Search

Highlights • The National Marrow Donor Program (NMDP) received preliminary search requests for over 3300 domestic and 3700 international allogeneic hematopoietic cell transplant candidates during the initial phase of the coronavirus disease 2019 (COVID-19) pandemic. • Despite a decrease in preliminary search requests, the number of unrelated donor grafts infused at domestic transplant centers following the initial phase of COVID-19 was only 4% less than the same period of time 1 year earlier. • Of over 2800 transportation legs and over 1600 transports completed through the NMDP, only 1 product was delivered outside of the requested time window in the initial period after COVID-19., The impact of the coronavirus disease 2019 (COVID-19) pandemic on hematopoietic cell transplant (HCT) donor registries and transplant center (TC) practices is underreported. This article reports on the National Marrow Donor Program (NMDP) Be The Match Registry and its coordinating the provision of unrelated donor (URD) products to domestic and international TCs during the initial 3 months of the COVID-19 pandemic (March through May 2020). Specifically, NMDP data are presented for disease indications for transplant, URD search volumes and availability, graft requests and processing, courier utilization and performance, and conversion rates from formal donor search and workup to graft collection and shipment. Data following the onset of COVID-19 are compared to the immediate 3 months prior to the COVID-19 pandemic (December 2019 through February 2020) and the same quarter 1 year prior to COVID-19 (March through May 2019). During the initial onset of COVID-19 and compared to 1 year prior, TCs requested and the NMDP performed less donor searches. More multiple URD and direct to workup requests were processed by the NMDP, which likely reflected reductions in donor availability. Yet TCs continued to perform allogeneic transplants for acute disease indications like acute leukemia and myelodysplasia, using more cryopreserved grafts than before COVID-19. In comparison to prepandemic patient cycle conversion rates and durations, the NMDP was able to convert patient cycles at nearly the same or higher rates and in similar or shorter periods of time. Last, despite significant challenges caused by the pandemic, including interruptions in domestic courier services and travel restrictions, graft products were delivered to and received by TCs in similar periods of time than before COVID-19. Taken together, these data show that NMDP service line operations continued to function effectively during the early phases of the COVID-19 pandemic, ensuring requests for and delivery of URD products to domestic and international allogeneic HCT recipients.

Acute graft-versus-host disease (GVHD) continues to be a major cause of morbidity and mortality after allogeneic hematopoietic cell transplant (HCT) in pediatric patients (ie, children and adolescent and young adults) and limits broader application of the therapy. Pediatric HCT patients have faced major obstacles to access clinical trials that test new agents for GVHD prevention and treatment. According to a recent search, only 6 clinical trials of interventions for prevention or treatment of acute GVHD were conducted specifically in pediatric patients in the United States over the past decade, with 8 internationally. In this review, we summarize the studies that were performed and specifically enrolled and reported on pediatric patients after allogeneic HCT and provide a listing of studies currently under way.

We compared characteristics of myeloid neoplasms (MNs) following allogeneic hematopoietic cell transplantation (HCT) versus autologous HCT using a Japanese HCT registry database. Among 43 788 patients who underwent allogeneic (n = 18 874) or autologous HCT (n = 24 914) for non-myeloid malignancies or non-malignant diseases, 352 developed MNs. The cumulative incidence of MNs was lower after allogeneic HCT than after autologous HCT (0.3% vs. 1.8% at 10 years, respectively, p < .001). Compared with autologous HCT, MNs following allogeneic HCT developed in younger patients (median, 42 vs. 57 years old, respectively) and sooner after HCT (median, 16 vs. 33 months, respectively). Approximately half of MNs following allogeneic HCT were donor-derived and occurred later than recipient-derived MNs (median, 26 vs. 6 months, respectively, p = .003). In multivariate analysis, reduced-intensity conditioning and cord blood transplantation were associated with MN development after allogeneic HCT. Overall survival was similar in patients who developed MNs following allogeneic versus autologous HCT (18% vs. 22% at 5 years, respectively, p = .48). Patient age ≥ 55 years, the presence of previous HCT, AML subtype, and chromosome 5 or 7 abnormalities were adverse factors for overall survival after MN diagnosis. Further research is warranted to elucidate the mechanisms of MN development following allogeneic HCT.

BACKGROUND: Telehealth involves the use of telecommunication and information technology for the delivery of clinical care and may be a mechanism to alleviate the burden of visits faced by patients undergoing hematopoietic cell transplantation (HCT). Few studies have evaluated the feasibility and acceptability of telehealth visits in the care of HCT patients. METHODS: We conducted 27 telehealth visits with 25 patients undergoing HCT using a videoconferencing system that allows for real-time, two-way interactions and administered satisfaction surveys to patients and providers. RESULTS: Of the 25 patients included in the study, 20 (80%) and five (20%) were undergoing autologous and allogeneic HCT, respectively. The telehealth visits were distributed as follows: 3 inpatient visits upon admission for HCT; 11 inpatient visits between 2–14 days post-HCT; 4 inpatient visits prior to discharge after HCT; 8 outpatient, post-HCT follow-up visits; and 1 handoff to a community oncologist. Out of a total of 54 provider assessments, 7 providers (13%) were unable to complete some part of the physical examination, but no provider reported being unable to manage patients’ symptoms through telehealth. 81% of patients were either satisfied or very satisfied with the telemedicine session. Overall satisfaction was higher among patients than providers (mean scores 4.12 vs. 2.64; scale 1–5, 1: very poor; 5: excellent). Technological barriers resulting in delays and suboptimal physical examination were largely responsible for provider dissatisfaction. CONCLUSIONS: The use of telehealth to deliver comprehensive follow-up care to HCT patients is feasible across different HCT types but is dependent upon quality of data streaming and videoconferencing technologies.

OBJECTIVE CD204+ tumor-associated macrophages are associated with adverse outcomes of various malignancies. We performed a study to elucidate the role of CD204+ macrophages in allogeneic hematopoietic cell transplantation (allogeneic HCT). METHODS In a total of 81 patients who received allogeneic HCT for non-remission malignant lymphoma, immunohistochemical staining of CD204 using specimens preserved before allogeneic HCT was performed. According to the average number of CD204+ macrophages in a high-power field, patients were categorized into three groups: low (

Simple Summary Bendamustine is a chemotherapeutic agent used to treat a variety of cancers. It has recently been used in the context of allogeneic hematopoietic cell transplantation (HCT), a treatment mostly used to treat blood cancers. Given before or after transplantation of donor blood or bone marrow cells, bendamustine has been shown to reduce the side effects of the transplant, including graft-versus-host disease, where the donated cells attack the recipient’s tissues, while also promoting the anti-cancer effects of the transplant. These are exciting findings and show that bendamustine may be used to influence the immune system, called immunomodulation, in a beneficial manner. We report our research and review the available literature outlining these immunomodulatory effects of bendamustine, in hopes that it will promote further investigations utilizing this agent in allogeneic transplants, ultimately improving patient outcomes. Abstract Bendamustine (BEN) is a unique alkylating agent with efficacy against a broad range of hematological malignancies, although investigations have only recently started to delve into its immunomodulatory effects. These immunomodulatory properties of BEN in the context of hematopoietic cell transplantation (HCT) are reviewed here. Pre- and post-transplant use of BEN in multiple murine models have consistently resulted in reduced GvHD and enhanced GvL, with significant changes to key immunological cell populations, including T-cells, myeloid derived suppressor cells (MDSCs), and dendritic cells (DCs). Further, in vitro studies find that BEN enhances the suppressive function of MDSCs, skews DCs toward cDC1s, enhances Flt3 expression on DCs, increases B-cell production of IL-10, inhibits STAT3 activation, and suppresses proliferation of T- and B-cells. Overall, BEN has a broad range of immunomodulatory effects that, as they are further elucidated, may be exploited to improve clinical outcomes. As such, clinical trials are currently underway investigating new potential applications of BEN in the setting of allogeneic HCT.

Allogeneic hematopoietic cell transplantation (HCT) has been firmly integrated in the treatment algorithm of acute myeloid leukemia (AML) patients. Optimization of donor choice, supportive care, conditioning regimens, and monitoring of residual disease have led to a constant improvement of outcomes. Specifically, more and more patients at higher ages are offered allogeneic HCT as the therapeutic option with the highest curative potential.

The use of potentially inappropriate medications (PIMs) using Beers criteria and its impact on older allogeneic hematopoietic cell transplantation (HCT) recipients is not known. Here the use of any PIMs and their therapeutic classes in reduced-intensity conditioning allogeneic HCT recipients were compared between older (≥65 years; n = 114) and younger (40 to 64 years; n = 240) patients during their initial HCT admission, defined as the number of days that a patient received 1 or more PIMs between day −14 and day +28. Poisson regression was used to determine rate ratios (RRs) in the 2 groups. In the ≥65 years group, we evaluated the impact of PIMs on Common Terminology Criteria for Adverse Events (CTCAE) grade 3–4 toxicities within 100 days and on overall mortality within 1 year post-HCT. The rate of any PIM use was similar in the older and younger groups (RR, .98; 95% confidence interval [CI], .90 to 1.06; P = .65). In terms of PIM classes, the older group had a 48% higher rate of gastrointestinal (GI) medication use (RR, 1.48; 95% CI, 1.32 to 1.65; P < .01) and a 25% higher rate of genitourinary (GU) medication use (RR, 1.25; 95% CI, 1.02 to 1.53; P = .03). Compared with males, females had a 19% higher rate of central nervous system (CNS) medication use (RR, 1.19; 95% CI, 1.03 to 1.37; P = .02) and a 30% higher rate of benzodiazepine use (RR, 1.30; 95% CI. 1.09 to 1.54; P < .01). A high-risk HCT-CI was associated with a higher rate of use of any PIMs (RR, 1.13; 95% CI, 1.01 to 1.26; P = .02), CNS medications (RR, 1.26; 95% CI, 1.04 to 1.53; P = .02) and GU medications (RR, 1.46; 95% CI, 1.09 to 1.94; P = .01). Compared with matched sibling donor HCT recipients, umbilical cord blood transplantation recipients had higher rates of GI medication use (RR, 1.32; 95% CI, 1.14 to 1.53; P < .01) and anticholinergic medication use (RR, 1.30; 95% CI, 1.06 to 1.61; P = .01). In the ≥65 years group, increasing duration of narcotic use was associated with a 1.3-fold (95% CI, 1.0 to 1.7; P = .05) higher risk of overall mortality and a 1.6-fold (95% CI, 1.02 to 2.69) greater odds of CTCAE grade 3–4 toxicities (P = .04). Our data show that older recipients (≥65 years) were as likely as their younger counterparts to receive PIMs. Among older recipients, the use of PIMs, particularly narcotics, was associated with higher mortality and higher incidence of grade 3–4 toxicities. Identifying and reducing the use of PIMs in older HCT recipients may help decrease the burden of adverse events and associated health care costs.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative-intent therapy for patients with hematological malignancies, but despite advances in the field in recent years, there is still a significant risk of post-transplant mortality. In addition to relapse of the underlying malignancy, the key contributors to this high mortality are graft-versus-host disease (GVHD) and infection. The intestinal microbiota is the collective term describing the community of bacteria, fungi, viruses and protozoa that resides in the human gastrointestinal tract. Bacterial communities have been studied most comprehensively, and disruption of these communities has been associated with the development of a variety of medical conditions in large clinical associative studies. Preclinical studies suggest a mechanistic role for the intestinal microbiota in the instruction and maintenance of both intestinal and systemic immune cell function. This review outlines our current understanding of the relationship between gut bacteria and allo-HCT outcomes, including infection, immune reconstitution, GVHD and relapse, drawing on evidence from both clinical associative studies and preclinical mechanistic studies.

BACKGROUND Hematopoietic cell transplantation (HCT) outcomes, including infectious complications, change between centers and countries. Thus, the aim of this study was to report the incidence of infections and isolated pathogens among recipients of HCT and the association with mortality at a tertiary referral center in Mexico. METHODS Two hundred and eighty-two patients undergoing autologous or allogeneic HCT between January 2005 and December 2018 at the National Institute of Medical Sciences and Nutricion Salvador Zubiran were included. RESULTS In autologous HCT (n = 176), within the preengraftment and the early postengraftment, 130 (74%) and 31 (18%) recipients presented infections, respectively. Within the preengraftment, the early postengraftment, and the late postengraftment, 81 (76%), 34 (33%), and 58 (60%) allogeneic HCT recipients presented infections, respectively. Non-relapse mortality (NRM) as a result of infections occurred in 1 (0.6%) and 5 (5%) autologous and allogeneic HCT recipients, respectively. CONCLUSIONS Our results demonstrated that despite our limited resources, infections were not a significant burden for NRM among HCT recipients. More importantly, the isolation rates were higher than international studies, which could be explained by the existence of a specialized infectious diseases department and laboratory, which we consider key elements for the establishment of an HCT program worldwide.

Allogeneic hematopoietic cell transplantation (HCT) remains the only curative therapy for many hematological malignant and non-malignant disorders. However, key obstacles to the success of HCT include graft-versus-host disease (GVHD) and disease relapse due to absence of graft-versus-tumor (GVT) effect. Over the last decade, advances in "omics" technologies and systems biology analysis, have allowed for the discovery and validation of blood biomarkers that can be used as diagnostic test and prognostic test (that risk-stratify patients before disease occurrence) for acute and chronic GVHD and recently GVT. There are also predictive biomarkers that categorize patients based on their likely to respond to therapy. Newer mathematical analysis such as machine learning is able to identify different predictors of GVHD using clinical characteristics pre-transplant and possibly in the future combined with other biomarkers. Biomarkers are not only useful to identify patients with higher risk of disease progression, but also help guide treatment decisions and/or provide a basis for specific therapeutic interventions. This review summarizes biomarkers definition, omics technologies, acute, chronic GVHD and GVT biomarkers currently used in clinic or with potential as targets for existing or new drugs focusing on novel published work.

Key Points Vancomycin exposure in the pre-engraftment period was associated with an increased risk for CMV reactivation after allogeneic HCT. Some gram-positive bacteria may protect against CMV reactivation.

After autologous hematopoietic cell transplantation (HCT) in the first complete remission (CR1), patients with acute myeloid leukemia (AML) may relapse and undergo allogeneic HCT in the second complete remission (CR2). The aim of this study was to analyze the outcome of allogeneic HCT performed in CR2 comparing patients with prior consolidation by autologous HCT versus patients with chemotherapy consolidation. Included were 2619 adults with allogeneic HCT in CR2 from 2000 to 2017 with (n = 417) or without (n = 2202) prior autologous HCT. Patient groups were not entirely comparable; patients with prior autologous HCT were younger, had less often a favorable cytogenetic profile, had more commonly donors other than matched siblings, and more often received reduced-intensity conditioning. In multivariate analysis, nonrelapse mortality risks in patients with prior autologous HCT were 1.34 (1.07 to 1.67; P = .01) after adjustment for age, cytogenetic risk, transplant year, donor, conditioning intensity, sex matching, interval diagnosis-relapse, and relapse-allogeneic HCT as compared with chemotherapy consolidation. Similarly, risks of events in leukemia-free survival and graft-versus-host disease, relapse-free survival were higher with prior autologous HCT, 1.17 (1.01 to 1.35), P = .03 and 1.18 (1.03 to 1.35), P = .02, respectively. Risk of death was also higher, 1.13 (0.97 to 1.32), P = .1, but this was not significant. Postremission consolidation with autologous HCT for AML in CR1 increases toxicity of subsequent allogeneic HCT in CR2.

PD-1 blockade is an effective therapy in relapsed/refractory (R/R) classical Hodgkin Lymphoma (cHL) who have relapsed after or are ineligible for autologous hematopoietic cell transplantation (HCT). Although single-agent anti-PD-1 monoclonal antibodies (mAb’s) are associated with high response rates and durable remissions, available results to date suggest that a large majority of patients will eventually progress on therapy. Many of these patients are potential candidates for allogeneic HCT (allo-HCT) after receiving anti-PD-1 mAb’s, and allo-HCT remains for now the only treatment with demonstrated curative potential in this setting. However, initial reports suggested that allo-HCT in this setting may be associated with increased risk of early transplant-related toxicity, likely driven by lingering effects of PD-1 blockade. Furthermore, many patients with R/R cHL who undergo allo-HCT will relapse after transplantation, most often with limited treatment options. Here again, PD-1 blockade appears to yield high response rates, but with an increased risk of attendant immune toxicity. Many questions remain regarding the use of PD-1 blockade before or after allo-HCT, especially in relation to the feasibility, outcome, optimal timing, and method of allo-HCT after PD-1 blockade. Despite the scarcity of prospective data, these questions are unavoidable and must be tackled by clinicians in the routine care of patients with advanced cHL. We provide consensus recommendations of a working group based on available data and experience, in an effort to help guide treatment decisions until more definitive data are obtained.

To evaluate the outcomes and prognostic factors following allogeneic haematopoietic cell transplantation (HCT) for adult acute myeloid leukaemia (AML) in second complete remission (CR2), we retrospectively analysed the Japanese registration data of 1080 adult AML patients in CR2 who had received allogeneic HCT. The probability of overall survival and the cumulative incidence of relapse at 3 years was 66% and 19%, respectively. In multivariate analysis, older age, poor cytogenetics and shorter duration of first complete remission were significantly associated with a higher overall mortality. Our data demonstrated the significant efficacy of allogeneic HCT for adult AML in CR2.

Although day +100 survival among allogeneic hematopoietic cell transplantation (HCT) recipients has improved over time, longer-term survival remains a challenge. The aim of this study was to identify prognostic factors for survival among patients surviving longer than 100 days using baseline characteristics and factors identified within the first 100 days after transplantation. Of 413 patients undergoing a first allogeneic HCT between 2006 and 2014, 335 survived >100 days post-transplantation. The majority underwent a myeloablative transplantation (75%) with a bone marrow (BM) (52%) graft source. One-year all-cause mortality (ACM) was 29%, with 16% relapse mortality (RM) and 12% nonrelapse mortality. In multivariable analysis, high-risk disease (hazard ratio [HR], 1.55; P = .003), non-cytomegalovirus infection (HR, 1.79; P = .003), more days hospitalized (HR, 1.16; P < .001), and relapse (HR, 4.38; P < .001) within the first 100 days were associated with increased risk of ACM. Patients with higher income (HR, .89; P = .024) and those who received BM (HR, .52; P < .001) or umbilical cord blood (HR, .40; P = .002) relative to peripheral blood stem cells had lower risk of ACM. Our study identifies risk factors for adverse long-term survival in 100-day survivors, a time point when patients frequently are discharged from transplantation centers. In addition to disease- and transplantation-related factors, low socioeconomic status was associated with worse long-term survival, highlighting the need for focused efforts to improve outcomes in vulnerable patient populations.

Correspondence: Donor body mass index does not predict graft versus host disease following hematopoietic cell transplantation

We conducted a study to analyze and report on indicators of hematopoietic cell transplant (HCT) physician time use and HCT center output measures. HCT centers in Australia and New Zealand (A&NZ) were invited to provide demographic and time use details for physicians participating in HCT patient care (HCT physicians). Resource details for adult and pediatric centers were included. From a total of 46 centers that were invited to participate, completed data were received from 37 centers (80%) representing 185 HCT physicians, with a median age of 48 (range, 33 to 72), of whom 31% were women. Just over half of HCT physicians cited prior work experience in large overseas HCT centers (97, 52%) and over one-third (79, 43%) possessed postgraduate qualifications other than specialist training. Total annual mean HCTs per HCT physician full-time equivalent (FTE) were 14.2 for centers performing both allogeneic and autologous HCT, 6.6 for autologous only centers, and 10.6 for all centers. For all HCT physicians surveyed the mean proportion of time spent on HCT related tasks was 31.7%. In A&NZ, for centers that perform both allografts and autografts, there was a mean of 4.0 allogeneic HCT annually per HCT bed, compared with 2.6 for the United States and 7.1 allogeneic HCT annually per HCT physician FTE (United States, 6.3). Projections of the A&NZ HCT physician workforce indicated that the numbers of HCT physicians are likely to stay within the region of 170 to 190 for the next 10 years, whereas HCT activity will likely continue to climb steadily. Healthcare and government authorities should be prepared to enable and support greater HCT activity in A&NZ in the future.

Recent studies in both mice and humans have demonstrated that the intestinal microbiota can affect hematopoiesis. Here, we performed experiments in preclinical mouse models for syngeneic and allogeneic HCT. To study the metabolic effects of intestinal flora depletion on post-transplant hematopoiesis in humans, we performed HCT experiments using a metabolic chamber and bomb calorimetry of feces. Taken together, we show that the intestinal microbiota supports post-transplant hematopoietic reconstitution in HCT recipients through its role in dietary energy uptake.

Outcomes with conventional chemotherapy for older patients with acute myeloid leukemia (AML) remain disappointing, with few cures. For younger patients with AML, allogeneic hematopoietic cell transplantation (HCT) offers the best chance for cure, but this strategy is seldomly used for older patients. With recently improved methodologies, transplantation has become increasingly safe, suggesting that its use in older patients be reconsidered. This report will address four issues: the current frequency of transplantation for AML according to patient age; the impact of patient age on transplant outcomes; the comparative outcomes of transplantation versus chemotherapy for older patients with AML; and possible methods to improve the outcome of allogeneic HCT in older patients with AML.

Introduction: The gut microbiome is a potentially modifiable factor in treatment related outcomes in allogeneic hematopoietic cell transplant (HCT). Prior studies have linked pre- or mid-treatment gut microbiome diversity with risk for treatment related morbidity and mortality. However, these studies have been limited by the inclusion of one or only a few institutions and the lack of longitudinal sampling with high quality metadata. These limitations complicate the interpretation of microbiome alterations over the course of HCT. Methods: To overcome these, we devised and implemented a large-scale biospecimen collection protocol in conjunction with BMT CTN 1703, a randomized, multicenter, Phase III trial of tacrolimus/methotrexate vs. post-transplant cyclophosphamide/tacrolimus/mycophenolate mofetil in reduced intensity conditioning (RIC) allogeneic HCT (NCT03959241). Patients enrolled on 1703 were optionally co-enrolled in the companion immune and microbiome profiling study, 1801 (MI-IMMUNE). This involved blood, urine and stool sampling before conditioning (PCON), then weekly starting on day 0 through day 77 (through day 84 for blood), and on days 98, 180, 270, 365 and 730. For all enrolled participants where the donor consented, residual donor cells were saved from the empty hematopoietic stem cell product bag for later analysis. Additionally, the protocol included one-time blood, urine and stool sample collection from consented matched related donors (MRDs) prior to stem cell collection. Starting with protocol version 4.0 on February 1, 2021, participation in 1801 stool collection was required for the first six out of eighteen sample collection timepoints. Participation in later stool and urine timepoint collections remained optional. Here we review the feasibility of creating a multi-institutional biobank. Additionally, we assess the success of our strategies by calculating sample collection compliance and standard deviation in compliance across centers for each timepoint. Results: On June 18, 2021, BMT CTN 1703/1801 closed to accrual with 431 patients enrolled on 1703; 323 patients from 36 centers were co-enrolled on 1801. 304 (94%) provided study samples, making this the largest prospective microbiome and immune profiling study in HCT patients to date. As of July 6, 2021, 3,683 blood, 2,668 urine, and 2,098 stool samples had been collected. Across the first 6 timepoints for all participating centers, blood, urine and stool sample collection averaged 93%, 82%, and 74% compliance, respectively. Of the 99 (30%) patients enrolled on 1801 with a MRD, 34 (34%) donors consented to sample collection. Sample collection compliance was lower for MRDs than for patients on the study with 76%, 74%, and 62% of expected blood, urine and stool samples collected, respectively, from this group. For stool collection exclusively, a median of 5 samples were collected per patient across the first 6 timepoints (median of 6 across all timepoints) with 93 (31%) of patients completing a full sample set through Day 28. 139 (46%) patients provided at least one sample after day 28; these represented 37% of the total samples collected to date. The PCON sample, which provides an important measure of pre-treatment gut microbiome diversity, had the third highest compliance with 74% of patients providing a sample. Surprisingly, Day 28 had the lowest compliance (66%) and highest standard deviation (37%) possibly because this timepoint often falls around the time of hospital discharge. Between PCON and day 28, the standard deviation between sites in the average collection compliance (24%) and number of samples collected per patient (1.1) was small indicating the successful adoption of stool collection across institutions. Table 1 summarizes sample collection statistics. Conclusion: Overall this study has resulted in a large, novel biobank of blood, urine and stool samples from patients undergoing RIC allogeneic HCT at 36 centers across the US. This will serve as a valuable resource for investigating the role of the gut microbiome in long term health outcomes following HCT. Although the results of 1801 are forthcoming given ongoing sample collection, the size and composition of the biobank to date clearly demonstrate the feasibility of implementing multi-institutional stool collection. This study represents a critical step towards the large-scale adoption of microbiome sampling as a diagnostic tool. Figure 1 Figure 1. Disclosures Chhabra: GSK: Honoraria. Clark: Kadmon: Consultancy. Horowitz: Mesoblast: Research Funding; Shire: Research Funding; Vertex: Research Funding; Stemcyte: Research Funding; Vor Biopharma: Research Funding; Janssen: Research Funding; Miltenyi Biotech: Research Funding; Kiadis: Research Funding; Sobi: Research Funding; Kite/Gilead: Research Funding; Pfizer, Inc: Research Funding; Jazz Pharmaceuticals: Research Funding; Magenta: Consultancy, Research Funding; Medac: Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding; Daiicho Sankyo: Research Funding; Xenikos: Research Funding; Omeros: Research Funding; Orca Biosystems: Research Funding; Pharmacyclics: Research Funding; Regeneron: Research Funding; Tscan: Research Funding; Takeda: Research Funding; CSL Behring: Research Funding; Genentech: Research Funding; Gamida Cell: Research Funding; Chimerix: Research Funding; Bristol-Myers Squibb: Research Funding; bluebird bio: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Allovir: Consultancy; Actinium: Research Funding; Sanofi: Research Funding; Seattle Genetics: Research Funding. Jenq: Microbiome DX: Consultancy; Merck: Consultancy; Prolacta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kaleido: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seres: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; LisCure: Consultancy, Membership on an entity's Board of Directors or advisory committees; MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karius: Consultancy. Levine: Equillium Bio: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Research Funding; Kamada: Research Funding; Biogen: Research Funding; Omeros: Membership on an entity's Board of Directors or advisory committees; Symbio: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Talaris Therapeutics: Membership on an entity's Board of Directors or advisory committees; Viracor: Patents & Royalties: GVHD biomarker patent with royalties from Viracor; Mesoblast: Consultancy, Research Funding; X4 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Murthy: CRISPR Therapeutics: Research Funding. Riches: ATARA Biotherapeutics: Other: Payment; BioIntelect: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Payment. Sung: Merck: Research Funding; Novartis: Research Funding; Enterome: Research Funding; Seres: Research Funding; AVROBIO: Consultancy; Abbott Nutrition: Honoraria; Clasado: Other: Research Product; DSM: Other: Research Product. Al Malki: Neximmune: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Rigel Pharma: Consultancy; Hansa Biopharma: Consultancy; CareDx: Consultancy. Rezvani: Kaleido: Other: One-time scientific advisory board; Nohla Therapeutics: Other: One-time scientific advisory board; Pharmacyclics-Abbvie: Research Funding; US Department of Justice: Consultancy. Bolaños-Meade: Incyte Corp: Consultancy. Holtan: Incyte: Consultancy, Research Funding; Generon: Consultancy. Saber: Govt. COI: Other. Hamadani: Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau; Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy; Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding. Kean: Bluebird Bio: Research Funding; Bristol Myers Squibb: Patents & Royalties: From clinical trial data, Research Funding; Vertex: Consultancy; Novartis: Consultancy; Gilead: Research Funding; Regeneron: Research Funding; EMD Serono: Consultancy. Perales: Cidara: Honoraria; Servier: Honoraria; Incyte: Honoraria, Other; Equilium: Honoraria; Takeda: Honoraria; Novartis: Honoraria, Other; Nektar Therapeutics: Honoraria, Other; NexImmune: Honoraria; MorphoSys: Honoraria; Omeros: Honoraria; Karyopharm: Honoraria; Sellas Life Sciences: Honoraria; Merck: Honoraria; Miltenyi Biotec: Honoraria, Other; Medigene: Honoraria; Bristol-Myers Squibb: Honoraria; Kite/Gilead: Honoraria, Other; Celgene: Honoraria.

Introduction: Randomized trials demonstrated ~95% efficacy of SARS-CoV-2 spike messenger RNA (mRNA) vaccines. Patients (pts) after allogeneic hematopoietic cell transplant (HCT) have a variable period of immune deficiency and the impact of diagnosis, treatment regimens, GvHD, and immunosuppression on vaccine (vacc) immunogenicity is unknown. Methods: We performed a retrospective analysis of 149 consecutive pts (Table) who received a SARS-CoV-2 vacc between 12/17/2020, and 5/21/21, and were tested for anti-SARS-CoV-2 S1/S2 antibodies. Serology testing was performed with the Liaison® SARS-CoV-2 S1/S2 IgG assay (DiaSorin) with ≥15 AU/mL defined as a positive result. Pts with prior COVID-19 infection were excluded. Pts received mRNA-1273/Moderna (n= 46), BNT162b2/Pfizer-BioNTech (n= 100) or Jannsen vacc (n= 3). Reactogenicity was not investigated. Demographic and treatment variables were tested for prediction of vaccine response using Chi-square test or Fisher's exact test for categorical variables and two-sample t test for continuous variables. Univariate and multivariable logistic regression analyses with backward selection using Akaike information criterion (AIC) were used to examine interdependence of those variables and odds ratios (OR) with 95% confidence intervals (CI). Results: Pts underwent HCT from a related HLA matched sibling (n=36), related haploidentical (n= 23), or matched/mismatched unrelated donor (n= 89). 93% received fludarabine in the HCT conditioning regimen (data not shown). All pts received a calcineurin inhibitor (CNI) and 76 pts received ATG for GvHD prophylaxis. All pts achieved at least mixed donor lymphoid engraftment (data not shown). Median time from HCT to 1st vaccination was 26 months (range, 3-258 months). Median age at time of vaccination was 61 years (range, 24-78) and 75 (50%) were female. Serology was tested at a median of 37 days (range, 6-119 days) after the second vacc dose. Serology was tested 101 pts (67%) tested positive for anti-SARS-CoV-2 S1/S2 antibodies (vacc responders). Of the responders, the median time from HCT to 1st vacc was 45.5 months (range, 3-258, SD 39.78). Among the 23 pts between 3-9 months after HCT, 26% (n=6) had a positive antibody response, but all were receiving ongoing immunosuppression at time of vaccination. 29% (n=29) vacc responders were receiving prednisone (pred) in the management of cGvHD at the time of vaccination. 48 pts did not mount an antibody response (vacc non-responders). Of the non-responders, 30 pts were receiving cGvHD treatment at the time of vacc, 31 pts were taking pred, and 20 pts were taking CNIs. In univariate analysis, we found a history of prolonged use of pred (>8 weeks) and/or CNIs, on current treatment for cGvHD at time of vacc, and receipt of rituximab in the preceding 12 months predicted for lack of response (Table). Active use of pred and treatment with pred >8 weeks in the preceding 12 months prior to vacc predicted vacc non-response [OR 0.221; 95% CI (0.106 - 0.456); p8 weeks was not [OR 2.00; 95% CI (0.55-7.298; p=0.293] in multivariable analysis. Other significant predictors for non-response in the multivariable analysis include pt use of ruxolitinib [OR, 0.233, 95% CI, (0.067-0.808); p=0.022], and rituximab within 1 year [OR, 0.026, 95% CI, (0.007-0.099); p Discussion: In this study, we found that 67% allogeneic HCT pts developed anti-SARS-CoV-2 S1/S2 antibodies after SARS-CoV-2 vaccination. Predictors of non-response after adjustment for potential confounders, were factors that are expected to suppress immune response including active use of immunosuppressive medications. Consistent with prior studies, anti-CD20 therapy likely impairs humoral response to vaccination. Ruxolitinib also appears to impair response. However, a proportion of pts being actively treated for cGvHD responded to vaccination and these pts should still be encouraged to receive vaccination in consideration of the COVID-19 mortality risk. Many questions remain including the protective benefit of immune response, the duration of response, and the potential value of booster vaccinations in non-responders. Figure 1 Figure 1. Disclosures Rowley: ReAlta Life Sciences: Consultancy.

Microbial diversity is associated with improved outcome in patients receiving allogeneic hematopoietic cell transplantation (allo-HCT), however, the mechanism underlying this observation is unclear. Unconventional T cells recognize specific metabolites of bacterial biosynthesis and their role in the post-HCT immunity has not yet been fully clarified. Here we have performed an observational study (n = 174 patients) using 16S rRNA sequencing of early post-HCT patient stool samples (day 7-21 after HCT) paired with multiparameter flow cytometry (performed at day 30 and day 100 after HCT) to explore the relationship between the intestinal microbiome early after HCT and the unconventional T cell populations in circulation. Our data extend findings of other groups suggesting that mucosal-associated invariant T (MAIT) cells are dependent on a diverse microbiome and are also associated with favorable allo-HCT outcome. In addition, we report for the first time that the Vδ2 subset of γδ T cells is positively correlated with MAIT cells as well as independent predictors of favorable transplant outcome. We first focused on MAIT cells as these cells respond to metabolites of the bacterial riboflavin biosynthesis pathway and should therefore be responsive to changes in the gut microbiome. MAIT cell frequency on day 30 after HCT was significantly higher in peripheral blood stem cell (PBSC) graft recipients who had higher peri-engraftment stool diversity (day 7-21; p=0.014, n=118, α-diversity measured using Simpson's reciprocal index, Figure A). Patients with higher-than-median MAIT cell frequency had improved 2-year overall survival (p=0.047, n=118 PBSC recipients, Figure B) and lower non-relapse mortality (p=0.031) compared with patients with lower-than-median frequency. High dimensional flow cytometry analysis using clustering algorithms Uniform Manifold Approximation and Projection (UMAP) and Self Organizing Map (FlowSOM) identified the Vδ2 subset of γδ T cells as the only differentially abundant population associated with higher MAIT cell frequency, and furthermore, frequencies of these two cell types were highly correlated (R=0.38, p=2.8e-05, Figure C). Vδ2 cells are activated by the bacterial metabolite, 4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), an intermediate of the microbial isoprenoid biosynthetic pathway. Vδ2 cell frequencies were higher in patients with higher stool α-diversity (p=0.0026, n=118 PBSC recipients, Figure D) and interestingly, appeared protective with regard to acute graft versus host disease (aGVHD), as we observed a higher frequency of Vδ2 cells among patients who had no or grade 1 disease compared with patients who experienced grade 2-4 aGVHD (p=0.013). We next used Linear Discriminant effect Size (LefSE) analysis to identify statistically significant differences between bacterial taxa in our groups of interest (threshold p>0.01 and effect size>4) and observed that higher MAIT and Vδ2 cell numbers are associated with higher abundance of bacteria belonging to the phylum Bacteroidetes and lower MAIT and Vδ2 cell numbers are associated with higher abundance of the members of the phylum Firmicutes. Furthermore, using the PICRUSt2 algorithm, which uses 16S amplicon abundance data to predict the abundance of functional pathways, we observed a significantly increased predicted abundance of HMBPP, the phosphoantigen ligand for Vδ2 cells, in the patients with higher circulating Vδ2 cell frequencies (p=0.00054). Our findings confirm our hypothesis that a diverse microbiota supports the reconstitution of protective unconventional T cell populations, namely MAIT and Vδ2 cells, which are in turn associated with a favorable HCT outcome. Although further studies are needed to dissect the functional contribution of these cells to the post-transplantation immune milieu, our work offers a valuable insight into the interplay between the intestinal microbiome and reconstitution of immune subsets after allo-HCT and may aid in the design of microbiota-targeted interventions. Figure 1 Figure 1. Disclosures Gomes: Xbiome: Current Employment. Zappasodi: iTeos Therapeutics: Consultancy; Astra Zeneca: Research Funding; Bristol Myers Squibb: Research Funding. Ponce: CareDx: Consultancy, Honoraria; Takeda Pharmaceuticals: Research Funding; Generon Pharmaceuticals: Consultancy; Kadmon pharmaceuticals: Consultancy, Honoraria; Ceramedix: Consultancy, Honoraria; Seres Therapeutics: Consultancy, Research Funding. Giralt: JENSENN: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Peled: Seres: Other: Intellectual Property Rights, Research Funding and Travelfees; DaVolterra: Consultancy; Other: Other: Jonathan U. Peled had filed intellectual property applications related to the microbiome (referencenumbers #62/843,849, #62/977,908, and #15/756,845); MaaT Pharma: Consultancy. Perales: Cidara: Honoraria; Celgene: Honoraria; Merck: Honoraria; MorphoSys: Honoraria; Nektar Therapeutics: Honoraria, Other; Equilium: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Kite/Gilead: Honoraria, Other; Medigene: Honoraria; Novartis: Honoraria, Other; Sellas Life Sciences: Honoraria; Servier: Honoraria; Miltenyi Biotec: Honoraria, Other; Omeros: Honoraria; Incyte: Honoraria, Other; NexImmune: Honoraria. van den Brink: Rheos: Honoraria; Merck & Co, Inc: Honoraria; Therakos: Honoraria; Amgen: Honoraria; GlaskoSmithKline: Other: has consulted, received honorarium from or participated in advisory boards; Synthekine (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Kite Pharmaceuticals: Other; Notch Therapeutics: Honoraria; Nektar Therapeutics: Honoraria; Priothera: Research Funding; Wolters Kluwer: Patents & Royalties; Juno Therapeutics: Other; Frazier Healthcare Partners: Honoraria; DKMS (nonprofit): Other; Seres: Other: Honorarium, Intellectual Property Rights, Research Fundingand Stock Options; Forty-Seven, Inc.: Honoraria; Lygenesis: Other: has consulted, received honorarium from or participated in advisory boards ; WindMILTherapeutics: Honoraria; Pharmacyclics: Other; Jazz Pharmaceuticals: Honoraria; Novartis (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Da Volterra: Other: has consulted, received honorarium from or participated in advisory boards; Ceramedix: Other: has consulted, received honorarium from or participated in advisory boards ; MagentaTherapeutics: Honoraria; Pluto Therapeutics: Current holder of stock options in a privately-held company, Other: has consulted, received honorarium from or participated in advisory boards .

This cohort study examines safety and antibody responses after 1 and 2 doses of BNT162b2 mRNA vaccine in recipients of allogeneic hematopoietic stem cell transplant (HSCT).

RA Marsh, JW Leiding, BR Logan. J Clin Immunol . 2019;39(7):653–667 To evaluate the long-term effect of allogenic hematopoietic stem cell transplant (HCT) on chronic granulomatous disease (CGD)–associated inflammatory bowel disease (IBD) and assess the impact of IBD on transplant outcomes. A total of 145 patients with CGD who underwent allogenic HCT at 26 unique Primary Immune Deficiency Treatment Consortium (PIDTC) centers were included in this study. This was a retrospective study to evaluate clinical characteristics, laboratory findings, treatment and outcomes of patients with CGD who underwent allogenic HCT. CGD status was confirmed by …

Background Diagnosing sepsis among allogeneic hematopoietic cell transplant (aHCT) recipients remains challenging. Existing criteria, for use in hospitalized patients, have limited predictive accuracy among aHCT recipients and their use may lead to missed events or antibiotic overuse. We developed bedside bacterial sepsis prediction tools (criteria and decision tree [DT]) for aHCT recipients and compared them against Systemic Inflammatory Response Syndrome (SIRS), quick Sequential Organ Failure Assessment (qSOFA) and National Early Warning Score (NEWS) criteria. Methods Adult aHCT recipients transplanted between September 2010–2019 with ≥ 1 potential infection (PI) within 100 days post-transplantation were randomly assigned to model/validation (7/3) cohorts. Tools included demographic and clinical factors and were built against a bacterial sepsis endpoint (gram-negative, Staphylococcus aureus, or Streptococcus species bacteremia). The tools were developed using best subset selection with rare event logistic regression (criteria) and classification tree (DT) algorithms. Criteria scores were estimated using a beta/10 integer weighting approach and tool predictive performances were compared against existing criteria. Results Between September 2010–2019, 1571 recipients with ≥ 1 PI contributed 7755 PIs and 238 sepsis events. The DT model included 7 terminal nodes based on 3 predictors: temperature, respiratory rate (RR), and sex. The criteria model contained 10 categories with 4 predictors: RR, temperature, pulse, and diastolic blood pressure (Figure 1). Our criteria and DT had AUCs of 71.1% (95% Confidence Interval (CI): 64.3, 77.9%) and 70.0% (CI: 63.7, 76.2%). SIRS had the highest AUC of existing criteria – 64.7% (CI: 57.1, 71.9%). Our criteria had the highest net benefit (for probabilities < 10%) and, at a 7+ cut-point, had a sensitivity of 73.8% (CI: 61.5–84.0%) and specificity of 55.0% (CI: 52.9, 57.1%) (Figure 2). Conclusion We developed aHCT recipient-specific bedside bacterial sepsis prediction tools with higher AUCs than existing criteria. Tools targeted to high-risk populations may lead to fewer missed sepsis events and, in turn, reduce sepsis related mortality among this high-risk population. Disclosures Steven A. Pergam, MD, MPH, Chimerix, Inc (Scientific Research Study Investigator)Global Life Technologies, Inc. (Research Grant or Support)Merck & Co. (Scientific Research Study Investigator)Sanofi-Aventis (Other Financial or Material Support, Participate in clinical trial sponsored by NIAID (U01-AI132004); vaccines for this trial are provided by Sanofi-Aventis)

Background The American Geriatric Society has established criteria (Beers criteria) for Potentially Inappropriate Medications (PIMs) in older (65+y) adults (J Am Geriatr Soc. 2019 Apr;67(4):674-694). The use of PIMs in allogeneic hematopoietic cell transplant (allo-HCT) and its impact on outcomes is unknown. Methods The use of PIMs, in defined categories [anticholinergics, central nervous system (CNS), benzodiazepines, gastrointestinal (GI), genitourinary (GU), and narcotics] in older (≥ 65y) allo-HCT recipients were compared to younger recipients [(40-64y undergoing reduced intensity conditioning (RIC)] during initial HCT admission (day-14 to +28 post HCT). Use of PIMs was defined as the number of days a patient received 1 or more PIMs between d-14 to +28. Medications were retrieved from medical records and categorized by Beers criteria for 354 allo-HCT recipients ≥ 40y in 2 groups (40-64y RIC, n=240; and 65+y RIC, n=114). Poisson regression determined the log use of PIMs in the 2 groups. In 65+y group, we evaluated the impact of PIMs on the incidence of CTCAE grade 3 and 4 toxicities; and non-relapse mortality (NRM). All analyses were adjusted or length of hospital stay. Results All PIMs: The median (range) days of all PIMs in 65+y RIC recipients [94 (24-279)] was similar to 40-64y RIC recipients [101 (8-441), p=0.48, confirmed in Poisson regression (Figure 1) [65+y RIC vs 40-64y RIC log change 0.0, p=1.0). Patients with a high (vs. low) HCT-CI score received more days of all PIMs (p=0.02). PIM Categories (Figure 1) were compared and 65+y recipients received fewer days of benzodiazepines (log change -0.18, p=0.04) or narcotics (-0.21, p=0.04), but more days of anticholinergics (0.22, p=0.03) and GI PIMs (0.16, p 65+y group: In adjusted regression analysis, increasing days of narcotics was associated with a 1.6 fold (95% CI 1.1-2.6, p=0.03) higher risk of NRM. Increasing days of narcotics was also associated with a 1.66 fold (95% CI 1.02-2.69) greater odds of grade 3-4 toxicities, p=0.04 (Figure 2). More days of all PIMs was associated with a 5 times greater odds of discharge to rehab or a nursing facility (95% CI 1.43-10.0, p Conclusions Older recipients (65+y) receive PIMs as frequently as younger recipients (40-64y). Females, those with a high HCT-CI and UCB recipients receive PIMs more frequently. Amongst older recipients, use of PIMs, particularly narcotics, was associated with a higher NRM and higher risks of grade 3-4 toxicities. Identifying and reducing use of PIMs in older HCT recipients may help lower the burden of adverse events and associated health care costs.

Matched related or unrelated donor allogeneic HCT has occasionally been applied in patients with severe CDA type II and proven to be curative. We report on the first patient with CDA to undergo haploidentical bone marrow transplantation with PT-CY. A 12-year-old boy with severe hemosiderosis, and a, consequently, disturbed BM microenvironment, developed recurrent graft failures and required salvage with two additional haploidentical HCTs. He achieved complete donor chimerism and transfusion independence after the third HCT. Our case underscores the risks associated with performing haploidentical HCT in older pediatric patients with CDA and severe chronic iron overload.

Cytomegalovirus (CMV) results in significant morbidity and mortality following hematopoietic cell transplantation (HCT). Establishing the cost and clinical impact is imperative to the selection of appropriate CMV preventative strategies. This is a retrospective cohort study of consecutive patients undergoing their first allogeneic HCT between January 1, 2009, and December 31, 2013. Detailed clinical and institutional cost data were obtained from the start of conditioning through 1-year post-transplantation. Baseline characteristics, resource utilization, costs, and outcomes were compared between patients with and without clinically significant CMV infection (csCMVi). One hundred seventy out of 388 patients (44%) developed csCMVi within 1 year after HCT. Within the first year post-HCT, patients with csCMVi had a significantly longer transplantation-related length of stay (mean, 91.7 days versus 78.3 days; P.0001) and more frequent and prolonged hospitalizations (mean, 2.4 versus 1.7 admissions [P.0001]; mean, 39.1 versus 31.5 inpatient days [P = .001]) without significantly more admissions to the intensive care unit (28.2% versus 21.6%; P = .408). The use of granulocyte colony-stimulating factor was greater in patients with csCMVi (73.5% versus 54.1%; P = .0001), although no significant differences were demonstrated in mean platelet or red blood cell (RBC) transfusions. Total costs were also higher in patients with csCMVi (mean cost difference, $45,811; 95% CI, $26,385 to $67,544). However, the incidence of graft-versus-host disease (GVHD) and selected infectious complications was not significantly different between the 2 groups. There were no significant differences in 1-year and 5-year post-transplantation overall survival (OS) or nonrelapse mortality (NRM) between those with and those without csCMVi, although relapse of underlying disease was significantly lower in the csCMVi group. Overall, our data show that allogeneic HCT recipients with csCMVi had significantly greater medical resource utilization and costs than those without csCMVi. However, clinical outcomes, including GVHD, infections, and mortality, were similar in the 2 groups. Further study is needed to determine the cost-effectiveness of CMV preventive modalities.

IntroductionInflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking.MethodsWe collected data retrospectively from 145 patients with CGD who had received allogeneic HCT at 26 Primary Immune Deficiency Treatment Consortium (PIDTC) centers between January 1, 2005 and June 30, 2016.ResultsForty-nine CGD patients with IBD and 96 patients without IBD underwent allogeneic HCT. Eighty-nine percent of patients with IBD and 93% of patients without IBD engrafted (p = 0.476). Upper gastrointestinal acute GVHD occurred in 8.5% of patients with IBD and 3.5% of patients without IBD (p = 0.246). Lower gastrointestinal acute GVHD occurred in 10.6% of patients with IBD and 11.8% of patients without IBD (p = 0.845). The cumulative incidence of acute GVHD grades II-IV was 30% (CI 17-43%) in patients with IBD and 20% (CI 12-29%) in patients without IBD (p = 0.09). Five-year overall survival was equivalent for patients with and without IBD: 80% [CI 66-89%] and 83% [CI 72-90%], respectively (p = 0.689). All 33 surviving evaluable patients with a history of IBD experienced resolution of IBD by 2years following allogeneic HCT.ConclusionsIn this cohort, allogeneic HCT was curative for CGD-associated IBD. IBD should not contraindicate HCT, as it does not lead to an increased risk of mortality. This study is registered at clinicaltrials.gov NCT02082353.

Hematopoietic stem cell transplantation (HCT) has been an integral component in the treatment of many hematologic malignancies. Since the development of HCT nearly 50 years ago, the role of this modality has evolved as newer treatment approaches have been developed and integrated into the standard of care. In the last decade, novel and highly active targeted therapies and immunotherapies have been approved for many hematologic malignancies, raising the question of whether HCT continues to retain its prominent role in the treatment paradigms of various hematologic malignancies. In this review, the authors have described the current role of autologous and allogeneic HCT in the treatment of patients with acute leukemias, aggressive B-cell lymphomas, and multiple myeloma and discussed how novel targeted therapies and immunotherapies have changed the potential need, timing, and goal of HCT in patients with these diseases.

We analyzed outcomes of 126 patients with hematologic malignancies, who relapsed after first allogeneic hematopoietic cell transplantation (HCT) and received subsequent allografts. In 17 cases, the original donors were utilized, while in 109 cases different donors were identified. The 2-year overall survival (OS), relapse, and non-relapse mortality (NRM) rates were 33%, 42%, and 33%, respectively. Patients with early relapse after first allogeneic HCT (within 100 days vs. 100 days to 12 months vs. >12 months) had higher relapse rates (50% vs. 47% vs. 34%, respectively; p = .01) and worse OS (15% vs. 25% vs. 45%, respectively, p = .005) at 2 years after second allogeneic HCT. In conclusion, second allogeneic HCT should be considered in patients who relapse after first allografts, especially in those who relapse after more than a year. Utilizing a different donor for the second allotransplant including umbilical cord blood or HLA-haploidentical, related donors did not adversely impact outcomes.

Graft versus host disease (GVHD) is a common complication of allogeneic hematopoietic cell transplantion (HCT) and a major cause of posttransplant morbidity and mortality. Despite recent advancements in our knowledge regarding pathophysiology of GVHD, success in treatment has been limited. Mesenchymal stem cells (MSC) have immunomodulatory and antiinflammatory properties that can be exploited for the prevention and treatment of GVHD, with established preliminary results in early-phase clinical trials. In this chapter, we briefly review HCT and GVHD, and evaluate the evidence for MSC therapy in GVHD.

Patients undergoing hematopoietic cell transplantation (HCT) experience decline in their physical activity during their transplant admission. There is limited experience with prospective monitoring of transplant recipients. We therefore measured physical activity and sleep patterns of subjects undergoing autologous and allogeneic HCT. Eighty-three patients were consented for this study. Sixty-three patients competed the study and had their physical activity prospectively assessed using the fitness-tracking device Fitbit HR. Outcomes included adherence, physical activity, readmission, hematopoietic engraftment, and 100-day survival. Sixty percent of patients (n = 37) underwent autologous HCT, and 40% (n = 26) underwent allogenic HCT. Both groups had a comparable number of steps at admission to the hospital. The number of daily steps during the study period was lower in the allogeneic group (2159 versus 3008, P = .07), as was the minimum number of steps recorded over the transplant admission (allogeneic HCT = 395 versus autologous HCT = 848, P = .01). Patients undergoing allogeneic HCT were less active on the day before discharge (1956 steps versus 3183 steps, P = .08). In multivariate analysis, physical activity was not associated with HCT-related outcomes. Patients undergoing HCT experience significant decline in their physical activity during their transplant admission that does not recover by the time of discharge. This effect can be objectively measured using fitness tracking devices.

2538 Background: Allogeneic HCT is a potentially curative therapy for many patients with AML that relies on a graft-versus-leukemia (GvL) effect. Patients who relapse after allogeneic HCT have a poor prognosis and few treatment options. Donor lymphocyte infusion (DLI) can achieve a GvL effect in some patients, however, efficacy is frequently associated with the development graft-versus-host disease (GVHD). There is a substantial need for treatment approaches that enhance the benefit of GVL while decoupling toxicities associated with GVHD. Methods: We report ongoing results from a first-in-human study (NCT04284228) of a non-genetically engineered, donor-derived adoptive cellular therapy product, NEXI-001, which contains multiple populations of CD8+ T cells that recognize different HLA 02.01-restricted peptides from the WT1, PRAME, and Cyclin A1 antigens. NEXI-001 contains T cell memory subtypes that combine anti-tumor potency with long-term persistence. Results: At the time of this analysis, 7 patients with relapsed AML after allogeneic HCT were enrolled. Five Patients were treated with single infusions of NEXI-001 at three different dose levels: 50, 100 and 200 million. Currently, the median follow-up is 5 months. Significantly, GVHD, cytokine release syndrome, neurotoxicity, or NEXI-001-related adverse events were not observed. NEXI-001 treatment resulted in reductions in red blood cell and platelet transfusions and increased donor chimerism. Decreases in myeloblasts in bone marrow and peripheral blood and reduction in the size of an extramedullary myeloid sarcoma were suggestive of an anti-leukemia effect (Table). Correlative studies indicate that NEXI-001 CD8+ cells undergo a rapid proliferation after infusion and are also associated with a robust hostlymphocyte recovery that occurs as quickly Day 3 after infusion. NEXI-001 infused CD8+T cells are detectable by multimer staining in peripheral blood of patients and proliferate over time. TCR sequencing analyses determined that infused NEXI-001 cells contain T cell clones that were undetectable in the peripheral blood of patients at baseline but were detected in blood and bone marrow and persist over time. Conclusions: NEXI-001 has the potential to enhance GvL effect without the associated toxicities of GVHD, cytokine release syndrome, and neurotoxicity. Due to these encouraging results, the trial will proceed with an evaluation of repeated NEXI-001 dosing Clinical trial information: NCT04284228. [Table: see text]

Hematopoietic cell transplantation (HCT) is a treatment for hematologic malignancies and disorders. Patients who receive HCT can face long-term physical and psychosocial effects. Survivorship care guides (care guides), which describe screening and preventive care practices were mailed to allogenic HCT recipients at clinically important timepoints (6, 12, and 24 months after HCT). The primary objective of this study was to evaluate how patients perceived and used the care guides. A cross-sectional, time-series survey was sent to all National Marrow Donor Program/Be The Match allogeneic HCT recipients from September 2012 to November 2016 after the care guides were sent; patients or caregivers could respond. Respondents who returned all 3 surveys were included (554 patients; 65 caregivers), for an overall response rate of 13% (maintenance rate of 45%). The majority of patients and caregivers strongly agreed or agreed that the care guides helped them understand that post-HCT care is important to staying healthy and that they were more familiar with recommended tests at check-up appointments. Most patients who did not share the care guides with their doctors at any of the timepoints believed their doctor knew which tests were needed. Results from this study can help inform and guide development of future tools and evaluations of educational resources for patients after HCT. Tools and educational resources, such as survivorship care guides, have the potential to help empower patients to be more knowledgeable and to understand and advocate for their survivorship care needs.

The efficacy of primary prophylaxis with atovaquone in preventing Toxoplasma reactivation and disease in hematopoietic cell transplant (HCT) recipients is unknown. We describe 2 cases of atovaquone prophylaxis failure in pre-HCT Toxoplasma-seropositive (pre-HCTSP) recipients who underwent allogeneic HCT (allo-HCT) and review the literature on atovaquone prophylaxis in HCT recipients.

Machine learning techniques are widely used nowadays in the healthcare domain for the diagnosis, prognosis, and treatment of diseases. These techniques have applications in the field of hematopoietic cell transplantation (HCT), which is a potentially curative therapy for hematological malignancies. Herein, a systematic review of the application of machine learning (ML) techniques in the HCT setting was conducted. We examined the type of data streams included, specific ML techniques used, and type of clinical outcomes measured. A systematic review of English articles using PubMed, Scopus, Web of Science, and IEEE Xplore databases was performed. Search terms included “hematopoietic cell transplantation (HCT),” “autologous HCT,” “allogeneic HCT,” “machine learning,” and “artificial intelligence.” Only full-text studies reported between January 2015 and July 2020 were included. Data were extracted by two authors using predefined data fields. Following PRISMA guidelines, a total of 242 studies were identified, of which 27 studies met the inclusion criteria. These studies were sub-categorized into three broad topics and the type of ML techniques used included ensemble learning (63%), regression (44%), Bayesian learning (30%), and support vector machine (30%). The majority of studies examined models to predict HCT outcomes (e.g., survival, relapse, graft-versus-host disease). Clinical and genetic data were the most commonly used predictors in the modeling process. Overall, this review provided a systematic review of ML techniques applied in the context of HCT. The evidence is not sufficiently robust to determine the optimal ML technique to use in the HCT setting and/or what minimal data variables are required.

Chronic Myelomonocytic Leukemias are frequently diagnosed in older adults. Their prognosis is heterogeneous, but several prognostic factors can identify patients with an expected survival of a few years only, including among younger patients eligible for allogeneic stem cell transplantation. Based on the retrospective data available, we discuss how to identify CMML patients for whom curative therapy must be envisaged. We emphasize that, although transplantation remains the only path to cure in CMML, it can be envisaged in only a minority of patients. Despite increased donor availability, its potential remains limited by significant rates of mortality caused both by the procedure and by post-transplantation relapses. We review the options available to bridge patients to transplant, the management of transplantation itself (choice of donor, graft source and condition regimen), and finally the potential for post-transplantation interventions. Our review underscores the need for further prospective studies of allogeneic stem cell transplantation in CMML.

Background Advance directives (AD) offer the opportunity for goal-concordant care at the end of life (EOL). However, fewer than half of HCT recipients have a documented AD. We hypothesized that the use of a novel AD-the Stanford What Matters Most Letter (Letter AD)-developed to assess patients' values, goals, and EOL wishes would result in a greater proportion of AD completion among HCT recipients. We therefore conducted a prospective, randomized, controlled study of the traditional California AD vs. the Letter AD in adult allogeneic HCT recipients. Methods Patients >= 18 years old undergoing first allogeneic HCT at Stanford University were eligible. Prior to HCT conditioning, enrolled patients were randomly assigned to complete either the traditional California AD or the Letter AD, and all patients received a sociodemographic survey and a survey evaluating their opinions regarding the AD form they received. Patients were asked to return all research forms at the time of their transplant admission; a research assistant placed a reminder call to each patient prior to scheduled transplant. The primary endpoint was AD completion; secondary endpoints included EOL wishes as documented on the AD and patient preferences and opinions regarding the AD version they received. Results Between March 2017 and August 2018, 212 patients were eligible, of whom 126 (59.4%) were enrolled and randomized. Among the 84 who declined, the primary reason was already having an AD (N=34). The median age was 57 years (IQR 45-64); 54.8% were male; 58.7% were non-Hispanic White; and 72.3% had AML/MDS. There were no statistically significant differences in baseline socio-demographics between study arms. The overall AD completion rate was 71.6% and did not differ between the Traditional and Letter AD study arms (70.3% vs 72.6%, P=0.78). Preferences for EOL among responders are described in Table 1. The Letter AD uncovered that 66.7%, 42.2%, and 46.7% of patients actively wished to die gently/naturally, at home, and/or with hospice, respectively, whereas the traditional AD found that 62.2% wished to not prolong life if recovery was unlikely. Figure 1 portrays participant responses to the AD opinion survey; non-significant trends suggested that patients found the Letter AD favorable in terms of identifying what matters most to them, describing medical preferences to family, and stimulating thinking about the topic. Conclusion Completion rates of AD amongst allogeneic HCT recipients on this study were high and did not differ based upon AD version. Most patients wish to die naturally/do not wish to prolong care at EOL. Non-significant trends favored the Letter AD over the Traditional AD across several domains of patient preference.

Allogeneic HCT practice patterns for PID changed between 1974–2016. Three-year survival improved to >70% for SCID and non-SCID patients after 1999, and further increased to 94% for SCID patients transplanted 2010–2016 following newborn screening diagnosis.