to leukocyte engraftment in HAPLO vs. MATCHED transplants, others have shown specific differences in leukocyte populations after a HAPLO vs. MATCHED transplant, with CD4⁺ T cells following a HAPLO transplant skewed in favor of regulatory T cells (Tregs), and engrafted NK cell subsets skewed in favor of immature NK cell subsets (CD16^–, CD56^bright)¹⁷.

Our group previously showed that HAPLO grafts are associated with a higher risk of grade 2–4 acute GvHD and moderate-severe chronic GvHD⁷, necessitating immunosuppressive therapy. While use of immunosuppressive therapy for GvHD is likely contributory to impaired immunity in HAPLO grafts, it does not account for increased incidence of post-transplant infections in the present study. Since posaconazole is given prophylactically to patients receiving immunosuppressive therapy for GvHD, increased IFI would not be expected to correlate with development of GvHD; that said, majority of invasive fungal infections occurred in the absence of GvHD in the present study, with both increased GvHD (data not shown) and a trend for increased IFI in patients with HAPLO grafts.

Compared with other cohorts of patients who received HAPLO grafts with PTCy-based prophylaxis, we observed a relatively high frequency of early post-transplant BSI in HAPLO grafts (43%), though the frequency of early post-transplant BSI in MATCHED grafts was relatively low (21%). In early studies of HAPLO grafts with PTCy-based GvHD prophylaxis, Mikulska and colleagues observed a pre-engraftment BSI in 38% of HAPLO transplants², while Esquirol and colleagues reported pre-engraftment BSI in only 20% of HAPLO grafts¹⁸. In recent studies comparing infections in HAPLO grafts vs. MATCHED grafts in which all patients received GvHD prophylaxis, HAPLO grafts were not associated with increased risk of pre-engraftment BSI: Irene et al. reported pre-engraftment BSI in 45% of HAPLO transplants vs. 40.5% of non-HAPLO transplants¹⁹, while Oltolini et al. reported pre-engraftment BSI in 32% of HAPLO transplants vs. 30% in MATCHED transplants²⁰. It can be supposed that the relatively high rate of pre-engraftment BSI in non-HAPLO grafts in the study of Oltolini et al. is related to the inclusion of single antigen mismatched grafts in the non-HAPLO group (41% of patients in non-HAPLO group),²⁰ while it in the study of Irene et al., it is not specified if single antigen mismatched grafts were included or excluded.¹⁹ In the present study, single antigen mismatched grafts were excluded in order to more accurately test for an effect of HLA mismatch on post-transplant infections, as the effect of a single HLA mismatch cannot be predicted to confer the same effect on immune reconstitution and infectious risk as a MATCHED graft or a HAPLO graft. It was also hypothesized in Oltolini et al. that the use of a less toxic threosulfan-based conditioning regimen may have reduced the mucosal injury predisposing patients to BSI²⁰, of patients with HAPLO grafts may be particularly susceptible², though an effect of conditioning regimen on risk of BSI was not observed in the present study, with majority of patients received a thiotepa-busulfan-fludarabine (TBF) conditioning regimen and no apparent difference in risk of BSI according to the number of days of busulfan (TBF1 vs. TBF2 vs. TBF3). Compared with the abovementioned studies, there were also differences in institutional protocols for post-transplant infection prophylaxis, which also likely influence infectious risk. Patients in the studies of Oltolini et al. and Irene et al. received antibacterial and antifungal prophylaxis with a fluoroquinolone and azole during the pre-engraftment period,^19,20 while in the present study, post-transplant infection prophylaxis was limited to acyclovir, trimethoprim-sulfamethoxazole, and letermovir in CMV-seropositive patients, and posaconazole in patients receiving steroid therapy for GvHD.

Limitations of this study are the retrospective nature, and the fact that MATCHED grafts had peripheral blood as a stem cell source, compared to bone marrow for HAPLO transplants, although a comparison of the two sources in HAPLO grafts has not revealed significant differences in speed of engraftment²¹. That said, we find that patients with a HAPLO donor had an increased risk of BSI and CMV reactivation and a trend for increased risk of IFI and EBV infection/reactivation, compared with MATCHED transplants. These findings call for diligent monitoring in patients undergoing a HAPLO transplant.

Competing interests:

The authors declare no competing interests.

Acknowledgements

This study was supported by Associazione Italiana Ricerca contro il Cancro (AIRC) grant to AB.

Author contributions:

JDM and AB designed the study and drafted the paper. EG, SG, PC, EM, FS, LL, II, FA, MAL, AF, AB, and SS provided clinical data. EG, PC, and SS critically reviewed the paper.

Competing interests:

The authors declare no conflict of interest.

Data availability statement:

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Tables 1 to 3 are available in the Supplementary Files section.

The authors have declared there is NO conflict of interest to disclose.

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Editorial decision: revise
29 Mar, 2023
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Reviewer #1 agreed at journal
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You are reading this latest preprint version

Effect of HLA Mismatch on Post-Transplant Infections in Allogeneic Hematopoietic Stem Cell Transplantation with PTCy-Based GvHD Prophylaxis

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Abstract

Figures

Introduction

Patients And Methods

Patients

Infections

Statistical analysis

Results

Patient characteristics

Engraftment

Post-transplant infections

Bloodstream infections

CMV and EBV infection/reactivation

Invasive fungal infections

Infection-related mortality

Discussion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1