Bone Marrow Transplantation https://doi.org/10.1038/s41409-021-01328-4 ARTICLE Severe infections and infection-related mortality in a large series of haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide Albert Esquirol 1 Maria Jesús Pascual2 Mi kwon3 Ariadna Pérez4 Rocio Parody5 Christelle Ferra 6 ● ● ● ● ● ● Irene Garcia Cadenas 1 Beatriz Herruzo2 Nieves Dorado3 Rafael Hernani 4 Isabel Sanchez-Ortega5 ● ● ● ● ● Anna Torrent6 Jorge Sierra 1 Rodrigo Martino 1 Spanish Group for Hematopoietic Stem cell Transplantation ● ● ● (GETH) Received: 22 December 2020 / Revised: 10 April 2021 / Accepted: 22 April 2021 © The Author(s), under exclusive licence to Springer Nature Limited 2021 Abstract Severe infections and their attributable mortality are major complications in recipients of allogeneic hematopoietic stem cell 1234567890();,: 1234567890();,: transplantation (alloSCT). We herein report 236 adult patients who received haploSCT with PTCy. The median follow-up for survivors was 37 months. The overall incidence of bloodstream infections by gram-positive and gram-negative bacteria at 37 months was 51% and 46%, respectively. The incidence of cytomegalovirus infection was 69%, while Epstein Barr virus infections occurred in 10% of patients and hemorrhagic cystitis in 35% of cases. Invasive fungal infections occurred in 11% at 17 months. The 3-year incidence of infection-related mortality was 19%. The median interval from transplant to IRM was 3 months (range 1–30), 53% of IRM occurred >100 days post-haploSCT. Risk factors for IRM included age >50 years, lymphoid malignancy, and developing grade III-IV acute GvHD. Bacterial infections were the most common causes of IRM (51%), mainly due to gram-negative bacilli BSI. In conclusion, severe infections are the most common causes of NRM after haploSCT with PTCy, with a reemergence of gram-negative bacilli as the most lethal pathogens. More studies focusing on the severe infections after haploSCT with PTCy and differences with other types of alloSCT in adults are clearly warranted. Introduction Over the last decade, several haploidentical hematopoietic stem cell transplantation (haploSCT) strategies have been Supplementary information The online version contains developed to overcome HLA barriers [1–4], improving the supplementary material available at https://doi.org/10.1038/s41409- 021-01328-4. high incidence of graft rejection and graft versus host dis- ease associated with earlier haploSCT experiences. Cur- * Albert Esquirol rently, haploSCT has become a real alternative for patients aesquirol@santpau.cat lacking identical donor, mostly after the introduction of 1 Hematology Department, Hospital de la Santa Creu i Sant Pau, post-transplant cyclophosphamide [5–11]. IIB-Sant Pau and Jose Carreras Leukemia Research Institutes, Bloodstream infections (BSI) are the most common severe Universitat Autonoma of Barcelona, Barcelona, Spain infections and are a major cause of mortality in patients 2 Hematology Department, Hospital Regional Universitario, undergoing allogeneic hematopoietic stem cell transplantation Malaga, Spain (alloSCT) [12], with an incidence ranging from 13 to 46% 3 Hematology Department, Hospital Gregorio Marañón, [13]. Many risk factors for BSI and severe infectious com- Madrid, Spain plications exist, such as prolonged severe neutropenia, mye- 4 Hematology Department, Hospital Clinico Universitario, loablative conditioning regimens, severe mucosal damage, Valencia, Spain use of broad-spectrum antibiotics; acute graft versus host 5 Hematology Department, Hospital de Bellvitge, Barcelona, Spain disease, prolonged corticosteroids, and previous infectious 6 Hematology Department, Hospital Germans Trias i Pujol, history [13–16]. Moreover, delayed immune recovery, as seen Badalona, Spain with ex-vivo T cell-depleted alloSCT leads to high incidence A. Esquirol et al. of late infections in the haploSCT setting, as reported with the Myeloablative conditioning (MAC) regimens were fludar- Perugia platforms [1, 17]. abine (40 mg/m2 IV) from day −6 to −3 and busulphan Post-transplant cyclophosphamide (PTCy) was a major (3.2 mg/kg IV) from day −6 to −3 (FluBu4) [22]; or milestone in the haploSCT setting. PTCy removes selec- thiotepa (5 mg/kg IV) on days −7 and −6, fludarabine (50 tively alloreactive donor T cells that are proliferating in mg/m2 IV) on days −5, −4, and −3 and busulphan (1 mg/ response to host alloantigen while preserving non- kg/6 h on days −5, −4, and −3 oral dose, or 3.2 mg/kg/day alloreactive donor T cells [18], with surprisingly fast IV dose on the same days) (TBF) [23]. quantitative immune reconstitution [4, 19]. Despite initial Reduced-intensity conditioning regimens (RIC) con- encouraging results with PTCy [20], infection-related sisted of fludarabine (30 mg/m2 IV) from day −6 to −2, mortality (IRM) is still the most common cause of mortal- cyclophosphamide (14.5 mg/kg IV) on days −6 and −5 and ity, and possibly higher than in alloSCT from HLA identical busulphan (3.2 mg/kg IV) on days −4 and −3 (FluCyBu2). sibling donor (21% vs. 13%, p = 0.002) [11]. Likewise, If the TBF platform was used as RIC, busulphan was IRM was higher in haploSCT without PTCy than a matched reduced from three to 2 days (days −5 and −4). cohort of recipients of HLA identical sibling alloSCT (26 + All patients received PTCy (50 mg/kg IV on days +3 6% vs. 10 + 4%, p = 0.04) [21]. and +4) as GvHD prophylaxis followed by cyclosporine Currently, despite several advances that have improved combined with MMF or tacrolimus alone since day +5 the outcomes after alloSCT, infectious complications remain [22, 23]. Intravenous MESNA was given at a dose of 10 a significant problem and a major cause of transplant failure. mg/kg/6 h on days +3 and +4 (total daily dose of 40 mg/ In the present study, we describe the incidence of kg) as hemorrhagic cystitis (HC) prevention. infections and causative pathogens in different post-SCT Each institution chose to use either peripheral blood (PB) periods (pre-engraftment [<31 days] (PE), early post- or bone marrow (BM) as the stem cell (SC) source. The engraftment [31–100 days] and late post-engraftment target dose of CD34 + cells/kg of recipient weight to be [>100 days]), the IRM and causative pathogens, as well infused was 5 × 106/kg (range 4–6 × 106/kg) in recipients of as the overall transplant outcomes, in a large retrospective PBSC transplantation (PBSCT), while the target dose total series of haploSCT with PTCy as graft versus host disease nucleated cells (TNC)/kg recipient weight in BM recipients (GvHD). was 3 × 108/kg. The centers selected the haploidentical donor based on availability and their preference among the first-degree Patients and methods relatives. Donor-specific anti-HLA antibodies (DSA) were studied in all patients; a local protocol of desensitisation Patients was in place in case of inevitable high DSA titers were found (details not shown). Two-hundred thirty-six adult consecutive patients were transplanted between November 2013 and November 2018 in six centers of the Spanish transplant group (Grupo Definitions and supportive care Español de Transplante Hematopoyético [GETH]). All patients received a haploSCT using PTCy as GvHD pro- The definitions used in the current study are also shown in phylaxis [16] followed by calcineurin inhibitors, with or detail in the Supplementary online material. without mycophenolate mofetil (MMF). Transplants were In general, any bacterial, viral, or invasive fungal infection done according to the local institutional protocols, and all (IFI) requiring intravenous treatment or hospitalization was patients signed informed consent. As a general rule, considered a severe infectious episode. In the case of common exclusion criteria were a poor performance status (ECOG ≥ bacterial skin contaminants (mostly coagulase-negative sta- 3 or Karnofsky score <60%), HIV infection, impaired car- phylococci), a bloodstream infection (BSI) was diagnosed diac or pulmonary functions, active viral hepatitis, and renal only if ≥2 consecutive blood cultures were positive for the failure (creatinine > x 1.5 ULN). The information was same species. Infection data were collected retrospectively evaluated retrospectively for each patient. until the patient’s death or last follow-up, using standardized definitions of severe infections after SCT based on the most recent guidelines (https://www.ebmt.org/working-parties/ Conditioning regimens, Gvhd prophylaxis, infectious-diseases-working-party-idwp). Common respira- and stem cell source tory virus infections and virus-related hemorrhagic cystitis were also included in the study. Cytomegalovirus (CMV) The conditioning regimens were selected by each institution infection was defined as the presence of at least 2 consecutive according to patients’ characteristics and local protocols. (within a minimum interval of 48 h) positive results of a Severe infections and infection-related mortality in a large series of haploidentical hematopoietic. . . polymerase chain reaction (PCR) test for CMV in peripheral analyses. Overall survival (OS) was defined as the time blood (PB) with a viral load >1000 IU/mL, while CMV from day 0 to date of death by any cause, and progression- disease was defined as the demonstration of CMV in biopsy free survival (PFS) was the time from day 0 to disease or autopsy specimens from clinically involved visceral sites progression or death. The Kaplan Meier method was used by culture and/or histology or if CMV was detected in sam- for estimating the actuarial PFS and OS, and the log rang ples from clinically-defined sites of disease. Epstein-Bar virus test was used to study the univariate impact of any given (EBV) infection was defined as the presence of at least 2 variable on OS and PFS. The cumulative incidence (CI) consecutive (within a minimum interval of 7 days) positive estimate with competing risk(s) analysis was used to cal- results of a PCR test for EBV in peripheral blood (PB) with a culate the incidence of acute and chronic GVHD, non- viral load >1000 e.g.c./mL, with or without evidence of EBV- relapse mortality (NRM), relapse, and infection-related related post-transplant lymphoproliferative disease (EBV- mortality (IRM). The competing risk for NRM was relapse, PTLD). Human herpes virus 6 disease was defined as the while for relapse it was NRM. Competing risks for acute presence of positive PCR test in cerebrospinal fluid in patients and chronic GvHD were disease relapse and NRM up to with neurological symptoms (encephalitis), and a positive 100 days after stem cell infusion for acute GvHD and until intestinal biopsy (colitis). the last follow up for chronic GvHD. Competing risk for All patients were nursed in HEPA-filtered rooms. Anti- IRM was NRM not due to infection or relapse. Competing microbial prophylaxis was given following institutional risk of infection during a period of infectious risk was NRM policies, but which can be summarized as follows. Bacterial or relapse during the time period. Gray test was used to prophylaxis consisted of ciprofloxacin or levofloxacin dur- study the impact of any given variable on a CI. We used ing neutropenia or until the start of broad-spectrum anti- landmark studies to find the incidence of infections in dif- biotics. Antifungal prophylaxis was administered according ferent time points, and thus time-dependent variables which to the protocols at each site, with either fluconazole and a occurred before each landmark point were included as pre-emptive strategy; or a mold-active antifungal agent binary variables. If the patients were alive at every time (posaconazole, voriconazole or other systemic antifungal point they were categorized in two groups (with or without drugs) until engraftment or whenever the patient was given infection). Patients who died before the time of any given steroids for the treatment of GVHD. Prophylaxis against landmark point were excluded from the next time point. The Pneumocystis jirovecci consisted of cotrimoxazole until day time points: day 100 (late post- was used if cotrimoxazole was contraindicated. For pre- engraftment) were used for infections by GPB, GNB, and vention of Cytomegalovirus (CMV)-related disease, all conventional respiratory virus infection. For CMV and institutions followed a preemptive approach with poly- EBV, hemorrhagic cystitis and fungal infections, the time merase chain reaction (PCR) monitoring; the treatment points selected were <31 and ≥31 days. COX regression started with positive PCR consisted of ganciclovir or fos- analysis was used for multivariate analysis with doc- carnet if severe neutropenia or ganciclovir toxicities. Acy- umentation of proportional hazards over time for each clovir was recommended for a minimum of 1-year post- outcome and covariate analyzed. In addition, variables or HSCT or until immunosuppressive therapy was stopped. events that occurred post-transplant but before a given Galactomannan testing and CMV PCR analysis were per- landmark point were analyzed as possible risk factors for formed twice weekly, and Epstein-Barr virus (EBV) PCR IRM, NRM and relapse in the framework of Cox models as analysis was performed weekly until day +100, in case of time-dependent covariates (for instance, occurrence of EBV infection, rituximab was used. Intravenous immu- aGVHD), switching from absent to present at the moment noglobulin (IVIG) replacement was recommended when- of occurrence of each covariate/event. ever the total IgG blood level was < 400 mg/dL, especially if the patient had prior infection by encapsulated bacteria or were considered to be at high risk of humoral Results immunodeficiency-linked opportunistic infections. All cen- ters started the practice of vaccination after 6th months Patient and donor characteristics unless patients had severe active GvHD or were receiving IVIG therapy Patient and donor characteristics are shown in Table 1. The median follow up of survivors was 37 months (range Statistical analyses 12–82). The median patient age was 50 years (range 17–71), and 61% were male. Seventy-six patients (32%) SPSS statistics (IBM SPSS Statistics 21) and R studio had acute myeloid leukemia (AML), which was the most programs (R studio, Boston, MA) were used for statistical common underlying disease, followed by lymphoma in 70 A. Esquirol et al. Table 1 Patient and donors’ characteristics. Table 1 (continued) Number of cases 236 CD34 + cells infused (×106/kg) Patients’ characteristics N (%) (median, range) Median age [range] 50 (17–71) Median follow-up in survivors, months 37 [1–82] (range) Age ≥50 years/≥60 years 115 (49%)/57 (24%) Donors’ characteristics Male and female sex 144 (61%)/92 (39%) Male and female sex 132 (56%)/104 (44%) Female donor to male recipient 64 (27%) Donor relationship with patient Underlying disease Mother/Father 13 (6%)/23 (10%) AML 76 (32%) Son/Daughter 61 (26%)/41 (17%) MDS 39 (17%) Brother/Sister 55 (23%)/39 (16%) ALL 22 (9%) Other donors 4 (2%) Non-Hodgkin’s lymphoma 39 (17%) Donor and recipient CMV IgG combination Hodgkin disease 31 (13%) D+/ R + − 112 (48%) CLL 8 (3%) D−/R+ 69 (29%) CML or other MPS 12 (5%) D+/ R− 29 (12%) Multiple myeloma 5 (2%) D−/R− 25 (11%) Biphenotypic acute leukemia 2 (1%) Aplasia 1 AML acute myeloid MDS Myelodysplastic syndrome, ALL acute lymphoblastic leukemia, CLL chronic lymphocytic leukemia, CML Prolymphocytic leukemia 1 chronic myeloid leukemia, MPN myeloproliferative neoplasm, HSCT Response at transplant hematopoietic stem cell transplantation, AlloSCT allogeneic stem cell Complete remission (first and second) 130 (55%) transplantation, FluBu fludarabine-busulfan, FluBuBy fludarabine- busulfan-cyclophosphamide, TBF thiotepa-fludarabine-busulfan, Flu- Third complete remission 16 (7%) CyTBI fludarabine-cyclophosphamide-total body irradiation, FluATG Partial remission 33 (14%) fludarabine-ATG, GvHD graft versus host disease, PTCy post- Stable disease 17 (7%) transplantation cyclophosphamide, MMF mycophenolate mofetil, Progression or refractory disease 33 (14%) CMV cytomegalovirus, D donor, R recipient. Induction chemotherapy aplasia 5 (2%) Primary graft failure 2 (1%) Refined Disease Risk Index (rDRI) patients (30%). Twenty-seven patients (11%) had failed a Low rDRI 29 (12%) first alloSCT. One hundred thirty-five patients (57%) were in early Intermediate rDRI 125 (54%) disease phase at transplant (first and second CR; and post- High rDRI 72 (31%) induction aplasia), although 79 patients (34%) had a high or Very High rDRI 7 (3%) very high refined Disease Risk Index (rDRI) [24]. MAC Prior HSCT, num. (%) 77 (33%) regimen was used in 32% of the transplants (75 patients). Previous aloSCT 27 (11%) One hundred thirty-two donors (56%) were male, and the Conditioning regimen most common donors used was a son (26%) or a daughter FluBu 23 (10%) (17%). An IgG seropositive CMV donor for a seropositive FluBuCy 87 (37%) patient was the most frequent combination in 112 donor- TBF 121 (51%) patient CMV serostatus (48%), only 23% of patients were Other (FluCyTBI, FluATG) 5 (2%) CMV seronegative. Conditioning intensity Myeloablative 75 (32%) Hematological recovery; acute and chronic GVHD Reduced intensity 161 (68%) Stem cell source One hundred ninety-one patients (81%) received PBSC. The Peripheral blood stem cells 191 (81%) median number of CD34 + in PBSCT was 5.4 × 106/kg (range Bone marrow 45 (19%) 1.95–11.42), while the TNC infused in BM recipients was GvHD prophylaxis following PTCy 3.5 × 106/kg (range 0.84–19.6). The CI of neutrophil and Cyclosporine with MMF 115 (49%) platelet recovery was 94% (95% CI, 91–97%) and 90% (95% Tacrolimus 121 (51%) CI, 86–94%), respectively. Six patients (2.5%) had primary 5,4 (1.95–11.42) graft failure. Nine patients died early (before day +21) without engraftment (with a severe infection as primary cause of death), including 5/27 (19%) previously allotransplanted patients. Severe infections and infection-related mortality in a large series of haploidentical hematopoietic. . . In the 221 remaining patients, the median time to neu- Fifty-six percent of patients developed at least one trophil (>0.5 × 109/L) and platelet (>20 × 109/L) recovery bacterial infection (19% of patients had gram-positive was 18 days (range 9–49) and 26 days (range 10–156), bacterial infections, 15% had gram-negative bacterial respectively. infections, and 22% had both types of bacterial infections). The CI of grade II-IV and III-VI acute GvHD at day CMV infection (CMV-I) was found in 69% of patients, +100 was 31% (95% C.I., 25–37%) (79 patients) and 11% and 52% had at least one non-CMV viral infection. An (95% C.I., 7–15%) (30 patients), respectively; 5 patients invasive fungal infection (IFI) occurred in 41 patients died as a consequence of steroid-refractory grade III-IV (17%), including 10% of possible, probable, or proven acute GvHD. invasive aspergillosis. Specific pathogens involved, their The CI of limited, moderate, and severe chronic GvHD at distribution post-transplant, and the median time to onset 37 months was 16% (95% C.I., 12–22%), 8% (95% C.I., of the major types of infections per time period are shown 5–11%), and 7% (95% C.I., 4–10%), respectively. Four in detail in Table 4. patients died due to severe chronic GvHD. There were 43 cases of IRM; the median interval from transplant to IRM was 3 months (range 10–927); eight (19%) Transplant outcomes died during the PE period, 12 patients (28%) developed a lethal infectious complication in the early post-engraftment period, The OS at 12 and 37 months was 64% (95% C.I., 61–67%) and 23 patients (53%) died beyond +100 days. In 51% (22 and 50% (95% C.I., 46–54%), respectively, and the PFS was patients), the cause of IRM was bacterial, 16% (7 patients) 57% (95% C.I., 54–60%) and 47% (95% C.I., 44–50%), developed a lethal viral infection, 5% (2 patients) an IFI, and respectively. Several variables had an independent impact on two patients had a mixed bacterial and fungal infection. In 23% these outcomes in multivariate analysis (MVA); first and sec- of clinically documented IRM no microbiological doc- ond CR at transplant, patients ≤ 50 years and grade III-IV acute umentation was reported. The documented primary causes of GvHD for OS; and first and second CR at transplant, rDRI and IRM and NRM are shown in Table 3. patient age ≤ 50 years for PFS [Table 2]. All IS was discontinued in 161 of patients (68%) at a The CI incidence of relapse at 12 and 37 months was median time post-transplant of 199 days (range 1–37 months), 17% (95% CI, 12–22%) and 21% (95% CI, 16–26%), and seven of these patients died as a consequence of infection respectively. Variables that impacted on relapse in MVA (4.3% IRM). Six of these seven patients died after day +100. were the disease response at transplant (first and second CR In 75 patients (32%) discontinuation of IS therapy had vs. other responses) and low-intermediate rDRI [Table 2]. not been possible at last follow-up. Thirty-three patients Forty patients (17%) died owing to relapse. died before 100 days, and the main causes of death were The CI of non-relapse mortality (NRM) was 26% (95% infection (19 patients, 25% IRM), while of the 42 patients CI, 21–31%) and 31% (95% CI, 25–37%) at 12 and who received IS drug/s after day +100, 17 died due to 37 months. Prior alloSCT, age ≥50 years and grade III–IV infections (40% IRM) and 12 patients were still alive at last acute GVHD were risk factors in the MVA [Table 2]. The follow-up more than 1 year post-transplant. main cause of NRM was an IRM (58% of NRM, 43 patients) [Table 3]. Bacterial infections Infection-related mortality and severe infectious The incidence of PE ( < day +31), early post-engraftment complications (day +31 to +100) and late post-engraftment (> day +100) infections by gram-positive bacteria (GPB) was 20% (95% The CI of IRM at 12 months was 17% (95% C.I., 12–22%) C.I., 15–25%), 11% (95% C.I., 7–15%) and 20% (95% C.I., and 19% (95% C.I., 14–24%) at 37 months, and the vari- 14–26%), respectively, with an overall incidence of ables with an independent impact in the MVA analysis were 51%. The median time of infection was 10 days (range age ≥ 50 years, lymphoid malignancy as underlying disease 0–28), 72 days (range 32–97), and 7 months (range 3–29), (vs. myeloid), and development of grade III-IV acute GvHD respectively. [Table 2]. One hundred twenty-two infection episodes by GPB Six hundred twenty-three severe infectious episodes were reported (shown in detail in Table 4) of which 46% were reported in the 236 patients, with 2.6 infections per (56 episodes) occurred in the PE period. Staphylococcus patient (range 0–8). Only 17 patients (7%) did not develop spp. and Enterococcus spp. were the most frequent any severe infections. In addition, 14% (32 patients) GPB. Six of seven patients with Streptococcus spp. infec- developed a clinically defined severe infection without tion in the late post-engraftment period were caused by microbiological documentation, and 10% required ICU Streptococcus pneumoniae. Only eight GPB (6%) presented admission due to a severe infection. antibiotic resistance (Methicillin-resistant Staphylococcus Table 2 Univariate (UVA) and multivariate (MVA) analysis (37 months). IRM NRM Relapse OS PFS UVA MVA UVA MVA UVA MVA UVA MVA UVA MVA Incidence % (HR. 95% C.I.) Incidence % (HR. 95% C.I.) Incidence % (HR. 95% C.I.) Probability % (HR. 95% C.I.) Probability % (HR. 95% C. I.) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) Disease status at transplant Complete remission (1st and 20 (13–27) NA 27 (19–34) NA 11 (5–16) 0.26 (0.14–0.5) 61 (57–65) 0.41 (0.28–0.6) 59 (54–64) 0.44 2nd)a (0.3–0.63) Other status/responses 18 (10–25) 36 (26–46) 35 (25–45) 34 (29–39) 31 (26–36) p value 0.1 0.7 0.07 0.05 0.001 0.001 0.001 0.001 0.001 0.001 rDRI Low-intermediate* 20 (13–26) NA 30 (23–38) NA 16 (10–22) 0.44 54 (50–58) NA 52 (48–56) 0.64 (0.24–0.79) (0.44–0.9) High-very high 17 (8–25) 30 (19–40) 32 (21–42) 40 (34–46) 39 (33–45) p value 0.7 0.6 0.66 0.38 0.001 0.006 0.008 0.07 0.003 0.02 Prior alloSCT No* 18 (11–23) NA 28 (22–34) 0.55 (0.33–0.9) 19 (14–25) NA 52 (48–56) NA 49 (45–53) NA Yes 26 (9–42) 44 (26–63) 26 (9–42) 29 (21–38) 29 (20–38) p value 0.3 0.3 0.02 0.02 0.3 0.8 0.001 0.117 0.001 0.09 Recipient years at transplant <50* 13 (7–199 0.34 25 (17–33) 0.5 (0.3–0.83) 21 (14–29) NA 54 (49–59) 0.62 (0.43–0.9) 52 (47–57) 0.65 (0.17–0.64) (0.45–0.9) ≥50 26 (17–34) 37 (28–46) 20 (12–28) 44 (39–49) 42 (37–47) p value 0.02 0.002 0.06 0.008 0.7 0.35 0.13 0.02 0.2 0.023 Grade 3–4 acute GvHD No* 17 (11–22) 0.47 (0.23–0.9) 26 (20–33) 0.41 21 (15–26) NA 53 (49–57) 0.48 50 (46–54) NA (0.24–0.72) (0.29–0.78) Yes 36 (18–53) 58 (41–76) 17 (3–31) 28 (20–36) 24 (16–32) p value 0.03 0.05 0.001 0.002 0.6 0.22 0.007 0.003 0.02 0.07 Underlying disease Myeloid* 15 (9–22) 0.49 (0.26–0.9) 28 (20–36) NA 18 (11–25) NA 51 (46–56) NA 50 (45–55) NA Lymphoid 23 (15–31) 33 (24–42) 24 (16–33) 49 (44–54) 44 (39–49) p value 0.1 0.032 0.4 0.8 0.34 0.72 0.4 0.7 0.24 0.3 a Reference variables in the MVA. In addition to the variables included in the table, other variables analyzed in the UVA and subsequently included in the MVA were: patient and donor sex, stem cell source, type of conditioning regimen (myeloablative vs. reduced-intensity), TBF conditioning vs. other, type of GvHD prophylaxis (tacrolimus vs. cyclosporine-MMF). A. Esquirol et al. Severe infections and infection-related mortality in a large series of haploidentical hematopoietic. . . Table 3 Causes of nonrelapse mortality. Pre-engraftment Early post-engraftment Late post-engraftment (<31 days) (31–100 days) (>100 days) Causes of IRM N 43 (58%) 8 (19) 12 (28) 23 (53) Gram positive bacterial (N 7) 2 3 2 Enterococcus faecium 2 Enterococcus faecalis 1 1 Streptococcus mitis 1 Stretococcus pneumoniae 1 Methicillin resistance 1 Staphylococcus aureus Gram negative bacterial (N 13) 2 2 9 Escherichia coli 1 ESBL Escherichia coli 1 Pseudomonas aeruginosa 1 Multidrug resistance 1 1 1 Pseudomonas aeruginosa Klebsiella pneumoniae 2 ESBL or KPC Klebsiella 1 1 pneumoniae Acinetobacter baumannii 1 Stenotrophomonas maltophila 1 Serratia marcescens 1 Viral infection (N 7) 1 3 3 CMV disease (pneumonitis) 1 2 1 Metapneumovirus 1 Human herpes 6 virus 1 EBV-PTLD 1 Invasive fungal infection (N 2) 1 1 Probable IFI 1 1 Gram negative bacterial + 1 1 fungal infection (N 2) Gram negative and positive 2 bacterial (N 2) Without positive 2 3 5 microbiological (N 10) Other causes of NRM N 26 4 (15) 9 (35) 13 (50) (35%) Graft rejection 1 2 2 Sinusoidal obstruction syndrome 2 1 Idiophatic encephalitis 2 1 Refractory acute GvHD 2 3 Chronic GvHD 4 Other NRM causes 1 2 3 Secondary neoplasms N 5 (7%) 5 Other NRM causes: non-infectious endocarditis (x1), adult respiratory distress syndrome (x1), refractory bleeding (x1), alveolar refractory bleeding (x2) and sudden death (x1). NRM non relapse mortality, IRM infection-related mortality, ESBL extended-spectrum beta-lactamase, CMV cytomegalovirus, PT-LPD post- transplant lymphoproliferative disorder, EBV Epstein-Barr virus, IFI invasive fungal infection, PTLD post-transplant lymphoproliferative disease. A. Esquirol et al. Table 4 Microbiological etiology in time of onset. Pre-engraftment Early post-engraftment Late post-engraftment (<31 days) (31–100 days) (>100 days) Total infectious episodes N = 623 205 (33) 214 (34) 204 (33) (100%) Gram positive bacteria N = 122 56 (46) 25 (20) 41 (34) (20%) Median time of GPB infections 10 days (0–28) 72 days (32–97) 7 months (3–29) days or months (range) Staphylococcus spp 31 13 22 Enterococcus spp 17 10 10 Streptococcus spp 5 7 Corynebacterium spp 2 Bacillus spp 1 Listeria monocytogenes 2 1 Nocardia spp 1 Gram N = egative bacterial 23 (21) 34 (32) 50 (47) N = 107 (17%) Median time of GNB infections 13 days (0–28) 51 days (35–97) 7 months (3–33) days or months (range) Escherichia coli 10 8 17 Pseudomonas aeruginosa 7 10 14 Klebsiella pneumoniae 2 7 8 Stenotrophomonas maltophilia 3 1 3 Serratia marcescens 1 2 1 Enterobacter cloacae 5 1 Haemophilus influenzae 4 Veillonella spp 1 Acinetobacter baumannii 1 Leptotricia trevisanii 1 Clostridium difficile N = 17 (3%) 10 (59) 5 (29) 2 (12) Median time of CD infection days 5 days (2–20) 42 days (32–47) – or months (range) Viral infections Cytomegalovirus N = 155 (25%) 58 (38) 84 (54) 13 (8) Median time of CMV infections 21 days (0–30) 42 days (31–100) 5 months (3–31) days or months (range) Reactivation 54 84 12 Disease 4 – 1 Epstein–Barr Virus N = 23 (4%) 5 (22) 18 (72) Median time of EBV infections – 85 days (69–98) 5 months (3–20) days or months (range) Reactivation – 5 16 EBV-PTLD 2 Hemorrhagic cystitis N = 77 32 (42) 37 (48) 8 (10) (12%) Median time of HC infection days 14 days (0–30) 45 days (31–98) 4 months (3–7) or months (range) BK Poliomavirus-related 20 31 3 Adenovirus 1 3 1 Without viral infection 11 3 4 Severe infections and infection-related mortality in a large series of haploidentical hematopoietic. . . Table 4 (continued) Pre-engraftment Early post-engraftment Late post-engraftment (<31 days) (31–100 days) (>100 days) Upper respiratory tract viral 2 (6) 10 (29) 22 (65) infections N = 34 (5%) Median time of URT infections – 70 days (63–84) 10 months (4–42) days or months (range) Influenza virus 5 10 Respiratory syncytial virus 5 2 Parainfluenza virus 1 6 Rhinovirus 1 2 Adenovirus 2 Lower respiratory tract viral 5 (18) 3 (11) 20 (71) infections N = 28 (4%) Median time of LRT infections 17 days (19–22) – 7 months (3–37) days or months (range) Respiratory syncytial virus 2 8 Influenza virus 1 1 6 Parainfluenza virus 1 1 Coronavirus 1 1 Rhinovirus 1 3 Metapneumovirus 1 1 Other viral infections N = 19 5 (26) 5 (26) 9 (48) (3%) Median time of other virus 15 days (5–21) 63 days (40–93) 5,5 months (3–12) infections days or months (range) Human herpes type 6 virus 1 3 3 Adenovirus 3 1 Rotavirus 2 Herpes simplex virus 2 Hepes zoster virus 2 Enterovirus 1 Norovirus 1 Invasive fungal infections N = 41 14 (34) 13 (32) 14 (34) (7%) Median time of fungal infections 10 days (0–28) 72 day (31–99) 11 months (4–46) days or months (range) Possible IA 2 2 2 Probable IA 5 1 2 Proven IA 1 3 4 Pneumocystis jirovecci pneumonia 2 Candida spp uncomplicated 6 7 3 fungemia Penicillinum spp 1 GPB gram positive bacteria, GNB gram negative bacteria, CD clostridium difficile, CMV cytomegalovirus, EBV-PTLD EBV-related Post- transplant lymphoproliferative disease, HC Hemorrhagic cystitis, URT upper respirtory tract, LRT lower respiratory tract, IA invasive aspergillosis. aureus (MRSA) and MR S. epidermidis, with 4 infections Enterococcus faecium, three in the post-engraftment period each). All GPB infections were BSI except for 3 cases of caused by Streptococcus mitis, Enterococcus faecalis, and listeriosis and one case of nocardiosis. MRSA and two late infections (> +100 days) due to There were 7 cases of IRM caused by GPB infections Enterococcus faecalis and Streptococcus pneumoniae (16% of IRM), two infections before +30 days due to (shown in detail in Table 3). A. Esquirol et al. With respect to infections by gram-negative bacteria Community/conventional respiratory virus (CRV) infections (GNB), the incidence of PE ( < day +31), early post- engraftment (day +31 to +100) and late post-engraftment Sixty-two episodes of CRV infections were reported, and the (> day +100) infections was 10% (95% C.I., 6–14%), 14% incidence of at least one episode of CRV infection was 4% (95% C.I., 9–19%) and 22% (95% C.I., 16–28%), respec- (95% C.I., 1–7%) in the PE period, 5% (95% C.I., 2–8%) in tively, with an overall incidence of 46%. The median time the early post-engraftment and 15% (95% C.I., 10–20%) in the of infection was 13 days (range 0–28), 51 days (range late post-engraftment period. Only one patient died as a con- 35–97), and 7 months (range 3–33). Details are shown in sequence of metapneumovirus pneumonia. Table 4. One hundred seven GNB infections occurred, all Upper (URTI) and lower (LRTI) respiratory tract infections were BSI, and as apposed to GPB infections the highest rate by a CRV accounted for 34 and 28 episodes (55% and 45%), of GNB infections occurred in the late post-engraftment respectively (details shown in Table 4). Both URTI and LRTI period risk, with 50 episodes (47%) of GNB infections. The occurred mostly in the late post-engraftment period (65 and most common pathogens isolated were Escherichia coli, 71% of CRV infections, respectively). The most CRV in URTI Pseudomonas aeruginosa, and Klebsiella pneumoniae, were influenza viruses (14 episodes), respiratory sincytial virus which accounted for 83/107 (78%) of GNB infections (7 episodes) and parainfluenza viruses (7 episodes), whereas among these three species, 16% were antibiotic-resistant respiratory sincytial virus (10 episodes) and influenza viruses (6 (eight multidrug-resistant (MDR) Pseudomonas aerugi- episodes) were the most common in LRTI. nosa, three extended-spectrum beta-lactamase producing (ESBL) Escherichia Coli and seven ESBL or carbapena- Other viral infections mase producing Klebsiella pneumoniae). Other innately MDR species included 7 infections by Stenotrophomonas A very frequent complication in haploSCT protocols with maltophila and one case of Acinetobacter baumanii. PTCy is hemorrhagic cystitis (HC), as confirmed in the current The causes of IRM by GNB are shown in detail in study. The incidence of HC until +30 days was 14% (95% C. Table 3, which accounted for 30% of IRM (13 patients); I., 10–18%) and after day +31 it was 21% (95% C.I., two lethal infections in the PE period (MDR Pseudomonas 16–26%), for an overall incidence of 35%. BK-polyomavirus- aeruginosa and ESBL Escherichia coli), two in the early related HC was diagnosed in 54 cases (70% of HC), while post-engraftment period (MDR Pseudomonas aeruginosa, adenovirus-related HC was found in five cases (6% of HC). No and ESBL Klebsiella pneumonia), and 9 patients in the late viral pathogen was identified in 18/77 cases of HC (23%), 11 post-engraftment period (one Pseudomonas aeruginosa and of which occurred early post-transplant. one MDR Pseudomonas aeruginosa; one ESBL Klebsiella Human Herpes virus type 6 infection was diagnosed in 7 pneumoniae and two Klebsiella pneumoniae, one Escher- patients, with two cases of encephalitis and 5 cases of ichia coli, one Serratia marcescense, Stenotrophomona colitis. Other less common cutaneous and intestinal viral maltophilia and Acinetobacter baumannii). infections are shown in Table 4. Virus infections Invasive fungal infections CMV and EBV Infections The incidence of invasive fungal infections (IFI) was 4% (95% C.I., 3–5%) before +31 days and 7% (95% C.I., The incidence of CMV infection (CMV-I) in PE period 4–10%) after day +31, for a 3-year incidence of 11%. The (< day +31) and post-engraftment period (≥31 days) was 25% most common IFI was invasive aspergillosis (IA), with eight (95% CI, 20–30%) and 44% (95% CI, 38–50%), respectively. cases of proven IA, eight probable IA and six cases of pos- In three patients were showed the CMV infection after sible IA. An IFI was the primary cause of death for two 12 months. Among CMV seropositive patients the incidence patients with proven IA and one probable IA. Pneumocystis of CMV-I was 78% (95% C.I., 72–84%), whereas it was 24% jirovecci pneumonia was diagnosed in the late post engraft- (95% C.I., 12–36%) in seronegative recipients. Five patients ment period in only two patients, while uncomplicated can- developed CMV pneumonitis, in four cases before day +31 didemia occurred in 16 patients (7%) [details in Table 4]. and one on day +155, and four died from this complication. The incidence of EBV reactivation was 10% (95% CI, 6–14%), mainly in the late post-engraftment period (18/23 Discussion cases). Fifteen patients were treated with rituximab due to high EBV DNAemia (>1000 e.g.c./mL). EBV-related post- In the current study, we describe the incidence of severe transplant lymphoproliferative disorder (EBV-PTLD) was infections and the IRM in a large series of adult recipients of diagnosed in two patients and was lethal in one of these cases. a haploSCT with PTCy. As previously described in other Severe infections and infection-related mortality in a large series of haploidentical hematopoietic. . . studies infectious complications are the main cause of of in vivo or ex vivo T-cell depletion is of course a major NRM, as occurs with other types of alloSCT [25, 26]. The determinant for the low incidence [42]. 3-year incidence of NRM was 31% and 19% for IRM in the In haploSCT with PTCy the incidence of HC has been present study. reported to range from 19% to 60% [38, 44]. Recent pub- In our series, the 3-year incidence of GPB and GNB lications showed a higher incidence of HC in haploSCT infections was 51% and 46%, respectively (246 episodes), with PTCy than in alloSCT from matched related donors similar to the incidence reported by others which range also with PTCy (55% vs. 25%) [44, 45], suggesting that the from 35% to 62% [27–30], albeit somewhat different use of PTCy is not the main risk factor for the higher definitions were used in different studies. The rates of incidence of HC in haploSCT. As expected, BK Poly- GPB infections were similar in the pre-engraftment and omavirus was the most common virus linked to HC (70% of late post-engraftment period, while GNB infections were cases) in our series. In the haploSCT setting donor T lym- more common in the late post-engraftment period (> day phocytes are HLA mismatched with urothelial viral antigen- +100). Risk factors for these late GNB infections have presenting cells, compromising the immune effector T cell been reported, although we did not analyze their risk response [45]. Although there is no treatment nor prophy- factors due to the large number of species involved laxis for viral-related HC, the continuous intravenous and thus small numbers per pathogen [14]. Bacterial infusion of MESNA has been recently reported to reduce infections were the most common causes of IRM (51%, the incidence of HC when compared with bolus adminis- 22 patients), mainly GNB infections (30%, 13 patients). tration (5.6% vs. 27.8%) [46], although this requires con- As expected, Escherichia coli, Pseudomonas aeruginosa, firmation with further studies. and Klebsiella pneumoniae were the most common GNB A low incidence of IFI was found (11% at 3 years), species [14, 27, 29, 31]. especially during the early aplastic post-transplant period Antibiotic resistance appeared to contribute to IRM. A (4%) and with a very low impact on IRM. Due to the low MDR strain was involved in 6/13 (46%) deaths by GNB, incidence, we were unable to analyze the risk factors for while only 16/83 (19%) overall isolated were MDR, and developing an IFI. three additional patients died due to Acinetobacter bau- Among the patients on immunosuppressive drugs (IS) mannii, Serratia marcescens, and Stenotrophomonas during the entire study follow-up, 40% of all IRM (17 maltophilia. Knowledge of the epidemiology of MDR patients) occurred in patients after +100 days and 44% of GNB in each hospital as well as prior infections by these all IRM occurred before day +100 (19 patients). However, pathogens in any given patient is crucial in establishing in the 161 patients who discontinued IS post-transplant the the best empirical antibiotic strategy [14, 32, 33]. On the IRM was low (7 patients, 4.3% rate of and 16% of all the other hand, a high incidence of GPB was found during the cases of IRM). study; however, antibiotic resistance was rare among GPB The present study shares the limitations inherent to ret- (6%), and only one patient died due to MRSA infection. rospective studies, including potential selection bias; and Regarding CMV-I, a high incidence was found in our the uncertainty of whether all infections were captured and series (24% during PE period and 45% beyond ≥31 days), in included in the study. However, the study gives a useful contrast to a low rate of CMV disease (2%), as reported by picture of the overall epidemiology of different severe others [27, 29, 34–36]. A higher incidence of CMV-I in infections and their impact on IRM in the setting of adult haploSCT with PTCy compared with other donor types has haploSCT with PTCy in our country. been reported previously [27, 36–38]. Initial studies hypo- In conclusion, our national study shows that IRM is the thesized that the high incidence of CMV-I correlated with main cause of NRM in the haploSCT setting with PT-Cy. A delayed CD4 + T cell and dendritic cell recovery [39, 40]. major cause of IRM were GNB infections, possibly higher Also, CMV-I has a strong impact on the integrity and het- in patients with MDR GNB infections. Studies focusing on erogeneity of the T cell repertoire, leading to CD8 + effector the immunological reconstitution, especially in patients memory T cell expansion and contraction of naïve cells [41]. without severe GVHD, may help in understanding the high However, a recent report found that CMV-specific-T-cell incidence of late infections linked to cellular immunity, reconstitution in T-cell replete haploSCT with PTCy was such as CMV and viral-related HC. comparable to other types of alloSCT without PTCy [42]. More studies are necessary to define the relationship between Funding This project has been funded by La Marató de TV3 Foundation CMV-I and immunological reconstitution. file number: 20133230. AGAUR 2017 SGR 1395 from the Catalan Interestingly, we found a low incidence of EBV-I (10%) Government and a grant from “Obra Social La Caixa” Barcelona Spain. PERIS SLT002/16/0043 from the Catalan Government and FIS PI17/ and EBV-PTLD (2 patients), as recently reported by other 01246 from the Instituto de Salud Carlos III, Ministerio de Economía y groups [27, 43]. The immunological hypothesis for the low Competitividad, Spain. Tercel RD16/0011/0028 Instituto de Salud Car- incidence of EBV-I and EBV-PTLD is unclear, but the lack los III, Ministerio de Economía y Competitividad, Spain. A. Esquirol et al. Compliance with ethical standards transplantation and comparison with HLA-identical sibling trans- plantation. Clin Infect Dis. 2018;67:S162–S173. Conflict of interest The authors declare no competing interest. 14. Girmenia C, Bertaina A, Piciocchi A, Perruccio K, Algarotti A, Busca A, et al. Incidence, risk factors and outcome of pre- engraftment gram-negative bacteremia after allogeneic and auto- Publisher’s note Springer Nature remains neutral with regard to logous hematopoietic stem cell transplantation: an Italian Pro- jurisdictional claims in published maps and institutional affiliations. spective Multicenter Survey. Clin Infect Dis. 2017;65:1884–96. 15. Herbers A, Haan A, van der Velden W, Donnelly J, Blijlevens N. References Mucositis not neutropenia determines bacteremia among hema- topoietic stem cell transplant recipients. Transpl Infect Dis. 1. Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S, 2014;16:279–85. et al. Full haplotype-mismatched hematopoietic stem-cell trans- 16. Modi A, Rybicki L, Majhail NS, Mossad SB. Severity of acute plantation: a phase II study in patients with acute leukemia at high gastrointestinal graft-vs-host disease is associated with incidence risk of relapse. J Clin Oncol. 2005;23:3447–54. of bloodstream infection after adult allogeneic hematopoietic stem 2. Federmann B, Bornhauser M, Meisner C, Kordelas L, Beelen DW, cell transplantation. Transpl Infect Dis. 2020;22:e13217. Stuhler G, et al. Haploidentical allogeneic hematopoietic cell trans- 17. Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti plantation in adults using CD3/CD19 depletion and reduced intensity F, et al. Treatment of high-risk acute leukemia with T-cell- conditioning: a phase II study. Haematologica. 2012;97:1523–31. depleted stem cells from related donors with one fully mismatched 3. Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, et al. HLA haplotype. N. Engl J Med. 1998;339:1186–9. Haploidentical hematopoietic stem cell transplantation without 18. Luznik L, O’Donnell PV, Fuchs EJ. Post-transplantation cyclo- in vitro T-cell depletion for the treatment of hematological phosphamide for tolerance induction in HLA-haploidentical bone malignancies. Bone Marrow Transpl. 2006;38:291–7. marrow transplantation. Semin Oncol. 2012;39:683–93. 4. Luznik L, O’Donnell P, Symons H, Chen AR, Leffell MS, 19. Kanakry CG, Fuchs EJ, Luznik L. Modern approaches to HLA Zahurak M, et al. HLA haploidentical bone marrow transplanta- haploidentical blood or marrow transplantation. Nat Rev Clin tion for hematologic malignancies using nonmyeloablative con- Oncol. 2016;13:10–24. ditioning and high-dose, posttransplantation cyclophosphamide. 20. Raiola AM, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Biol Blood Marrow Transpl. 2008;14:641–50. Gualandi F, et al. Unmanipulated haploidentical bone marrow 5. Raiola AM, Dominietto A, di Grazia C, Lamparelli T, Gualandi F, transplantation and posttransplantation cyclophosphamide for Ibatici A, et al. Unmanipulated haploidentical transplants com- hematologic malignancies after myeloablative conditioning. Biol pared with other alternative donors and matched sibling grafts. Blood Marrow Transpl. 2013;19:117–22. Biol Blood Marrow Transpl. 2014;20:1573e1579. 21. Arcese W, Cerretti R, Sarmati L, Cudillo L, De Angelis G, 6. Ruggeri A, Labopin M, Sanz G, Piemontese S, Arcese W, Baci- Mariotti B, et al. Matched-pair analysis of transplant from hap- galupo A, et al. Comparison of outcomes after unrelated cord loidentical, unmanipulated bone marrow donor versus HLA blood and unmanipulated haploidentical stem cell transplantation identical sibling for patients with hematologic malignancies. Biol in adults with acute leukemia. Leukemia 2015;29:1891–900. Blood Marrow Transpl. 2020;S1083-8791:30089–6. 7. Ciurea SO, Zhang M-J, Bacigalupo AA, Bashey A, Appelbaum 22. Gayoso J, Balsalobre P, Kwon M, Herrera P, Bermúdez A, Sampol FR, Aljitawi OS, et al. Haploidentical transplant with post- A, et al. Busulfan based myeloablative conditioning regimens for transplant cyclophosphamide vs matched unrelated donor trans- haploidentical transplantation in high risk acute leukemias and plant for acute myeloid leukemia. Blood 2015;126:1033–40. myelodysplastic syndromes. Eur J Haematol. 2018;101:332–9. 8. Kwon M, Bautista G, Balsalobre P, Sanchez Ortega I, Montesino P, 23. Esquirol A, Pascual MJ, Ortiz M, Piñana JL, Ferra C, Garcia Bermudez A, et al. Haplo-cord transplantation compared to hap- Cadenas I, et al. Single-agent GvHD prophylaxis with tacrolimus loidentical transplantation with post-transplant cyclophosphamide in after post-transplant high-dose cyclophosphamide is a valid option patients with AML. Bone Marrow Transpl. 2017;52:1138–43. for haploidentical transplantation in adults with hematological 9. Bashey A, Solomon SR. T-cell replete haploidentical donor malignancies. Bone Marrow Transpl. 2017;52:1273–9. transplantation using post-transplant CY: an emerging standard- 24. Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio of-care option for patients who lack an HLA-identical sibling ME, et al. Validation and refinement of the Disease Risk Index for donor. Bone Marrow Transpl. 2014;49:999–1008. allogeneic stem cell transplantation. Blood 2014;123:3664–71. 10. Brissot E, Labopin M, Ehninger G, Stelljes M, Brecht A, Ganser 25. Ullmann AJ, Schmidt-Hieber M, Bertz H, Heinz WJ, Kiehl M, A, et al. Haploidentical versus unrelated allogeneic stem cell Krüger W, et al. Infectious diseases in allogeneic haematopoietic transplantation for relapsed/refractory acute myeloid leukemia: a stem cell transplantation: prevention and prophylaxis strategy report on 1578 patients from the Acute Leukemia Working Party guidelines 2016. Ann Hematol. 2016;95:1435–55. of the EBMT. Haematologica 2019;104:524–32. 26. Forcina A, Lorentino F, Marasco V, Oltolini C, Marcatti M, Greco 11. Bashey A, Zhang A, Jackson K, Brown S, Ridgeway M, Solh M, R, et al. Clinical Impact of Pretransplant Multidrug-Resistant et al. Comparison of outcomes of hematopoietic cell transplants Gram-Negative Colonization in Autologous and Allogeneic from T-replete haploidentical donors using post-transplantation Hematopoietic Stem Cell Transplantation. Biol Blood Marrow cyclophosphamide with 10 of 10 HLA-A, -B, -C, -DRB1, and Transpl. 2018;24:1476–82. -DQB1 allele-matched unrelated donors and HLA-identical sib- 27. Crocchiolo R, Bramanti S, Vai A, Sarina B, Mineri R, Casari E, ling donors: a multivariable analysis including disease risk index. et al. Infections after T-replete haploidentical transplantation and Biol Blood Marrow Transpl. 2016;22:125–33. high-dose cyclophosphamide as graft-versus-host disease pro- 12. Atilla E, Atilla PA, Bozdağ SC, Demirer T. A review of infectious phylaxis. Transpl Infect Dis. 2015;17:242–9. complications after haploidentical hematopoietic stem cell trans- 28. Fayard A, Daguenet E, Blaise D, Chevallier P, Labussière H, plantations. Infection. 2017;45:403–11. Berceanu A, et al. Evaluation of infectious complications after 13. Yan CH, Wang Y, Mo XD, Sun YQ, Wang FR, Fu H, et al. Inci- haploidentical hematopoietic stem cell transplantation with post- dence, risk factors, microbiology and outcomes of pre-engraftment transplant cyclophosphamide following reduced-intensity and bloodstream infection after haploidentical hematopoietic stem cell myeloablative conditioning: a study on behalf of the francophone Severe infections and infection-related mortality in a large series of haploidentical hematopoietic. . . society of stem cell transplantation and cellular therapy (SFGM- 37. Tischer J, Engel N, Fritsch S, Prevalsek D, Hubmann M, TC). Bone Marrow Transpl. 2019;54:1586–94. Schulz C, et al. Virus infection in HLA-haploidentical hemato- 29. Slade M, Goldsmith S, Romee R, DiPersio JF, Dubberke ER, poietic stem cell transplantation: incidence in the context Westervelt P, et al. Epidemiology of infections following hap- of immune recovery in two different transplantation settings. Ann loidentical peripheral blood hematopoietic cell transplantation. Hematol. 2015;94:1677–88. Transpl Infect Dis. 2017;19:e12629. 38. McCurdy SR, Luznik L. Immune reconstitution after T-cell 30. Oltolini C, Greco R, Galli L, Clerici D, Lorentino F, Xue E, et al. replete HLA-haploidentical transplantation. Semin Hematol. Infections after allogenic transplant with post-transplant cyclo- 2019;56:221–6. phosphamide: impact of donor HLA-matching. Biol Blood Mar- 39. Chang YJ, Zhao XY, Huang XJ. Immune reconstitution after row Transpl. 2020;26:1179–88. haploidentical hematopoietic stem cell transplantation. Biol Blood 31. Averbuch D, Tridello G, Hoek J, Mikulska M, Akan H, Yanez L, Marrow Transpl. 2014;20:440–9. et al. Antimicrobial Resistance in Gram-Negative Rods Causing 40. Suessmuth Y, Mukherjee R, Watkins B, Koura DT, Finstermeier Bacteremia in Hematopoietic Stem Cell Transplant Recipients: K, Desmarais C, et al. CMV reactivation drives post-transplant T Intercontinental Prospective Study of the Infectious Diseases cell reconstitution and results in defects in the underlying TCRβ Working Party of the European Bone Marrow Transplantation repertoire. Blood. 2015;125:3835–50. Group. Clin Infect Dis. 2017;65(11):1819–28. 41. Huntley D, Giménez E, Pascual MJ, Remigia MJ, Amat P, 32. Scheich S, Lindner S, Koenig R, Reinheimer C, Wichelhaus TA, Vazquez L, et al. Reconstitution of cytomegalovirus-specific T- Hogardt M, et al. Clinical impact of colonization with multidrug- cell immunity following unmanipulated haploidentical allogeneic resistant organisms on outcome after allogeneic stem cell trans- hematopoietic stem cell transplantation with posttransplant plantation in patients with acute myeloid leukemia. Cancer 2018; cyclophosphamide. Bone Marrow Transplant. 2020;55:1347–56. 124:286–96. 42. Kanakry JA, Kasamon YL, Bolaños-Meade J, Borrello IM, Brodsky 33. Goldsmith SR, Slade M, DiPersio JF, Westervelt P, Lawrence SJ, RA, Fuchs E, et al. Absence of posttransplantation lymphoproli- Uy GL, et al. Cytomegalovirus viremia, disease, and impact on ferative disorder after allogeneic blood or marrow transplantation relapse in T-cell replete peripheral blood haploidentical hemato- using posttransplantation cyclophosphamide as graft-versus-host poietic cell transplantation with post-transplant cyclopho- disease prophylaxis. Biol Blood Marrow Transpl. 2013;19(10): sphamide. Haematologica 2016;101:e465–e468. 1514–7. 34. Lin CH, Su YJ, Hsu CY, Wang PN, Teng CJ. Haploidentical 43. Lunde LE, Dasaraju S, Cao Q, Cohn CS, Reding M, Bejanyan N, allogeneic hematopoietic stem cell transplantation increases the et al. Hemorrhagic cystitis after allogeneic hematopoietic cell risk of cytomegalovirus infection in adult patients with acute transplantation: risk factors, graft source and survival. Bone leukemia. Transpl Infect Dis. 2019;20:e13096. Marrow Transpl. 2015;50:1432–7. 35. Huntley D, Giménez E, Pascual MJ, Hernández-Boluda JC, Gago 44. Copelan OR, Sanikommu SR, Trivedi JS, Butler C, Ai J, Ragon B, Vázquez L, et al. Incidence, features, and outcomes of cyto- BK, et al. Higher incidence of hemorrhagic cystitis following megalovirus DNAemia in unmanipulated haploidentical allogeneic haploidentical related donor transplantation compared with mat- hematopoietic stem cell transplantation with post-transplantation ched related donor transplantation. Biol Blood Marrow Transpl. cyclophosphamide. Transpl Infect Dis. 2020;22:e13206. 2019;25:785–90. 36. Stasi A, Milton DR, Poon LM, Hamdi A, Rondon G, Chen J, et al. 45. Arango M, Cardona D. Hemorrhagic cystitis after haploidentical Similar transplant outcomes for AML/MDS patients with haploi- transplantation with post-transplant cyclophosphamide: protective dentical versus 10/10 HLA matched unrelated and related donors. effect of MESNA continuous infusion. Biol Blood Marrow Biol Blood Marrow Transpl. 2014;20:1975–81. Transpl. 2020;26(8):1492–6.