Abstract
Background.
Fungal infections (FI) after allogeneic hematopoietic cell transplant (HCT) are associated with increased morbidity and mortality. Neutropenia, HLA mismatch, graft versus host disease (GVHD), and viral infections are risk factors for FI.
Objectives.
The objectives of this CIBMTR registry study were to compare the incidence and density of FI occurring within 180 days after HCT in matched sibling (Sib) transplants receiving either calcineurin inhibitor (CNI)-based or PTCy-based GVHD prophylaxis and related haploidentical transplants receiving PTCy, and to examine the impact of FI by day 180 on transplant outcomes.
Study Design.
Patients who received their first HCT between 2012 and 2017 for acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndromes and received related haploidentical transplant with PTCy (HaploCy, N = 757) or Sib transplant with PTCy (SibCy, N = 403) or CNI (SibCNI, N = 1605) were analyzed. The incidence of FI by day 180 post-HCT was calculated as a cumulative incidence with death as the competing risk. The association of FI on overall survival (OS), non-relapse mortality (NRM), chronic GVHD, and relapse at 2 years post HCT were examined in Cox proportional hazards regression models. Factors significantly associated with the outcome variable at a 1% level were kept in the final model.
Results.
By Day 180 post HCT, 56 (7%) HaploCy, 24 (6%), SibCy, and 59 (4%) SibCNI developed ≥1 FI (<0.001). The cumulative incidence (99% confidence interval) of yeast FI was 5.2% (3.3–7.3), 2.2% (0.7–4.5), and 1.9% (1.1–2.9) (p=.001), and mold FI was 2.9% (1.5–4.7). 3.7% (91.7–6.6) and 1.7% (1.0–2.6) (p=0.040) for HaploCy, SibCy, and SibCNI, respectively. FI were associated with an increased risk of death with an adjusted hazard ratio [HR] (99% confidence interval) of 4.06 (2.2–7.6); 4.7(2.0–11.0) and 3.4 (1.8–6.4) for HaploCy; SibCy and SibCNI compared with SibCNI without FI, respectively (p<.0001; for all). Similar associations were noted for transplant-related mortality. FI did not impact relapse or chronic GVHD.
Conclusions:
Rates of FI by Day 180 ranged between 1.9–5.2% for yeast and 1.7%−3.7% for molds across the 3 cohorts. Use of PTCy was associated with higher rates of yeast infections only in Haplo HCT and mold infections in Haplo and Sib HCT. Presence of FI by Day 180 was associated with increased risk for overall mortality and transplant-related mortality at 2 years regardless of donor or PTCy. While rates of FI were low with PTCy, FI were associated with increased risk of death, underscoring the need for improved management strategies.
Keywords: Fungal infection, Post-transplant Cyclophosphamide, Graft versus host disease, Haploidentical hematopoietic cell transplantation, Mortality
Introduction
Invasive fungal infections (IFI) after haploidentical hematopoietic cell transplantation (HCT) are associated with increased mortality [1, 2]. Risk factors for early IFI (≤ day 40 post HCT) include neutropenia, type of conditioning regimen, and donor HLA mismatch, while graft-versus-host disease [GVHD], receipt of corticosteroids, secondary neutropenia, and viral infections are associated with increased risk for late IFI (>40 days post HCT) [1, 3, 4]. Posttransplant cyclophosphamide (PTCy)-based GVHD prophylaxis is associated with improved GVHD-free, relapse-free survival [5, 6] and is increasingly used beyond haploidentical donor HCT. PTCy is associated with delayed immune reconstitution [7]. An association of PTCy with viral infections due to Cytomegalovirus (CMV), non-CMV herpes viruses, and community respiratory viruses (CRVI) has been reported in CIBMTR registry studies [6, 8, 9]. CIBMTR collects data on microbiologically documented fungal infections (FI) by site. Neither details pertaining to the certainty of diagnosis (probable versus definite) including assessment for invasive vs superficial infection nor treatment information were collected until after 2017. Additionally, discrete data for antifungal prophylaxis was also not captured in the CIBMTR database prior to 2017.
We conducted a CIBMTR registry study to examine the association of haploidentical donor source and/or PTCy with FI by comparing 3 cohorts; Haploidentical donor (≥2 antigen/allele mismatched) with PTCy (HaploCy); HLA identical sibling (Sib) transplant with PTCy (SibCy), and Sib transplant with calcineurin inhibitor (CNI) based GVHD prophylaxis (SibCNI). We also investigated the impact of FI on overall survival (OS), transplant-related mortality (TRM), relapse, and chronic GVHD (cGVHD) by 2 years after HCT.
Patients and methods
Study population
A total of 11,964 patients aged ≥2 years receiving their first HCT for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS) between 2012 and 2017 were identified in the CIBMTR registry. Umbilical cord blood–, unrelated donor–, or single-mismatch–related donor transplantations were excluded. Unrelated donor transplantation was excluded as there were few matched unrelated donors with PTCy reported on comprehensive report forms. We excluded patients with reported T-cell manipulation with CD34 selection, ex vivo T-cell depletion, anti-thymocyte globulin, or alemtuzumab to avoid confounders for infection. The study was restricted to centers that reported HaploCy patients and SibCNI patients to limit center bias for reporting, surveillance, prophylaxis, and treatment. We excluded patients who received PTCy as monotherapy for GVHD prophylaxis as few such patients were reported (n = 10). Among the SibCNI cohort, GVHD prophylaxis was limited to tacrolimus/cyclosporine + methotrexate ± other or tacrolimus/cyclosporine + mycophenolate mofetil ± other. The final study groups consisted of 757 patients with haploidentical donors (≥2 antigen/allele) HaploCy), 403 with SibCy, and 1,605 with SibCNI HCT.
Data source
CIBMTR is a research collaboration between the National Marrow Donor Program (NMDP)/Be The Match and the Medical College of Wisconsin (MCW). About 375 medical centers worldwide submit clinical data to CIBMTR about hematopoietic cell transplantation (HCT) and other cellular therapies, such as chimeric antigen receptor T cells (CAR-Ts). Currently, CIBMTR’s Research Database includes long-term clinical data from more than 635,000 patients [10–14]. CIBMTR subjects data to a series of automated and manual quality checks. In addition, CIBMTR audits each transplant center periodically. These validations and verifications produce high-quality data. If a center fails to meet data quality standards, its data are removed (embargoed) from research studies. CIBMTR protects the privacy and human rights of participants, obeys international laws and ethical guidelines [15]. The NMDP/Be The Match Institutional Review Board (IRB) reviews CIBMTR’s research. Patients and/or guardian(s) give informed consent for research.
Infection data are reported only on the CRF. Centers report infections in accordance with instructions in the forms manual [11]. Data collected include an organism, infection site, and onset date. There are no detailed data on prophylaxis prior to 2017, diagnostic methodology, treatment, nor classification on the certainty of diagnosis of FI by EORTC criteria [16]. Reported organisms are denoted in the footnotes of Table 3.
Table 3.
Number of patients with fungal infection by Day 180.
| Variable | Haplo Cy N(%) | HLACy N(%) | SibsCy N(%) | P value |
|---|---|---|---|---|
| Number of patients | 757 | 403 | 1605 | |
| Any Fungal infection a | <0.001 | |||
| Yes | 56 (7) | 24 (6) | 59 (4) | |
| No | 701 (93) | 379 (94) | 1546 (96) | |
| 1 infection | 41 (5) | 19 (5) | 54 (3) | |
| 2 infections | 14 (2) | 4 (<1) | 3 (<1) | |
| 3+ infections | 1 (<1) | 1 (<1) | 2 (<1) | |
| No | 701 (93) | 379 (94) | 1546 (96) | |
| Time from transplant to any Fungal infection by day 180, median (range), days | 55 (1 – 179) | 67 (<1 – 156) | 61 (3 – 175) | 0.568 |
| Candida b | 0.001 | |||
| Yes | 30 (4) | 8 (2) | 25 (2) | |
| No | 727 (96) | 395 (98) | 1580 (98) | |
| Time from transplant to Candida, median(range), Days | 60 (8 – 179) | 29 (<1 – 141) | 51 (3 – 171) | 0.771 |
| Sites of Candida | ||||
| Blood | 0.853 | |||
| Yes | 12 (40) | 3 (38) | 10(40) | |
| No | 18 (60) | 5 (62) | 15 (60) | |
| GI | 0.706 | |||
| Yes | 4 (13) | 0 | 3 (12) | |
| No | 26 (87) | 8 (100) | 22 (88) | |
| Lung | 0.948 | |||
| Yes | 6 (20) | 2 (25) | 5 (20) | |
| No | 24 (80) | 6 (75) | 20 (80) | |
| Sinuses | 0.644 | |||
| Yes | 4 (13) | 2 (25) | 3 (12) | |
| No | 26 (87) | 6 (75) | 22 (88) | |
| CNS | 0.030 | |||
| Yes | 0 | 1 (13) | 0 | |
| No | 30 | 7 (88) | 25 | |
| GU | 0.691 | |||
| Yes | 2 (7) | 0 | 3 (12) | |
| No | 28 (93) | 8 (100) | 22 (88) | |
| Skin | 0.572 | |||
| Yes | 1 (3) | 0 | 0 | |
| No | 29 (97) | 8 | 25 | |
| Other sites | 0.310 | |||
| Yes | 1 (3) | 0 | 3 (12) | |
| No | 29 (97) | 8 | 22 (88) | |
| Other yeastc by day180 | 0.021 | |||
| Yes | 11 (1) | 2 (<1) | 7 (<1) | |
| No | 746 (99) | 401(99) | 1598(99) | |
| Time from transplant to other yeast, median(range), Days | 61 (1 – 173) | 96 (58 – 134) | 114 (25 – 135) | |
| Sites of other yeast | ||||
| Blood | 0.689 | |||
| Yes | 3 (27) | 0 | 2 (29) | |
| No | 8 (89) | 2 | 5 (71) | |
| GI | 0.650 | |||
| Yes | 1 (9) | 0 | 0 | |
| No | 10 (91) | 2 | 7 | |
| Lung | 0.846 | |||
| Yes | 4 (36) | 1 (50) | 2 (29) | |
| No | 7 (64) | 1 (50) | 5 (71) | |
| Sinuses | 0.322 | |||
| Yes | 1 (9) | 1 (50) | 2 (29) | |
| No | 10 (91) | 1 (50) | 5 (71) | |
| GU | 0.129 | |||
| Yes | 4 (36) | 0 | 0 | |
| No | 7 (64) | 2 | 7 | |
| Skin | 0.435 | |||
| Yes | 0 | 0 | 1 (14) | |
| No | 9 | 2 | 6 (86) | |
| Aspergillusd by day180 | 0.221 | |||
| Yes | 15 (2) | 9 (2) | 20 (1) | |
| No | 742 (98) | 394 (98) | 1585 (99) | |
| Time from transplant to Aspergillus, median(range), Days | 76 (2 – 179) | 81 (6 – 110) | 70 (3 – 175) | 0.703 |
| Sites of Aspergillus | ||||
| Blood | 0.764 | |||
| Yes | 8(54) | 3 (33) | 7 (35) | |
| No | 7 (47) | 6 (67) | 13 (65) | |
| Lung | 0.646 | |||
| Yes | 4 (27) | 4 (44) | 6 (30) | |
| No | 11 (73) | 5 (56) | 14 (70) | |
| Sinuses | 0.507 | |||
| Yes | 3 (20) | 1 (11) | 6 (30) | |
| No | 12 (80) | 8 (89) | 14 (70) | |
| CNS | 0.541 | |||
| Yes | 0 | 0 | 1 (5) | |
| No | 15 | 9 | 19 (95) | |
| Non-aspergillus mold e | 0.051 | |||
| Yes | 8 (1) | 6 (1) | 7 (<1) | |
| No | 749 (99) | 397 (99) | 1598(99) | |
| Time from transplant to Non-aspergillus mold, median(range), Days | 28 (13 – 153) | 98 (56 – 156) | 126 (36 – 154) | 0.099 |
| Sites of Non-aspergillus mold | ||||
| Blood | 0.976 | |||
| Yes | 1 (13) | 1 (17) | 1 (14) | |
| No | 7 (88) | 5 (83) | 6 (86) | |
| Lung | 0.720 | |||
| Yes | 1 (13) | 1 (17) | 2 (29) | |
| No | 7 (88) | 5 (83) | 5 (71) | |
| Sinuses | 0.361 | |||
| Yes | 1 (13) | 2 (33) | 2 (29) | |
| No | 7 (88) | 4 (67) | 5 (71) | |
| Skin | 0.857 | |||
| Yes | 2 (25) | 1 (17) | 1 (14) | |
| No | 6 (75) | 5 (83) | 6 (86) | |
| Other sites | 0.857 | |||
| Yes | 2 (25) | 1 (17) | 1 (14) | |
| No | 6 (75) | 5 (83) | 6 (86) | |
| Pneumocystis (PCP / PJP) f | 0.035 | |||
| Yes | 0 | 2 (<1) | 1 (<1) | |
| No | 757 | 401(99) | 1604(99) | |
| Time from transplant to Pneumocystis (PCP / PJP), median(range), Days | N/A | 75 (31 – 119) | 163 (163 – 163) | 0.221 |
Patients may have had >1 FI
Candida: Includes Candida not otherwise specified (NOS), Candida albicans, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida glabrata, Candida guillermondi, Candida lusitaniae, Candida non-albicans, Other Candida, specify.
Other yeast: Includes Cryptococcus neoformans, Cryptococcus gattii, Yeast, NOS, Histoplasma (capsulatum), Blastomyces (dermatitidis), Coccidioides spp.
Aspergillus: Aspergillus NOS, Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Aspergillus ustus, Aspergillus terreus
Other mold: Fusarium spp., Zygomycetes NOS, Mucorales spp., Scedosporium spp.
The site was lung in all cases of Pneumocystis.
Statistical analysis
Comparative analysis was performed between three cohorts, HaploCy, SibCy, and SibCNI, to assess the impact of FI occurring by day +180 after transplant. Uni- and multivariable analyses were used to determine the 2-year outcomes of OS, TRM, relapse, and cGVHD [17]. The cumulative incidence function with death as a competing risk was used to estimate the probability of FI, TRM, relapse, and cGVHD. The OS was estimated using the Kaplan–Meier method. FI is a time-dependent variable, and events may occur early after HCT. To account for the impact of FI before day 180, univariate analyses for outcomes were examined by applying dynamic landmark analyses using multiple landmark time points for different time-dependent variables including FI onset, neutrophil engraftment, and GVHD post HCT. This approach allows examination of the interaction of two time-dependent post-transplant variables with known interactions by ascribing one variable as ‘fixed’ based on the median and interquartile range and examining the cumulative incidence of the other event with death as a competing risk [17].
Multivariable analyses employed Cox proportional hazard models for outcomes by 2-years after transplant. The main effect of the presence/absence of FI was kept in all models as a time-dependent variable. Variables examined in the Cox model are shown in Table 1. The proportional hazards assumptions for each factor in the Cox model were tested. If covariates violated the proportional hazards assumptions, time-dependent covariates were added. A stepwise selection procedure was used to identify significant risk factors with a significance level of 0.01 [99% Confidence Interval (CI)]. Interactions between the main effect and significant covariates were tested. Center effects were tested using the score test, and all models were adjusted for center effect [18].
Table 1.
Variables for Multivariable analysis for Fungal Infection [each analysis –Yeast, mold]
| 2y OS, 2y TRM, 2y Rel, 2y cGVHD |
|---|
|
|
| Main Effect Variable: Groups by fungal infection |
| • HaploCy with fungal infection vs HaploCy no fungal infection vs SibCy with fungal infection vs |
| SibCy no fungal infection vs SibCNI with fungal infection vs SibCNI no fungal infection (ref) |
| Other variables to be examined |
| • Graft type: Marrow (ref) vs peripheral blood (PB) |
| • Donor/Recipient Gender: Male (M)-M (ref) vs M-Female (F) v F-F v F-M |
| • HCT-CI: 0 (ref) vs 1 −2 vs 3–4 vs 5+ |
| • Fungal infection prior to HCT: No [ref] vs Yes |
| • Disease risk: Acute Leukemia (AL) favorable cytogenetics (cyto), early/intermediate stage (ref) vs AL intermediate/nl cyto, early stage, vs AL poor cyto, early stage; vs AL int/nl cyto, intermediate stage vs AL poor cyto, intermediate stage vs AL advanced (all cyto categories) vs Myelodysplastic syndrome (MDS) very low/low vs MDS intermediate vs MDS high/very high |
| • Recipient Age (years): ≤ 20 (ref) vs 21 – 40 vs 41 – 60 v >60 |
| • Donor Age: ≤ 20 (ref) vs 21 – 40 vs >40 |
| • K/PLS: ≥ 90 (ref) vs 80 – 89 vs <80 |
| • Conditioning intensity: Myeloablative (ref) vs RIC/NMA |
| • TBI: No (ref) vs Yes <800 v ≥ 800 |
| • Time from dx to HCT: <6 months (m) (ref) vs 6 – 12 m vs >12 m |
| • Year of HCT: 2012 – 2014 (ref) vs 2015 – 2017 |
| • Neutrophil engraftment prior to infection (time dependent) |
| • Acute GVHD Grade 2 – 4 (time dependent) occurring prior to fungal infection |
Note: OS: overall survival; TRM: transplant-related mortality; Rel: Relapse; cGVHD: chronic graft versus host disease; HaploCy: Haploidentical donor with post-transplant Cyclophosphamide, Sib: Matched sibling donor; CNI calcineurim inhibitor. HCT-CI: HCT comorbidity index. K/LPS: Karnosky/Lansky Performance status; TBI: Total body irradiation; RIC: reduced intensity; NMA: non-myeloablative
Results
A subset of demographic, disease, and transplant characteristics stratified by HaploCy (n= 757), SibCy (n=403), and SibCNI (n=1,605) cohorts are presented in Table 2 and previously published [6]. The SibCy cohort had a significantly younger median age and wider distribution across all age groups, with ages among HaploCy, and SibCNI recipients clustering at the sixth decade and beyond. Performance status was modestly, but significantly, worse within the HaploCy cohort. Racial and ethnic minorities made up a significantly higher proportion of both the HaploCy and SibCy groups. Among the HaploCy and SibCy cohorts, 99% and 95%, respectively, received a calcineurin inhibitor (CNI) in addition to PTCy. The donors in the SibCNI cohort were significantly older.
Table 2.
Characteristics of the study cohorts.
| Variable | HaploCy N (%) | SibCy N (%) | SibCNI N (%) | P-value |
|---|---|---|---|---|
| Number of patients | 757 | 403 | 1605 | |
| Male | 459 (61) | 243 (60) | 933 (58) | |
| Age, median (range), years | 58 (3–78) | 46 (3–75) | 57 (2–78) | <0.001 |
| K/LPS <80 | 119 (16) | 65 (16) | 200 (12) | <0.001 |
| HCT-CI =>3 | 348 (46) | 175 (44) | 761 (48) | 0.817 |
| Prior Fungal infection | 63 (8) | 44 (11) | 125 (8) | 0.138 |
| Race/Ethnicity | <0.001 | |||
| Caucasian, non-Hispanic | 444 (59) | 239 (59) | 1109 (69) | |
| Caucasian, Hispanic | 72 (10) | 45 (11) | 134 (8) | |
| African-American, non-Hispanic | 131 (17) | 56 (14) | 107 (7) | |
| Asian, non-Hispanic | 52 (7) | 29 (7) | 97 (6) | |
| Other/Missing | 58 (7) | 34 (8) | 158 (10) | |
| Donor age, median (range), years | 36 (9–76) | 45 (4–72) | 54 (2–82) | <0.001 |
| Recipient CMV status | 0.04 | |||
| Positive | 543 (72) | 273 (68) | 1067 (67) | |
| Disease Status | <0.001 | |||
| AML/ALL, early | 308 (41) | 189 (47) | 719 (45) | |
| AML/ALL, intermediate | 143 (19) | 77 (19) | 210 (13) | |
| AML/ALL, advanced | 97 (13) | 61 (15) | 144 (9) | |
| AML/ALL, unknown | 6 (<1) | 2 (<1) | 15 (<1) | |
| MDS, early | 76 (10) | 24 (6) | 179 (11) | |
| MDS, advanced | 127 (17) | 50 (12) | 338 (21) | |
| Peripheral blood stem cells | 449 (59) | 272 (67) | 1405 (88) | <0.001 |
| Myeloablative conditioning regimen | 314 (41) | 222 (55) | 935 (58) | <0.001 |
| TBI (cGy) | <0.001 | |||
| No | 226 (30) | 169 (42) | 1169 (73) | |
| Yes and >800 | 115 (15) | 80 (20) | 264 (16) | |
| Growth Factor | 620 (82) | 319 (79) | 379 (24) | <0.001 |
| GVHD prophylaxis | <0.001 | |||
| Cyclophosphamide | 757 | 4030 | 0 | |
| TAC/CSA + MMF +- others | 0 | 0 | 362 (23) | |
| TAC/CSA + MTX +- others | 0 | 0 | 1243 (77) | |
| Time from diagnosis to transplant, median (range), months | 7 (1–165) | 7 (<1–396) | 5 (1–556) | <0.001 |
| Year of transplant | <0.001 | |||
| 2012–2014 | 170 (22) | 87 (22) | 806 (50) | |
| 2015–2017 | 587 (78) | 316 (78) | 799 (50) | |
| Median follow-up, months | 25 (3–74) | 25 (3–69) | 37 (2–75) |
Note: HaploCy: Haploidentical donor with post-transplant Cyclophosphamide; Sib: Matched sibling donor; CNI calcineurim inhibitor; K/LPS: Karnofsky /Lansky performance status; HCT-CI: HCT comorbidity index; CMV: cytomegalovirus; AML: acute myelogenous leukemia; ALL: Acute lymphoblastic leukemia; MDS: myelodysplastic syndrome; TBI: Total body irradiation; TAC: tacrolimus; CSA: cyclosporin; MMF: mycophenolate mofetil
AML was the most common indication for HCT across cohorts, but a higher proportion of SibCNI patients had MDS. Although a higher proportion of PTCy recipients had advanced disease at the time of transplant, most patients with ALL and AML were in complete remission. The use of bone marrow as a graft source differed significantly; 41%, 33%, and 12% for HaploCy, SibCy, and SibCNI, respectively (P<.001). HaploCy recipients received reduced-intensity conditioning regimens more frequently. Both HaploCy and SibCy received TBI as part of their conditioning and planned growth factor more commonly than SibCNI patients. Neutrophil engraftment is listed in Table S1.
Fungal infections
By day 180, 56 (7%) HaploCy, 24 (6%) SibCy and 59 (4%) SibCNI, developed ≥1 FI (p<0.001). The onset of the first FI was similar across the 3 groups (p=0.568) (Table 3). Candida infection occurred in 30 (4%), 8 (2%) and 25 (2%) of HaploCy, SibCy and SibCNI respectively (p=0.04). Aspergillus infection occurred in 15 (2%), 9(2%) and 20 (1%) of HaploCy, SibCy and SibCNI respectively (p=0.22). Less than 1% of patients in each cohort developed Pneumocystis jiroveci pneumonia (Table 3).
Figure 1 shows the percentage of patients for each FI. Candida infections comprised 73.2%, 80%, and 78.5% of yeast FI in HaploCy, SibCy, and SibCNI, respectively; Candidemia comprised 40%, 37.5%, and 40% of Candida infections, respectively. Aspergillus infections comprised 65%, 60%, and 74% of all mold infections in HaploCy, SibCy, and SibCNI, respectively.
Figure 1: Percent of patients by cohort with reported infection.
a A patient may have had >1 FI.
FI Density: To account for multiple infections and variable number of days alive during the study, we calculated the rate of infection per patient for yeast and mold FI over the first 180 days post-HCT (Figure 2). The yeast FI/per patient/180 days at risk were 0.063 for HaploCy, 0.028 for SibCy, and 0.022 for SibCNI; (p=<.001). The mold FI/per patient/180 days at risk were 0.036 for Haplo CY and 0.047 for SibCy, and 0.019 SibCNI; (p=.009)
Figure 2. Density score for yeast and mold infections in HaploCy, SibCy and SibCNI cohorts.
Note: Infection density score was measured by the number of yeast or mold infections per patient days at risk in the first 180 days after transplant.
Yeast includes: Candida spp., not otherwise specified (NOS), C. albicans, C. krusei, C. parapsilosis, C.tropicalis, C.glabrata, C. guillermondi, C. lusitaniae, Candida non-albicans, Other Candida, Other yeast, C. neoformans, C. gattii, Yeast, NOS, H.capsulatum, B.dermatitidis, Coccidioides spp.
Mold includes: Aspergillus spp., NOS, A. flavus, A. fumigatus, A. niger, A. ustus, A. terreus, Other Aspergillus, Fusarium spp., Zygomycetes spp., Mucorales spp., Rhizopus spp., Scedosporium spp., mold, NOS.
Figure 3 shows the cumulative incidence of yeast and mold FI. HaploCy had higher incidence of yeast FI (5.2%) compared with SibCy (2.2%) and SibCNI (1.9%) p<0.001. PTCy cohorts had a higher incidence of mold FI (HaploCy 2.9%; SibCy 3.7%) compared with SibCNI (1.7%); (p=0.040). When assessing the incidence of yeast FI or mold FI or for the cohorts, based on time to neutrophil engraftment (median 16 days; IQR 14 – 19), the significance was lost. Similarly, when assessing the incidence of yeast and mold FI based on at the time to onset of aGVHD (median 38 days; IQR 26 – 63) the significance was lost.
Figure 3. Cumulative incidence of yeast and mold FI by day 180 by study cohort.
Association of FI with transplant outcomes
Overall survival (OS)
Within 2 years of HCT, 375 (49.5%), 179 (44.4%), and 753 (46.9%) had died in the HaploCy, SibCy, and SibCNI cohorts, respectively. The causes of death are detailed in Table S2. Overall, 12 (1.6%), 3 (0.7%), and 13 (0.8%) patients in HaploCy, SibCy, and SibCNI, respectively died of FI.
Table S3 shows the univariate dynamic landmark analyses examining the impact of presence/absence of FI on outcomes of OS and TRM at Day 100, 1 year and 2 years using the median time to FI [IQR] as the fixed event [Yeast FI: median 57 days (IQR 15 – 122); Mold FI: median 78 days (IQR 28 – 136)]. Overall survival was inferior for patients developing yeast FI by 57 days after HCT whereas the mold FI did not significantly impact OS by univariate analyses.
In multivariable analyses, presence of FI increased the risk of death in HaploCy and SIbCy compared to the reference group (SibCNI, no FI) (Figure 4, Table 4). Additional factors associated with increased risk of death included age>60 years, advanced acute leukemia, high/very high-risk MDS, development of acute GVHD prior to FI, and lack of neutrophil engraftment prior to FI.
Figure 4. Association of fungal infections with HCT outcomes.
Forest plots of the main effect variable of the presence/absence of fungal infection by HaploCy, SibPCy and SibCNI cohorts. FI no, SibCNI, is the reference group. Adjusted hazard ratio (aHR), (99% Confidence Interval [CI]), P value for overall survival (OS) (top Left), transplant-related mortality (TRM) (Top right), relapse (bottom right) and chronic graft versus host disease (cGVHD) (bottom left).
Abbreviations FI: fungal infection; d180, day 180 post HCT.
Table 4.
Multivariable analyses for HCT outcomes by 2 years.
| Variable | N | HR | 99% CI | P-value | Overall p-value |
|---|---|---|---|---|---|
| 1.Overall survival | |||||
| Group for impact of IFI (Main effect) | |||||
| FI no, SibCNI | 1527 | 1.00 | <.0001 | ||
| FI yes, HaploCy | 56 | 4.06 | (2.18–7.56) | <.0001 | |
| FI yes, SibCy | 24 | 4.70 | (2.01–11.0) | <.0001 | |
| FI yes, SibCNI | 58 | 3.42 | (1.84–6.35) | <.0001 | |
| FI no, HaploCy | 685 | 1.22 | (1.01–1.46) | 0.0064 | |
| FI no, SibCy | 372 | 1.12 | (0.89–1.41) | 0.2207 | |
| Age at transplant, years | |||||
| 0–20 | 236 | 1.00 | <.0001 | ||
| 21–40 | 487 | 0.87 | (0.6–1.27) | 0.3466 | |
| 41–60 | 955 | 1.31 | (0.91–1.9) | 0.0572 | |
| >60 | 1044 | 1.64 | (1.07–2.5) | 0.0027 | |
| Disease risk | |||||
| AL favorable cyto, early/intermediate stage | 69 | 1.00 | <.0001 | ||
| AL intermediate/nl cyto, early stage | 675 | 0.98 | (0.54–1.77) | 0.9162 | |
| AL poor cyto, early stage | 439 | 0.95 | (0.54–1.67) | 0.8280 | |
| AL int/nl cyto, intermediate stage | 215 | 1.09 | (0.61–1.95) | 0.6914 | |
| AL poor cyto, intermediate stage | 126 | 1.27 | (0.68–2.36) | 0.3321 | |
| AL advanced (all cyto categories) | 296 | 1.91 | (1.04–3.51) | 0.0065 | |
| MDS very low/low | 312 | 0.91 | (0.51–1.62) | 0.6678 | |
| MDS intermediate | 227 | 1.60 | (0.93–2.76) | 0.0257 | |
| MDS high/very high | 164 | 2.05 | (1.08–3.89) | 0.0038 | |
| Other/not test/missing | 199 | 1.27 | (0.67–2.44) | 0.3360 | |
| Acute GVHD grade II-IV | |||||
| No | 1744 | 1.00 | |||
| Yes | 978 | 1.65 | (1.35–2.02) | <.0001 | |
| Neutrophil engraftment | |||||
| No | 69 | 1.00 | |||
| Yes | 2653 | 0.19 | (0.11–0.33) | <.0001 | |
| 2. Transplant-related mortality | |||||
| Group for impact of IFI (Main effect) | |||||
| FI no, SibCNI | 1510 | 1.00 | <.0001 | ||
| FI yes, HaploCy | 55 | 8.36 | 4.36–16.03 | <.0001 | |
| FI yes, SibCy | 22 | 7.94 | 2.48–25.46 | <.0001 | |
| FI yes, SibCNI | 58 | 7.55 | 3.89–14.65 | <.0001 | |
| FI no, HaploCy | 676 | 1.61 | 1.16–2.23 | 0.0002 | |
| FI no, SibCy | 370 | 1.42 | 0.99–2.02 | 0.0112 | |
| Disease risk | |||||
| AL favorable cyto, early/intermediate stage | 68 | 1.00 | <.0001 | ||
| AL intermediate/nl cyto, early stage | 667 | 1.15 | 0.49–2.68 | 0.6765 | |
| AL poor cyto, early stage | 435 | 0.85 | 0.37–1.94 | 0.6058 | |
| AL int/nl cyto, intermediate stage | 211 | 0.98 | 0.44–2.18 | 0.9418 | |
| AL poor cyto, intermediate stage | 126 | 0.96 | 0.37–2.50 | 0.9069 | |
| AL advanced (all cyto categories) | 294 | 1.16 | 0.50–2.69 | 0.6414 | |
| MDS very low/low | 310 | 1.47 | 0.60–3.60 | 0.2687 | |
| MDS intermediate | 225 | 1.92 | 0.78–4.75 | 0.0632 | |
| MDS high/very high | 160 | 2.33 | 0.90–6.04 | 0.0217 | |
| Other/not test/missing | 195 | 1.37 | 0.53–3.55 | 0.3886 | |
| Acute GVHD grade II-IV | |||||
| No | 1724 | 1.00 | <.0001 | ||
| Yes | 967 | 2.79 | 1.85–4.21 | <.0001 | |
| Neutrophil engraftment | |||||
| No | 69 | 1.00 | <.0001 | ||
| Yes | 2622 | 0.12 | 0.07–0.20 | <.0001 | |
| 3. Relapse (adjusted for center effect) | |||||
| Group for impact of IFI (main effect) | |||||
| FI no, SibCNI | 1506 | 1.00 | 0.7521 | ||
| FI yes, HaploCy | 55 | 1.15 | (0.48–2.73) | 0.6831 | |
| FI yes, SibCy | 22 | 1.45 | (0.53–3.94) | 0.3386 | |
| FI yes, SibCNI | 58 | 0.90 | (0.42–1.95) | 0.7300 | |
| FI no, HaploCy | 675 | 1.11 | (0.85–1.45) | 0.3312 | |
| FI no, SibCy | 369 | 1.03 | (0.76–1.4) | 0.8081 | |
| Time from diagnosis to transplant (<= 4 months) | |||||
| <6 month | 326 | 1.00 | <.0001 | ||
| 6 month-1Y | 148 | 0.72 | (0.56–0.94) | 0.0012 | |
| >=1Y | 144 | 0.44 | (0.3–0.64) | <.0001 | |
| Time from diagnosis to transplant (> 4 months) | |||||
| <6 month | 1354 | 1.00 | 0.2151 | ||
| 6 month-1Y | 647 | 1.03 | (0.77–1.38) | 0.8186 | |
| >=1Y | 684 | 0.86 | (0.65–1.13) | 0.1480 | |
| TBI (<= 11 months) | |||||
| No | 721 | 1.00 | 0.0109 | ||
| Yes <800 | 378 | 1.12 | (0.85–1.48) | 0.2725 | |
| Yes >=800 | 153 | 0.71 | (0.5–1.02) | 0.0158 | |
| TBI (> 11 months) | |||||
| No | 1520 | 1.00 | 0.0003 | ||
| Yes <800 | 711 | 1.85 | (1.19–2.89) | 0.0004 | |
| Yes >=800 | 454 | 1.71 | (1.05–2.78) | 0.0045 | |
| Conditioning regimen intensity | |||||
| Myeloablative | 1434 | 1.00 | 0.0011 | ||
| RIC/NMA | 1251 | 1.29 | (1.05–1.57) | 0.0011 | |
| Disease risk | |||||
| AL favorable cyto, early/intermediate stage | 68 | 1.00 | <.0001 | ||
| AL intermediate/nl cyto, early stage | 666 | 0.61 | (0.35–1.07) | 0.0240 | |
| AL poor cyto, early stage | 435 | 0.84 | (0.48–1.48) | 0.4357 | |
| AL int/nl cyto, intermediate stage | 211 | 0.89 | (0.51–1.55) | 0.6026 | |
| AL poor cyto, intermediate stage | 126 | 1.26 | (0.69–2.32) | 0.3200 | |
| AL advanced (all cyto categories) | 294 | 1.86 | (1.09–3.16) | 0.0027 | |
| MDS very low/low | 310 | 1.02 | (0.6–1.74) | 0.9297 | |
| MDS intermediate | 225 | 1.17 | (0.65–2.12) | 0.4930 | |
| MDS high/very high | 160 | 2.18 | (1.16–4.09) | 0.0014 | |
| Other/not test/missing | 190 | 1.09 | (0.61–1.93) | 0.7042 | |
| Acute GVHD grade II-IV | |||||
| No | 1720 | 1.00 | <.0001 | ||
| Yes | 965 | 0.78 | (0.68–0.9) | <.0001 | |
| 4. Chronic GVHD | |||||
| Main effect variable, IFI | |||||
| FI no, SibCNI | 1527 | 1.00 | 0.0106 | ||
| FI yes, HaploCy | 56 | 0.80 | (0.36–1.81) | 0.4876 | |
| FI yes, SibCy | 24 | 1.18 | (0.35–3.98) | 0.7306 | |
| FI yes, SibCNI | 57 | 0.76 | (0.35–1.64) | 0.3520 | |
| FI no, HaploCy | 685 | 0.77 | (0.57–1.03) | 0.0203 | |
| FI no, SibCy | 372 | 0.72 | (0.56–0.92) | 0.0007 | |
| Graft type | |||||
| Bone Marrow | 633 | 1.00 | <.0001 | ||
| Peripheral blood | 2088 | 2.14 | (1.57–2.93) | <.0001 | |
| Acute GVHD grade II-IV | |||||
| No | 1744 | 1.00 | <.0001 | ||
| Yes | 977 | 1.47 | (1.21–1.78) | <.0001 |
Note: All analyses are adjusted for center affect. Only significant variables are shown. FI: Fungal infection; AL: Acute leukemia; cyto: cytogenetics; GVHD: Graft versus host disease; TBI: Total Body irradiation; RIC/NMA: reduced intensity/non-myeloablative.
Transplant Related Mortality (TRM)
The presence of FI was associated with increased risk for TRM compared with SibCNI without FI. The adjusted hazard ratios were 8.36, 7.94, and 7.55-fold for HaploCy, SibCy, and SibCNI, respectively (Figure 4). HaploCy without FI was associated with increased TRM compared to SibCNI without FI (aHR 1.66). Additional factors associated with increased TRM were aGVHD, lack of neutrophil engraftment, and high/very high-risk MDS (compared with acute leukemia) (Table 4).
Relapse
The risk of relapse was similar across all groups examined (Figure 4). Factors associated with a lower risk of relapse include transplant occurring > 6 months from diagnosis (although this effect was lost beyond 4 months post HCT) and development of aGVHD. Factors associated with a higher risk of relapse included, non-myeloablative/reduced-intensity conditioning regimen, and transplant for high-/very high-risk MDS or advanced acute leukemia (Table 4).
cGVHD
There was no association between FI and cGVHD (Figure 4). Use of PTCy in the absence of FI was associated with lower risk of cGVHD. The adjusted Hazard Ratio [aHR] (99% confidence interval) was 0.77 (0.57–1.03) for HaploCy p=0.0203 and SibCy 0.72 (0.56–0.92) p=0.0007, respectively (Figure 4). Notably, the development of FI in the PTCy groups resulted in similar risk of cGVHD as the SibCNI group without FI. Factors associated with increased cGVHD included peripheral blood stem cell allograft and Grade II–IV aGVHD (Table 4).
Association of FI on HCT outcomes within each cohort
The association of FI on HCT outcomes within each cohort was examined in multivariable models (Figure S1). FI was associated with increased risk of death HaploCy (aHR 3.34), SibCy (4.21 and SibCNI (3.4) compared with each respective group without FI (p<.0001 for all). For TRM, the aHR were 5.20 (p<.0001), 5.61 (p<.0001), and 7.55 (p=.0003) for HaploCy, SibCy and SibCNI, respectively. There was no association between FI and cGVHD or FI and relapse within each cohort.
Discussion
In this CIBMTR study, we analyzed the incidence fungal infections among patients who received haploidentical or matched Sib HCT with PTCy- based GVHD prophylaxis compared with a contemporaneous control cohort of Sib HCT with CNI-based GVHD prophylaxis. Fungal infection (FI) was defined as the isolation of a fungal pathogen from any site or a fungal marker in plasma and reported to CIBMTR by the Centers.
The overall incidence of FI by Day 180 was low across the 3 cohorts ranging from 2%−5% for yeast and 1.7%−3.7% for mold FI. Within each cohort, presence of FI increased the risk of death (adjusted HR ranging from 3.3 to 4.2; p<.00011) and related mortality (adjusted HR ranging from 5.2–7.56; p<.0003) compared to no FI. The risk of FI post HCT is dynamic and multifactorial. Risk factor for early FI (day 0–40 post HCT) include neutropenia and for late FI (>day40 post-HCT) HLA mismatch, lymphopenia, GVHD, use of corticosteroids, secondary neutropenia, and viral infections including CMV and respiratory viruses [1, 3, 19]. The reported incidence of FI in the first-year post-HCT is between 7% −20% [1, 3, 19, 20] and has decreased after implementation of mold-active prophylaxis [2, 21, 22]. FI, and specifically mold FI, are associated with increased risk of death [19, 23]. Understanding the impact of novel GVHD prevention strategies on FI post HCT is a key step in developing effective strategies for prevention and management.
Due to its success and feasibility, PTCy for GVHD prevention is used widely in mismatched transplants and is increasingly used for matched HCT [5, 24, 25]. In a recent randomized trial, PTCy/Tac/MMF demonstrated a higher 1-year GVHD/relapse or progression-free survival compared to Tac/MTX due significant improvements in GVHD risk. Grade 3 infection rates and CMV reactivation were similar between the two arms [26]. While the selective depletion of proliferating alloreactive T-cells by PTCy results in less GVHD, the skewing of T-cell repertoire may lead to delayed immune reconstitution [7]. Higher overall rates of infections [27] and specific viral infections have been reported with PTCY [6, 8, 9] [28].
In the present study, the incidence of FI by Day 180 across HaploCy, SIbCy and SIbCNI ranged between 1.9 and 5.2% for yeast FI and 1.7% and 3.7% for mold FI. A prior CIBMTR study conducted between 2008 – 2011 in unrelated donor HCT with CNI-based GVHD prophylaxis and using similar methodology for reporting infections as our study, reported an 12–18% incidence of fungal infections by 1 year post HCT for transplanted [19]. An Italian registry study, including only probably/definite invasive fungal infections, reported an incidence 6.7% by 100 days and 8.8% by 1 year [20]. We hypothesize that implementation of effective antifungal prophylaxis and/or shorter follow up (180 days vs 1 year in prior studies) may partially explain the lower incidence of FI in the current study compared to prior studies. The lack of information on antifungal prophylaxis, limits our ability to test this hypothesis. Future studies in well curated cohorts may address this question. A single institution study recently reported 14% incidence of invasive fungal infections using PTCy for GVHD ppx [29]. With regards to FI types, HaploCy had a higher incidence for yeast infections compared with SibCy or SibCNI (P=0.001). The difference was lost when assessing landmarks for the median, lower, and upper quartiles for time to neutrophil engraftment or onset of GVHD in the entire cohort, irrespective of donor source and GVHD prophylaxis. Since the present study was observational, additional imbalances in patient characteristics may have contributed to higher incidence of yeast infections in haploCY compared to SibCNI. A recent single institution study reported 9% incidence of invasive yeast infections by 1 year post HCT. The majority of FI by yeasts occurred by Day 30 and were associated with cytokine release syndrome and use of tocilizumab [29]. Optimal preventive strategies will need to take consideration of local epidemiology and drug interactions. While the overall incidence of molds was low, both PTCy cohorts had higher incidence and higher infection density score for mold FI compared with SibCNI. CMV and respiratory viruses have been associated with increased risk of mold FI with CNI based GVHD prophylaxis [1, 30] possibly due to differences in the kinetics of immune reconstitution. With regards, to mold FI, differences in kinetics of neutrophil engraftment and immune reconstitution, may have partially contributed to increased incidence of mold FI after PTCy and merit further studies. In dynamic landmark analyses when assessing the incidence of mold FI, based on time to neutrophil engraftment the significance across the cohorts was lost.
Despite decreasing incidence of FI in the last decade, FI remain associated with increased mortality [2, 31]. In the present study, FI adversely impacted OS and TRM. Regardless of donor source or PTCy, presence of FI was associated with up to 7-fold increase in transplant-related mortality, in agreement with prior studies [2, 3]. Our study has several limitations inherent to a multicenter transplant registry study. First, the choice for haploidentical graft or use of PTCY-based prophylaxis for Sib transplant was at the discretion of each center. Second, details on antifungal prophylaxis, empirical or preemptive antifungal treatment, and targeted therapy for FI were not available. FI diagnoses are reported by the sites and were not standardized by the EORTC criteria. For example, Candida species recovered from non-sterile sites accounted for >50% of yeast FI. While this may have resulted in an overestimation of FI by yeast overall, the distribution of sites of infection was similar across the 3 cohorts. To minimize center bias for the decision of donor type and GVHD we limited our analyses to centers with patients in both the SibCNI group and PTCy cohorts and used a center effect in the analyses. Nonetheless, approaches to prophylaxis, diagnosis, treatment, and reporting of fungal infections, likely varied within and across centers over the study period and could potentially contribute to confounding. Additional limitations include that duration and dosage corticosteroids, lymphopenia, and the potential interactions between CMV and community respiratory viral infections and FI risk were not analyzed. Effective CMV prophylaxis with letermovir was not available during the study. The long-term impact of letermovir on fungal and viral infections in patients receiving PTCy merits further study. Lastly, the small number of FI precluded meaningful analyses by FI type or site of infection. Acknowledging these limitations, our study provides comprehensive real-world data on the incidence and long-term impact of FI with PTCy-based GVHD prophylaxis in haploidentical and matched related donor HCT. The relatively large sample size in each cohort and the use of 99% confidence interval further support the validity of our findings.
In summary, the incidence of yeast and mold FI by Day 180 with PTCY-based GVHD prophylaxis and current standards of care was low. Compared with SIbCNI, PTCY was associated with increased risk of yeast FI in Haplo HCT, and increased risk for mold in Haplo and Sib HCT. While the rates of FI were low, FI were associated with decreased OS and increased TRM across all cohorts, underscoring the need improved strategies for prevention and treatment of FI post HCT.
Supplementary Material
Highlights.
In a CIBMTR registry study, the rates of fungal infections (FI) and the impact of FI on mortality after haploidentical (haplo) or matched sibling (Sib) donor HCT with posttransplant cyclophosphamide (Cy) were compared with Sib HCT with calcineurin inhibitor (CNI) based GVHD prophylaxis.
Overall, rates of FI by Day 180 in HaploCy, SibCy and SibCNI ranged from 1.9%−5.2% for FI caused by yeast, and 1.7% - 3.7% for FI caused by molds.
Compared with SibCNI, rates of FI by yeast were higher for HaploCy but no SIbCy; rates of FI by mold were higher in HaploCy and SibCy.
In multivariable analyses, presence of FI was associated with increased risk of mortality at 2 years post HCT in all three cohorts.
Acknowledgements
The authors would like to thank the CIBMTR Infection and Immune Reconstitution Working Committee for their support.
The CIBMTR is supported primarily by the Public Health Service U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); 75R60222C00011 from the Health Resources and Services Administration (HRSA); N00014-21-1-2954 and N00014-23-1-2057 from the Office of Naval Research; Support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, Gateway for Cancer Research, Pediatric Transplantation and Cellular Therapy Consortium and from the following commercial entities: AbbVie; Actinium Pharmaceuticals, Inc.; Adaptimmune; Adaptive Biotechnologies Corporation; ADC Therapeutics; Adienne SA; Allogene; Allovir, Inc.; Amgen, Inc.; Angiocrine; Astellas Pharma US; Atara Biotherapeutics; BeiGene; bluebird bio, inc.; Bristol Myers Squibb Co.; CareDx Inc.; CSL Behring; CytoSen Therapeutics, Inc.; Elevance Health; Eurofins Viracor, DBA Eurofins Transplant Diagnostics; Gamida-Cell, Ltd.; GlaxoSmithKline; HistoGenetics; Incyte Corporation; Janssen Research & Development, LLC; Janssen/Johnson & Johnson; Jasper Therapeutics; Jazz Pharmaceuticals, Inc.; Karius; Kiadis Pharma; Kite, a Gilead Company; Kyowa Kirin; Legend Biotech; Magenta Therapeutics; Mallinckrodt Pharmaceuticals; Merck & Co.; Mesoblast; Millennium, the Takeda Oncology Co.; Miltenyi Biotec, Inc.; MorphoSys; Novartis Pharmaceuticals Corporation; Omeros Corporation; OptumHealth; Orca Biosystems, Inc.; Ossium Health, Inc.; Pfizer, Inc.; Pharmacyclics, LLC, An AbbVie Company; PPD Development, LP; Regimmune; Sanofi; Sarah Cannon; Sobi, Inc.; Stemcyte; Takeda Pharmaceuticals; Talaris Therapeutics; Vertex Pharmaceuticals; Vor Biopharma Inc.; Xenikos BV.
Conflicts of Interest and Financial Disclosure Statement:
Dr. Papanicolaou reports support in part by the National Cancer Institute at the National Institutes of Health, Center Support Grant P30 CA008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health; serving as an investigator for MSD and Shire/Takeda; research funding from MSD paid to her Institution, serving on DSMBs for Allovir, Vera, Amplyx and Armatta; serving on EAC for Octapharma; consulting and other fees from MSD, Cidara, Takeda/Shire, Behring and SymBio.
Dr. Batista reports honoraria for Medical Education from Knight and Merck Sharp Dohme, and research grants from National Health Institute- National Cancer Institute (NIH-NCI), National Council for Scientific and Technological Development (CNPq) and Sao Paulo Research Foundation (FAPESP).
Dr. Hill reports compensation (consulting) for Century Therapeutics, Eversanna Life Science Services, LLC, Gilead, HVTN DSMB, Karius, Moderna DSMB, Pfizer (previously Amplyx/Medpace), SymBio, Takeda, Up-to-Date, and Allovir; research support from Deverra, Karius, Merck, Oxford Immunotec, and Allovir; and significant payments (Scientific Advisory Board) for Karius - limit $10,000.
Dr. Liu reports compensation (advisor/consultant/speaker) for Agios, Pfizer, CTI Biopharm, Nkarta, Servier and Rigel; Research support (Funding paid to my institution) for clinical trials from Alexion, Astellas, Nkarta, ImmuOnco, Cellularity, Marker and Merck.
Dr. Sharma reports compensation (consulting) for Spotlight Therapeutics, Medexus Inc., Vertex Pharmaceuticals, Sangamo Therapeutics, Editas Medicine; research funding for CRISPR Therapeutics; significant payments from Clinical Trial site-PI: CRISPR Therapeutics, Vertex Pharmaceuticals, Novartis Pharmaceuticals, Magenta Therapeutics, and Beam Therapeutics; relationships: RCI BMT Medical Monitor; honoraria from Vindico Medical Education; and other interests include Co-Chair, ASTCT Content Committee, Scientific Executive Committee, Sickle Cell Transplant Advocacy & Research Alliance (STAR), Stem Cell Engineering Committee, International Society for Cell & Gene Therapy (ISCT) and PTCTC Supportive Care Committee.
Dr. Waller receives research support from Sanofi, CRISPR, Allogene, CSL, Partners Therapeutics, Novartis, and Secura Biotech. He has served on scientific advisory boards for Sanofi, Alliogene, and Allovir. He holds founders equity in Cambium Medical Technology and Cambium Oncology.
Dr. Wingard reports consulting fees from Celgene, Cidara, Takeda, Orca, Ansun, F2G.
Dr. Young reports compensation to the University of Minnesota for work on clinical trials for AlloVir, Ansun, F2G, NobelPharma, Pulmocide, Scynexis, Shire/Takeda.
Dr. Perales reports honoraria from Adicet, Allovir, Caribou Biosciences, Celgene, Bristol-Myers Squibb, Equilium, Exevir, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Nektar Therapeutics, Novartis, Omeros, OrcaBio, Syncopation, VectivBio AG, and Vor Biopharma; serving on DSMBs for Cidara Therapeutics, Medigene, and Sellas Life Sciences, and the scientific advisory board forNexImmune; ownership interests in NexImmune and Omeros; has received institutional research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis; has received institutional research support in excess of $5,000 for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis; and has equity interest Omeros.
Dr. Chemaly reports compensation (advisor/consultant/speaker) for Merck, Takeda, Karius, Therapeutics Partners, Ansun, Viracor, Genentech, Qiagen, Oxford Immunotec, Astellas, Roche, AiCuris, and Shinogi; significant payments (grants and funding paid to my institution for research) from Merck, Ansun, AiCuris, Viracor, Karius, Genentech, Freestyle, and Takeda.
Dr. Riches reports being an employee of IQVIA Biotech, a clinical research organization.
Dr Ustun reports honoria from Takeda and Blueprint (speaker bureau).
Footnotes
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